Good morning, everyone. Welcome to the TD Cowen 6th Annual Novel Mechanisms in Neuropsychiatry virtual summit. I'm covering analyst, Ritu Baral, and I will be hosting today with my colleague, Managing Director Joseph Thome, across a number of our neuropsych companies under coverage, some not under coverage, and we will be featuring a private company showcase panel later today as well. To start off the day, we have one of my most frequent inbounds and covered company, Helus Pharma, formerly known as Cybin Inc. With us from Helus, we have new CEO, Michael Halstead, and Chief Medical Officer, Amir Inamdar. Welcome, Michael. Welcome, Amir. Thank you so much for the time this morning.
Thank you, Ritu, really appreciate you making the time and everyone joining us today. As you said, I am the new CEO here. I joined in early August. Very excited about Helus Pharma, the potential we have with a number of different programs to really significantly impact an area of great importance, and that's the mental health treatment paradigm. Maybe before we really get started, Ritu, I'll just give people just a real high-level overview of the company.
That would be great.
For those that aren't as familiar. Helus Pharma is developing novel serotonergic agonists for the treatment of several different mental health areas. We have really a platform is how I think about the number of programs that we have ongoing. Our late stage HLP-003 program, that is deuterated psilocin is the molecule. It is in phase III development for adjunctive MDD, and hopefully we'll get a chance to discuss that indication. I just think it was an incredible choice by the company to move forward in the adjunctive MDD space in terms of potential patient benefit. We are on track towards our expected readout in the fourth quarter of our first phase III trial in that program, and then of course, have the full phase III program that is ongoing, supporting that with an anticipated NDA filing in 2028.
Importantly, we also have a number of other programs, both mid-stage and then early stage. HLP-004, which is deuterated DMT, is in phase II development for generalized anxiety disorder, another very important indication. Hopefully we will have a chance to talk about that. I do think that is a very important program. We also have our library of earlier stage compounds, our HLP-005 program, that I really think has potential in a number of therapeutic areas related to mental health. We anticipate that we will be moving the lead candidate forward out of that program in 2027. Importantly, underlying that platform is a really nice broad IP foundation. Intellectual property, obviously critical, and the Helus Pharma team has done a very nice job of developing the intellectual property portfolio to support, obviously, the clinical development and then long-term commercialization.
Again, very pleased with the platform we have, the potential, and number of programs that the company has, and obviously excited about our upcoming phase III readout in adjunctive MDD.
Before the end of the year. Thank you for going over that, especially the IP portion, which hopefully we will dig into later. We will have chance to go over HLP-004. Let us start with HLP-003, as you mentioned, deuterated psilocin. How does that differ from the active psilocybin that others are developing?
Sure, and I will let, in just a minute, our Chief Medical Officer, Amir Inamdar, walk you through a bit of the detail around what we have seen in preclinical studies and other areas. Just high level, so psilocybin, the parent molecule, inactive, has to be dephosphorylated in the body to psilocin, the active metabolite. Our compound is deuterated psilocin. We believe that that provides several benefits as you think about the drug development process, improved stability, efficiency of delivery, and also importantly, reduced drug load. So can get the similar effects as the parent with a reduced drug load of the deuterated psilocin. Maybe, Amir, just a minute if you want to talk about what we have seen-
Yeah
-in terms of studies that we've done.
Absolutely. Thank you, Michael. We do believe that deuteration of psilocin results in real tangible benefits. We've seen this in our preclinical studies where we saw that deuterated psilocin gets into the brain about twice as fast compared to psilocin from psilocybin, and it achieves higher exposures in the brain compared to psilocybin. We think this is clinically important, and we've seen that with 16 mgs of HLP-003 compared to what is typically given in efficacy studies of psilocybin, which is 25 mgs. HLP-003 delivers a Cmax, the peak plasma concentration, that's about 1.5 times higher than 25 mgs of psilocybin, and AUC or exposure, which is about 2.5 times higher. We think this is clinically relevant. I can speak a little bit about that in a bit. We also believe and know that deuteration shifts the metabolism.
