VYN201 for Vitiligo: Promising Data Showcases Potential of BET Inhibition

VYNE Therapeutics recently presented pre-clinical and phase 1b data demonstrating promise in nonsegmental vitiligo at the Society for Investigative Dermatology Annual Meeting last weekend in Dallas, Texas.

Iain Stuart, PhD, the chief scientific officer at VYNE, recently spoke with Dermatology Times to discuss the potential of BET inhibitors such as VYN201 in the therapeutic landscape of vitiligo.

"This disease state has had marked, marked unmet need for many, many years. It has been overlooked by industry with respect to new therapies, and even the therapies that are coming through now are all based on one pharmacology," Stuart said. "We think that's unacceptable. We think the potential for BET inhibition could be very broad, and not just in vitiligo, but into all the dermatologic and immunologic diseases. The very fact that we have shown the very first clinical dataset in an autoimmune disease, and it happened to be vitiligo, was particularly encouraging."

Transcript

Iain Stuart, PhD: Hi, I'm Dr Iain Stuart. I'm the Chief Scientific Officer at VYNE Therapeutics.

Dermatology Times: What is VYN201 and its mechanism of action? How does it compare to available therapies for vitiligo?

Stuart: So VYNE's inhibit platform has really 2 verticals: VYN201 and VYN202. VYN201 is a locally-administered pan-bromodomain and extraterminal inhibitor. It's a small molecule. VYN202 is a BD2-selective bromodomain and extraterminal inhibitor.

BET proteins play a key role in the regulation of gene transcription through a phenomena called epigenetic interactions. Now, that really is a science the grew out of a lot of work in oncology. Epigenetic interactions can be viewed through readers, writers, and erasers. Bromodomain and extraterminal proteins recognize acetylated lysines that protrude out the structural chromatin array and the nucleus of a cell. We're obviously focusing on signals or aberrant inflammatory signals, and B cells and T cells. But fundamentally, that's the key mechanism.

As epigenetic readers, they actually recruit transcriptional factors that help with the process of building what's called a transcript for a particular protein. Obviously, we are interested in inflammatory proteins, and then how that's ultimately translated into affiliate foreign protein. That actually has direct applicability in oncology, but also in autoimmune diseases. That's really where we are quite different from any other company that are looking at BET inhibitors. If you want to look specifically at the utility of BET inhibitors in immunoinflammatory disorders and profibrotic diseases.

VYN201 itself is called a soft drug. We specifically selected the molecule to have a very high first pass metabolism, so that anything that passes through the skin; VYN201 is topically applied. We also have formulations for injectable forms into the joint and as an inhaled form. Anything that passes through the skin is rapidly detoxified through the liver. The hope there is obviously to improve, markedly, the benefit-risk profile of BET inhibitors.

With respect to other mechanisms that are being viewed in vitiligo, they are primarily all built around JAK inhibition. The JAK-STAT pathway is obviously very well-established in dermatology and in a wide variety of specialities. But for the most part, most of the meds and early-stage development programs are based around JAK inhibition.

Dermatology Times: How do the phase 1 and pre-clinical data support the development of VYN201?

Stuart: That's a great question. We presented 2 papers at SID: a pre-clinical paper and a clinical paper. The pre-clinical paper really did focus on certain cellular processes that are key to the pathogenesis of vitiligo. Vitiligo is a disease of CD positive T-cell behavior. CD T-cells expand rapidly in patients' skin who have vitiligo, and they're primed towards attacking melanocytes. Melanocytes are obviously the cells that generate melanin and give us our color and our pigment.

What we found in our pre-clinical studies when we compared to another JAK inhibitor called ruxolitinib, is that VYN201 was so superior in preventing that expansion in in-vitro testing. We also found that the ex-vivo model of what's called melanocytology, so this was based on a human recombinant reformed epidermis, where we can actually induce the loss of color. We also saw a decrease in the matrix metalloproteinase called MMP-9. MMP-9 has been implicated and vitiligo as a key
pathogenic molecule that drives the depigmentation of skin by detaching, or essentially destabilizing, melanocytes that sit right at the epidermal and dermal junction of your skin. What happens is that this detachment causes melanocytes to drift up through the skin and is lost. That's why when you see patients with vitiligo, the first areas they tend to lose the pigment is around the mouth, the eyes, the axilla, the groin, backs of hands, tops of feet, anywhere where skin rubs or people are scratching, because the melanocytes literally drift to the surface and are last to the mechanical processes. It's very comforting to see that we can reduce that key marker. Correspondingly, E-cadherin, which is a protein that holds melanocytes and keratinocytes together, we could actually prevent that loss as well.

