FTY720 shows significant benefits in helping MS patients over one year in Phase II data published in New England Journal of Medicine
Oral treatment for multiple sclerosis (MS) maintains significant reductions in inflammatory disease activity and clinical relapses for up to one year
Comprehensive Phase III program now underway worldwide
24-month Phase II treatment data to be presented at European Congress for Treatment and Research in Multiple Sclerosis (ECTRIMS) in September
More than two million people estimated to suffer from multiple sclerosis, one of the leading causes of neurological disability in young adults[1]
Basel, September 13, 2006 - Clinical trial results published in the New England Journal of Medicine showed significant benefits for patients suffering from relapsing multiple sclerosis (MS) who were treated with FTY720 (fingolimod), in development with potential to become the first orally effective compound to help patients with this debilitating neurological disease.
The Phase II trial data showed that FTY720 taken once-daily during the initial six months of treatment reduced the rate of inflammatory disease activity - as measured by magnetic resonance imaging (MRI) - by up to 80% and cut clinical relapses by more than 50% compared to placebo[2].
In patients who continued taking FTY720 during the subsequent six-month extension, low levels of disease activity were maintained as measured by both MRI and relapses. Both these measures also decreased in patients who switched from placebo to FTY720.
"These results demonstrate that once-daily oral FTY720 provides an improvement in MRI measures of inflammation as well as in relapse-related clinical endpoints in patients with relapsing multiple sclerosis," said Professor Ludwig Kappos, chief trial investigator and head of the Department of Neurology at the University Hospital in Basel, Switzerland.
"If the magnitude of benefits shown in this Phase II study is confirmed in the larger-scale Phase III program, oral FTY720 could potentially have a major impact in the way MS will be treated in the future," said Professor Kappos.
Phase III clinical trials program underway
Based on the positive Phase II results, Novartis launched earlier in 2006 a Phase III clinical trials program called FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis). This 24-month, randomized, double-blind, placebo-controlled study program is designed to include over 2,000 patients worldwide with the relapsing-remitting form of multiple sclerosis between ages 18 and 55. Study participants will be randomized equally to either receive once-daily treatment with 1.25 mg or 0.5 mg of FTY720 or placebo for up to 24 months.
MS affects more than two million people worldwide
More than two million people worldwide are estimated to suffer from MS, which is one of the leading causes of neurological disability in young adults. It is the most common inflammatory and neurodegenerative disorder of the central nervous system, including the brain, spinal cord and optic nerves[3].
The symptoms of MS can range from tingling, numbness, pain, slurred speech and blurred or double vision, to muscle weakness, poor balance or coordination, and tremors. These symptoms can have a significant impact on the patient's employment, social activities and overall quality of life.
Conventional first-line multiple sclerosis therapies offer an average reduction in relapse rates in the range of 30-35% in two-year studies. These medicines also require frequent injections, ranging from daily to weekly[4],[5],[6]
FTY720 is the first in a new class of disease-modifying treatments called sphingosine 1-phosphate receptor (S1P-R) modulators and has a novel mode of action different from all currently marketed MS therapies. FTY720 has been developed by Novartis and licensed from Mitsubishi Pharma Corporation.
An analysis of two-year Phase II data with FTY720 will be presented at the European Congress for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Madrid in September 2006.
Phase II study results in NEJM
The Phase II study described in the New England Journal of Medicine was conducted at 32 centers in 11 countries (in Europe and Canada) to evaluate the effect of FTY720 on disease activity as measured by MRI and clinical relapses as well as safety and tolerability.
In the initial placebo-controlled phase, 281 patients were randomized equally to receive FTY720 (1.25 mg or 5 mg) or placebo once-daily for six months. Of the 255 patients who completed this part of the study, 98% volunteered to continue in the extension phase[7]. Patients in the placebo group were then re-randomized to receive either 1.25 mg or 5 mg of FTY720 and were blinded for an additional six months. Those already on FTY720 continued with their original treatment.
The study showed that oral FTY720 provided significant and rapid improvement in MRI measures of inflammation and in relapse-related clinical endpoints in patients with relapsing MS. Inflammatory disease activity as measured by the total cumulative number of gadolinium (Gd) enhancing MRI lesions was significantly reduced by up to 80% (p<0.001 in FTY720 1.25 mg, p<0.006 in FTY720 5 mg) compared to placebo over six months of treatment. At six months, the proportion of patients free of Gd-enhancing lesions was also greater in both FTY720 groups compared to placebo (p<0.001 for both groups), with a separation between the curves becoming evident from two months onwards.
Relapse rates were reduced by 55% in the FTY720 1.25 mg group (p=0.009) and by 53% in the FTY720 5 mg group (p=0.014) compared to placebo. Time to first confirmed relapse was also significantly prolonged in both FTY720 groups compared to placebo (p=0.007 in FTY720 1.25 mg, p=0.01 in FTY720 5 mg)[8].
In both groups taking FTY720 (i.e. 1.25 mg or 5 mg), patients who had experienced a reduction in their annualized relapse rate of more than 50% compared to placebo during the first six months of the study maintained this low relapse rate during the subsequent six months of the extension[9]. More than 80% of patients who received FTY720 for up to 12 months were free from lesions showing active inflammation on MRI at month 12, irrespective of their treatment dose[9].
In patients who switched from placebo to either dosage of FTY720 after six months, the annualized relapse rate was reduced by at least 70% during the six-month extension compared to the period on placebo[9].
In the six month placebo-controlled phase of the study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis) and dyspnea, plus diarrhea, and nausea [10]. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and increase in blood pressure were also observed. There were no unexpected safety findings during the six-month extension phase as compared to the six-month placebo-controlled phase [11]. The ongoing Phase III study program includes comprehensive safety monitoring which will provide further assessment on the safety profile.
Disclaimer
This release contains certain forward-looking statements relating to Novartis' business, which can be identified by the use of forward-looking terminology such as "to be presented", "potential to become", "if the magnitude of benefits.confirmed", "could potentially", "will", or similar expressions, or by express or implied discussions regarding potential future regulatory submissions or approvals or regarding potential future revenue from fingolimod. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with fingolimod to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that fingolimod will be submitted for approval or will be approved for sale for any indications or labeling in any market. Nor can there be any guarantee that fingolimod will achieve any sales or any particular level of sales. In particular, management's expectations regarding fingolimod could be affected by, among other things, unexpected clinical trial results, including additional analysis of existing clinical data or new clinical data; unexpected regulatory actions or delays or government regulation generally; Novartis' ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
About Novartis
Novartis has been a leader in the neuroscience area for more than 50 years, having pioneered early breakthrough treatments for Alzheimer's disease, Parkinson's disease, attention deficit/hyperactivity disorder, epilepsy, schizophrenia and migraine. Novartis continues to be active in the research and development of new compounds, and is committed to addressing unmet medical needs and to supporting patients and their families affected by these disorders.
Novartis AG (NYSE: NVS) is a world leader in offering medicines to protect health, treat disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. Novartis is the only company with leadership positions in both patented and generic pharmaceuticals. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. In 2005, the Group's businesses achieved net sales of USD 32.2 billion and net income of USD 6.1 billion. Approximately USD 4.8 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 97,000 people and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.
References
1 Multiple Sclerosis International Federation (http://www.msif.org/en/ms_the_disease/index.html
2 N Engl J Med, 355;11, www.NEJM.org, September 14, page 1130 (Table 2)
3 Multiple Sclerosis International Federation (http://www.msif.org/en/ms_the_disease/index.html
4 L.D. Jacobs et al. Intramuscular Interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann
Neurol 1996, 39: 285-294.
5 IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I.
Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655-
661.
6 K.P. Johnson et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple
sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995; 45: 1268-
1276.
7 N Engl J Med, 355;11, www.NEJM.org, September 14, page 1128 (Figure 1)
8 N Engl J Med, 355;11, www.NEJM.org, September 14, page 1131 (Table 2B)
8 N Engl J Med, 355;11, www.NEJM.org, September 14, page 1133 (Table 3)
10 N Engl J Med, 355;11, www.NEJM.org, September 14, page 1134-1135 (Table 4 and 4B)
11 N Engl J Med, 355;11, www.NEJM.org, September 14, page 1136 (Table 5)
# # #
Media contacts
John Gilardi
Novartis Global Media Relations
+41 61 324 3018 (direct)
+41 61 324 2200 (main)
john.gilardi@novartis.com
Irina Ferluga
Novartis Pharma Communications
+ 41 61 324 24 22 (direct)
+ 41 79 824 11 21 (mobile)
irina.ferluga@novartis.com
Investor Relations contacts
International: +41 61 324 79 44
North America: +1 212 830 24 33
e-mail: investor.relations@novartis.com
Tuesday, September 19, 2006
Campath beats Rebif?
Genzyme Reports Interim Results from Trial of Campath® for Multiple Sclerosis
Date: September 14, 2006
Two-Year, Pre-Planned Interim Analysis Demonstrates Robust, Statistically Significant Treatment Effect of Campath Compared to Rebif®
Genzyme Corporation (Nasdaq: GENZ) today announced two-year interim results from a Phase 2 trial comparing Campath® (alemtuzumab) with Rebif® (interferon beta-1a) for the treatment of multiple sclerosis. The results derive from a pre-specified analysis conducted after two years of treatment for 334 patients in the planned three-year trial. This review was conducted in conjunction with an independent data and safety monitoring board.
As previously announced, dosing of alemtuzumab in this study was suspended in September 2005 after three patients developed immune thrombocytopenic purpura (ITP), a treatable condition in which patients experience a low platelet count as a result of an immune response directed against the platelets. At that time, most patients had received two cycles of therapy with alemtuzumab. Treatment with Rebif in the control arm has continued without interruption. The trial remains on clinical hold in the United States, and Genzyme is working closely with clinical investigators and regulatory agencies to complete the study and ensure that the risk of ITP is well understood and managed. The company discourages physicians and patients from using alemtuzumab for MS outside of a clinical trial setting in which procedures are in place for managing ITP risk.
Efficacy Results
Analysis of the first co-primary endpoint showed that patients taking alemtuzumab at high and low doses experienced at least a 75 percent reduction in the risk for relapse after at least two years of follow up when compared to patients treated with interferon beta-1a. This difference was statistically significant in favor of the alemtuzumab patients at both high and low doses, with a p-value less than the pre-specified value (p=0.00328) assigned for the two-year interim analysis.
Analysis of the other co-primary endpoint showed that patients taking alemtuzumab at high and low doses experienced at least a 65 percent reduction in the risk for progression of clinically significant disability when compared to patients treated with interferon beta-1a. This difference was statistically significant in favor of the alemtuzumab patients at both high and low doses, with a p-value less than the pre-specified value (p=0.01194) assigned for the two-year interim analysis.
Results of additional secondary and tertiary efficacy endpoints, including MRI data, functional assessments, and quality of life measures, support the findings seen in the co-primary endpoints.
"These results continue to demonstrate that alemtuzumab has great potential to make a meaningful impact on the treatment of multiple sclerosis," said Richard A. Moscicki, MD, chief medical officer for Genzyme. "We will work with regulatory agencies in the United States and Europe, as well as our clinical investigators, to successfully complete this important trial and to prepare for the initiation of a Phase 3 trial in the first half of 2007."
Genzyme has requested a meeting with the U.S. Food and Drug Administration to present these data and to address the next steps in the development of alemtuzumab. The company has already received scientific advice from the European Medicines Agency for moving forward with a Phase 3 study.
Safety Results and Risk Management
Dosing of alemtuzumab in this study was suspended in the United States in September 2005 after three patients were diagnosed with ITP. The first patient to present with ITP died from the disease. Genzyme immediately implemented enhanced monitoring for ITP and has since created a comprehensive risk management plan to help physicians and patients participating in the trial detect ITP early and minimize the risk of complications. These efforts have been effective and have enabled the identification of all five additional patients with ITP symptoms. All patients requiring medical treatment for ITP have responded well. To date, a total of six patients have been diagnosed with ITP in this trial.
Other than ITP, serious adverse events related to treatment occurred among four patients treated with the low dose of alemtuzumab and four treated with the high dose. Two patients treated with interferon beta-1a experienced serious adverse events related to treatment. Common non-serious adverse events included infusion reactions in the alemtuzumab patients and flu-like symptoms in patients using interferon beta-1a. The incidence of all thyroid adverse events, including Graves' disease, was less than expected compared to reports in the literature on the use of Campath in MS. Safety information from the study related both to ITP and thyroid disorders will be presented in two weeks at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.
Phase 2 Trial Design
The phase 2 trial randomized 334 patients with active relapsing-remitting multiple sclerosis at 49 medical centers in Europe and the United States. Patients in the trial were treated with alemtuzumab at one of two doses (12 or 24/mg per day for five days at initial treatment, and three days of re-treatment), or interferon beta-1a (44 mcg administered three times per week, as indicated in its product label). The alemtuzumab regimen was administered once per year by intravenous infusion, while the interferon beta-1a regimen was administered three times per week by subcutaneous injection.
The randomized trial compares the safety and efficacy of alemtuzumab with interferon beta-1a using two primary endpoints: the rate of relapse of MS symptoms, and the time to progression of clinically significant disability (time to Sustained Accumulated Disability over six months as measured by Expanded Disability Status Scale [EDSS]). Although treating physicians are aware of which treatment patients received, independent (blinded) neurologists assessed the disability efficacy endpoint.
About Multiple Sclerosis
Multiple Sclerosis (MS) is a chronic, debilitating disease in which the immune system attacks the person's brain and spinal cord. The disease causes a wide range of symptoms including fatigue, difficulty walking, numbness, and vision problems, and can progress to cause severe disability. Relapsing-remitting MS is the most common form of this disease.
About Campath
Campath (alemtuzumab), is indicated in the United States for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. Campath continues to be available for its labeled indication in leukemia. Determination of the effectiveness of Campath is based on overall response rates. A randomized, controlled phase 3 trial demonstrating clinical benefits in previously untreated patients with B-CLL has been completed, and final safety and efficacy results have been submitted for presentation at a medical meeting later this year. Campath is a humanized monoclonal antibody that binds to a specific target, CD52, on cell surfaces directing the body's immune system to destroy malignant cells. It is the first and only monoclonal antibody approved by the FDA for the treatment of patients with B-CLL.
Genzyme is developing alemtuzumab in oncology, multiple sclerosis and other indications. Schering AG holds exclusive worldwide marketing and distribution rights to Campath. The product is marketed in the U.S. by Berlex Laboratories, a U.S. affiliate of Schering AG. Campath was launched in the U.S. in June 2001, and in Europe, where it is named MabCampath®, in August 2001.
About Genzyme
One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. This year marks the 25th anniversary of Genzyme's founding. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 8,500 employees in locations spanning the globe and 2005 revenues of $2.7 billion. Genzyme has been selected by FORTUNE as one of the "100 Best Companies to Work for" in the United States.
With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as heart disease and other areas of unmet medical need.
This press release contains forward-looking statements, including statements about clinical trial results, regulatory plans and expected timelines for alemtuzumab, including the initiation of a Phase 3 trial in MS patients and the timing thereof, and the ability to manage patient safety and recommence alemtuzumab administration in the ongoing Phase 2 clinical trial in MS. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include, among others: that final results of the clinical trial demonstrate safety and efficacy comparable to the interim data that have emerged to date, the actual timing and content of submissions to and decisions made by the regulatory authorities, institutional review boards, data safety monitoring boards and treating physicians regarding the continued administration of alemtuzumab to MS patients, Genzyme's ability to develop and obtain approval of a patient safety plan, and the other risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission. Please see the disclosure under the heading "Factors Affecting Future Operating Results" in the Management's Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme's Quarterly Report on Form 10-Q for the quarter ended June 30, 2006 for a more complete discussion of these and other risks. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.
Genzyme and Campath® are registered trademarks of Genzyme Corporation. Rebif® is a registered trademark of Serono, Inc.
Terms and Conditions of Use | Privacy Policy | © 2002-2006 Genzyme Corporation. All rights reserved.
Date: September 14, 2006
Two-Year, Pre-Planned Interim Analysis Demonstrates Robust, Statistically Significant Treatment Effect of Campath Compared to Rebif®
Genzyme Corporation (Nasdaq: GENZ) today announced two-year interim results from a Phase 2 trial comparing Campath® (alemtuzumab) with Rebif® (interferon beta-1a) for the treatment of multiple sclerosis. The results derive from a pre-specified analysis conducted after two years of treatment for 334 patients in the planned three-year trial. This review was conducted in conjunction with an independent data and safety monitoring board.
