Marinus May Have Figured Out PCDH19: Implications For CDKL5, PPD & RSE

[Figure omitted: a fossil. Caption: “A Cleoniceras ammonite fossil. Source”]

An elegant and surprisingly simple hypothesis may just have strengthened Marinus’ foothold in the orphan pediatric epilepsy space.

Buried in a seemingly mundane press release by Marinus Pharmaceuticals (MRNS) is an important give-away regarding the company’s prospects in treating orphan pediatric epilepsies. A poster presentation titled “Preliminary Evidence of a Predictive Clinical Biomarker in PCDH19-related Epilepsy: Significant Treatment Effect of Ganaxolone In Biomarker-Positive Patients” suggests that the ‘behind the scenes work’ previously alluded to by MRNS’ CEO has been yielding fruit.

Let’s wind back the tape a little. A 2016 readout of MRNS’ PhII trial in children with PCDH19 epilepsies yielded encouraging results which were however skewed by a few extreme outlier patients:

[Figure omitted: a patient-level table from the PhII PCDH19 trial, showing per-patient change in seizure frequency and seizure-free days, patients 1 to 11.]

Were it not for patients 9, 10 and 11, ganaxolone would have demonstrated an unequivocally meaningful reduction in seizure frequency and increase in seizure free days. Back in 2017, when I first covered the name, a critical commentator pointed to the above table to claim that such variability must mean that ganaxolone has no treatment effect. That seemed preposterous, due to the fact that any improvement in children with PCDH19 or CDKL5 mutations points to some degree of efficacy, whereas there might be some as of yet unknown underlying variability in these patient populations. Patient 11, for instance, appears to suffer from an underlying pathology that is quite different than the rest of the cohort.

The question for MRNS ever since these ‘mixed’ data in PCDH19 has been whether they could figure out what accounts for outlier patients and whether there is a reliably biomarker to be used in identifying patients most susceptible to ganaxolone therapy.

The title of the poster they’ll present at the American Epilepsy Society meeting in New Orleans suggests they might have cracked that nut. Curious about what this biomarker might be, I asked a knowledgeable source in the CNS area, who swiftly pointed me to this 2015 paper which establishes the link between PCDH19 and allopregnanolone deficiency.

Ganaxolone being, of course, a synthetic derivative of allopregnanolone.

If, as we now suspect, the variability in the prior PCDH19 data can be attributed to whether a patient suffered from allo deficiency or not, then MRNS have a clear-cut way ahead for a registrational trial in PCDH19. Inclusion criterium: patient must suffer from allopregnanolone deficiency, and all of a sudden, you have a much ‘cleaner’ dataset (think patients 1-7).

That dataset would then be consistent with the significant & durable reduction in seizure frequency observed in their PhII trial of ganaxolone in CDKL5 patients.

In other words: PCDH19 has just joined the ranks of CDKL5 as the company’s second orphan pediatric indication with a high probability of success.

For PPD, the link is evident given that Sage’s (SAGE) work with injectable allopregnanolone (‘brexanolone’) has thoroughly validated the allo deficiency hypothesis. If ganaxolone’s efficacy in the relevant subset of PCDH19 patients comes down to it acting as an ‘allo substitute’, then it is highly likely to succeed in PPD as well.

For RSE, there is less of a direct takeaway from the PCDH19 allo hypothesis. What really comes into play here is the preclinically demonstrated synergistic effect between ganaxolone and benzodiazepines. In RSE, the company is using a high-dose IV formulation of ganaxolone following administration of SOC benzos to patients who have life threatening seizures.

If the trial succeeds – which I expect it will – Marinus will have unlocked a 50k patients / year opportunity which they can price at a premium. CDKL5 & PCDH19 are much smaller markets but the company stands to obtain a priority review voucher as a ‘reward’ for conducting orphan pediatric work there. And of course, they will also be able to charge a pretty penny for a lifelong therapy.

The top-line readout from the company’s PhII trial of ganaxolone IV in women with severe PPD is expected sometime this quarter. An interim readout in RSE is also due before the end of the year. I wholeheartedly recommend loading up at these levels, as the company’s value could quickly surpass $1bn following positive data in both indications.

Disclosure: I am/we are long MRNS. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.