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Item 1. Business

2025-03-06 compared with 2024-03-01 · 198 added, 168 removed, 368 unchanged (50% of the section changed)

ITEM 1 - BUSINESS

We are a clinical-stage biopharmaceutical company focused on developing proprietary, innovative and differentiated therapies for the treatment of immuno-inflammatory conditions.

In August 2021, we entered into a transaction with Tay Therapeutics Ltd., formerly known as In4Derm Ltd.

("Tay"), providing us 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 our access to this library of new chemical BET inhibitor compounds, we plan to develop product candidates for a diverse set of indications.

Based on data generated to date, we have chosen to focus our initial efforts for this platform on select therapeutic areas in immuno-inflammatory disease.

Our 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, we initiated a Phase 1a/b clinical trial evaluating a VYN201 ointment for the treatment of nonsegmental vitiligo.

In the first quarter of 2023, we 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, we 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.

We have initiated Phase 2b preparatory activities and expect 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.

We are a clinical-stage biopharmaceutical company focused on developing differentiated therapies to treat chronic inflammatory and immune-mediated conditions with high unmet need.

We have exclusive worldwide rights to research, develop and commercialize products containing small molecule bromodomain and extra-terminal domain (“BET”) inhibitors for the treatment of any disease, disorder or condition in humans, which we licensed from Tay Therapeutics Ltd., formerly known as In4Derm Ltd ("Tay").

BET proteins are epigenetic enablers of transcription that regulate the expression of specific genes.

Each BET protein consists of two bromodomains (“BD1” and “BD2”) and one end terminal (“ET”) domain.

Through our transaction with Tay, we obtained access to a library of new small molecule BET inhibitor compounds including those that inhibit both BD1 and BD2 (“pan-BD” BET inhibitor) and that selectively inhibit BD2 (“BD2-selective” BET inhibitor).

Through our access to this library of new BET inhibitors, which comprise our InhiBET™ portfolio, we plan to develop product candidates for a diverse set of therapeutic indications.

We have chosen to initially focus our development efforts with these molecules on immune-mediated inflammatory diseases, which are not being targeted by current BET inhibitors in development.

Our lead program is repibresib gel (also known as VYN201 ), a topically administered, small molecule pan-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, repibresib produced consistent reductions in pro-inflammatory and disease-related biomarkers and improvements in disease severity across a variety of inflammatory and fibrotic preclinical models.

In November 2022, we initiated a Phase 1 clinical trial evaluating a topical formulation of repibresib first in healthy volunteers (Phase 1a) and then in subjects (Phase 1b) with nonsegmental vitiligo (NSV), an immune-mediated condition that has a high unmet need and only one approved therapy.

In the first quarter of 2023, we announced positive preliminary safety and tolerability, including hematology data, and predicted pharmacokinetic results (minimal systemic exposures) from the Phase 1a portion of the trial .

We initiated the Phase 1b portion of the trial in NSV subjects in January 2023 and announced positive data from the Phase 1b trial in October 2023.

We showed significant clinical improvements in vitiligo involving the face, which has the greatest psychosocial impact on patients, after 16 weeks of treatment using the Facial-Vitiligo Area Scoring Index ("F-VASI").

We initiated a Phase 2b trial with repibresib ge l in NSV subjects in June 2024.

The Phase 2b trial is a randomized, double-blind, vehicle-controlled trial evaluating the efficacy, safety and pharmacokinetics of once-daily repibresib gel in NSV subjects in three dose cohorts (1%, 2% or 3% concentrations) compared to vehicle over 24 weeks, followed by a 28-week active treatment extension with subjects on vehicle crossing over to active doses.

We enrolled approximately 45 patients in each arm and expect to report top-line results from the 24-week double-blind portion of the trial in mid-2025.

Our 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, we believe 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.

We submitted an Investigational New Drug application (“IND”) for VYN202 to the U.S.

Food & Drug Administration (the "FDA") in December 2023.

We recently received correspondence from the FDA informing us that our Phase 1a clinical trial is on hold and requesting that we submit data from an additional nonclinical study.

We recently completed the additional nonclinical study which achieved preliminary results consistent with our expectations at the outset of the study.

We plan to submit the requested nonclinical information to the FDA by the end of the first quarter of 2024 and, if cleared by the FDA, we expect to initiate our 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, we plan 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.

We intend to advance our product candidates through clinical development toward regulatory approval.

As part of our strategy to maximize the value of our pipeline, we may partner with larger pharmaceutical companies to expand and accelerate the development of our programs and explore therapeutic areas outside of our core focus in immunology.

BET Inhibition and Immuno-Inflammatory Disease

Prior studies have shown that while BD1 modulates cell-cycling and homeostatic functions, BD2 regulates gene expression of pro-inflammatory mediators in cells.

VYN202 has been designed to achieve potential class-leading potency and selectivity for BD2 vs.

By maximizing BD2 selectivity, we believe VYN202 has the potential to be a potent oral immunomodulator option for both acute control and chronic management of immune-mediated inflammatory conditions, without the hematologic and gastrointestinal adverse effects associated with earlier generation systemic pan-BD BET inhibitors that were being developed in oncologic settings.

We have completed a Phase 1a single ascending dose/multiple ascending dose ("SAD/MAD") trial of VYN202 in healthy volunteers and announced positive data from this trial in December 2024.

We observed that VYN202 had a favorable safety and tolerability profile with no drug-related adverse events historically associated with earlier generation, less BD2-selective BET inhibitors.

VYN202 also demonstrated robust pharmacodynamic activity including evidence of target engagement and inhibition of several inflammatory biomarkers relevant to immune-mediated disorders in ex vivo stimulation assays.

