Tuesday, November 27, 2007
London, UK; Tokyo, Japan; 26 November 2007: GW Pharmaceuticals plc (AIM: GWP) and Otsuka Pharmaceutical Co., Ltd. today announced that the first US Phase II/III dose-ranging trial has been initiated to evaluate the efficacy and safety of Sativex® in the treatment of pain in patients with advanced cancer, who experience inadequate analgesia during optimized chronic opioid therapy.
The principal investigator of this study is Dr. Russell K. Portenoy, Chairman of the Department of Pain Medicine and Palliative Care at Beth Israel Medical Center in New York City. This five-week, placebo-controlled study will include approximately 40 centers primarily in the US and recruit a total of 336 patients. Patients enrolled in this study must have advanced cancer for which there is no known curative therapy and have a clinical diagnosis of cancer-related pain, which is not wholly alleviated with their current opioid treatment. The primary objective of the study is to evaluate the potential role and dose range of Sativex in these patients as an adjunct to their pre-existing pain medications. The primary endpoint of the study will be the response rate for patients at the end of 5 weeks of therapy, as defined by a 30% or greater reduction in the 11-point, Numeric Rating Scale (NRS).
Commenting on the importance of this study, Dr. Portenoy, said, “Studies suggest that more than one-third of patients with cancer, and more than three-quarters of those with advanced disease, have chronic pain. Large surveys indicate that optimal opioid therapy does not yield sufficient relief in a substantial proportion of these patients. There is a clear need for new treatments to improve these outcomes and it is our hope that cannabinoid formulations may represent an important option in the future. This US-based study is a welcome step in assessing the role of Sativex® as a potential new treatment for cancer pain."
Dr Geoffrey Guy, GW’s Chairman, said, “GW has spent many years preparing for the US development of Sativex® and has established open and positive interactions with relevant federal agencies. The start of the first large scale US clinical trial is a major milestone for the company and for the future prospects for Sativex®. We are delighted to be working in close collaboration with our partner, Otsuka, in advancing Sativex® toward the goal of obtaining US regulatory approval."
Dr. Taro Iwamoto, President of Otsuka Pharmaceutical Development and Commercialization, Inc., likewise noted that “Otsuka is very excited to be working with GW Pharmaceuticals for the development of this potential alternative approach to the treatment of advanced cancer pain. The initiation of this US clinical trial for Sativex is consistent with our mission to develop products for better health.”
Sativex® is an investigational new product composed primarily of two cannabinoids: CBD (cannabidiol,) and THC (delta 9 tetrahydrocannabinol). Sativex® will be administered as a metered dose oro-mucosal spray each 100µL spray contains 2.7mg THC and 2.5mg CBD. The Sativex® formulation is standardized by both composition and dose and is supplied in small spray vials. The components of Sativex have been shown to bind to cannabinoid receptors that are distributed throughout the central nervous system and in immune cells.
This Phase II/III dose ranging study will attempt to replicate and extend data from a previous, two-week clinical trial in 177 patients conducted in Europe. In this European study, Sativex® was administered to patients with terminal cancer and persistent pain that was not fully relieved by current strong opioid therapy. The primary endpoint of this study was the change from baseline to endpoint in the NRS pain score. Sativex, as adjunctive treatment to strong opioid therapy, was associated with a larger decrease in NRS score than was placebo and strong opiods (p=0.014). In addition, 43% of patients who received Sativex®, while remaining on opioids, exhibited at least a 30% decrease in their pain score compared to 21% of patients receiving placebo and opioids (p= 0.024)
Treatment related adverse events in this study were reported by 85% of patients receiving Sativex and by 75% of patients receiving placebo. The most common adverse events (> 10%) reported by patients in this study were somnolence (15% Sativex® vs. 13% placebo); nausea (12% Sativex® vs. 11% placebo) and dizziness (12% Sativex® vs. 5% placebo). Serious adverse events reported by more than one patient receiving Sativex were urinary retention (n=2) and progression of the underlying cancer (n=6).
GW Pharmaceuticals plc Today: +44 20 7831 3113
Dr Geoffrey Guy , Chairman Thereafter: + 44 1980 557000
Justin Gover, Managing Director
Mark Rogerson , Press and PR Tel: + 44 7885 638810
Financial Dynamics Tel: +44 20 7831 3113
David Yates, Ben Atwell
For Otsuka: US Inquiry
Debbie Kaufmann Tel: +1 240 683 3568
Hideki Shirai firstname.lastname@example.org
Notes to Editors
On 14 February 2007, GW and Otsuka entered into a major long term strategic alliance. The relationship commenced with the signing of an exclusive license agreement to develop and market Sativex® GW’s lead product, in the US. Under this agreement, GW and Otsuka jointly oversee US clinical development and regulatory activities as well as the commercialization strategy. GW is responsible for carrying out the US clinical development program, the costs of which are borne by Otsuka. Otsuka will be responsible for the marketing and sales activities in the US.
On 9 July 2007, GW and Otsuka signed a global research collaboration for the study of cannabinoids in the field of Central Nervous System (CNS) and oncology to research, develop and commercialize a range of candidate cannabinoid products.
About Otsuka Pharmaceutical Co., Ltd
Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka - people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.
The Otsuka Pharmaceutical Group comprises 99 companies and employs approximately 31,000 people in 17 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned US$7.2 billion in annual revenues in fiscal 2006.
Focusing on the central nervous system, the circulatory, respiratory, and digestive systems, ophthalmology and dermatology, Otsuka’s pharmaceutical product business engages in the research and development, manufacture and sale of pharmaceuticals, aiming to maximize the assets of a global network to address unmet medical meets.
