Monday, December 31, 2007
Lilly to Acquire Exclusive Rights to Novel Late-Stage Molecule for the Treatment of Multiple Sclerosis
INDIANAPOLIS, IN and EDMONTON, ALBERTA – Eli Lilly and Company (NYSE:LLY) and BioMS Medical Corp. (TSX:MS) today announced that the two companies have entered into a licensing and development agreement granting Lilly exclusive worldwide rights to BioMS Medical's lead multiple sclerosis (MS) compound, MBP8298. The compound is currently being evaluated in two pivotal phase III clinical trials in secondary progressive MS (SPMS) and one phase II clinical trial in relapsing-remitting MS (RRMS).
Under the terms of the agreement, Lilly and BioMS Medical will collaborate on the development of MBP8298 and will also share in certain development costs with Lilly being responsible for future R&D, manufacturing and marketing activities. BioMS Medical will receive an upfront payment of $87 million, as well as potential development and sales milestones up to $410 million and escalating royalties on sales commensurate with the current stage of development of the product if MBP8298 is successfully commercialized. BioMS Medical will continue to oversee the current clinical trials. Other terms of the deal were not disclosed.
"Lilly is pleased to add yet another promising late-stage compound to our portfolio,” said Dr. William W. Chin, M.D., vice president of discovery research and clinical investigation for Lilly. "Multiple sclerosis is a disease with significant unmet patient needs. MBP8298 has shown potential in slowing the progression of secondary progressive MS, and thus may provide an effective therapeutic option for patients with this debilitating disease. We are also hopeful that MBP8298 may prove beneficial in treating patients with relapsing remitting MS. We intend to fully leverage our expertise in neuroscience to continue the development of this novel molecule."
“We are very pleased to collaborate with Lilly on the worldwide development of MBP8298,” said Kevin Giese, President and CEO at BioMS Medical. “Lilly’s well established leadership in the neurology arena and considerable resources, expertise and proven ability to launch first-in-class drugs will help MBP8298 to realize its full development and commercial potential.”
The transaction is expected to become effective in the first quarter of 2008, contingent upon clearance under the Hart-Scott-Rodino Anti-Trust Improvements Act, if required. At closing, Lilly would expect a charge to earnings for acquired in-process research and development. The exact amount of the charge has not yet been determined, but is estimated to be $0.05 per share. Lilly's 2008 pro forma adjusted earnings per share guidance remains unchanged at $3.85 to $4.00. On a reported basis, including the charge for this transaction with BioMS Medical, Lilly now expects its 2008 earnings per share to be in the range of $3.80 to $3.95.
MBP8298 is a synthetic peptide that consists of 17 amino acids having a sequence identical to that of a portion of human myelin basic protein (MBP). MBP8298 is being developed for the potential treatment of multiple sclerosis (MS), an autoimmune disease caused by immune attack against normal components of the central nervous system. The sequence of MBP8298 is associated with the autoimmune process in MS patients with certain immune response genes (HLA types DR2 and/or DR4); MS patients having these genes represent 65 to 75 percent of all MS patients.
The apparent mechanism of action of MBP8298 is the induction or restoration of immunological tolerance with respect to ongoing immune attack as a result of high doses of peptide delivered periodically by the intravenous route. The potential benefit of MBP8298 for any individual patient is therefore expected to be related to the role this peptide plays in that patient’s immune system. The degree of immunomodulation achieved will depend on the relationship among the peptide, HLA molecules and T cells.
The results of phase II and long-term follow-up treatment of MS patients with MBP8298, published in 2006 in the European Journal of Neurology (EJN), showed that MBP8298 safely delayed median time to disease progression for five years (versus placebo) in progressive MS patients with HLA types DR2 and/or DR4. Thus, MBP8298 has the potential to be used as a tailored therapy for patients genetically determined to express the appropriate HLA molecules.
MBP8298 is being developed in three late-stage clinical trials:
MAESTRO-01: A pivotal phase II/III trial for secondary progressive MS (SPMS) patients in Canada and Europe.
MAESTRO-03: A pivotal phase III trial for SPMS patients in the United States.
MINDSET-01: A phase II trial for relapsing-remitting MS (RRMS) patients in Europe.
About Multiple Sclerosis
Multiple sclerosis (MS) is thought to affect as many as 2.5 million people worldwide, including approximately 75,000 in Canada, 400,000 in the United States and more than 500,000 in Europe. It is a disease that affects more women than men, with onset typically occurring between 20 and 50 years of age. MS is caused by damage to myelin, the protective sheath surrounding nerve fibers in the central nervous system, which interferes with messages from the brain to the body. Symptoms of MS may include vision problems, loss of balance, numbness, difficulty walking and paralysis. Approximately 40 percent of all MS patients have the secondary progressive form of the disease.
BioMS Medical Conference Call
BioMS Medical management will host a conference call at 8:30 a.m. (EST) on Tuesday December 18, 2007 to discuss the global licensing and development agreement with Lilly. Participants may listen via an audio web cast, accessible through the Company’s website at www.biomsmedical.com or via telephone. The telephone conference number is 416-644-3420 or toll-free at 1-800-731-6941.
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers – through medicines and information – for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.
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 being evaluated in two pivotal phase III clinical trials for secondary progressive MS patients, MAESTRO-01 in Canada and Europe and MAESTRO-03 in the United States . It additionally is being evaluated for relapsing remitting MS patients in a Phase II trial in Europe entitled MINDSET-01. For further information please visit our website at www.biomsmedical.com .
VP Corporate Communications
firstname.lastname@example.org Tony Hesby
Executive VP Corporate Affairs
email@example.com Amanda Stadel
Investor Relations Manager
For decades, Congress, the United States Supreme Court, and the Social Security Administration have recognized that the informality of SSA’s process is a critical aspect of the program. Creating unreasonable procedural barriers to eligibility is inconsistent with Congress’ intent to keep the process informal and non-adversarial, and with the intent of the program itself, which is to correctly determine eligibility for claimants, awarding benefits if a person meets the statutory requirements.
On October 29, 2007, the Social Security Administration (SSA) published proposed regulations that make significant changes to the SSA appeals process, including hearings before administrative law judges (ALJs). Comments must be submitted on or before December 28, 2007 to the Commissioner of Social Security, P.O. Box 17703, Baltimore MD 21203.
While there are some notable potential improvements to the process, for example, a 75-day hearing notice and retaining the claimant’s right to administrative review of an unfavorable ALJ decision, we also have serious concerns, from a claimant’s perspective, that many changes and new requirements are unfair and limit the rights of people with disabilities.
While it is appropriate to deny a claim because the evidence establishes that the individual does not meet the statutory definition of disability, it is wrong to deny benefits to an otherwise eligible, disabled individual who falls between procedural “cracks” or who is unable to submit relevant evidence because of procedural limitations.
For people with disabilities, it is important that SSA improve its process for making disability determinations. We strongly support efforts to reduce unnecessary delays for claimants and to make the process more efficient, so long as the steps proposed do not affect the fairness of the process to determine a claimant’s entitlement to benefits. Any changes to the process must be measured against the extent to which they ensure fairness and protect the rights of people with disabilities.
The most significant proposed change would close the record to new evidence in two ways by:
* Restricting the submission of evidence at the ALJ and Review Board (the replacement for the Appeals Council) regardless of its relevance to proving a claimant’s disability; and
* Limiting the scope of review and ability to submit new evidence after a federal court or Review Board remands a case because of legal errors. To exacerbate the adverse effect of these changes, claimants would be advised to file new applications, potentially with detrimental consequences, and restricted in their ability to reopen prior claims.
Is there reason to believe that the real purpose of the changes is to reduce allowances? The proposed rule assumes that fewer claims would be allowed, with a more than $1.5 billion reduction in benefit payments over the next ten years. From our perspective as advocates for claimants with disabilities, this is not acceptable.
1. The record essentially closes five days before the hearing with limited exceptions. All new evidence would need to be filed five business days before the ALJ hearing date. Evidence submitted after that date is considered “late.” The ALJ would have the discretion to ignore any evidence submitted within five days of the hearing or later, regardless of its relevance or importance, or that it was beyond the claimant’s control to obtain the evidence. Why is restricting the submission of evidence unfair to people with disabilities?
* We believe that these proposed restrictions violate a claimant’s right under the Social Security Act (the Act). The Act guarantees the right to a hearing with a decision based on evidence “adduced at the hearing.” The proposed changes eliminate the ALJ’s duty to fully and fairly develop the record. This duty is especially heightened for unrepresented claimants.
* The proposed changes will force individuals to file court cases just to have SSA consider evidence that was improperly rejected earlier in the process. The NPRM changes are more restrictive than the Act, which allows a federal court to send a case back to SSA where there was a good reason why new and material evidence was not submitted earlier.
* The proposed changes are inconsistent with the realities of claimants obtaining representation. Many individuals seek and obtain representation shortly before or even after the ALJ hearing date, since the hearing is the first in-person contact with a disability adjudicator. Under the NPRM, an ALJ would be able to exclude relevant evidence in this situation.
* The proposed changes are inconsistent with the realities of obtaining medical evidence. We strongly support early submission of evidence but there are many legitimate reasons why it is not provided earlier. The 75-day hearing notice will be a great help but there is no requirement that medical providers turn over records during that time period. Also, there are cost or access restrictions, such as HIPAA requirements, that prevent the ability to obtain evidence in a timely way.
* The proposed changes are inconsistent with the realities of claimants’ medical conditions. Medical conditions are not static. They may worsen over time and/or diagnoses may change. Some conditions, e.g., multiple sclerosis, autoimmune disorders, or certain mental impairments, may take longer to diagnose definitively. The severity of the impairment may change, e.g., a seemingly minor cardiac impairment results in a heart attack. It may take more time to fully understand and document the combined effects of multiple impairments. Some claimants may be unable to accurately describe their impairments or limitations either because they are in denial, lack judgment, do not understand their disability, or the impairment by definition makes this a difficult task. The purpose of the disability determination process is to determine whether the claimant is eligible for benefits to which he or she is statutorily entitled. Excluding evidence that is relevant to the determination is inconsistent with the purpose of the process.
2. Individuals who appeal erroneous ALJ decisions will be limited in new evidence they can submit in a “remand” hearing.
* We support the proposed change that restores the claimant’s right to seek administrative review of an unfavorable ALJ decision. But that right is severely curtailed by new and significant limits on review by the Review Board (RB) or the federal courts. If the RB or court finds that the ALJ decision was wrong and remands the case for a new ALJ hearing, the NPRM limits the remand hearing to consideration of the claimant’s condition on or before the date of the original ALJ decision. This means that even if the original impairment(s) worsened during the appeal, which could be months or years, the individual could not submit new evidence of this change.