We initiated a Phase 1b trial in February 2025 in adult subjects with moderate-to-severe plaque psoriasis.

The Phase 1b trial is a randomized, double-blind, placebo-controlled trial of once daily treatment with VYN202 capsules dosed for 12 weeks, to primarily evaluate the safety of VYN202 across four cohorts (0.25 mg, 0.5 mg, 1 mg doses and placebo), with secondary objectives that include pharmacokinetics and preliminary evidence of efficacy via endpoints evaluating improvements from baseline in psoriasis area and severity index (PASI) scores.

The trial will also include a 4-week safety follow-up visit after completion of the 12-week dosing period.

We expect to enroll approximately 80 subjects with moderate-to-severe plaque psoriasis and to report top-line results from the placebo-controlled trial by the end of 2025.

Additionally, we anticipate that the data from the Phase 1b trial in plaque psoriasis subjects will provide key insights into VYN202's potential activity across a range of immune-mediated diseases.

We intend to advance our product candidates through further phases of clinical development toward regulatory approval.

As part of our strategy to maximize the value of our pipeline, we may partner with larger pharmaceutical companies to expand and accelerate the development of our programs and explore other indications and therapeutic areas outside of our core focus in immune-mediated diseases.

BET Proteins:

Key Epigenetic Regulators of NF-kB, an Orchestrator of Inflammation

BET proteins are epigenetic enablers of transcription that regulate the expression of specific genes.

Each BET protein consists of two bromodomains (BD1 and BD2) and one end terminal domain.

BD1 and BD2 enable chromatin remodeling and recruit transcription factors to facilitate gene transcriptions.

In some cases, BET proteins can activate oncogenes, thereby leading to increased cell proliferation and survival and an increase in solid tumors and hematologic malignancies.

In some cases, BET proteins can activate oncogenes via BD1, thereby leading to increased cell proliferation and survival that may lead to formation of solid tumors and hematologic malignancies.

BET inhibitors have the potential to downregulate the expression of such oncogenes.

These observations have resulted in the generation and clinical investigation of BET inhibitors in several cancer subtypes by pharmaceutical companies, including large pharmaceutical companies.

In addition to impacting oncogenetics, BET proteins regulate the expression of many immunity-associated genes and pathways by directing the transcription of a wide range of pro-inflammatory and immunoregulatory genes, leading to increased cytokine expression that activate B cells and T cells and subsequent inflammatory processes.

Inhibiting BET proteins prevents the formation of complexes required to facilitate transcription, thereby suppressing the subsequent translation of the corresponding protein.

As such, BET inhibitors could present as an attractive, non-steroidal, therapeutic option for the treatment of immuno-inflammatory diseases.

The following graphic depicts the inhibition of BET proteins and the subsequent disruption of inflammatory gene transcription and cytokine expression.

These observations have resulted in the generation and clinical investigation of BET inhibitors in several cancer subtypes by various pharmaceutical companies, including large pharmaceutical companies.

In addition, BET proteins can regulate the expression of a wide range of pro-inflammatory genes, primarily through the NF-kB pathway.

NF-kB is a critical transcription factor in inflammation that orchestrates production of key inflammatory cytokines and activation of multiple immune cell types.

The dysregulation of NF-kB pathway activation can lead to several chronic immune-mediated conditions.

BET Inhibition:

A Potential Novel Mechanism for the Treatment of Immune-Mediated Conditions

Inhibition of BET proteins can prevent the continual dysregulated/hyperactivated signaling of the NF-kB pathway which occurs in many autoimmune diseases.

A known family of drugs, corticosteroids, have demonstrated efficacy in treating inflammation predominantly by inhibiting the NF-kB pathway.

These are a widely used class of anti-inflammatory and immunosuppressive drugs, but their therapeutic use when given systemically is limited by many endocrine and metabolic side effects mediated by other pathways that are also impacted by these agents.

By inhibiting the NF-kB pathway through the specific bromodomain BD2, BET inhibition could be a novel, non-steroidal, mechanism for the treatment of immune-mediated diseases without the non-immune side effects of corticosteroids.

Because most of such diseases are heterogenous and driven by multiple immune pathways, BET inhibition has the potential to address a broad range of immune-mediated diseases due to its potential impact on many of these pathways.

The diagram below depicts the role of BET proteins in gene transcription via the NF-kB pathway, and the subsequent effect of disrupting this process on expression of inflammatory cytokines.

Our Platform and Product Candidates

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Through our partnership with Tay, we have 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 our InhiBET platform and through our preclinical and clinical activities, we are evaluating the impact that BET inhibitor compounds have on regulating pro-inflammatory cytokines.

We are targeting indications whose pathogenesis is linked to the proliferation of these specific cytokines.

We have selected development candidates and are developing formulations that are designed to maximize the anti-inflammatory effect of the drug while minimizing safety concerns.

Through our InhiBET development platform, we believe we can demonstrate the potential utility of these BET inhibitor compounds and develop therapies for a variety of immuno-inflammatory conditions.

The following chart provides an overview of our current pipeline of product candidates being developed using our InhiBET platform:

VYN201 - Locally Administered Pan-BD BET Inhibitor

Our lead BET inhibitor candidate in development is VYN201.

VYN201 was developed using the InhiBET platform and is a locally administered pan-BD BET inhibitor.

See "Development and License Agreements—Tay License Agreements." Utilizing our InhiBET platform and through our preclinical and clinical activities, we are evaluating the impact that BET inhibitor compounds have on regulating proinflammatory cytokines.

