Research News Fall 2009
By Susan Wells Courtney; Reviewed by Dr. Jack Burks
Extavia Receives FDA Approval for Treatment of MS
In addition to the recent approval of Extavia, other drug updates include Fampridine-SR, oral cladribine, Copaxone, Tysabri, and fingolimod.
On August 14, 2009, the United States Food and Drug Administration (FDA) approved Extavia® (interferon beta-1b) for the treatment of relapsing forms of multiple sclerosis (MS).
Extavia is also approved for individuals who have had a clinically isolated syndrome (CIS), which refers to those who experience a single attack of one or more symptoms characteristic of MS, with a high risk of developing clinically definite MS (CDMS). Marketed by Novartis Pharmaceuticals Corporation, Extavia is the same medicinal interferon beta-1b product as Betaseron®. No changes will occur in the marketing of Betaseron, which will continue to be available by prescription to MS patients. Extavia became available by prescription in the United States in October 2009.
Novartis offers nursing support and education to individuals who may be prescribed Extavia. A telephone helpline as well as one-on-one training with injection procedures are among the services provided. Extavia is given at the same dose and frequency as Betaseron: 250 micrograms administered via subcutaneous (under the skin) injection every other day. Patients may choose between traditional injections or using an autoinjector. Support services will include insurance advocacy and a reimbursement program for those who qualify.
Extavia will be joining six other disease-modifying therapies (DMTs) in the marketplace, all of which have been previously approved by the FDA for the treatment of MS. In addition to Betaseron, these include: Avonex® and Rebif® (interferon beta-1a); Copaxone® (glatiramer acetate); Novantrone® (mitoxantrone); and Tysabri® (natalizumab). Betaseron has been used in the United States for more than 16 years. For individuals with relapsing forms of MS, it has been shown to reduce relapse rates by 34 percent, and may slow disease progression. For individuals with CIS, almost 75 percent did not progress to CDMS (as indicated by having a second relapse) following two years of treatment.
Flu-like symptoms and injection site reactions are among the commonly reported side effects with interferon beta-1b. These can often be minimized by gradual dose titration (starting with a low dose and increasing the dose slowly) and closely following injection instructions, along with the prophylactic use of analgesics during treatment initiation. Allergic reactions are among the rare complications of interferon use.
Self-injection techniques should be re-evaluated periodically to ensure that proper procedures are being followed. As with other injectable treatments for MS, rotating the injection sites is important, although the specific rotation recommended for Extavia may differ slightly from that of Betaseron. Blood monitoring and liver function tests are also recommended at regular intervals. Additionally, female patients considering Extavia should be warned about the potential risks of interferon use with pregnancy. This drug should be used with caution in patients who also experience depression.
Novartis was given the rights to seek approval for its own branded version of interferon beta-1b through an agreement with Bayer Schering, the company which markets Betaseron. Outside of the United States, Extavia is presently available in 12 European countries for the treatment of MS. Betaseron is also available outside of the United States and is marketed as Betaferon®.
Novartis has information lines for anyone who has questions about Extavia. Members of the MS community may call (866) 925-2333 for more information. Healthcare professionals with product-specific questions may call 866-EXTAVIA, or (866) 398-2842. Information is also available on Extavia’s website at www.extavia.com.
Please note that this article also appears on MSAA’s website at www.mymsaa.org under “Recent News.” To speak with a Helpline consultant about MS, its treatments, and MSAA’s programs and services, or for additional support, individuals may call MSAA’s Helpline at (800) 532-7667.
FDA Reviews Fampridine-SR Study Data
The United States’ Food and Drug Administration (FDA) is presently reviewing the New Drug Application (NDA) for 10 mg daily doses of oral Fampridine-SR, an investigational drug that improves the conduction of impulses between damaged nerves. This increase in communication between damaged nerves could increase neurological function, such as strength and endurance.
Individuals with relapsing forms of MS, as well as individuals with progressive forms of MS, were included in the trials. Results from the Phase II and Phase III studies showed that a significantly greater number of “Timed Walk Responders” were in the treated group versus the placebo group. A “Timed Walk Responder” refers to someone who experienced a consistent improvement in walking speed when taking the drug, versus his or her timed walking speed when not taking the drug.
Developed by Acorda Therapeutics and manufactured by Elan Corporation, Fampridine-SR is a sustained-release version of 4-aminopyridine (4AP). In earlier studies, larger doses of the drug were given; however, the risk of seizures with this drug became a concern. With the sustained-release version, the risk of seizures did not differ from the placebo group. The most common adverse events included urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, and back pain.
The FDA’s Advisory Committee voted in early October 2009 to recommend approval. The FDA’s decision-making body has extended its deadline for completing its review of Fampridine-SR’s study data to January 22, 2010. The FDA could potentially approve this drug for individuals with MS at that time.
Application Submitted to FDA for Oral Cladribine Tablets
On September 30, 2009, EMD Serono announced that a New Drug Application (NDA) had been submitted to the FDA for the investigational, oral form of cladribine for the treatment of relapsing forms of MS. This drug has been designated by the FDA as a Fast Track product, for an expedited review.
The CLARITY study was a two-year Phase III trial of two dose levels of cladribine tablets versus placebo in 1,326 randomized relapsing-remitting patients. Tablets were given in two or four treatment courses per year, with four to five consecutive once-daily doses per treatment course.
