What The Sage-217 Results In PPD Mean For Marinus

About: Marinus Pharmaceuticals (MRNS), SAGE
by: Jérôme Verony

While Sage-217 displays statistically significant efficacy in a pivotal PhIII trial in PPD, placebo response at day 3 is suggestive of sampling error.

SAGE-217 shows some unexpected safety signals, notably a marked increase in upper respiratory tract infections.

SAGE faces difficult choices around its commercial strategy for Zulresso and ultimately, 217 as well.

The MRNS IV-to-oral switch with a single, safe molecule still looks like the future gold standard.


Sage Therapeutics (SAGE) today announced much-awaited data for its orally available synthetic neurosteroid SAGE-217. The molecule demonstrated a 4.2 point reduction in HAM-D score vs placebo by the end of 2 weeks of therapy, the trial's primary endpoint.

This is dramatically below results hoped for by a majority of respondents (n=127) to a twitter survey a few days ago, with the majority expecting either a reduction higher than 9 points or a reduction in the 5-9 points range:

While the 217 results may not have matched sky-high investor expectations, Sage stock is still experiencing a notable 42% bump as of the writing of this article. Is investor enthusiasm getting ahead of strategic thinking?

Sage-217 efficacy in PPD

On the basis of this 151 patient PhIII trial, Sage-217 is clearly efficacious at end of 2-week therapy (-17.8 vs. -13.6; p=0.0029), with Sage further noting a stat sig (but therapeutically much less relevant) reduction starting around day 3 (-12.5 vs. -9.8; p=0.0255), as I will discuss further down.

The 2.7 point improvement observed over placebo at day 3 is of no particular importance for the real-life treatment of PPD patients as it neither compares favorably to Sage's own Zulresso or to Marinus' data generated in PPD to date, which I discussed here but will recap below. If Sage-217 is approved, patients will take a full 2 week course of therapy for full effect.

Indication Drug Efficacy at primary endpoint (HAM-D) Notable AEs
Severe PPD Zulresso -17.7 at 60h LoC
IV Ganaxolone -16.9 at 60h
SAGE-217 -17.8 at 2 weeks Upper respiratory tract infections
Moderate PPD Zulresso -14.2 at 60h LoC
Oral ganaxolone -13.2 at day 28; -15.7 at day 36

Comparison of HAM-D score reductions in moderate and severe PPD achieved by Zulresso, ganaxolone IV & oral and SAGE-217. Source: Author based on company data.

However, rapid onset of effect is crucial in severely depressed patients. Looking at the above table, 217 generated efficacy in severe PPD at end of week 2 that is comparable to the efficacy of Zulresso as well as Marinus' Ganaxolone IV at 60h. In other words, the rapid onset of action observed with Zulresso and Ganaxolone IV remains unbeaten all the while keeping in mind that Marinus are currently exploring an even shorter IV - 24h or less - which could further raise the bar for onset of efficacy.

The fact that Sage tested 217 in severe PPD rather than in the more prevalent moderate PPD population indicates that the drug is meant as an oral follow-up to Zulresso in patients with severe PPD instead of a standalone therapy in moderate PPD, where an oral-only might be appropriate.

A word on placebo responses

In my most recent article discussing Sage and competitor Marinus Pharmaceuticals (MRNS), I highlighted the importance of placebo responses when evaluating datasets in neuro-psych. I noted that Ganaxolone IV had obtained PhII data in what seemed like a representative patient sample given that placebo response clocked in at 12.7 at 60h - in-line with the 12-14 points observed in Sage's 2 PhIII trials of Zulresso. At its primary endpoint (2 weeks of therapy), 217 was up against a 13.6 point placebo response, which cannot be directly compared to the 60h endpoints in the Zulresso and Ganaxolone IV studies. Placebo response at day 3 in the 217 trial appears more relevant (3 days = 72h) and it clocked in at 9.8 points. This is peculiarly low for a trial in severe PPD when compared to Sage's own prior PhIII trial in this population with Zulresso (-14 points) and Marinus' Magnolia trial of Ganaxolone IV (-12.7).

