Building on positive phase II data in an ultra-rare form of pediatric epilepsy, Marinus Pharmaceuticals Inc. is kicking off a pivotal phase III test of oral ganaxolone, its GABA A receptor agonist and sole clinical candidate. The drug, which like many candidates failed at first in another indication, appears to have the potential to help treat cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, an early-onset condition that mostly affects girls. The study has a treatment period of 17 weeks and will measure percent reduction in seizures as its primary endpoint. If successful, ganaxolone would become the first drug approved for the indication.

Though an extremely small indication, the study, expected to take about 18 months to enroll and to read out shortly thereafter, could lead Marinus to file its first new drug application for the FDA orphan-designated drug. Shares of the Radnor, Pa.-based company held steady on Tuesday, closing just $0.03 lower at $6.96.

The global study, called Marigold, is a double-blind, placebo-controlled trial. It will enroll about 70 patients between the ages of 2 and 21 with a confirmed disease-related CDKL5 gene variant. During a six-week baseline period, participants will be monitored while taking up to four current anti-seizure medicines. After that, they'll be randomized to receive either oral ganaxolone (up to 1,800 mg/day) or a placebo for 17 weeks, in addition to their existing anti-seizure treatment. The study's primary efficacy endpoint is percent reduction in seizures, while secondary endpoints will capture data on non-seizure-related outcomes, such as certain changes in behavioral and sleep disturbances that were seen as improvements in previous clinical studies with ganaxolone.

Following the treatment period, all patients that meet certain eligibility requirements will have the opportunity to receive ganaxolone in the open label phase of the study. While most participants in the study are expected to take a liquid suspension formulation of the medicine, they'll also have the option of taking it via an oral capsule.

CDKL5 deficiency disorder, or CDD, is caused by a mutation of the CDKL5 gene, located on the X chromosome. It's a gene that encodes proteins essential for normal brain function. The condition is characterized by difficult-to-control seizures – in Marinus' phase II study, the median number of seizures per patient over 28 days was 350 – and severe neurodevelopmental impairment. Existing anti-epilepsy medications do not work well to control it. Most children with the condition cannot walk, talk, or feed themselves, and many are in wheelchairs and dependent on others for their care, the company said. The company estimates that there are just 1,000 people with CDD worldwide.

So far, ganaxolone has been administered to more than 200 children, some as young as four months old, and has been dosed for more than four years. In an open label phase II study, Marinus found that oral ganaxolone, in addition to baseline treatment, showed "a sizable and durable seizure-frequency reduction with a large increase in the number of seizure-free days in the majority of patients and with some reporting behavioral benefits." (See BioWorld Today, Jan. 24, 2017.)

That study included seven patients, five who responded to the medicine and four were considered "high responders" and continue to take the medicine today, Marinus' CFO, Ed Smith, told BioWorld. The company has yet to determine what marks a responder vs. a non-responder, but is continuing to explore and evaluate that in the phase III program.

In addition to CDD, Marinus' team continues to test ganaxolone in both severe and moderate postpartum depression (PPD) and refractory status epilepticus. The company is running the phase II double-blind, placebo-controlled Magnolia study in severe PPD. Part A of that study is evaluating varying doses of an I.V. formulation of the drug. It will read out in the third quarter of this year with an outcome that will inform part B of the same study, which will start later this year to evaluate outpatient short-course I.V.-to-oral therapy. A second study, called Amaryllis, is evaluating oral capsules of ganaxolone for the treatment of moderate PPD. The company expects to have data from that study in the fourth quarter of 2018. Finally, Marinus is also testing I.V.-administered ganaxolone in a proof-of-concept-oriented phase II study for the treatment of second-line refractory status epilepticus. In 2016, ganaxolone missed its primary endpoint in a phase III study in drug-resistant focal onset seizures, leading to the discontinuation of that program and a deep dent in company shares, which closed at $1.62.

In addition to Marinus, many investors are also keeping a close eye on Cambridge, Mass.-based Sage Therapeutics Inc. and its SAGE-217 program, a positive allosteric modulator optimized for selectivity to synaptic and extrasynaptic GABA A receptors. Just last week, Sage said that it anticipates announcing top-line data from the placebo-controlled pivotal trial of the candidate in PPD in the fourth quarter of this year. (See BioWorld, June 13, 2018.)

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