Sanofi’s BTK Inhibitor Seen to Effectively Reduce Brain Lesions in Phase 2 Trial

The investigational, oral BTK inhibitor SAR442168 can limit the number of new inflammatory brain lesions in people with relapsing forms of multiple sclerosis (MS), results from a Phase 2b clinical trial show.

“The results of this study give hope that SAR442168 may become an important treatment for relapsing MS,” Daniel Reich, MD, PhD, a senior investigator at the National Institutes of Health and principle investigator for the Phase 2b trial, said in a press release from Sanofi, the company developing this small molecule therapy under a licensing agreement with Principia Biopharma.

Sanofi also announced that it is planning to conduct four Phase 3 trials, in both relapsing and progressive MS patients.

SAR442168, formerly known as PRN2246, works by inhibiting Bruton’s tyrosine kinase (BTK), a protein that is important for the activity of inflammatory cells like B-cells and microglia. These cells drive the inflammation that causes nervous system damage in MS. By blocking BTK, SAR442168 aims to lessen this inflammation.

A previous Phase 1 study (ACTRN12617001457336) in healthy volunteers showed that SAR442168 has a reasonable safety profile, and is able to cross the blood-brain barrier. This barrier tightly regulates what substances from the bloodstream can access the brain, and crossing it is often a challenge for therapies targeting the brain.

The Phase 2b clinical trial (NCT03889639), a dose-determining study that concluded in January, enrolled people with relapsing forms of MS (relapsing-remitting MS or RRMS, and active secondary progressive MS or active SPMS).

Participants were randomly divided into two groups. In one group, 66 patients were given placebo for four weeks, then, they were given one of four doses of SAR442168 (5, 15, 30, or 60 mg), taken by mouth once a day for 12 weeks. The second group (64 patients) underwent the same 16-week treatment regime, but in the reverse order: first an assigned SAR442168 dose for 12 weeks, then four weeks of placebo.

An advantage of this crossover trial design is that each participant can provide their own placebo data, so there is no need for a placebo-only study arm.

The trial’s main goal (endpoint) was the number of new lesions on a MRI scan of the brain, specifically new T1 lesions. The number of new or enlarging T2 lesions was assessed as a secondary endpoint.

The difference between these lesion types is that T1 lesions are areas of active, ongoing inflammation; T2 lesions are areas where inflammation has caused damage, regardless of whether there is ongoing inflammation at the time of the scan.

Newly released data suggest that, compared to the placebo period, treatment with SAR442168 at its highest daily dose (60 mg tablet) resulted in an 85% relative reduction in new T1 lesions, and an 89% relative reduction in T2 lesions. Different statistical models were used to analyze each lesion type, based on their patterns of appearance in the study.

A dose-response relationship in the reduction of new T1 lesions was observed with the different SAR442168 doses tested.

No new safety concerns were identified in the Phase 2b trial. There was only one serious adverse event — an MS relapse — reported in a SAR442168-treated patient. The most common adverse events were headache (3%–13%), upper respiratory tract infection (3%–6%), and nasopharyngitis (3%–9%).

“We believe that our brain-penetrant BTK inhibitor shows promise for reducing both neuroinflammation and neurodegeneration, markers of disability progression in people living with MS. The effect on brain lesions seen in our Phase 2b study is encouraging,” said John Reed, MD, PhD, global head of research and development at Sanofi.

“As we go forward, we will explore whether our brain-penetrant BTK inhibitor offers strong efficacy and exceptional safety for a broad spectrum of MS patients with either relapsing or progressive forms of disease. Our phase 3 program is moving rapidly to initiate four pivotal clinical trials,” Reed added.

Among the 129 patients who completed this Phase 2b trial, 123 enrolled in a long-term follow-up study (NCT03996291) to further assess SAR442168’s safety and tolerability. People here will initially continue treatment at the dose given in the Phase 2 study, then move to the determined optimal dose, which will also be the dose for the planned Phase 3 trials.

“In the context of compelling, emerging data about the role of the brain’s innate immune system in smoldering MS lesions, there is also good reason to believe that SAR442168 — due to its molecular mechanism of action and ability to cross the blood-brain barrier — may have additional effects that we need to study more deeply,” Reich said.

“In my view, it’s important to move forward with broad and innovative testing of this BTK inhibitor in phase 3 studies in MS.”