Ponesimod, Up for Approval, Shows ‘Clear Superiority’ Over Aubagio, Janssen Exec Says

Ponesimod may soon be a new oral therapy for people with relapsing multiple sclerosis (MS) in Europe, and a filing for its approval in the U.S. is likely within weeks.

Janssen Pharmaceuticals, its developer, submitted an application to the European Medicines Agency (EMA) in early March, a first ponesimod filing made to meet regulatory deadlines in Europe.

A similar request to the U.S. Food and Drug Administration (FDA) is expected “within this month,” Luc Truyen, MD, PhD, global head of development and external affairs for neuroscience at Janssen (part of Johnson & Johnson), said in an interview with Multiple Sclerosis News Today.

Phase 3 trial data showing ponesimod — whose brand name is “still under discussion” — lowered relapse rates and eased fatigue more effectively than Aubagio (teriflunomide), an established and oral MS therapy, support the EMA application.

Results also supported a good safety profile, and a rapid reversibility that could be useful should treatment need to quickly cease for family planning or other life events.

“First and foremost,” what best distinguished ponesimod from Aubagio “is a high degree of efficacy — again, clear superiority over a widely used oral,” Truyen said.

Then, there’s “rapid reversibility,” he added. “Within one week, lymphocyte counts start to return to normal, which is relevant for many situations, vaccinations that are coming, pregnancy desire.” 

Efficacy over an approved oral therapy

The Phase 3 OPTIMUM (NCT02425644) clinical trial tested ponesimod in 1,133 people with relapsing forms of MS — mostly relapsing-remitting MS (RRMS), followed by active secondary progressive MS (SPMS, about 15% of patients). Participants were randomized to either ponesimod tablets at 20 mg daily or Aubagio tablets at 14 mg daily for 108 weeks.

Aubagio, a first-line MS therapy marketed by Sanofi, and ponesimod both work by limiting the activity of the immune system, though through different specific mechanisms.

Aubagio prevents the proliferation of immune cells involved in MS, while ponesimod ‘traps’ immune cells in lymph nodes by affecting the protein sphingosine-1-phosphate receptor 1 (S1P1).

Two other approved and oral MS therapies, Gilenya (fingolimod) and Mayzent (siponimod), both by Novartis, also work by acting on S1P receptors. Gilenya, first approved by the FDA in September 2010, targets all receptors; Mayzent, approved in March 2019, is specific to receptors 1 and 5, and also claims quick “reversibility.”

Truyen said that Aubagio, approved in September 2012, was seen as the “up and coming” treatment for relapsing MS when scientists were designing OPTIMUM, which opened in June 2015.

“The foresight of using it against an active oral, I can’t take much credit for. It was our colleagues from Actelion [which first developed ponesimod; now also part of J&J] who had that,” Truyen said, noting that oral MS therapies have had “more and more utilization” in recent years. 

Topline results showed OPTIMUM met its primary endpoint, with ponesimod lowering annual relapse rates by 30.5% compared to Aubagio (0.202 vs. 0.290 relapses/year).

“I think comparing against [another] mechanism of action in wide use is going to give the most relevant information for patients and prescribers to make treatment decisions,” he said. “Being the first one doing this with clear superiority to me is quite exciting.” 

A neurologist, Truyen thinks the decrease seen in relapses particularly beneficial to patients going about their lives.

“One of the key features” of relapses, he said, is that they create “quite a high degree of uncertainty” in everyday life. “With this new intervention, you reduce that level of uncertainty by 30%. That, to me, is a clinically relevant outcome … There is a third less chance [of a relapse]; I think that’s quite important to know.”

Fatigue and other measures

A new scale, measuring patient-reported fatigue over a preceding week, was developed for OPTIMUM in collaboration with the FDA, and fatigue placed as a key secondary trial goal. With this scale, patients rated how fatigue affected their lives in the last week, with dimensions including physical and mental tiredness, weakness, and energy levels.

The scale has not been validated outside of OPTIMUM; the trial itself is helping to validate this tool.