The breaking down of the drug in the body changes because of deuteration, and it does so in clinically meaningful ways, such that the risk of relevant drug-drug interactions, we believe, becomes very low. Happy to talk about the clinical implications of what we think deuteration does.
Great. Yes. We're going to move next to the study that we'll be reading out probably in November, we estimate. The phase III APPROACH adjunct MDD study. Could you guys walk us through the design, the inclusion criteria, and including, because it is adjunct, what background medications are allowed, are prohibited, and then we're going to go into the treatment effect and expectations.
Sure. Amir, as the architect of the study, it would be great if you could provide some details there.
Yeah. What you really are saying, it is going to be my fault whatever happens in the study, right?
Not at all.
No. It is a very simple, simplistic design, and I like simplicity in clinical trials, especially in phase III trials. An active dose of 16 mg HLP-003 compared with an inactive placebo, two doses given three weeks apart with a primary endpoint at six weeks, a secondary endpoint at 12 weeks. We have actually kept the design of the study virtually identical to what we had in phase II, with some very minor exceptions. What we have done is in phase II, we saw one dose had about an effect of about 13 points on the MADRS. That was after one dose, and we had all patients receiving a second administration, and that gave us an incremental benefit of about five and a half points on the MADRS. So what we have done in our phase III is we have rolled in the second dose.
The primary endpoint is at six weeks compared to three weeks in the phase II. We may be able to benefit from that second dose as well. That's essentially how the study looks like. We've made no material changes to the inclusion, exclusion, except increasing the threshold on the MADRS. In phase II, we had a cutoff of 21 points on the MADRS for inclusion. In phase III, what we've done is we've upped it to 24. That just ensures that we get the right quality of patients in our study. What the study is doing is it's enrolling patients with moderate to severe MDD. 24, that's where exactly the threshold is. They are on a stable dose of antidepressant medication but are inadequately responding. We allow patients to remain on their background SSRIs, SNRIs, the usual.
What we do exclude from that group of antidepressants is monoamine oxidase inhibitors. That's a mechanistic exclusion for safety reasons as well. Tricyclic antidepressants, we exclude as well. The other drugs that would typically be excluded in an MDD type of study would be antipsychotics, mood stabilizers. The usual. From an antidepressant point of view, we exclude largely the tricyclic antidepressants and the monoamine oxidase inhibitors.
Some of the exclusion criteria, the MAOIs, et cetera, are for mechanistic safety reasons. Do I understand it right, the antipsychotics and others are more for sort of trial purity and powering reasons? Is there any sort of overlap of mechanism that would preclude real-world background use due to mechanisms?
Actually, you're right. Antipsychotics would interfere with the therapeutic efficacy or benefit or the pharmacodynamic effects of this class of drugs in general.
In general.
These are often in psychedelic trials. Antipsychotics would be used as rescue medications.
Block the trip. The others such as mood stabilizers, like let's say lithium, or one of the antiepileptics like sodium valproate, which is used as a mood stabilizer as well. There is twofold, the reason we are excluding them. One is, of course, the background mood stabilizer in a way indicates that the patient has maybe something else than depression. So they are more commonly used in bipolar disorder rather than in unipolar depression. So that's a red flag, and we don't want to include those patients. Mechanistically as well, we don't know enough in terms of how they interfere.
Let's go to effect size. Can you talk about what effect size this study is powered to detect? Maybe we'll just start with what data Michael and Amir, what data are you going to release with top line? If there's not just the top-line MADRS, but any key secondary endpoints, and then we'll get into the actual numbers of MADRS in APPROACH.