For additional information, visit www.otsuka-global.com
GW was founded in 1998 and listed on the AiM, a market of the London Stock Exchange, in June 2001. Operating under license from the UK Home Office, the company researches and develops cannabinoid pharmaceutical products that alleviate pain and other neurological symptoms in patients who suffer from serious ailments. GW has assembled a team of over 100 scientists with extensive experience in developing both plant-based prescription pharmaceutical products and medicines containing controlled substances. GW occupies a world leading position in cannabinoids and has developed an extensive international network of the most prominent scientists in the field. For further information, please visit www.gwpharm.com
This news release may contain forward-looking statements that reflect GWs current expectations regarding future events, including development and regulatory clearance of the GW’s products. Forward-looking statements involve risks and uncertainties. Actual events could differ materially from those projected herein and depend on a number of factors, including (inter alia), the success of the GW’s research strategies, the applicability of the discoveries made therein, the successful and timely completion of uncertainties related to the regulatory process, and the acceptance of Sativex® and other products by consumer and medical professionals.
Porton Down, UK, 12 November 2007 - GW Pharmaceuticals plc (AIM: GWP) today announces that The International Association of the Study of Pain has published online the results of a study in its official journal Pain, showing that Sativex® successfully treats peripheral neuropathic pain1.
The trial was a multi centre, double-blind, randomised, placebo-controlled parallel group study, conducted in 125 patients with peripheral neuropathic pain characterised by allodynia. The publication of these data follows the previous announcement of preliminary results of this study.
In the study, Sativex demonstrated significant superiority to placebo in reducing pain, as measured on a 0-10 Numeric Rating Scale (p=0.004), the primary endpoint of the study. Statistically significant improvements were also seen in the Neuropathic Pain Scale composite score (p=0.007), sleep disturbance (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patients Global Impression of Change (p<0.0001).
Sativex was well-tolerated in this study, with the majority of adverse events being mild or moderate. There were no treatment-related serious adverse events.
The five week trial was conducted in patients who were experiencing significant levels of neuropathic pain and who had failed to gain adequate relief from currently available analgesic medications. Patients enrolled in the study continued to take their existing medication throughout the trial. Sixty-nine percent of patients were taking opioid analgesics. Hence, improvements obtained on Sativex were over and above those obtained on currently available treatments.
Professor Turo Nurmikko, Principal Investigator, Professor of Pain Science and Consultant Pain Physician at the Walton Centre for Neurology and Neurosurgery, Liverpool, commented, "Peripheral neuropathic pain can be extremely disabling and is one of the most difficult types of chronic pain to treat. This study demonstrates that Sativex is effective in the relief of peripheral neuropathic pain. In particular, considering the refractory nature of their pain and that patients remained on their existing analgesia, the improvements seen on Sativex are very encouraging."
Dr Stephen Wright, Director of Research & Development at GW, noted "We are pleased that this important study has been published in Pain, a highly regarded and influential journal. This recognition of the high quality of GW clinical research and of the importance of these findings provides further evidence of the utility of Sativex in the relief of neuropathic pain, an area of significant unmet medical need."
This study is part of a broad programme of clinical trials aimed at securing future regulatory approval for Sativex in neuropathic pain. It is intended to conduct further Phase III clinical trials targeted at neuropathic pain following initial regulatory approval for Sativex in Multiple Sclerosis in Europe.
- ends -
GW Pharmaceuticals plc Today: +44 (0)20 7831 3113
Dr Geoffrey Guy, Executive Chairman
Justin Gover, Managing Director
Dr Stephen Wright, R&D Director
Financial Dynamics Tel: +44 (0)20 7831 3113
David Yates, Ben Atwell
Notes to Editors
Sativex (THC:CBD), an endocannabinoid system modulator, is derived from whole plant extracts of two specifically bred cannabis plant varieties. The extracts are combined to produce a standardised formulation containing two major components of cannabis, the cannabinoids D9-tetrahydrocannabinol(THC) and cannabidiol(CBD).
Sativex is formulated into a pump action oromucosal (mouth) spray designed for self-administration by the patient. This formulation allows for flexible dosing, ideal for the variable nature of MS. Each spray of Sativex delivers a fixed dose of 2.7mg THC and 2.5mg CBD. Sativex was generally well tolerated in the study.
Allodynia is the occurrence of pain in response to a normally non-painful stimulus (e.g. clothes touching against the skin). It is often intense and can occur in patients suffering from a range of conditions that damage the peripheral nerves (e.g. diabetes, post-herpetic neuralgia) and is a highly reliable marker of neuropathic pain. Neuropathic pain can be difficult to diagnose and may be confused with nociceptive pain (caused by bodily injury - 'visceral' or 'somatic'). The presence of allodynia can confirm that the pain experienced by the patient is truly neuropathic.
Neuropathic pain is caused by damage to or dysfunction of the nervous system. It is usually chronic and accompanied by unpleasant burning or shooting sensations, or extreme sensitivity to touch. The classification of central or peripheral neuropathic pain is determined by the location of the damage or dysfunction in the nervous system.
It is estimated that at least 1 per cent. of the world's population suffers from neuropathic pain, including over 600,000 patients in UK.
Neuropathic pain can be associated with many conditions including multiple sclerosis, stroke, cancer, spinal cord injury, physical trauma and peripheral neuropathy resulting from diabetes. It can also occur in patients who have previously suffered from shingles, a condition known as post-herpetic neuralgia.
Neuropathic pain is one of the most difficult types of chronic pain to treat. Since treatment options are limited, doctors often prescribe a combination of therapies in an attempt to relieve symptoms.
