Long-term Ponvory Treatment Safe, Effective in RRMS, Trial Data Show
Treatment over 8 years found to lower relapse rate in adults
Long-term treatment with Ponvory (ponesimod) safely and effectively reduces the rate of relapses, slows disability worsening, and prevents brain volume decline in adults with relapsing-remitting multiple sclerosis (RRMS).
That’s according to eight years of data from patients enrolled in a now-completed Phase 2 clinical trial (NCT01006265) and its ongoing extension study (NCT01093326).
Notably, more than 60% of patients remained relapse-free with long-term Ponvory use.
These findings support the therapy’s beneficial effects and favorable safety profile over the long term, with no new safety concerns reported, the researchers noted.
The data were detailed in the study, “Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results From Randomized Phase 2b Core and Extension Studies,” published in the journal Neurology.
Developed by Actelion (now part of Janssen), Ponvory is an oral disease-modifying therapy (DMT) approved in the U.S. and Europe for relapsing types of MS.
The therapy is designed to “trap” immune cells in lymph nodes, preventing them from getting into the brain and spinal cord, where they can promote MS-driving inflammation. It works by modulating receptor proteins called S1P.
Ponvory in clinical trials
Regulatory approvals in both the U.S. and the EU were mainly based on the results of the Phase 3 OPTIMUM trial (NCT02425644). That trial tested 20 mg of Ponvory against 14 mg of Aubagio (teriflunomide) — another approved oral MS DMT — in more than 1,000 adults with relapsing MS.
Results showed that Ponvory outperformed Aubagio across all endpoints over two years of daily treatment. It worked better than the older medication at lowering relapse rates, reducing evidence of brain damage, and easing fatigue.
Ponvory’s optimal dose had been determined in a previous six-month Phase 2 trial that evaluated the safety and effectiveness of three therapy doses: 10, 20, and 40 mg. Those doses were tested against a placebo in 464 RRMS patients.
Previously reported data showed that the 20 mg dose was superior to the lower dose at significantly reducing the number of brain lesions and the risk of a first confirmed relapse. It also was associated with a better safety profile than the higher dose.
Patients completing the Ponvory trial were invited to enter its ongoing open-label extension study, in which all participants would receive the therapy for up to about 12.5 years. Those originally assigned to Ponvory would continue treatment with the same dose, while those previously given the placebo would be randomly assigned to one of the three therapy doses.
The newly published data concern safety and efficacy findings from long-term treatment with Ponvory within the core trial and its extension study.
As of March 31, 2019, after a median of nearly eight years of treatment, 214 (49.2%) of the 435 participants who received at least one dose of Ponvory during the core and/or extension study were still on the medication. Nearly 43% had discontinued treatment prematurely, while two patients (0.5%) interrupted Ponvory use due to planned pregnancy.
The most common reasons for treatment discontinuation included tolerability problems/adverse events (34.4%) and patient decision (29%).
Notably, throughout the core and extension studies, there was a consistent dose-dependent reduction in disease activity across all or nearly all analyzed outcomes.
That means that patients receiving higher doses had a lower relapse rate and a longer time to a first confirmed relapse.These participants also had fewer brain lesions, and were less likely to experience confirmed disability accumulation (CDA) — defined as worsening disability that lasted at least six months.
About a year in the extension study, however, the 40 mg dose was discontinued due to poor tolerability. Data showed a higher rate of treatment discontinuation due to adverse events (side effects) relative to the other two doses, specifically 17.9% versus 8.3–12.2%. At that point, those given the higher dose were re-randomized, or randomly switched, to one of the two other doses.
A comparative analysis about five years later showed that the 10 mg dose had a lower benefit-risk profile compared with the 20 mg dose. The 20 mg dose was associated with a 30% lower relapse rate and a 46% lower risk of CDA compared with the 10 mg dose. The approved dose also lowered the number of new or enlarging brain lesions by 61%.
These results led to the discontinuation of the lower dose, after which all participants were switched to 20 mg of Ponvory.
At the last assessment, patients in the 20 mg group had received treatment for up to 9.4 years. Long-term treatment with this dose was associated with sustained low levels of disease activity across all outcomes.
The annualized rate for confirmed relapses dropped between the first and second years of treatment, after which it stabilized, resulting in a median of 0.15 confirmed relapses per year across both trials. That rate was 0.10 for patients who were still on treatment at the time of the analyses, compared with 0.28 for those who discontinued or completed the treatment early.
Patients in the 20 mg dose group “experienced a confirmed relapse, on an average, every 6.5 years,” the researchers wrote, adding that these effects “were generally comparable to those of other S1P receptor modulators,” such as Gilenya (fingolimod) and Mayzent (siponimod).
Long-term treatment data
Over the eight years of treatment, a total of 64% of the patients given 20 mg of Ponvory remained free of a confirmed relapse and 20.4% experienced confirmed disability progression.
The number of brain lesions also remained consistently low throughout treatment, and patients showed a mean brain volume reduction of 2.4%, or an average of 0.3% decline per year. The observed brain shrinkage more closely resembled estimates for healthy people (0.1–0.3% loss per year) than those for MS patients (0.5–1% loss per year), the data showed.
The approved dose of Ponvory was generally well-tolerated over long term, with most adverse events being mild to moderate in severity. Their rates also were consistent with those reported for the core study, and there were “no new or unexpected safety concerns,” the team wrote.
The most common adverse events included common cold (30%), headache (24%), and upper respiratory tract infection (21%).
These findings highlight that 20 mg of Ponvory “appeared to be the optimal dose based on the favorable benefit/risk maintained over long-term treatment,” the researchers wrote.
“The results observed in clinical and MRI parameters suggest that the effect on MS disease control were maintained” with the 20-mg dose over eight years of treatment, with “no new safety concerns,” they added.
The extension study is expected to finish in October 2023.
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