Iain Stuart, PhD: VYN202 Positive Safety and Tolerability in Phase 1a

VYNE Therapeutics recently announced that its novel oral small molecule VYN202, a BD2-selective bromodomain and extra-terminal domain (BET) inhibitor, showed promising safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase 1a placebo-controlled, single-ascending dose clinical trial.¹

Read more from Dermatology Times.

Iain Stuart, PhD, Chief Scientific Officer of VYNE Therapeutics, recently spoke with Dermatology Times to discuss the outcomes of the phase 1a trial, details of the upcoming multiple ascending dose trial, and the potential of BET inhibition in immuno-inflammatory conditions.

Transcript

Iain Stuart, PhD: My name is Iain Stuart. I'm the Chief Scientific Officer of VYNE Therapeutics.

Dermatology Times: Can you explain the significance of the single ascending dose results in the context of the overall phase 1a trial for VYN202?

Stuart: Last week, we announced data from the first part of our very first human clinical study evaluating our BD2-selective BET inhibitor VYN202. This is a 2-part study: a single ascending dose phase and a multiple ascending dose phase. Our announcement from last week covered just the single ascending dose phase; as the name suggests, healthy volunteers were administered a single dose a capsule of VYN202 in cohorts, and as we evaluated safety and pharmacokinetics and effect on biomarkers, we then escalated to the next dose. Obviously, we reviewed safety very closely, because this was a first in-human study.

The data that we announced last week was really from 5 treatment cohorts. We have found that we have dose-dependent pharmacokinetics, which is obviously very encouraging. And predictable pharmacokinetics, that the safety profile of the information we have at least from a single dose is certainly very supportive for the continued development of VYN202. Almost as excitingly, our effects on key biomarkers that we posited as being very important for both target engagement of the VYN202 to the BD2 BET protein and effect on key inflammatory biomarkers was in line with expectations, despite the fact that we only treated healthy volunteers with a single dose.

Coming back to the pharmacokinetics, we looked at drug levels in blood or plasma and in urine, and obviously we saw good dose dependent pharmacokinetics. Interestingly, on the safety side, we focus on adverse events of special interest to the class, and we're very encouraged by where we are, but we're also very cautious. We're in the middle of it, and it is only a single dose, but so far so good. On the biomarkers, so there's a specific biomarker called HEXIM1. There's a protein that's upregulated when you inhibit BET protein. As the effect of BET proteins go down, this marker goes up again; we saw a very nice correlation between increasing blood levels or pharmacokinetics with VYN202 and increasing levels of HEXIM1. It's all well and good to say, "Yeah, okay, you can get your drug into the blood, but is it getting to the target?" That really gives us some comfort that, yes, absolutely, it's getting to the target in a quite predictable way.

We also did some very interesting work on inflammatory biomarkers. The way that we do that is we actually stimulate immune response in patients blood ex vivo. We don't stimulate it in vivo. As we take blood samples from the patients when we're doing pharmacokinetic sampling, we can also stimulate using a particular stimulant in the collection tubes to generate release of specific cytokine profiles that, obviously, we're interested in for the molecule. And again, despite the fact that it was only a single dose, we started to see quite a nice separation between patients who had received placebo and patients that received VYN202. We had lower levels of certain counts key cytokines for patients that were exposed to VYN202, relative to ones that had placebo. Again, we're very cautious with the single dose, and there's certainly some very interesting signs that we're having a nice target engagement that is correspondingly impacting the release of key inflammatory cytokines that we know are pathogenic in, for example, psoriasis.

Dermatology Times: Can you elaborate on the pharmacodynamic effects observed in relation to inflammatory biomarkers, particularly HEXIM1, and their relevance to conditions like psoriasis and rheumatoid arthritis?

Stuart: HEXIM1 itself is primarily a targeting biomarker for protein, for our pharmacology, so it's not directly related to the pathogenesis of psoriasis, but what it would be is, again, that is a kind of signaling molecule that would be significantly suppressed. The other way, if you had very aberrant inflammatory signaling, ie, the BET protein is hyper activated, and BET proteins are transcriptional factors, so they have a very key role in progressing inflammatory signaling within the nucleus of, for example, a T cell. When you have this transcellular signaling that's obviously hyper activated in many auto diseases, BET proteins are obviously a very important part of that, similar to JAK inhibitors in the JAK-STAT pathway, which is a separate pathway. What we've found here is that, yes, we can inhibit the BET protein in humans to be at the corresponding upregulation of the HEXIM1 on the inflammatory markers side. Again, we haven't communicated too much just now because we're in the middle of the study, but again, some key biomarkers related to psoriasis have also been suppressed. But the panel is much broader than that, and it also looks at maybe potential other indications beyond psoriasis as well. We are considering, obviously, rheumatoid arthritis as a separate indication for VYN202.

