A U.S. Food and Drug Administration advisory committee today recommended that the agency approve marketing of fingolimod capsules (formerly called Gilenia, Novartis International AG) for the treatment of relapsing multiple sclerosis. If approved, fingolimod would be the first oral disease-modifying therapy for the treatment of MS. While the FDA is not required to follow the recommendations of its advisory committees, it usually does. According to Novartis, the agency is expected to make a final decision about whether to approve the drug in September 2010.
During an all-day meeting held June 10, 2010, the FDA advisory committee reviewed data about the effectiveness and safety of fingolimod, as well as a proposed plan designed to monitor and mitigate risks – called Risk Evaluation Mitigation Strategies (REMS) that would likely be mandated to monitor safety if the agent is approved. The committee also heard public testimony from individuals and patient advocacy groups, including the National MS Society, which testified to the unmet need for more therapies for people with MS.
Among its discussions, the advisory committee recommended that fingolimod be approved at the dose (0.5 mg once daily) recommended by Novartis and that:
• Fingolimod demonstrated substantial evidence of effectiveness for the treatment of relapsing MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability;
• the safety data currently known justify the drug’s approval, and the FDA should require a post-marketing study that would proactively gather information about adverse events and longer-term safety, the effects on a broader range of people than were included in the trials, and possible complications of taking other medications including steroids along with fingolimod;
• patients should be monitored during the first dose for possible lowering of heart rate and other potential heart effects, and that some assessments for potential adverse events related to eye (especially macular edema) and lung function be required, to an extent to be determined by the FDA;
• the FDA should consider requiring a study to evaluate whether a lower dose would be as effective as the recommended dose, with fewer adverse events;
• this therapy should be approved as a first-line therapy, meaning that patients would be eligible to take fingolimod without having to try an alternative therapy first.
About the drug: Fingolimod is a new class of therapy in development for treating multiple sclerosis. It binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells, that have been implicated in causing nervous system damage in MS. The drug appears to induce immune cells to remain in lymph nodes, where they can do little harm, preventing them from migrating into the brain and spinal cord.
Positive results from two large-scale phase III clinical trials have been published showing that fingolimod significantly reduced multiple sclerosis relapse rates. One of the trials also suggested that fingolimod could slow the progression of disability. (New England Journal of Medicine January 20, 2010.) Read more about these studies on our Website. In December 2009, Novartis applied to the FDA and European regulators for marketing approval of this compound for the treatment of relapsing MS.
What Clinical Trials Found: According to the published results, a large-scale, two-year phase III trial known as FREEDOMS involved 1,272 people with relapsing-remitting MS. Over two years, fingolimod at either of two doses was able to significantly reduce relapse rates (the primary endpoint of the study) and slow disability progression (a secondary endpoint) compared to an inactive placebo. Annual relapse rates were 0.18 for the lower dose, 0.16 with the higher dose, and 0.40 for those on placebo (a reduction of 54% and 60% over placebo, respectively). Disease progression was measured by two standard MS clinical assessment tools known as the EDSS and MSFC, and after 24 months both doses showed slower progression compared to placebo. Secondary measures of disease activity and progression also favored both fingolimod doses, including MR imaging to detect tissue injury and brain atrophy.
The second paper detailed positive results from a one-year clinical trial, called the TRANSFORMS study, comparing two different doses of fingolimod with Avonex® (interferon beta-1a, Biogen Idec). That study involved 1,292 individuals with relapsing-remitting MS. Both doses of fingolimod were able to reduce relapse rates over one year (the primary endpoint of the study), and also reduced disease activity on MR brain imaging. The annualized relapse rate in those taking the lower dose of fingolimod was 0.16, compared to 0.33 in those on Avonex (a comparative reduction of 52%). Those taking the higher dose of fingolimod experienced an annualized relapse rate of 0.20 (a reduction of 38% compared with Avonex). Time to sustained disability progression was no different in the fingolimod and Avonex groups.
At the 2010 meeting of the American Academy of Neurology (Abstract P03.125), investigators reported on an extension of the TRANSFORMS study involving 1027 of the original participants. Those taking fingolimod stayed on the same dose, and those who had been on weekly interferon beta 1a received either 0.5 mg or 1.25 mg of fingolimod for one year. The annualized relapse rate (primary outcome) and inflammatory activity on MRI scans were significantly lower for those taking fingolimod for the entire two-year period compared to those switching to fingolimod at the beginning of the second year.
Safety: In the clinical trials, the lower dose was better tolerated. A few participants experienced a transient reduction in heart rate and blockage of heart conduction (atrioventricular conduction block) which generally normalized after the first dose. There was a slight elevation of blood pressure starting during the second month of therapy. Macular edema (swelling of the center of the retina inside the eye) occurred more frequently with those on the higher dose of fingolimod in both studies.