GW Pharmaceuticals plc
GW was founded in 1998 and listed on the AIM, a market of the London Stock Exchange, in June 2001. Operating under license from the UK Home Office, the company researches and develops cannabinoid pharmaceutical products that alleviate pain and other neurological symptoms in patients who suffer from serious ailments.
GW has assembled a team of over 100 scientists with extensive experience in developing both plant-based prescription pharmaceutical products and medicines containing controlled substances. GW occupies a world leading position in cannabinoids and has developed an extensive international network of the most prominent scientists in the field. For further information, please visit www.gwpharm.com
1. Nurmikko T, Serpell M, et al. Sativex Successfully Treats Neuropathic Pain Characterised by Allodynia: a Randomised, Double-Blind, Placebo-Controlled Trial. Pain. 2007: doi:10.1016/j.pain.2007.08.028M
By Brandon Keim November 26, 2007
With the help of an ingenious protein hack, scientists have used stem cells to grow new immune systems in mice -- a technique that could someday treat human autoimmune diseases.
In a study published in Science, Stanford University researchers described how blood-forming stem cells generated new immune systems when injected into mouse bone marrow. That wasn't particularly surprising; the real breakthrough took place before the stem cell injections, when the researchers erased the old immune systems.
Traditionally, this is done with radiation and chemicals that also destroy surrounding tissue and sometimes cause brain damage, infertility or cancer. Instead of these scorched-earth therapies, the Stanford scientists gave the mice an antibody designed to neutralize existing blood-forming, or hemapoietic, stem cells. Hematopoietic cells are the building blocks of the immune system; with the old cells out of the way, the researchers added new ones, then sat back and watched fresh immune systems grow.
Duplicating this feat in humans is the holy grail of treatments for for autoimmune diseases, in which bodies are attacked by their own defense systems. But before that happens, more mouse work needs to be finished. The Stanford mice were engineered to possess non-functioning immune systems: they had the necessary components, but the system wasn't on-line.
The researchers must next make their technique work in fully functional mice. Then they need to figure out how to design human-specific antibodies, as the mouse antibodies targeted proteins not present in our own cells.
But if they can do this, the ramifications are enormous: an estimated 20 million Americans suffer from autoimmune diseases, including type 1 diabetes, arthritis and multiple sclerosis. Many other conditions, including chronic fatigue syndrome and obesity, are suspected of having an autoimmune component.
Monday, November 19, 2007
Hollis-Eden Pharmaceuticals Presents Data Demonstrating TRIOLEX(TM) Provides Benefit in Additional Animal Model of Rheumatoid Arthritis
Findings Presented at 36th Annual Autumn Immunology Conference
SAN DIEGO--(BUSINESS WIRE)--Nov. 19, 2007--Hollis-Eden Pharmaceuticals, Inc. (NASDAQ:HEPH), the world leader in the development of a new class of small molecule compounds based on endogenous steroid hormones, is presenting new data this week at the 36th Annual Autumn Immunology Conference, held in Chicago, Illinois, November 16-19, showing that its drug candidate TRIOLEX(TM) (HE3286) provided benefit in an animal model of collagen antibody induced arthritis (CAIA). As previously reported, TRIOLEX, a novel orally bio-available anti-inflammatory cleared by the U.S. Food and Drug Administration for a Phase I/II clinical trial in rheumatoid arthritis (RA), has also demonstrated benefit to date in animal models of collagen induced arthritis (CIA), systemic lupus erythematosus, multiple sclerosis and ulcerative colitis without immune suppressive side effects.
The new data, presented in an oral presentation, are from studies performed by Dr. David Boyle at The University of California, San Diego (UCSD) showing that treatment with TRIOLEX significantly reduced disease in the murine model of CAIA in a dose dependent fashion, with the highest dose completely eliminating disease. In the CAIA model, disease is induced by injecting animals with arthrogenic antibodies, a method that largely bypasses the animal's own cellular immune system. Severe joint inflammation occurs within hours after the injection of antibodies. TRIOLEX was highly effective in this model whether treatment began 1 day or 5 days after injection with antibodies. Benefit at the peak of disease was associated with a significant reduction of interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3) messenger RNA from the joints of TRIOLEX-treated animals when compared to placebo-treated controls. IL-6 and MMP-3 are thought to be among the most important drivers of disease and tissue destruction in human RA. Methotrexate, the current standard of care in RA, is far less effective in the CAIA model than in models of collagen induced arthritis (CIA), where disease is driven by the animal's own cellular immune system.
Methotrexate, a chemotherapy treatment, is focused on treating the cellular infiltration aspect of RA, while other treatments such as corticosteroids and non-steroidal anti-inflammatory agents focus on treating the antibody aspect of the disease. Due to the previously reported activity of TRIOLEX in the CIA animal model and this newly reported activity in the CAIA model, the Company believes that TRIOLEX may be effective at treating both aspects of RA without the immune suppressive side effects associated with some currently prescribed drugs.
Hollis-Eden believes TRIOLEX may act by inhibiting the activation of the NF-kappaB pathway. NF-kappaB is a transcription factor that controls many of the genes involved in the inflammatory signaling pathway, including TNF-alpha, IL-1-beta and IL-6. These cytokines are thought to be key inflammatory mediators that play an important underlying role in many major diseases, including autoimmune disorders. Unlike currently prescribed corticosteroids that can cause immune suppression and bone loss, animal studies to date show that TRIOLEX does not interact with the glucocorticoid receptor and only partially inhibits the NF-kappaB pathway without causing immune suppression or bone loss.
