Ponesimod for RRMS

Ponesimod (formerly ACT-128800) is an investigational drug being developed by Actelion to treat multiple sclerosis (MS).

Ponesimod is to be taken once a day by mouth.

How ponesimod works

Ponesimod is a selective sphingosine-1-phosphate receptor 1 (S1P1) immunomodulator.

The therapy stops immune cells (lymphocytes) from leaving lymph nodes, by blocking S1P signalling. This reduces the number of circulating immune cells, preventing them from infiltrating target issues. In people with relapsing-remitting multiple sclerosis (RRMS), ponesimod prevents immune cells from crossing the blood-brain barrier and damaging myelin. Myelin is a protective sheath that insulates nerve cells, and is damaged in patients with MS.

The immune cell count reduction is rapid, dose-dependent, and maintained with continued dosing. The drug’s effect is reversible when discontinued.

Studies of ponesimod for RRMS

A current Phase 3 study, OPTIMUM, (NCT02425644) aims to compare the effectiveness and safety of posenimod to teriflunomide (Aubagio) in reducing relapses in RRMS patients. This study has finished recruiting approximately 1,100 participants, who will either be treated once daily with ponesimod (20 mg per day), or receive teriflunomide (14 mg per day) for 108 weeks. The results are expected in 2019.

Another Phase 3 study, POINT,  (NCT02907177) will compare the effectiveness, safety and tolerability of posenimod in 20 mg doses in people with RRMS who are currently being treated with Tecfidera. The study will be conducted under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). It is currently recruiting participants.

Earlier studies showed promising results. It has been tested at different doses (10 mg, 20 mg and 40 mg) in Phase 2 studies (NCT01006265). This study found that ponesimod significantly reduced the number of new active lesions on monthly MRI brain scans and reduced the frequency of relapses. These results were published in the Journal of Neurology, Neurosurgery and Psychiatry. An extension study published in 2013 confirmed the findings.

So far, studies have suggested that ponesimod does not cause lymphotoxicity by destroying or depleting lymphocytes (immune cells) or interfering with their cellular function.

Though no detailed information has been provided yet, the most reported side effects for ponesimod are shortness of breath and asymptomatic liver enzyme elevations.

Note: Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

Janssen Asks EMA to Approve Oral Ponesimod to Treat Relapsing MS

Janssen has submitted an application to the European Medicines Agency (EMA) asking that ponesimod be approved as an oral treatment for adults with relapsing multiple sclerosis (MS) in the European Union.

Ponesimod (formerly ACT-128800) is an experimental treatment that targets the sphingosine-1-phosphate receptor 1 (S1P1), and reportedly with high selectivity. In doing so, it works to ‘trap’ immune cells in lymph nodes, limiting the damage they can do to the nervous system.

The MS therapies Gilenya (fingolimod) and Mayzent (siponimod), both of which are already approved in Europe, are also S1P1 receptor modulators, working through a similar mechanism of action.

The company’s Marketing Authorisation Application for ponesimod is based on data from the Phase 3 clinical trial OPTIMUM (NCT02425644). In this trial, 1,133 people with relapsing-remitting MS (RRMS) or active secondary progressive MS  (SPMS) were randomly assigned to either ponesimod at 20 mg or Aubagio (teriflunomide) at 14 mg, both taken by mouth once a day for two years (108 weeks).

Aubagio, by Sanofi, is an approved first-line therapy for MS. Like ponesimod, it works by reducing the activity of the immune system, albeit through different mechanisms.

Topline results from OPTIMUM showed that the annualized relapse rate (ARR) was significantly reduced by 30.5% with ponesimod, as compared to Aubagio, treatment — on average, 0.202 relapses per year in the ponesimod group and 0.290 among those given Aubagio.

A significant reduction (56%) in the number of new active, inflammatory brain lesions visible on a magnetic resonance imaging (MRI) scan was also seen with ponesimod treatment, as compared to Aubagio. There was also a trend towards lesser disability progression with ponesimod, but this did not reach statistical significance.

Ponesimod did lead to a statistically significant reduction in reported fatigue relative to Aubagio.

“Fatigue remains a challenging, yet invisible, symptom among those living with MS. We are encouraged by the results ponesimod shows in alleviating this symptom, as well as the reduction in new inflammatory lesions and disability accumulation,” Husseini Manji, MD, FRCPC, the Global Therapeutic Area head for Neuroscience at Janssen Research & Development, said in a press release.

“We look forward to collaborating closely with the EMA as the application process progresses,” Manji added.

Ponesimod’s safety was consistent with the that reported in previous trials, and with the known safety profile of other S1P receptor modulators.

“More than 2.3 million people worldwide live with MS — including 700,000 in Europe alone — and of this population, approximately 85 percent are initially diagnosed with relapsing MS. This submission is an important milestone as we work to bring a new treatment option to those living with relapsing forms of MS,” Mathai Mammen, MD, PhD, the global head of Janssen Research & Development, concluded.

Marisa Wexler, MS

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.