VYNE Therapeutics Inc. and its subsidiaries (VYNE) is a clinical-stage biopharmaceutical company focused on developing proprietary and differentiated therapies for the treatment of immuno-inflammatory conditions.
In August 2021, the company entered into a transaction with Tay Therapeutics Ltd., formerly known as In4Derm Ltd. (‘Tay’), providing the company with exclusive worldwide rights to research, develop and commercialize products containing bromodomain and extra-terminal domain (‘BET’) inhi...
VYNE Therapeutics Inc. and its subsidiaries (VYNE) is a clinical-stage biopharmaceutical company focused on developing proprietary and differentiated therapies for the treatment of immuno-inflammatory conditions.
In August 2021, the company entered into a transaction with Tay Therapeutics Ltd., formerly known as In4Derm Ltd. (‘Tay’), providing the company with exclusive worldwide rights to research, develop and commercialize products containing bromodomain and extra-terminal domain (‘BET’) inhibitors for the treatment of any disease, disorder or condition in humans. Through the company’s access to this library of new chemical BET inhibitor compounds, the company plans to develop product candidates for a diverse set of indications. Based on data generated as of December 31, 2023, the company had chosen to focus its initial efforts for this platform on select therapeutic areas in immuno-inflammatory disease.
The company’s lead program is VYN201, a locally administered pan-bromodomain (‘BD’) BET inhibitor designed as a ‘soft’ drug to address diseases involving multiple, diverse inflammatory cell signaling pathways while providing low systemic exposure. In preclinical testing, VYN201 produced consistent reductions in pro-inflammatory and disease-related biomarkers and improvements in disease severity across a variety of inflammatory and fibrotic models. In November 2022, the company initiated a Phase 1a/b clinical trial evaluating a VYN201 ointment for the treatment of nonsegmental vitiligo. In the first quarter of 2023, the company announced positive preliminary safety and tolerability, pharmacokinetic and hematology data from the Phase 1a portion of the trial. The first nonsegmental vitiligo patient was dosed in the Phase 1b portion of the trial in January 2023, and on October 30, 2023, the company announced positive data from the Phase 1b trial, in which significant clinical improvement in facial vitiligo area scoring index (‘F-VASI’) was observed in the 1% and 2% dose cohorts after 16 weeks of treatment. The company has initiated Phase 2b preparatory activities and expects to advance a gel formulation of VYN201 into a longer duration Phase 2b trial to evaluate optimal dosing and peak efficacy in patients with active or stable nonsegmental vitiligo in the second quarter of 2024 with top line results from the 24-week double-blind portion of the trial anticipated in mid-2025.
The company’s second program is VYN202, an oral small molecule BD2-selective BET inhibitor. VYN202 has been designed to achieve potential class-leading selectivity (BD2 vs. BD1), maximum potency versus BD2 and optimal oral bioavailability. By maximizing BD2 selectivity, VYN202 has the potential to be a more conveniently-administered non-biologic treatment option for both acute control and chronic management of immuno-inflammatory indications, where the damaging effects of unrestricted inflammatory signaling activity are common. The company submitted an Investigational New Drug application (‘IND’) for VYN202 to the U.S. Food & Drug Administration (the ‘FDA’) in December 2023. The company recently received correspondence from the FDA informing the company that its Phase 1a clinical trial is on hold and requesting that the company submit data from an additional nonclinical study. The company recently completed the additional nonclinical study which achieved preliminary results consistent with the company’s expectations at the outset of the study. The company plans to submit the requested nonclinical information to the FDA by the end of the first quarter of 2024 and, if cleared by the FDA, the company expects to initiate its Phase 1a single ascending dose/multiple ascending dose trial in healthy volunteers in the second quarter of 2024, with top line results from the trial anticipated in the second half of 2024. If the Phase 1a portion of the trial is successfully completed, the company plans to initiate Phase 1b trials in subjects with moderate-to-severe plaque psoriasis and moderate-to-severe adult-onset rheumatoid arthritis, with top line results anticipated in the second half of 2025.