Rheumatoid arthritis is driven by both a cellular and antibody mediated autoimmune response and, as a result, combinations of highly immune suppressive drugs are commonly used to treat both aspects of active disease. Annual sales in the U.S. of drugs to treat RA are expected to reach $14 billion by 2009, driven by the increase in the aging population and use of new expensive biological treatments. Celebrex, a commonly used drug for RA that inhibits the cox-2 enzyme, recorded U.S. annual sales in excess of $2 billion in 2006.
"We are extremely encouraged by these new data in the CAIA model of rheumatoid arthritis," said Dr. James M. Frincke, Chief Scientific Officer at Hollis-Eden Pharmaceuticals. "In our first clear look into the inflamed joint tissue itself, we found that TRIOLEX virtually eliminated messenger RNA to IL-6 and MMP-3 in this animal model, key players thought to drive inflammation and tissue destruction in RA and other autoimmune disorders."
"These findings provide additional, impressive preclinical evidence of the anti-inflammatory activity of TRIOLEX," said Richard Hollis, Chairman and CEO of Hollis-Eden Pharmaceuticals. "The observation that TRIOLEX treats both collagen induced arthritis and collagen antibody induced arthritis in animal models bodes well for the compound's potential efficacy since it appears able to address both cell and antibody mediated elements of RA. Inflammation is increasingly understood to play a role in multiple diseases of aging, including RA and other autoimmune disorders, metabolic disorders, cardiovascular diseases and cancer, and we believe that this work furthers validates the potential of our compounds to possibly provide therapeutic benefit in these major clinical applications. We are currently conducting a Phase I/II clinical trial with TRIOLEX for type 2 diabetes and are evaluating the ability to use safety and dosing data from that trial to accelerate development of the compound for rheumatoid arthritis."
Hollis-Eden Pharmaceuticals, Inc. is a world leader in the development of a proprietary class of adrenal steroid hormones as novel pharmaceuticals for human health. Through its Hormonal Signaling Technology Platform, Hollis-Eden is developing a new series of small molecule compounds that are metabolites or synthetic analogs of endogenous hormones derived by the adrenal glands from the body's most abundant circulating adrenal steroid. These steroid hormones, designed to restore the biological activity of cellular signaling pathways disrupted by disease and aging, have been demonstrated in humans to possess several properties with potential therapeutic benefit -- they regulate innate and adaptive immunity, reduce nonproductive inflammation and stimulate cell proliferation. The Company's clinical drug development candidates include TRIOLEX, a next-generation compound currently in a clinical trial for the treatment of type 2 diabetes and being prepared for clinical trials in rheumatoid arthritis, and HE3235, a next-generation compound selected for cancer. In addition to these clinical development candidates, Hollis-Eden has an active research program that is generating additional new clinical leads that are being further evaluated in preclinical models of a number of different diseases. For more information on Hollis-Eden, visit the Company's website at www.holliseden.com.
This press release contains forward-looking statements within the meaning of the federal securities laws concerning, among other things, the potential and prospects of the Company's drug discovery program and its drug candidates. Any statement included in this press release that are not a description of historical facts are forward-looking statements that involve risks, uncertainties, assumptions and other factors which, if they do not materialize or prove correct, could cause the Company's actual results to differ materially from historical results or those expressed or implied by such forward-looking statements. Such statements are subject to certain risks and uncertainties inherent in the Company's business, including, but not limited to: the ability to complete preclinical and clinical trials successfully and within specified timelines, if at all; the ability to obtain regulatory approval for TRIOLEX (HE3286), APOPTONE (HE3235) or any other investigational drug candidate; the Company's future capital needs; the Company's ability to obtain additional funding; the ability of the Company to protect its intellectual property rights and to not infringe the intellectual property rights of others; the development of competitive products by other companies; and other risks detailed from time to time in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. Except as required by law, the Company undertakes no obligation to update or revise the information contained in this press release as a result of new information, future events or circumstances arising after the date of this press release.
CONTACT: Hollis-Eden Pharmaceuticals, Inc.
Scott Rieger, Director, Corporate Communications
SOURCE: Hollis-Eden Pharmaceuticals, Inc.
Tuesday, November 13, 2007
A drug currently used to treat high blood pressure and heart failure has been found to reduce the symptoms of multiple sclerosis in mice. The discovery that amiloride can reduce the degeneration of nerve tissue in mice suggests it could have a therapeutic potential for people who have MS. However, despite the positive findings, the researchers warn that clinical trials in people, to test the drug's full potential, are crucial before it is given as a treatment for the disease.
The research led by Professor Lars Fugger of the Medical Research Council Human Immunology Unit and Department of Clinical Neurology at Oxford University is published in Nature Medicine. Professor Fugger said:
''This drug [amiloride] is already licensed for another purpose. Looking for new ways to use established drugs is usually cheaper than starting the discovery process from scratch, we've had a really positive result.''
The search for therapeutic potential began with studies of the role of a channel called ASIC1 that creates an opening in the cell membrane. ASIC1 works by sensing acid levels around the cell and lets sodium and calcium molecules into cells. This process is an important part of the process of sensing pain and touch. Using mice with a condition that mimics some aspects of the human form of multiple sclerosis the scientists found that the ASIC1 channel also contributes to degeneration of the axon, the long stem of the nerve. When the channel remains open, sodium and calcium can flood into the cell in higher than normal proportions.
Professor Fugger explained:
''When sodium and calcium levels accumulate in excessive proportions within nerve cells, the axon, the bit that carries messages from one nerve to the next, is damaged. We found that this damage was reduced in mice given amiloride. The drug appears to work by blocking the action of the channel that lets sodium and calcium molecules into the cell.''