As previously announced, dosing of alemtuzumab in this study was suspended in September 2005 after three patients developed immune thrombocytopenic purpura (ITP), a treatable condition in which patients experience a low platelet count as a result of an immune response directed against the platelets. At that time, most patients had received two cycles of therapy with alemtuzumab. Treatment with Rebif in the control arm has continued without interruption. The trial remains on clinical hold in the United States, and Genzyme is working closely with clinical investigators and regulatory agencies to complete the study and ensure that the risk of ITP is well understood and managed. The company discourages physicians and patients from using alemtuzumab for MS outside of a clinical trial setting in which procedures are in place for managing ITP risk.
Efficacy Results
Analysis of the first co-primary endpoint showed that patients taking alemtuzumab at high and low doses experienced at least a 75 percent reduction in the risk for relapse after at least two years of follow up when compared to patients treated with interferon beta-1a. This difference was statistically significant in favor of the alemtuzumab patients at both high and low doses, with a p-value less than the pre-specified value (p=0.00328) assigned for the two-year interim analysis.
Analysis of the other co-primary endpoint showed that patients taking alemtuzumab at high and low doses experienced at least a 65 percent reduction in the risk for progression of clinically significant disability when compared to patients treated with interferon beta-1a. This difference was statistically significant in favor of the alemtuzumab patients at both high and low doses, with a p-value less than the pre-specified value (p=0.01194) assigned for the two-year interim analysis.
Results of additional secondary and tertiary efficacy endpoints, including MRI data, functional assessments, and quality of life measures, support the findings seen in the co-primary endpoints.
"These results continue to demonstrate that alemtuzumab has great potential to make a meaningful impact on the treatment of multiple sclerosis," said Richard A. Moscicki, MD, chief medical officer for Genzyme. "We will work with regulatory agencies in the United States and Europe, as well as our clinical investigators, to successfully complete this important trial and to prepare for the initiation of a Phase 3 trial in the first half of 2007."
Genzyme has requested a meeting with the U.S. Food and Drug Administration to present these data and to address the next steps in the development of alemtuzumab. The company has already received scientific advice from the European Medicines Agency for moving forward with a Phase 3 study.
Safety Results and Risk Management
Dosing of alemtuzumab in this study was suspended in the United States in September 2005 after three patients were diagnosed with ITP. The first patient to present with ITP died from the disease. Genzyme immediately implemented enhanced monitoring for ITP and has since created a comprehensive risk management plan to help physicians and patients participating in the trial detect ITP early and minimize the risk of complications. These efforts have been effective and have enabled the identification of all five additional patients with ITP symptoms. All patients requiring medical treatment for ITP have responded well. To date, a total of six patients have been diagnosed with ITP in this trial.
Other than ITP, serious adverse events related to treatment occurred among four patients treated with the low dose of alemtuzumab and four treated with the high dose. Two patients treated with interferon beta-1a experienced serious adverse events related to treatment. Common non-serious adverse events included infusion reactions in the alemtuzumab patients and flu-like symptoms in patients using interferon beta-1a. The incidence of all thyroid adverse events, including Graves' disease, was less than expected compared to reports in the literature on the use of Campath in MS. Safety information from the study related both to ITP and thyroid disorders will be presented in two weeks at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.
Phase 2 Trial Design
The phase 2 trial randomized 334 patients with active relapsing-remitting multiple sclerosis at 49 medical centers in Europe and the United States. Patients in the trial were treated with alemtuzumab at one of two doses (12 or 24/mg per day for five days at initial treatment, and three days of re-treatment), or interferon beta-1a (44 mcg administered three times per week, as indicated in its product label). The alemtuzumab regimen was administered once per year by intravenous infusion, while the interferon beta-1a regimen was administered three times per week by subcutaneous injection.
The randomized trial compares the safety and efficacy of alemtuzumab with interferon beta-1a using two primary endpoints: the rate of relapse of MS symptoms, and the time to progression of clinically significant disability (time to Sustained Accumulated Disability over six months as measured by Expanded Disability Status Scale [EDSS]). Although treating physicians are aware of which treatment patients received, independent (blinded) neurologists assessed the disability efficacy endpoint.
About Multiple Sclerosis
Multiple Sclerosis (MS) is a chronic, debilitating disease in which the immune system attacks the person's brain and spinal cord. The disease causes a wide range of symptoms including fatigue, difficulty walking, numbness, and vision problems, and can progress to cause severe disability. Relapsing-remitting MS is the most common form of this disease.
About Campath
Campath (alemtuzumab), is indicated in the United States for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. Campath continues to be available for its labeled indication in leukemia. Determination of the effectiveness of Campath is based on overall response rates. A randomized, controlled phase 3 trial demonstrating clinical benefits in previously untreated patients with B-CLL has been completed, and final safety and efficacy results have been submitted for presentation at a medical meeting later this year. Campath is a humanized monoclonal antibody that binds to a specific target, CD52, on cell surfaces directing the body's immune system to destroy malignant cells. It is the first and only monoclonal antibody approved by the FDA for the treatment of patients with B-CLL.
Genzyme is developing alemtuzumab in oncology, multiple sclerosis and other indications. Schering AG holds exclusive worldwide marketing and distribution rights to Campath. The product is marketed in the U.S. by Berlex Laboratories, a U.S. affiliate of Schering AG. Campath was launched in the U.S. in June 2001, and in Europe, where it is named MabCampath®, in August 2001.
About Genzyme
One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. This year marks the 25th anniversary of Genzyme's founding. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 8,500 employees in locations spanning the globe and 2005 revenues of $2.7 billion. Genzyme has been selected by FORTUNE as one of the "100 Best Companies to Work for" in the United States.
With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as heart disease and other areas of unmet medical need.
This press release contains forward-looking statements, including statements about clinical trial results, regulatory plans and expected timelines for alemtuzumab, including the initiation of a Phase 3 trial in MS patients and the timing thereof, and the ability to manage patient safety and recommence alemtuzumab administration in the ongoing Phase 2 clinical trial in MS. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include, among others: that final results of the clinical trial demonstrate safety and efficacy comparable to the interim data that have emerged to date, the actual timing and content of submissions to and decisions made by the regulatory authorities, institutional review boards, data safety monitoring boards and treating physicians regarding the continued administration of alemtuzumab to MS patients, Genzyme's ability to develop and obtain approval of a patient safety plan, and the other risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission. Please see the disclosure under the heading "Factors Affecting Future Operating Results" in the Management's Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme's Quarterly Report on Form 10-Q for the quarter ended June 30, 2006 for a more complete discussion of these and other risks. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.
Genzyme and Campath® are registered trademarks of Genzyme Corporation. Rebif® is a registered trademark of Serono, Inc.
Terms and Conditions of Use | Privacy Policy | © 2002-2006 Genzyme Corporation. All rights reserved.
Monday, September 18, 2006
Multiple Sclerosis, an informative overview
FOR THE COMPLETE ARTICLE, by Marjorie Lazoff, MD, Medical Editor, Medical Computing Today; Contributing Editor, MSR's NetView, PLEASE CLICK ON THE TITLE LINK.
Multiple Sclerosis
Last Updated: October 31, 2005
Author: Marjorie Lazoff, MD, Medical Editor, Medical Computing Today; Contributing Editor, MSR's NetView
Marjorie Lazoff, MD, is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Editor(s): Edmond Hooker, MD, Assistant Clinical Professor, Department of Emergency Medicine, University of Louisville, Wright State University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; J Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health System; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Rick Kulkarni, MD, Assistant Professor of Medicine, David Geffen UCLA School of Medicine; Director of Informatics, Department of Emergency Medicine, UCLA/Olive View-UCLA Medical Center
Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Background: Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disease of the CNS. Patients with MS commonly present with an individual mix of neuropsychological dysfunction, which tends to progress over years to decades.
The diagnosis of MS is based on a classic presentation (ie, optic neuritis, transverse myelitis, internuclear ophthalmoplegia, paresthesias) and on the identification of other neurologic abnormalities, which may be indicated by the patient history and exam. Typical findings on an MRI also help establish a diagnosis of MS.
Patients with atypical presentations and/or a normal or atypical MRI may require evoked potential studies, to uncover subclinical neurologic abnormalities, or cerebral spinal fluid (CSF) analysis, which also serves to exclude treatable disorders and document MS-like immune activity in the CNS.
By convention, the confidence in the diagnosis of MS is described as definite, probable, or possible MS. It includes a classification with respect to clinical presentation, which correlates somewhat with the prognosis and is useful in clinical trials.
About 70% of patients present with the more favorable relapsing-remitting (RR) type, which is characterized by acute exacerbations with full or partial remissions.
For patients with RR, the FDA has approved the long-term use of beta-interferons and glatiramer acetate, which is a synthetic form of myelin basic protein (MBP) that has fewer side effects than interferon. In rigorous trials that had different end points, both demonstrated reductions of approximately 33% in both clinical disease activity and progression of MS lesions on MRI. Opinions vary on when in the course of MS to initiate treatment with these agents. The literature favors beta-interferons, although adverse effects are more troublesome than with glatiramer acetate. Research is active and ongoing.
The remaining patients present with chronic progressive MS, which is subdivided further into (a) primary-progressive (PP), (b) relapsing-progressive (RP), which is a pattern combining features of RR and RP and is intermediate in clinical severity, and (c) secondary-progressive (SP), which many patients with RR progress to over time.
Treatment for those with chronic progressive MS is less satisfying than for those with RR. Patients with SP type may respond to beta-interferons, and one study found modest impact on disease progression when the patients were given a low dose of methotrexate.
The group of idiopathic inflammatory demyelinating syndromes, including MS, is shown in Table 1 at the end of this article. Emergency physicians should be familiar with optic neuritis, acute transverse myelitis, and acute disseminated encephalitis. In any given patient, each syndrome may be unrelated to MS, or it may be a presenting symptom or an exacerbation of MS.
Not included in Table 1 are 2 other clinical syndromes that share features of MS and may represent 2 opposite ends of the MS spectrum.
Acute fulminant MS, which often results in death or extensive morbidity within days
A forme fruste or benign MS with uncharacteristically slow, if any, disease progression over the decades
Patients with established MS may present to the ED because of a relapse or because of complications of MS (eg, bladder dysfunction, impaired swallowing or cough reflex, prolonged immobilization, nutrition/hydration complications, adverse effects of medication). Of those that present because of a relapse, 80% have exacerbations of previous, rather than new, deficits.
ED assessment includes the elimination of other treatable etiologies and a search for known precipitants of relapses (eg, fever, exercise, infection). Ruling out asymptomatic urinary tract infection (UTI) in patients with MS and distinguishing the flulike symptoms that may occur with chronic interferon therapy from a true infection are important. No firm correlation exists between MS exacerbations and trauma, allergic responses, immunization, or physical or emotional stress, but this remains especially controversial.
The development of new focal deficits in a patient without known MS can be a diagnostic challenge. Patients who present with optic neuritis, transverse myelitis, disseminated encephalitis, or other signs and symptoms that are evocative of MS require exclusion of treatable etiologies. However, confirmation or exclusion of MS lies outside the scope of ED evaluation. Determining the extent of ED evaluation and the need for admission versus outpatient referral often is a judgment call.
Pathophysiology: MS is regarded as an autoimmune disease. Most of what is known about MS is derived from its model in animal research, which is experimental allergic encephalomyelitis.
The autoantigen in MS most likely is one of several myelin proteins (eg, proteolipid protein [PLP], myelin oligodendrocyte glycoprotein [MOG], MBP). Microglial cells and macrophages perform jointly as antigen-presenting cells, resulting in activation of cytokines, complement, and other modulators of the inflammatory process, targeting specific oligodendroglia cells and their membrane myelin.
The pathologic hallmark of MS is multicentric, multiphasic CNS inflammation and demyelination. Originally, each MS lesion was thought to evolve through episodes of demyelination and remyelination into a chronic burned-out plaque with relative preservation of axons and gliosis. Thus, the neuropsychological dysfunction occurred, despite an essentially intact neural network, until late in the disease course. However, recent studies have demonstrated that axonal transections do occur during acute exacerbations; furthermore, axonal damage, as measured by magnetic resonance spectroscopy, was found to correlate with clinical disability. Clearly, more work is needed to understand the associations among inflammation-mediated demyelination, axonal injury, and clinical disability.
For unclear reasons, lesions characteristically involve the optic nerve and periventricular white matter of the cerebellum, brain stem, basal ganglia, and spinal cord. Identifying MS lesions in gross specimens is difficult, as is identifying MS lesions in gray matter on radiographic images; hence, the predilection for white matter may not be disease related. The peripheral nervous system rarely is involved.
Frequency:
In the US: MS is the most common debilitating illness among young adults. The incidence is 0.5-1 per 1000 people, and the general population has a 0.2% lifetime risk of acquiring MS. Approximately 25,000 new cases are diagnosed each year.
Internationally: Approximately 1 per 1,000,000 people acquire MS.
Mortality/Morbidity:
MS affects quality of life rather than duration of life.
Worsening disability from any cause is strongly associated with increased mortality rate.
Deaths attributable to MS are the result of fulminant MS, which is rare; complications from chronic disability (eg, pneumonia, pulmonary embolism, infected decubiti); and suicide.
Race:
Incidence is higher in Caucasians than in other races for which incidences are known. The incidence may be twice as high in Caucasians as in other races. MS essentially is unknown among Eskimos and Bantus, and it is rare among Native Americans and Asians.
MS is 5 times more prevalent in temperate climates than in the tropics, but the risk seems to be associated entirely with childhood years spent in a temperate climate. The risk of acquiring MS is higher in those who have lived in a temperate climate before age 15, but not in those who move to a temperate climate after age 15.
Sex:
Throughout adulthood the female-to-male ratio is 2:1. The sex ratio is more pronounced in those younger than 16 years (ie, approaches 3:1), but it is less pronounced in those older than the fifth decade. On average, men present 1-2 years later than women, and men have a greater tendency for having the progressive disease at onset.
Age:
MS rarely occurs in those younger than 20 years or those older than 50 years. The occurrence of MS is even more rare in those younger than 15 years and in those older than 60 years.
CLINICAL
History: The review of systems should concentrate on the evidence of bladder, kidney, lung, or skin infection and irritative or obstructive bladder symptoms.
Classic MS symptoms:
Sensory loss (ie, paresthesias) usually is an early complaint.
Motor (eg, muscle cramping secondary to spasticity) and autonomic (eg, bladder, bowel, sexual dysfunction) spinal cord symptoms may be present.
Cerebellar symptoms (eg, Charcot triad of dysarthria, ataxia, tremor) may occur.
Constitutional symptoms, especially fatigue (which occurs in 70% of cases) and dizziness, may be present.
Subjective difficulties with attention span, concentration, memory, and judgment may be noted any time during the disease course.
About 50% of patients with MS have impairment, usually mild, in information processing on neuropsychological testing.
Depression is common, but euphoria is less common.
Over the course of the disease, 5-10% of patients develop an overt psychiatric disorder (eg, manic depression, paranoia, major depression) or dementia.
Eye symptoms, including diplopia on lateral gaze, occur in 33% of patients.
Trigeminal neuralgia may occur.
Optic neuritis (ON) (ie, inflammation or demyelination of optic nerve) is the initial presentation of 15% of patients with MS. Fifty percent of all patients who present with ON have MS. Isolated episodes of ON, even if they are recurrent, do not represent MS.
Acute onset (ie, occurring over minutes or hours, rarely days) of single eye visual blurring, decreased acuity (ie, usually scotoma), decreased color perception, and/or discomfort of the moving eye(s) are symptoms that are indicative of ON.
The 3 phenomena associated with ON or compressive/ischemic neuritis are as follows:
Phosphenes, or flashes of light, usually are precipitated by eye movements.
Uhthoff phenomenon or deterioration of vision is induced by exercise, a hot meal, or a hot bath.
The Pulfrich effect occurs when latencies between the eyes are unequal, resulting in a sense of disorientation in moving traffic.
Acute transverse myelitis
Partial acute transverse myelitis, rather than total, usually is a manifestation of MS. Strongly consider mechanical compression in the differential diagnosis.
Acute partial loss of motor, sensory, autonomic, reflex, and sphincter function below the level of the lesion indicates acute transverse myelitis.
Devic syndrome is acute transverse myelitis accompanied by bilateral ON.
Acute disseminated encephalitis is pathophysiologically and radiographically identical to MS. It is characterized by acute onset of motor, sensory, cerebellar, and cranial nerve dysfunction with encephalopathy, progressing to coma and eventual death in 30% of such cases.
MS as a sole symptom is unusual, but MS may present with many other typical MS presentations, including the following:
Aphasia or dysphasia
Hemianopsia
Seizures (5% of patients with MS)
Significant motor complaints without sensory deficits or dysautonomia (eg, bladder)
Physical: Classic MS findings on neurologic examination include the following:
Eye:
Optic neuritis
Acutely, 50% of patients present with retrobulbar involvement; hence, funduscopy results are normal. "The patient sees nothing and the doctor sees nothing."
Anterior involvement causes papillitis, and differentiating this from papilledema is important. When inflammation involving the retina is extensive, look for presence of a macular star.
