2020-02-07| R&DTrials & Approvals

Sanofi’s BTK Inhibitor Meets Primary Endpoint in Phase 2 Trial Amidst Criticism

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

Sanofi today announced positive results for its phase 2b study analyzing a BTK inhibitor (SAR442168), an oral, brain penetrant small molecule used in treating patients with relapsed multiple sclerosis. The study met its primary endpoint and showed a reduction in brain lesion activity in patients upon treatment.

Multiple Sclerosis (MS)

MS is a chronic disease that affects 1.2 million people in the US and Europe alone. The disease progresses when the immune system starts attacking the myelin sheath, the fatty layer that covers the nerve axons aiding quick neuronal communication. In the absence of the sheath, brain firing is affected which disturbs the entire neuronal circuitry across the body. Despite current treatments, managing MS is a big challenge. Many patients continue to suffer and one in four goes on to acquire progressive forms of the disease.

Multiple Drugs in Trials

Several trials are ongoing to find the best drug for MS. Compounds like Roche’s Ocrevus that targets the CD20 protein, Merck KGaA’s Evobrutinib that targets BTK and Biogen’s Avonex are currently under investigation. Sanofi also joined the race in 2017 when Principia Biopharma licensed SAR442168, another BTK inhibitor to the company. The trial for SAR442168 was already underway on two different indications when Principia decided to license the drug to Sanofi for its commercialization as MS drug. SAR442168 is an investigational Bruton’s tyrosine kinase inhibitor that can cross the blood-brain barrier and is predicted to modulate both B cell function and CNS microglial cells linked to neuroinflammation without changing their numbers.

The Phase 2b Trial

SAR442168 was evaluated in a randomized, double-blind, placebo-controlled, cross over, 12-week dose-ranging trial in 128 patients with recurring MS. The patients were divided into two groups. The first group (n=60) received one of the four doses of the drug for the first 12 weeks, then crossed over to placebo for four weeks and the second group first received the placebo for 4 weeks followed by the drug for 12 weeks. This data generated a dose-response relationship that showed a reduction of new active gadolinium-enhancing T1-hyperintense brain lesions after 12 weeks of treatment. With this result, Sanofi claims that its phase2b trial has met the primary endpoint.

Criticism Levied Against the Trial

However, Sanofi has received lots of criticism from the investors on showing this data. Kerrisdale Capital pointed to the flaws in the trial design and called it confusing and inconclusive. Instead of a straightforward head to head matchup between pure drug and pure placebo, the trial performed crossovers between them. Kerrisdale also criticized the use of MRI scans to measure brain lesions as a measure of drug effectiveness rather than measuring direct relapse rates or MS progression. Also, the idea of the treatment is based on the theory that B cells are involved in the MS. To date, no evidence exists to support the use of BTK inhibitors in treating MS.

Future Plans

Although the results from the Phase2B trial have not been disclosed yet, the company is excited about taking it into the phase 3 trial. “Building on Sanofi’s heritage in multiple sclerosis, we are encouraged by these clinical results and look forward to rapidly advancing our brain-penetrant BTK inhibitor into pivotal clinical trials” said John Reed, Sanofi’s global head of R&D. Starting in the middle of this year, the phase 3 trial will investigate the effects of the drug on MS relapse rates, disability progression and underlying nervous system damage by using the drug dose determined from the phase 2b trial.

Amidst all the criticism, Sanofi still hopes for a positive outcome in the phase 3 trial. John Reed mentions “This molecule may be the first B-cell targeted MS therapy that not only inhibits the peripheral immune system but also crosses the blood-brain barrier to suppress immune cells that have migrated into the brain, while also modulating the brain-resident microglia cells that have been implicated in MS progression.”




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