We are targeting indications whose pathogenesis is linked to excessive production of these cytokines.

We have selected development candidates and are developing formulations that are designed to maximize the anti-inflammatory effect of the drugs while minimizing safety concerns.

Through our InhiBET development platform, we believe we can demonstrate the potential utility of these BET inhibitor compounds and develop therapies for a variety of immune-mediated diseases.

Repibresib - Locally Administered Pan-BD BET Inhibitor

Our lead BET inhibitor candidate in development is repibresib gel, which was developed using the InhiBET platform and is a topically-administered 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.

Our goal 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.

We have 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, we announced positive data from our 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 to date, we believe VYN201 has the potential to be highly versatile by serving as a locally acting therapy with low systemic exposure.

Nonsegmental Vitiligo

Our goal with the repibresib program is to develop a therapy that delivers potent, localized anti-inflammatory effects and can be rapidly cleared through the body's metabolic processes to avoid systemic effects.

We have conducted several preclinical studies which have demonstrated repibresib’s anti-fibrotic and anti-inflammatory activities and the ability to significantly reduce the expression of key cytokines relevant to certain autoimmune diseases, including vitiligo, psoriasis, rheumatoid arthritis, and idiopathic pulmonary fibrosis.

In October 2023, we announced positive data from our Phase 1b trial of repibresib gel in subjects with NSV, which demonstrated clinical proof-of-concept for the use of this BET inhibitor to treat an immune-mediated disease.

We initiated a Phase 2b trial with repibresib gel in NSV subjects in June 2024.

Based on data generated to date, we believe repibresib has the potential to be highly versatile across multiple indications by serving as a locally-acting therapy with low systemic exposure.

Nonsegmental Vitiligo (NSV)

Vitiligo is a chronic autoimmune depigmenting disorder of the skin, characterized by the loss of pigment-producing cells known as melanocytes.

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Approximately 90% of vitiligo cases are characterized as nonsegmental, in which white patches appear symmetrically on both sides of the body.

There is currently 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 to date, we believe that 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 we observed from the preclinical vitiligo model described below, we commenced a Phase 1 clinical trial evaluating VYN201 topical ointment for the treatment of nonsegmental vitiligo in November 2022.

There is currently only one drug, OPZELURA® (ruxolitinib) cream, approved by the FDA for the treatment of NSV.

That product includes a boxed safety warning on its label.

Based on preclinical and clinical data generated to date, we believe that repibresib gel has the potential to offer a targeted, efficacious, and a safe treatment option for NSV that lowers the disease recurrence rate and can be effective for all skin phototypes with few side effects.

Ph a se 1 Clinical Trial

Based in part on the data we observed from the preclinical vitiligo model described below, we commenced a Phase 1 clinical trial evaluating repibresib topical ointment for the treatment of NSV in November 2022.

The trial was conducted at 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.

In the Phase 1a portion of the trial, single ascending and multiple ascending doses of repibresib 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 repibresib.

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.

There were no clinically-relevant treatment emergent adverse events, abnormal clinical laboratory results or electrocardiogram findings, and no discontinuations.

We 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, we announced positive results from 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 repibresib in 29 patients across the three dose cohorts.

Exploratory efficacy of repibresib was also evaluated, including its ability to arrest the progression of skin depigmentation and support skin repigmentation in patients with active disease using F-VASI scoring.

In October 2023, we 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, we plan to evaluate a once-daily gel formulation of VYN201 for our upcoming Phase 2b trial in patients with nonsegmental vitiligo, which we expect to initiate in the second quarter of 2024.

We believe 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 our expected timing for initiating the trial, we anticipate top line results from the 24-week double-blind portion of the trial to be available in mid-2025.

There were no clinically-relevant treatment emergent adverse events in any cohort.

Ph a se 2 Clinical Trial

Last year, we reformulated repibresib in a once-daily gel for our Phase 2b trial in subjects with NSV, which we initiated in the second quarter of 2024.

The ongoing Phase 2b trial is a randomized, double-blinded, vehicle-controlled trial evaluating subjects with NSV for 24 weeks, followed by a separate active treatment extension phase for an additional 28 weeks, with vehicle subjects crossing over to active doses at Week 24.

The trial is evaluating four arms (three active arms, one vehicle arm) of once-daily repibresib gel, with each arm enrolling approximately 45 subjects with active or stable NSV.

The primary efficacy endpoint of the trial is an evaluation of the proportion of subjects achieving F-VASI50 at Week 24 compared to vehicle.

In January 2025, we announced the completion of enrollment in the trial.

We anticipate top-line results from the 24-week double-blind portion of the trial to be available in mid-2025.

Preclinical Studies for Multiple Indications

We conducted a preclinical study using an ex vivo skin model of vitiligo.

The objectives of this study were to evaluate the potential of VYN201 to:

The objectives of this study were to evaluate the potential of repibresib to:

• reduce matrix metalloproteinase-9 (“MMP-9”) secretion, which allows for melanocyte stabilization and limits loss of melanocytes/depigmentation in vitiligo;

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• minimize the loss of melanocytes by assessing melanin pigment content;

• affect the expression of genes commonly associated with melanogenesis (melanin synthesis, melanosome maturation and transport).

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.

• increase the expression of genes commonly associated with melanogenesis (melanin synthesis, melanosome maturation and transport).

In the preclinical study, repibresib reduced the expression of key pro-inflammatory biomarkers relevant to the pathogenesis of vitiligo and resulted in marked reduction in melanocyte loss.

Repibresib 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 1.0% concentrations.

