Exciting advances in the treatment of multiple sclerosis (MS) occurred in 2010 and continues as the MS pipeline remains robust.
There were many key developments in the treatment of multiple sclerosis (MS) in 2010. These exciting advances are expected to continue as the MS pipeline remains robust, with additional MS approvals anticipated in the coming year.
2010 in Review
Ampyra (dalfampridine) was approved on January 22, 2010, as the first therapy specifically to treat a symptom of MS. It is a potassium channel blocker indicated to improve walking in patients with MS as demonstrated by an increase in walking speed. Dalfampridine is an oral medication dosed at 10 mg twice daily. The primary measure of efficacy in the pivotal trials was walking speed (in ft per sec) as measured by the Timed 25-foot Walk, using a responder analysis.
In 1 of the pivotal trials, 35% of patients were determined to be responders to dalfampridine. Walking speed change from baseline was 0.51 ft/sec in the dalfampridine-treated responders, 0.16 ft/sec in the dalfampridine-treated nonresponders, and 0.1 ft/sec in the placebo group. Dalfampridine is contraindicated in patients with moderate or severe renal impairment and in those patients who have had a history of seizures. The most common adverse events were urinary tract infections, insomnia, dizziness, headache, and nausea.
Gilenya (fingolimod), the first oral disease modifying therapy for MS, was approved by the FDA on September 21, 2010. Fingolimod is the first approved drug to act as a sphingosine 1-phosphate receptor modulator. Fingolimod is dosed as 0.5 mg by mouth once daily. The primary end point in the FREEDOMS pivotal placebo controlled trial involving 1272 patients with relapsing-remitting MS was reduction in relapse rates. Relapse rates were reduced in this study from an annualized rate of 0.40 for those receiving placebo to 0.18 for those taking fingolimod 0.5 mg daily (a comparative reduction of 54%).
In the TRANSFORMS trial, fingolimod safety and efficacy was evaluated versus interferon beta-1a intramuscular (Avonex). The annualized relapse rate in those taking fingolimod was 0.16, compared with 0.33 in those taking Avonex (a comparative reduction of 52%). The most common adverse events associated with fingolimod include headache, influenza, diarrhea, back pain, increases in liver function tests, and cough.
Nuedexta (dextromethorphan and quinidine) is a dual-action glutamate inhibitor and was approved on October 29, 2010. It is indicated for the treatment of pseudobulbar affect, which impacts approximately 10% of the MS population and is characterized by sudden, inappropriate, and unpredictable outbursts of crying, laughing, or anger and irritability. It is a neurological disorder secondary to a variety of neurologic conditions, including traumatic brain injury, amyotrophic lateral sclerosis, and several types of dementias, in addition to MS. The dextromethorphan/quinidine combination is dosed at one 20-mg/10-mg capsule given orally once daily for 7 days and then a maintenance dose of one 20-mg/10-mg capsule given every 12 hours.
The primary efficacy outcome in the STAR pivotal trial was changes in crying or laughing episode rates as recorded in patient diaries. On day 15 of the trial, patients in the dextromethorphan/quinidine 20-mg/10-mg group reported a mean decrease in laughing or crying episodes of between 4 and 5 fewer episodes per day as compared with those receiving placebo, who reported a mean decrease of approximately 2 fewer episodes per day. The most common adverse events associated with dextromethorphan/quinidine were diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, and urinary tract infection.
Looking to 2011 and Beyond
Cladribine is an oral agent currently under review for approval by the FDA. The FDA granted Priority Review status for cladribine tablets in July 2010, which was set to end on November 28, 2010. However, Merck recently announced the FDA has extended its review period by 3 months to February 28, 2011. It is anticipated that cladribine will compete with fingolimod and the other disease modifying MS agents as a first-line therapy for relapsing forms of MS.