The company intends to advance its product candidates through clinical development toward regulatory approval. As part of the company’s strategy to maximize the value of the company’s pipeline, the company may partner with larger pharmaceutical companies to expand and accelerate the development of its programs and explore therapeutic areas outside of the company’s core focus in immunology.
Platform and Product Candidates
InhiBET BET Inhibitor Platform
Through the company’s partnership with Tay, the company has exclusive worldwide rights to research, develop and commercialize products containing certain BET inhibitor compounds for the treatment of any disease, disorder or condition in humans. See ‘—Development and License Agreements—Tay License Agreements.’ Utilizing the company’s InhiBET platform and through the company’s preclinical and clinical activities, the company is evaluating the impact that BET inhibitor compounds have on regulating pro-inflammatory cytokines. The company is targeting indications whose pathogenesis is linked to the proliferation of these specific cytokines. The company has selected development candidates and are developing formulations that are designed to maximize the anti-inflammatory effect of the drug while minimizing safety concerns. Through the company’s InhiBET development platform, the company can demonstrate the potential utility of these BET inhibitor compounds and develop therapies for a variety of immuno-inflammatory conditions.
VYN201 - Locally Administered Pan-BD BET Inhibitor
The company’s lead BET inhibitor candidate in development is VYN201. VYN201 was developed using the InhiBET platform and is a locally administered pan-BD BET inhibitor. It is a first-in-class ‘soft’ pan-BD BET inhibitor that is being developed to address diseases involving multiple, diverse inflammatory cell signaling pathways. The company’s intention with the VYN201 program is to develop a therapy that delivers a potent, localized anti-inflammatory effect and can be rapidly cleared through the body's metabolic processes to avoid systemic absorption. The company has conducted several preclinical studies which have demonstrated VYN201's anti-fibrotic and anti-inflammatory activity and the ability to significantly reduce the expression of key cytokines relevant to certain autoimmune diseases, including in psoriasis, idiopathic pulmonary fibrosis and rheumatoid arthritis. In October 2023, the company announced positive data from its Phase 1b trial of VYN201 in subjects with nonsegmental vitiligo, which demonstrated clinical proof-of-concept for the use of this BET inhibitor to treat immuno-inflammatory disease. Based on data generated as of December 31, 2023, VYN201 had the potential to be highly versatile by serving as a locally acting therapy with low systemic exposure.
Nonsegmental Vitiligo
Vitiligo is a chronic autoimmune depigmenting disorder of the skin, characterized by the loss of pigment-producing cells known as melanocytes. Vitiligo is the most common depigmenting skin condition, with a prevalence estimated at 0.5-2% of the world population. An article published in the scientific journal JAMA Dermatology in 2021 estimated that there were between 1.9 million and 2.8 million cases of vitiligo in the United States. Approximately 90% of vitiligo cases are characterized as nonsegmental, in which white patches appear symmetrically on both sides of the body. There is only one drug, OPZELURA (ruxolitinib) cream, approved by the FDA for the treatment of nonsegmental vitiligo, and that product includes a black box safety warning on its label. Based on preclinical and clinical data generated as of December 31, 2023, VYN201 has the potential to offer a targeted and efficacious treatment option that lowers the disease recurrence rate and can be effective for all skin tones with fewer side effects.
Phase 1 Clinical Trial
Based in part on the data the company observed from the preclinical vitiligo model described below, the company commenced a Phase 1 clinical trial evaluating VYN201 topical ointment for the treatment of nonsegmental vitiligo in November 2022. The trial was conducted at the U.S.-based clinical centers. In the Phase 1a portion of the trial, single ascending and multiple ascending doses of VYN201 were applied topically once daily to 30 healthy volunteers in five dose cohorts for two weeks with a one-week safety follow-up visit to evaluate the safety, tolerability and pharmacokinetics of VYN201. Evaluated doses included 0.025%, 0.1%, 0.5%, 1.0%, and 2.0% concentrations. There were no serious adverse events and no dose adjustments were required. There were no clinically relevant treatment emergent adverse events, abnormal clinical laboratory results or electrocardiogram findings. No healthy volunteers withdrew from the trial for any reason. The company selected the 0.5%, 1.0% and 2.0% doses for further evaluation in the Phase 1b portion of the trial.