Dermatology Times: With the multiple ascending dose phase now underway, what are the key objectives you hope to achieve, and how will they influence the next stages of development?

Stuart: Now that we are moving beyond a single dose, safety is always paramount in any clinical sector. We assess safety as we escalate through doses, and now we are supporting healthy volunteers with up to 14 doses. This is a 2-week multiple ascending dose study, uniquely focused on gathering safety information—not just adverse events, but also hematological changes and serum chemistry, along with all the analytes we want to assess. That is a key component. That's a key component of that. Secondarily is how pharmacokinetics change over repeat doses. Obviously, we have a single dose, but what happens after 14 doses? Is there significant accumulation? Is there a time to a steady-state blood level? Is that within 2 weeks? Is it potentially longer? Many questions could be addressed in the multiple ascending dose. Then correspondingly, once we complete the multiple ascending dose, that will certainly be very informative for dose selection, medical studies, and psoriasis.

Dermatology Times: What does the success of VYN202 mean for the broader category of BET inhibitors in immuno-inflammatory therapies?

Stuart: We're relatively unique there. We're only aware of 1 other significant project. They're evaluating a BET inhibitor in autoimmune disease, and that's also our program VYN201 for the treatment of vitiligo. There's certainly been a lot of preclinical evidence over the years showing the utility potential of a BET inhibitor in autoimmune diseases, but the pharmacology itself was born in oncology, and really has mostly remained there because of some of the more challenging dose limiting toxicities associated with the class in general from early generation molecules. But our whole inhibit platform that VYN201 and 202 came from was specifically built to address these safety concerns. On the VYN201, side, which is called a pan-BD inhibitor, so it binds equally as well to both bromodomains, BD1 and BD2, that would potentially, if it was significant blood levels, pharmacokinetics, potentially have some more challenging safety concerns. The way that we were addressing safely with VYN201 is applying typically in context of dermatology. However, we also have formulations that are a little bit more tissue targeted, such an intra articular injection and an inhaled formulation. Obviously, the lung itself is also a barrier as well as skin. But just as importantly, VYN201 is what's called a soft drug, so it has a very high first pass metabolism, so it's rapidly detoxified by the liver. Therefore, we can keep the drug levels very low in the broader circulation, keep the effect in the tissue, that we really want want the effect to take place for.

VYN202 is obviously an oral medication. We can use a soft drug approach. Obviously, the way we address this is hyper targeting of the BD2 binding domain. Most of the data with not just ourselves, but others have generated over the years, have shown that the BD1 binding domain appears to be more associated with some of the more challenging, post limiting toxicities with the class. We spent a better part of 2 years optimizing the chemistry to make sure we just targeted the BD2 binding domain as best we can. Interestingly, data that we've also generated has shown that the BD1 binding domain really doesn't play a significant role as an anti inflammatory target. It really doesn't. It has more impact on the regulation of genes associated with general cell health, cell cycling, division and program death, etc, whereas BD2 seems to be inextricably linked to an inflammatory pathway called the NF-κB process, which many autoimmune diseases leverage as part of their inflammatory processing, cellular process. Really for 2 reasons, it makes sense to target BD2: the safety question and the greater relevance in relation to an anti inflammatory region.

Other than VYN202, I think the most exciting thing we have running just now is obviously our phase 2 study just now evaluating VYN201 gel treatment on nonsegmental vitiligo. We're very busy there running that study now. What's really interesting about it, and I was quite surprised when I started, is the dirth of treatment options for patients with vitiligo compared to other dermatological conditions such as psoriasis, acne, rosacea, etc. There's a huge unmet need there for new therapies. We only have 1 drug approved, and that's Opzelura by Incyte, and that's a JAK inhibitor, topically applied. Most of the other drugs in development now are also JAK inhibitors, so we see it as a significant point of differentiation. Therefore VYN201, it's not a JAK inhibitor, it's a different and unique mode of action addressing tremendous unmet need in dermatology. We're really excited to progress for this study. Obviously, read out the data around the middle time of next year, and hopefully everything goes well and we continue into pivotal programs and later development.

[Transcript has been edited for clarity.]

Reference

1. VYNE Therapeutics announces positive phase 1a SAD data for VYN202, a novel BD2-Selective BET inhibitor. News release. BioSpace. September 12, 2024. Accessed September 23, 2024. https://www.biospace.com/press-releases/vyne-therapeutics-announces-positive-phase-1a-sad-data-for-vyn202-a-novel-bd2-selective-bet-inhibitor