In addition, repibresib significantly upregulated WNT16, a member of the WNT family of genes, suggestive of increased melanogenesis.

The WNT/β-catenin signaling pathway is known to be dysregulated in vitiligo and is believed to play a key role in melanocyte regeneration.

We 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 additional in vitro assays using human CD8+ t-cells with repibresib:

• Repibresib was found to potently inhibit the differentiation of CD8+ T-cells that are known to induce both a cytotoxic and destabilizing effect on melanocytes, the primary cell type that produces melanin in skin.

• Repibresib inhibited the release of interferon-gamma which is a cytokine known to drive differentiation of CD8+ T-cells.

Plaque Psoriasis

We evaluated the impact of repibresib 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 the inflammatory cytokine, interleukin-17, or IL-17.

Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, psoriatic arthritis, inflammatory bowel disease, and multiple sclerosis.

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.

A further 7-day treatment phase evaluated three doses of repibresib (0.001%, 0.01% and 0.1% concentrations) compared to a highly potent topical corticosteroid (clobetasol propionate 0.05% cream) used as a positive control, and a vehicle control.

An imiquimod-naive control group (healthy control group) was also included for vehicle treatment.

In these studies, treatment with repibresib significantly reduced the expression of several key proinflammatory cytokines relevant to Th17-mediated autoimmune diseases.

A dose-dependent improvement in the signs of inflammation was observed in repibresib treatment groups, and treatment with repibresib at all concentrations was well tolerated in the study.

Idiopathic Pulmonary Fibrosis

We evaluated an inhaled formulation of VYN201 in an established mouse model of idiopathic pulmonary fibrosis.

We evaluated an inhaled formulation of repibresib in an established mouse model of idiopathic pulmonary fibrosis.

Lung fibrosis was induced in mice using a single intratracheal dose of bleomycin.

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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

untreated and unstimulated control, placebo, and one of four doses of repibresib (0.1, 0.2, 0.5, and 1.0 mg/mL), with six mice in

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%).

Treatment with repibresib 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 repibresib 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.

Thoracic tomography revealed that repibresib treatment groups experienced a dose-dependent improvement in functional lung volume compared to the placebo control group.

Rheumatoid Arthritis

We 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.

We conducted a preclinical study showing that intra-articular injections of repibresib 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).

Each treatment group of seven mice was injected with either (i) an intra-articular dose of vehicle, (ii) an intra-articular dose of repibresib (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.

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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.

Treatment with repibresib 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.

In addition, limbs treated with repibresib 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, we believe 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

We submitted an IND for VYN202 to the FDA in December 2023.

We recently received correspondence from the FDA informing us that our Phase 1a clinical trial is on hold and requesting that we submit data from an additional nonclinical study.

We recently completed the additional nonclinical study which achieved preliminary results consistent with our expectations at the outset of the study.

We plan 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, we plan 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.

VYN202 is an oral, small molecule BD2-selective BET inhibitor that has been designed to achieve potential class-leading potency and selectivity for BD2 vs.

Systemic BET inhibitors have historically targeted both BD1 and BD2 less selectively, which we believe caused gastrointestinal toxicity and bone marrow suppressive effects like thrombocytopenia.

By maximizing BD2 selectivity, we believe VYN202 may alleviate the toxicities observed by other less BD2-selective BET inhibitors in development for oncology and have the potential to be a potent, oral immunomodulator option for both acute control and chronic management of immune-mediated conditions, where the damaging effects of unrestricted inflammatory signaling activities are common.

Phase 1a SAD/MAD Clinical Trial

We have completed a Phase 1a SAD/MAD trial of VYN202 in healthy volunteers and announced positive data from this trial in December 2024.

We observed that VYN202 had a favorable safety and tolerability profile with no drug-related adverse events historically associated with earlier generation, less BD-selective BET inhibitors.

In February 2025, we initiated a Phase 1b trial in adult subjects with moderate-to-severe plaque psoriasis.

The Phase 1b trial is a randomized, double-blind, placebo-controlled trial to primarily evaluate the safety of VYN202 administered orally once a day across four cohorts (0.25 mg, 0.5 mg, 1 mg doses and placebo), with secondary objectives that include pharmacokinetics and preliminary evidence of efficacy via endpoints evaluating improvements from PASI scores after 12 weeks.

We expect to enroll approximately 80 subjects with psoriasis and to report top-line results from the placebo-controlled trial by the end of 2025.

Additionally, we anticipate that the data from the Phase 1b trial in psoriasis subjects will provide key insights into VYN202’s potential activity across a range of immune-mediated diseases.

Preclinical Data in Multiple Indications

We 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.

Plaque Psoriasis

We evaluated VYN202 in an established mouse model of psoriasis that was used earlier with repibresib gel (see above).

After inducing a psoriasis phenotype in BALB/c mice, treatment was administered intraperitoneally with VYN202 doses,

deucravacitinib (an allosteric TYK2 inhibitor approved for the treatment of moderate-to-severe plaque psoriasis), 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

Mice receiving VYN202 3 mg/kg had approximately 95% mean reduction in 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-1β, IL-6, IL-22, IL-23, and TNF-α) compared to the placebo group.

Rheumatoid Arthritis

We 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).

We evaluated VYN202 in two preclinical models of rheumatoid arthritis.

In a 21-day collagen-induced arthritis (CIA) model, signs and symptoms of inflammatory arthritis were induced in Lewis rats.

Each treatment group orally received placebo, GSK620 (an early generation less 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.

The administration of VYN202 10 mg/kg also achieved a 98% lower expression of anti-collagen II antibody compared to placebo.