The Phase 1b portion was a 16-week open-label trial assessing the safety, tolerability and pharmacokinetics of once-daily VYN201 in 29 patients across the three dose cohorts. Exploratory efficacy of VYN201 was also evaluated, including its ability to arrest the progression of skin depigmentation and support skin repigmentation in patients with active disease, through changes in F-VASI. On October 30, 2023, the company announced positive results from the Phase 1b portion of the trial. Significant clinical improvement was observed in the 1.0% and 2.0% cohorts with rapid onset of action and a dose-dependent response. Mean percentage reduction in F-VASI score from baseline after 16 weeks of treatment was 7.5%, 30.2% and 39.0% for the 0.5%, 1.0% and 2.0% cohorts, respectively. VYN201 was generally well tolerated with no clinically relevant treatment emergent adverse events across all dose cohorts.
Following extensive testing, the company plans to evaluate a once-daily gel formulation of VYN201 for its upcoming Phase 2b trial in patients with nonsegmental vitiligo, which the company expects to initiate in the second quarter of 2024. The gel formulation may provide additional clinical benefits based on improved dermal penetration properties compared to the ointment that was evaluated in the Phase 1b trial. The Phase 2b trial is anticipated to be a 24-week randomized, double-blinded, vehicle-controlled trial with a separate active treatment extension phase to 52 weeks. Pending FDA acceptance of the protocol, the trial will evaluate three or four arms (including vehicle) of once-daily treatment with VYN201 gel, with each arm enrolling between 40 and 50 patients with active or stable nonsegmental vitiligo. The primary efficacy endpoint of the trial will be an evaluation of the proportion of subjects achieving FVASI50 at week 24 compared to vehicle. Based on the company’s expected timing for initiating the trial, the company anticipates top line results from the 24-week double-blind portion of the trial to be available in mid-2025.
Preclinical Studies for Multiple Indications
Vitiligo
The company conducted a preclinical study using an ex vivo skin model of vitiligo.
In the preclinical study, VYN201 reduced the expression of key pro-inflammatory biomarkers relevant to the pathogenesis of vitiligo and resulted in marked reduction in melanocyte loss. VYN201 produced a dose-dependent reduction in MMP-9 and soluble E-cadherin and substantially reduced the loss of melanin pigment in the basal layers of skin at the 0.1% and 1% concentrations. In addition, VYN201 significantly upregulated WNT16, a member of the WNT family of genes. The WNT/ß-catenin signaling pathway is known to be dysregulated in vitiligo and is believed to play a key role in melanocyte regeneration.
Psoriasis
The company evaluated the impact of VYN201 on Th17-mediated inflammation in an established preclinical animal model of psoriasis and an ex vivo human tissue study. T-helper 17, or Th17, cells are a CD4+ T-cell subset characterized by production of interleukin-17, or IL-17, a highly inflammatory cytokine that plays an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. In the animal model, depilated mice were topically dosed with imiquimod cream to induce a psoriasis phenotype over a 7-day induction phase. A further 7-day treatment phase evaluated three doses of VYN201 (0.001%, 0.01% and 0.1% concentrations) compared to a highly potent glucocorticosteroid product positive control (clobetasol propionate 0.05% cream) and vehicle control. An imiquimod-naive control group (healthy control group) was also included for VYN201 vehicle treatment. In these studies, treatment with VYN201 significantly reduced the expression of several key pro-inflammatory cytokines relevant to Th17-mediated autoimmune diseases. A dose-dependent improvement in the signs and symptoms of inflammation was observed in VYN201 treatment groups, and treatment with VYN201 at all concentrations was well tolerated in the studies.
