Sanofi's Brain-permeable BTK Inhibitor SAR442168 Phase IIb Was Clinically Successful, Significantly Reducing Disease Activity!

- Mar 06, 2020-

Sanofi (Sanofi) recently announced that its Phase IIb study of the drug SAR442168 (formerly R & D code: PRN2246) in the treatment of relapsing multiple sclerosis (RMS) has reached the primary and secondary endpoints. Magnetic resonance imaging (MRI) shows that SAR442168 significantly reduces the disease activity associated with multiple sclerosis (MS), and the number of new gadolinium (Gd) enhanced T1 and new or enlarged T2 high signal lesions is relatively reduced by ≥85 %. In this study, SAR442168 was well tolerated and there were no new safety findings.

SAR442168 has the potential to be the first disease modification therapy to address the source of multiple sclerosis (MS) damage in the brain. Sanofi will initiate four phase III clinical trials to evaluate SAR442168 in the treatment of relapsing and progressive multiple sclerosis.

The phase II study aimed to assess the dose-response relationship after 12 weeks of SAR442168 treatment by measuring the number of new brain injuries on magnetic resonance imaging. The study evaluated four doses (range: 5mg-60mg) for 12 weeks of treatment, and used placebo data obtained after 4 weeks of placebo treatment. In the main goal of measuring the number of new gadolinium-enhanced T1 high-signal lesions, a multiple comparison procedure and model were applied to the dose-response data, showing that the exponential model provided the best fit (p = 0.03). Compared with placebo, the 60mg dose of SAR442168 reduced the number of newly developed Gd-enhanced T1 hypersignal lesions by 85%. Among the secondary targets for measuring the number of new or enlarged T2 high-signal lesions, the linear model is the most suitable (p <0.0001). Compared with placebo, the 60mg dose of SAR442168 treatment reduced the number of lesions by 89%.

In the phase IIb trial, no new safety signals were found, and within 12 weeks, only one serious adverse event (MS recurrence) was reported in patients treated with SAR442168. The most common adverse reactions were headache (3-13%), upper respiratory tract infection (3-6%) and nasopharyngitis (3-9%).


Differentiated features of SAR442168 (original R & D code-PRN2246)

Dr. Daniel Reich, academic principal investigator of the Phase IIb study, senior researcher of the National Institutes of Health, and head of the Department of Translational Neuroradiology at the National Institute of Neurological Disorders and Stroke, said: "The results of this study give us hope that SAR442168 has potential It has become an important treatment for relapsed MS. In the context of convincing and emerging data on the role of the innate immune system of the brain in smoldering (smoldering) MS lesions, there are also good reasons to believe , Due to its molecular mechanism of action and ability to cross the blood-brain barrier, SAR442168 may have an additional role that we need to study more deeply. In my opinion, in the phase III study of MS, BTK inhibitors were extensively and innovatively tested Is very important. "

John Reed, MD, Sanofi ’s global head of research and development, said: "We believe that our brain-permeable BTK inhibitors have the potential to reduce neuroinflammation and neurodegenerative disease in patients with multiple sclerosis, which is a sign of disability progression. We are at The impact on brain damage seen in the phase IIb study is encouraging. As the research progresses, we will explore whether this brain-permeable BTK inhibitor provides powerful efficacy and excellent safety for patients with relapsed or progressive MS Sex. Our Phase III project is rapidly launching 4 key clinical trials. "


SAR442168 (PRN2246) can act on the peripheral and central nervous system simultaneously

BTK inhibitors are thought to regulate adaptive (B cell activation) and congenital (CNS microglia) immune cells associated with neuroinflammation and neurodegenerative lesions of the brain and spinal cord, and their clinical significance is being investigated.

SAR442168 is an oral, brain-permeable, selective, small molecule Bruton tyrosine kinase (BTK) inhibitor. In Phase I clinical trials, the drug showed the ability of BTK to bind and penetrate the blood-brain barrier.

SAR442168 (original R & D code: PRN2246) is licensed from Principia Biopharma, and Sanofi has global rights to the development and commercialization of the drug. The company plans to initiate four phase III clinical trials to investigate the impact of SAR442168 on MS recurrence rate, disability progression, and potential central nervous system damage. A phase III trial for the treatment of relapsing and progressive multiple sclerosis is scheduled to start in the middle of this year.

In the United States and Europe, approximately 1.2 million people are diagnosed with MS, an unpredictable chronic disease that attacks the central nervous system. Despite current treatments, many MS patients will continue to experience disability accumulation, and one in four MS patients suffer from progressive disease with limited or no treatment options. The global MS treatment market exceeds 20 billion euros per year.

The vast majority of patients with multiple sclerosis experience disability during the course of the disease. SAR442168 is a small molecule that not only suppresses the peripheral immune system, but also crosses the blood-brain barrier, inhibits immune cells migrating to the brain, and also regulates microglial cells in the brain that are related to the progression of multiple sclerosis. treatment. (