In a 21-day adjuvant-induced arthritis (AIA) model in Lewis rats, test animals were randomly assigned to 7 groups:

two vehicle groups, dexamethasone, upadacitinib, and VYN202 at one of three different dose strengths (0.1, 1, or 10 mg/kg).

All but one of the vehicle groups were induced with the adjuvant to replicate signs and symptoms of inflammation on the paws and joints of the animals.

Induced animals were then orally administered either vehicle, reference compound or VYN202 doses for 15 consecutive days.

Compared to the vehicle+adjuvant group, all strengths of VYN202 had a significant effect on inhibiting inflammation in the paws, comparable to the reference compound, upadacitinib.

The highest concentration of VYN202 resulted in an approximately 88% reduction in paw volume compared to the vehicle group.

Histopathology scores showed VYN202 had a significant effect on preventing ankle inflammation compared to the control group with VYN202 10 mg/kg having a 67% reduction compared to control and upadacitinib 10 mg/kg demonstrating a 56% reduction compared to control.

Manufacturing

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We require all of our CMOs to comply with these requirements and currently employ internal and external resources to manage our manufacturing contractors.

The relevant manufacturers of our product candidates for our current preclinical and clinical trials have advised us 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

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Pursuant to the Option Agreement, Tay granted us 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, we 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.

We paid a $1.0 million non-refundable cash payment to Tay upon execution of the Option Agreement, 50% of which was to be used by Tay in the development of the Oral BETi Compounds.

Pursuant to the Option Agreement, we agreed to use commercially reasonable efforts to 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.

We paid a $1.0 million non-refundable cash payment to Tay upon execution of the Option Agreement.

Under the terms of the Option Agreement, our option (the "Oral Option") with respect to the Oral BETi Compounds was to expire on June 30, 2022, but in June 2022, we and Tay entered into a letter agreement to extend the option term to February 28, 2023.

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See "Part II—Item 7.

Management's Discussion and Analysis of Financial Condition and Results of Operations—Collaboration Arrangements—Agreements with Tay Therapeutics—Evaluation and Option Agreement" for a discussion regarding payments made to Tay in connection with the extension of the term for the Oral Option.

License for Locally Administered Pan-BD BET Inhibitor Program (VYN201)

In August 2021, we exercised our option with respect to the VYN201 program and entered into a license agreement (the "VYN201 License Agreement") granting us a worldwide, exclusive license that is sublicensable through multiple tiers to exploit certain of Tay’s pan-BD BET inhibitor compounds in all fields.

Management's Discussion and Analysis of Financial Condition and Results of Operations—Development and License Agreements—Agreements with Tay Therapeutics—Evaluation and Option Agreement" for a discussion regarding payments made to Tay in connection with the extension of the term for the Oral Option.

License for Locally Administered Pan-BD BET Inhibitor Program (Repibresib)

In August 2021, we exercised our option with respect to the repibresib program and entered into a License Agreement (the "Repibresib License Agreement") granting us a worldwide, exclusive license that is sublicensable through multiple tiers to exploit certain of Tay’s pan-BD BET inhibitor compounds in all fields.

We have the sole responsibility for development, regulatory, marketing and commercialization activities to be conducted for the licensed products at our sole cost and discretion.

We are 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, we 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.

We made a $0.5 million cash payment to Tay in 2021 in connection with entering into the VYN201 License Agreement.

Pursuant to the VYN201 License Agreement, we agreed to make cash payments to Tay upon the achievement of specified clinical development and regulatory approval milestones with respect to each licensed topical product in the United States of up to $15.75 million for all indications.

Pursuant to the Repibresib 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 Repibresib License Agreement, we 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.

We made a $0.5 million cash payment to Tay in 2021 in connection with entering into the Repibresib License Agreement.

Pursuant to the Repibresib License Agreement, we agreed to make cash payments to Tay upon the achievement of specified clinical development and regulatory approval milestones with respect to each licensed topical product in the United States of up to $15.75 million for all indications, of wh ich $1.8 million has been paid or accrued through December 31, 2024.

Tay is entitled to additional milestone payments upon the achievement of regulatory approvals in certain non-U.S.

jurisdictions.

In addition, with respect to any products we commercialize under the VYN201 License Agreement, we will pay tiered royalties to Tay on net sales of such licensed products by us, our affiliates, or sublicensees, of 5%, 7.5% and 10% based on tiered annual net sales bands subject to specified reductions.

In addition, with respect to any products we commercialize under the Repibresib License Agreement, we will pay tiered royalties to Tay on net sales of such licensed products by us, our affiliates, or sublicensees, of 5%, 7.5% and 10% based on tiered annual net sales of licensed products under the Repibresib License Agreement and the VYN202 License Agreement, subject to specified reductions.

We are obligated to pay royalties until the latest of (1) the tenth anniversary of the first commercial sale of the relevant licensed product, (2) the expiration of the last valid claim of the licensed patent rights covering such licensed product in such country and (3) the expiration of regulatory exclusivity for the relevant licensed product in the relevant country, on a licensed product-by-licensed product and country-by-country basis.

Pursuant to the Repibresib License Agreement, we were granted a sublicense under certain intellectual property which was licensed to Tay by the University of Dundee (“Dundee”) pursuant to a certain license agreement between Tay and Dundee effective as of July 24, 2020 and amended and restated on October 8, 2021 (the “Head License”).

On February 13, 2025, Tay and Dundee entered into an agreement for the termination of the Head License and assignment of such intellectual property from Dundee to Tay.

Upon termination of the Head License, the Repibresib License Agreement was accordingly amended to reflect the assignment of the intellectual property to Tay upon its payment in full to Dundee.