Idiopathic Pulmonary Fibrosis
The company evaluated an inhaled formulation of VYN201 in an established mouse model of idiopathic pulmonary fibrosis. Lung fibrosis was induced in mice using a single intratracheal dose of bleomycin. Fibrosis was left to develop for seven days, and thoracic tomography images were obtained to stage fibrotic development. Animals were assigned to six treatment groups: untreated and unstimulated control, placebo, and one of four doses of VYN201 (0.1, 0.2, 0.5, and 1.0 mg/ml), with six mice in each group. Each treatment group was dosed intratracheally every other day for 14 days. Changes in blood oxygen saturation, Ashcroft scoring (a standardized numerical scale used to quantify the extent of lung fibrosis in histological samples), lung hydroxyproline (a tissue biomarker for fibrosis), and volumetric lung function were assessed. Treatment with VYN201 at 0.5 mg/ml and 1 mg/ml resulted in statistically significant reductions in Ashcroft scores and levels of hydroxyproline compared to the placebo control group at day 21. In addition, mean blood oxygen saturation for the VYN201 1 mg/ml group was 92.4% at day 21, an 8.8% improvement compared to the placebo group (83.6%). Mean blood oxygen saturation for the untreated and unstimulated control group was 95.2%. Thoracic tomography revealed that VYN201 treatment groups experienced a dose-dependent improvement in functional lung volume compared to the placebo control group.
Rheumatoid Arthritis
The company conducted a preclinical study showing that intra-articular injections of VYN201 resulted in significant inhibition of inflammation in a validated animal model of rheumatoid arthritis. In the preclinical study, inflammatory arthritis was induced in BALB/c mice. Each treatment group of seven mice was injected with either (i) an intra-articular dose of VYN201 vehicle, (ii) an intra-articular dose of VYN201 (with one of four concentrations ranging from 0.01 to 10 mg/kg), (iii) an intra-articular dose of dexamethasone (1 mg/kg) or (iv) a systemic dose of dexamethasone (1 mg/kg, via intraperitoneal injection). The intra-articular doses were administered on days 0, 3, 6 and 9 while the dexamethasone systemic injections were given daily beginning at day 0 through 11. Each animal treated with the intra-articular injections received the injection in the ankle of one rear paw. The untreated rear paw was assessed to evaluate any potential anti-inflammatory systemic effect. Treatment response was evaluated based on an assessment of paw thickening or swelling (in millimeters) and arthritis scoring based on a five-point composite severity scale of redness, swelling of the ankles and wrists, and paw thickness. Scoring in this model ranges from 0 (normal) to 4 (extensive signs and symptoms of arthritis).
Treatment with VYN201 resulted in marked inhibition of paw thickening at the 1 and 10 mg/kg doses. At both doses, the inhibition of paw thickening was statistically significant in the treated paw relative to the untreated rear paw on day 12 (p<0.01). In addition, limbs treated with VYN201 at the 1 and 10 mg/kg dose levels had an average arthritis score of 0.57 and 0.67, respectively, or near normal. The arthritis score was significantly lower in the treated paw at both doses relative to the non-treated paws on day 12 (p<0.05).
VYN202 - Oral BD2-Selective BET Inhibitor
VYN202 is an oral small molecule BD2-selective BET inhibitor that has been designed to achieve potential class-leading selectivity (BD2 vs. BD1), maximum potency versus BD2 and optimal oral bioavailability. Systemic BET inhibitors have historically targeted both BD1 and BD2 less selectively, causing gastrointestinal toxicity and bone marrow suppressive effects like thrombocytopenia. By maximizing BD2 selectivity, VYN202 may alleviate the therapeutic limiting toxicities observed by other less BD2-selective BET inhibitors in development for oncology and have the potential to be a more conveniently-administered non-biologic treatment option for both acute control and chronic management of immuno-inflammatory indications, where the damaging effects of unrestricted inflammatory signaling activity are common.
