Janssen Submits Marketing Authorization Application for Ponesimod in Relapsing Multiple Sclerosis, Demonstrating Superiority Over Aubagio in Phase III Trial

March 5, 2020 News /BioonBIOON/ -- Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson (JNJ), recently announced that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA), seeking approval for ponesimod for the treatment of adult patients with relapsing multiple sclerosis (RMS).

Ponesimod is a novel, oral, selective sphingosine-1-phosphate receptor 1 (S1P1) modulator that functionally inhibits S1P protein activity and sequesters lymphocytes within lymph nodes, thereby reducing the number of circulating lymphocytes capable of crossing the blood-brain barrier. In patients with multiple sclerosis (MS), lymphocyte infiltration into the brain damages myelin. Myelin is a protective sheath that insulates nerve cells. Damage to myelin can slow or halt nerve conduction, resulting in the neurological symptoms and signs associated with multiple sclerosis.

This application is based on the results of the head-to-head Phase III OPTIMUM study (NCT02425644). The study was conducted in adult patients with relapsing multiple sclerosis (RMS) to compare the efficacy, safety, and tolerability of ponesimod versus Aubagio (Chinese brand name: Aobajie; generic name: teriflunomide). Aubagio, an oral medication from Sanofi, was approved by the U.S. FDA in September 2012 for the treatment of RMS. As a leading oral therapy for multiple sclerosis (MS), it has been marketed in more than 70 countries and regions worldwide. In China, Aubagio (Aobajie) was approved for marketing in July 2018, becoming the first oral disease-modifying therapy (DMT) approved in the country for the treatment of multiple sclerosis.

Notably, the OPTIMUM study is the first large-scale, controlled, head-to-head study comparing two oral therapies for relapsing multiple sclerosis (RMS). The data demonstrated that ponesimod (20 mg once daily) was superior to Aubagio (14 mg once daily) in terms of the primary endpoint and multiple secondary endpoints.

Specific data are as follows: (1) For the primary endpoint, from baseline to Week 108 of treatment, compared with the Aubagio treatment group, the ponesimod treatment groupAnnualized Relapse Rate (ARR) was statistically significantly reduced by 30.5%(ARR: 0.202 vs. 0.290, p=0.0003). (2) Regarding key secondary endpoints, based on the Week 108 Fatigue Symptoms and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS) scores, the ponesimod treatment group, compared with the Aubagio treatment group,Fatigue symptoms were significantly reduced statistically(mean difference: -3.57, p=0.0019). (3) Regarding other secondary endpoints, compared with the Aubagio treatment group, the ponesimod treatment groupA 56% Significant Reduction in the Number of Combined Isolated Activity Lesions (CUAL) in the Brain(p < 0.0001). (4) The safety profile of ponesimod observed in this study was consistent with that reported in previous studies and the known safety profiles of other S1P receptor modulators. The most common treatment-emergent adverse events (TEAEs) in the ponesimod treatment group were elevated alanine aminotransferase (ALT), nasopharyngitis, headache, and upper respiratory tract infection.。

Molecular Structure of Ponesimod (Image Source: MedChemExpress)

Multiple Sclerosis (MS) is a chronic central nervous systemAutoimmunityMultiple sclerosis is an inflammatory demyelinating disease affecting 2.3 million people worldwide, with a higher prevalence in women than in men. The disease is characterized by demyelination and axonal loss, leading to neurological impairment and severe disability. The main subtype of multiple sclerosis (MS) is relapsing MS (RMS), which accounts for 85% of MS patients and includes clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). A relapse is defined as the onset of new, worsening, or recurrent neurological symptoms lasting more than 24 hours, in the absence of fever or infection. Relapses may resolve completely within days or weeks, or result in persistent deficits and the accumulation of disability.

Currently, sphingosine-1-phosphate (S1P) receptors have become an important target for new drug development in the field of multiple sclerosis (MS). In March 2019,NovartisMayzent (siponimod) Approved in the United StatesFDAApproved for the treatment of adult patients with RMS, including active secondary progressive multiple sclerosis (SPMS), relapsing-remitting multiple sclerosis (RRMS), and clinically isolated syndrome (CIS). Notably, Mayzent is the first therapy specifically approved for patients with active SPMS in the past 15 years. The active pharmaceutical ingredient of Mayzent is siponimod, a next-generation, selective sphingosine-1-phosphate (S1P) receptor modulator that selectively binds to S1P receptor 1 (S1P1) and receptor 5 (S1P5).

The regulatory application documents for the oral S1P receptor modulator ozanimod, developed by Celgene (acquired by Bristol-Myers Squibb), for the treatment of RMS are under review in the United States.FDAand the review by the European Medicines Agency (EMA), this drug can selectively bind to S1P1 and S1P5 with high affinity, and its mechanism of action is similar toNovartisSimilar to Mayzent. Ozanimod selectively binds to S1P1, which is believed to inhibit the migration of a specific subset of activated lymphocytes into inflammatory sites, reduce circulating levels of T and B lymphocytes—thereby exerting anti-inflammatory effects—and alleviate immune-mediated attacks on neural myelin. Due to ozanimod’s unique mechanism of action, patients’ immune surveillance functions are preserved. Furthermore, ozanimod’s binding to S1P receptor 5 (S1PR5) activates specialized cells within the central nervous system, promoting remyelination and preventing synaptic defects, ultimately helping to prevent neurological damage. Through the combined effects of “reducing damage” and “enhancing repair,” ozanimod has the potential to improve symptoms in various immune-mediated diseases.

It should be noted that ozanimod was previously in February 2018 by the United StatesFDARefusal to approve, on the grounds that the nonclinical and clinical pharmacology sections of the New Drug Application (NDA) were insufficient for a comprehensive review. This regulatory setback dealt a severe blow to the ozanimod program, leaving competitorsNovartissecured an opportunity to overtake. In March 2019, Celgene resubmitted its New Drug Application (NDA) to the U.S. FDA and simultaneously submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). Regarding U.S. regulatory matters,FDAThe final review decision will be made on March 25 this year.

If approved, ozanimod will face competition from multiple oral medications, such asNovartisNovartis’ Gilenya and Mayzent, Sanofi’s Aubagio, Biogen’s Tecfidera and Vumerity, Merck’s Mavenclad, and Roche’s Ocrevus, an antibody drug requiring only two infusions per year. In addition to multiple sclerosis, ozanimod is currently being developed for various immune-inflammatory indications, including ulcerative colitis (UC) and Crohn’s disease (CD). (Bioon.com)

Original Source:Janssen submits European Marketing Authorization Application for ponesimod for treatment of adults with relapsing multiple sclerosis