In the CLARITY pivotal trial, patients were assigned to receive placebo or 1 of 2 cumulative doses of cladribine over 96 weeks, either 3.5 or 5.25 mg per kg of body weight. Depending on the cumulative dosing group and body weight, patients took either 1 or 2 cladribine 10-mg tablets in 2 or 4 short courses (4 to 5 days) for the first 48 weeks, then in 2 short courses starting at week 48 and week 52, for a total of between 8 and 20 days of treatment per year. The primary end point in the CLARITY trial was relapse rate at 96 weeks. The 3.5 mg/ kg cladribine group had an annualized relapse rate of 0.14, and the 5.25 mg/ kg cladribine group had an annualized relapse rate of 0.15 compared with an annualized relapse rate for the placebo group of 0.33 (a relative reduction of 57.6% and 54.5% respectively vs placebo). Adverse events included headache, lymphocytopenia, nasopharyngitis, upper respiratory tract infection, nausea, and reactivation of herpes zoster. Cladribine given intravenously (IV) is currently approved in the United States as an agent for hairy cell leukemia.
Dimethyl fumarate is currently wrapping up phase III trials for relapsing remitting MS. Biogen Idec expects results from the phase III trials DEFINE and CONFIRM to be available in the first half of 2011. DEFINE is determining if dimethyl fumarate (study drug name BG00012) can decrease the number of MS relapses, decrease the number of brain lesions, and slow disease progression. DEFINE is evaluating dimethyl fumarate given orally at a dose of two 120-mg capsules twice daily, dimethyl fumarate given orally at a dose of two 120-mg capsules 3 times daily, or placebo. CONFIRM is looking at similar primary end points, but will be comparing the 2 dosing regimens of dimethyl fumarate against glatiramer acetate (Copaxone) 20 mg given subcutaneously once daily. The drug, if approved, is slated to be marketed under the name Panaclar. There are also phase II studies currently ongoing looking at dimethyl fumarate as add-on treatment in conjunction with glatiramer acetate or an interferon.
Alemtuzumab is a monoclonal antibody currently approved as Campath in the United States for chronic lymphocytic leukemia. Genzyme is conducting 2 phase III trials for its use in relapsing forms of MS and results are expected mid-2011. Genzyme expects to file for FDA approval in 2012. Doses of alemtuzumab being studied are 12 or 24 mg per day given IV once daily for 5 consecutive days at the start of therapy and then 1 year later, 12 or 24 mg given once per day for 3 consecutive days. The CARE-MS I trial is looking at patients who have not been previously treated for MS and contains the 12 mg alemtuzumab protocol vs interferon beta 1-a (Rebif).
The CARE-MS II trial is looking at patients who have received an adequate trial of disease-modifying therapy but continued to relapse while being treated and will be looking at the 2 dosing regimens of alemtuzumab vs interferon beta-1a (Rebif). Alemtuzumab is expected to be marketed as Lemtrada if it gains approval for MS and is anticipated to be viewed as a second-line agent depending upon the outcome of CARE-MS I and II.
Laquinimod is an oral agent currently in phase III development by Teva Pharmaceuticals. Laquinimod is given as 0.6 mg capsule once daily. Results from a phase III trial of the drug called ALLEGRO are expected to be released in April 2011 at the American Academy of Neurology Annual Meeting. Teva has stated that the drug did meet its primary end point in ALLEGRO of decreasing relapse rate versus placebo and did not show alarming safety signals. Results from a second phase III trial named BRAVO are expected in third quarter 2011, after which time Teva is expected to file for FDA approval. BRAVO will study oral laquinomod 0.6 mg once daily against placebo and interferon beta 1-a (Avonex).