After several weeks, optic atrophy may be seen.
An afferent pupillary defect may be seen in the affected eye.
Visual acuity usually is impaired (ie, subtle to total blindness).
The classic finding is bilateral (unilateral much less common) internuclear ophthalmoplegia (INO), a lesion in the median longitudinal fasciculus (MLF) resulting in a weakness in adduction of the ipsilateral eye with nystagmus on abduction of the contralateral eye, an incomplete or slow abduction of the ipsilateral eye upon lateral gaze, with complete preservation of convergence.
Other eye findings include abnormal pupillary responses, acquired pendular nystagmus or sinusoidal involuntary oscillations of one or both eyes, and/or loss of smooth eye pursuit.
Regardless of the stage or classification, most authorities question the diagnosis of MS in a patient without at least one of these findings.
Spinal cord involvement:
Acute transverse myelitis
Sphincter paralysis and unchanging level
Distinguish from Guillain-Barré syndrome
Paralysis, spasticity, and hyperreflexia are indicative of upper motor neuron dysfunction (ie, lateral corticospinal tracts). Decreased joint position and vibration sense (ie, dorsal columns) are common findings.
Decreased pain and temperature (ie, lateral spinothalamic tracts) are less common. The sparing of these symptoms may be diagnostically helpful.
The degree of corticospinal tract findings tends to correlate with bladder, bowel, and sexual dysautonomias.
Cerebellar findings: Disequilibrium, truncal or limb ataxia, scanning (ie, monotonous) speech, intention tremor, and saccadic dysmetria are common cerebellar findings.
Lhermitte sign: Neck flexion results in an electric shocklike feeling in the torso or extremities
Acute disseminated encephalitis
Most commonly, altered mental status and/or personality changes
Focal findings (eg, cranial nerve defects, hemiparesis, focal seizures, autonomic dysfunction)
Cranial nerve defects
Ataxia
Dysphasia
Meningismus, usually less common and pronounced than in meningitis
Unusual findings in MS include the absence of eye findings and isolated motor, sensory, cerebellar, and cranial nerve lesions.
Causes: MS commonly is believed to result from an autoimmune process. What triggers the autoimmune process is not clear, but the nonrandom nature of its geographic distribution suggests an isolated or additive environmental effect and/or inadvertent activation and dysregulation of CNS immune processes by a retroviral infection that was perhaps acquired in childhood. On the basis of bench research findings, some authorities implicate human herpesvirus-6 (HHV-6) variant B group 2, while others implicate Chlamydia pneumonia.
Polygene inheritance accounts for a familial rate of 10-20%; yet, most studies confirm that a monozygotic twin has only a 30% risk of acquiring MS, suggesting a genetic predisposition to an environmental viral agent.
As in systemic lupus erythematosus (SLE), human leukocyte antigen (HLA) patterns of patients with MS tend to differ from those of the general population.
Although no present studies support a connection between hepatitis B vaccination and MS, worldwide anecdotal reports prompted the Centers for Disease Control and Prevention (CDC) to investigate this possibility (see the CDC Web site Multiple Sclerosis and the Hepatitis B Vaccine).
Optic neuritis is attributable to MS in 50% of cases; the remaining 50% of cases are probably postinfectious. Ischemic optic neuropathy, arteriovenous malformations, tumors, and other compressive lesions usually present more gradually with additional symptoms or atypical features, but these complications should be pursued aggressively in any patient presenting with ON.
Acute transverse myelitis, when not attributable to MS, most likely is infectious (eg, Epstein-Barr virus [EBV], Lyme [rare]) or postinfectious. An important ED exclusion in these patients is mechanical compression by tumor, abscess, or aneurysm.
Acute disseminated encephalitis involves a poorly defined immune-mediated demyelinating process.
Multiple Sclerosis
Last Updated: October 31, 2005
Author: Marjorie Lazoff, MD, Medical Editor, Medical Computing Today; Contributing Editor, MSR's NetView
Marjorie Lazoff, MD, is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Editor(s): Edmond Hooker, MD, Assistant Clinical Professor, Department of Emergency Medicine, University of Louisville, Wright State University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; J Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health System; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Rick Kulkarni, MD, Assistant Professor of Medicine, David Geffen UCLA School of Medicine; Director of Informatics, Department of Emergency Medicine, UCLA/Olive View-UCLA Medical Center
Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography
Background: Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disease of the CNS. Patients with MS commonly present with an individual mix of neuropsychological dysfunction, which tends to progress over years to decades.
The diagnosis of MS is based on a classic presentation (ie, optic neuritis, transverse myelitis, internuclear ophthalmoplegia, paresthesias) and on the identification of other neurologic abnormalities, which may be indicated by the patient history and exam. Typical findings on an MRI also help establish a diagnosis of MS.
Patients with atypical presentations and/or a normal or atypical MRI may require evoked potential studies, to uncover subclinical neurologic abnormalities, or cerebral spinal fluid (CSF) analysis, which also serves to exclude treatable disorders and document MS-like immune activity in the CNS.
By convention, the confidence in the diagnosis of MS is described as definite, probable, or possible MS. It includes a classification with respect to clinical presentation, which correlates somewhat with the prognosis and is useful in clinical trials.
About 70% of patients present with the more favorable relapsing-remitting (RR) type, which is characterized by acute exacerbations with full or partial remissions.
For patients with RR, the FDA has approved the long-term use of beta-interferons and glatiramer acetate, which is a synthetic form of myelin basic protein (MBP) that has fewer side effects than interferon. In rigorous trials that had different end points, both demonstrated reductions of approximately 33% in both clinical disease activity and progression of MS lesions on MRI. Opinions vary on when in the course of MS to initiate treatment with these agents. The literature favors beta-interferons, although adverse effects are more troublesome than with glatiramer acetate. Research is active and ongoing.
The remaining patients present with chronic progressive MS, which is subdivided further into (a) primary-progressive (PP), (b) relapsing-progressive (RP), which is a pattern combining features of RR and RP and is intermediate in clinical severity, and (c) secondary-progressive (SP), which many patients with RR progress to over time.
Treatment for those with chronic progressive MS is less satisfying than for those with RR. Patients with SP type may respond to beta-interferons, and one study found modest impact on disease progression when the patients were given a low dose of methotrexate.
The group of idiopathic inflammatory demyelinating syndromes, including MS, is shown in Table 1 at the end of this article. Emergency physicians should be familiar with optic neuritis, acute transverse myelitis, and acute disseminated encephalitis. In any given patient, each syndrome may be unrelated to MS, or it may be a presenting symptom or an exacerbation of MS.
Not included in Table 1 are 2 other clinical syndromes that share features of MS and may represent 2 opposite ends of the MS spectrum.
Acute fulminant MS, which often results in death or extensive morbidity within days
A forme fruste or benign MS with uncharacteristically slow, if any, disease progression over the decades
Patients with established MS may present to the ED because of a relapse or because of complications of MS (eg, bladder dysfunction, impaired swallowing or cough reflex, prolonged immobilization, nutrition/hydration complications, adverse effects of medication). Of those that present because of a relapse, 80% have exacerbations of previous, rather than new, deficits.
ED assessment includes the elimination of other treatable etiologies and a search for known precipitants of relapses (eg, fever, exercise, infection). Ruling out asymptomatic urinary tract infection (UTI) in patients with MS and distinguishing the flulike symptoms that may occur with chronic interferon therapy from a true infection are important. No firm correlation exists between MS exacerbations and trauma, allergic responses, immunization, or physical or emotional stress, but this remains especially controversial.
The development of new focal deficits in a patient without known MS can be a diagnostic challenge. Patients who present with optic neuritis, transverse myelitis, disseminated encephalitis, or other signs and symptoms that are evocative of MS require exclusion of treatable etiologies. However, confirmation or exclusion of MS lies outside the scope of ED evaluation. Determining the extent of ED evaluation and the need for admission versus outpatient referral often is a judgment call.
Pathophysiology: MS is regarded as an autoimmune disease. Most of what is known about MS is derived from its model in animal research, which is experimental allergic encephalomyelitis.
The autoantigen in MS most likely is one of several myelin proteins (eg, proteolipid protein [PLP], myelin oligodendrocyte glycoprotein [MOG], MBP). Microglial cells and macrophages perform jointly as antigen-presenting cells, resulting in activation of cytokines, complement, and other modulators of the inflammatory process, targeting specific oligodendroglia cells and their membrane myelin.
The pathologic hallmark of MS is multicentric, multiphasic CNS inflammation and demyelination. Originally, each MS lesion was thought to evolve through episodes of demyelination and remyelination into a chronic burned-out plaque with relative preservation of axons and gliosis. Thus, the neuropsychological dysfunction occurred, despite an essentially intact neural network, until late in the disease course. However, recent studies have demonstrated that axonal transections do occur during acute exacerbations; furthermore, axonal damage, as measured by magnetic resonance spectroscopy, was found to correlate with clinical disability. Clearly, more work is needed to understand the associations among inflammation-mediated demyelination, axonal injury, and clinical disability.
For unclear reasons, lesions characteristically involve the optic nerve and periventricular white matter of the cerebellum, brain stem, basal ganglia, and spinal cord. Identifying MS lesions in gross specimens is difficult, as is identifying MS lesions in gray matter on radiographic images; hence, the predilection for white matter may not be disease related. The peripheral nervous system rarely is involved.
Frequency:
In the US: MS is the most common debilitating illness among young adults. The incidence is 0.5-1 per 1000 people, and the general population has a 0.2% lifetime risk of acquiring MS. Approximately 25,000 new cases are diagnosed each year.
Internationally: Approximately 1 per 1,000,000 people acquire MS.
Mortality/Morbidity:
MS affects quality of life rather than duration of life.
Worsening disability from any cause is strongly associated with increased mortality rate.
Deaths attributable to MS are the result of fulminant MS, which is rare; complications from chronic disability (eg, pneumonia, pulmonary embolism, infected decubiti); and suicide.
Race:
Incidence is higher in Caucasians than in other races for which incidences are known. The incidence may be twice as high in Caucasians as in other races. MS essentially is unknown among Eskimos and Bantus, and it is rare among Native Americans and Asians.
MS is 5 times more prevalent in temperate climates than in the tropics, but the risk seems to be associated entirely with childhood years spent in a temperate climate. The risk of acquiring MS is higher in those who have lived in a temperate climate before age 15, but not in those who move to a temperate climate after age 15.
Sex:
Throughout adulthood the female-to-male ratio is 2:1. The sex ratio is more pronounced in those younger than 16 years (ie, approaches 3:1), but it is less pronounced in those older than the fifth decade. On average, men present 1-2 years later than women, and men have a greater tendency for having the progressive disease at onset.
Age:
MS rarely occurs in those younger than 20 years or those older than 50 years. The occurrence of MS is even more rare in those younger than 15 years and in those older than 60 years.
CLINICAL
History: The review of systems should concentrate on the evidence of bladder, kidney, lung, or skin infection and irritative or obstructive bladder symptoms.
Classic MS symptoms:
Sensory loss (ie, paresthesias) usually is an early complaint.
Motor (eg, muscle cramping secondary to spasticity) and autonomic (eg, bladder, bowel, sexual dysfunction) spinal cord symptoms may be present.
Cerebellar symptoms (eg, Charcot triad of dysarthria, ataxia, tremor) may occur.
Constitutional symptoms, especially fatigue (which occurs in 70% of cases) and dizziness, may be present.
Subjective difficulties with attention span, concentration, memory, and judgment may be noted any time during the disease course.
About 50% of patients with MS have impairment, usually mild, in information processing on neuropsychological testing.
Depression is common, but euphoria is less common.
Over the course of the disease, 5-10% of patients develop an overt psychiatric disorder (eg, manic depression, paranoia, major depression) or dementia.
Eye symptoms, including diplopia on lateral gaze, occur in 33% of patients.
Trigeminal neuralgia may occur.
Optic neuritis (ON) (ie, inflammation or demyelination of optic nerve) is the initial presentation of 15% of patients with MS. Fifty percent of all patients who present with ON have MS. Isolated episodes of ON, even if they are recurrent, do not represent MS.
Acute onset (ie, occurring over minutes or hours, rarely days) of single eye visual blurring, decreased acuity (ie, usually scotoma), decreased color perception, and/or discomfort of the moving eye(s) are symptoms that are indicative of ON.
The 3 phenomena associated with ON or compressive/ischemic neuritis are as follows:
Phosphenes, or flashes of light, usually are precipitated by eye movements.
Uhthoff phenomenon or deterioration of vision is induced by exercise, a hot meal, or a hot bath.
The Pulfrich effect occurs when latencies between the eyes are unequal, resulting in a sense of disorientation in moving traffic.
Acute transverse myelitis
Partial acute transverse myelitis, rather than total, usually is a manifestation of MS. Strongly consider mechanical compression in the differential diagnosis.
Acute partial loss of motor, sensory, autonomic, reflex, and sphincter function below the level of the lesion indicates acute transverse myelitis.
Devic syndrome is acute transverse myelitis accompanied by bilateral ON.
Acute disseminated encephalitis is pathophysiologically and radiographically identical to MS. It is characterized by acute onset of motor, sensory, cerebellar, and cranial nerve dysfunction with encephalopathy, progressing to coma and eventual death in 30% of such cases.
MS as a sole symptom is unusual, but MS may present with many other typical MS presentations, including the following:
Aphasia or dysphasia
Hemianopsia
Seizures (5% of patients with MS)
Significant motor complaints without sensory deficits or dysautonomia (eg, bladder)
Physical: Classic MS findings on neurologic examination include the following:
Eye:
Optic neuritis
Acutely, 50% of patients present with retrobulbar involvement; hence, funduscopy results are normal. "The patient sees nothing and the doctor sees nothing."
Anterior involvement causes papillitis, and differentiating this from papilledema is important. When inflammation involving the retina is extensive, look for presence of a macular star.
After several weeks, optic atrophy may be seen.
An afferent pupillary defect may be seen in the affected eye.
Visual acuity usually is impaired (ie, subtle to total blindness).
The classic finding is bilateral (unilateral much less common) internuclear ophthalmoplegia (INO), a lesion in the median longitudinal fasciculus (MLF) resulting in a weakness in adduction of the ipsilateral eye with nystagmus on abduction of the contralateral eye, an incomplete or slow abduction of the ipsilateral eye upon lateral gaze, with complete preservation of convergence.
Other eye findings include abnormal pupillary responses, acquired pendular nystagmus or sinusoidal involuntary oscillations of one or both eyes, and/or loss of smooth eye pursuit.
Regardless of the stage or classification, most authorities question the diagnosis of MS in a patient without at least one of these findings.
Spinal cord involvement:
Acute transverse myelitis
Sphincter paralysis and unchanging level
Distinguish from Guillain-Barré syndrome
Paralysis, spasticity, and hyperreflexia are indicative of upper motor neuron dysfunction (ie, lateral corticospinal tracts). Decreased joint position and vibration sense (ie, dorsal columns) are common findings.
Decreased pain and temperature (ie, lateral spinothalamic tracts) are less common. The sparing of these symptoms may be diagnostically helpful.
The degree of corticospinal tract findings tends to correlate with bladder, bowel, and sexual dysautonomias.
Cerebellar findings: Disequilibrium, truncal or limb ataxia, scanning (ie, monotonous) speech, intention tremor, and saccadic dysmetria are common cerebellar findings.
Lhermitte sign: Neck flexion results in an electric shocklike feeling in the torso or extremities
Acute disseminated encephalitis
Most commonly, altered mental status and/or personality changes
Focal findings (eg, cranial nerve defects, hemiparesis, focal seizures, autonomic dysfunction)
Cranial nerve defects
Ataxia
Dysphasia
Meningismus, usually less common and pronounced than in meningitis
Unusual findings in MS include the absence of eye findings and isolated motor, sensory, cerebellar, and cranial nerve lesions.
Causes: MS commonly is believed to result from an autoimmune process. What triggers the autoimmune process is not clear, but the nonrandom nature of its geographic distribution suggests an isolated or additive environmental effect and/or inadvertent activation and dysregulation of CNS immune processes by a retroviral infection that was perhaps acquired in childhood. On the basis of bench research findings, some authorities implicate human herpesvirus-6 (HHV-6) variant B group 2, while others implicate Chlamydia pneumonia.
Polygene inheritance accounts for a familial rate of 10-20%; yet, most studies confirm that a monozygotic twin has only a 30% risk of acquiring MS, suggesting a genetic predisposition to an environmental viral agent.
As in systemic lupus erythematosus (SLE), human leukocyte antigen (HLA) patterns of patients with MS tend to differ from those of the general population.
Although no present studies support a connection between hepatitis B vaccination and MS, worldwide anecdotal reports prompted the Centers for Disease Control and Prevention (CDC) to investigate this possibility (see the CDC Web site Multiple Sclerosis and the Hepatitis B Vaccine).