The research has shown that not only is the ASIC1 channel a suitable target for drugs that aim to protect against neurodegeneration in research but that amiloride might be beneficial in treatment.
Overall this suggests that drugs targeted at the ASIC1 channel, like amiloride, could help reduce the level of nerve damage caused by multiple sclerosis. The research team are now beginning to plan a clinical trial that will aim to find out if amiloride is beneficial in treating the symptoms of multiple sclerosis in people.
Original research paper: Acid-sensing ion channel 1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system is published in Nature Medicine.
MR Imaging Intensity Modeling of Damage and Repair In Multiple Sclerosis: Relationship of Short-Term Lesion Recovery to Progression and Disability
American Journal of Neuroradiology 28:1956-1963, November-December 2007
© 2007 American Society of Neuroradiology
D.S. Meier, Department of Radiology, Center for Neurological Imaging, Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston Mass
H.L. Weiner, Department of Neurology, Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston Mass
C.R.G. Guttmann, Department of Radiology, Center for Neurological Imaging, Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, Boston Mass
Please address correspondence to Dominik Meier, PhD, Center for Neurological Imaging, Brigham and Women's Hospital, 221 Longwood Ave, RF 396, Boston, MA 02115; e-mail: email@example.com
BACKGROUND AND PURPOSE: Formation of lesions in multiple sclerosis (MS) shows pronounced short-term fluctuation of MR imaging hyperintensity and size, a qualitatively known but poorly characterized phenomenon. With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T2 lesion formation to those of contrast enhancement and markers of long-term progression of disease.
MATERIALS AND METHODS: We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T2 prolongation and shortening, respectively. Patterns of activity, duration, and residual hyperintensity within new T2 lesions were measured and evaluated for relationships to disability, atrophy, and clinical phenotype in long-term follow-up.
RESULTS: Significant T2 activity was observed for 8 to 10 weeks beyond contrast enhancement, which suggests that T2 MR imaging is sensitive to noninflammatory processes such as degeneration and repair. Larger lesions showed longer subacute phases but disproportionally more recovery. Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage. Higher rates of disability or atrophy were associated with subjects whose lesions showed greater residual hyperintensity.
CONCLUSION: Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in progressive MS smaller and of shorter activity than in relapsing-remitting MS. Associations of lesion dynamics with rates of atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward degenerative disease activity and greater proximity to a progressive stage, possibly allowing staging of the progression of MS earlier, before atrophy or disability develops.
Wednesday, November 07, 2007
Initiation Of Enrollment In Pivotal Phase III Clinical Study Of Oral Laquinimod For Relapsing-Remitting Multiple Sclerosis
Jerusalem, Israel and Lund, Sweden, November 7, 2007 - Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech AB (OMX NORDIC: ACTI) announced today the initiation of enrollment in the Allegro trial (assessment of oral laquinimod in preventing progression of multiple sclerosis). Allegro is a global pivotal, 24/30-month, double-blind, Phase III study designed to evaluate the efficacy, safety and tolerability of the oral investigational compound laquinimod versus placebo in the treatment of relapsing-remitting multiple sclerosis (RRMS). The Allegro trial aims to enroll approximately 1,000 patients with RRMS.
"Currently there are several RRMS treatments available; however, they are all administered via injection or infusion. An orally administered therapy brings us one step closer to offering patients and physicians a highly effective, new, convenient and less invasive method of drug delivery," said Doug Jeffery, M.D., Ph.D., Associate Professor, Wake Forest University Baptist Medical Center. "Previous Phase II studies have demonstrated positive results for laquinimod, and we hope that results from this pivotal Phase III trial will further reinforce these findings."
Recently, Teva concluded a 36-week extension of the 36-week Phase IIb core trial, which demonstrated that laquinimod 0.6 mg met its primary endpoint. The data from this extension trial further confirmed and strengthened the results from the initial 36-week Phase IIb trial. The majority of the patients that have participated in the trial are now receiving treatment with laquinimod in a continued open-label extension trial.
"The initiation of Phase III clinical trial is a critical milestone for Teva in our commitment to the MS community," said Moshe Manor, Group Vice President - Global Innovative Resources, of Teva Pharmaceutical Industries Ltd."We are excited about the development of Laquinimod, which together with Copaxone, will broaden our MS platform and position Teva as a leading company in the MS field".
Additional new data, presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on October 13, 2007 in Prague, demonstrated that laquinimod reduced inflammation, demyelination and axonal damage in an animal model experimental autoimmune encephalomyelitis (EAE), indicating that the compound may have both anti-inflammatory and neuroprotective properties.
Based on encouraging results from various animal models, laquinimod is now being investigated for other autoimmune diseases.
"We are very pleased to see how Teva has successfully advanced the laquinimod clinical trial program in order to bring a novel, first-in-class product to the market for the treatment of MS," said Sven Andr�asson, President and CEO of Active Biotech AB.
The efficacy, safety, and tolerability of laquinimod will also be studied in an additional Phase III pivotal trial in RRMS (BRAVO), which is expected to begin enrollment in the first quarter of 2008. This trial is a multinational, multi-center, randomized, parallel-group, placebo-controlled study which will compare the effects of laquinimod to those of placebo, and provide risk-benefit data comparing once-daily orally administered laquinimod to a product presently used for treatment of RRMS (an active comparator). This study plans to enroll approximately 1,200 participants who will be followed for 24 months.