After eight weeks, fatigue levels were significantly lower, on average, among patients treated with ponesimod than those given Aubagio.  

This scale showed for “the first time” ponesimod’s superiority in easing “a symptom that on a day-to-day basis is present in about 80% of patients with MS,” Truyen said, adding he thinks that “quite relevant.”

Another secondary trial goal was the development of new lesions, as visible on brain imaging scans. Compared to Aubagio, ponesimod treatment resulted in 56% fewer lesions. Truyen views this finding as indicative of a greater degree protection conferred by ponesimod over Aubagio.

“In the ponesimod arm … we reduce [cumulative active lesions] by 56%. By half, to me, would seem to be quite a relevant thing for patients to know as they make their treatment choices,” he said.

Disability progression was also measured in OPTIMUM. While there was a trend toward lesser progression on ponesimod, no statistically significant difference was seen against Aubagio.

Truyen, however, pointed out that Aubagio itself has been shown to effectively lessen disability progression compared to a placebo. As such, even a non-significant difference in this context is meaningful, he said, because it suggests at least a similar lessening of disability with ponesimod.

Safety considerations

Ponesimod’s safety profile in OPTIMUM was generally consistent with that reported in previous trials testing the investigational therapy.

Of note, there were higher rates of liver test abnormalities — such as elevated blood levels of proteins associated with liver damage — in the ponesimod-treated group than in the Aubagio group (22.7% vs. 12.2%).

“As you can imagine, we looked hard at that, and there were a number of things at play,” Truyen said.

First, he pointed out that cutoffs used for some of these liver tests have changed since earlier ponesimod trials. “So, there was a certain artifact of saying something is now three times above normal, whereas in the prior study, that threshold would have been higher.”

Second, while liver test abnormalities were observed with ponesimod’s use, no adverse events related to liver function were reported in treated patients.

“There were not actually any adverse events related to [ponesimod], whereas in Aubagio, there were,” Truyen said. “Aubagio has a frequency of significant liver test abnormalities with side effects. We didn’t see that really on ponesimod.”

Truyen also highlighted ponesimod’s relatively short half-life as a safety feature, because it allows the therapy to quickly clear the body in the event treatment needs to be stopped. 

“Within one week [of stopping treatment], the compound is washed out and the pharmacodynamic effect wanes so that we have a fully reconstituted circulating T-cell population,” he said. “With other treatments in this class, that time is significantly longer.”

A break in treatment could be necessary should people be preparing for a vaccination or pregnancy.

Another, and perhaps “undervalued,” safety feature of ponesimod is that “we have no drug-drug interactions” with its use, Truyen said. This could allow more flexibility in prescribing ponesimod without concerns that it will interfere with, or cause unexpected side effects with, other medications an individual is taking. 

Another Phase 3 trial, called POINT (NCT02907177), was expected to evaluate ponesimod’s efficacy and safety as an add-on treatment to Tecfidera (dimethyl fumarate) in people experiencing continued disease progression despite treatment.

However, this trial has been stopped “for practical reasons,” he said.

Essentially, healthcare providers were reluctant to place people already failing to respond to Tecfidera in a trial where they might receive a placebo as add-on. “Our recruitment rates were very low to the point where we said, ‘you know, the time it will take for us to get a definitive answer is going to … practically untenable,’” Truyen said.

While no plans now exist for additional studies of ponesimod, either alone or in combination with other MS therapies, “I think that time will come,” Truyen said.

“I think … there are combinations that should be looked at because, as you know, we still are not good enough,” he said. Using disease progression as an example, he noted this includes addressing both inflammation and a “repair capability. A natural combination that would come to mind is treatments that affect the occurrence of new lesions versus treatments that affect repair.”

For now, data from OPTIMUM point to ponesimod as highly effective across a variety of treatment goals, including relapses and fatigue, and with a manageable safety profile. 

“We are excited, Janssen with our Actelion colleagues … to have filed ponesimod,” Truyen said, “which we feel is going to be a differentiated new treatment option in this field.”