* Claimants with disabilities will be disadvantaged by this change. The NPRM states that this change “will not unduly disadvantage claimants” but our position is that it most certainly will. SSA says that a claimant can file a new application if his or her condition worsens during the time between the ALJ’s first decision and the remand proceedings. However, a new application, in many cases, is a poor and even disadvantageous substitute for the appeal. For all claimants, benefits could be lost from the effective date of the first application. Title II claimants would be particularly harmed because they would need to complete a five-month waiting period for cash benefits and Medicare benefits could be delayed because of the 24-month Medicare waiting period and many Title II workers could be permanently foreclosed from eligibility for benefits if their insured status had expired.
* The proposed change can be interpreted as establishing time-limited benefits. The language of the proposed regulation is ambiguous and can be interpreted to mean that, in a remand proceeding, the individual could only be found eligible for a time-limited period ending no later than the date of the first ALJ decision. Under this interpretation, because they would not be found to be disabled on an ongoing basis, claimants with disabilities would: (1) not be protected by use of the medical improvement standard; (2) would lose their automatic access to Medicaid and Medicare; (3) would lose access to most SSI and Title II work incentives. This interpretation must be rejected by SSA because of the serious repercussions.
* The proposed change is inconsistent with the Act and limits the ability of the federal courts to remedy legal errors. Currently, if a case is appealed to court and is remanded back to SSA, the court reverses and vacates the first ALJ decision. Since there is no longer a final decision by SSA, the claim remains “open” on remand. The proposed change would limit the ALJ’s ability on remand to consider new and material evidence, even if the court orders SSA to consider such new evidence. SSA cannot limit the court’s authority on appeal to remedy errors in the first ALJ decision.
3. Forcing Individuals with Disabilities to File Multiple Applications Is Neither Fair Nor Efficient. By closing the record to new evidence and limiting the period that can be considered to determine eligibility, claimants would unnecessarily be forced to file multiple applications. A claimant will be required to file a new application for consideration of any change in disability after the date of the original ALJ decision, even if the change is related to the impairments considered in the prior application. This is an onerous burden to place on claimants. Why would the agency force an individual to file additional applications when the claim for disability could be resolved by making the decision based on a complete record?
* We are concerned that the impetus for these changes is a reduction in allowances since the NPRM makes clear that closing the record is intended to result in a $1.5 billion reduction in benefit payments over the next ten years. Does this mean that SSA assumes that claimants will be confused and discouraged and will not file new applications? Do the “savings” include those claimants who file new applications and lose benefits from the effective date of the first application or are permanently foreclosed from eligibility? If so, this is a particularly inappropriate and harmful change.
* Claimants may jeopardize eligibility by reapplying. Requiring claimants to file new applications simply to submit new evidence relevant to their impairments may severely jeopardize, if not foreclose, eligibility for benefits. Benefits could be lost from the effective date of the first application, which in Title II cases can be as much as 12 months before the application date. Workers who are eligible for Title II disability benefits are particularly harmed. Cash benefits could be delayed because of the Title II 5-month waiting period and Medicare benefits could be delayed because of the 24-month Medicare waiting period.
* Eligibility may be foreclosed forever because of the Title II recency of work test. Under this test, to be eligible for disability insurance benefits, the worker must have worked 20 of the last 40 quarters to be insured. This means that onset of disability must occur during the insured status period, which usually ends 5 years (20 quarters) after work stops. If the worker’s insured status expired before the first ALJ’s decision, the worker may never be eligible when a new application is filed. The following example describes the dilemma faced by individuals under the proposed change.
Example: The claimant files for Title II benefits in January 2007, based on a heart condition. The claimant’s insured status expires December 31, 2007. The first ALJ decision is issued in January 2008, finding that the claimant was not disabled before her insured status expired. One month later, the claimant has a serious heart attack. After recuperating for several months, she files a new application. The new application will be denied because there is a final decision – the ALJ decision – that she was not “disabled” prior to December 31, 2007.
* Under current procedures, if the claimant appeals to federal court and asks for a remand based on new and material evidence that was not available earlier, the court has the authority to remand the case to have SSA consider the new evidence. On remand, the ALJ is able to find that the later evidence shows that her original impairment was more serious and that she in fact was disabled before her insured status expired. Under the NPRM, the ALJ would be precluded from considering the new evidence and, if a new application is filed, it likely would be denied
* Urging claimants to reapply is inconsistent with Congressional intent. Previously, SSA notices misled claimants regarding the consequences of reapplying instead of appealing. A 1990 law requires SSA to include clear and specific language in notices describing the adverse consequences of reapplying. More than 15 years after Congress acted on this problem, it is troubling that the concept of reapplication is still imbedded in SSA’s thinking and used as a justification for preventing the consideration of all evidence relevant to the claim.
* Requiring new applications is administratively inefficient and will increase SSA’s workload. The proposed change is administratively inefficient because it would require SSA to handle even more applications at a time when it otherwise expects an increase in filings and would cause further congestion in the front end of the process. Many individuals, who are unable to avail themselves of the online application process, will require the personal involvement of SSA claims representatives. This is particularly problematic at a time when the agency is faced with its lowest staffing level in more than 30 years.
4. Individuals would be limited in their ability to reopen prior applications. Exacerbating the problems with restrictions on submitting evidence and limits on the period during which eligibility can be determined, the NPRM severely limits the claimant’s right to reopen prior applications. Reopening a prior application can be very important for people with disabilities who clearly meet the disability standard but were unable to adequately articulate their claim in the first application, were unable to obtain critical evidence, or have an impairment that is difficult to diagnose, such as multiple sclerosis or certain mental impairments.
Reopening situations currently do not arise frequently, but when they do, they usually have compelling fact patterns involving claimants who did not understand the importance of appealing an unfavorable decision, often claimants with mental impairments who repeatedly file new applications instead of appealing. When they finally obtain representation on a subsequent claim, new and material evidence is submitted that may establish disability as of the earlier application. Reopening is discretionary and cannot be required, but it can be used to right obvious wrongs.
This proposed change eliminates ALJ discretion to reopen an earlier decision where new and material evidence shows that the claimant was disabled at an earlier time. Under the NPRM, to assure that claimants cannot “circumvent” the strict new limits for submitting evidence after the record is closed, the NPRM eliminates “new and material evidence” as a basis for reopening a decision by the ALJ or the Review Board. This is unfair for claimants in a number of situations, such as: claimants who are not able to get a proper diagnosis for a considerable period of time (multiple sclerosis, for example); claimants who were unrepresented and whose cases were poorly developed; claimants with mental impairments that prevent or inhibit their ability to cooperate with development of claims; cases where physicians refuse to provide medical records until unpaid bills are paid; and bankrupt hospitals who are unable to provide records. The proposal also could result in a total loss of eligibility if Title II disability insured status previously expired.
5. Other Proposed Changes Make the Process Too Formal and Unfair to Individuals. There are many other proposed changes, including new time limits, which make the process overly complicated and legalistic. These changes may well become procedural traps for claimants, especially those who are unrepresented.
New time limits. Additional new time limits, beyond normal appeal deadlines, would be established with no “good cause” extension including: (1) Objecting to the time or place of the hearing (30 days after receiving the hearing notice); (2) Objecting to the issues in the hearing notice (5 business days before the hearing); (3) Requesting subpoenas for missing records (20 days before the hearing); and (4) Filing brief to Review Board (with appeal or within 10 days of filing).
1. Possible limits on issues before the ALJ. There is a new requirement that the appeal to the ALJ must include a statement that lists the “medically determinable impairments” preventing work. Does this limit the impairments considered by the ALJ or will some ALJs use this requirement to limit impairments that can be considered? Claimants should not be limited only to those impairments listed on their appeal request. The claimant also must object to issues in the hearing notice within 5 business days of the hearing, with no extension. The current process is flexible and allows raising objections “at the earliest possible opportunity.” What happens if the claimant obtains legal representation within 5 days of the hearing? Is the representative precluded from raising issues? This is inconsistent with due process.
2. Rescheduling hearings for “good cause.” The NPRM deletes the criteria in current regulations for circumstances when the ALJ will change the time and/or place of the hearing and when the ALJ has the discretion to change the time and/or place. The current “good cause” factors for have been severely curtailed, placing nearly total discretion in the ALJ. Without these criteria, will more hearings be dismissed inappropriately because the claimant is unable to attend?
3. Inability to object to telephone hearings. The claimant will be informed in the notice if the hearing is to be held in person, by video teleconference or by telephone. For the first time, the ALJ is authorized to direct the claimant to appear by telephone “under certain extraordinary circumstances.” There is no provision in the proposed rule to object to a hearing scheduled to be held by telephone. An ALJ could determine that “extraordinary circumstances” exist and hold a hearing by telephone without allowing the claimant an opportunity to object. Claimants should be given the right to object.
4. Dismissal of appeal for failure to appear at a prehearing or posthearing conference. If neither the claimant nor the representative appears at a prehearing or posthearing conference, the ALJ would have the discretion to dismiss the appeal. Like current process, this is an extreme penalty that should be reserved only if both the claimant and representative miss the actual ALJ hearing without good cause. Dismissal on this basis should not be left to the ALJ’s discretion.
5. The contents of the appeal to the Review Board (RB). The appeal to the RB must be in writing and the NPRM lists what “should” be included: a written statement that identifies the ALJ’s errors, explains why it should be reversed or modified, and cites applicable law and specific facts in the record. These requirements are very formal and legalistic, and assume that the claimant is represented by an experienced legal representative. We are concerned that the failure to raise issues in the appeal statement will be deemed a waiver of the right to have them considered by the RB or that the RB will give less consideration to appeals that do not include a statement meeting these requirements.
6. Payment required for a copy of the record. Claimants would be penalized for appealing to the RB by a new requirement to pay for requested copies of the record or the hearing recording, unless there is a “good reason” not to pay. This change may violate the Privacy Act which grants an individual the right of access to his or her own records. The current procedure should be retained which provides that the Appeals Council will not charge for a duplicate hearing recording or a copy of the claims file.
7. Submitting evidence to the Review Board. In addition to the strict limits for submitting new evidence to the RB, the NPRM requires that the claimant “must submit” a statement with the additional evidence explaining why he or she believes the strict criteria are met. Will this turn into a trap for unrepresented claimants? Will the RB refuse to consider the additional evidence if such a statement is not submitted? In addition, while the claimant must meet strict limits for submitting new evidence under the NPRM, the RB is free to obtain new evidence either by remanding the case to the ALJ or by obtaining it on its own if it can be done “more quickly” and would not “adversely affect” the claimant’s rights. There is no further explanation and there is no requirement that the RB proffer the new evidence to the claimant before issuing a decision.