The amendment does not change any of Tay’s or VYNE’s rights or obligations under the Repibresib License Agreement, except that any obligations owed by VYNE to Dundee with respect to repibresib are now owed to Tay.

License for Selective BET Inhibitor Program (VYN202)

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We made a cash payment of $3.75 million to Tay in connection with entering into the VYN202 License Agreement.

Pursuant to the terms of the VYN202 License Agreement, we agreed to make cash payments to Tay of up to $43.75 million upon the achievement of specified clinical development and regulatory approval milestones with respect to each licensed oral product in the United States for all indications.

Pursuant to the terms of the VYN202 License Agreement, we agreed to make cash payments to Tay of up to $43.75 million upon the

achievement of specified clinical development and regulatory approval milestones with respect to each licensed oral product in the United States for all indications, of which $1.3 million has been paid or accrued through December 31, 2024.

Tay is entitled to additional milestone payments upon the achievement of regulatory approvals in certain non-U.S.

jurisdictions.

In addition, with respect to any products we commercialize under the VYN202 License Agreement, we will pay tiered royalties to Tay on net sales of such licensed products by us, our affiliates, or sublicensees, of 5%, 7.5% and 10% based on tiered annual net sales bands subject to specified reductions.

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It is uncertain whether the issuance of any third party patent would require us to alter our development strategies, alter our processes, obtain licenses or cease certain activities.

Our breach of any license agreements or failure to obtain a license to proprietary rights that we may

require to develop our current and future product candidates may have a material adverse impact on us.

Our breach of any license agreements or failure to obtain a license to proprietary rights that we may require to develop our current and future product candidates may have a material adverse impact on us.

If third parties prepare and file patent applications in the United States that also claim technology to which we have rights, we may have to participate in derivation, interference or other proceedings in the United States Patent and Trademark Office ("USPTO") to determine derivation or priority of invention.

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Our BET inhibitor patent portfolio is licensed in and/or is being developed by us and comprises or is derived from several PCT applications, various national applications and certain provisional applications.

Our patent portfolio in relation to our VYN201 program includes a granted patent in the United Kingdom and pending compound and composition patent applications licensed by us from Tay and the University of Dundee.

As of December 31, 2024, our patent portfolio in relation to our repibresib program includes a granted patent in the United Kingdom, Indonesia, Israel, India, Mexico, and South Africa and pending compound and composition patent applications licensed by us from Tay.

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.

Our patent portfolio in relation to our VYN202 program includes pending compound and composition patent applications licensed by us from Tay.

Subject to being granted and payments of the appropriate maintenance fees, each patent will expire in 2040, without accounting for any potential patent term adjustment in the U.S.

A PCT application covering methods of use, which published as WO 2023/081720, was filed nationally in ten jurisdictions, including the U.S., China, Europe, Eurasia, and Japan.

Subject to being granted and payments of the appropriate maintenance fees, each patent will expire in 2042, without accounting for any potential patent term adjustment in the U.S.

In addition, a PCT application, which published as WO 2024/220589, was filed nationally in ten jurisdictions, including the U.S., China, Europe, Eurasia, and Japan.

Subject to being granted and payments of the appropriate maintenance fees, each patent will expire in 2042, without accounting for any potential patent term adjustment in the U.S.

In addition, a PCT application, which published as WO 2024/220589, and a provisional application directed to various uses of repibresib have been filed.

Subject to the PCT application being filed nationally, filing a non-provisional application, and these patent applications being granted and payments of the appropriate maintenance fees, each patent will expire in 2042 and 2044, respectively, without accounting for any potential patent term adjustment in the U.S.

As of December 31, 2024, our patent portfolio in relation to our VYN202 program includes a granted patent in the United Kingdom and pending compound and composition patent applications licensed by us 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.

Subject to being granted and payments of the appropriate maintenance fees, each patent will expire

in 2042, without accounting for any potential patent term adjustment in the United States.

Two additional compound and composition PCT applications were also filed in relation to VYN202 and our oral BD2-selective BET inhibitor program exclusively licensed by us 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.

Subject to these PCT applications being filed nationally, one of which published as WO 2024/018423, and the patent applications being granted and payments of the appropriate maintenance fees, the patents will expire in 2043, without accounting for any potential patent term adjustment in the United States.

In addition, a provisional application directed to VYN202 method of use has been filed.

Subject to filing a non-provisional and this patent application being granted and payments of the appropriate maintenance fees, this patent would expire in 2045, without accounting for any potential patent term adjustment in the United States.

Patents extend for varying periods according to the date of patent filing or grant and the legal term of patents in various countries where patent protection is obtained.

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and other treatments including various lasers and ultraviolet light-based therapies.

In addition, there are several prescription product

candidates under development that could potentially be used to treat vitiligo and compete with VYN201, if approved, including but not limited to oral JAK inhibitors being developed by Incyte, Pfizer and AbbVie.

We intend to develop VYN202 for the treatment of moderate-to-severe plaque psoriasis and moderate-to-severe adult-onset rheumatoid arthritis, each of which is a competitive market.

The psoriasis market includes several approved antibody therapies, including COSENTYX, marketed by Novartis;

In addition, there are several prescription product candidates under development that could potentially be used to treat vitiligo and compete with repibresib gel, if approved, including but not limited to oral JAK inhibitors being developed by Incyte, Pfizer and AbbVie.

We intend to develop VYN202 for the treatment of various immune-mediated conditions.

Our initial proof-of-concept indication is moderate-to-severe plaque psoriasis which is a competitive market.

