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VYNE's Iain Stuart, PhD, Talks Promise of VYN202 and BET Inhibition in Inflammatory and Psoriatic Disease

News
Article

Iain Stuart, PhD, discusses VYN202's status and potential in psoriasis and immuno-inflammatory diseases.

On June 13, VYNE Therapeutics announced the successful dosing of the first healthy volunteers in the phase 1a trial of VYN202, an oral small molecule BD2-selective bromodomain and extra-terminal domain (BET) inhibitor.1-2

This first-in-human trial will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of VYN202, with top-line data expected later this year.

Iain Stuart, PhD, Chief Scientific Officer of VYNE Therapeutics, recently spoke with Dermatology Times to share insights into the significance of this trial, the potential impact of VYN202 on the treatment landscape, and VYNE's vision for the future of immuno-inflammatory disease management.

Transcript

Iain Stuart, PhD: I'm Iain Stuart. I'm the Chief Scientific Officer for VYNE Therapeutics.

Dermatology Times: Can you elaborate on the design and objectives of the phase 1a trial for VYN202? How do the single and multiple ascending dose components contribute to the overall understanding of the drug's profile?

Stuart: The phase 1a study that we announced, first healthy volunteers dosed a couple of weeks ago, is a single ascending and multiple ascending dose trial. We anticipate that we'll be evaluating up to 5 dose levels in the single ascending dose and up to 3 dose levels for the multiple ascending dose. As you know, VYN202 is an orderly-administered drug. So the primary objective, like any phase one a study, is obviously safety. This is a first in human evaluation of VYN202 capsules, so safety will be the key focus area. Obviously, the safety is in relation to treatment adverse events that may potentially emerge during treatment. We'll be looking at clinical and hematological results, but we will also be looking at pharmacokinetics and how the drug is absorbed and distributed and ultimately excreted in the body, and we'll be looking at human metabolites that are formed.

We will be looking at some specific biomarkers in relation to VYN202. The first one is called hexanone. Now hexanone is a gene that's upregulated when you inhibit proteins. And as we know, VYN202 is a BET protein inhibitor. We'll be able to begin to see the correlation between the blood levels of VYN202 and how it affects the primary target of the of the drug. Secondarily, we will be looking at a series of inflammatory proteins, and obviously with healthy volunteers, generally speaking, if in a good, healthy shape, these levels of these inflammatory proteins would be quite low. What we're doing is actually taking bloods at the bedside, and we can actually generate an immune response, and we can stimulate the production of inflammatory proteins. We compare patients who have been exposed to VYN202 to patients who've been exposed to placebo. Within each of the single ascending and multiple ascending dose cohorts, we'll have patients who are healthy volunteers who have been treated with placebo and treated with VYN202 in its active form. In the multiple ascending dose, we'll be treating patients for up to 14 days. Clearly, there we're looking at how the exposure levels develop under repeat dosing. Of course, if there's any additional safety information we can gather over over those 2 weeks. We're very excited to start this study. VYN202 is a very potent and very selective BD2 inhibitor, and this is really the start for for this drug.

Dermatology Times: VYN202 has showed consistent improvements in disease severity across various models in preclinical testing. Could you provide more details on these models and the specific outcomes observed?

Stuart: VYN202, as a BD2-selective BET inhibitor, has a quite substantial effect on inhibiting the release of inflammatory proteins that really drive the pathogenesis of many autoimmune diseases, and, of course, in the context of our discussion, really a lot of dermatological conditions, as well. There's really 2 primary preclinical packages that we evaluated that are really relevant here. One is we evaluated VYN202 in a mouse model of psoriasis. This model, we can actually induce a psoriasiform-like plaque. It looks very similar to human psoriasis on the backs of mice, and then we can treat that with various interventions. In that particular study, we saw a very nice clinical response, whereas the redness, the flakiness, and the thick, thick skin that the induced animals experienced was almost completely clinically cured.