Planned Phase 1 Clinical Trial
The company submitted an IND for VYN202 to the FDA in December 2023. The company recently received correspondence from the FDA informing the company that its Phase 1a clinical trial is on hold and requesting that the company submits data from an additional nonclinical study. The company recently completed the additional nonclinical study which achieved preliminary results consistent with the company’s expectations at the outset of the study. The company plans to submit the requested nonclinical information to the FDA by the end of the first quarter of 2024 and, if cleared by the FDA, expect to initiate a Phase 1a single ascending dose/multiple ascending dose trial in healthy volunteers in the second quarter of 2024, with top line results anticipated in the second half of 2024. If the Phase 1a portion of the trial is successfully completed, the company plans to initiate Phase 1b trials of VYN202 in subjects with moderate-to-severe plaque psoriasis and moderate-to-severe adult-onset rheumatoid arthritis, with top line results anticipated in the second half of 2025.
Preclinical Data in Multiple Indications
Psoriasis
The company evaluated VYN202 in an established mouse model of psoriasis. After inducing a psoriasis phenotype in BALB-C mice, treatment was administered intraperitoneally with one of VYN202, deucravacitinib (an allosteric TYK2 inhibitor), or placebo. VYN202 and deucravacitinib at equivalent dosing resulted in comparable onset of action and efficacy. Mice receiving VYN202 3 mg/kg had approximately 95% mean reduction in psoriasis area and severity index (‘PASI’) score from baseline by day 7 of treatment, which was consistent with the results in the deucravacitinib 3 mg/kg group. Treatment with VYN202 3 mg/kg reduced the expression of IL-17A, a major effector cytokine involved in the pathogenesis of psoriasis, by 93% compared to placebo. Treatment with VYN202 at all doses also resulted in a marked reduction of other disease-related cytokines (IL-1ß, IL-6, IL-22, IL-23, and TNF-a) compared to the placebo group.
Rheumatoid Arthritis
The company evaluated VYN202 in a preclinical model of rheumatoid arthritis. In a 21-day collagen-induced arthritis model, signs and symptoms of inflammatory arthritis were induced in Lewis rats. Each treatment group orally received one of placebo, GSK620 (an early generation BD2-selective BET inhibitor) at 10 mg/kg, or VYN202 at one of three different dose strengths (1, 3, or 10 mg/kg). Daily treatment with VYN202 10 mg/kg resulted in a 71% reduction in the overall signs and symptoms of rheumatoid arthritis at day 21 and a 79% lower paw volume (a measure of swelling) compared to mice receiving placebo. Of the animals treated with the highest dose of VYN202, 75% presented with normal joint histopathology at the end of the study, whereas animals treated with placebo experienced marked inflammatory cell infiltrate, granulation tissue, bone erosion and cartilagenous ulceration. Treatment with VYN202 10 mg/kg also achieved a 98% lower expression of Immunoglobin G1, a biomarker associated with rheumatoid arthritis, compared to treatment with placebo.
Manufacturing
The company requires all of its CMOs (contract manufacturing organizations) to comply with these requirements and employs internal and external resources to manage its manufacturing contractors. The relevant manufacturers of the company’s product candidates for its preclinical and clinical trials have advised the company that they are compliant with both the FDA’s Good Laboratory Practices (‘GLP’) and the FDA's current Good Manufacturing Practice (‘cGMP’).
Development and License Agreements
Agreements with Tay
Evaluation and Option Agreement
In April 2021, the company entered into an Evaluation and Option Agreement (the ‘Option Agreement’) with Tay. Pursuant to the Option Agreement, Tay granted the company an exclusive option to obtain certain exclusive worldwide rights to research, develop and commercialize products containing Tay’s BET inhibitor compounds for the treatment of any disease, disorder or condition in humans. Pursuant to the Option Agreement, the company agreed to use commercially reasonable efforts to stabilize, develop and manufacture a product with a pan-BD BET inhibitor as its active ingredient, and Tay agreed to provide a mutually agreed data package and select a new chemical entity development candidate from its Oral BETi Compounds.
Under the terms of the Option Agreement, the company’s option (the ‘Oral Option’) with respect to the Oral BETi Compounds was to expire on June 30, 2022, but in June 2022, the company and Tay entered into a letter agreement to extend the option term to February 28, 2023. In February 2023, the company and Tay entered into an additional letter agreement pursuant to which the option term was further extended to April 30, 2023. The company exercised the Oral Option for VYN202 on April 28, 2023.