The psoriasis market includes several approved anti-IL-17 antibody therapies, including COSENTYX, marketed by Novartis;

TALTZ, marketed by Eli Lilly;

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Furthermore, the oral PDE4 inhibitor, OTEZLA, marketed by Amgen, and oral TYK2 inhibitor, SOTYKTU, marketed by Bristol Myers Squibb, are approved for the treatment of psoriasis.

In addition, we are aware of other oral therapeutic candidates including TYK2 inhibitors, oral IL-17 inhibitors, and oral IL-23 inhibitors being developed by Janssen Pharmaceuticals, Takeda Pharmaceutical Company, Ventyx Biosciences, and LEO Pharma, among others.

In addition, we are aware of other oral therapeutic candidates including other TYK2 inhibitors, oral IL-17 inhibitors, and oral IL-23 inhibitors being developed by Takeda Pharmaceutical Company, Ventyx Biosciences, Eli Lilly, LEO Pharma, Janssen Pharmaceuticals, among others.

We anticipate our second indication, subject to adequate levels of funding, will be rheumatoid arthritis which is also a competitive market.

Medications for the treatment of rheumatoid arthritis include corticosteroids and disease-modifying anti-rheumatic drugs ("DMARDs").

DMARDs include (i) methotrexate, sulfasalazine, leflunomide and hydroxychloroquine, (ii) biologic DMARDs, and (iii) targeted synthetic DMARDs such as JAK inhibitors.

These drugs are produced and sold, or are approved for marketing, by large pharmaceutical companies, including AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Pfizer, Novartis, UCB, Regeneron Pharmaceuticals, and Roche.

In addition, several other companies are developing drugs for the treatment of rheumatoid arthritis that, if approved, would compete with VYN202, if approved.

These drugs are produced and sold, or are approved for marketing, by large pharmaceutical companies, including AbbVie, Amgen, Bristol Myers Squibb, Johnson & Johnson, UCB, Roche, Eli Lilly, and Pfizer.

In addition, several other

companies are developing drugs for the treatment of rheumatoid arthritis that, if approved, could compete with VYN202 if the indication is pursued and approved.

The commercial opportunity for our product candidates, if approved, could be reduced or eliminated if our competitors develop and commercialize drugs that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any drug we may develop.

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The process required by the FDA prior to marketing and distributing a new drug product in the United States generally involves the following:

• completion of laboratory tests, animal studies and formulation studies in compliance with the FDA’s GLP or other applicable regulations;

• completion of laboratory tests, animal studies and formulation studies in compliance with the FDA’s Good Laboratory Practice ("GLP") or other applicable regulations;

• submission to the FDA of an application for an IND which must become effective before human clinical trials may begin;

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• performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice ("GCP") requirements to establish the safety and efficacy of the proposed drug for its intended use;

• preparation and submission to the FDA of a NDA or supplemental NDA;

• preparation and submission to the FDA of an NDA or supplemental NDA;

• satisfactory completion of an FDA advisory committee review, if applicable;

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• satisfactory completion of FDA audits of clinical trial sites and the sponsor’s clinical trial records to assure compliance with GCPs and the integrity of the clinical data;

• payment of user fees and FDA review and approval of the NDA;

• payment of user fees and FDA review and approval of an NDA;

• compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy ("REMS") and the potential requirement to conduct post-approval studies.

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In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

W e recently received correspondence from the FDA informing us that our Phase 1a clinical trial for VYN202 is on hold and requesting that we submit data from an additional nonclinical study in support of our IND.

We expect to submit the requested information by the end of the first quarter of 2024.

In addition, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing review and reapprove the trial at least annually.

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The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

Submission of a NDA to the FDA

The results of the preclinical studies and clinical trials, together with other detailed information, including information on the manufacture, control and composition of the product, are submitted to the FDA as part of a NDA requesting approval to market the product candidate for a proposed indication.

Submission of an NDA to the FDA

The results of the preclinical studies and clinical trials, together with other detailed information, including information on the manufacture, control and composition of the product, are submitted to the FDA as part of an NDA requesting approval to market the product candidate for a proposed indication.

Under the Prescription Drug User Fee Act ("PDUFA") as amended, applicants are required to pay fees to the FDA for reviewing an NDA.

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The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

Before approving a NDA, the FDA may inspect the facilities at which the product is manufactured or facilities that are significantly involved in the product development and distribution process, and will not approve the product unless cGMP compliance is satisfactory at such facilities.

Before approving an NDA, the FDA may inspect the facilities at which the product is manufactured or facilities that are significantly involved in the product development and distribution process, and will not approve the product unless cGMP compliance is satisfactory at such facilities.

The FDA may deny approval of a NDA if applicable statutory or regulatory criteria are not satisfied, or it may require additional testing or information, which can delay the approval process.

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Both fast track and breakthrough therapy products are also eligible for accelerated approval and/or priority review, if relevant criteria are met.

Under the FDA’s accelerated approval regulations, the FDA may approve a drug for a serious or life-threatening illness that provides meaningful therapeutic benefit to patients over existing treatments based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

In clinical trials, a surrogate endpoint is a measurement of laboratory or clinical signs of a disease or condition that substitutes for a direct measurement of how a patient feels, functions, or survives.

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All promotional materials for product candidates approved under accelerated approval regulations are subject to prior review by FDA.

Once a NDA is submitted for a product intended to treat a serious condition, the FDA may assign a priority review designation if FDA determines that the product, if approved, would provide a significant improvement in safety or effectiveness.

