The optimal daily dosage of 20 mg ponesimod effectively and safely controlled relapsing-remitting multiple sclerosis (MS) for a follow-up duration of 8 years, according to study findings published in Neurology.
At the onset of disease, relapsing-remitting MS accounts for approximately 85% of all cases, making it the most common phenotype. Disease-modifying therapies are essential for MS treatment to control disease. Ponesimod, an orally active, selective sphingosine-1-phosphate receptor 1 modulator, has demonstrated a significant and dose-dependent decrease in inflammatory magnetic resonance imaging (MRI) activity and beneficial effect on the clinical outcomes in patients with relapsing-remitting MS in a phase 2b Core study, the researchers explained.
The objective of the current study was to evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and the long-term efficacy and safety of ponesimod 20 mg. This was done by using combined data from phase 2 Core and the Extension studies conducted in patients with relapsing-remitting MS.
The 24-week, randomized, placebo-controlled study consisted of 464 patients with relapsing-remitting MS from October 2009 and November 2010 and transitioned those who completed the Core study into an Extension study between May 2010 and July 2011. The Extension study consisted of 3 treatment periods with treatment period 1 (TP1) lasting 96 weeks and treatment periods 2 and 3 lasting up to 432 weeks.
In the 24-week study, the researchers randomly divided patients into 4 groups — the placebo group (n=121) and those receiving 10 mg (n=108), 20 mg (n=116), or 40 mg (n=119) ponesimod once daily.
Adding the Extension study, the median treatment duration with ponesimod was 7.95 years. After about 8 years of treatment, 214 (49.2%) patients remained on ponesimod with 186 (42.8%) discontinuing their treatment prematurely and 2 (0.5%) interrupting treatment due to planned pregnancy.
Patients did not tolerate the 40 mg dosage of ponesimod well with 47.7% (n=72) discontinuing treatment, so the researchers stopped using this dosage by the end of TP1. Similarly, the researchers discontinued the 10 mg dosage at the end of TP2 after analysis confirmed decreased risk-benefit compared with the 20 mg dosage.
Patients taking the 20 mg ponesimod demonstrated decreased clinical and magnetic MRI activity of their relapsing-remitting MS with a 43.9% confirmed relapse rate with over 64% of patients not experiencing a relapse.
The annualized relapse rate [ARR] was 0.154. The risk-benefit analysis revealed a 30% reduction in the 20 mg group compared with the 10 mg group. The 6-month confirmed disability accumulation per the Expanded Disability Status Score (EDSS) was 20.4% with the risk-benefit analysis indicating a 46% lower rate of disability accumulation in the 20 mg group compared with the 10 mg group.
The average number of new or growing T2 lesions on MRI totaled 1.85 for the 10 mg group, 0.68 for the 20 mg group, and 1.68 for the 40 mg group.
The most frequently reported adverse events while patients took ponesimod included nasopharyngitis (30%), headache (24%), and upper respiratory tract infections (21%).
Study limitations included necessary unblinding of the sponsor to patient treatment assignment during the TP1, the effect of selection bias on long-term analysis results, lack of placebo control in the Extension study, and lack of consistent assessment using the EDSS.
“In conclusion, ponesimod 20 mg appeared to be the optimal dose based on the favorable benefit/risk maintained over long-term treatment,” the researchers stated. “Results observed in clinical and MRI parameters suggest that the effect on MS disease control were maintained with ponesimod 20 mg… [with] no new safety concerns…during the combined study periods.”
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Freedman MS, Pozzilli C, Havrdova EK, et al. Long-term treatment with ponesimod in relapsing-remitting multiple sclerosis: Results from randomized phase 2b core and extension studies. Neurology. Published online June 6, 2022. doi:10.1212/WNL.0000000000200606