Encouraging results for many new and future therapies for MS were discussed at ECTRIMS this month.
Although October is recognized as Breast Cancer Awareness Month, this year multiple sclerosis was in the spotlight just as frequently. A plethora of exciting developments in the field of multiple sclerosis (MS) was unveiled at the Annual European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) congress held on October 7-10, 2015 in Barcelona, Spain. Reported at the congress, new data reinforces strengths of already approved therapies and sets the stage for therapies of the future.
According to the reports on Genentech’s ocrelizumab, the drug is effective in relapsing and primary progressive MS, which makes it the first investigational agent effective in both patient populations.1 In patients with relapsing MS, ocrelizumab treatment is superior to interferon beta-1a (Rebif®, as shown by two identical phase 3 studies, OPERA I and OPERA II. Ocrelizumab, administered by IV infusion in the dose of 600 mg every 6 months, significantly reduced annualized relapse rate by 46% in the OPERA I and by 47% in the OPERA II study over the 2-year period (P < 0.0001 in each study). Comparator, interferon beta-1a, was administered as a subcutaneous injection in the dose of 44ug 3 times per week.
Conducted in patients with primary progressive MS, the ORATORIO study has compared ocrelizumab to placebo and found that ocrelizumab slows the progression of clinical disability. The risk of progression of clinical disability, measured by the Extended Disability Status Scale, was significantly reduced by 24% in the ocrelizumab group for at least 12 weeks (P = 0.0321). In this study, ocrelizumab was administered every 6 months by IV infusion as two 300-mg doses 2 weeks apart.
To date, ocrelizumab is the most successful attempt of drug manufacturers to find treatment for progressive MS. At the end of 2014, Novartis announced that the INFORMS study, which compared fingolimod and placebo in patients with primary progressive MS, did not meet its primary endpoint.2 Just a few days ago, another drug manufacturer, Biogen, has announced that natalizumab (TYSABRI®) was not superior to placebo in slowing the disability progression in patients with secondary progressive MS, ie, failed to meet both primary and secondary endpoints in the phase 3 ASCEND study.3
Ocrelizumab, a humanized monoclonal anti-CD20 antibody, binds to extracellular domain of CD20 antigen of B cells. The drug’s efficacy highlights an important role of B cells in MS pathology. The superiority of ocrelizumab, which targets B cells, over interferon beta-1a, which targets T cells, may indicate a central role of B cells in pathology of progressive MS.
Manufacturers of approved disease-modifying therapies for relapsing MS have also reported positive news during the ECTRIMS congress. Long-term efficacy of alemtuzumab (Lemtrada®), dimethyl fumarate (TECFIDERA®), and fingolimod (Gilenya®) has been demonstrated in several phase 3 studies. Sanofi and its subsidiary Genzyme have reported sustained effects of twice-a-year alemtuzumab in CARE-MS I and CARE-MS II studies.4 Patients enrolled in the studies, each of which lasted 2 years, were followed for an additional 3 years. The 2 doses of alemtuzumab were given at months 0 and 12; 60% of patients enrolled in CARE-MS I and 68% of patients enrolled in CARE-MS II did not receive additional treatment through month 60.
New data on efficacy and safety of dimethyl fumarate were presented at the congress.5 First, superior efficacy of dimethyl fumarate compared to placebo was reported in patients with early relapsing MS: the drug significantly reduced annualized relapse rate by 63% (P < 0.0001) and the risk of 12-week confirmed disability progression by 40% (P = 0.0066). These data were collected in 2 phase 3 studies, DEFINE and CONFIRM, conducted by Biogen. Second, post-hoc analysis of the CONFIRM study revealed that dimethyl fumarate is superior to glatiramer acetate in reducing inflammatory disease outcomes (hazard ratio of 0.77; 95% confidence interval, 0.59-0.99; P = 0.0446). And third, integrated post-hoc analysis of the CONFIRM, DEFINE, and ENDORSE studies demonstrated a favorable risk-benefit profile of dimethyl fumarate over the 6-year follow-up period. ENDORSE is an ongoing, phase 3 extension study: enrolled patients will be followed for up to 8 years.