License for Locally Administered Pan-BD BET Inhibitor Program (VYN201)
In August 2021, the company exercised its option with respect to the VYN201 program and entered into a license agreement (the ‘VYN201 License Agreement’) granting the company a worldwide, exclusive license that is sublicensable through multiple tiers to exploit certain of Tay’s pan-BD BET inhibitor compounds in all fields. The company has the sole responsibility for development, regulatory, marketing and commercialization activities to be conducted for the licensed products at the company’s sole cost and discretion.
The company is required to use commercially reasonable efforts to develop and, if approved, commercialize such products. Pursuant to the VYN201 License Agreement, a joint development committee consisting of one representative from each party reviews the progress of the development plan for the licensed products. Pursuant to the VYN201 License Agreement, the company may develop a product that contains or incorporates a specific BET inhibitor, whether alone or in combination with other active ingredients, in any form, formulation, presentation, or dosage, and for any mode of administration.
License for Selective BET Inhibitor Program (VYN202)
On April 28, 2023, the company exercised the Oral Option and entered into a license agreement (the ‘VYN202 License Agreement’) with Tay granting the company a worldwide, exclusive license that is sublicensable through multiple tiers to exploit certain of Tay’s Oral BETi Compounds in all fields. The company has the sole responsibility for development, regulatory, marketing and commercialization activities to be conducted for the licensed products at the company’s sole cost and discretion, and shall use commercially reasonable efforts to develop and, if approved, commercialize such products. The company may sublicense its rights to a third party without Tay’s consent. Pursuant to the VYN202 License Agreement, a joint development committee consisting of one representative from each party reviews the progress of the development plan for the licensed products.
Intellectual Property
The company’s BET inhibitor patent portfolio is licensed in and/or is being developed by the company and comprises or is derived from several PCT applications, various national applications and certain provisional applications.
The company’s patent portfolio in relation to the company’s VYN201 program includes a granted patent in the United Kingdom and pending compound and composition patent applications licensed by the company from Tay and the University of Dundee. A PCT application covering the compound, which published as WO 2020/216779, was filed nationally in more than 15 jurisdictions, including the U.S., China, Europe, Eurasia, and Japan. Subject to being granted (without terminal disclaimers) and payments of the appropriate maintenance fees, each will expire in 2040. In addition, a PCT application, which published as WO 2023/081720, and several provisional applications directed to various uses thereof have been filed. Subject to the PCT being filed nationally, filing a non-provisional, and these patent applications being granted (without terminal disclaimers) and payments of the appropriate maintenance fees, each will expire in 2042 and 2044, respectively.
The company’s patent portfolio in relation to its VYN202 program includes pending compound and composition patent applications licensed by the company from Tay. A PCT application covering the compound, which published as WO 2023/275542, was filed nationally in more than 15 jurisdictions, including the U.S., China, Europe, Eurasia, and Japan. Subject to being granted (without terminal disclaimers) and payments of the appropriate maintenance fees, each will expire in 2042. Two additional compound and composition PCT applications were also filed in relation to VYN202 and the company’s oral BD2-selective BET inhibitor program exclusively licensed by the company from Tay. Subject to these PCT applications being filed nationally, one of which published as WO 2024/018423, and the patent applications being granted (without terminal disclaimers) and payments of the appropriate maintenance fees, they will expire in 2043.
Government Regulation
The company recently received correspondence from the FDA informing the company that its Phase 1a clinical trial for VYN202 is on hold and requesting that the company submit data from an additional nonclinical study in the support of the company’s IND. The company expects to submit the requested information by the end of the first quarter of 2024.
Research and Development
The company’s total research and development expenses were $16.3 million for the year ended December 31, 2023.
History
The company was founded in 2003. It was incorporated in 2003. The company was formerly known as Menlo Therapeutics Inc. and changed its name to VYNE Therapeutics Inc. in 2020.
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