About the Author: Nancy Schorr is the Executive Director of NOSSCR, the National Organization of Social Security Claimants Representation, an organization committed to providing the highest quality of representation and advocacy on behalf of people seeking Social Security Disability and Supplemental Security Income.
COPENHAGEN, Denmark, Dec. 13, 2007 – Genmab A/S (OMX: GEN) announced today details of a planned Phase II study of ofatumumab (HuMax-CD20) for the treatment of relapsing remitting multiple sclerosis (RRMS). Approximately 324 patients will be enrolled in the study which will be conducted under Genmab’s collaboration with GlaxoSmithKline (GSK). The study is expected to begin in the first quarter of 2008.
Ofatumumab is an investigational, fully human, next generation monoclonal antibody that targets a unique epitope of the CD20 receptor on the surface of B-cells. Other anti-CD20 antibodies currently available or in development bind to a different epitope on the CD20 receptor. Ofatumumab is being developed under a co-development and commercialization agreement between Genmab and GlaxoSmithKline.
“Multiple sclerosis is a debilitating disease for which there are currently few treatments,” said Lisa N. Drakeman, Ph.D., Chief Executive Officer of Genmab. “We hope our fully human antibody, ofatumumab, may offer another potential treatment option for patients suffering from this incapacitating disease.”
About the trial
The double blind randomized trial will consist of two parts. Part A will include approximately 36 patients in one of three increasing dose cohorts (100 mg, 300 mg or 700 mg of ofatumumab) randomized to receive ofatumumab or placebo. An independent data monitoring committee (IDMC) will evaluate the safety of each sequential cohort prior to progression to the next cohort. When all patients in Part A have had their week 4 MRI scan, the IDMC will evaluate the data before Part B of the study begins.
Part B will consist of a 48 week treatment period of approximately 288 patients. Patients will be randomized to treatment with 100 mg, 300 mg, or 700 mg of ofatumumab or placebo. After week 24, patients on an active dose will receive re-treatment with the same dose of ofatumumab or placebo. Patients on placebo will receive ofatumumab at the highest tolerated dose from Part A.
The objective of the study is to determine the safety and tolerability of three doses of ofatumumab and the dose response of ofatumumab on disease activity on MRI in patients with RRMS. The primary endpoints are safety and cumulative number of new Gd-enhanced lesions from week 8 to week 24.
About Relapsing Remitting Multiple Sclerosis
Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system. MS is twice as common in females as in males, occurs with a peak incidence at the age of 35 years and incidence varies widely in different populations and ethnic groups. The etiology of MS remains unknown, but the geographic variation points towards possible environmental and genetic factors. The most common form of MS is relapsing remitting MS characterized by unpredictable recurrent attacks where the symptoms usually evolve over days and are followed by either complete, partial or no neurological recovery. No progression of neurological impairment is experienced between attacks.
Tuesday, December 11, 2007
BioMS Medical's phase III U.S. multiple sclerosis trial receives positive safety review from Data Safety Monitoring Board
EDMONTON, Dec. 11 /CNW/ - BioMS Medical Corp. (TSX: MS), a leading developer in the treatment of multiple sclerosis (MS), today announced that the independent Data Safety Monitoring Board (DSMB) has reviewed data from the Company's on-going MAESTRO-03 U.S. pivotal phase III clinical trial of MBP8298 for the treatment of secondary progressive MS and recommended that the trial continue.
This was the first of several regularly scheduled reviews by the DSMB that will occur over the duration of the trial. The purpose of the DSMB is to provide objective, independent safety monitoring of the trial.
The MAESTRO-03 U.S. pivotal phase III clinical trial is a randomized, double-blind study enrolling approximately 510 patients at more than 60 clinical sites 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 (up to 75% of all MS patients are HLA-DR2 and/or HLA-DR4 positive).
Recently the Company announced that more than 133 patients have been enrolled in its MAESTRO-03 trial. An interim safety and efficacy analysis will be performed on data from the first 133 patients enrolled when they have completed 24 months of the clinical trial.
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 being evaluated in two pivotal phase III clinical trials for secondary progressive MS patients, MAESTRO-01 in Canada and Europe and MAESTRO-03 in the United States. It additionally is being evaluated for relapsing remitting MS patients in a Phase II trial in Europe entitled MINDSET-01. For further information please visit our website at www.biomsmedical.com.
This press release may contain forward-looking statements, which reflect the Company's current expectation regarding future events. These forward-looking statements involve risks and uncertainties that may cause actual results, events or developments to be materially different from any future results, events or developments expressed or implied by such
forward-looking statements. Such factors include, but are not limited to, changing market conditions, the successful and timely completion of clinical studies, the establishment of corporate alliances, the impact of competitive products and pricing, new product development, uncertainties related to the regulatory approval process and other risks detailed from time to time in the Company's ongoing quarterly and annual reporting. Certain of the assumptions made in preparing forward-looking statements include but are not limited to the following: that MBP8298 will continue to demonstrate a satisfactory safety
profile in ongoing and future clinical trials; and that BioMS Medical Corp. will complete the respective clinical trials within the timelines communicated in this release. We undertake no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
For further information: Tony Hesby, Ryan Giese, Corporate
Communications, BioMS Medical Corp., (780) 413-7152, (780) 408-3040 Fax, E-mail: firstname.lastname@example.org, Internet: www.biomsmedical.com; James Smith, Investor Relations, (416) 815-0700 ext. 229, (416) 815-0080 Fax, E-mail: email@example.com
ALISO VIEJO, Calif., December 10, 2007 - AVANIR Pharmaceuticals (NASDAQ:AVNR) today announced that it has initiated enrollment of patients in the STAR (Safety, Tolerability and Efficacy Results of AVP-923 in PBA) trial, a confirmatory Phase III trial of Zenvia™ (dextromethorphan/quinidine [DM/Q]) in patients with pseudobulbar affect (PBA). The randomized, multi-center, international STAR trial will compare active treatment with Zenvia 30/10 mg (DM/Q) and Zenvia 20/10 mg (DM/Q) to placebo during a three-month, double-blinded phase, followed by a three-month, open-label extension study. The STAR trial is being conducted under a Special Protocol Assessment (SPA) from the U.S. Food and Drug Administration (FDA).
"We are pleased to initiate the STAR trial on schedule, which keeps us on track to complete patient enrollment within the next 15 to 18 months and report top-line data in the second half of calendar 2009," said Randall Kaye, MD, Chief Medical Officer of AVANIR. "We believe this single confirmatory Phase III STAR trial, in addition to certain pre-clinical studies already underway, will be sufficient to provide a complete response to the FDA's October 2006 approvable letter for Zenvia in the treatment of PBA."
"PBA represents an area of high unmet medical need. Currently, no FDA-approved treatment is available for the more than one million patients in the United States estimated to suffer from involuntary crying or laughing episodes of PBA," said Daniel Wynn, MD, Director, Clinical Research, Co-Director, Consultants in Neurology Multiple Sclerosis Center, Northbrook, Illinois and STAR Trial Steering Committee member. "If approved, we expect that Zenvia could considerably reduce the distress caused by PBA for those individuals and their caregivers."
About the STAR Trial
The STAR trial will enroll 270 multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS) patients who exhibit signs and symptoms of PBA at approximately 50 sites in the U.S., Canada and Latin America. The primary efficacy analysis will be based on the changes in crying/laughing episode rates recorded in patient diaries. Secondary endpoints for this clinical trial include: 1) Center for Neurologic Study-Lability Scale (CNS-LS) score; 2) Neuropsychiatric Inventory Questionnaire (NPI-Q); 3) SF-36 Health Survey; 4) Beck Depression Inventory (BDI-II); and 5) Pain Rating Scale score (MS patients only). Safety and tolerability of Zenvia will be determined by reporting adverse events, physical exam, vital signs, electrocardiogram, respiratory function tests and clinical assessment of clinical laboratory variables. For more information visit www.pbatrial.com.
Zenvia is a combination of two well-characterized compounds: the therapeutically active ingredient dextromethorphan and the enzyme inhibitor quinidine, which serves to increase the bioavailability of dextromethorphan. This first-in-class drug candidate is believed to help regulate excitatory neurotransmission in two ways: through pre-synaptic inhibition of glutamate release via sigma-1 receptor agonist activity and through postsynaptic glutamate response modulation via uncompetitive, low-affinity NMDA antagonist activity. Zenvia is currently in development for the treatment of pseudobulbar affect (PBA) and diabetic peripheral neuropathic (DPN) pain. In October 2006, the Company received an approvable letter for the treatment of Zenvia in PBA. The Company has initiated a confirmatory Phase III study under a Special Protocol Assessment (SPA) agreement with the FDA utilizing a new lower quinidine dose formulation of Zenvia to address safety concerns raised in the Agency's approvable letter for Zenvia in the treatment of PBA. For more information about the Agency's SPA process see http://www.fda.gov/cder/guidance/3764fnl.htm. In April 2007 AVANIR announced successfully meeting all primary endpoints in the Phase III study of Zenvia in DPN pain. The Company is conducting a formal PK study to assess alternative lower-dose quinidine formulations of Zenvia for DPN pain that are intended to deliver similar efficacy and improved safety/tolerability versus the formulations previously tested for this indication.
Pseudobulbar affect (PBA), also known as involuntary emotional expression disorder (IEED) and emotional lability, is a neurologic disorder that occurs secondary to neurologic disease or brain injury causing sudden and unpredictable episodes of crying, laughing, or other emotional displays. PBA is estimated to impact more than 1 million people in the United States with underlying neurologic conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson's disease, dementias including Alzheimer's disease, stroke, and traumatic brain injury. PBA episodes may occur when disease or injury damages the area of the brain that controls normal expression of emotion. This damage can disrupt brain signaling causing a "short circuit" and triggering involuntary PBA episodes. PBA has been shown to impair the lives of patients in both social and occupational settings. There are currently no FDA approved treatments for PBA.
AVANIR Pharmaceuticals is focused on developing, acquiring and commercializing novel therapeutic products for the treatment of chronic diseases. AVANIR's products and product candidates address therapeutic markets that include the central nervous system (CNS), inflammation and infectious diseases. AVANIR's lead product candidate, Zenvia, is being developed for the treatment of PBA and is the subject of an approvable letter from the U.S. Food and Drug Administration for that indication. The Company has initiated a confirmatory Phase III study under a Special Protocol Assessment (SPA) agreement with the FDA utilizing a new lower quinidine dose formulation of Zenvia to address safety concerns raised in the Agency's approvable letter for Zenvia in the treatment of PBA. Additionally, in April 2007 AVANIR announced meeting all primary endpoints in a Phase III clinical trial with Zenvia in patients with DPN pain. The Company is conducting a formal PK study to assess alternative lower-dose quinidine formulations of Zenvia for DPN pain that are intended to deliver similar efficacy and improved safety/tolerability versus the formulations previously tested for this indication. AVANIR has also licensed a compound to Novartis International Pharmaceuticals Ltd. for the treatment of inflammatory disease. AVANIR's infectious disease drug candidate, AVP-21D9, is a human monoclonal antibody in pre-clinical development for the treatment of anthrax with funding provided to date from NIH/NIAID grants. The Company's first commercialized product, Abreva®, is marketed in North America by GlaxoSmithKline Consumer Healthcare and is the leading over-the-counter product for the treatment of cold sores. Further information about AVANIR can be found at www.avanir.com.