Teriflunomide is an oral agent currently in phase III development by sanofi-aventis. Results from a phase III trial of the drug called TEMSO showed that patients who were given a 7- or 14- mg tablet of teriflunomide orally once daily showed a reduction in relapse rates as compared with placebo. Annualized relapse rates were 0.370 in the teriflunomide 7 mg group, 0.369 in the teriflunomide 14 mg group, and 0.539 in the placebo group (corresponding to a relative risk reduction of 31.2% and 31.5% vs placebo). Side effects that were more common in the treatment groups were diarrhea, nausea, alanine aminotransferase increases, and mild hair thinning. TOWER is an additional phase III trial and results are expected in 2012, after which sanofi-aventis is expected to file a New Drug Application with the FDA. TENERE is a phase III trial looking at teriflunomide in a head-to-head comparison with interferon beta-1a (Rebif). TERACLES is a newly initiated phase III trial that will set out to show whether or not the addition of 7 or 14 mg of teriflunomide will reduce relapses in patients who are also being treated with interferon beta.
Daclizumab is a humanized monoclonal antibody indicated in the United States for prophylaxis of acute organ rejection in patients receiving renal transplants. It was marketed as Zenepax, but discontinued by Roche in 2009 due to diminishing market demand for that indication. Biogen Idec is currently conducting phase III trials for daclizumab in MS. A phase III trial started in March 2010 is being conducted to determine efficacy of preventing MS relapse. Study dosing of daclizumab is 150 mg subcutaneously once every 4 weeks versus interferon beta-1a (Avonex) 30 mg intramuscularly given once weekly for 96 to 144 weeks. The study is aiming for enrollment of 1500 patients and is expected to be complete in January 2014.
In addition to the above-mentioned drugs in development, there are many other advances ongoing in MS. Merck/EMD Serono has a new formulation of Rebif currently under review at the FDA, designed to reduce injection site reactions and antibody formation. Biogen is in Phase III testing with a pegylated version of Avonex. The pegylated Avonex study is assessing 125 mcg subcutaneously every 2 weeks or every 4 weeks with 1-year results expected mid-2011.
Teva is working on a lower volume injection for Copaxone (0.5 ml vs the 1 ml currently available), but was handed a setback as the FDA issued a complete response letter to Teva in December 2010. It stated that they will not approve the application as-is because the FDA feels that even a formulation change could impact clinical outcomes because the mechanism of action of glatiramer acetate is not fully understood. This statement may also impact the multiple manufacturers who are awaiting FDA decision on a generic version of glatiramer acetate. Teva is also evaluating Copaxone 40 mg subcutaneously 3 times per week dosing.
Gilenya (fingolimod), already approved for relapsing remitting MS, is in phase III for treatment of primary progressive MS. Rituximab is now being evaluated on whether or not it has effect on secondary progressive MS. Cyclophosphamide is in phase III to evaluate its use in secondary progressive MS. Studies in earlier phases of development are ongoing as well. Estriol 8 mg orally once daily is being studied in phase II combination with glatiramer acetate 20 mg subcutaneously once daily. Roche is preparing to start a phase III trial of ocrelizumab 400 or 600 mg IV every 24 weeks versus Rebif 44 mcg subcutaneously 3 times weekly.
In addition to the disease-modifying treatment pipeline, significant work is being done to help alleviate symptoms of MS through pharmacotherapy and rehabilitation. The National MS Society, the Consortium of Multiple Sclerosis Centers, The MS Foundation, and other important organizations are working to serve patients and to add to the understanding of factors that influence whether or not a person develops MS, which will bring about a better understanding of the ultimate goal—how to prevent MS from occurring. SPT
The above information is a selective summary of publicly available information. Please consult the sources, available at www.SpecialtyPharmacyTimes.com, for complete information.
Stacey Ness, PharmD, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence and persistency programs, and chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, Hematology and Oncology Pharmacy Association and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. Dr. Ness is currently the Associate Director of Specialty Services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, New Jersey. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc. Significant work is also being done to help alleviate symptoms of MS through pharmacotherapy and rehabilitation.
Dr. Ness is Associate Director of Specialty Services at Managed Health Care Associates Inc in Florham Park, New Jersey.