We also ran in parallel with that, a comparison with deucravacitinib, the allosteric TYK2 inhibitor that was approved last year, and that also had a very good clinical response, as well. We were excited on that particular data set, and really started us on the path to take VYN202 into moderate and severe plaque psoriasis study. In addition to the clinical outcomes in our model, we also saw a very nice suppressive effect on key cytokines or inflammatory proteins that drive the pathogenesis of psoriasis, such as IL-17, IL-23, TNF alpha, which is always some of the more older generation of monoclonals targeted there, and downstream IL-6. It did tie in nicely with a good clinical outcome, as well.

The second model we also evaluated was in the rheumatoid arthritis model. Similarly, we had a very nice clinical response there; we saw nice reduction inflammation, this was in the rat, and inflammation in the animal's limbs, and the pathology of arthritis and also correspondingly on biomarkers, as well. What we're planning to do is to progress both of these indications with VYN202, starting with plaque psoriasis and then arthritis.

Dermatology Times: What specific pharmacokinetic and pharmacodynamic parameters are you most interested in evaluating during this phase 1a trial, and why are these parameters critical for VYN202’s development?

Stuart: The key thing with pharmacokinetics is predictability of linearity. As we start to expose patients to higher and higher doses, we obviously want to see if that exposure is linear. As we double the dose, we may see double the exposure. Because obviously, if we see something that's markedly different, we obviously have to take that into consideration for doses that we ultimately select for later development. On the pharmacodynamic component and effect on biomarkers, as I talked about the hexanone biomarker, that's a key target engagement biomarker for us, we naturally would like to see a corresponding increase in the expression of hexanone, because that then ties neatly to target engagement of VYN202, to the BET proteins. The inflammatory biomarkers that I was talking about: again, we'd like to see some down regulation or amelioration of some of these key inflammatory proteins that we know are relevant to the pathogenesis of the diseases that we are wanting to progress with.

Dermatology Times: What are the subsequent phases of clinical development for VYN202, and what timelines are you anticipating for these phases?

Stuart: The phase 1a study that's running just now, as I talked about, is really 2 parts: a single ascending dose and a multiple ascending dose. We anticipate having data from the single ascending dose in the late summer of this year, and from the multiple ascending dose, sometime towards the back end of Q3 and into Q4 of this year. Again, assuming success, we don't see anything of particular concern. We'll be moving into these phase 1b disease model studies and patients with more severe psoriasis and more severe arthritis, and due to start towards the back end of this year and run, really for the balance of 2025, with data towards the second half of 2025, for both sides.

Dermatology Times: Looking ahead, what is your long-term vision for VYN202 and its impact on the treatment landscape for immuno-inflammatory diseases?

Stuart: We think VYN202 has a very broad applicability based on a preclinical data that were generated to date. Thinking even beyond moderate or severe psoriasis and arthritis, we see this direct application to other autoimmune diseases, both within dermatology and outside of dermatology. The parallel we like to look at is how broadly JAK inhibitors, for example, have been applied over the years. We see a similar potential path for BET inhibitors, as well. Clearly, we are hyper focused at the moment in generating proof of principle data in psoriasis and in arthritis, but clearly, with many opportunities beyond that, to really maximize the potential value to patients for VYN202.

With respect to BET inhibition, this is a brand new modality, not just in dermatology, but in autoimmunity. We're really excited to introduce this. I'm very happy that it happens to be our first assessments are in dermatological diseases. Watch this space. We will be spending a lot of time executing on this particular program as we hope for success, and as I said, reported data towards the second half of next year.

[Transcript has been edited for clarity.]

References

  1. VYNE Therapeutics announces dosing of first participants in phase 1a trial of novel BD2-selective BET inhibitor VYN202. News release. VYNE Therapeutics. June 13, 2024. Accessed July 2, 2024. https://vynetherapeutics.com/press-releases/vyne-therapeutics-announces-dosing-of-first-participants-in-phase-1a-trial-of-novel-bd2-selective-bet-inhibitor-vyn202/
  2. Hebebrand M. First patients dosed with VYN202 for inflammatory diseases. Dermatology Times. June 13, 2024. Accessed July 2, 2024. https://www.dermatologytimes.com/view/first-patients-dosed-with-vyn202-for-inflammatory-diseases
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