A phase 2b clinical trial of Sanofi’s BTK inhibitor SAR442168 in relapsing multiple sclerosis has met its primary endpoint. Sanofi responded to the data by outlining plans to start four phase 3 trials of the Principia Biopharma-partnered asset in relapsing and progressive forms of MS.
The midphase trial assessed the ability of SAR442168 to reduce the number of new brain lesions in relapsing MS as measured by magnetic resonance imaging (MRI). Sanofi predicted SAR442168 could have a positive effect on brain lesions based on evidence it modulates the activity of adaptive and innate immune cells involved in the central nervous system (CNS) neuroinflammation seen in relapsing MS patients.
Sanofi is yet to share data from the trial but, based on the available information, the company seems confident SAR442168 works as hoped. Having hit the primary endpoint, Sanofi sketched out plans to run four phase 3 trials in relapsing and progressive forms of MS.
The trials are set to get underway around the middle of the year. Sanofi will design the studies to look at the effect of its BTK inhibitor on outcomes including MS relapse rates, disability progression and underlying CNS damage.
Sanofi’s willingness to bet on a broad phase 3 program and the confidence it implies contrasts with the views of some people outside the company. Last month, Sahm Adrangi's Kerrisdale Capital made Principia, the biotech that outlicensed SAR442168 to Sanofi, the latest target of a short attack, in part in the belief that the drug has “a mode of action that seems irrelevant to the etiology of MS.”
Kerrisdale thinks BTK inhibitors target the wrong step in the MS disease pathway. As the short seller sees it, BTK inhibitors “suppress the creation of new B-cell lineages in the bone marrow” but fail to address the rogue lineages that “have already developed and matured.” That rationale led Kerrisdale to predict BTK inhibitors will be far less effective than anti-CD20 drugs such as Roche’s Ocrevus and Novartis’ ofatumumab, which wipe out memory B cells.
The top-line findings of the phase 2b and Sanofi’s response to them could be seen as a rebuttal to Kerrisdale’s hypothesis. However, Kerrisdale, in its attack last month, expressed skepticism that the trial can yield conclusive data, pointing to a design that “seems almost designed to be confusing and inconclusive” to make its case.
Sanofi split 128 subjects into eight cohorts. The cohorts received one of four doses of SAR442168 for 12 weeks, either preceded or followed by four weeks of placebo. Kerrisdale criticized the lack of a “straightforward head-to-head match-up between pure drug and pure placebo” as well as the focus on short-term MRI scans rather than “practical outcomes like relapse rates or disability progression.”
The decision to move SAR442168 into phase 3 positions Sanofi to show conclusively whether the drug is effective. SAR442168 is set to enter late-stage development in the wake of Merck KGaA’s BTK inhibitor evobrutinib, which moved into two phase 3 trials that are pitting it against Biogen’s Avonex last year.
Sanofi presented the top-line findings from the SAR442168 trial on the same day as it published its fourth-quarter results (PDF). In the results, Sanofi revealed it has removed a phase 2 viral vector prime and rgp120 prime boost vaccine against HIV from its pipeline.