Woes mount for Marinus with investor lawsuit, trial failure

2024-06-17

临床3期优先审批临床结果上市批准

来源: FiercePharma

Two days after it was slapped with an investor lawsuit, Marinus Pharmaceuticals reported the failure of a trial for its seizure candidate IV ganaxolone.

The failure of Marinus Pharmaceuticals’ trial for ganaxolone as a treatment for persistent seizures has left the Philadelphia company facing the daunting prospect of conducting a new study to keep its hopes alive in the indication.

Monday, Marinus revealed that the phase 3 RAISE trial testing ganaxolone, which is an intravenous (IV) formulation of its approved oral antiseizure drug Ztalmy, met only one of two primary objectives in refractory status epilepticus (RSE).

The report came just two days after a class-action lawsuit was filed against the company by shareholders, which accused Marinus of “securities fraud or other unlawful business practices.”

Since mid-April—when Marinus revealed that it had stopped enrollment in the trial and that it was evaluating cost-cutting stratigies—its share price has tumbled 81% from $7.52 to $1.46.

In April, Marinus left some hope, saying that an independent data monitoring committee had recommended that the study be continued and that the company would decide whether to continue the development of IV ganaxolone when top-line results were ready.

But those hopes vanished Monday with the data release. The study—which pitted IV ganaxolone against placebo plus standard of care—met one of its two co-primary endpoints. The drug halted seizures within 30 minutes at an 80% success rate compared to a 13% figure for placebo.

As for the other co-primary endpoint, the study did not meet statistical significance as 63% of ganaxolone patients did not progress to IV anesthesia within 36 hours, compared to 51% of those on placebo.

Marinus’ chief medical officer Joseph Hulihan, M.D., offered a potential explanation for the failure of the study, saying in a release that patients were enrolled late in their course status, with ganaxolone initiated, on average, 38 hours after onset, which was inconsistent with the urgency emphasized in treatment guidelines.

He also noted imbalances in the baseline characteristics between the two treatment arms—including more ganaxolone patients entering in stupor or coma or on mechanical ventilation—which might have prejudiced the results.

Additionally, Aatif Husain, M.D., the chief of the division of epilepsy, sleep and clinical neurophysiology at Duke University Medical Center, questioned the design of the trial, saying in the release that “objective measures” such as electroencephalogram (EEG) monitoring should be used in future trials “to assess control status of epilepticus rather than endpoints dependent on a proxy measure such as use of IV anesthesia.”

Preliminary EEG analysis indicated that ganaxolone demonstrated reductions in seizure burden through 36 hours with an 88% median reduction compared to 38% for placebo, Marinus said in its release.

The company reiterated its belief in ganaxolone as a treatment for RSE and said it will discuss with the FDA how to move forward in the indication.

In the U.S., RSE sends roughly 150,000 patients to the emergency room per year. Those who are unresponsive to first- or second-line therapy are put into a medically induced coma to stop seizures, an option that leads to poor outcomes including higher infection rates and longer hospitalizations.

Marinus also is investigating ganaxolone as a treatment for another rare genetic seizure disorder, tuberous sclerosis complex, which causes nonmalignant tumors in the brain, skin, kidney heart, eyes and lungs and leads to epilepsy in most patients.

In March 2022, ganaxolone was approved as Ztalmy for patients age 2 and older with seizures associated with the rare genetic condition CDKL-5 deficiency disorder. Marinus gained a priority review voucher with the nod, which it sold to Novo Nordisk for $110 million. Ztalmy is a liquid that's administered orally three times per day.

Ztalmy generated sales of $7.5 million in the first quarter of 2024, and the company expects the full-year number to reach between $33 million and $35 million.

Monday, Marinus said it has cash and cash equivalents to continue operations into the second quarter of next year, with the projection including the “impact of cost reduction plans announced earlier this quarter and recent amendments to [two credit agreements].”