Optic neuritis is attributable to MS in 50% of cases; the remaining 50% of cases are probably postinfectious. Ischemic optic neuropathy, arteriovenous malformations, tumors, and other compressive lesions usually present more gradually with additional symptoms or atypical features, but these complications should be pursued aggressively in any patient presenting with ON.
Acute transverse myelitis, when not attributable to MS, most likely is infectious (eg, Epstein-Barr virus [EBV], Lyme [rare]) or postinfectious. An important ED exclusion in these patients is mechanical compression by tumor, abscess, or aneurysm.
Acute disseminated encephalitis involves a poorly defined immune-mediated demyelinating process.
Chronic Progressive MS in pictures
Using MRI studies, researchers at Harvard Medical School assembled this "a year in the life of a patient with the chronic progressive form of" multiple sclerosis.
Please click on the link (title of the arcticle) for the views.
Please click on the link (title of the arcticle) for the views.
Saturday, September 16, 2006
State House passes bills for adult stem cell research
9/13/2006, 6:15 p.m. ET
By TIM MARTIN
The Associated Press
LANSING, Mich. (AP) — The state House passed bills Wednesday aimed at encouraging the creation of a network of stem cell banks for umbilical cords and adult stem cells donated by patients. But Democrats, while voting in favor of the bills, said they were frustrated the Republican-led Legislature hasn't passed bills that would foster embryonic stem cell research in Michigan. Rep. Andy Meisner, D-Ferndale, said the bills passed Wednesday are a "step in the right direction" for Michigan research. But he wants action on his package of bills that would allow more embryonic stem cell research, which he said holds "great promise that the current legislation before us does not address."
Several other states are focusing their research efforts on embryonic stem cell research. Meisner says Michigan's laws on embryonic stem cell research are among the most restrictive in the nation. Some Republicans have ethical concerns about embryonic stem cell research, which is opposed by groups such as the Michigan Catholic Conference and Right to Life of Michigan. Some within the GOP say there is still plenty of potential for medical breakthroughs related to multiple sclerosis, diabetes and Parkinson's disease through adult stem cell research. Rep. Jack Hoogendyk, a Republican from Kalamazoo, said the research holds the potential to "turn medical waste into miracles."
Four of the five cord bank bills passed the House unanimously. They next head to the Senate. The only one that sparked dissension Wednesday was a bill to fund the measure with $5 million from the 21st Century Jobs Fund recently established to generate more investment in life sciences and other high- tech businesses in Michigan. Some Democrats said they were concerned with the funding mechanism and the authority to use the money from that particular fund. The funding bill passed the House by a 74-32 vote. Other bills in the Republican-introduced package would require the state to promote the cord bank through educational materials and provide a tax credit for cash donations to nonprofit cord banks.
___
The stem cell bills are House Bills 6291-6295.
___
On the Net:
Michigan Legislature: http://www.legislature.mi.gov
Copyright 2006 Associated Press. All rights reserved.
This material may not be published, broadcast, rewritten, or redistributed.
© 2006 Michigan Live. All Rights Reserved.
By TIM MARTIN
The Associated Press
LANSING, Mich. (AP) — The state House passed bills Wednesday aimed at encouraging the creation of a network of stem cell banks for umbilical cords and adult stem cells donated by patients. But Democrats, while voting in favor of the bills, said they were frustrated the Republican-led Legislature hasn't passed bills that would foster embryonic stem cell research in Michigan. Rep. Andy Meisner, D-Ferndale, said the bills passed Wednesday are a "step in the right direction" for Michigan research. But he wants action on his package of bills that would allow more embryonic stem cell research, which he said holds "great promise that the current legislation before us does not address."
Several other states are focusing their research efforts on embryonic stem cell research. Meisner says Michigan's laws on embryonic stem cell research are among the most restrictive in the nation. Some Republicans have ethical concerns about embryonic stem cell research, which is opposed by groups such as the Michigan Catholic Conference and Right to Life of Michigan. Some within the GOP say there is still plenty of potential for medical breakthroughs related to multiple sclerosis, diabetes and Parkinson's disease through adult stem cell research. Rep. Jack Hoogendyk, a Republican from Kalamazoo, said the research holds the potential to "turn medical waste into miracles."
Four of the five cord bank bills passed the House unanimously. They next head to the Senate. The only one that sparked dissension Wednesday was a bill to fund the measure with $5 million from the 21st Century Jobs Fund recently established to generate more investment in life sciences and other high- tech businesses in Michigan. Some Democrats said they were concerned with the funding mechanism and the authority to use the money from that particular fund. The funding bill passed the House by a 74-32 vote. Other bills in the Republican-introduced package would require the state to promote the cord bank through educational materials and provide a tax credit for cash donations to nonprofit cord banks.
___
The stem cell bills are House Bills 6291-6295.
___
On the Net:
Michigan Legislature: http://www.legislature.mi.gov
Copyright 2006 Associated Press. All rights reserved.
This material may not be published, broadcast, rewritten, or redistributed.
© 2006 Michigan Live. All Rights Reserved.
Friday, September 15, 2006
Tysabri Follow-up
Several people have asked questions regarding TYSABRI, its recent re-introduction after the 2005 withdrawal as a result of reports of deaths of a few MS patients from progressive multifocal leukoencephalopathy (PML), a rare and frequently fatal, demyelinating disease of the central nervous system. As reported, these deaths occured in MS patients that were also taking Avonex.
As many people that know me are aware, I raised serious questions regarding the FDA approval of TYSABRI in the first place, given its then very brief clinical trials data. Over the past two decades, the FDA has taken greater and greater risks with health by a) accelerating the approval of drugs with increasingly less clinical trials data, and b) accepting increasingly lower threshholds for drug effectiveness prior to market release. While I agree that patients with many illnesses should have broader open opportunity to make decisions about new therapies, particularly when they are dealing with truly life-threatening diseases, too often in recent years, the pharmaceutical industry-influenced FDA has approved drugs that often show limited incremental benefit over drugs that are already on the market. In my opinion, this raises serious questions.
However, as long as the FDA is willing to pursue such strategies, it is in the hand of patients and physicians whether or not to try these newer drug therapies.
Based on the clinical trials data that were used for FDA approval, Biogen and Elan claim that TYSABRI "two-year data from the AFFIRM monotherapy trial showed that treatment with TYSABRI reduced the risk of disability progression by 42% (p is less than 0.001), the primary endpoint of the study, and led to a 67% reduction (p is less than 0.001) in the annualized relapse rate compared to placebo. TYSABRI treatment also resulted in sustained and statistically significant reductions in brain lesion activity as measured by MRI.
While the number of incidences of PML were low, and none were reported with TYSABRI therapy alone, I feel that it is only prudent that given the availability of competing immunosupressant or immunomodulating therapies for multiple sclerosis, that people weigh two important criteria:
1. The effectiveness of the alternative drugs;
2. Their own experience and tolerance of those drugs.
It is true, based on the data, that TYSABRI appears to be more effect than the alternative "CRAB" drugs in reducing relapse rates and the number of enhanced brain lesions.
DISABILITY PROGRESSION:
While TYSABRI has shown to reduce the risk of disability progression by 42% as compared to placebo, AVONEX data shows a reduction of 37%; BETASERON data shows a reduction of 29%; COPAXONE data shows a reduction of 50%; REBIF (PRISMS STUDY) data shows a reduction of 30%.
RELAPSE RATE:
While TYSABRI has shown to reduce the relapse rate by 66% (AFFIRM STUDY) as compared to placebo, AVONEX data shows a reduction of 44%; BETASERON data shows a reduction of 73%; COPAXONE data shows a reduction of 32%; REBIF data (PRISMS STUDY) shows a reduction of 32%.
Now here's food for thought: Keep in mind that there are several clinical studies that measure these important metrics. Some show better results than others, so it is difficult to offer truly direct comparisons. Additionally, keep in mind that while many of these data results are impressive, not every patient that takes on of these drugs actually receives all or any of the benefit. That's the dirty little secret that the pharmaceutical companies and many neurologists do not adequately disclose. In fact, of those that have participated in various of the clinical trials, in some cases as few as 35% of those taking a particular agent actually received benefit.
And then there are the statin drugs. While they have only been in small, early stage clinical trials - mainly because their manufacturers simply do not see the benefit of investing tens of millions or more in complete clinical trials when they are generating billions of dollars of revenues with these somewhat benign oral drugs in the anti-cholesterol market - there is modest evidence that statins may be of important benefit in at least reducing the number of brain lesions. More trials need to be conducted to gauge their effectiveness in reducing relapse rate and disability progression.
The conclusion of this piece is not that MSers should shy away from TYSABRI or any other therapy. Rather, be fully educated about the relative risks and benefits, the financial and side effects costs, and seek the guidance of a neurologist that specializes in multiple sclerosis.
As many people that know me are aware, I raised serious questions regarding the FDA approval of TYSABRI in the first place, given its then very brief clinical trials data. Over the past two decades, the FDA has taken greater and greater risks with health by a) accelerating the approval of drugs with increasingly less clinical trials data, and b) accepting increasingly lower threshholds for drug effectiveness prior to market release. While I agree that patients with many illnesses should have broader open opportunity to make decisions about new therapies, particularly when they are dealing with truly life-threatening diseases, too often in recent years, the pharmaceutical industry-influenced FDA has approved drugs that often show limited incremental benefit over drugs that are already on the market. In my opinion, this raises serious questions.
However, as long as the FDA is willing to pursue such strategies, it is in the hand of patients and physicians whether or not to try these newer drug therapies.
Based on the clinical trials data that were used for FDA approval, Biogen and Elan claim that TYSABRI "two-year data from the AFFIRM monotherapy trial showed that treatment with TYSABRI reduced the risk of disability progression by 42% (p is less than 0.001), the primary endpoint of the study, and led to a 67% reduction (p is less than 0.001) in the annualized relapse rate compared to placebo. TYSABRI treatment also resulted in sustained and statistically significant reductions in brain lesion activity as measured by MRI.
While the number of incidences of PML were low, and none were reported with TYSABRI therapy alone, I feel that it is only prudent that given the availability of competing immunosupressant or immunomodulating therapies for multiple sclerosis, that people weigh two important criteria:
1. The effectiveness of the alternative drugs;
2. Their own experience and tolerance of those drugs.
It is true, based on the data, that TYSABRI appears to be more effect than the alternative "CRAB" drugs in reducing relapse rates and the number of enhanced brain lesions.
DISABILITY PROGRESSION:
While TYSABRI has shown to reduce the risk of disability progression by 42% as compared to placebo, AVONEX data shows a reduction of 37%; BETASERON data shows a reduction of 29%; COPAXONE data shows a reduction of 50%; REBIF (PRISMS STUDY) data shows a reduction of 30%.
RELAPSE RATE:
While TYSABRI has shown to reduce the relapse rate by 66% (AFFIRM STUDY) as compared to placebo, AVONEX data shows a reduction of 44%; BETASERON data shows a reduction of 73%; COPAXONE data shows a reduction of 32%; REBIF data (PRISMS STUDY) shows a reduction of 32%.
Now here's food for thought: Keep in mind that there are several clinical studies that measure these important metrics. Some show better results than others, so it is difficult to offer truly direct comparisons. Additionally, keep in mind that while many of these data results are impressive, not every patient that takes on of these drugs actually receives all or any of the benefit. That's the dirty little secret that the pharmaceutical companies and many neurologists do not adequately disclose. In fact, of those that have participated in various of the clinical trials, in some cases as few as 35% of those taking a particular agent actually received benefit.
And then there are the statin drugs. While they have only been in small, early stage clinical trials - mainly because their manufacturers simply do not see the benefit of investing tens of millions or more in complete clinical trials when they are generating billions of dollars of revenues with these somewhat benign oral drugs in the anti-cholesterol market - there is modest evidence that statins may be of important benefit in at least reducing the number of brain lesions. More trials need to be conducted to gauge their effectiveness in reducing relapse rate and disability progression.
The conclusion of this piece is not that MSers should shy away from TYSABRI or any other therapy. Rather, be fully educated about the relative risks and benefits, the financial and side effects costs, and seek the guidance of a neurologist that specializes in multiple sclerosis.
Thursday, September 14, 2006
New Drug Reduces MS Symptoms
09.13.06, 12:00 AM ET
WEDNESDAY, Sept. 13 (HealthDay News) -- Swiss researchers report that an oral drug called fingolimod was effective in preventing relapses in people with multiple sclerosis.
"If the phase III [clinical trial] is successful, a new once-daily oral medication could be available for treatment of relapsing MS in approximately three to four years," said lead researcher Dr. Ludwig Kappos, head of the outpatient clinic for neurology/neurosurgery and MS-Research Group at University Hospital in Basel.
Results of the phase II trial are published in the Sept. 14 issue of the New England Journal of Medicine.
However, Kappos, as well as authors of an accompanying editorial in the journal, cautioned that this study was small and short-term. Long-term side effects are unknown, and as with other drugs used to treat MS that suppress immune system activity, could potentially be serious.
"These are very exciting preliminary findings of an experimental drug," said Dr. Patricia O'Looney, director of biomedical research programs at the National Multiple Sclerosis Society. "It's not a cure, but the results were very dramatic. The relapse rate was reduced by almost 50 percent in both treatment groups. But, there were some side effects: some upper respiratory tract infections, elevated liver enzymes, and there was some concern about heart rate changes. That's the reason why longer-term studies are necessary."
Multiple sclerosis is a disease that affects the central nervous system, especially the fatty tissue -- called myelin -- that surrounds nerve cells. The disorder is thought to be an autoimmune disease, but its exact cause remains unknown. About 400,000 Americans have multiple sclerosis, according to the National Multiple Sclerosis Society. Many people with the disease have periods where symptoms disappear, followed by relapses or flare-ups.
Treatments are currently available to help keep symptoms at bay, but there is no cure for this disease. The most recently approved drug for MS treatment, available by infusion, is Tysabri (natalizumab). The drug was approved in November 2004, but then pulled off the market three months later because several patients developed a rare, but fatal brain infection known as progressive multifocal leukoencephalopathy (PML). In June 2006, the U.S. Food and Drug Administration allowed Tysabri to return to the market -- under strict prescribing guidelines -- because for some people, the benefits of the medication outweigh the potential risk.
No cases of PML were reported in the six-month trial of oral fingolimod.
Two hundred and fifty-five patients participated in the new trial. They were randomly assigned into one of three groups. One group took a placebo daily, while the other two groups took oral fingolimod in either a 1.25 milligram dose or a 5 milligram dose.
Using MRI scans to assess disease activity, the researchers found that the relapse rate was more than 50 percent lower for both groups taking fingolimod compared to the placebo group, according to Kappos.
Both groups on fingolimod experienced more side effects than those on a placebo, and the group taking the higher dose experienced more adverse effects than those on the lower dose, according to the study. The most frequent complaints were shortness of breath, upper respiratory infections, headache and gastrointestinal problems.
In an accompanying editorial, Harvard researchers wrote, "The results of the current proof-of-concept study by Kappos et al, are certainly promising and should provide a strong incentive for long-term follow-up trials on a large scale."
"The results from this short-term study are very promising and fingolimod needs to be further examined," said O'Looney. "The best news for people with MS is that there are so many clinical trials that are taking place now to try to find better therapies, and some, like fingolimod, are oral therapies. Hopefully, some of these therapies will reduce disease activity even greater than currently approved therapies."
WEDNESDAY, Sept. 13 (HealthDay News) -- Swiss researchers report that an oral drug called fingolimod was effective in preventing relapses in people with multiple sclerosis.
"If the phase III [clinical trial] is successful, a new once-daily oral medication could be available for treatment of relapsing MS in approximately three to four years," said lead researcher Dr. Ludwig Kappos, head of the outpatient clinic for neurology/neurosurgery and MS-Research Group at University Hospital in Basel.
Results of the phase II trial are published in the Sept. 14 issue of the New England Journal of Medicine.
However, Kappos, as well as authors of an accompanying editorial in the journal, cautioned that this study was small and short-term. Long-term side effects are unknown, and as with other drugs used to treat MS that suppress immune system activity, could potentially be serious.
"These are very exciting preliminary findings of an experimental drug," said Dr. Patricia O'Looney, director of biomedical research programs at the National Multiple Sclerosis Society. "It's not a cure, but the results were very dramatic. The relapse rate was reduced by almost 50 percent in both treatment groups. But, there were some side effects: some upper respiratory tract infections, elevated liver enzymes, and there was some concern about heart rate changes. That's the reason why longer-term studies are necessary."
Multiple sclerosis is a disease that affects the central nervous system, especially the fatty tissue -- called myelin -- that surrounds nerve cells. The disorder is thought to be an autoimmune disease, but its exact cause remains unknown. About 400,000 Americans have multiple sclerosis, according to the National Multiple Sclerosis Society. Many people with the disease have periods where symptoms disappear, followed by relapses or flare-ups.