All primary and secondary endpoints were reached in this trial, including a 55 to 58-percent reduction in annual relapse rates, as well as a reduction in gadolinium-enhanced lesions as seen by magnetic resonance imaging (MRI) scans. Most common side effects, such as headache and nausea, were similar between all three groups. Lymphopenia (low level of lymphocytes in the blood) and herpes zoster infection occurred more often in the treated groups; four individuals taking cladribine developed malignancies.
A safety registry for cladribine is being planned and will help to determine the long-term safety of this drug. If approved in the coming months, cladribine tablets could be the first oral disease-modifying therapy (DMT) available for individuals with relapsing forms of MS.
Copaxone Approved for Treatment of Early MS
Copaxone® (glatiramer acetate) is one of the seven approved DMTs for the long-term treatment of relapsing forms of MS. Teva Neuroscience markets this drug, which is given via daily subcutaneous injections.
Earlier this year, the results of the PreCISe Phase III study were presented to the FDA. This study found that individuals who initially experience a single neurological event suggestive of MS (known as a clinically isolated syndrome or “CIS”), were 45 percent less likely to develop clinically definite MS during the study period when given Copaxone, compared to those in the placebo group. In 25 percent of the treated patients, conversion to clinically definite MS was delayed by 115 percent (from 336 days for placebo to 772 days for Copaxone).
From these findings, the FDA expanded its approval of Copaxone in March 2009, for the early treatment of patients who have experienced a CIS and have MRI features consistent with MS. The results of this trial were published in the October 6, 2009 issue of Lancet.
New Cases of PML with Tysabri
Tysabri® (natalizumab) is also one of the seven approved DMTs for the long-term treatment of relapsing forms of MS. It is administered via intravenous infusion every four weeks and is generally recommended for patients who have not responded adequately to, or who cannot tolerate, another treatment for MS. Tysabri is marketed by Biogen Idec and Elan Pharmaceuticals, Inc.
Patients taking this drug are at an increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), a sometimes fatal viral infection of the brain. All patients now receive the drug through safety monitoring programs such as the Tysabri Outreach: Unified Commitment to Health (TOUCH™) Prescribing Program and registered infusion centers and pharmacies in the United States; and the international Tysabri Global Observation Program In Safety (TYGRIS). As of October 2009, more than 60,000 patients had been treated with the drug worldwide. The reported cases of PML are now at 24, since its re-release in 2006 after a temporary suspension due to the discovery of PML in patients taking Tysabri.
The European Medicines Agency (EMEA) is conducting a risk-benefit evaluation of Tysabri to see if any additional steps may be necessary to ensure the safety of patients taking the drug. Presently, the TOUCH program in the United States is able to monitor patients more closely than through the international program. Studies are ongoing to see if it is possible to predict which individuals may be at risk for this condition. If PML is suspected or diagnosed, the Tysabri treatment is immediately discontinued; the patient then undergoes plasmapheresis (also known as plasma exchange or “PE”), to help clear the drug from the patient’s blood system. Sometimes this procedure of rapidly clearing Tysabri from the blood can precipitate an Immune Reconstitution Inflammatory Syndrome (IRIS), which can cause additional symptoms.
Initial Phase III Study Results Reported for Fingolimod
Fingolimod (FTY720) is an investigational, oral medication taken daily for the long-term treatment of MS. Studies are now being conducted with relapsing-remitting as well as primary-progressive types of MS. Its parent company is Novartis Pharmaceuticals Corporation.
Previously, a 36-month Phase II study showed that 60 percent of relapsing-remitting MS patients remained relapse-free and had a low rate of disease activity as observed on MRI. An extension study, FREEDOMS II, is evaluating long-term safety, tolerability, and efficacy; all participants are receiving fingolimod. There have been two deaths from Herpes virus infection in the FREEDOMS trials.
On September 30, 2009, initial results from the FREEDOMS Phase III studies of low-dose and high-dose fingolimod versus placebo were announced. According to a press release from Novartis, fingolimod reduced relapse rates by 54 to 60 percent compared to those taking a placebo. Disability progression was reduced by 30 to 32 percent.
Fingolimod was generally well tolerated and had fewer adverse events with the lower dose than the higher dose. In the TRANSFORMS trial of fingolimod versus Avonex, fingolimod patients had fewer relapses. Novartis is planning to submit fingolimod’s study results to the FDA (as well as to European agencies) at the end of 2009, for possible approval.
Plans to Submit Study Data for Zenvia
One of the lesser-known symptoms of MS is pseudobulbar affect (PBA), a neurologic condition characterized by uncontrolled, inappropriate, and/or exaggerated episodes of crying, laughing, or other emotional display, occurring with only minimal or no stimulation to invoke such a response. Presently, no FDA-approved drugs are available to treat PBA.
Avanir Pharmaceuticals has been conducting trials with their investigational drug, Zenvia™ (dextromethorphan/quinidine), for the treatment of PBA. On August 11, 2009, Avanir announced that Zenvia had met is primary endpoint of effectiveness in treating PBA, in the confirmatory Phase III STAR trial. Two dose levels and a placebo were compared in this 12-week study. The two doses were both lower-dose formulations than those used in previous studies, and have an improved safety and tolerability profile.
A 47.2 percent incremental reduction in the rate of episodes was experienced by the higher-dose group, compared to the placebo group. The lower-dose group also had an incremental reduction in episodes compared to placebo, and the higher-dose group reported an 88-percent mean reduction of episodes compared to their rates at baseline (prior to taking the drug).
Avanir plans to submit study data to the FDA in the first half of 2010. To learn more about PBA, please visit www.pbainfo.org. Readers may also visit www.mymsaa.org or call MSAA’s Helpline at (800) 532-7667 for more information.