Sure. In terms of power, we haven't provided that specific information yet. What we have said to people is that if you look at the other late-stage trials in the class, it sort of is similarly powered as you would expect. In terms of the anticipated readout here in Q4 this year, of course, you'll get the primary endpoint, so that's the six weeks after the two doses, as Amir Inamdar discussed. Then you get the secondary endpoint of 12 weeks showing durability of effect, et cetera. Also the usual safety data, adverse event information that you would see in your top-line readout. Then, similar to every study readout, as we get additional data, we'll then be rolling that out at subsequent medical conferences, as you would expect.
Understood. Amir, you mentioned the prior phase II showed a 13-point placebo-adjusted at week three with a single dose. That is phase II, and across drug development, you do see sort of a diminution of effect between phase II and phase III. How are you guys approaching what true precedent should be for this 2-treatment, week six top-line MADRS, and also what response and remission rates would you see as clinically meaningful?
Maybe, Amir, why don't I'll sort of speak to overall how we're thinking about this, how we would suggest that people think about it, and maybe if you could speak to the responder-remitter expectations. Ritu Baral, first and foremost, this is an adjunctive trial. I always try and emphasize that for people. We're adding therapy on top of standard of care. These people are presumably getting some benefit, obviously not optimal. They need an adjunctive treatment, but again, you're showing an effect on top of they're already on medication. That's really an important context as you're thinking about comparisons, et cetera. Really, the adjunctive setting is its own setting, and cross-comparing against monotherapies or other trials in other indications, I don't think it's helpful or relevant. What's really important here is first and foremost, of course, approvability, right?
Yeah.
There, as you've seen with the adjunctive antipsychotics, 2-3 points, clearly approvable from an FDA perspective.
Yeah.
What is clinically meaningful, right? That's, of course, very important. The clinician perspectives really matter here, obviously. There, anything around 3 points, again, look to the adjunctive antipsychotics. There's a number of them out on the market. They have the side effect burdens that I think people are aware of. These really significant in terms of the cardiometabolic, the sexual dysfunction. There's a litany here that prescribers, and patients most importantly, have to deal with, but yet they're all widely used products in the adjunctive setting.
That sort of 3 points is from a clinically meaningful perspective, I think is relevant. Then I encourage people to think about this from the commercial perspective, right? There, the best adjunctive antipsychotic has got 4- 5 points of improvement on the MADRS. Even if you said to me, "Michael, what do you think about a 4- 5-point result here in terms of drug efficacy?" I would say that combined with the other key features, the durability that we've seen in our phase II and would hope to see then play out in the phase III, which is we saw up to 12 months of durability of effect off of the two doses that Amir referenced, right? We'll see in phase III, is that two doses in our long-term extension trial will help us with this.
Is it two doses, three or four doses? In any event, with a very limited number of doses, seeing that long-term durability. Then as importantly, the safety and tolerability profile that we've seen, mild to moderate adverse events, mostly transitory on day of treatment. Now, contrast that to the side effect burden of the antipsychotics that currently dominate the adjunctive space. Again, as people are thinking about what would be success, what is a strong commercial product that we could deliver real patient benefit, that clinicians would be excited by, that there is a good payer story to assemble. Then, of course, build long-term value, deliver that patient benefit. I go to that drug effect, the durability, and the safety tolerability profile, and our competition really is the adjunctive antipsychotics indicated in this space.
I think that really is the right way for people to think about trials in the adjunctive space and our trial.
With those long-term side effects being those cumulative long-term metabolic effects.
It is a significant burden and you see that with the antipsychotics, in terms of low compliance, that having to switch patients therapy to therapy to therapy and the side effect burden is throughout the duration of treatment. I think it really speaks to the unmet need in this therapeutic area, given that patients tolerate these issues because we need a better option.
Amir, what about response and remission? Also, as part of that, could you address what you think the MADRS trajectory will look like over those six weeks, sort of the shape of the curve, especially with this
Yeah
second dose?
