Janssen's Ponesimod Demonstrates Superiority Over Aubagio in Phase 3 Head-to-Head Trial for Relapsing Multiple Sclerosis

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Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, recently announced the results of the OPTIMUM Phase III head-to-head clinical study of ponesimod, a novel oral selective S1P1 receptor modulator, at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The study was conducted in adult patients with relapsing multiple sclerosis (RMS) and compared ponesimod (20 mg) with Sanofi’s multiple sclerosis drug Aubagio (teriflunomide) 14 mg tablets.

This study is the first large-scale, head-to-head trial comparing two oral multiple sclerosis (MS) therapies for the treatment of relapsing multiple sclerosis (RMS). This also marks the first publication of the study data, with results demonstrating that ponesimod exhibited superior efficacy compared to Aubagio in terms of the primary endpoint and most secondary endpoints.

OPTIMUM is a head-to-head, prospective, multicenter, randomized, double-blind, active-controlled, parallel-group Phase III study conducted at 162 clinical centers across 28 countries worldwide. The study enrolled a total of 1,133 adult patients with relapsing multiple sclerosis (RMS) to evaluate the efficacy, safety, and tolerability of ponesimod at a 20 mg dose compared with the standard 14 mg dose of Aubagio. In the study, randomization was stratified by prior disease-modifying therapy within the previous two years and by baseline Expanded Disability Status Scale (EDSS) score.

In the study, patients received pharmacological treatment for 108 weeks. The primary endpoint was the annualized relapse rate (ARR) from baseline to the end of the study. The key secondary endpoint was the change from baseline in fatigue-related symptoms at Week 108 of treatment, as assessed by the Fatigue Symptoms and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS). Additionally, the study evaluated other endpoints: the cumulative number of combined unique active lesions (CUAL) assessed by MRI, confirmed disability accumulation (CDA) from baseline to Week 12, and CDA from baseline to Week 24.

The results showed that the study met its primary endpoint: over 108 weeks of treatment, ponesimod reduced the annualized relapse rate (ARR) by 30.5% compared with Aubagio, a statistically significant difference. Regarding key secondary endpoints, based on measurements at Week 108 using the FSIQ-RMS, the effect of ponesimod on fatigue symptoms was statistically significant compared with Aubagio. For other secondary endpoints: ponesimod significantly reduced the cumulative number of combined unique active lesions (CUALs) by 56% compared with Aubagio; for 12-week confirmed disability accumulation (CDA), the rates were 10.1% in the ponesimod group and 12.4% in the Aubagio group, with no statistically significant difference.

In the study, the safety profile of ponesimod was consistent with that observed in previous studies and with the known safety profiles of other S1P receptor modulators. The most common adverse reactions included nasopharyngitis, headache, upper respiratory tract infection, and elevated alanine aminotransferase levels.

Prior to the advent of disease-modifying therapies for multiple sclerosis (MS) in the early 1990s, the average annualized relapse rate (ARR) in patients with typical relapsing multiple sclerosis (RMS) was approximately 1.5 per year. Currently, with existing therapies, the ARR in RMS patients has been reduced to approximately 0.3 per year. In the OPTIMUM study, ponesimod, added to Aubagio background therapy, further reduced the ARR by 30.5%. These data, combined with the favorable safety profile observed in the study, highlight the potential of ponesimod as a new therapeutic option for MS. Based on these study results, Johnson & Johnson will submit marketing applications for ponesimod for the treatment of RMS to regulatory authorities in the United States and the European Union.

Molecular Structure of Ponesimod (Image Source: MedChemExpress)

Ponesimod is one of the two late-stage projects from Actelion that Johnson & Johnson acquired for $30 billion in 2017. Last year, the company halted the Phase III clinical trial of another drug for the treatment of Clostridium difficile-associated diarrhea, making ponesimod the last remaining late-stage opportunity to generate profits from the pipeline products obtained through this transaction. Ponesimod is a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator that functionally inhibits S1P activity and sequesters lymphocytes within lymph nodes, thereby reducing the number of circulating lymphocytes.

Currently, S1P has become an important target for new drug development in the field of multiple sclerosis (MS). In March this year, Novartis’ Mayzent was approved by the U.S. FDA for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS), including active secondary progressive multiple sclerosis (SPMS), relapsing-remitting multiple sclerosis (RRMS), and clinically isolated syndrome (CIS). This drug is the first and only therapy specifically approved for the treatment of patients with active SPMS in the past 15 years.

In June this year, the marketing authorization applications for Celgene’s oral S1P receptor modulator ozanimod for the treatment of RMS were accepted in the United States and the European Union. Ozanimod selectively binds to S1P1 and S1P5 with high affinity, and its mechanism of action is the same as that of Novartis’ Mayzent.

Ponesimod is not the only drug to successfully challenge Aubagio. Just last month, Novartis announced that Arzerra, an anticancer biologic acquired through its 2015 asset swap with GSK, demonstrated superior efficacy to Aubagio in Phase III clinical trials. The study enrolled more than 1,800 patients, and the data showed that Arzerra significantly reduced the annualized relapse rate compared with Aubagio. Novartis aims to submit a marketing application for Arzerra in multiple sclerosis (MS) by the end of the year. If approved, this would mark a turning point for Arzerra beyond its current oncology indications; the drug is currently approved for the treatment of chronic lymphocytic leukemia. Facing competition from Johnson & Johnson and AbbVie’s blockbuster hematologic cancer drug Imbruvica, Novartis and its partner Genmab discontinued marketing of Arzerra outside the United States in 2018. This Friday, Novartis will present the Phase III data comparing Arzerra with Aubagio for the treatment of MS at the ECTRIMS conference.

Reference Source:

1、New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio? (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS)

2、J&J multiple sclerosis hopeful tops Sanofi’s Aubagio at reducing relapse, fatigue

3、Efficacy and safety of ponesimod compared to teriflunomide in patients with relapsing multiple sclerosis: results of the randomized, active-controlled, double-blind, parallel-group phase 3 OPTIMUM study