Speaking to Psychedelic Alpha, Gilgamesh Chief Strategy and Development Officer Jorge Quiroz pointed out that after day 29 in the second arm, some patients are almost close to zero on the MADRS. That explains “why we have this unbelievable remission rate”, he told us.

Quiroz described these results, and the effect size of 1.0, as “extraordinary”. For context, conventional antidepressants tend to have an effect size in the region of 0.3.

On the safety front, Gilgamesh says its candidate was “safe and well tolerated with most side effects self-resolving within two hours of dosing”. Quiroz told us that no interventions were required at any dose.

There were three drop-outs in the second arm, all following the first 10 mg dose. In discussing those, Quiroz emphasised that the implied 15% drop-out rate in that arm is in line with other depression studies, and shared that of the three drop-outs one was lost to follow-up and two withdrew consent, though those cases were not treatment-emergent adverse event related, he told us.

The company also thinks it’s going to be less exposed to methodological concerns from the agency on topics like functional unblinding. That’s in part because its 1 mg dose is “very psychoactive in this population of patients”, according to Quiroz, who says the company has examined the dose “quite profoundly.”

He says the team were “a bit surprised but also very happy” when they discovered this, “because that is helping us to decrease the criticism of functional unblinding that always goes with psychedelics.” Indeed, Yale Professor Gerard Sanacora, quoted in the company’s press release, emphasised that “the use of a psychoactive control dose helps to manage the confound of functional unblinding, which is an issue with this class of investigational medicines”.

It is worth noting, however, that the company did not directly measure expectancy or blinding. Quiroz told us that the study was run with one CRO and that they hadn’t planned to measure these in advance. These measures will be included in future studies, he added, “knowing now that it will be very relevant for the agency.”

The apparent psychoactivity of that 1 mg comparator dose might explain the reasonable antidepressant response observed by Day 14 following the first dose in arm 1, which is in stark contrast to the very low placebo responses seen in some other industry trials (which, in some cases, border on nocebo responses). Though, companies like Cybin and GH Research have employed inactive placebos as opposed to low-dose comparator arms, which should temper any comparison here.

The company describes its lead candidate as a “novel, rapid-acting 5-HT2A receptor agonist and 5-HT releaser”, which is under development for moderate-to-severe MDD. But the extent to which the serotonin releaser side of the equation contributes to the efficacy observed in this study remains unclear. “We know that in vitro we have that activity”, Quiroz told us, “but we cannot dissect from the clinical data what is due to what.”

The company’s Chief Operating Officer, Yoni Falkson, chimed in to clarify that the candidate is not a ‘maximal serotonin releaser like MDMA’, clearly keen to distance their investigational drug from others’. Quiroz concurred: “It’s not the full serotonin release”, the Chief Strategy & Development Officer said, “so we’re not expecting adverse events driven by that [mechanism], and in fact we’re not seeing them.”

The role of GM-2505’s serotonin-releasing characteristics versus its 5-HT2A agonism remains unclear, for now, as does the role of the subjective effects it precipitates.

As such, while the results will likely be heralded as a welcome ‘win’ for psychedelic drug developers, especially those whose candidates preserve the trip, we’re no closer to parsing out the relative contributions of the subjective effects versus the more neurobiological mechanisms thought to undergird these drugs’ beneficial effects.

We asked the company whether it has a conviction one way or another, perhaps a sensitive topic given that Gilgamesh is working with AbbVie on its trip-less psychoplastogens. Falkson reminded us that the startup has “a broad portfolio” with candidates across “multiple mechanisms and approaches.”

Gilgamesh’s approach, he said, “is to make best in class medicines that target mechanisms that we really believe in…rather than saying, ‘it has to be psychedelics’, or ‘it has to be NMDA, or 5-HT2A’”.

While the company has a broad pipeline, it emphasises just how engineered each candidate is. Speaking to GM-2505, Quiroz pointed out that “it was not that we found this drug…it was engineered to act this way”, explaining that the company designed it to have both 5-HT2A agonist and serotonin releaser properties and to be relatively short in duration, so as to be amenable to in-clinic use cases.

Clearly buoyed by this cut of data, Quiroz is upbeat. “We are very content with the work because the clinic demonstrated that the effort in the lab was well-guided”, he said.

In terms of what’s next, the company says it will advance to late-stage development of the candidate, with specifics pending discussions with the FDA. They’re hoping to pivot to an intramuscular formulation for that program.

“We obviously want to move aggressively, but all this is pending discussions with FDA, other regulatory authorities, all the normal pieces,” Falkson told us.

It’s not yet clear what dose(s) the company would employ in future studies of the drug. “We need to explore if 15 mg is better than 10 mg,” Quiroz said, “and we have different positions internally so this is something that we want to figure out when moving forward”.

He did say that there was no dose relationship with adverse events, perhaps suggesting the company’s dose selection would primarily be guided by hunches about efficacy.

In terms of how the drug might be used in the real world, if eventually approved, it might be best thought of as a more episodic alternative to esketamine (Spravato). That hinges, to some extent, on patients being ready for discharge after a couple of hours or so, and—crucially—greater durability of effect than the blockbuster nasal spray. (On that discharged timeline, Quiroz acknowledged that it may end up being slightly longer than the 2 hour period, such as 2.5 hours, but “with the data in hand, two hours seems to be the time frame that is needed”, he said.)

“I think what we know so far is that two doses did better than one dose,” Quiroz said, adding, “most likely, moving forward, the frequency of administration will be much lower than the one that is required with the esketamine.” He described that as “ a huge commercial advantage.”

“It’s very much different than esketamine”, Falkson added. There’s more work to be done to ascertain what kind of maintenance protocol the drug might entail, he added, “but from what we know, we have high confidence it’s going to be just a few times per year.” ∎