Yeah. I think when you talk about response and remission, you've got to really look at the totality of data. When you think about how much improvement you're seeing in MADRS, what's the durability? What are the safety data, and how do these results compare with the available adjunctive therapies? What we're looking at is the key question. Does HLP-003 provide meaningful added benefit for patients who remain symptomatic despite background antidepressant therapy? We're looking to improve on standard of care. With the second administration at three weeks, we would anticipate some added benefit, incremental benefit, but importantly, we're looking at durability from a second dose, which would be consistent with our phase II data.
Got it. I neglected to mention my colleague and VP, Athena Chin, who is also joining me today on our coverage companies. As we move to the safety aspect of the discussion, I want to first start with discharge criteria. If you guys can talk to some of the discharge, what criteria must patients meet in this trial before they can be discharged following administration? What implications do those criteria have for real world? Then Athena will follow up on safety.
Yeah. I think the response to that is twofold. I think we need to make a distinction between what are the acute effects of the drug, where the patient will require intensive oversight. Then there will likely be a post-acute recovery period, after which the clinician makes an assessment of whether an individual patient is ready to go back home. That assessment will be based on a number of different criteria, and the investigator or the clinician has to be satisfied that the patient is fit to go back home with the appropriate supports. In terms of acute effects and acute monitoring, that will include largely a mixture of physiological symptoms. Things like blood pressure, heart rate, which are on target effects. We know these need to be monitored.
Class 1.
Yeah. Mental status examination. Those will be the acute stage effects followed by a variable discharge period.
All right.
Thank you. Before we continue on safety, we do have an audience question. On the phase IIa placebo response, could you speak more about how that differed from other trials of the same class? Do you think it's a factor of patients being on a stable dose of antidepressants versus the Johnson & Johnson SPRAVATO trials?
Yeah. Traditionally in MDD studies, we see a placebo effect which is larger than what we see in this class of drugs. We see about 10- 12 points on the MADRS with the daily dosing drugs, and we think that is largely to do with the daily dosing element of those drugs. Every time a patient receives a pill, whether that's placebo or active, they expect a benefit. Placebo effect accumulates over time. At six weeks, you're really looking at 10- 12 points, whereas with this class of drugs you see something smaller between 1.5 to 4 or 5 points. You do see a placebo effect, but you see that only on the day of dosing. When you look at the curves, you will see a drop in placebo, but that's only on the day of dosing.
It doesn't accumulate over time. That's why we see that effect smaller compared to traditional antidepressant drugs.
Athena, this was coming from your more traditional depression trials. As I was exposed to the psychedelic space and how well placebo effect has been controlled in these trials, it really is, I think, a significant distinction. Of course, we have to see our phase III reads out, but obviously that's positive support as I look towards overall success of the trial.
Got it. Just a last question on HLP-003. Given the concern for suicidality with the psilocybin agent, how do you think KOLs and FDA will view any suicidality in the MDD population versus prior studies in the TRD population, given a higher background suicidality rate?
Yeah, look, well, suicidality is a feature, an important clinical feature of major depressive disorder, unfortunately. So we are bound to see these cases in our clinical trials. But what we can do is mitigate that risk. We closely monitor those patients. Eventually regulators and KOLs will look at any events in context. They'll look at baseline severity in the population, the timing, severity, relationship to treatment, and importantly, whether there's an imbalance between active versus placebo. So right now what we do is monitor in a rigorous manner, in a transparent manner, and interpret within the broader safety of the data set.
Do you know what is considered an imbalance, whether that is a percentage difference or how do the regulators look at that?
That would be an increased frequency in the active arm compared to the inactive arm. Then, of course, whether that becomes statistically significant is a different case. Suicidality is an important safety signal, and it will be dealt with the attention that it deserves.
Well, and with that, we are over time. So thank you, Michael. Thank you, Amir, for joining us today. Next up, we do have a fireside chat with Definium Therapeutics at 9:30 A.M. Stay tuned. Thank you.