Sanofi's BTK inhibitor rilzabrutinib failed Phase III pemphigus trial

Sanofi (Nasdaq: SANofi) today announced that the Phase 3 PEGASUS trial of rilzabrutinib for pemphigus, a rare autoimmune skin disease, failed to meet its primary or key secondary endpoint. But the company noted that the drug's safety profile in trials was consistent with previous studies.

The PEGASUS trial is a global, randomized, double-blind, placebo-controlled, pivotal Phase 3 trial designed to evaluate the efficacy of RILzabrutinib versus placebo. Subjects were recruited for moderate to severe pemphigus with newly diagnosed or recurrent chronic disease. Pemphigus is an immune-mediated blistering skin disease with few clinical treatment options. This type of pemphigus may account for three quarters of all pemphigus patients, according to demographics. All patients can be treated with a gradual reduction of corticosteroid dose, which is the current standard of treatment for the disease.

The primary efficacy endpoint of the PEGASUS Phase iii trial was that patients receiving rilzabrutinib from 29 weeks to 37 weeks were able to achieve a lasting complete remission of symptoms (no new or existing lesions) with the minimum dose of corticosteroids. The percentage of patients who met the primary endpoint in the rilzabrutinib group did not differ significantly from that in the placebo group. Commenting on the critical trial failure, Naimish Patel, Sanofi's head of global development, immunology and Inflammation, said, "While the results of the phase 3 trial of Rilzabrutinib are disappointing, However, Sanofi continues to believe that the Rilzabrutinib clinical program has great potential to address the unmet therapeutic needs of patients with immune-mediated disease."

The drug was not originally developed by Sanofi. In August 2020, Sanofi announced the acquisition of Principia Biopharma for $3.68 billion, resulting in the acquisition of Rilzabrutinib, the company's oral BTK inhibitor. BTK, a member of the Tec family of non-receptor tyrosine kinases, is a key kinase in THE B cell receptor (BCR) signaling pathway and plays an important regulatory role in the differentiation and development of B cells. BTK is involved in innate and adaptive immune responses and is an important signaling molecule in immune-mediated diseases. Previous studies have shown that rilzabrutinib blocks inflammatory immune cells, cancelling damaging autoantibody signals and preventing the production of new autoantibodies without depleting B cells.

BTK inhibitors have also been a hot area of research and development for other pharmaceutical manufacturers in the industry. In 2013, Ibrutinib became the first BTK inhibitor to be approved by the FDA, and its approval was epoch-making. Subsequently, second-generation BTK inhibitors Acalabrutinib and Zanubrutinib were approved in 2017 and 2019, respectively, with improved off-target side effects and drug resistance compared to Ibrutinib. Earlier this month, The U.S. Food and Drug Administration (FDA) approved Brukinsa, a BTK inhibitor, for the treatment of adult patients with macroglobulinemia (WM).

Rilzabrutinib has previously been granted orphan Drug designation by the US Food and Drug Administration (FDA) for the treatment of pemphigus vulgaris and orphan Drug designation by the European Commission for the treatment of pemphigus vulgaris. In addition, Rilzabrutinib is receiving a Phase 3 trial for autoimmune thrombocytopenia and a Phase 2 study for autoimmune disease IGG4-related disease.

In November 2020, the drug was granted fast track status by the FDA and is expected to become the first Bruton tyrosine kinase (BTK) inhibitor for THE treatment of ITP. A phase 2 study of the drug for asthma, atopic dermatitis, chronic spontaneous urticaria and tepid autoimmune hemolytic anemia is also expected to start this year.