Similar news regarding Novartis’ fingolimod was released. Analysis of pooled data from 2 phase 3 trials, FREEDOMS and FREEDOMS II, confirmed a favorable long-term safety of fingolimod.6 A greater number of patients on fingolimod vs placebo had no evidence of disease activity, NEDA-4, for up to 7 years.
A report of efficacy of a nonpharmacological intervention for MS-associated fatigue was presented at the congress. In a randomized controlled study, Poettgen and colleagues have evaluated the ability of a fully automated online cognitive behavioral therapy program to reduce fatigue in patients with MS.7 At 3 months, participation in the program significantly reduced fatigue, anxiety, and subjective cognitive impairment, but not depression or coping.
The findings presented at the congress should indeed encourage the 400,000 people living with MS in the United States.8 Let’s hope that clinicians treating these people will soon have new, better therapies to help those who currently have few options – Genentech plans to apply for FDA approval of ocrelizumab in early 2016.
1. Genentech’s Ocrelizumab First Investigational Medicine to Show Positive Pivotal Study Results in Both Relapsing and Primary Progressive Forms of Multiple Sclerosis [press release]. South San Francisco, CA: Genentech; October 8, 2015. http://www.gene.com/media/press-releases/14609/2015-10-08/genentechs-ocrelizumab-first-investigati Accessed October 27, 2015.
2. Novartis provides update on fingolimod Phase III trial in primary progressive MS (PPMS) [press release]. Basel, Switzerland: Novartis; December 1, 2014. https://www.novartis.com/news/media-releases/novartis-provides-update-fingolimod-phase-iii-trial-primary-progressive-ms-ppms Accessed October 27, 2015.
3. Biogen Reports Top-Line Results from Phase 3 Study Evaluating Natalizumab in Secondary Progressive MS. [press release]. Cambridge, MA: Business Wire; October 21, 2015. http://www.businesswire.com/news/home/20151021005273/en/ Accessed October 27, 2015.
4. Treatment Effects Maintained Over Five Years in Majority of Patients with Relapsing Remitting Multiple Sclerosis who Received Genzyme's Lemtrada® (alemtuzumab) in Clinical Trials [press release]. Paris, France: Sanofi; October 8, 2015. http://en.sanofi.com/NasdaQ_OMX/local/press_releases/treatment_effects_maintained_o_1957284_08-10-2015!07_00_00.aspx Accessed October 27, 2015.
5. New Data Show Strong, Sustained Effects of TECFIDERA® (Dimethyl Fumarate) in Newly-Diagnosed and Early Disease Course Multiple Sclerosis Patients [press release]. Cambridge, MA: Business Wire; October 7, 2015. http://media.biogen.com/press-release/neurology/new-data-show-strong-sustained-effects-tecfidera-dimethyl-fumarate-newly-dia Accessed October 27, 2015.
6. Long-term efficacy of Gilenya® reinforced by new 'no evidence of disease activity' (NEDA-4) analysis in MS patients over seven years [press release]. Basel, Switzerland: Novartis; October 8, 2015. https://www.novartis.com/news/media-releases/long-term-efficacy-gilenya®-reinforced-new-no-evidence-disease-activity-neda-4 Accessed October 27, 2015.
7. Poettgen J, et al. Online fatigue management program for patients with multiple sclerosis - a randomized controlled trial. Presented at: ECTRIMS; Oct 8, 2015; Barcelona, Spain; http://onlinelibrary.ectrims-congress.eu/ectrims/2015/31st/116705/jana.poettgen.online.fatigue.management.program.for.patients.with.multiple.html?f=m3s546633 Accessed October 28, 2015.
8. MS Prevalence. National Multiple Sclerosis Society Web site. http://www.nationalmssociety.org/About-the-Society/MS-Prevalence Accessed October 28, 2015.