Elevations in liver enzymes, without accompanying symptoms, were common in those receiving fingolimod. In both studies, a small number of serious herpes infections occurred, including two deaths from herpes infections that occurred in the TRANSFORMS trial in people taking the higher dose of fingolimod.
Other phase III clinical trials of fingolimod, including one involving people with primary progressive MS, are still under way, as are extension studies involving those who’ve completed trials. These and other studies that may be required post-marketing should provide additional data on the safety and efficacy of fingolimod.
Comment: “If the FDA agrees that fingolimod is safe and effective, this would represent significant progress for people with MS – the first oral disease modifying therapy -- and would help address the unmet need for additional therapies,” said National MS Society Chief Medical Advisor Dr. Aaron Miller, Professor of Neurology and Medical Director of the MS Center at Mount Sinai Medical Center in New York City. Dr. Robert Lisak, MD, Chair of Neurology and Professor of Immunology and Microbiology at Wayne State University School of Medicine in Detroit, agreed. “I would welcome having another treatment option for my patients, particularly an oral medication that might make it easier for people to get on and stay on therapy. Taking a disease-modifying therapy is the best way we have of reducing MS disease activity and future deterioration. However, we will need to monitor all new therapies for any long-term safety issues.”
If approved, the decision to take an oral MS therapy should be made by people with MS in collaboration with their MS doctors, taking into account a variety of factors, including the effectiveness of any therapy they are currently using, and weighing potential risks and benefits, costs and lifestyle factors.
FAQ About June 10 FDA Advisory Committee’s Recommendation to
Approve Oral Fingolimod for Relapsing MS
Q. What is fingolimod?
A. Fingolimod is different than current MS therapies on the market and represents a new class of therapy, for one because it is taken orally rather than by injection or infusion, and secondly because of its mode of action. Fingolimod binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells that have been implicated in causing nervous system damage in MS. The drug appears to force immune cells to remain in lymph nodes where they can do little harm, and prevents them from migrating into the brain and spinal cord. Fingolimod is considered a disease-modifying agent, and if it is approved, it would not be taken along with other disease-modifying therapies.
Q. Does this announcement mean that fingolimod is approved and available for MS?
A. No, this does not mean that fingolimod is approved and available. The FDA will take this committee’s recommendation into account as it completes its review of the clinical trials’ benefit and safety data. The agency is expected to make a decision by September 2010. The FDA is not required to follow the advice of its advisory committees, but it usually does. The Society will have updates as we learn more from FDA announcements.
Q. What is the official brand name of fingolimod?
A. At present fingolimod, or FTY 720, does not have an approved name for marketing. The name proposed by Novartis – Gilenia -- was not accepted by the FDA. The usual reason the agency might reject a proposed name is that it may be too similar to the name of an approved drug, which could cause confusion in prescribing and dispensing the medications.
Q. What types of MS might fingolimod be approved to treat?
A. The application to the FDA requested approval to market fingolimod for the treatment of relapsing forms of MS (http://www.nationalmssociety.org/about-multiple-sclerosis/relapsing-ms/index.aspx). In other words, people who experience periodic MS attacks, such as those who have relapsing-remitting MS or secondary-progressive MS with relapses. However, this agent is also being tested in people with primary-progressive MS (http://www.nationalmssociety.org/about-multiple-sclerosis/progressive-ms/primary-progressive-ms/index.aspx) who experience steady worsening without acute attacks. If the FDA approves fingolimod for relapsing MS, and if it shows significant benefit in primary-progressive trials, it is likely that the sponsor will apply to expand its labeling to include progressive forms of MS. Read more about the clinical trial of fingolimod in primary-progressive MS, which is currently recruiting participants.
Q. How is fingolimod taken?
A. Fingolimod comes in capsules. If approved for marketing, it will likely be taken by mouth once a day, which is how it was taken during the clinical trials.
Q. How effective is fingolimod?
A. In a large-scale, two-year phase III trial known as FREEDOMS, involving 1,272 people with relapsing-remitting MS, fingolimod at either of two doses was able to significantly reduce relapse rates (the primary endpoint of the study) and slow disability progression (a secondary endpoint) compared to an inactive placebo. Annual relapse rates were 0.18 for the lower dose (which is the dose the sponsor is asking the FDA to approve) and 0.40 for those on placebo - a reduction of 54% over placebo. Disease progression was measured by two standard MS clinical assessment tools, the EDSS and the MSFC. After 24 months, both doses slowed progression compared to placebo. Secondary measures of disease activity and progression, including MR imaging to detect tissue injury and brain atrophy, also favored both fingolimod doses. Details of two large-scale clinical trials were published early online on January 20, 2010 in the New England Journal of Medicine -- the two-year placebo-controlled trial and the one-year trial comparing fingolimod to interferon beta-1a.