Treatments are currently available to help keep symptoms at bay, but there is no cure for this disease. The most recently approved drug for MS treatment, available by infusion, is Tysabri (natalizumab). The drug was approved in November 2004, but then pulled off the market three months later because several patients developed a rare, but fatal brain infection known as progressive multifocal leukoencephalopathy (PML). In June 2006, the U.S. Food and Drug Administration allowed Tysabri to return to the market -- under strict prescribing guidelines -- because for some people, the benefits of the medication outweigh the potential risk.
No cases of PML were reported in the six-month trial of oral fingolimod.
Two hundred and fifty-five patients participated in the new trial. They were randomly assigned into one of three groups. One group took a placebo daily, while the other two groups took oral fingolimod in either a 1.25 milligram dose or a 5 milligram dose.
Using MRI scans to assess disease activity, the researchers found that the relapse rate was more than 50 percent lower for both groups taking fingolimod compared to the placebo group, according to Kappos.
Both groups on fingolimod experienced more side effects than those on a placebo, and the group taking the higher dose experienced more adverse effects than those on the lower dose, according to the study. The most frequent complaints were shortness of breath, upper respiratory infections, headache and gastrointestinal problems.
In an accompanying editorial, Harvard researchers wrote, "The results of the current proof-of-concept study by Kappos et al, are certainly promising and should provide a strong incentive for long-term follow-up trials on a large scale."
"The results from this short-term study are very promising and fingolimod needs to be further examined," said O'Looney. "The best news for people with MS is that there are so many clinical trials that are taking place now to try to find better therapies, and some, like fingolimod, are oral therapies. Hopefully, some of these therapies will reduce disease activity even greater than currently approved therapies."
Wednesday, September 13, 2006
Infection may raise MS relapse risk: study
Friday, September 8, 2006
NEW YORK (Reuters Health) - Results of a study of adults with relapsing remitting multiple sclerosis point to a significant association between viral and bacterial infections and increased risk of relapse.
Investigators, in a report in the journal Neurology, note that published epidemiologic environmental observations point to infection as a possible causative factor or trigger in the onset of MS.
"Microorganisms induce strong immune responses specific for their own antigens, but microbial infections can also trigger responses against self-antigens, promoting inflammatory responses," they point out.
"Since no single microorganism has been identified as a clear etiologic agent in MS, a more likely explanation for the epidemiologic environmental observations is that infections introduce a proinflammatory bias in immune responsiveness in MS patients that is capable of triggering disease activity and exacerbations."
Dr. Jorge Correale from Raul Carrea Institute for Neurological Research in Buenos Aires, Argentina, and colleagues say their study supports this line of thinking.
The researchers followed 60 MS patients who were instructed to report as soon as they experienced symptoms of an infection.
The team found a threefold increase in the rate of MS exacerbations during the "at-risk period" ranging from 2 weeks prior to 5 weeks after the onset of symptoms of infection, compared with time periods outside this window.
Any MS attack during the at-risk period was considered temporally related to the infection.
When a narrower "at-risk" time window was considered around infection (2 weeks prior to 2 weeks after symptom onset), the risk of MS exacerbation was elevated fourfold.
"Viral and bacterial infections were equally associated with exacerbations," Dr. Correale and colleagues note.
The researchers also observed a significant increase in disease activity on magnetic resonance imaging among 20 patients who underwent serial imaging studies, as well as increased T cell activation and proinflammatory cytokine concentrations during infection-related MS exacerbations.
Relapses temporally linked to systemic infection caused more severe and sustained deficit than exacerbations with onset outside the at risk window, the researchers also report.
SOURCE: Neurology, August 22, 2006.
Copyright © 2006 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
NEW YORK (Reuters Health) - Results of a study of adults with relapsing remitting multiple sclerosis point to a significant association between viral and bacterial infections and increased risk of relapse.
Investigators, in a report in the journal Neurology, note that published epidemiologic environmental observations point to infection as a possible causative factor or trigger in the onset of MS.
"Microorganisms induce strong immune responses specific for their own antigens, but microbial infections can also trigger responses against self-antigens, promoting inflammatory responses," they point out.
"Since no single microorganism has been identified as a clear etiologic agent in MS, a more likely explanation for the epidemiologic environmental observations is that infections introduce a proinflammatory bias in immune responsiveness in MS patients that is capable of triggering disease activity and exacerbations."
Dr. Jorge Correale from Raul Carrea Institute for Neurological Research in Buenos Aires, Argentina, and colleagues say their study supports this line of thinking.
The researchers followed 60 MS patients who were instructed to report as soon as they experienced symptoms of an infection.
The team found a threefold increase in the rate of MS exacerbations during the "at-risk period" ranging from 2 weeks prior to 5 weeks after the onset of symptoms of infection, compared with time periods outside this window.
Any MS attack during the at-risk period was considered temporally related to the infection.
When a narrower "at-risk" time window was considered around infection (2 weeks prior to 2 weeks after symptom onset), the risk of MS exacerbation was elevated fourfold.
"Viral and bacterial infections were equally associated with exacerbations," Dr. Correale and colleagues note.
The researchers also observed a significant increase in disease activity on magnetic resonance imaging among 20 patients who underwent serial imaging studies, as well as increased T cell activation and proinflammatory cytokine concentrations during infection-related MS exacerbations.
Relapses temporally linked to systemic infection caused more severe and sustained deficit than exacerbations with onset outside the at risk window, the researchers also report.
SOURCE: Neurology, August 22, 2006.
Copyright © 2006 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
New Multiple Sclerosis Treatment Reduces Relapse Rate By 90%
22 Jul 2006
Multiple Sclerosis patients who receive a brief course of Mitoxantrone, and then Copaxone, experience a reduced replase rate of 90%, according to a five-year study carried out at The Walton Centre for Neurology, Liverpool, UK. A further ten controlled studies are being launched at 10 centres in the UK. A reduced relapse rate of 90% means the difference between being bedridden and holding down a job and actively raising a family for many MS patients.
You can read about this study in the Journal of Neurology, August issue.
Mitoxantrone is used for treating cancer patients, it is so powerful that it can only be used for a short time. Copaxone is a slow-acting disease-moderating drug for MS patients. In this study, doctors decided to overlap the treatments because they wanted to give some time for copaxone to build up its effect.
Head researcher, Dr Mike Boggild, said "This regime has proved remarkably effective. Though there are certain risks, associated particularly with use of Mitoxantrone, we have been able to limit these by using this agent for just a short induction period. Balanced against the high risk of early disability for these patients, the outcomes appear to justify this approach.”
Dr. Boggild started treating with Karen Ayres, 28, in 2002. Karen Ayres has MS. Since 2002 she has not suffered any relapses at all. Ayres said she came to see Dr. Boggild during her second relapse. She was unable to walk or feed herself - she was barely able to wave her hand. A few weeks after treatment started she walked out of the rehab centre unaided. She says that since the beginning of this treatment she has managed to lead a completely normal life - she has travelled to five continents and is currently doing a PhD in Psychology at Leeds University, UK.
Ayres was one of 27 patients treated during this open trial. Many of them experienced similar remarkable reductions in relapses.
This study was not a controlled one. This means there was not one group of patients on the drug treatment compared to another group on a placebo. The ten new studies are controlled ones.
The treatment does have potentially serious side-effects, including leukaemia and cardiac problems. However, for many MS patients, it is still worth the risk.
Journal of Neurology
Written by: Christian Nordqvist
Editor: Medical News Today
Multiple Sclerosis patients who receive a brief course of Mitoxantrone, and then Copaxone, experience a reduced replase rate of 90%, according to a five-year study carried out at The Walton Centre for Neurology, Liverpool, UK. A further ten controlled studies are being launched at 10 centres in the UK. A reduced relapse rate of 90% means the difference between being bedridden and holding down a job and actively raising a family for many MS patients.
You can read about this study in the Journal of Neurology, August issue.
Mitoxantrone is used for treating cancer patients, it is so powerful that it can only be used for a short time. Copaxone is a slow-acting disease-moderating drug for MS patients. In this study, doctors decided to overlap the treatments because they wanted to give some time for copaxone to build up its effect.
Head researcher, Dr Mike Boggild, said "This regime has proved remarkably effective. Though there are certain risks, associated particularly with use of Mitoxantrone, we have been able to limit these by using this agent for just a short induction period. Balanced against the high risk of early disability for these patients, the outcomes appear to justify this approach.”
Dr. Boggild started treating with Karen Ayres, 28, in 2002. Karen Ayres has MS. Since 2002 she has not suffered any relapses at all. Ayres said she came to see Dr. Boggild during her second relapse. She was unable to walk or feed herself - she was barely able to wave her hand. A few weeks after treatment started she walked out of the rehab centre unaided. She says that since the beginning of this treatment she has managed to lead a completely normal life - she has travelled to five continents and is currently doing a PhD in Psychology at Leeds University, UK.
Ayres was one of 27 patients treated during this open trial. Many of them experienced similar remarkable reductions in relapses.
This study was not a controlled one. This means there was not one group of patients on the drug treatment compared to another group on a placebo. The ten new studies are controlled ones.
The treatment does have potentially serious side-effects, including leukaemia and cardiac problems. However, for many MS patients, it is still worth the risk.
Journal of Neurology
Written by: Christian Nordqvist
Editor: Medical News Today
Multiple Sclerosis Damage Also Found In "Normal" Brain Tissue
31 Aug 2006
The effects of multiple sclerosis (MS) extend beyond visibly affected areas into large portions of the brain that outwardly appear normal, according to a study appearing in the September issue of Radiology.
"This disease process in the normal-appearing brain tissue affects the brain globally and has substantial clinical impact," said the study's lead author, Hugo Vrenken, Ph.D., from the Multiple Sclerosis Center at VU University Medical Center in Amsterdam, The Netherlands.
MS is a chronic, autoimmune disease characterized by the destruction of myelin, the protective layers that surround nerve cells. It can affect numerous body functions, and symptoms may include visual and speech impairment, memory loss, depression, muscle weakness, loss of coordination, numbness or pain, bowel and bladder problems and sexual dysfunction.
MS affects approximately 400,000 people in the United States and as many as 2.5 million worldwide, mostly women between the ages of 20 and 50, according to the National Multiple Sclerosis Society.
"The areas of demyelination, or lesions, in patients with MS can be visualized with magnetic resonance imaging (MRI). However, the volume of lesions visible at MRI only correlates moderately with clinical disability measurements," Dr. Vrenken said. "This may be due to disease activity outside the visible lesions."
To gain a better understanding of the effects of MS on the whole brain, Dr. Vrenken and colleagues studied T1 changes in normal-appearing white and gray brain matter in patients with MS.
T1 is a measurement of proton relaxation after exposure to a magnetic field and a radiofrequency (RF) pulse. Due to this RF pulse, protons in the body first reach an excited state and then relax back to a state of equilibrium by funneling the excess energy to the surrounding tissues. T1 refers to the time required for protons to relax to the equilibrium state in this particular manner.
The researchers investigated T1 changes in 67 patients with MS and 24 healthy control volunteers. T1 graphs of normal appearing white and gray matter were significantly different for patients with MS than for controls. Moreover, these graphs differed among patients with MS based on the type of disease: secondary progressive (SP), relapsing-remitting (RR) or primary progressive (PP). The results were most pronounced in patients with SP disease, where at least 31 percent of normal-appearing white matter and 20 percent of cortical normal-appearing gray matter were affected. In RR disease, 16 percent of normal-appearing white matter and 9 percent of cortical normal-appearing gray matter were affected. In PP disease, the normal-appearing white and gray matter affected were 11 percent and 8 percent, respectively. These changes were found throughout the brain, including areas remote from localized lesions that are typically associated with MS.
"These findings demonstrate that in MS, disease processes outside MR-visible lesions are not limited to a few sites but act throughout the brain and affect large fractions of normal-appearing white and gray matter," Dr. Vrenken said. The researchers also explored correlations between the areas of the brain being analyzed in the patients with MS and the level of atrophy or clinical disability present.
"The results suggest that the damage to normal-appearing brain tissue plays a larger role in the progression of atrophy and clinical disability than do the visible lesions," Dr. Vrenken said.
###
Journal attribution required.
Radiology is a monthly scientific journal devoted to clinical radiology and allied sciences. The journal is edited by Anthony V. Proto, M.D., School of Medicine, Virginia Commonwealth University, Richmond, Va. Radiology is owned and published by the Radiological Society of North America, Inc. (RSNA.org/radiologyjnl)
The Radiological Society of North America (RSNA) is an association of more than 38,000 radiologists, radiation oncologists, medical physicists and related scientists committed to promoting excellence in radiology through education and by fostering research, with the ultimate goal of improving patient care. The Society is based in Oak Brook, Ill. (RSNA.org - http://rsna.org/)
"Whole-Brain T1 Mapping in Multiple Sclerosis: Global Changes of Normal-appearing Gray and White Matter." Collaborating with Dr. Vrenken on this paper were Jeroen J. G. Geurts, M.Sc., Ph.D., Dirk L. Knol, Ph.D., L. Noor van Dijk, M.D., Vincenzo Dattola, M.D., Bas Jasperse, M.D., Ronald A. van Schijndel, M.Sc., Chris H. Polman, M.D., Ph.D., Jonas A. Castelijns, M.D., Ph.D., Frederik Barkhof, M.D., Ph.D., and Petra J. W. Pouwels, Ph.D.
Contact: Heather Babiar
Radiological Society of North America
The effects of multiple sclerosis (MS) extend beyond visibly affected areas into large portions of the brain that outwardly appear normal, according to a study appearing in the September issue of Radiology.
"This disease process in the normal-appearing brain tissue affects the brain globally and has substantial clinical impact," said the study's lead author, Hugo Vrenken, Ph.D., from the Multiple Sclerosis Center at VU University Medical Center in Amsterdam, The Netherlands.
MS is a chronic, autoimmune disease characterized by the destruction of myelin, the protective layers that surround nerve cells. It can affect numerous body functions, and symptoms may include visual and speech impairment, memory loss, depression, muscle weakness, loss of coordination, numbness or pain, bowel and bladder problems and sexual dysfunction.
MS affects approximately 400,000 people in the United States and as many as 2.5 million worldwide, mostly women between the ages of 20 and 50, according to the National Multiple Sclerosis Society.
"The areas of demyelination, or lesions, in patients with MS can be visualized with magnetic resonance imaging (MRI). However, the volume of lesions visible at MRI only correlates moderately with clinical disability measurements," Dr. Vrenken said. "This may be due to disease activity outside the visible lesions."
To gain a better understanding of the effects of MS on the whole brain, Dr. Vrenken and colleagues studied T1 changes in normal-appearing white and gray brain matter in patients with MS.
T1 is a measurement of proton relaxation after exposure to a magnetic field and a radiofrequency (RF) pulse. Due to this RF pulse, protons in the body first reach an excited state and then relax back to a state of equilibrium by funneling the excess energy to the surrounding tissues. T1 refers to the time required for protons to relax to the equilibrium state in this particular manner.
The researchers investigated T1 changes in 67 patients with MS and 24 healthy control volunteers. T1 graphs of normal appearing white and gray matter were significantly different for patients with MS than for controls. Moreover, these graphs differed among patients with MS based on the type of disease: secondary progressive (SP), relapsing-remitting (RR) or primary progressive (PP). The results were most pronounced in patients with SP disease, where at least 31 percent of normal-appearing white matter and 20 percent of cortical normal-appearing gray matter were affected. In RR disease, 16 percent of normal-appearing white matter and 9 percent of cortical normal-appearing gray matter were affected. In PP disease, the normal-appearing white and gray matter affected were 11 percent and 8 percent, respectively. These changes were found throughout the brain, including areas remote from localized lesions that are typically associated with MS.
"These findings demonstrate that in MS, disease processes outside MR-visible lesions are not limited to a few sites but act throughout the brain and affect large fractions of normal-appearing white and gray matter," Dr. Vrenken said. The researchers also explored correlations between the areas of the brain being analyzed in the patients with MS and the level of atrophy or clinical disability present.
"The results suggest that the damage to normal-appearing brain tissue plays a larger role in the progression of atrophy and clinical disability than do the visible lesions," Dr. Vrenken said.
###
Journal attribution required.
Radiology is a monthly scientific journal devoted to clinical radiology and allied sciences. The journal is edited by Anthony V. Proto, M.D., School of Medicine, Virginia Commonwealth University, Richmond, Va. Radiology is owned and published by the Radiological Society of North America, Inc. (RSNA.org/radiologyjnl)
The Radiological Society of North America (RSNA) is an association of more than 38,000 radiologists, radiation oncologists, medical physicists and related scientists committed to promoting excellence in radiology through education and by fostering research, with the ultimate goal of improving patient care. The Society is based in Oak Brook, Ill. (RSNA.org - http://rsna.org/)
"Whole-Brain T1 Mapping in Multiple Sclerosis: Global Changes of Normal-appearing Gray and White Matter." Collaborating with Dr. Vrenken on this paper were Jeroen J. G. Geurts, M.Sc., Ph.D., Dirk L. Knol, Ph.D., L. Noor van Dijk, M.D., Vincenzo Dattola, M.D., Bas Jasperse, M.D., Ronald A. van Schijndel, M.Sc., Chris H. Polman, M.D., Ph.D., Jonas A. Castelijns, M.D., Ph.D., Frederik Barkhof, M.D., Ph.D., and Petra J. W. Pouwels, Ph.D.
