Marinus pushes on despite mid-stage doubts

The group’s determination to conquer another rare epilepsy, tuberous sclerosis complex, looks questionable.

Pressing into phase 3 despite lacklustre mid-stage data is always a gamble, and Marinus Pharmaceuticals has become the latest group to roll the dice. Yesterday, the company reported far from convincing phase 2 results with its oral Gaba modulator ganaxolone in the rare epilepsy tuberous sclerosis complex, but it is still planning a pivotal trial.

Even usually supportive sellside analysts said the outcome of the phase 3 study was now hard to call, and the group's stock fell 10% this morning. It is true that options are needed for patients refractory to current therapies, the population enrolled in the phase 2 Calm study, but perhaps Marinus could have designed Calm better.

Keep Calm and carry on

For a start, the trial was small, enrolling just 23 patients, and single arm. Even without a control group, the results were not impressive. There was a median 17% reduction in the primary endpoint, 28-day seizure frequency versus baseline – much weaker than the 48% drop seen in an interim analysis of 12 patients in February, and also short of the 20-25% benefit over placebo that is considered clinically relevant, Leerink analysts noted.

On the plus side, ganaxolone did show a meaningful 50% responder rate, with 30% of patients hitting this threshold. And patients in the study had few options, having failed to control their seizures on two or more anti-epileptic medications, including Jazz Pharmaceuticals’ Epidiolex and Novartis’s Afinitor, both approved specifically for tuberous sclerosis complex.

However, the number of discontinuations raised a red flag: four patients dropped out after having adverse events, one of which was a seizure classed as treatment related. Another patient left the trial due to a lack of efficacy.

Undeterred, Marinus plans to start the 160-patient, placebo-controlled TrustTSC pivotal trial in the fourth quarter. It will have the same primary endpoint as Calm, but a longer maintenance period, at 12 weeks rather than eight. The group believes it has learnt lessons from its mid-stage experience. Marinus plans to adjust ganaxolone’s titration schedule to improve its safety and tolerability profile.

The company expects to see a placebo response in the low double digits, and hopes to show a 20-25% delta over placebo. But the Calm data do not exactly spur confidence in this outcome.

More advanced

Tuberous sclerosis complex is not ganaxolone’s most advanced indication; that is another rare epilepsy, CDKL5 deficiency disorder, for which Marinus recently filed the project with the FDA, backed by a single pivotal study, Marigold.

The asset’s chances look better here but there are still reasons to be cautious: there was a lower-than-expected placebo response, which could have flattered ganaxolone’s performance, and the study also did not meet its predefined secondary endpoints (Marinus finds a path forward in rare epilepsies, September 15, 2020).

Marinus is also developing an intravenous formulation of ganaxolone for refractory status epilepticus, where readout of the Raise phase 3 study was recently delayed from the current half to the second half of 2022, due to Covid-19.

As for tuberous sclerosis complex, the remaining pipeline looks bare. Zogenix said in 2019 that it was planning a basket trial including patients with the disorder, but this has not yet emerged. Meanwhile, an investigator-sponsored study of sirolimus, an mTOR inhibitor like Afinitor, is due to complete next year.

Still, the main rival for Marinus would be Epidiolex; the cannabinoid drug is forecast to bring in $1.4bn in 2026, according to sellside consensus compiled by Evaluate Pharma, with about a third of this expected to come from tuberous sclerosis complex.

Before Marinus has a chance of competing, though, it needs to produce a result in phase 3.

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