Siponimod NDA Accepted by FDA for Secondary Progressive MS

Bruce Bebo, PhD, Executive Vice President Research, National MS Society

Bruce Bebo, PhD

Novartis has announced the FDA acceptance of the company’s new drug application (NDA) for siponimod (BAF312), an oral, once-daily medication under investigation for the treatment of secondary progressive multiple sclerosis in adults. Additionally, a marketing authorization application was accepted by the EMA. Regulatory action is anticipated in March 2019 in the US and late 2019 in Europe.

The NDA is backed by data from the phase III EXPAND study, which compared the efficacy and safety of siponimod versus placebo in those living with typical secondary progressive multiple sclerosis.¹

“We are excited to see a potential new treatment on the horizon,” Bruce Bebo, executive vice president research, National MS Society, United States, said in a statement.² “It is a significant milestone in our unrelenting search for treatments that can benefit adults living with secondary progressive MS who currently have few options.”

EXPAND, the randomized, double-blind trial, included 1651 participants in 31 countries, who were randomized 2:1 to receive 2 mg of siponimod once daily or placebo. In total, 1099 participants received siponimod and 546 placebo, but of those, 82% (n=903) and 78% (n=424) of the siponimod and placebo participants completed the trial, respectively. At the onset of the study, more than 50% of patients relied on a walking aid. Participants were a mean age of 48, with the average time since symptom onset being 16.8 years.

In the first 12 months, there was a 75% decrease in T2 lesion volume for the intervention group from baseline 10286 mm3 (205 mm3 for the siponimod group versus 818 mm3 with placebo), decreasing further by month 24 to 83% (163 mm3 with siponimod, 940 mm3 with placebo; P <.001). The number of new or enlarging T2 lesions was 1 in the intervention group compared to 3.78 in the placebo arm ( P <.0001) at month 12, and at month 12, this dropped to an average of .49 new lesions in the intervention arm compared to 3.44 in placebo.

Researchers reported that participants treated with siponimod reported a statistically significant reduction in disability progression risk. Through a model-based approach in the analyses, researchers noted that the estimated risk reduction for disability progression sustained at 3 months ranged from 14% to 20% compared to placebo for non-relapsing participants, with that risk reduction at 6 months developing to 29% to 33%.

The advanced analyses showed that 288 (26%) of 1096 participants receiving siponimod and 173 (32%) of 545 participants receiving placebo had 3-month confirmed disability progression (hazard ratio [HR], 0.79; 95% CI 0.65 to 0.95; relative risk reduction 21%; P = .013). Siponimod also significantly delayed the risk of 6-month confirmed disability progression (26% versus placebo, P = .0058).

Adverse effects occurred in 89% of participants in the intervention arm versus 82% of those receiving placebo. Serious adverse effects were reported in 18% and 15% of the siponimod and placebo groups, respectively. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo.

In an interview with NeurologyLive, when asked about the pipeline of treatments for progressive multiple sclerosis, Fred Lublin, MD, Director, Corinne Goldsmith Dickerson Center for Multiple Sclerosis, Mount Sinai, expressed his excitement. He mentioned that at the moment, the most successful therapy was the recent clinical developments of siponimod, the next generation of fingolimod, that has demonstrated modest effects on secondary progressive disease.

REFERENCES

1. Kappos L, Bar-Or A, Cree B, Fox R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase III study. The Lancet. 2018;391(10127):1263—1273.

doi

: 10.1016/S0140-6736(18)30475-6.

2. Novartis announces FDA and EMA filing acceptance of

siponimod

, the first and only drug shown to meaningfully delay disability progression in typical SPMS patients [news release]. Basel, Switzerland: Novartis; Oct. 8, 2018. https://www.novartis.com/news/media-releases/novartis-announces-fda-and-ema-filing-acceptance-siponimod-first-and-only-drug-shown-meaningfully-delay-disability-progression-typical-spms-patients. Accessed Oct. 8, 2018.