Forward Looking Statements
Statements in this press release that are not historical facts, including statements that are preceded by, followed by, or that include such words as "estimate,""intend,""anticipate,""believe,""plan,""goal,""expect," or similar statements, are forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from the future results expressed or implied by such statements. There can be no assurance that the proceeds received by the Company from the recent sale of the Company's FazaClo® operations, together with the Company's other available funds, will be sufficient to fund the Company's operations as currently anticipated, or that the Company will be able to commence and complete planned clinical trials within the projected time periods. There can also be no assurance that any additional Phase III trial for Zenvia will be successful, that any new doses of Zenvia will be safe and effective, or that the FDA will approve Zenvia for any indication. Risks and uncertainties affecting the Company's financial condition and operations also include the risks set forth in AVANIR's most recent Annual Report on Form 10-K and subsequent Quarterly Reports on Form 10-Q, and from time-to-time in other publicly available information regarding the Company. Copies of this information are available from AVANIR upon request. AVANIR disclaims any intent to update these forward-looking statements.
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Dec 10, 2007
MONDAY, Dec. 10 (HealthDay News) -- Combining an antibiotic with a medication currently used to treat multiple sclerosis may slow progression of the disease, according to researchers at the Louisiana State Health Sciences Center in Shreveport.
Their study included 15 patients (average age 44.5) with relapsing-remitting MS who'd been taking interferon for at least six months and were experiencing symptoms and developing new brain lesions.
For four months, the patients took 100 milligrams daily of the antibiotic doxycycline in addition to their interferon therapy. During the study, they had monthly neurological examinations, MRI brain scans and blood work.
At the end of the four months, 60 percent of the patients had a more than 25 percent reduction in the number of brain lesions. Patients also had lower disability scores. One patient relapsed. Side effects were mild and included only the known side effects of the two drugs individually, rather than side effects caused by combining the two medications, the researchers said.
The study, funded by Biogen Idec Inc., was posted online Dec. 10 and will be published in the February 2008 print issue of the Archives of Neurology.
"There is a growing interest in combination therapy in patients with MS to stabilize the clinical course, reduce the rate of clinical relapses and decelerate the progressive course of the underlying pathologic mechanism," the study authors wrote. "Overall, data from this cohort suggest that the treatment combination of oral doxycycline and interferon beta-1a may be safe and effective in some patients with MS; however, further controlled clinical trials are warranted to demonstrate safety and efficacy in a larger patient population."
Monday, December 10, 2007
Vaccinating children against the hepatitis B virus does not seem to raise that child's risk of developing Multiple Sclerosis, according to an article published in Archives of Pediatrics & Adolescent Medicine (JAMA/Archives), December 2007 issue.
Numerous studies have looked at the potential link between the hepatitis B vaccine and MS (multiple sclerosis) among adults, explain the researchers. The majority of them did not find a notable raised MS risk in the short or long term, except for one which indicated there might be a slight increased risk within 36 months of taking the vaccine (adults).
The authors explain "Some of these epidemiologic studies have been criticized for methodological limitations. This controversy created public misgivings about hepatitis B vaccination. Hepatitis B vaccination in children remained low in several countries despite vaccination campaigns supporting early vaccination against hepatitis B in children as a means of inducing strong and long-lasting immunity and despite high levels of hepatitis B-related morbidity and mortality worldwide."
Yann Mikaeloff, M.D., Ph.D., of Hôpital Bicêtre, Le Kremlin Bicêtre, France, and team analyzed data on 143 children who developed MS before reaching the age of 16 - they all had an episode of MS happen during 1994-2003. They matched each patient to eight control participants from the general French population - they were all of the same age, sex, and lived in the same area, but did not have MS. Vaccination records and data on family MS history (as well as other autoimmune diseases) were collected via telephone interviews.
In the 36 months preceding the first MS episode, about 32% of both the 143 MS patients and the 1,122 had been vaccinated against hepatitis B. "Vaccination against hepatitis B within the three-year study period was not associated with an increased rate of a first episode of MS. The rate was also not increased for hepatitis B vaccination within six months of the index date or at any time since birth or as a function of the number of injections or the brand of hepatitis B vaccine," the researchers wrote.
The writers concluded "Vaccination against hepatitis B does not seem to increase the risk of a first episode of MS in childhood."
"Hepatitis B Vaccination and the Risk of Childhood-Onset Multiple Sclerosis"
Yann Mikaeloff, MD, PhD; Guillaume Caridade, MSc; Mélanie Rossier, MSc; Samy Suissa, PhD; Marc Tardieu, MD, PhD
Arch Pediatr Adolesc Med. 2007;161(12):1176-1182.
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Written by - Christian Nordqvist
Copyright: Medical News Today
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Early Treatment with COPAXONE® Demonstrated Robust Protection against Progression to Clinically Definite Multiple Sclerosis in the PreCISe Study
Efficacy Is Attained and the Study Is Stopped after Interim Analysis and Supports Filing of COPAXONE® For Patients with a First Clinical Event Suggestive of MS
Jerusalem, Israel, December 3, 2007 - Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) today announced the positive results from a pre planned interim analysis of the PreCISe trial in patients presenting with a first clinical event and MRI features suggestive of multiple sclerosis (MS). The results showed that treatment with COPAXONE® (glatiramer acetate injection) reduced the risk of developing clinically definite MS (CDMS) by 44 percent versus placebo, and prolonged the quartile time to disease conversion to 722 days versus 336 days (+386 days, +115%) in those patients receiving placebo (hazard ratio 0.56, p=0.0005). At the time of the interim analysis, the proportion of patients who had developed CDMS was reduced from 43 percent in the placebo group to only 25 percent in the COPAXONE® group. Based on these results, Teva plans to file a request for marketing authorization of COPAXONE® in Europe, the U.S. and Canada for the treatment of patients with a first clinical event suggestive of MS.
Professor Paul O'Connor, Neurology Division Chief at St. Michael's Hospital, Toronto, Canada and the chairman of the study's independent data monitoring committee (DMC), said, "We are deeply impressed by Teva's commitment to continue developing COPAXONE® for patients presenting with a first clinical event and MRI suggestive of MS. After analyzing the data from the PreCISe study at the interim analysis, the DMC recommended that the placebo arm of the trial be stopped, as COPAXONE® successfully met the efficacy endpoint of the study; all placebo patients will now be given the opportunity to receive active treatment with COPAXONE® for two years."
This study further demonstrated the beneficial effect of early treatment with COPAXONE® on disease activity and burden, also in its early stages, as measured by both short-term clinical and magnetic resonance imaging (MRI) disease outcomes. COPAXONE® is the only relapsing remitting MS (RRMS) treatment with data from a long-term, prospective, ongoing study which demonstrated that in those patients adhering to therapy, 92 percent still walk unassisted after a mean of 10 years of therapy and 18 years of disease duration.
Professor Giancarlo Comi, Department of Neurology, San Raffaele Scientific Institute, Milan, Italy, and principal investigator of the study said, "We are very pleased by the results of this trial. These data on COPAXONE® demonstrated the importance of treating patients early on to provide rapid, early control of progression to CDMS, and stand to improve therapy options for the treatment of patients with first clinical event and a high risk to develop MS."
Moshe Manor, Group Vice President - Global Innovative Resources of Teva Pharmaceutical Industries, Ltd., said "The interim results of this study, which showed that early treatment with COPAXONE® delayed progression to CDMS, together with the unmatched long-term efficacy, tolerability and favorable safety profile supporting COPAXONE®, position it now also as the outstanding treatment option for patients with a first clinical event suggestive of MS and RRMS patients."
About the Study
The multi-national, multi-center, prospective, double-blind, randomized, Phase III PreCISe study was conducted in approximately 100 centers located in the U.S., Europe, Argentina, Israel, Nordic countries, Australia and New Zealand and included a total of 481 patients presenting with a single clinical episode and MRI suggestive of MS. Patients included are those who had a unifocal disease manifestation (i.e., clinical evidence of a single lesion). Patients received either COPAXONE® 20mg/day or placebo as a subcutaneous injection and continued treatment for up to 36 months, unless a second attack was experienced and they were diagnosed with clinically definite MS. Patients who converted to CDMS continued the trial on active treatment for additional two years. The primary efficacy outcome was time to CDMS, based on a second clinical attack. The pre-planned interim analysis was performed on data accumulated from approximately 80 percent of the three-year placebo-controlled study exposure. Over the period up to the interim analysis, the proportion of patients developing CDMS was reduced from 43 percent in the placebo group to only 25 percent in the COPAXONE® group (p< 0.0001).
COPAXONE® was also very well tolerated in the PreCISe study, with only 13 percent overall dropouts during the up to three-year study period, similar to that observed in RRMS patients treated with COPAXONE®. All patients in the study participate in a follow-up study with COPAXONE® to prospectively assess the impact of early versus delayed treatment with COPAXONE® on the long-term course of the disease for a total observation time of up to five years.
Current data suggest COPAXONE® is a selective MHC (Major Histocompatability Complex) class II modulator. COPAXONE® is indicated for the reduction of the frequency of relapses in RRMS. COPAXONE® is very well tolerated and the most common side effects of COPAXONE® are redness, pain, swelling, itching, or a lump or an indentation at the site of injection, weakness, infection, pain, nausea, joint pain, anxiety, and muscle stiffness.
COPAXONE® is now approved in 47 countries worldwide, including the United States, all European countries, Canada, Mexico, Australia, and Israel. In Europe, COPAXONE® is marketed by Teva Pharmaceutical Industries Ltd. and sanofi-aventis. In North America, COPAXONE® is marketed by Teva Neuroscience, Inc.
See additional important information at http://www.copaxone.com/pi/index.html or call 1-800-887-8100 for electronic releases. For hardcopy releases, please see enclosed full prescribing information.
Teva Pharmaceutical Industries Ltd., (NASDAQ: TEVA) 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. 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 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
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Kevin Mannix, Investor Relations
Teva Pharmaceutical Industries Ltd.
Teva North America
The materials presented here were prepared by independent authors under the editorial supervision of Medscape and do not represent a publication of the European Committee for Treatment and Research in Multiple Sclerosis. These materials and the related activity are not sanctioned by the European Committee for Treatment and Research in Multiple Sclerosis or the commercial supporter of the conference and do not constitute an official part of that conference.