About Multiple Sclerosis
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 the 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. Demyelination is the destructive breakdown of the fatty tissue that protects nerve endings.
Allegro is a multinational, multi-center, randomized, double-blind, parallel-group, placebo-controlled study, currently enrolling approximately 1,000 patients with RRMS. The globally conducted study will include centers in the United States as well as centers throughout Canada, Europe, and Israel. To learn more about Allegro, visit www.TevaClinicalTrials.com or call 1-866-550-0614.
Laquinimod is a novel once-daily, orally administered immunomodulatory compound that is being developed as a disease-modifying treatment for RRMS. Active Biotech developed laquinimod and licensed it to Teva Pharmaceutical Industries, Ltd. in June 2004. A recent Phase IIb study in 306 patients was presented at the 2007 Annual Meeting of the American Academy of Neurology (AAN). The data demonstrated that an oral 0.6 mg dose of laquinimod, administered daily, significantly reduced magnetic resonance imaging (MRI) disease activity by 40 percent versus placebo (p=0.0048) in RRMS patients, and was well tolerated. Looking into the median data of the primary end point laquinimod 0.6mg reduces disease activity (MRI) by 55% compared to placebo. Laquinimod showed consistent and robust effect (statistical significant) on all secondary MRI end points.
In addition, the study showed a favorable trend toward reducing annual relapse rates and the number of relapse-free patients compared with placebo. Treatment with both 0.3 and 0.6 mg doses were well tolerated with only some transient and dose-dependent increases in liver enzymes reported. To date 460 MS patients have received laquinimod in various clinical trials.
Active Biotech AB
Active Biotech AB (OMX NORDIC: ACTI) 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 targeted therapy, primarily renal cancer. Further key projects in clinical development comprise the three orally administered compounds TASQ for prostate cancer, 57-57 for SLE and RhuDex® for RA. In addition, the autoimmunity project I-3D is in preclinical development. www.activebiotech.com
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 pharmaceuticals and active pharmaceutical ingredients. Over 80 percent of Teva's sales are in North America and Western Europe.
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 successfully develop and commercialize additional pharmaceutical products, the introduction of competing generic equivalents, the extent to which Teva may obtain U.S. market exclusivity for certain of its new generic products and regulatory changes that may prevent Teva from utilizing exclusivity periods, competition from brand-name companies that are under increased pressure to counter generic products, or competitors that seek to delay the introduction of generic products, the impact of consolidation of our distributors and customers, potential liability for sales of generic products prior to a final resolution of outstanding patent litigation, including that relating to the generic versions of Allegra®, Neurontin®, Lotrel®, and Famvir®, the effects of competition on our innovative products, especially Copaxone® sales, 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, our ability to achieve expected results though our innovative R&D efforts, Teva�s ability to successfully identify, consummate and integrate acquisitions, potential exposure to product liability claims to the extent not covered by insurance, dependence on the effectiveness of our patents and other protections for innovative products, significant operations worldwide that may be adversely affected by terrorism, political or economical instability or major hostilities, supply interruptions or delays that could result from the complex manufacturing of our products and our global supply chain, environmental risks, fluctuations in currency, exchange and interest rates, 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 or revise any forward-looking statement, whether as a result of new information, future events or otherwise.
Dan Suesskind, Chief Financial Officer
Teva Pharmaceutical Industries Ltd.
Corp. E. V.P. - Global pharmaceutical Markets
Chief Executive Officer
Teva Pharmaceutical Industries Ltd.
Teva North America
Liraz Kalif / Kevin Mannix,
Teva Pharmaceutical Industries Ltd.
Teva North America
Sven Andr�asson President & CEO
+46 46 19 20 49
Tomas Leanderson Chief Scientific Officer
+46 46 19 20 95
Cecilia Hofvander Manager Corporate Communication
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By Mike Nagle
06/11/2007 - UK biopharmaceutical firm Apitope has developed a vaccine that could halt multiple sclerosis in its relentless march to destroy nerve cells.
The drug, called ATX-MS-1467, has now been tested in humans for the first time - in six Secondary Progressive Multiple Sclerosis (SPMS) patients in a Phase I/IIa trial - and the results so far are encouraging. No safety issues have been unearthed and one patient also showed good clinical improvement in their symptoms.
The immune system attacks proteins it sees as dangerous and helps protect us from a myriad of pathogens. Occassionally these attacks can be devastating if it mistakenly sees proteins in our own body as dangerous and sets about destroying them. This autoimmune reaction leads to numerous diseases, such as Type I diabetes.
In the case of MS, the immune system wipes out the myelin sheath around nerve cells - an insulating layer that allows the cells to effectively conduct electrical signals. This causes the nerves to die and the symptoms of MS to appear, including visual problems, weakness, difficulties with balance and speech, severe fatigue, pain, impaired mobility and often disability.
According to the MS International Federation, around 2.5 million people suffer from the incurable, progressive disease.
Current therapies aim to reduce the inflammation around the nerve cells to offset further damage or, alternatively, to suppress the immune system. However, these broad approaches also suffer from significant side-effects such as an increased susceptibility to infections and a greater risk of cancer.
Apitope has taken a different approach with their peptide based vaccine that seeks to retune the immune system so it no longer overreacts to proteins in the myelin sheath. One of these proteins in called myelin basic protein (MBP). This protein is chopped up inside a cell into different peptide strips. Some of these strips or epitopes then bind to a protein called major histocompatability complex (MHC) class II and are carried to the surface of the cell where they are presented to the immune system.
Dr Keith Martin, CEO of Apitope, explained to DrugResearcher.com that if certain danger signals are present, then the MBP peptide epitopes can 'switch on' T cells and cause an inflammatory response that damages the myelin.
