ECTRIMS – Novartis multiple sclerosis life cycle looks more assured
Siponimod could figure more prominently in Novartis’s outlook after release of data from the phase III Expand trial in secondary progressive multiple sclerosis. A statistically significant delay in disease progression suggests that it has a good shot of being launched in an indication for which there are no disease-modifying treatments.
With a more pronounced benefit shown in younger patients with more active MS, it might be difficult to unravel the best population. The line marking the beginning of secondary progressive disease is not crystal clear, and many patients who progress continue taking the same drug for their earlier relapsing form of disease. Still, Celgene and Actelion, both with late-stage projects acting on sphingosine-1-phosphate (S1P) receptors like siponimod, might have missed an opportunity by not testing in secondary disease.
Expand randomised more than 1,600 patients, with 1,100 to siponimod, formerly known as BAF312, and 546 to placebo. Patients had secondary progressive disease, defined as continuous progression of neurological disability regardless of relapses, often marked by incomplete recovery from relapses.
The primary endpoint was the time to three-month confirmed disease progression as measured by the expanded disability status scale. The statistically significant 21% risk reduction on this primary measure was backed up by a similar delay in six-month disability progression – a 26% reduction in risk – as a secondary endpoint, along with positive findings on annualised relapse rate, and lesion and brain volume changes.
The study recorded a miss, however, on time to a 20% or greater worsening on a timed 25-foot walk test over three months, a benefit that would have been of interest to patients had it been positive.
Prespecified subgroups included patients with prior relapses, those with active lesions, and patients with rapidly progressing disease, which saw respective 33%, 36% and 35% reduction in risk. These findings prompted primary investigator Ludwig Kappos, neurology department chairman at University Hospital Basel, to describe the ideal population as “younger patients with more active disease”.
Dr Kappos added, however: "Even if you don't have early-phase disease, you can still obtain a benefit."
As the results were unveiled at the ECTRIMS meeting in London, Novartis stated in a news release that it would discuss the data with health authorities, so it is not clear whether Expand will be sufficient for a regulatory submission. Lack of a specific treatment for secondary progressive MS would argue in its favour.
On the other hand, the US FDA and European Medicines Agency may want to flesh out the issue of defining progression into secondary disease, and they might demand confirmatory trials.
Dr Kappos said regulators had indicated that if the results of Expand were sufficiently robust Novartis might be able to submit on a single trial, although this will be left to discussions with the agency staff.
Regulators may also look closely at cardiovascular safety data. Novartis’s first-generation S1P modulator Gilenya had the effect of slowing heart rate on some patients, requiring all patients to be monitored for six hours after the first dose, including electrocardiogram readings before and after.
With the siponimod programme Novartis has sought to avoid the effect on heart rate through dose titration. Because of the dose titration the monitoring "will not be necessary" with siponimod, Dr Kappos said.
Despite the onerous first-dose requirements Gilenya has climbed to third position in the MS space, and in 2017 will overtake Copaxone, as Teva's intellectual property erodes, to take second spot behind Biogen’s Tecfidera. However, patent expiry awaits for Gilenya in 2019, so siponimod could represent a well-timed franchise extension.
Siponimod now has a modest outlook compared with other MS treatments in development, and even among projects acting on the S1P pathway it is small – Celgene’s ozanimod has a consensus 2022 forecast of $447m in MS, while siponimod’s is $134m, according to EvaluatePharma. This could be down to Novartis’s reluctance to talk it up (Siponimod rides to Novartis’s rescue, August 25, 2016).
Upgrades seem due, although there will be some uncertainty until Novartis announces the next steps. The outlook will become clearer once regulators’ views are known or further trials are initiated.