Release Date: November 29, 2007;
The Impact and Burden of Multiple Sclerosis
Prevalence, Epidemiology, and Economic Burden
The national and regional prevalence of multiple sclerosis (MS) in France was reported at the 2007 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting, showing the overall prevalence in France and its 22 regions using the same methodology for the first time. The computerized database of the National Health Insurance system (Caisse Nationale d'Assurance Maladie [CNAM]) assessed 80% of the French population or 54,974,101 people. The national and regional prevalence was estimated on October 10, 2004. There were 49,626 cases of MS on the CNAM database on the prevalence date. The national prevalence was 90.3 per 100,000 (2.6 female-to-male ratio). The northern and eastern regions had a higher prevalence (101.1-122.2 per 100,000) compared with the western and southern regions (78.5-84.3), with the central region having an intermediate prevalence (84.3-101.1 per 100,000). The prevalence in Northeast France was 1.5 times that of Southwest France. These observations are consistent with the previously reported data of the heterogeneous distribution of MS in Europe between Northern and Southern European countries.
In Japan there is a geographic phenotype difference in MS. Two distinct subtypes of MS occur in Asians: optic-spinal multiple sclerosis (OCMS or neuromyelitis optica) and conventional multiple sclerosis (CMS). From 4 nationwide surveys in Japan taken in 1972, 1982, 1989, and 2004, 9900 patients with MS were seen with a prevalence of 7.7/100,000. OCMS was more common in southern Japan, whereas CMS was more common in the north. Peak age of onset in patients declined from their early 30s in 1972 to their early 20s in 2004. The proportion of patients with OCMS decreased over the observation period from 1972 to 2004. The frequency of CMS remained predominant in the northern regions.
In another epidemiologic presentation from Japan, an increasing incidence of MS in the Tokachi province of Hokkaido (the northernmost island of Japan) was noted over a 30-year period. Two epidemiologic surveys were conducted to assess the prevalence of MS in 2001 and 2006. The Tokachi province had a population of 350,000 in 2001 and 360,000 in 2006. In 2001 the prevalence of MS that satisfied the Poser criteria was 8.6/100,000 and 13.1/100,000 in 2006. The mean age at the prevalence day was 41.0 years old and the mean age at onset was 28.4. The mean duration of disease was 12.6 years. The rate of primary progressive MS was 4%; relapsing-remitting MS was 70%; and secondary progressive MS was 26%. The prevalence of OCMS was 1.7/100,000 in both 2001 and 2006 showing no change compared with CMS. From prior data, it was known that the mean annual incidence increase of MS was 0.15 from 1975 to 1989 but 0.68 from 1990 to 2004. It appears that the increased prevalence of MS in northern Japan may be due to the increased incidence since 1990.
Since disease-modifying therapies (DMTs) have been available, considerable healthcare resources are used by MS patients. A healthcare utilization survey was carried out from a Health Insurance Portability and Accountability Act (HIPAA)-compliant commercial administrative claims database. The database contained integrated inpatient, outpatient, and pharmacy records on over 12 million persons from all major US regions, with the diagnostic International Classification of Diseases, Ninth Revision (ICD-9) code for MS (340.xx) as the first or second diagnosis. The time span analyzed ranged from June 2005 to June 2006. The results found 12,216 identified MS patients, 77% of whom were women, and 84% aged 30-59 years (mean, 47 years). Fifty-six percent used at least 1 DMT. Interferon (IFN) beta-1a (intramuscular) was most common (19.8%), followed by glatiramer acetate (19.4%), INF IFN beta-1a subcutaneous (10.2%), IFN beta-1b (9.2%), and mitoxantrone (0.9%). Six percent received 2 or more DMTs. Those who used DMT were more likely to use symptomatic treatments: Forty-three percent used medications for depression, 31% for spasticity, 25% for bladder symptoms, 19% for fatigue, and 28% for pain or dysesthesiae. Twelve percent of patients were admitted to a hospital (56% condition-related); 11% had emergency department visits (13% condition-related); 2.4% had intensive care unit stays (44% condition-related); and 1.8% had skilled nursing facility stays (58% condition-related). Even though DMTs are available to the majority of MS patients, only 56% of the MS patients in this particular survey chose to take DMTs, but a significant amount of healthcare resources was still used by this group creating costs beyond the cost of the DMTs. This could be interpreted to suggest that improved treatments are needed to reduce the current healthcare as well as personal burden of MS.
Impact on Patients' Quality of Life and Cognition
Studies examining the impact of stressful life events on MS exacerbations have given conflicting results. However, a study of war stress from the Carmel Medical Center in Haifa, Israel, after the Hezbollah-Israeli war in 2006, showed a significant increase in MS exacerbations compared with similar time periods prior to the war. The influence of psychological coping strategies was also examined.
Participants in the study were 156 MS patients with relapsing-remitting MS, all residents of northern Israel who were followed regularly at the MS clinic. The number of severe relapses treated with steroids during and following the war were compared with similar time periods at the preceding year. Exposure to war events, resulting subjective stress, and psychological coping strategies were evaluated by means of structured interviews. The results of the study indicated that 18 relapses occurred compared with 1-7 relapses in similar time periods over the 13 months prior to the war (P = .001-.02, McNemar's test). The percentage of patients reporting intense stress among wartime relapse patients compared with remission patients was significant (44% vs 20%, P = .03). The percentage of patients reporting high levels of stress from rocket attacks was higher in relapsing patients (67% vs 42%, P = .05). Home evacuation stress was higher in relapsing patients (33% vs 11%, P = .02). Active coping mechanisms, such as planning ahead for home displacement, were used less frequently by patients with relapses (17% vs 47%, P = .01).
Three variables were selected as predictors of wartime relapse by a logistic regression model: subjective sense of stress, distress associated with displacement, and MS relapse in the previous year. Active coping reduced the risk for an exacerbation. The conclusions of the study indicated that the risk for an exacerbation is increased by wartime stress but can be reduced with active coping measures. This suggests a role for preventive measures in dealing with stress-related exacerbations.
Fatigue is the most frequent complaint of MS patients, even those with low Expanded Disability Status Scale (EDSS) scores. Fatigue affects quality of life for many individuals and is the main burden on the health and socioeconomic system. Two studies with longitudinal evaluation over 2 years analyzed variables in regard to fatigue in MS. In the study from the Karolinska Institutet in Stockholm, Sweden, 219 outpatients were assessed every 6 months with the Fatigue Severity Scale (FSS). Personal and environmental factors (sex, age, sense of coherence, living with a partner, living with children, work status, and immunomodulatory treatment) were correlated. The results showed that the FSS varied over the 2 years, with 54% changing FSS category 1 or several times. Twenty-seven percent were persistently fatigued and 19% never fatigued. In those patients who had increased or persistent fatigue, mood and disease-related factors were significantly different: depression (P = .001), weak sense of coherence (P = .02), living with a partner vs not living with a partner (P = .02), not working (P = .05), more than 10 years since the diagnosis of MS and with a moderate EDSS score compared with a mild EDSS (P = .001), more than 10 years since the diagnosis of MS and with a moderate EDSS compared with a severe EDSS score (P = .02), and a moderately progressive course compared with a mild course (P = .001). The conclusions of this study were that fatigue persistently affected at least 27% of the MS population and that those with a moderate course were at greatest risk, especially with an associated depression.
Another longitudinal study of fatigue showed that depression and physical impairment were significantly associated with persistent fatigue in a group of 267 MS patients followed over 2 years. Thirty-seven percent of the patients had persistent fatigue; 38% had sporadic fatigue; and 25% had no fatigue. Persistent and sporadic fatigue were not associated with disease duration, but they were significantly associated with physical impairment, primary progressive MS, insomnia, heat-sensitive fatigue, sudden-onset fatigue, and mood disturbance.
Studies have shown that up to 65% of MS patients have cognitive dysfunction and that cognitive dysfunction is the greatest cause for disability. However, cognitive dysfunction is not well evaluated in the EDSS score nor in the routine office or clinic evaluation. There is a growing awareness that cognitive dysfunction in MS is underappreciated, and the large number of poster and platform presentations concerning cognition in MS at the ECTRIMS 2007 meeting reflects that awareness. It is important that both the practicing neurologist and academic neurologist take into consideration the cognitive function of their MS patients when evaluating the patient for DMT so that prevention of disability can be possibly achieved. Walking with a cane may not be a reason for loss of employment, but inability to follow or carry out directions or inability to formulate a plan of action may be disabling.
A significant percentage of patients with clinically isolated syndromes (CIS) were found to have significant cognitive dysfunction when evaluated with a comprehensive neuropsychological battery. In an evaluation of 15 patients with CIS vs 15 healthy controls, 53.3% of the CIS patients compared with 0% of the controls had cognitive dysfunction. Patients were significantly impaired on tasks evaluating attention (46.6%), long-term verbal and nonverbal memory (33.3%), visuospatial skills (26.6%), executive function (20%), and learning (20%).
In a retrospective review of 71 MS patients with severe cognitive impairment in the first 10 years of their disease, 15 of the patients presented with cognitive impairment as their first and primary symptom. The characteristics of these 15 patients were mean age of onset, 43 years old; 11 women, 4 men; and mean delay from symptom onset to diagnosis, 2.6 years. Oligoclonal bands in the cerebrospinal fluid were present in all but 1 patient. The cognitive dysfunction had a severe impact on daily living activities and remained the predominant feature of the disease for all patients even though physical disability remained mild (mild pyramidal, sensory, cerebellar, brainstem, or bladder signs in 11 of 15) or absent (in 4). Initial MRI pattern showed diffuse and confluent lesions in the periventricular white matter with severe cortical atrophy (n = 7, pattern A). Others showed focal white matter lesions typical of MS with little or no atrophy (n = 8, pattern B). Two patients' MRIs evolved from pattern B to pattern A in 2-5 years. Clinicians need to be aware that MS-related cognitive dysfunction can be disabling even with little or no physical disability.
Available Pharmacologic Therapies
There are 6 US Food and Drug Administration (FDA)-approved DMTs in the United States at this time. These DMTs are IFN beta-1a (intramuscular or subcutaneous), IFN beta-1b, glatiramer acetate, mitoxantrone, and natalizumab. All of these treatments have shown significant reduction of relapse rate and MRI lesions compared with controls. There are some data from pivotal studies to suggest a reduction of disability but long-term prevention of disability needs further evaluation.
