Novartis Announces FDA, EMA Filing Acceptance of Siponimod

Novartis announced that both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have accepted the company's New Drug Application (NDA) and Marketing Authorization Application (MAA) respectively, for investigational oral, once-daily siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis (SPMS) in adults. This phase of multiple sclerosis (MS) can substantially impact lives, due to physical and cognitive impairments. To bring this treatment to the MS community as quickly as possible, Novartis used a review voucher to expedite the review of siponimod in the US. Regulatory action for siponimod is anticipated in the US in March of 2019 and in Europe in late 2019.

More than 80% of people with relapsing-remitting MS (RRMS) - the most common form of the condition at diagnosis - go on to develop SPMS, with or without relapses. SPMS is a form of MS that leads to progressive, irreversible disability, such as the need for enhanced walking aids and wheelchairs, bladder dysfunction and cognitive decline, largely independent of relapses. Following the initial RRMS course, there is a gradual increase in the number of patients transitioning to SPMS, with around 25% progressing by 10 years post-onset, 50% by 20 years and more than 75% by 30 years.

"We are excited to see a potential new treatment on the horizon," said Bruce Bebo, Executive Vice President Research, National MS Society, United States. "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."

"Siponimod is the first investigational medicine to show a significant delay in disability progression in typical SPMS patients," said Paul Hudson, Chief Executive Officer, Novartis Pharmaceuticals. "With siponimod, we underpin our strong commitment to the MS community by reimagining care for people whose lives have been considerably disrupted by this devastating illness. We are closely working with the FDA and EMA to ensure siponimod is available for patients as soon as possible."

The regulatory application is based on data from the EXPAND study, a randomized, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of siponimod versus placebo in people living with typical SPMS. At study initiation, more than 50% of patients in the EXPAND study relied on a walking aid. Results from the pivotal study showed siponimod significantly reduced the risk of three-month confirmed disability progression versus placebo (primary endpoint; 21% versus placebo, p=0.013). Siponimod also meaningfully delayed the risk of six-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression. Further, more advanced analyses of the EXPAND study showed that siponimod reduced the risk of disability progression largely disassociated from relapses (three-month disability progression, range 14-20%; six-month disability progression 29-33%).

In addition, Novartis conducted the BOLD study, a randomized, double-blind, placebo-controlled, adaptive dose-ranging, Phase II study in patients with RRMS. The study showed that siponimod significantly reduced the annualized rate of relapses (ARR) over six months compared to placebo (ARR siponimod 2 mg vs. placebo 0.20 vs. 0.58 (p=0,041)).

In Switzerland, Swissmedic granted fast track authorization procedure for siponimod in SPMS. Discussions with additional health authorities regarding siponimod are ongoing.

Siponimod is an investigational, selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor. Siponimod binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with multiple sclerosis. This leads to the anti-inflammatory effects of siponimod. Siponimod also enters the CNS and binds to the S1P5 sub-receptor on specific cells in the CNS (oligodendrocytes and astrocytes). By binding to these specific receptors, siponimod has the potential to modulate damaging cell activity, and preclinical studies suggest that it may prevent synaptic neurodegeneration and promote remyelination in the CNS.

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