Q. Should I switch from my current therapy to fingolimod?
A. If fingolimod is approved, the decision about whether to take it should be made in collaboration with your MS doctor, taking into account a variety of factors including the effectiveness of any therapy you are currently using, the potential risks and benefits, as well as costs and lifestyle factors.
Q. What are the potential side effects of fingolimod?
A. In clinical trials, some participants experienced a transient reduction in heart rate and blockage of heart conduction (atrioventricular conduction block) which generally normalized after the first dose. There was a slight elevation of blood pressure starting during the second month of therapy. Macular edema (swelling of the center of the retina inside the eye) occurred more frequently with those on the higher dose of fingolimod than the dose being proposed in the sponsor’s application. Elevations in liver enzymes, without accompanying symptoms, were common in those receiving fingolimod. A small number of serious herpes infections occurred, including two deaths from herpes infections that occurred in people taking a higher dose of fingolimod than the dose that the sponsor is proposing to market.
Q. Has fingolimod been proven to be “better” than other disease-modifying therapies?
A. No, fingolimod has not been demonstrated to be “better” than other disease modifying therapies. So far, the only comparison to an existing disease-modifying therapy has been in the one-year, head-to-head “TRANSFORMS” trial against Avonex® (interferon beta-1a, Biogen Idec). This trial suggested short-term superiority of fingolimod, but the trial was too short to be definitive in terms of comparing long-term benefits of the two therapies. In this trial, fingolimod caused more serious side effects than Avonex. Fingolimod has not been compared to other available disease-modifying therapies.
Q. If it is approved, how long would a person take fingolimod?
A. Based on the advisory committee discussions, it is likely that an individual could potentially take fingolimod indefinitely.
Q. If fingolimod is approved, will people taking it have to get any special medical tests or monitoring?
A. The clinical trials showed that there is the potential for significant side effects in some patients even at the lower dose being proposed for marketing. Therefore, it is likely that monitoring would be required if fingolimod is approved for clinical use. Details of a risk management plan (“Risk Evaluation Mitigation Strategies”) that would likely be mandated to monitor safety will be negotiated between the FDA and the sponsor before the agent is approved.
Q. If it is approved, what will fingolimod cost?
A. At this point, there is no information available about what fingolimod may cost – but the actual cost to a person with MS will depend on the provisions of his or her insurance coverage.
Q. If fingolimod is approved, would it be immediately available to everyone who gets a prescription, or would there be a waiting list?
A. According to Novartis representatives, if fingolimod is approved, the company would ensure that there is an adequate supply when the drug becomes available by prescription.
Q. If fingolimod is approved by the FDA, will my health insurance cover it?
A. Coverage will depend on individual insurance plans. It is likely that fingolimod’s sponsor, Novartis, will provide support services to help patients and healthcare professionals access the therapy. Details of support services are likely to be made available by Novartis if and when the agent is approved.
Q. Where can I get additional information about the support that Novartis will provide to help people gain access to fingolimod?
UPDATE: New phone #
A. If and when fingolimod is approved for use, physicians and people with MS can contact Novartis for more information at: 888-NOW-NOVA (888-669-6682)
Q. Are there other oral disease-modifying therapies in development for MS?
A. Yes, there are others in development. Cladribine (sponsored by EMD Serono) has been shown to reduce MS relapses and slow progression in relapsing-remitting MS. It has been submitted to the FDA for marketing approval, but the application has not yet been accepted by the FDA.
Additional oral agents currently in phase III clinical trials are: teriflunomide (sponsored by sanofi-aventis), BG00012 (sponsored by Biogen Idec), and laquinimod (sponsored by Teva Pharmaceutical Industries). They are being tested in relapsing MS and in people at high risk for MS, after earlier trials suggested potential benefits against disease activity.
Q. I’ve been hearing news about other new treatments in development for MS. What are some details?
A. Oral disease-modifying therapies are only one of many exciting treatments moving through the MS pipeline and other promising research avenues that address ways to stop MS progression, restore function and end MS forever. Just a few therapies being tested include the hormone estriol, adult stem cell transplantation, and infused drugs that require infrequent dosing. The National MS Society has established a Rapid Response Fund to pursue new and unexpected research opportunities when they arise, a recent example being our expedited funding of research exploring the potential relationship between CCSVI and the MS disease process. Check our Website for information on an upcoming live Webcast on June 30 on What’s new in MS research and treatment?
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