Because cognitive dysfunction is the main cause of disability in patients with MS, and brain atrophy is highly associated with cognitive dysfunction, reduction of brain atrophy is a potentially important marker for the prevention of disability -- more important than the EDSS. In the AFFIRM study there was a more rapid brain parenchymal fraction (BPF) reduction in patients receiving natalizumab compared with patients receiving placebo during the first year (0.56 vs 0.24%) than the second year (0.24% vs 0.43%). The question of why this may have occurred includes a time lag between inflammation and subsequent tissue loss (or atrophy in which the decrease in BPF during the first year may be an inevitable consequence of inflammation and tissue damage that occurred prior to initiation of treatment) or "pseudoatrophy" as an initial decrease in BPF from resolution of edema and inflammatory infiltrate rather than actual tissue loss.
To answer these questions, an analysis was conducted on the kinetics of brain atrophy during the first year of treatment with natalizumab from the AFFIRM study. Drs. Fisher and Rudick from the Cleveland Clinic Foundation, Cleveland, Ohio, presented further evaluation of the kinetics of brain atrophy and the relationship between inflammatory lesions and BPF during natalizumab treatment. The study was a randomized, double-blind, placebo-controlled, phase 2 study of 213 patients, of which 148 (100 natalizumab, 48 placebo) had analyzable MRI scans. The scans were performed at 1 month prior to the study, at month 0 (baseline), monthly for 6 months, and at months 9 and 12. The 2 treatment arms of natalizumab (3 mg/kg and 6 mg/kg) were combined for all statistical analyses. The results showed an initial decrease in BPF in the early treatment period, followed by a leveling off after month 4 to the end of the treatment period (month 12). This pattern of BPF change is most suggestive of pseudoatrophy, which is consistent with an anti-inflammatory effect followed by a reduced atrophy rate in the late treatment phase. Therefore, this pattern of decrease in brain volume during the study suggests that natalizumab may have a beneficial effect on brain atrophy, beginning about 4 months after treatment initiation.
As of September 21, 2007, a total of 26,200 patients have been exposed to natalizumab, with no new cases of progressive multifocal leukoencephalopathy reported. Seventeen thousand patients remain on natalizumab as of October 2007. The overall rate of serious hypersensitivity reactions is 0.64%, usually at the second infusion. Testing for the presence of persistent antibodies to natalizumab (detected on 2 occasions at least 6 weeks apart) prior to redosing following a prolonged dose interruption is recommended because reduced efficacy and increased risk for hypersensitivity reactions are more common in these patients. Twenty-four women in the United States and Austria with MS and exposure to natalizumab at any time during the first 3 months of pregnancy have enrolled in a pregnancy registry. Twenty-one pregnancies were ongoing as of August 23, 2007 with 1 live birth, 1 spontaneous abortion, and 1 elective abortion.
Physical therapy is a mainstay of patients of all types with physical disabilities. Studies of MS patients have shown variable results, probably due to many reasons, such as fatigue, instability of the disease, and small sample size. The type of physical therapy also varies. In a study from Belgium, the benefit between bilateral exercise ("in-phase") and alternating exercise ("antiphase") was evaluated at various speeds of repetition for 10 weeks. Exercise rates of 0.75 Hz, 1.00 Hz, 1.25 Hz, and 1.50 Hz were used. Patients had mild-to-moderate disabilities (EDSS scores from 1.5 to 6.5). Coordination accuracy and stability were measured at baseline and at 10 weeks. The results showed that physical intervention programs with emphasis on strength do not influence motor control of the lower limbs after a 10-week intervention period. Antiphase training is performed with the lowest accuracy at the lowest frequency but improves when frequency increases. This is a particular finding in MS patients and contrasts with the current literature in regard to healthy subjects. This study also found that motor control and the EDSS were not correlated, probably due to the fact that EDSS is a rough picture of the distance that an MS patient can walk, whereas motor control is about stability and accuracy.
A comprehensive rehabilitation program showed improvement of MS patients with primarily pyramidal impairment and mild-to-moderate MS in both activities of daily living and mobility. In a study with 200 patients in an inpatient multidisciplinary program, patients were assessed at the beginning and end of admission with the EDSS. Functional status was evaluated with the Barthel Index and Rivermead Mobility Index. Sixty-five percent were women, with a mean age of 50 and mean duration of disease of 17.3 years. All patients were enrolled in an individualized, goal-oriented, multidisciplinary inpatient program on the basis of practical skills of daily living. Results of rehabilitation were assessed in the whole sample as well as by comparing 3 subgroups: a mild group (EDSS 2-5.5), moderate group (EDSS 6-65), and severe group (EDSS 7-8.5). The results of the program showed greater improvement in patients in the mild and moderate groups, although the severe group did show some improvement. Pyramidal impairment was the greatest predictor of mobility and activities of daily living.
In another rehabilitation study, patients were randomized to 3 treatment groups: outpatient, inpatient, and day hospital. There were 9 patients in each group for a total of 27 patients. The outpatient group (mean EDSS of 6.0) had 1-hour rehabilitation training twice weekly; the inpatient group (mean EDSS of 5.5) had more than 2 hours daily; and the day hospital group (mean EDSS of 6.5) had 2 hours daily. Outcome measures were Berg Scale, Barthel Index, and Hauser Ambulation Scale. The program lasted 5 weeks. The results showed that all patients improved in outcome measures except for ambulation, but there was no difference among the groups. The conclusion was that outpatient rehabilitation is equally effective as inpatient or day hospital therapy, and outpatient rehabilitation saves time and economic resources.
Supported by an independent educational grant from Genentech
Moreau R, Kazaz E, Clerc L, et al. Prevalence of multiple sclerosis in France and its 22 regions. Mult Scler. 2007;13(suppl2):S103. Abstract.
Osoegawa M, Fukazawa T, Fujihara K, et al. Temporal and geographical changes of multiple sclerosis phenotype in Japanese: nationwide survey results over 30 years. Mult Scler. 2007;13(suppl2):S101-102. Abstract.
Houzen H, Niino M, Kikuchi S, et al. Increasing risk of multiple sclerosis in Japan. Mult Scler. 2007;13(suppl2):S102. Abstract.
Chin P, Laouri M, Broder M, et al. Healthcare utilization among insured multiple sclerosis patients in the U.S. from 2005-2006. Mult Scler. 2007;13(suppl2):S261. Abstract.
Golan D, Somer E, Dishon S, et al. War stress, psychological coping mechanisms and exacerbations of multiple sclerosis. Mult Scler. 2007;13(suppl2):S238. Abstract.
Johansson S, Ytterberg C, Hillbert J, et al. A longitudinal study of variations in perceived level of energy and predictors of fatigue in multiple sclerosis. Mult Scler. 2007;13(suppl2):S115. Abstract.
Lerdal A, Celius EG, Krupp L, et al. Longitudinal patterns of fatigue in patients with multiple sclerosis. Mult Scler. 2007;13(suppl2):S114-115. Abstract.
Rao SM. Neuropsychology of multiple sclerosis. Curr Opin Neurol. 1995;8:216-220.
Kocer B, Nazliel B, Irkec C. Cognitive dysfunction in patients with clinically isolated syndrome. Mult Scler. 2007;13(suppl2):S114. Abstract.
Assouad R, Tourbah A, Sedel F, et al. Cognitive presentation in multiple sclerosis. Mult Scler. 2007;13(suppl2):S114. Abstract.
Miller DH, Soon D, Fernando KT, et al; AFFIRM Investigators. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68:1390-401.
Fisher E, Rudick R, Dalton CM, et al. The kinetics of brain atrophy during the first year of treatment with natalizumab. Mult Scler. 2007;13(suppl2):S168. Abstract.
Panzara M, Belcher G, Kooijmans M, et al. Use of natalizumab in patients with relapsing multiple sclerosis: updated safety results from TOUCH and TYGRIS. Mult Scler. 2007;13(suppl2):S169. Abstract.
Alders G, Gijbels D, Feys P, et al. The effect of physical intervention programs on coordination quality of the lower limbs in persons with multiple sclerosis. Mult Scler. 2007;13(suppl2):S132. Abstract.
Grasso MG, Triosi E, Tonin A, et al. Effectiveness of multiple sclerosis rehabilitation. Mult Scler. 2007;13(suppl2):S130. Abstract.
Giusti A, Viti B, Pirani G, et al. The effectiveness of neurological rehabilitation in multiple sclerosis: comparison between different rehabilitative settings. Mult Scler. 2007;13(suppl2):S130. Abstract.
Evaluating New Data for the Treatment of MS
New and Emerging Pharmacologic Treatments
Several new treatments for multiple sclerosis (MS) are in phase 2 or phase 3 trials. The combined analyses of subcutaneous cladribine were presented by Dr. S. Cook for the Cladribine Clinical Study Group.[1,2] The safety profile of cladribine at parenteral doses of up to 2.1 mg/kg was similar to placebo, with a sustained lymphocytic depleting effect consistent with its therapeutic mechanism. The parenteral trials included MS patients with relapsing remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). Since parenteral doses of 0.7 to 2.1 mg/kg can be achieved with oral preparations, 2 oral studies are now underway. One study, CLARITY, is a monotherapy, phase 3 trial for patients with RRMS and an Expanded Disability Status Scale (EDSS) score of 0-5.5 for a 2-year period. It has 3 treatment arms; Group 1 receives 10-mg cladribine tablets for 4-5 days on weeks 1, 5, 9, and 13 in the first year. Group 2 receives cladribine for the first 2 treatment periods but placebo for the third and forth treatments. Group 3 receives placebo for all 4 treatments. At this time, enrollment is completed with 1329 patients. The primary efficacy parameter is the relapse rate from baseline to week 96. The other oral cladribine study, ONWARD, is a phase 2b study that combines IFN-beta-1a (subcutaneous 3 times weekly, 44 mcg) with oral cladribine in an otherwise similar design. The primary efficacy parameter is number of new Gd+ T1 lesions from baseline to week 96. A new subcutaneous formulation of IFN-beta-1a is being used in this trial.
Two phase 3 trials are underway with an oral fumaric acid derivation (BG00012) in patients with RRMS. BG00012 has been shown in vitro to inhibit expression of cytokines and adhesion molecules involved in inflammation, with resultant anti-inflammatory and neuroprotective effects. A phase 2b double-blind, placebo-controlled, 24-week study with a 24-week safety extension showed a significant 69% reduction of Gd+ T1 lesions at 720 mg/day of BG00012 compared with placebo. Additionally, patients receiving BG00012 had 48% fewer T2 lesions and 53% fewer T1 lesions compared with placebo (all P = .001). Two phase 3 studies are now underway: DEFINE (a double-blind, placebo-controlled study of 2 doses of BG00012 240 mg 2 or 3 times a day vs placebo) and CONFIRM (same design but with an added comparator of glatiramer acetate). They are 2-year studies of 1000 patients and 1200 patients, respectively, with RRMS and an EDSS score of 0-5.0. The primary efficacy parameter of DEFINE is the proportion of patients relapsing over the 2 years, and the primary efficacy parameter of CONFIRM is the rate of clinical relapse at 2 years.