Contact: Heather Babiar
Radiological Society of North America
Positive Results From Phase II Trial Of Rituxan In Relapsing-Remitting Multiple Sclerosis
02 Sep 2006
Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) announced today that a Phase II study of Rituxan® (Rituximab) for relapsing-remitting multiple sclerosis (RRMS) met its primary endpoint. The study of 104 patients showed a statistically significant reduction in the total number of gadolinium enhancing T1 lesions observed on serial MRI scans of the brain at weeks 12, 16, 20 and 24 in the Rituxan-treated group compared to placebo. Genentech and Biogen Idec will continue to analyze the study results and will submit the data for presentation at an upcoming medical meeting.
"These initial results exceeded our expectations," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. "Showing a significant benefit at 24 weeks in this small Phase II trial supports our hypothesis that selective B-cell targeted therapy may play an important role in the treatment of MS."
"Biogen Idec is committed to offering multiple options for people living with MS, a devastating disease. We are very encouraged by these data and look forward to learning more about the potential of Rituxan as a therapy to treat MS," said Alfred Sandrock, M.D., Ph.D., senior vice president, neurology research and development, Biogen Idec.
Rates of overall adverse events and serious adverse events were comparable between the two treatment groups. Serious infectious adverse events occurring in Rituxan-treated patients included gastroenteritis and bronchitis. The overall rates of infection were comparable among the two treatment groups with an increase in the rates of nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis in the Rituxan-treated patients. There were more first infusion-related reactions with Rituxan, the majority of which were mild to moderate and were generally reversible with medical intervention. The companies continue to monitor the long-term safety of Rituxan treatment.
About the Study
This Phase II randomized, double-blind, parallel-group, placebo-controlled, multi-center study was designed to evaluate safety and efficacy of Rituxan in adults with RRMS. A total of 104 patients at 48 sites in the U.S. and Canada were randomized to receive either a single treatment course of Rituxan or placebo. Gadolinium-enhancing lesions visible by MRI scans were assessed at 12, 16, 20 and 24 weeks. Patients will continue to be followed for 48 weeks.
About MS and RRMS
MS is a chronic autoimmune disease in which the immune system is thought to attack the body's own myelin, a fatty substance that surrounds and protects the nerve fibers of the brain, optic nerves and spinal cord. There are four types of MS with a wide variety of symptoms and different courses of disease progression.
MS is the leading cause of neurological disability in young adults. Neurological disability typically accumulates over time and includes muscle weakness and spasticity, balance and coordination problems, as well as memory impairment and depression. Other symptoms include numbness, pain, slurred speech and blurred vision. Many patients experience fatigue and problems with bladder, bowel or sexual function.
RRMS is the most common form of MS and accounts for approximately 65 percent of all MS cases. RRMS is characterized by acute exacerbations with full or partial recovery between attacks. The disease does not progress between attacks.
Rituxan Safety Profile in Oncology and Autoimmune Diseases
The safety profile of Rituxan has been established in more than 960,000 patient exposures over a period of eight years.
In general, the adverse events observed in patients with RA an autoimmune disease, were similar in type to those seen in patients with non-Hodgkin's lymphoma (NHL). The most common adverse events observed in patients treated with Rituxan for RA in clinical trials were infusion reactions and infections. No significant change in average immunoglobulin levels was observed in Rituxan-treated patients in clinical trials. There was no increase in hematologic malignancies, demyelinating events or risk of opportunistic infections (including tuberculosis) in Rituxan-treated patients over 24 weeks of treatment. Although 5 percent of Rituxan-treated patients developed human anti-chimeric antibodies (HACA), this was not associated with loss of clinical response or additional safety observations.
The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to: flu-like illness, fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema, hypotension and hypoxia. These symptoms vary in severity and generally are reversible with medical intervention.
Severe infusion reactions have been reported in patients treated with Rituxan, some with fatal outcomes in patients with NHL. These severe reactions typically occur during the first infusion. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. Patients who develop clinically significant infusion reactions should have their Rituxan infusion discontinued and receive medical treatment. Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of tumor lysis syndrome following treatment with Rituxan. Severe mucocutaneous skin reactions, some with fatal outcome, have been reported in association with Rituxan treatment. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving Rituxan in combination with chemotherapy for diffuse large B-cell (DLBCL), CD20-positive, non-Hodgkin's lymphoma. Other serious or potentially life-threatening adverse reactions that have been reported following Rituxan therapy include Hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, and cardiac arrhythmias.
About Rituxan
Rituxan is a therapeutic antibody that targets and selectively depletes CD20-positive B-cells without targeting stem cells or existing plasma cells. In addition to RRMS, Rituxan is being studied in primary progressive MS, for which there is currently no FDA-approved therapy. Rituxan is being studied in other autoimmune diseases with significant unmet medical needs, including systemic lupus erythematosus, lupus nephritis and ANCA-associated vasculitis.
Rituxan, discovered by Biogen Idec, first received FDA approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma. It was also approved in the European Union under the trade name MabThera® in June 1998. In addition, Rituxan received FDA approval in February 2006 for the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens in previously untreated patients, as well as in combination with methotrexate to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor antagonist therapies.
Genentech and Biogen Idec co-market Rituxan in the United States, and Roche markets MabThera in the rest of the world, except Japan, where Rituxan is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd. Rituxan has more than 960,000 patient exposures worldwide. For a copy of the Rituxan full prescribing information, including Boxed Warning, please call 1-800-821-8590 or visit http://www.gene.com.
About Genentech
Founded 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics for significant unmet medical needs. A considerable number of the currently approved biotechnology products originated from or are based on Genentech science. Genentech manufactures and commercializes multiple biotechnology products and licenses several additional products to other companies. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com.
About Biogen Idec
Biogen Idec creates new standards of care in oncology, neurology and immunology. As a global leader in the development, manufacturing, and commercialization of novel therapies, Biogen Idec transforms scientific discoveries into advances in human healthcare. For product labeling, press releases and additional information about the company, please visit http://www.biogenidec.com.
This press release contains a forward-looking statement regarding the potential of Rituxan to treat MS. Such statement is a prediction and involves risks and uncertainties such that the actual results may differ materially. Among other things, the potential of Rituxan could be affected by unexpected safety, efficacy or manufacturing issues, additional time requirements for data analysis and decision-making, the need for additional clinical studies, discussions with the FDA, FDA actions, failure to receive FDA approval, competition, reimbursement, intellectual property or contract rights, pricing, the ability to supply product, or product withdrawal. Please also refer to Genentech's and Biogen Idec's periodic reports filed with the Securities and Exchange Commission. Genentech and Biogen Idec disclaim, and do not undertake, any obligation to update or revise this forward-looking statement in this press release.
Genentech, Inc. (NYSE: DNA) and Biogen Idec, Inc. (Nasdaq: BIIB) announced today that a Phase II study of Rituxan® (Rituximab) for relapsing-remitting multiple sclerosis (RRMS) met its primary endpoint. The study of 104 patients showed a statistically significant reduction in the total number of gadolinium enhancing T1 lesions observed on serial MRI scans of the brain at weeks 12, 16, 20 and 24 in the Rituxan-treated group compared to placebo. Genentech and Biogen Idec will continue to analyze the study results and will submit the data for presentation at an upcoming medical meeting.
"These initial results exceeded our expectations," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. "Showing a significant benefit at 24 weeks in this small Phase II trial supports our hypothesis that selective B-cell targeted therapy may play an important role in the treatment of MS."
"Biogen Idec is committed to offering multiple options for people living with MS, a devastating disease. We are very encouraged by these data and look forward to learning more about the potential of Rituxan as a therapy to treat MS," said Alfred Sandrock, M.D., Ph.D., senior vice president, neurology research and development, Biogen Idec.
Rates of overall adverse events and serious adverse events were comparable between the two treatment groups. Serious infectious adverse events occurring in Rituxan-treated patients included gastroenteritis and bronchitis. The overall rates of infection were comparable among the two treatment groups with an increase in the rates of nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis in the Rituxan-treated patients. There were more first infusion-related reactions with Rituxan, the majority of which were mild to moderate and were generally reversible with medical intervention. The companies continue to monitor the long-term safety of Rituxan treatment.
About the Study
This Phase II randomized, double-blind, parallel-group, placebo-controlled, multi-center study was designed to evaluate safety and efficacy of Rituxan in adults with RRMS. A total of 104 patients at 48 sites in the U.S. and Canada were randomized to receive either a single treatment course of Rituxan or placebo. Gadolinium-enhancing lesions visible by MRI scans were assessed at 12, 16, 20 and 24 weeks. Patients will continue to be followed for 48 weeks.
About MS and RRMS
MS is a chronic autoimmune disease in which the immune system is thought to attack the body's own myelin, a fatty substance that surrounds and protects the nerve fibers of the brain, optic nerves and spinal cord. There are four types of MS with a wide variety of symptoms and different courses of disease progression.
MS is the leading cause of neurological disability in young adults. Neurological disability typically accumulates over time and includes muscle weakness and spasticity, balance and coordination problems, as well as memory impairment and depression. Other symptoms include numbness, pain, slurred speech and blurred vision. Many patients experience fatigue and problems with bladder, bowel or sexual function.
RRMS is the most common form of MS and accounts for approximately 65 percent of all MS cases. RRMS is characterized by acute exacerbations with full or partial recovery between attacks. The disease does not progress between attacks.
Rituxan Safety Profile in Oncology and Autoimmune Diseases
The safety profile of Rituxan has been established in more than 960,000 patient exposures over a period of eight years.
In general, the adverse events observed in patients with RA an autoimmune disease, were similar in type to those seen in patients with non-Hodgkin's lymphoma (NHL). The most common adverse events observed in patients treated with Rituxan for RA in clinical trials were infusion reactions and infections. No significant change in average immunoglobulin levels was observed in Rituxan-treated patients in clinical trials. There was no increase in hematologic malignancies, demyelinating events or risk of opportunistic infections (including tuberculosis) in Rituxan-treated patients over 24 weeks of treatment. Although 5 percent of Rituxan-treated patients developed human anti-chimeric antibodies (HACA), this was not associated with loss of clinical response or additional safety observations.
The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to: flu-like illness, fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema, hypotension and hypoxia. These symptoms vary in severity and generally are reversible with medical intervention.
Severe infusion reactions have been reported in patients treated with Rituxan, some with fatal outcomes in patients with NHL. These severe reactions typically occur during the first infusion. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and anaphylactic and anaphylactoid events. Patients who develop clinically significant infusion reactions should have their Rituxan infusion discontinued and receive medical treatment. Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of tumor lysis syndrome following treatment with Rituxan. Severe mucocutaneous skin reactions, some with fatal outcome, have been reported in association with Rituxan treatment. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Abdominal pain, bowel obstruction and perforation, in some cases leading to death, were observed in patients receiving Rituxan in combination with chemotherapy for diffuse large B-cell (DLBCL), CD20-positive, non-Hodgkin's lymphoma. Other serious or potentially life-threatening adverse reactions that have been reported following Rituxan therapy include Hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, and cardiac arrhythmias.
About Rituxan
Rituxan is a therapeutic antibody that targets and selectively depletes CD20-positive B-cells without targeting stem cells or existing plasma cells. In addition to RRMS, Rituxan is being studied in primary progressive MS, for which there is currently no FDA-approved therapy. Rituxan is being studied in other autoimmune diseases with significant unmet medical needs, including systemic lupus erythematosus, lupus nephritis and ANCA-associated vasculitis.
Rituxan, discovered by Biogen Idec, first received FDA approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma. It was also approved in the European Union under the trade name MabThera® in June 1998. In addition, Rituxan received FDA approval in February 2006 for the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens in previously untreated patients, as well as in combination with methotrexate to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor antagonist therapies.
Genentech and Biogen Idec co-market Rituxan in the United States, and Roche markets MabThera in the rest of the world, except Japan, where Rituxan is co-marketed by Chugai and Zenyaku Kogyo Co. Ltd. Rituxan has more than 960,000 patient exposures worldwide. For a copy of the Rituxan full prescribing information, including Boxed Warning, please call 1-800-821-8590 or visit http://www.gene.com.
About Genentech
Founded 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics for significant unmet medical needs. A considerable number of the currently approved biotechnology products originated from or are based on Genentech science. Genentech manufactures and commercializes multiple biotechnology products and licenses several additional products to other companies. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com.
About Biogen Idec
Biogen Idec creates new standards of care in oncology, neurology and immunology. As a global leader in the development, manufacturing, and commercialization of novel therapies, Biogen Idec transforms scientific discoveries into advances in human healthcare. For product labeling, press releases and additional information about the company, please visit http://www.biogenidec.com.
This press release contains a forward-looking statement regarding the potential of Rituxan to treat MS. Such statement is a prediction and involves risks and uncertainties such that the actual results may differ materially. Among other things, the potential of Rituxan could be affected by unexpected safety, efficacy or manufacturing issues, additional time requirements for data analysis and decision-making, the need for additional clinical studies, discussions with the FDA, FDA actions, failure to receive FDA approval, competition, reimbursement, intellectual property or contract rights, pricing, the ability to supply product, or product withdrawal. Please also refer to Genentech's and Biogen Idec's periodic reports filed with the Securities and Exchange Commission. Genentech and Biogen Idec disclaim, and do not undertake, any obligation to update or revise this forward-looking statement in this press release.
Tuesday, September 12, 2006
Once-daily novel oral agent for relapsing remitting MS patients, meets its primary end-point.
Laquinimod Phase IIb Trial Confirms Efficacy and Favorable Safety Profile and Shows Significant Reduction in the Rate of Inflammatory Disease Activity
Teva Pharmaceutical Industries (ISRAEL)
September 5, 2006
The once-daily novel oral agent for relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
JERUSALEM & LUND, Sweden--(BUSINESS WIRE)--Sept. 5, 2006--Teva Pharmaceutical Industries Ltd (Nasdaq: TEVA) and Active Biotech AB (ACTI.ST) today announced that a Phase IIb study designed to evaluate the safety and efficacy of laquinimod, a once-daily novel oral agent, in relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
Laquinimod treatment significantly reduced the rate of inflammatory disease activity, as measured by the cumulative number of Gadolinium enhancing lesions on brain MRI scans after 36 weeks of treatment. Laquinimod treatment also demonstrated a considerable reduction in the number of clinical relapses compared to placebo. This Phase IIb multi-center, randomized, double-blind, placebo-controlled study enrolled approximately 300 patients in 8 European countries and in Israel.
The evaluation of the safety and side-effect data confirmed the favourable safety profile that was seen in earlier phase II clinical trials. The majority of the patients who participated in the study are currently continuing treatment with laquinimod in an ongoing, blinded extension study.
"The study results with once daily oral laquinimod are very encouraging and further demonstrate our ongoing commitment to developing new classes of therapies for MS, including oral therapies, to treat the disease, as well as to improve the patients' quality of life", said Israel Makov, President and CEO of Teva Pharmaceutical Industries Ltd..
"As of today, nearly 400 patients have received laquinimod in various clinical trials over the last years. The data from the completed studies together with preclinical documentation, confirm laquinimod's efficacy and favorable safety profile in MS patients," said Sven Andreasson, President and CEO of Active Biotech AB.
The positive result of the clinical trial triggers a milestone payment to Active Biotech.
Further details about the study will be given at Teva's Innovative R&D Day in New York City on September 26th, 2006. A complete presentation of the Phase IIb data will be given at upcoming relevant scientific meetings.
Teva is discussing laquinimod's development plan with regulatory authorities in order to accelerate the clinical program into Phase III.
About Laquinimod
Laquinimod is a novel once-daily, orally administered immunomodulatory compound developed as a disease modifying treatment for multiple sclerosis (MS). Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries Ltd. in June 2004.
About MS
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by this disease, and that over one million people are affected worldwide. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves.
Patients with MS may experience physical symptoms and/or cognitive impairments, including weakness, fatigue, ataxia, physical dysfunction, bladder and bowel problems, sensory effects, and visual impairment. MS also has a significant impact on the sufferers' social functioning and overall quality of life.
About Active Biotech
Active Biotech AB is a biotechnology company focusing on research and development of pharmaceuticals. Active Biotech has a strong R&D portfolio with pipeline products focused on autoimmune/inflammatory diseases and cancer. Most advanced projects are Laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer immunotherapy with the primary indications renal cell cancer and non-small cell lung cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer 57-57 for SLE and RhuDex(R) for RA.