Thus, this 217 PhIII sample appears less representative of the broader population with severe PPD than Sage's prior trial in severe PPD. In fact, the 217 efficacy noted on day 3 (-12.5) falls below placebo responses noted at 60h both in Sage's prior PhIII in severe PPD (-14) and Marinus' Magnolia trial (-12.7).

Sage-217 safety in PPD

The safety of a novel CNS drug intended for a large-market indication is of paramount importance.

In November last year, I wrote that "we have reason to believe that SAGE-217 is first and foremost a sedative with a safety profile that needs to be further explored". While somnolence was noted as the most common adverse event for patients on 217 in this PhIII trial (12.8% SAGE-217; 8.2% placebo), this appears to be manageable and 217 is not as much of a sedative as we feared. However, another safety finding reported today is intriguing:

Source: SAGE PR

A marked increase in upper respiratory tract infections (7.7% SAGE-217; 1.4% placebo) is noted. This points to 217 exhibiting off-target activity that is unrelated to its GABAergic MOA and warrants an in-depth assessment before 217 is launched into a large-market indication. The development of other synthetic neurosteroids has been halted and at least one synthetic neurosteroid product has been relegated to veterinary use due to safety concerns.

Let's talk strategy

SAGE-217 met its primary endpoint but the data loose some of their lustre upon closer examination, as discussed above. Despite being potentiated by low placebo responses, 217's efficacy is far removed from what would be required to establish this oral drug as the be-all, end-all in PPD. Sage likely won't explore higher doses due to a safety profile that contains both expected (somnolence) and unexpected (upper respiratory tract infections) elements.

Meanwhile, Zulresso shows the strongest improvement at 60h in severe PPD to date, albeit closely followed by the highest dose of Ganaxolone IV tested by Marinus so far. Thus, Zulresso is not made redundant by 217 in the population of interest (severe PPD). It does however face a serious challenge from a safer and possibly shorter IV in the form of Marinus' Ganaxolone.

Moderate PPD is a question mark for 217: one wonders whether data in severe PPD will be sufficient to approve & prescribe 217 in moderate PPD - the largest chunk of the PPD population. The drug's safety profile may require further studies before FDA is comfortable approving 217 for a broader population given safety signals observed to date. Risk / benefit analysis for 217 that are favorable to the drug's use in severe PPD may fall short in moderate PPD (where no data has been generated), and reimbursement could be an issue if the drug is priced richly with a view on the real need in severe PPD.

Here is what Sage have to date:

  • a highly efficacious but cumbersome IV drug for which FDA have mandated a REMS and whose approval has been pushed back
  • an oral drug whose apparent efficacy at day 3 is insufficient to make Zulresso obsolete and whose safety profile is in need of clarification.

The competition is looming large while trading at a diminutive valuation: Marinus Pharmaceuticals (MRNS), valued at $170m vs Sage's $6.5bn (representing a 3700% premium for SAGE over MRNS), is currently exploring an IV-to-oral switch with Ganaxolone, a molecule benefiting from a 1600 patient safety database across adult and pediatric patients, and which has shown no safety signal beyond somnolence and dizziness. Based on PhII findings to date and the molecule's extensive safety database, Ganaxolone IV-to-oral would offer:

  • roughly equivalent efficacy to Zulresso in severe PPD
  • durable responses and the potential for extended therapy in moderate PPD
  • a superior safety profile

Furthermore, if successful in exploring its 24h IV, Marinus will have a virtually unbeatable competitive advantage over Sage: Sage is very unlikely to explore a higher dose & shorter duration course of Zulresso given its existing LoC issues and paradoxical dose-response effect. For patients, switching from IV to oral ganaxolone entails less complications than switching between Zulresso and 217. The intrinsic value of these franchises ultimately comes down to which drug physicians are most comfortable prescribing to the bulk of the PPD population. Competition around pricing is also a reality that Sage shareholders will have to contend with down the line.

Given the choice between a short IV to oral with a molecule that is proven to be extraordinarily safe, vs a lengthy infusion with Zulresso and its LoC issues followed by an oral drug with a poorly characterized safety profile, I know where my preference would lie.

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 (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.