Monoclonal Antibody Therapies
Alemtuzumab is a humanized monoclonal antibody against the T-cell antigen CD52 on lymphocytes. Two studies evaluating alemtuzumab (ALEM) in patients with RRMS were reported at the ECTRIMS meeting. One trial was in treatment-naive patients comparing 2 doses of ALEM (either 24 mg/day intravenously [IV] for 5 days at month 0 and for 3 days at month 12 or 12 mg/day) and subcutaneous IFN-I-beta 3 times weekly at 44 mcg. At 2 years, 84.4% of low-dose ALEM patients were relapse free, 90.6% of high-dose ALEM patients were relapse free, and 60.4% of IFN patients were relapse free (P = .0002 low-dose and P = .0001 high-dose). ALEM improved disability on the Multiple Sclerosis Functional Composite (MSFC) and EDSS scores. Relapses were reduced and delayed. Safety findings associated with ALEM were immune thrombocytopenic purpura (ITT) and autoimmune disorders of the thyroid gland. The other trial with ALEM included MS patients who had failed prior treatment with any IFN. The patients had to have had the onset of MS in the last 5 years, EDSS scores of 0-6, IFN for at least 6 of the last 24 months, and 2 relapses. Forty-five patients received 2 cycles of ALEM with 1 mg IV methylprednisolone prior to ALEM. Patients received ALEM 24 mg/day for 5 days (cycle 1) and then 24 mg/day for 3 days at month 12 (cycle 2). The result was a 9.3-fold reduction of relapse rate (relapses in 2 years prior to cycle 1 vs relapses in 2 years following; P = .0001). On disability measurements, 70% of patients had stable or improved MSFC. However, 4 cases of autoimmune thyroid disorder and 1 case of ITT developed in the 45 patients.
Daclizumab is a humanized monoclonal antibody that depletes CD25 from the cell surface of T cells and interacts specifically with the interleukin 2 receptor alpha chain (IL2RA). Daclizumab has shown promise as a therapy for both RRMS and SPMS in combination with INF and as monotherapy. The results of a recently completed phase 2 study with 230 patients with RRMS with EDSS scores of 0-5 and breakthrough disease while on any IFN were presented in a platform presentation. There were 230 patients at 51 sites in North America and Europe. There was a 24-week double-blind, placebo-controlled treatment period and a 48-week washout period. There were 3 arms to the study: placebo add-on, 1 mg/kg subcutaneously every 4 weeks, or 2 mg/kg subcutaneously every 2 weeks. Primary endpoint was new Gd+ lesions between weeks 8 and 24. Secondary endpoints were relapse rate and safety issues. The results indicated a 25% reduction of Gd+ lesions with 1 mg/kg add-on of daclizumub (not significant [NS]) and a 72% reduction of Gd+ lesions with 2 mg/kg every 2 weeks (P = .004). Relapse rate reduction was 35% in each dosing group (NS). Daclizumab was safe and well tolerated, with no significant safety issues.
Individually Tailored Therapy for SPMS and PPMS
SPMS without exacerbations is often considered a nonmodifiable disease state. It is a phase of MS considered to consist of neurodegeneration with axonal loss and cortical and spinal cord atrophy. However, there are a few ongoing trials for SPMS. One involves the intravenous administration of a synthetic peptide, MBP8298, for SPMS patients with HLA haplotypes DR2 and/or DR4. MAESTRO-01 is a multicenter, multinational clinical trial in which over 600 patients have been enrolled. An interim safety analysis of the first 508 patients, on a blinded basis, showed no significant safety concerns. An interim analysis of the first 200 patients at 2 years is expected in the third quarter of 2008. MAESTRO-03 is currently enrolling in the United States for SPMS patients without exacerbations to receive 500 mg MBP8298 or sterile water as placebo IV every 6 months.
Rituximab (RTX) is a monoclonal antibody that specifically targets CD20+ B cells. There may be a pathogenic role of B cells in MS, particularly in PPMS. In an ongoing placebo-controlled study, 439 patients with PPMS by the McDonald Criteria with greater than 1 year duration of disease, an EDSS score of 2-6.5, and cerebrospinal fluid (CSF) showing elevated IgG or oligoclonal bands in the past 24 months were randomized in a 2:1 manner to receive 1000 mg RTX twice every 24 weeks over 96 weeks (4 courses) or placebo. The patients are to be followed to 122 weeks with magnetic resonance imaging at -2, 0, 6, 48, 96, and 122 weeks. Primary endpoint is a 1-point increase in the EDSS sustained for at least 12 weeks. Secondary outcomes are change in baseline to week 96, T2 lesion volume, and brain volume. Results of enrollment are that 50.3% of the 439 patients are female with a mean age of 50.4 years; 56% had a baseline EDSS greater than 4 with a mean EDSS of 4.03. Sixty-five percent of patients had never had a disease-modifying treatment. At randomization, there was a mean Gd+ lesion of 0.7 with 75.2% with no new lesions, but 24.8% had greater than 1 Gd+ lesion. These are pooled demographic data from an ongoing blinded study. With nearly 25% of patients with baseline Gd+ lesions and all patients with active CSF due to inclusion criteria, an enrichment for active disease in this trial is suggested. This is consistent with active immunologic activity in this patient population and may increase the possibility for a therapeutic effect of RTX.
Neuromyelitis Optica Treatment Options
Neuromyelitis optica (NMO; called spinal-optical MS in Asia and also called Devic's disease) is a serious, inflammatory, demyelinating disease of the optic nerves and spinal cord. Many patients fail to respond to steroid therapy or other standard treatments, including chemotherapy, for MS. Five-year survival may be less than 80%. Dr. Khatri presented a series of 6 NMO patients who had failed high-dose methylprednisolone and prednisone treatment with plasma exchange (PE). All patients met diagnostic criteria for NMO and were serum NMO-IgG antibody positive. Three patients were white and 3 were African American (age range, 34-53; mean 40). All were female. EDSS ranged from 2 to 8.5 (mean 6.3). Following PE, all patients improved and stabilized (EDSS mean improved from 6.3 to 5.1). Four patients continue to receive PE (1 patient for the past 16 years). The frequency of maintenance PE varied from once a month to every 3 months. Because of insurance problems, 2 of the 4 patients had to stop PE for several months. This resulted in both patients becoming blind and bedridden, despite treatment with high-dose methylprednisolone and cyclophosphamide. When PE was restarted, there was dramatic improvement, although not to the prior functional state before it was stopped. The conclusion is that PE can be effective even on a long-term basis for some NMO patients refractory to other treatments.
Fampridine-SR (a sustained-release form of 4-aminopyridine) can be useful in improving central conduction of demyelinated axons in the central nervous system (CNS) by closing potassium channels. Clinically, it has been shown in phase 2 and phase 3 trials to improve pyramidal tract function as measured by the timed 25-foot walk. A meta-analysis of a phase 2 and a phase 3 fampridine trial was presented in a platform presentation discussing the results of the trials, the efficacy assessments, and the clinical validity of outcome measures in the 2 trials. Both were double-blind, placebo-controlled, 14-week studies of MS patients with ambulatory deficits. A total of 501 patients were included in the analysis, with a randomization ratio of 3:1 (drug:placebo). The results showed a significant improvement in ambulation for fampridine-treated patients over placebo (P = .001). The primary efficacy measurement was that of a "timed walk responder," which was a patient whose walking speeds for at least 3 of 4 treatment visits were faster than the fastest speed of any of the 4 pretreatment visits and one follow-up visit. Clinical impact was assessed with the 12-item Multiple Sclerosis Walking Scale, with significant improvement of fampridine over placebo patients (P = .001). Patient satisfaction was also high on both studies, with the Subject Global Impression score significantly better for fampridine treatment vs placebo (P = .001)
Low-dose naltrexone (LDN) has been popular among some MS patients as an alternative therapy. Naltrexone has long been approved by the US Food and Drug Administration as an orally administered treatment for heroin addiction. It is a semisynthetic opiate antagonist approved for use in a 50-mg dose. It has been used for the symptomatic treatment of pain, spasticity, and fatigue. In a study supported by the Italian Federation of Multiple Sclerosis, data supporting some benefit of LDN in PPMS patients were presented. Prior evidence has shown that when naltrexone is given at very low doses (5 mg), an upregulation of endorphins results and no opiate antagonism occurs. In 40 PPMS patients treated with LDN in an open-label manner as a pilot study for safety, LDN has been safe so far. Transient liver function test elevation, mild agitation, and sleep disturbance have occurred as the main side effects. Only 2 dropouts have occurred, 1 for protocol violation and 1 for severely increased hypertonia. Efficacy results are pending, but patients reporting a sense of well-being may have a neurochemical basis for that effect.
Ethics of Placebo-Controlled Clinical Trials
Dr. Chris Polman discussed the ethics of placebo-controlled trials in the treatment of MS in a platform presentation on behalf of the National MS Society International Advisory Committee on Clinical Trials in MS, which met in Washington, DC in March 2007. This committee updated the prior recommendation of the International Advisory Committee that had been published in 2001. The recommendations of the current Committee are in context of the newly available treatment since 2001. The prior recommendations basically said that placebo-controlled trials were allowable "if certain conditions were met." These conditions have been expanded and are more restrictive. The current Committee recommendations for placebo-controlled trials to be ethical are: (1) if there is no existing effective therapy (EET) for their type of MS (such as for PPMS or most SPMS); (2) if the patient refuses treatment (such as with injectable medications); (3) if no EET has been effective for their type of MS (more than 1 adequate trial for each class of medication) or intolerable side-effects have occurred; (4) the patient must be well informed not only through the informed consent (IC) process but there also should be a patient advocate present; (5) there should be a separation between the treating neurologist and research neurologist; (6) the IC process should be repeated throughout the clinical trial to be sure that the patient is aware of all other treatment options; and (7) in areas that are "resource-restricted," the trial drug must be available to the subjects after the trial has been completed.
Supported by an independent educational grant from Genentech
Cook S. Combined analysis of the safety and tolerability of cladribine from four randomized, double-blind, parallel-group, placebo-controlled trials in patients with multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S244-245 (abstract).
Cook S. Safety profile of cladribine following repeat treatment: a combined analysis of data from five clinical trials in patients with multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S245 (abstract).
Giovannoni G, Comi G, Cook S, et al. The CLARITY study (CLAdRIbine tablets Treating multiple sclerosis orallY): design of a phase III trial of oral cladribine in relapsing multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S245 (abstract).
Montalban X, Cohen BA, Jeffery DR, et al. Oral cladribine added to interferon beta-1a for active multiple sclerosis: a 96-week, double-blind, placebo-controlled phase IIb study. Multiple Sclerosis. 2007;13(suppl 2):S245-246 (abstract).