However, and this is where the Apitope vaccine comes in, if the epitope is presented to the immune system in the absence of these danger signals, a different subset of T cells are switched on (called regulatory T cells) and instead of causing damage, these can suppress the immune system reaction to the epitope in question and thus make it more 'tolerant' to myelin. They do this through producing interleukin-10 (IL-10), an anti-inflammatory cytokine.
One key part of this is to ensure the vaccine is only injected at sites where there are no danger signals. So, the clinicians doing the trial inject the drug in the periphery of the body and the regulatory T cells produced can then travel to the central nervous system (CNS) and begin to retune the immune system there.
One problem remained however. Not all fragments of MBP are capable of causing the immune system to become tolerant to the protein. For example, the MBP peptide made up of amino acids 89 to 101 can induce an immune response both in terms of priming for T cell reactivity and inducing autoimmune encephalomyelitis (EAE) - the commonly used animal model for MS.
However, the same peptide does not induce tolerance. So which peptides do and which don't? After much research, David Wraith, a Professor of Experimental Pathology at the University of Bristol, found the answer. He discovered that only peptide fragments that are the right size and shape to be presented to the immune system without further processing can go on to induce tolerance. The discovery led to the spin out of the company and also gave it its name and the name of this class of potential drug - Antigen Processing Independent epiTOPES or Apitopes. Prof. Wraith became the chief scientific officer at Apitope.
First, the team use bioinformatics to design peptides that will bind to MHC strongly and, crucially, ones that can also adopt the right shape to bind.
"If the peptide isn't the right shape, then it won't trigger a response," said Martin. "If they are in the right conformation, they won't require processing [and therefore will induce immune system tolerance]."
He added that in the case of MS, Apitope identified five different peptide epitopes that looked like they would work and then proceeded to test them in a number of in vitro assays. After that process, four remained and these are what make up ATX-MS-1467. The advantage to having four is that there are different subtypes of MHC class II molecules and these four can bind to different ones, such that the "vast majority" of MS patients will be theoretically responsive to the drug.
The initial signs are that the vaccine is effective. Given that the myelin sheath also contains other proteins that are thought to induce the immune system to attack, such as myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP), this is perhaps surprising at first. So how does a vaccine based only on MBP peptides also prevent these other proteins from sending the immune system into overdrive? The answer is 'bystander suppression'. The epitopes for a given protein antigen (in this case MBP) can also induce tolerance to other epitopes from the same antigen, and even epitopes from other antigens, such as MOG and PLP.
"Essentially, the activity of the mixture is greater than the sum of its parts," explained Martin.
Indeed, one patient on the trial has shown "remarkable improvement in her eyesight", explained Prof. Wraith.
"Since the optic nerve is acutely sensitive to inflammation and optic neuritis is often one of the first symptoms of MS, this early indication of efficacy is very encouraging. It suggests that treatment with ATX-MS-1467 can suppress the inflammation associated with MS," he continued.
The next step is to continue to monitor the six patients who have completed dosing in the Phase I/IIa trial so that a three month safety follow-up can be conducted. If the drug gets the all clear, Apitope will then continue with a Phase IIb proof-of-concept trial. If that proves successful, the firm will then look to partner the programme with a larger pharma company, although Martin said the company would be willing to partner earlier if the opportunity arose.
Way before this drug makes it anywhere near the market though, Apitope hope to begin generating revenues thanks to a MS diagnostic test they have developed.
Martin said that early diagnosis in MS is crucial as treatments that seek to slow down or halt the progression of the disease are obviously best given before the disease has had the chance to do too much damage. Even with existing treatments, there is evidence to suggest patients would have much better outcomes if they were diagnosed earlier he said.
Unfortunately, the current process of diagnosing the disease can take a while, leaving patients untreated while the disease damages their nerves. Apitope have developed a blood test that can diagnose the disease much more quickly. The test is still undergoing regulatory tests but Martin said that Apitope hopes it will be available to doctors by the end of 2009. The same test also has the potential to be extended as a tool for other autoimmune diseases such as rheumatoid arthritis and lupus.
Apitope's approach is also applicable to other immune hypersensitivity reactions and the firm has a programme to identify apitopes to prevent Factor VIII inhibitor formation, which can cause haemophilia. Martin said that he is confident the company will gain orphan drug status for this programme from the US Food and Drug Administration (FDA), although they haven't applied for it yet. This is important as the faster regulatory process for orphan drugs means that, if necessary, Apitope could bring that drug to market without a partner.
Scientists at Apitope are also conducting preclinical tests on Type I diabetes and allergy peptides.
The MS project remains the most advanced however, and it is this research that will make or break Apitope's approach to peptide induced tolerance. A great number of people with autoimmune diseases will be waiting with baited breath.
Monday, November 05, 2007
Author: Will Boggs, MD
Date: Wed, 31 October 2007
Magnetization transfer imaging (MTI) predicts deterioration in patients with primary progressive multiple sclerosis (PPMS), according to a report in the October issue of the Journal of Neurology, Neurosurgery, and Psychiatry.
"Abnormalities in PPMS are diffuse and occur early in the condition," Dr. Alan J. Thompson from the Institute of Neurology, London, UK told Reuters Health.
Dr. Thompson and associates investigated whether the magnetization transfer ratio (MTR), which reflects axonal loss, could predict clinical changes over one year in 31 patients diagnosed with definite or probable PPMS.
Lower MTR at baseline predicted progression of clinical symptoms, as shown by greater increases in Expanded Disability Status Scale (EDSS) and greater decreases in Multiple Sclerosis Functional Composite score (MSFC) over the course of one year, the investigators report.