Also in the pre-clinical paper, we showed potential for VYN201 to operate a key process that is dysfunctional in vitiligo. That process, or pathway, is substantially downregulated in patients with vitiligo, and it's actually key to allow melanocytes to differentiate and start to produce melanin or melanogenesis. We actually saw some upregulation of that as well. So that's some data from a pre-clinical paper.

In the clinical paper, we summarized the key data from an open-label phase 1b study with VYN201 where we were treating patients with nonsegmental vitiligo. That was for once-daily treatment for 16 weeks. It was an open-label trial. Obviously being a phase 1 study, the primary objective was safety, tolerability, and pharmacokinetics. We treated up to 29 patients across 3 cohorts, and we treated topically applied medications 0.5%, 1%, and 2%, so we actually saw some substantial improvement on vitiligo on the face. We really used that as our primary endpoint. It's called F-VASI, or Facial Vitiligo Area and Severity Index. We also saw great improvement there at our 1% and our 2% cohorts, and a very rapid onset of action, which was particularly encouraging, particularly when vitiligo studies take so long to see real recovery and pigmentation. That's one of the challenges of managing patients with vitiligo.

At the 16-week timepoint, we saw 39% improvement in our top dose of 2%. We also saw some very healthy movement and some key biomarkers from the non-facial areas. We took biopsies from lesions elsewhere on the body. Again, that helps support the hypothesis that VYN201 could potentially support the recovery of the pathway.

We also saw a nice reduction of MMP-9, which is what we saw in our pre-clinical study. Again, that does support both an anti-inflammatory mechanism but also potentially support a more proactive approach of allowing melanocytes to recover in the skin. So we're really pleased with that.

Safety from that study was very encouraging. Obviously, it's only 16 weeks of treatment for once-daily. We will continue that development program, but it's encouraging to this day.

Dermatology Times: How do these results inform future clinical trials involving VYN201?

Stuart: We certainly think the data supports advancement. VYN201 is a very differentiated therapy, as I said earlier on. The vast majority of drugs that are currently in development for vitiligo are JAK inhibitors and come along with all the associated safety precautions that come along with that class of molecule. There's a tremendous unmet need in vitiligo in general, and within the therapeutic space, there's basically no differentiation. We really think that there's a space here for VYN201.

What was particularly encouraging was this dataset from the phase 1b was the first clinical demonstration of a BET inhibitor in any autoimmune disease, which was very encouraging. Our hypothesis that BET is a key potential new target in immunobiology has been particularly encouraging for us, and to see that in a clinic was very supportive. We are moving into a phase 2b study very shortly this quarter in nonsegmental vitiligo.

The 2b trial will enroll up to 160 patients across 4 arms and will include both what's called active disease and stable disease patients. We will evaluate VYN201 as a topical gel at 1%, 2%, and 3% concentration strengths. Initially, for up to 24 weeks, in a double-blinded manor, and then once we get to the 24 week timepoint, patients receiving the vehicle, sometimes known as placebo, will be re-randomized to 1%, 2%, or 3% for a further 6 months for a total of 1 year of therapy. The first portion of the study we anticipate to read out in 2025.

I think the key thing here is that we hear you. We hear you that this disease state has had marked, marked unmet need for many, many years. It has been overlooked by industry with respect to new therapies, and even the therapies that are coming through now are all based on one pharmacology. We think that's unacceptable. We think the potential for BET inhibition could be very broad, and not just in vitiligo, but into all the dermatologic and immunologic diseases. The very fact that we have shown the very first clinical dataset in an autoimmune disease, and it happened to be vitiligo, was particularly encouraging. We're looking forward to continuing the program and involving the dermatology community in the next steps for VYN201.

[Transcript has been edited for clarity.]