Ponesimod in RRMS – long-term clinical trials

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Ponesimod, like fingolimod and siponimod preceding it block the ability of lymphocytes to leave the lymph nodes, thereby lowering circulating lymphocytes. As such the clinical effect is similar in the broad sense to that of it’s parent compounds – this includes efficacy and side effects. Unlike fingolimod (2nd line for active RRMS in the UK) and siponimod (reserved for active SPMS in the UK), however, at least in the UK it can be given for active relapsing-remitting MS as defined by clinical or imaging features i.e. by definition an early use of a highly-active agent in MS. The long-term data boasts a low 6 month confirmed disability accumulation (CDA) of 20.4% at an average of 7.9 years (see abstract below, the full article is available for free at the Neurology Journal website).

I picked this article not to talk about ponesimod per se, but about clinical trials and licensing. Ponesimod was given NICE approval in Feb 2022. If you read the methods blurb, the core study was rolled over into the extension study lasting a number of years after completion of 24 weeks i.e. participants in the study had access to a novel compound earlier than the wider world on an average of 7.9 years before it was licensed. This is a vital piece of information to take note as patients, since there maybe better treatment options out there compared to the current options but it’s still in trial format. Secondly, clinical trials now simply tend to roll over the existing trial participants into long-term studies than recruiting for newer separate studies. The main reason here is cost and convenience of not having to seek out newer participants. Those in the placebo arm also receive the opportunity after the core study has completed as they are also then switched to the active arm. So everyone wins out in the end. But, if you didn’t participate at the very beginning you lose out since it is by definition a closed system.

Of equal importance is that novel agents undergo clinical trials not only to test their usefulness (often coined ‘efficacy’ in clinical trial speak), but to iron out the details of side effects. In the case of ponesimod the side effects are similar to that of fingolimod/siponimod i.e. it’s an expected ‘class effect’ from a similar class of drugs. But, with newer and as yet untested agents in human beings the risk of the unknown is greater.

Ultimately, at the end of it it really comes down the risks vs benefit, but understanding the beast will put you in good stead.

I hope I have given you a snap shot or a starting point into this world so that you can think smarter and safer.

Abstract

Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis

Results From Randomized Phase 2b Core and Extension Studies

Mark S. Freedman, Carlo Pozzilli, Eva Kubala Havrdova, Alexandre Lemle, Michel Burcklen, Anna Larbalestier, Brian Hennessy, Tatiana Sidorenko, Andrea Vaclavkova, Tomas Olsson, on behalf of the Ponesimod Phase II Study Group

Objective To evaluate the dose-response relationship of 10, 20, and 40 mg ponesimod and long-term efficacy and safety of ponesimod 20 mg using an analysis of combined data from the phase 2 Core and Extension studies in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods In the Core study, 464 patients were randomized (1:1:1:1): placebo (n = 121), 10 mg (n = 108), 20 mg (n = 116), or 40 mg ponesimod (n = 119) once daily for 24 weeks. Patients who completed the Core study transitioned into the Extension study, which had treatment period 1 (TP1; up to 96 weeks) and TP2 and TP3 (up to 432 weeks). The 40 mg dose was discontinued due to low tolerability at the end of TP1, and the 10 mg dose was subsequently discontinued due to lower benefit-risk profile vs 20 mg at the end of TP2. All patients received 10 or 20 mg during TP2, followed by 20 mg in TP3. Annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), time to first confirmed relapse, MRI outcomes, and safety were evaluated.

Results A total of 435 patients received ≥1 dose of ponesimod (first randomized dose: 10 mg = 139, 20 mg = 145, and 40 mg = 151) at any time during the Core and/or the Extension study. As of March 31, 2019, 214 patients were still on ponesimod treatment. The median (range) of ponesimod exposure was 7.95 (0–9.36) years. Ponesimod 20 mg, from Core up to the end of TP3, was associated with sustained low clinical activity (ARR for confirmed relapses: 0.154; at week 432, Kaplan-Meier estimate for confirmed relapse was 43.9%, and 6-month CDA was 20.4%) and MRI disease activity, and over 64% of patients remained free of a confirmed relapse. Most common adverse events were nasopharyngitis (30%), headache (24%), and upper respiratory tract infection (21%).

Conclusion The effects on multiple sclerosis disease control were maintained with ponesimod 20 mg for approximately 8 years with no new safety concerns identified.

Classification of Evidence This study provides Class IV evidence that in individuals with RRMS, long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432), with 64% of patients remaining relapse-free.

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Neuro Doc Gnanapavan

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