About Teva
Teva Pharmaceutical Industries Ltd., headquartered in Israel, is among the top 20 pharmaceutical companies in the world and is the leading generic pharmaceutical company. The company develops, manufactures and markets generic and innovative human pharmaceuticals and active pharmaceutical ingredients, as well as animal health pharmaceutical products. Over 80% of Teva's sales are in North America and Europe. Teva's innovative R&D focuses on developing novel drugs for diseases of the central nervous system.
Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva`s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to Teva's ability to rapidly integrate Ivax Corporation's operations and achieve expected synergies, Teva`s ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic products, the impact of competition from brand-name companies that sell or license their own brand products under generic trade dress and at generic prices (so called "authorized generics") or seek to delay the introduction of generic product, the impact of consolidation of our distributors and customers, regulatory changes that may prevent Teva from exploiting exclusivity periods, potential liability for sales of generic products prior to a final resolution of outstanding litigation, including that relating to the generic versions of Allegra(R), Neurontin(R), Oxycontin(R) and Zithromax(R), the effects of competition on Copaxone(R) sales, including as a result of the reintroduction of Tysabri(R) into the market, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, Teva's ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims, dependence on patent and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism or major hostilities, environmental risks, fluctuations in currency, exchange and interest rates, operating results and other factors that are discussed in Teva's Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update publicly or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Contacts
Teva:
Teva Pharmaceutical Industries Ltd.
Dan Suesskind, + 972-2-589-2840
or
Teva North America
George Barrett, +1 215 591-3030
or
Teva Investor Relations
Liraz Kalif / Kevin Mannix
+972-3-926-7281 / (215) 591-8912
or
Active Biotech:
Sven Andreasson, +46 46 19 20 49
Tomas Leanderson, +46 46 19 20 95
Cecilia Hofvander, +46 46 19 11 22
Teva Pharmaceutical Industries (ISRAEL)
September 5, 2006
The once-daily novel oral agent for relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
JERUSALEM & LUND, Sweden--(BUSINESS WIRE)--Sept. 5, 2006--Teva Pharmaceutical Industries Ltd (Nasdaq: TEVA) and Active Biotech AB (ACTI.ST) today announced that a Phase IIb study designed to evaluate the safety and efficacy of laquinimod, a once-daily novel oral agent, in relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
Laquinimod treatment significantly reduced the rate of inflammatory disease activity, as measured by the cumulative number of Gadolinium enhancing lesions on brain MRI scans after 36 weeks of treatment. Laquinimod treatment also demonstrated a considerable reduction in the number of clinical relapses compared to placebo. This Phase IIb multi-center, randomized, double-blind, placebo-controlled study enrolled approximately 300 patients in 8 European countries and in Israel.
The evaluation of the safety and side-effect data confirmed the favourable safety profile that was seen in earlier phase II clinical trials. The majority of the patients who participated in the study are currently continuing treatment with laquinimod in an ongoing, blinded extension study.
"The study results with once daily oral laquinimod are very encouraging and further demonstrate our ongoing commitment to developing new classes of therapies for MS, including oral therapies, to treat the disease, as well as to improve the patients' quality of life", said Israel Makov, President and CEO of Teva Pharmaceutical Industries Ltd..
"As of today, nearly 400 patients have received laquinimod in various clinical trials over the last years. The data from the completed studies together with preclinical documentation, confirm laquinimod's efficacy and favorable safety profile in MS patients," said Sven Andreasson, President and CEO of Active Biotech AB.
The positive result of the clinical trial triggers a milestone payment to Active Biotech.
Further details about the study will be given at Teva's Innovative R&D Day in New York City on September 26th, 2006. A complete presentation of the Phase IIb data will be given at upcoming relevant scientific meetings.
Teva is discussing laquinimod's development plan with regulatory authorities in order to accelerate the clinical program into Phase III.
About Laquinimod
Laquinimod is a novel once-daily, orally administered immunomodulatory compound developed as a disease modifying treatment for multiple sclerosis (MS). Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries Ltd. in June 2004.
About MS
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by this disease, and that over one million people are affected worldwide. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves.
Patients with MS may experience physical symptoms and/or cognitive impairments, including weakness, fatigue, ataxia, physical dysfunction, bladder and bowel problems, sensory effects, and visual impairment. MS also has a significant impact on the sufferers' social functioning and overall quality of life.
About Active Biotech
Active Biotech AB is a biotechnology company focusing on research and development of pharmaceuticals. Active Biotech has a strong R&D portfolio with pipeline products focused on autoimmune/inflammatory diseases and cancer. Most advanced projects are Laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer immunotherapy with the primary indications renal cell cancer and non-small cell lung cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer 57-57 for SLE and RhuDex(R) for RA.
About Teva
Teva Pharmaceutical Industries Ltd., headquartered in Israel, is among the top 20 pharmaceutical companies in the world and is the leading generic pharmaceutical company. The company develops, manufactures and markets generic and innovative human pharmaceuticals and active pharmaceutical ingredients, as well as animal health pharmaceutical products. Over 80% of Teva's sales are in North America and Europe. Teva's innovative R&D focuses on developing novel drugs for diseases of the central nervous system.
Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva`s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to Teva's ability to rapidly integrate Ivax Corporation's operations and achieve expected synergies, Teva`s ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic products, the impact of competition from brand-name companies that sell or license their own brand products under generic trade dress and at generic prices (so called "authorized generics") or seek to delay the introduction of generic product, the impact of consolidation of our distributors and customers, regulatory changes that may prevent Teva from exploiting exclusivity periods, potential liability for sales of generic products prior to a final resolution of outstanding litigation, including that relating to the generic versions of Allegra(R), Neurontin(R), Oxycontin(R) and Zithromax(R), the effects of competition on Copaxone(R) sales, including as a result of the reintroduction of Tysabri(R) into the market, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, Teva's ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims, dependence on patent and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism or major hostilities, environmental risks, fluctuations in currency, exchange and interest rates, operating results and other factors that are discussed in Teva's Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update publicly or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Contacts
Teva:
Teva Pharmaceutical Industries Ltd.
Dan Suesskind, + 972-2-589-2840
or
Teva North America
George Barrett, +1 215 591-3030
or
Teva Investor Relations
Liraz Kalif / Kevin Mannix
+972-3-926-7281 / (215) 591-8912
or
Active Biotech:
Sven Andreasson, +46 46 19 20 49
Tomas Leanderson, +46 46 19 20 95
Cecilia Hofvander, +46 46 19 11 22
Once-daily novel oral agent for relapsing remitting MS patients, meets its primary end-point.
Laquinimod Phase IIb Trial Confirms Efficacy and Favorable Safety Profile and Shows Significant Reduction in the Rate of Inflammatory Disease Activity
Teva Pharmaceutical Industries (ISRAEL)
September 5, 2006
The once-daily novel oral agent for relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
JERUSALEM & LUND, Sweden--(BUSINESS WIRE)--Sept. 5, 2006--Teva Pharmaceutical Industries Ltd (Nasdaq: TEVA) and Active Biotech AB (ACTI.ST) today announced that a Phase IIb study designed to evaluate the safety and efficacy of laquinimod, a once-daily novel oral agent, in relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
Laquinimod treatment significantly reduced the rate of inflammatory disease activity, as measured by the cumulative number of Gadolinium enhancing lesions on brain MRI scans after 36 weeks of treatment. Laquinimod treatment also demonstrated a considerable reduction in the number of clinical relapses compared to placebo. This Phase IIb multi-center, randomized, double-blind, placebo-controlled study enrolled approximately 300 patients in 8 European countries and in Israel.
The evaluation of the safety and side-effect data confirmed the favourable safety profile that was seen in earlier phase II clinical trials. The majority of the patients who participated in the study are currently continuing treatment with laquinimod in an ongoing, blinded extension study.
"The study results with once daily oral laquinimod are very encouraging and further demonstrate our ongoing commitment to developing new classes of therapies for MS, including oral therapies, to treat the disease, as well as to improve the patients' quality of life", said Israel Makov, President and CEO of Teva Pharmaceutical Industries Ltd..
"As of today, nearly 400 patients have received laquinimod in various clinical trials over the last years. The data from the completed studies together with preclinical documentation, confirm laquinimod's efficacy and favorable safety profile in MS patients," said Sven Andreasson, President and CEO of Active Biotech AB.
The positive result of the clinical trial triggers a milestone payment to Active Biotech.
Further details about the study will be given at Teva's Innovative R&D Day in New York City on September 26th, 2006. A complete presentation of the Phase IIb data will be given at upcoming relevant scientific meetings.
Teva is discussing laquinimod's development plan with regulatory authorities in order to accelerate the clinical program into Phase III.
About Laquinimod
Laquinimod is a novel once-daily, orally administered immunomodulatory compound developed as a disease modifying treatment for multiple sclerosis (MS). Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries Ltd. in June 2004.
About MS
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by this disease, and that over one million people are affected worldwide. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves.
Patients with MS may experience physical symptoms and/or cognitive impairments, including weakness, fatigue, ataxia, physical dysfunction, bladder and bowel problems, sensory effects, and visual impairment. MS also has a significant impact on the sufferers' social functioning and overall quality of life.
About Active Biotech
Active Biotech AB is a biotechnology company focusing on research and development of pharmaceuticals. Active Biotech has a strong R&D portfolio with pipeline products focused on autoimmune/inflammatory diseases and cancer. Most advanced projects are Laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer immunotherapy with the primary indications renal cell cancer and non-small cell lung cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer 57-57 for SLE and RhuDex(R) for RA.
About Teva
Teva Pharmaceutical Industries Ltd., headquartered in Israel, is among the top 20 pharmaceutical companies in the world and is the leading generic pharmaceutical company. The company develops, manufactures and markets generic and innovative human pharmaceuticals and active pharmaceutical ingredients, as well as animal health pharmaceutical products. Over 80% of Teva's sales are in North America and Europe. Teva's innovative R&D focuses on developing novel drugs for diseases of the central nervous system.
Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva`s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to Teva's ability to rapidly integrate Ivax Corporation's operations and achieve expected synergies, Teva`s ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic products, the impact of competition from brand-name companies that sell or license their own brand products under generic trade dress and at generic prices (so called "authorized generics") or seek to delay the introduction of generic product, the impact of consolidation of our distributors and customers, regulatory changes that may prevent Teva from exploiting exclusivity periods, potential liability for sales of generic products prior to a final resolution of outstanding litigation, including that relating to the generic versions of Allegra(R), Neurontin(R), Oxycontin(R) and Zithromax(R), the effects of competition on Copaxone(R) sales, including as a result of the reintroduction of Tysabri(R) into the market, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, Teva's ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims, dependence on patent and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism or major hostilities, environmental risks, fluctuations in currency, exchange and interest rates, operating results and other factors that are discussed in Teva's Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update publicly or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Contacts
Teva:
Teva Pharmaceutical Industries Ltd.
Dan Suesskind, + 972-2-589-2840
or
Teva North America
George Barrett, +1 215 591-3030
or
Teva Investor Relations
Liraz Kalif / Kevin Mannix
+972-3-926-7281 / (215) 591-8912
or
Active Biotech:
Sven Andreasson, +46 46 19 20 49
Tomas Leanderson, +46 46 19 20 95
Cecilia Hofvander, +46 46 19 11 22
Teva Pharmaceutical Industries (ISRAEL)
September 5, 2006
The once-daily novel oral agent for relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
JERUSALEM & LUND, Sweden--(BUSINESS WIRE)--Sept. 5, 2006--Teva Pharmaceutical Industries Ltd (Nasdaq: TEVA) and Active Biotech AB (ACTI.ST) today announced that a Phase IIb study designed to evaluate the safety and efficacy of laquinimod, a once-daily novel oral agent, in relapsing remitting multiple sclerosis (MS) patients, met its primary end-point.
Laquinimod treatment significantly reduced the rate of inflammatory disease activity, as measured by the cumulative number of Gadolinium enhancing lesions on brain MRI scans after 36 weeks of treatment. Laquinimod treatment also demonstrated a considerable reduction in the number of clinical relapses compared to placebo. This Phase IIb multi-center, randomized, double-blind, placebo-controlled study enrolled approximately 300 patients in 8 European countries and in Israel.
The evaluation of the safety and side-effect data confirmed the favourable safety profile that was seen in earlier phase II clinical trials. The majority of the patients who participated in the study are currently continuing treatment with laquinimod in an ongoing, blinded extension study.
"The study results with once daily oral laquinimod are very encouraging and further demonstrate our ongoing commitment to developing new classes of therapies for MS, including oral therapies, to treat the disease, as well as to improve the patients' quality of life", said Israel Makov, President and CEO of Teva Pharmaceutical Industries Ltd..
"As of today, nearly 400 patients have received laquinimod in various clinical trials over the last years. The data from the completed studies together with preclinical documentation, confirm laquinimod's efficacy and favorable safety profile in MS patients," said Sven Andreasson, President and CEO of Active Biotech AB.
The positive result of the clinical trial triggers a milestone payment to Active Biotech.
Further details about the study will be given at Teva's Innovative R&D Day in New York City on September 26th, 2006. A complete presentation of the Phase IIb data will be given at upcoming relevant scientific meetings.
Teva is discussing laquinimod's development plan with regulatory authorities in order to accelerate the clinical program into Phase III.
About Laquinimod
Laquinimod is a novel once-daily, orally administered immunomodulatory compound developed as a disease modifying treatment for multiple sclerosis (MS). Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries Ltd. in June 2004.
About MS
Multiple Sclerosis (MS) is the leading cause of neurological disability in young adults. It is estimated that 400,000 people in the United States are affected by this disease, and that over one million people are affected worldwide. MS is a progressive, demyelinating disease of the central nervous system affecting the brain, spinal cord and optic nerves.
Patients with MS may experience physical symptoms and/or cognitive impairments, including weakness, fatigue, ataxia, physical dysfunction, bladder and bowel problems, sensory effects, and visual impairment. MS also has a significant impact on the sufferers' social functioning and overall quality of life.
About Active Biotech
Active Biotech AB is a biotechnology company focusing on research and development of pharmaceuticals. Active Biotech has a strong R&D portfolio with pipeline products focused on autoimmune/inflammatory diseases and cancer. Most advanced projects are Laquinimod, an orally administered small molecule with unique immunomodulatory properties for the treatment of multiple sclerosis, as well as ANYARA for use in cancer immunotherapy with the primary indications renal cell cancer and non-small cell lung cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer 57-57 for SLE and RhuDex(R) for RA.
About Teva
Teva Pharmaceutical Industries Ltd., headquartered in Israel, is among the top 20 pharmaceutical companies in the world and is the leading generic pharmaceutical company. The company develops, manufactures and markets generic and innovative human pharmaceuticals and active pharmaceutical ingredients, as well as animal health pharmaceutical products. Over 80% of Teva's sales are in North America and Europe. Teva's innovative R&D focuses on developing novel drugs for diseases of the central nervous system.
Safe Harbor Statement under the U. S. Private Securities Litigation Reform Act of 1995: This release contains forward-looking statements, which express the current beliefs and expectations of management. Such statements are based on management's current beliefs and expectations and involve a number of known and unknown risks and uncertainties that could cause Teva`s future results, performance or achievements to differ significantly from the results, performance or achievements expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to Teva's ability to rapidly integrate Ivax Corporation's operations and achieve expected synergies, Teva`s ability to successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic products, the impact of competition from brand-name companies that sell or license their own brand products under generic trade dress and at generic prices (so called "authorized generics") or seek to delay the introduction of generic product, the impact of consolidation of our distributors and customers, regulatory changes that may prevent Teva from exploiting exclusivity periods, potential liability for sales of generic products prior to a final resolution of outstanding litigation, including that relating to the generic versions of Allegra(R), Neurontin(R), Oxycontin(R) and Zithromax(R), the effects of competition on Copaxone(R) sales, including as a result of the reintroduction of Tysabri(R) into the market, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry, the difficulty of predicting U.S. Food and Drug Administration, European Medicines Agency and other regulatory authority approvals, the regulatory environment and changes in the health policies and structures of various countries, Teva's ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims, dependence on patent and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism or major hostilities, environmental risks, fluctuations in currency, exchange and interest rates, operating results and other factors that are discussed in Teva's Annual Report on Form 20-F and its other filings with the U.S. Securities and Exchange Commission. Forward-looking statements speak only as of the date on which they are made and the Company undertakes no obligation to update publicly or revise any forward-looking statement, whether as a result of new information, future developments or otherwise.
Contacts
Teva:
Teva Pharmaceutical Industries Ltd.