Once an NDA is submitted for a product intended to treat a serious condition, the FDA may assign a priority review designation if FDA determines that the product, if approved, would provide a significant improvement in safety or effectiveness.

A priority review means that the goal for the FDA to review an application is six months, rather than the standard review of ten months under current PDUFA guidelines.

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Certain requirements include, inter alia, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information on an annual basis or more frequently for specific events, product sampling and distribution requirements, complying with certain electronic records and signature requirements and complying with FDA promotion and advertising requirements.

drug’s approved labeling, known as “off-label use,” and other promotional activities, such as those considered to be false or misleading.

These promotion and advertising requirements include, among others, standards for direct-to-consumer advertising, prohibitions against promoting drugs for uses or patient populations that are not described in the drug’s approved labeling, known as “off-label use,” and other promotional activities, such as those considered to be false or misleading.

Failure to comply with FDA requirements can have negative consequences, including the immediate discontinuation of noncomplying materials, adverse publicity, enforcement letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties.

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CMS administers the Medicaid drug rebate program, in which pharmaceutical manufacturers pay quarterly rebates to each state Medicaid agency.

Generally, for branded prescription drugs marketed under NDAs, manufacturers are required to rebate the greater of 23.1% of the average manufacturer price or the difference between such price and the best price during a specified period.

An additional rebate for products marketed under NDAs is payable if the average manufacturer price increases at a rate higher than inflation, and other methodologies apply to new formulations of existing drugs.

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The ACA also includes funding of pharmaceutical costs for Medicare patients in excess of the prescription drug coverage limit and below the catastrophic coverage threshold.

There have been executive, judicial, Congressional, and political challenges to certain aspects of the ACA.

For example, the ACA's individual mandate was repealed by Congress in The Tax Cuts and Jobs Act of 2017 (the “Tax Act”), which was signed into law in December 2017 and became effective January 1, 2019.

On June 17, 2021, the U.S.

Supreme Court held that state and individual plaintiffs did not have standing to challenge the individual mandate provision of the ACA;

in so holding, the Supreme Court did not consider larger constitutional questions about the validity of this provision or the validity of the ACA in its entirety.

In addition, there have been a number of health reform initiatives by the Biden administration that have impacted the ACA.

For example, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022 (“IRA”) into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

There have been executive, judicial, Congressional, and political challenges and amendments to certain aspects of the ACA.

For example on August 16, 2022, the Inflation Reduction Act of 2022 ("IRA") was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the "donut hole" under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

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Congressional inquiries and federal and state legislation designed to, among other things, increase drug pricing transparency, expedite generic competition, review relationships between pricing and manufacturer patient assistance programs, and reform government program drug reimbursement methodologies.

At the federal level, in July 2021, the Biden administration released an executive order that included multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, the U.S.

Department of Health and Human Services (“HHS”) released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform.

The plan sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

In addition, the IRA, among other things (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

For example, the IRA, among other things (i) directs the U.S.

Department of Health and Human Services (“HHS”) to negotiate the price of certain high-expenditure, single-source drugs that have been on the market for at least 7 years covered under Medicare (the “Medicare Drug Price Negotiation Program”), and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

In addition, the Biden administration released an additional executive order on October 14, 2022, directing HHS to report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act, allowing an agency to grant a compulsory license on a privately owned patent to third parties, if the invention was developed with federal funding and the agency finds that certain statutory criteria apply.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.

On January 17, 2025, HHS selected fifteen additional drugs covered under Part D for price negotiation in 2025.

Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

Further, on December 7, 2023, an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act was announced, allowing an agency to grant a compulsory license on a privately owned patent to third parties, if the invention was developed with federal funding and the agency finds that certain statutory criteria apply.

factor an agency can use when deciding to exercise march-in rights.

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

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Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs.

We anticipate that these and other healthcare reform efforts will continue to result in additional downward pressure on drug pricing.

We anticipate that these and other healthcare reform efforts will continue to result in additional downward pressure on drug pricing, particularly in light of recent U.S.

Presidential and Congressional elections.

Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in payments from private payors.

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Such restrictions under applicable federal and state healthcare laws and regulations include the following:

either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare or Medicaid.

• the federal healthcare Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare or Medicaid.

The term “remuneration” has been broadly interpreted to include anything of value, including cash, improper discounts, and free or reduced price items and services.

17 unchanged sentences

federal analogues, such as to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third party payors, including private insurers;

that require drug companies to comply with the industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;

state laws that require drug companies to comply with the industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;

state and local laws that require the licensure of sales representatives;

19 unchanged sentences

All of our employees are located in the United States.

We intend to add a limited number of employees to support our pipeline development programs.

From time to time, we also retain independent contractors and consultants to support our organization.

1 unchanged sentence

None of our employees are represented by a labor union, and we consider our employee relations to be good.

Attracting, retaining and developing employees from a diverse range of backgrounds to support our research, development and clinical activities is an integral part of our human capital strategy and we believe we offer competitive compensation (including salary, incentive bonus, and equity) and benefits packages.

Attracting, retaining and developing employees from a wide range of backgrounds to support our research, development and clinical activities is an integral part of our human capital strategy and we believe we offer competitive compensation (including salary, incentive bonus, and equity) and benefits packages.

Corporate Information

2 unchanged sentences

in September 2020, following the merger between Foamix Pharmaceuticals Ltd.

and Menlo Therapeutics Inc.

(our predecessor company) in March 2020.

("Foamix") and Menlo Therapeutics Inc.

(our predecessor company) ("Menlo") in March 2020.

We are a “smaller reporting company,” as defined in Rule 12b-2 of the Exchange Act.

7 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business