Ponesimod enters field of DMTs for relapsing forms of MS
By Nancy A. Melville
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The Food and Drug Administration has approved once-daily oral ponesimod (Ponvory, Janssen) for the treatment of relapsing forms of multiple sclerosis (MS) in adults. Results from a pivotal phase 3 clinical trial show the drug was associated with nearly a third fewer annual relapses, compared with the MS drug teriflunomide.
In the multicenter, double-blind Oral Ponesimod Versus Teriflunomide in Relapsing Multiple Sclerosis (OPTIMUM) trial, published March 29, 2021, in JAMA Neurology, the primary endpoint was met, with ponesimod, a selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, shown to have a relative rate reduction of 30.5% versus teriflunomide in the annualized relapse rate (0.202 vs. 0.290; P < .001).
The trial also met secondary endpoints, with ponesimod being superior to teriflunomide in reducing fatigue on the Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (−0.01 vs. 3.56; mean difference, −3.57; P < .001).
The study is believed to be the first phase 3 trial to compare two oral disease-modifying therapies (DMTs) in relapsing forms of MS. The inclusion of a prospective comparison of the highly common and debilitating symptom of fatigue in MS also is an important feature of the OPTIMUM trial, the authors noted.
“Despite the well-known negative implications on quality of life and the high socioeconomic burden associated with fatigue, no previous phase 3 study in MS has addressed fatigue prospectively as a key outcome,” they wrote.
The study included 1,133 patients with relapsing forms of MS, including secondary progressive disease. Median age was 37 years.
Patients were randomized 1:1 to 20 mg of ponesimod (n = 567) or 14 mg of teriflunomide, an FDA-approved DMT (n = 566), once daily for 108 weeks. Those receiving ponesimod had a 14-day gradual up-titration starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators.
In additional outcomes, ponesimod was associated with a 56.1% relative risk reduction in combined unique active lesions on MRI per year, a key measure of focal inflammatory disease activity, versus teriflunomide (1.405 vs. 3.164; P < .001). Specifically, ponesimod reduced the number of new gadolinium-enhancing T1 lesions by 59%, and new or enlarging T2 lesions were reduced by 56%.
Disability measures were not statistically different between the two groups, with reductions in the confirmed accumulation of disability at 12 and 24 weeks of 17% and 16%, respectively.
Study coauthor Robert J. Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis and vice chair for research of the Neurological Institute, Cleveland Clinic, noted that a larger study may be necessary to better assess disability. “The pivotal trial was powered to identify a difference in the primary outcome – relapse rate,” he said in an interview. “It would take a much larger study to demonstrate a difference in disability. My interpretation is that the trial was underpowered to see a significant different in disability progression between the two therapies.”
For the exploratory endpoint of brain volume loss at week 108, ponesimod had a significantly reduced rate (0.34%; P < .001), and those in the ponesimod group were more likely to achieve the status of no evidence of disease activity, compared with teriflunomide (25.0% vs. 16.4%; P < .001).
Adverse events reported with ponesimod were consistent with previous studies of the drug and with other S1P1 receptor modulators, with no significant differences between the groups. The most common adverse events among those treated with ponesimod were upper-respiratory infection, hepatic transaminase elevation, and hypertension.
The FDA approval for forms of relapsing MS includes clinically isolated syndrome, relapsing
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Ponesimod and vaccine planning
A benefit of ponesimod is a rapid elimination and reversibility of effects, which can be important in situations such as pregnancy planning, as well as in vaccine planning.
In terms of the COVID-19 vaccine, specifically, Dr. Fox noted that data on ponesimod is lacking; however, a previous study with the S1P1 modulator fingolimod did show a reduced response to seasonal influenza vaccine tetanus toxin, suggesting that S1P1 medications in general may have a reduced response to vaccines. “Therefore, clinicians are generally recommending they get the complete COVID-19 vaccine, whether it’s one shot or two, 2 weeks prior to starting MS medications such as ponesimod,” he advised.
Patients who are already on the therapies are generally not recommended to stop the medications to get the COVID-19 vaccine because of concerns about the risk of MS activity returning, Dr. Fox noted. “Clearly, it’s a trade-off, and we don’t have all the data we want, so we are making the best recommendations we can with an incomplete dataset.”
Of note, Dr. Fox and colleagues published another study in March 2021 showing no increased risk of COVID-19 complications in patients treated with fingolimod. “By drug-family association, we are assuming this applies to other S1P1 medications, such as ponesimod,” he said.
A new alternative is a welcome addition
The addition of a new DMT showing efficacy in a head-to-head trial is therefore welcome, said Julie Fiol, RN, director of MS Information for the National MS Society. “We get very excited when there are new additions to the DMT armamentarium for MS.
“It’s significant that the trial design included an active comparator group instead of placebo, and that, even though the comparator was an FDA-approved therapy, there were still differences.”
With a host of reasons potentially determining why one DMT might not be the best choice for any individual, and those reasons possibly changing over time, new alternatives are important, she noted.
“Perhaps somebody isn’t tolerating side effects, or the medication isn’t doing as well to manage their disease as it once did,” Ms. Fiol said. “It’s therefore always great to have more options available to choose from if they need to switch their disease-modifying therapy.”
Recommendations from the National MS Society on COVID-19 vaccination of patients with MS who are or are not on medication, including ponesimod, are published on the society’s website.
The study was funded by Janssen Research & Development, and the OPTIMUM study was supported by Actelion Pharmaceuticals, part of Janssen Pharmaceutical. Dr. Fox’s disclosures include relationships with AB Science, Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, Sanofi, Teva, and TG Therapeutics. Ms. Fior had no disclosures to report.