Dan Suesskind, + 972-2-589-2840
or
Teva North America
George Barrett, +1 215 591-3030
or
Teva Investor Relations
Liraz Kalif / Kevin Mannix
+972-3-926-7281 / (215) 591-8912
or
Active Biotech:
Sven Andreasson, +46 46 19 20 49
Tomas Leanderson, +46 46 19 20 95
Cecilia Hofvander, +46 46 19 11 22
Drugs from Astrazeneca/Renovis and Sanofi-Aventis Have the Potential to Revolutionize the Treatment of Several Neurologic Indications
Press Release Source: Decision Resources, Inc.
Tuesday September 5, 8:00 am ET
New Drug Launches Will Propel Neuroprotectant Sales to Nearly $3 Billion in 2020, According to a New Report from Decision Resources
WALTHAM, Mass., Sept. 5 /PRNewswire/ -- Decision Resources, Inc., one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that neuroprotectants, including drugs from AstraZeneca/Renovis and Sanofi-Aventis, have the potential to revolutionize the treatment of several neurologic indications. Neuroprotectants will be used to treat acute neurologic indications such as acute ischemic stroke (AIS) and traumatic brain injury as well as neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
According to the new Pharmacor report entitled Neuroprotection: Analysis of Drug Development and Emerging Therapies, neuroprotectants will launch in the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan during the 2005 - 2020 study period, beginning with the launch in 2008 of AstraZeneca/Renovis's NXY-059 for the treatment of AIS.
The report finds that the high prevalence of AIS combined with the extensive unmet need for a safe treatment for the disease, and off-label use in the United States, will drive NXY-059 to blockbuster status with sales in the United States and Europe reaching over $1.5 billion in 2020. Along with NXY-059, Sanofi-Aventis's Xaprila (xaliprodene) and SR-57667 will be major players in this market, driving sales of neuroprotectants to nearly $3 billion in 2020. Sales of xaliprodene and SR-57667 will total over $1.2 billion by 2020, driven by the high prevalence of Alzheimer's disease and the requirement for chronic administration of these drugs. However, significant challenges exist in this market, compared to AIS.
"Prior to NXY-059's successful completion of the first Stroke Acute Ischemic NXY Treatment (SAINT-1) trial, approval for a neuroprotectant was elusive in the United States and Europe," said Andrea Witt, Ph.D., analyst at Decision Resources, Inc. "If the second SAINT trial provides similar results, the approval of NXY-059 will set a drug development and regulatory precedent by renewing the interest of drug makers in this field and will pave the way for the development of emerging neuroprotectants over the next decade."
About Neuroprotectants
Neuroprotectants are agents that have the potential to prevent neuronal death after injury that could be used in a wide range of neurologic indications, all characterized by acute unmet need.
Tuesday September 5, 8:00 am ET
New Drug Launches Will Propel Neuroprotectant Sales to Nearly $3 Billion in 2020, According to a New Report from Decision Resources
WALTHAM, Mass., Sept. 5 /PRNewswire/ -- Decision Resources, Inc., one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that neuroprotectants, including drugs from AstraZeneca/Renovis and Sanofi-Aventis, have the potential to revolutionize the treatment of several neurologic indications. Neuroprotectants will be used to treat acute neurologic indications such as acute ischemic stroke (AIS) and traumatic brain injury as well as neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
According to the new Pharmacor report entitled Neuroprotection: Analysis of Drug Development and Emerging Therapies, neuroprotectants will launch in the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan during the 2005 - 2020 study period, beginning with the launch in 2008 of AstraZeneca/Renovis's NXY-059 for the treatment of AIS.
The report finds that the high prevalence of AIS combined with the extensive unmet need for a safe treatment for the disease, and off-label use in the United States, will drive NXY-059 to blockbuster status with sales in the United States and Europe reaching over $1.5 billion in 2020. Along with NXY-059, Sanofi-Aventis's Xaprila (xaliprodene) and SR-57667 will be major players in this market, driving sales of neuroprotectants to nearly $3 billion in 2020. Sales of xaliprodene and SR-57667 will total over $1.2 billion by 2020, driven by the high prevalence of Alzheimer's disease and the requirement for chronic administration of these drugs. However, significant challenges exist in this market, compared to AIS.
"Prior to NXY-059's successful completion of the first Stroke Acute Ischemic NXY Treatment (SAINT-1) trial, approval for a neuroprotectant was elusive in the United States and Europe," said Andrea Witt, Ph.D., analyst at Decision Resources, Inc. "If the second SAINT trial provides similar results, the approval of NXY-059 will set a drug development and regulatory precedent by renewing the interest of drug makers in this field and will pave the way for the development of emerging neuroprotectants over the next decade."
About Neuroprotectants
Neuroprotectants are agents that have the potential to prevent neuronal death after injury that could be used in a wide range of neurologic indications, all characterized by acute unmet need.
BioMS Medical expands pivotal multiple sclerosis trial into Spain and Germany
BioMS Medical (CANADA)
September 7, 2006
Toronto Stock Exchange Symbol: MS
EDMONTON, Sept. 7 /CNW/ - BioMS Medical Corp (TSX: MS), a leading developer in the treatment of multiple sclerosis (MS), today announced it has received approval from the Spanish Agency for Medicines and Healthcare Products (SAMHP) in Spain and from the Federal Institute for Medicines and Medical Products in Germany to start patient enrolment for its pivotal phase II/III clinical trial of MBP8298, a proprietary synthetic peptide for the treatment of secondary progressive multiple sclerosis (SPMS).
Pivotal Phase II/III Multiple Sclerosis Trial
BioMS Medical is currently enrolling patients across Canada, the U.K., Sweden, Denmark and The Netherlands in its pivotal phase II/III clinical trial evaluating MBP8298 for the treatment of secondary progressive multiple sclerosis (SPMS). The trial is a randomized, double-blind study enrolling approximately 553 patients who will be administered either MBP8298 or placebo intravenously every six months for a period of two years. The primary clinical endpoint for the trial is defined as a statistically and clinically significant increase in the time to progression of the disease as measured by the Expanded Disability Status Scale (EDSS), in patients with HLA-DR2 and/or HLA-DR4 immune response genes. Time to disease progression in patients with other HLA-DR types will be assessed separately as an exploratory arm of the same study. To date the trial has successfully passed five safety reviews by its independent Data Safety Monitoring Board.
About BioMS Medical Corp.
BioMS Medical is a biotechnology company engaged in the development and commercialization of novel therapeutic technologies. BioMS Medical's lead technology, MBP8298, is for the treatment of multiple sclerosis and is currently in a pivotal phase II/III clinical trial across Canada and Europe. For further information please visit our website at www.biomsmedical.com.
This news release may contain certain forward-looking statements that reflect the current views and/or expectations of BioMS Medical with respect to its performance, business and future events. Such statements are subject to a number of risks, uncertainties and assumptions. Actual results and events may vary significantly.
For further information: Tony Hesby, Ryan Giese, Corporate Communications, BioMS Medical Corp., (780) 413-7152, (780) 408-3040 Fax, E-mail: rgiese@biomsmedical.com, Internet: www.biomsmedical.com; James Smith, Investor Relations, (416) 815-0700 ext. 229, (416) 815-0080 Fax, E-mail: jsmith@equicomgroup.com; Mr. Barry Mire, Investor Relations, Phone: (514) 939-3989, E-mail: bmire@renmarkfinancial.com
September 7, 2006
Toronto Stock Exchange Symbol: MS
EDMONTON, Sept. 7 /CNW/ - BioMS Medical Corp (TSX: MS), a leading developer in the treatment of multiple sclerosis (MS), today announced it has received approval from the Spanish Agency for Medicines and Healthcare Products (SAMHP) in Spain and from the Federal Institute for Medicines and Medical Products in Germany to start patient enrolment for its pivotal phase II/III clinical trial of MBP8298, a proprietary synthetic peptide for the treatment of secondary progressive multiple sclerosis (SPMS).
Pivotal Phase II/III Multiple Sclerosis Trial
BioMS Medical is currently enrolling patients across Canada, the U.K., Sweden, Denmark and The Netherlands in its pivotal phase II/III clinical trial evaluating MBP8298 for the treatment of secondary progressive multiple sclerosis (SPMS). The trial is a randomized, double-blind study enrolling approximately 553 patients who will be administered either MBP8298 or placebo intravenously every six months for a period of two years. The primary clinical endpoint for the trial is defined as a statistically and clinically significant increase in the time to progression of the disease as measured by the Expanded Disability Status Scale (EDSS), in patients with HLA-DR2 and/or HLA-DR4 immune response genes. Time to disease progression in patients with other HLA-DR types will be assessed separately as an exploratory arm of the same study. To date the trial has successfully passed five safety reviews by its independent Data Safety Monitoring Board.
About BioMS Medical Corp.
BioMS Medical is a biotechnology company engaged in the development and commercialization of novel therapeutic technologies. BioMS Medical's lead technology, MBP8298, is for the treatment of multiple sclerosis and is currently in a pivotal phase II/III clinical trial across Canada and Europe. For further information please visit our website at www.biomsmedical.com.
This news release may contain certain forward-looking statements that reflect the current views and/or expectations of BioMS Medical with respect to its performance, business and future events. Such statements are subject to a number of risks, uncertainties and assumptions. Actual results and events may vary significantly.
For further information: Tony Hesby, Ryan Giese, Corporate Communications, BioMS Medical Corp., (780) 413-7152, (780) 408-3040 Fax, E-mail: rgiese@biomsmedical.com, Internet: www.biomsmedical.com; James Smith, Investor Relations, (416) 815-0700 ext. 229, (416) 815-0080 Fax, E-mail: jsmith@equicomgroup.com; Mr. Barry Mire, Investor Relations, Phone: (514) 939-3989, E-mail: bmire@renmarkfinancial.com
Cannabis-derived MS treatment filed in Europe
Tuesday , September 05, 2006
Sativex, the cannabis-derived product developed by GW Pharmaceuticals could be finally set for approval after a delay of around two years.
UK regulator, the MHRA, rejected the drug in December 2004, calling for a second clinical trial to prove its efficacy, which the company has now conducted, and which, it believes, proves that Sativex works.
The company is seeking to treat multiple sclerosis spasticity, but hopes to eventually gain licences to treat peripheral neuropathic pain, MS neuropathic pain and cancer pain as well.
GW Pharmaceuticals has filed Sativex for approval through the decentralised procedure for licences in just four European countries, the UK, Denmark, Spain and the Netherlands.
Once approved, Sativex will be marketed in the UK by Bayer HealthCare and in the rest of Europe by Almirall.
Dr Stephen Wright, GW's R&D Director said: "We now have a sizeable body of positive clinical data to support the efficacy and safety of Sativex in MS spasticity. This is a complex data package and we have therefore reviewed the complete dossier with our marketing partners and discussed it in detail with a number of European regulators.
"These meetings have provided constructive and positive feedback. The conclusion of GW and its marketing partners, taking into account the views of the regulators, as well as the unmet needs of this target patient group, is that this body of data warrants serious regulatory evaluation."
Dr Geoffrey Guy, executive chairman of GW added: "This filing is one element of a broad-based regulatory strategy for Sativex, which is designed to maximise the opportunities for Sativex as well as to manage the risks associated with its development.
"Beyond the filing today in MS spasticity, the Phase III clinical trials programme continues and will provide further sets of clinical data to support additional regulatory filings in separate indications. This approach is aimed at creating several independent opportunities to obtain regulatory approvals for Sativex in the coming years."
Sativex is already approved in Canada to treat MS neuropathic pain and the company recently started a further phase III study in this indication. The study will complement existing phase III trial data, with a filing in Europe based on the results expected by the first half of 2008.
Sativex, the cannabis-derived product developed by GW Pharmaceuticals could be finally set for approval after a delay of around two years.
UK regulator, the MHRA, rejected the drug in December 2004, calling for a second clinical trial to prove its efficacy, which the company has now conducted, and which, it believes, proves that Sativex works.
The company is seeking to treat multiple sclerosis spasticity, but hopes to eventually gain licences to treat peripheral neuropathic pain, MS neuropathic pain and cancer pain as well.
GW Pharmaceuticals has filed Sativex for approval through the decentralised procedure for licences in just four European countries, the UK, Denmark, Spain and the Netherlands.
Once approved, Sativex will be marketed in the UK by Bayer HealthCare and in the rest of Europe by Almirall.
Dr Stephen Wright, GW's R&D Director said: "We now have a sizeable body of positive clinical data to support the efficacy and safety of Sativex in MS spasticity. This is a complex data package and we have therefore reviewed the complete dossier with our marketing partners and discussed it in detail with a number of European regulators.
"These meetings have provided constructive and positive feedback. The conclusion of GW and its marketing partners, taking into account the views of the regulators, as well as the unmet needs of this target patient group, is that this body of data warrants serious regulatory evaluation."
Dr Geoffrey Guy, executive chairman of GW added: "This filing is one element of a broad-based regulatory strategy for Sativex, which is designed to maximise the opportunities for Sativex as well as to manage the risks associated with its development.
"Beyond the filing today in MS spasticity, the Phase III clinical trials programme continues and will provide further sets of clinical data to support additional regulatory filings in separate indications. This approach is aimed at creating several independent opportunities to obtain regulatory approvals for Sativex in the coming years."
Sativex is already approved in Canada to treat MS neuropathic pain and the company recently started a further phase III study in this indication. The study will complement existing phase III trial data, with a filing in Europe based on the results expected by the first half of 2008.
Monday, September 11, 2006
Scientists Discover Why Statins Help MS
from the South Bend Tribune.com
August 30. 2006 6:59AM
Scientists discover why statins help MS
OUR HEALTH: TREATMENT WATCH
Scientists say statin drugs, well-known for lowering cholesterol, seem to reduce inflammation that causes nerve cell damage in people with multiple sclerosis.
Previous research, still considered preliminary, has suggested that MS patients who also take statins have less nerve damage over time.
Scientists at the University of North Carolina, at Chapel Hill, tested blood samples from people with relapsing-remitting MS to find out why.
They found that statins inhibited the formation of lymphocytes and monocytes. Those immune-system cells cause inflammation by attacking nerve cells in people with MS.
The researchers say statins may be used to enhance current treatments for MS, which slow the progressive disease but don't stop it.
The study was published July 25 in the online Journal of Neuroimmunology.
August 30. 2006 6:59AM
Scientists discover why statins help MS
OUR HEALTH: TREATMENT WATCH
Scientists say statin drugs, well-known for lowering cholesterol, seem to reduce inflammation that causes nerve cell damage in people with multiple sclerosis.
Previous research, still considered preliminary, has suggested that MS patients who also take statins have less nerve damage over time.
Scientists at the University of North Carolina, at Chapel Hill, tested blood samples from people with relapsing-remitting MS to find out why.
They found that statins inhibited the formation of lymphocytes and monocytes. Those immune-system cells cause inflammation by attacking nerve cells in people with MS.
The researchers say statins may be used to enhance current treatments for MS, which slow the progressive disease but don't stop it.
The study was published July 25 in the online Journal of Neuroimmunology.
Who Gets Multiple Sclerosis?
Multiple sclerosis is typically diagnosed in people between the ages of 20 and 50. Approximately two–thirds or more of people diagnosed with MS are women, though the precise reason for that has yet to be determined.
Some research has indicated that there may be genetic factors that cause one individual to be more susceptible to MS than other individuals. Research studies have yet to support the theory that MS is an inherited disease, however. MS is not contagious nor is it considered fatal. On average, people with MS can be expected to lead 93 percent the lifespan of a non–MS individual. That’s supposed to sound like good news but the reality is that life insurance companies will charge double or more for insurance if you have MS. Seems like that seven percent is very profitable for some businesses.
While MS can occur in anyone, MS seems to occur more frequently in people of northern European ancestry. Also, as previously mentioned, the rate of MS among populations seems to increase the further north or south you get from the Equator, again for reasons as yet unknown.
Depending on the source, anywhere from 400,000 to half a million or more people in the United States have MS. It is said that a new case is diagnosed every hour, 200 a week. In the United States alone, it is estimated that MS costs more than $9 billion annually.
Some research has indicated that there may be genetic factors that cause one individual to be more susceptible to MS than other individuals. Research studies have yet to support the theory that MS is an inherited disease, however. MS is not contagious nor is it considered fatal. On average, people with MS can be expected to lead 93 percent the lifespan of a non–MS individual. That’s supposed to sound like good news but the reality is that life insurance companies will charge double or more for insurance if you have MS. Seems like that seven percent is very profitable for some businesses.
While MS can occur in anyone, MS seems to occur more frequently in people of northern European ancestry. Also, as previously mentioned, the rate of MS among populations seems to increase the further north or south you get from the Equator, again for reasons as yet unknown.
Depending on the source, anywhere from 400,000 to half a million or more people in the United States have MS. It is said that a new case is diagnosed every hour, 200 a week. In the United States alone, it is estimated that MS costs more than $9 billion annually.
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