Sanofi's BTK inhibitor readout in chronic hives sets up phase 3 push

While Sanofi’s plans to use its blockbuster Dupixent to take on Xolair’s domination of the chronic spontaneous urticaria (CSU) market were derailed by an FDA rejection last year, the French drugmaker has posted phase 2 data (PDF) suggesting a BTK inhibitor may also have a shot at the crown.

Currently, Novartis and Roche’s Xolair is the go-to therapy for patients with CSU, the medical term for chronic hives, with symptoms that persist despite treatment with drugs such as antihistamines. The market appeared set to change with the expected approval of Sanofi and Regeneron’s Dupixent last year, but, in October, the FDA requested the companies bring more efficacy data.

In the meantime, it looks like Sanofi has another potential option in the form of a Bruton’s tyrosine kinase (BTK) inhibitor called rilzabrutinib. In data from the 160-person phase 2 RILECSU study presented at the 2024 American Academy of Allergy, Asthma and Immunology (AAAAI) Annual Meeting over the weekend, 400-mg doses of rilzabrutinib were evaluated at regimens of once, twice and three times a day.

In its conference poster, Sanofi focused on the results for the three-times-a-day regimen, which produced a “significant” 9.58-point reduction in weekly itch score from baseline at Week 12, compared with a 6.31-point reduction among those on placebo.

The company also described “significant” reductions in weekly urticaria score—of 17.95 compared to 11.20 for placebo—and a reduction in weekly hives severity score of 8.31 compared to 4.89.

The trial’s primary endpoint was change from baseline in weekly itch severity score at 12 weeks, although Sanofi didn’t say in the release whether this had been reached.

The data were taken from patients who had either not received Xolair or were incomplete responders to the approved drug. The findings will form the basis for a phase 3 program in the severe inflammatory condition, which is on track to kick off this year, Sanofi said in the release.

“These data reinforce the potential of rilzabrutinib as a treatment option for patients with moderate-to-severe CSU and we believe that the rapid improvement of itch could make a meaningful difference in alleviating the physical and psychosocial burden these patients suffer from,” Naimish Patel, M.D., Sanofi’s head of global development, immunology and inflammation, said in the release.

“Based on these data, later this year we will advance rilzabrutinib into phase 3 development in both CSU and prurigo nodularis, another skin disorder characterized by relentless itching,” Patel added. “We also look forward to data readouts for rilzabrutinib in 2024 with the opportunity to further demonstrate its potential impact across multiple immune-mediated diseases.”

Sanofi acquired rilzabrutinib as part of the Big Pharma’s $3.7 billion acquisition of Principia Biopharma in 2020. The company has previously described the BTK inhibitor as a “pipeline-in-a-product” based on its multiple potential indications in respiratory, dermatology and rheumatology.

The drug’s journey through the clinic hasn’t been without setbacks, notably a phase 3 fail in rare autoimmune skin disease pemphigus back in 2021. But Sanofi has persevered and now has a late-stage readout in immune thrombocytopenia due this year, along with phase 2 results in asthma, IgG4-related disease and warm autoimmune hemolytic anemia.

Sanofi will be hoping that rilzabrutinib avoids the problems that have plagued other BTK inhibitors. The Big Pharma has already dropped a program for another former Principia asset called tolebrutinib in the specific indication of myasthenia gravis after disappointing trial results.

Meanwhile, the FDA placed a series of partial holds on BTK inhibitors over the past year in response to questions about whether they cause liver injury, including tolebrutinib, Merck KGaA’s evobrutinib and Roche’s fenebrutinib.

Today's results will give Sanofi hope on that front, as rilzabrutinib was not linked to any events of cytopenia, bleeding or atrial fibrillation that the company said had been observed with some other BTK inhibitors. The treatment-emergent adverse events that were seen at a higher frequency among the rilzabrutinib cohorts included diarrhea, nausea and headache.