Gold R, Fox R, Dawson K, et al. Two phase 3 studies to determine the efficacy and safety of BG00012, a novel, oral fumaric acid derivative, in patients with relapsing multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S173 (abstract).
Coles AJ; on behalf of the CAMMS223 Study Group. Alemtuzumab improved multiple sclerosis functional composite scores and delayed time to first relapse at 2-year interim analysis compared to subcutaneous interferon beta-1a. Multiple Sclerosis. 2007;13(suppl 2):S166 (abstract).
Fox E, Mayer L, Sullivan H, et al. Two-year results with alemtuzumab in patients with active relapsing-remitting multiple sclerosis who have failed licensed beta interferon therapies. Multiple Sclerosis. 2007;13(suppl 2):S166-167 (abstract).
Montalban X, Wynn D, Kaufman et al. Preliminary CHOICE results: a phase 2, randomized, double-blind, placebo-controlled multicentre study of subcutaneous daclizumab in patients with active, relapsing forms of multiple sclerosis on interferon beta. Multiple Sclerosis. 2007;13(suppl 2):S18 (abstract).
Arfors L; on behalf of the MAESTRO-01 Investigators Group. Safety observations from administration of MBP8298 as part of the ongoing phase 3 MAESTRO-01 SPMS clinical trial. Multiple Sclerosis. 2007;13(suppl 2):S171-172 (abstract).
Hawker K, Freedman MS, O'Connor P, et al. Rituximab in patients with primary progressive multiple sclerosis: demographics in a phase II/III randomized, double-blind, placebo-controlled multicentre trial. Multiple Sclerosis. 2007;13(suppl 2):S165 (abstract).
Khatri B, Kramer J, Dukic M, Palencia M. Sustained long-term improvement with plasma exchange in patients with recurrent neuromyelitis optica unresponsive to corticosteroids. Multiple Sclerosis. 2007;13(suppl 2):S173 (abstract).
Goodman AD, Brown TR, Cohen JA, et al. Meta-analysis of phase 2 and 3 fampridine trials in multiple sclerosis: efficacy assessment and validation of clinical meaningfulness of outcome measure. Multiple Sclerosis. 2007;13(suppl 2):S33 (abstract).
Gironi M, Boneschi FM, Solaro C, et al. Pilot multicenter study of low dose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis. 2007;13(suppl 2):S176 (abstract).
Polman CH; on behalf of the National MS Society International Advisory Committee on Clinical Trials. A reconsideration of the ethics of placebo-controlled clinical trials in MS: outcomes of an international conference. Multiple Sclerosis. 2007;13(suppl 2):S17 (abstract).
Lublin FD, Reingold SC. Placebo-controlled clinical trials in multiple sclerosis: ethical considerations. National Multiple Sclerosis Society (USA) Task Force on Placebo-Controlled Clinical Trials in MS. Ann Neurol. 2001;49:677-681.
Exploring the Pathogenesis of MS and the Rationale for Current Treatments
Discussion of Key Cellular Players and Important Immune Responses
Dr. David Hafler presented a platform discussion reviewing the current and emerging understanding of the genetic basis of multiple sclerosis (MS). Persons with a first-degree relative are known to be at higher risk than the average person. The prevalence of MS is 0.1% in the general population, 2% to 4% in siblings, 5% in dizygotic twins, and 30% in monozygotic twins. MS may be considered a complex genetic disease involving many genomic expressions. It has been known for over 30 years that there is a major histocompatibility complex (MHC) on chromosome 6p21. It is also known that MS is a disease that involves the dysfunction of the CD4+CD25 high regulatory T-cell function.
In order to further elucidate the genetic basis of MS, a collaborative effort of US and UK researchers used a staged approach to identify risk alleles associated with MS. The first stage involved whole genomic association scans using the Affymetrix 500,000 SNP (single nucleotide polymorphisms) GeneChip (Santa Clara, California) to analyze DNA from 931 trio families (an MS patient and both parents). The second stage involved further analysis of the most frequently appearing SNPs. Further analysis identified the 2 most prevalent SNPs, IL2RA and IL7R. Although IL2RA has been identified in both patients with MS and patients with diabetes, it is likely that different variants are associated with each of these diseases because the risk for MS and DM do not coexist. Although there may be different variants of the same gene for IL2RA, this may open up a new area for genetic typing in MS, which could lead to specific therapeutic choices for patients who may be more likely to respond to one type of treatment vs another. Genetic screening is currently being used in the MAESTRO-03 study. Data from the MAESTRO-1 study showed that patients with DR2 or DR4 haplotypes were likely to respond to treatment in secondary progressive MS (SPMS), while MS patients with other markers did not, so one of the inclusion criteria in the MAESTRO-3 study is a blood test on the screening visit. The patient must be DR2 or DR4 positive to be in the study.
In a platform presentation following Dr. Hafler's presentation, Dr. Howard Weiner discussed circulating markers that have been found to differ between relapsing remitting MS (RRMS) and SPMS. The central question regarding MS treatment is whether early and aggressive immunotherapy will prevent the conversion to SPMS in the majority of patients. The specific identification of antibody patterns in MS may help achieve that goal because it is known that inflammatory antibodies are linked to brain pathology. The progression of RRMS to SPMS is likely to be due to neuronal degeneration triggered by inflammation.
Dendritic cells (DCs) are antigenic cells of the innate immune system that have the unique ability to induce primary immune responses. Circulating myeloid DCs were isolated from blood samples to determine if there were abnormalities in patients with MS and if myeloid DCs were related to disease stage. SPMS patients were found to have a greater percentage of myeloid DCs expressing CD80, IL-12, and TNF-alpha while having a lower percentage of PD-L1 compared with patients with RRMS or controls. A higher percentage of RRMS patients had DCs producing greater amounts of Th1 (IFN-alfa and TNF-alpha) and Th2 (IL-4, IL-13) compared with controls and SPMS patients. These results may be interpreted as showing that there is a loss of an inflammatory component in the immune system when MS patients transition from RRMS to SPMS. This may explain, in part, an immunologic basis for the different stages and clinical patterns of MS.
In a comparison of the treatment effects of FTY720 (a new oral treatment in human trials for MS), IFN-beta, and glatiramer acetate (GA) on experimental autoimmune encephalomyelitis (EAE), each of the 3 compounds were given to Lewis rats in a model of progressive EAE. For decades, EAE has been the experimental model for MS. FTY720 was administered at 3 mg/kg orally. At this dose, the onset of acute EAE was inhibited, and when given after recovery from an acute attack in an untreated animal, FTY720 inhibited further relapses. When FTY720 was given at a dose of 6 mg/kg orally during an acute exacerbation, the progressive phase of EAE was inhibited. GA failed to prevent the progressive phase at doses of 10 mg/kg orally or 5 mg/kg subcutaneously. GA at doses of 15 mg/kg orally or 10 gm/kg subcutaneously failed to prevent the onset or severity of relapses of EAE. IFN-beta given at 10,000 U intraperitoneally 3 times weekly failed to prevent the progressive phase of EAE.
Cerebrospinal Fluid Analysis in Clinically Isolated Syndromes
Clinically isolated syndromes (CIS) have been extensively evaluated by clinical and magnetic resonance imaging (MRI) criteria for risk to develop clinically definite MS (CDMS). The clinical diagnostic value of cerebrospinal fluid (CSF) analysis was presented from 104 patients presenting with a first clinical episode consistent with a demyelinating disease of the central nervous system. A diagnosis of either CIS or possible MS was made. The patients underwent neurologic evaluation, brain MRI, and CSF analysis and were followed from 2 to 6 years as to their course and final diagnosis according to the McDonald criteria. The results of the CSF evaluation showed a significant difference between the possible MS patients and CIS patients, with 82% of the possible MS patients having positive CSF for oligoclonal bands (IgGOB) while 18% of CIS patients had positive CSF for IgGOB. The conclusions of the authors were that "positive CSF" should be considered among the criteria of dissemination in time of lesions in MS.
Optical coherence tomography (OCT) is a noninvasive and relatively inexpensive way to measure the retinal fiber layer. Dr. Siger and colleagues presented data showing that by measuring the retinal nerve fiber layer (RNFL), the most proximal part of the optic nerve, a measure of axonal degeneration can be obtained. Fifty-one patients underwent OCT with RNFL measurements, 20 with optic neuritis (ON) and MS, 31 with MS and without ON, and 12 healthy controls. T2- and T1-weighted imaging lesion volume, T1/T2 ratio, and brain atrophy were analyzed and correlated with OCT. RNFL was also correlated with disease duration and neurologic status. The results showed that RNFL was significantly reduced compared with controls in the affected eye (ON) but not significantly different when compared with the unaffected eye. Reduction of RFNL was correlated with MRI measures of brain atrophy (P = .01) and increased T1 lesion (black holes) volume (P = .03). RNFL reduction also correlated with clinical data (Expanded Disability Status Scale: P = .004).
Supported by an independent educational grant from Genentech
Moreau R, Kazaz E, Clerc L, et al. Prevalence of multiple sclerosis in France and its 22 regions. Multiple Sclerosis. 2007;13(suppl 2):S103 (abstract).
Osoegawa M, Fukazawa T, Fujihara K, et al. Temporal and geographical changes of multiple sclerosis phenotype in Japanese: nationwide survey results over 30 years. Multiple Sclerosis. 2007;13(suppl 2):S101-102 (abstract).
Houzen H, Niino M, Kikuchi S, et al. Increasing risk of multiple sclerosis in Japan. Multiple Sclerosis. 2007;13(suppl 2):S102 (abstract).
Chin P, Laouri M, Broder M, et al. Healthcare utilization among insured multiple sclerosis patients in the U.S. from 2005-2006. Multiple Sclerosis. 2007;13(suppl 2):S261 (abstract).
Siger M, Dziegielewski K, Jasek L, et al. Optical coherence tomography in multiple sclerosis as a measure of brain atrophy. Multiple Sclerosis. 2007;13(suppl 2):S86 (abstract).
Authors and Disclosures
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Keith R. Edwards, MD
Assistant Clinical Professor of Neurology, Harvard Medical School, Boston, Massachusetts; Consulting Neurologist, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Disclosure: Keith R. Edwards, MD, has disclosed that he has served as an advisor or consultant to Allergan Pharmaceuticals, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, and Serono.
Iwona Misiuta, PhD, MHA
Scientific Director, Medscape LLC, New York, NY
Disclosure: Iwona Misiuta, PhD, MHA, has disclosed no relevant financial relationships.
Stephanie Kushner, PhD
Scientific Director, Medscape LLC, New York, NY
Disclosure: Stephanie Kushner, PhD, has disclosed no relevant financial relationships.