Lesion MTR was least significantly decreased, followed by normal appearing white matter MTR, and the latter significantly predicted EDSS change. Whole brain MTR was the most complete predictor of the MSFC change.
Predictions of clinical progression persisted after adjustment for intrasegmental volume, the investigators say, "demonstrating that the predictive value of MT imaging is independent of atrophy effects on MTR."
"We have followed this cohort for three years and are about to submit that data for publication; they reinforce these findings," Dr. Thompson added. "We will then go on to a five-year analysis, which will also include cognitive assessment, as MTI of gray matter appears to be particularly susceptible to change."
While MTI is unlikely to have a role in the initial diagnosis of MS, Dr. Thompson noted, it "may be helpful in detecting subtle change which may provide evidence towards establishing early diagnosis."
A common acne medication that has been available for over 30 years has the potential to delay the progress of multiple sclerosis and if proven effective, will offer an inexpensive option for the treatment of early MS, says the MS Society of Canada.
Clinical researchers in Calgary and 13 other Canadian centres will be taking an in-depth look at an oral therapy known as minocycline after initial studies have shown promising results. A new $4 million multi-centre clinical trial involving 200 participants from across Canada is being funded through the MS Society's related MS Scientific Research Foundation.
"The benefits of minocycline are straight forward: it's relatively cheap, has few side effects and can be taken in pill format," says Dr. Luanne Metz, principal investigator for the study and a professor of clinical neurosciences at the University of Calgary Faculty of Medicine. "The aim of our research is to see if this common drug can reduce the occurrence of further disease activity in people who have experienced an initial attack of MS symptoms and who are at high risk of progressing to definite MS. Without treatment, two thirds of people facing this circumstance are expected to be diagnosed with MS within 6 months. We believe minocycline can reduce this number. "
In MS, myelin, which is the protective coating of the nerve fibres of the brain and spinal cord, becomes inflamed. This inflammation can be seen as characteristic lesions by magnetic resonance imaging (MRI). Previous clinical tests of minocycline have shown an 84 per cent reduction of MS lesion activity on MRI.
"There is obvious benefit in delaying the rate of disease progression in MS, from improved quality of life to reduced healthcare expenses," says Dr. William McIlroy, national medical advisor for the MS Society of Canada. "The breadth of the study, the reputation of the researchers involved and the early clinical data supports the view that there is considerable promise for minocycline. We would not be involved if this were not the case."
Minocycline works by inhibiting the activities of an enzyme and immune cells that are keys to initiating MS attacks. It has been used in acne treatment for its anti-bacterial effects but studies have shown its anti-inflammatory properties could be important factors in slowing down MS. These insights were discovered through pioneering research funded by the MS Society of Canada and led by Dr. V. Wee Yong at the University of Calgary (U of C). Drs. Metz and Yong lead the MS program at the Hotchkiss Brain Institute at U of C where many of the early studies on minocycline took place.
In comparing minocycline to current therapies, the cost savings would be substantial. In generic form, minocycline is available for as low as $800 per year. Current MS therapies can cost between $18,000 and $40,000 per year. Researchers note that minocycline would not necessarily replace current therapies, but might delay the timeframe in which they would be required.
The study will be randomized and double-blind by design. Investigators will compare 100 mg of oral minocycline twice daily to placebo over a period of two years.
Enrolment will begin in early 2008 and 14 MS clinics are involved including institutions in Calgary, Vancouver, Burnaby, Edmonton, Red Deer, Saskatoon, London, Toronto, Kingston, Ottawa, Montreal, Quebec City, Sherbrooke and Halifax.
About the MS Society of Canada
Founded in 1948, the MS Society has a membership of 28,000, with seven regional divisions and nearly 120 chapters. The MS Society provides services for people with MS, family members and caregivers. The MS Society also offers a unique support network for children and teenagers with MS and their parents. The MS Society raises funds to support research and services almost entirely through individual and corporate donations and fundraising events across the country. The MS Society is the single largest funder of MS research in Canada.
By Eva von Schaper
Oct. 29 (Bloomberg) -- Bayer AG, Germany's largest drugmaker, will take a 152 million-euro ($219 million) charge after dropping plans to market a higher dose of its Betaferon multiple sclerosis treatment.
A study found the 500-microgram dose wasn't more effective at preventing patients' relapses than the 250-microgram form or Teva Pharmaceutical Industries Ltd.'s Copaxone, Leverkusen, Germany-based Bayer said in an e-mailed statement today.
Betaferon is one of the products Bayer needs for growth as it waits for income from newer medicines such as the cancer treatment Nexavar. Bayer gained Betaferon, also sold as Betaseron, in its 17 billion-euro purchase of German rival Schering AG.
``The standard Betaferon 250-microgram dose is the optimal Betaferon dose,'' Douglas Goodin, a professor of neurology at the University of California, San Francisco, said in the statement.
Bayer today said it expects revenue from Betaferon, which had first-half sales of 500 million euros, to rise between 7 and 9 percent this year and next. Bayer said it won't ask regulators to allow the higher dose version of the drug to go on sale.
The third-quarter charge will cover the writedown of assets from the study, dubbed BEYOND, as part of the Schering purchase, Bayer said.
Bayer shares fell 49 cents, or 0.8 percent, to 57.79 euros in Frankfurt. They've risen 42 percent this year.
To contact the reporter on this story: Eva von Schaper in Munich at firstname.lastname@example.org .
Last Updated: October 29, 2007 12:44 EDT