Slide 1: KOL Event: Update on the BET InhiBET Platform and VYN201
KOL Event: Update on the BET InhiBET Platform and VYN201 May 17, 2022
Slide 2: Forward Looking Statements
Forward Looking Statements This presentation includes forward - looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 , including, but not limited to statements regarding the development of VYNE’s product candidates, the timing of its clinical trials and regul
Slide 3: Purpose and goals of the 2022 KOL Event
3 Provide insight into the continued unmet medical need and necessity for multiple treatments options for vitiligo patients Provide investors with a background on BET inhibition and its applicability to address multiple immuno - inflammatory - mediated diseases Purpose Impact Potential 2022 KOL Even
Slide 4: Today's Agenda
4 Today’s Agenda KOL Event Focused on the InhiBET Œ Platform and VYN201 Topic Presenter Time Overview of VYNE David Domzalski President and CEO 10:05 – 10:15 Introduction to BET proteins Professor Gerald V. Denis, Ph.D. Boston University School of Medicine 10:15 – 10:30 Overview of VYN201 Iain Stuar
Slide 5: Investment Highlights
5 Investment Highlights (NASDAQ: VYNE) VYNE is focused on developing proprietary, innovative, and differentiated therapies for the treatment of immuno - inflammatory conditions Innovative Pipeline • Pipeline focused on major markets (Atopic Dermatitis and I&I) and rare skin diseases with high unmet
Slide 6: VYNE: Developing differentiated therapies for I&I conditions
VYNE: Developing differentiated therapies for the treatment of I&I conditions 6 FMX114: Combination therapy to address both the source & cause of inflammation associated with Atopic Dermatitis (AD) InhiBET TM BET Inhibitor Platform: Global rights to library of NCE BET inhibitors for any indication T
Slide 7: Preclinical Proof-of-Concept Data Summary for VYN201
Preclinical Proof - of - Concept Data Summary for VYN201 Based on established models, compared to active control and vehicle/placebo 7 VYN201 Potential “pipeline in a product” with broad utility across multiple routes of administration 1. Idiopathic pulmonary Fibrosis (IPF) 2. Data on file TH7 Infla
Slide 8: Summary of Locally Administered Pan-BD BETi Candidate Selection Criteria
8 Improved inflammation scores Reduction in inflammatory biomarker levels Good tolerability in animals Good local pharmacology Limited systemic drug accumulation Potential to address high unmet medical need Attractive market opportunity Summary of Locally Administered Pan - BD BETi Candidate Selecti
Slide 9: VYN201 Lead Indication Vitiligo
VYN201 Lead Indication Vitiligo 9
Slide 10: The Vitiligo Opportunity
Large Market 10 • Treatment is dominated by non - specific therapeutic options • VYN201 is a topically applied “soft” drug, designed to maximize target engagement in the skin and minimize systemic exposure The Vitiligo Opportunity A disabling disease and major unmet medical need • 0.5 to 2.0% of wor
Slide 11: Vitiligo – Disease Overview
Vitiligo – Disease Overview An acquired disorder of dermatologic pigmentation with high impact on self - esteem 11 Pathophysiology & Clinical Presentation • Vitiligo is a depigmenting skin disorder characterized by the loss of melanocytes, which causes typical non - scaly, chalky - white macules • P
Slide 12: Vitiligo – Treatment Paradigm
Vitiligo – Treatment Paradigm Current vitiligo treatment is dominated by non - specific therapeutic options 12 Current Treatment Paradigm and Unmet Need 1L Corticosteroids Phototherapy Topical Calcineurin Inhib . Excimer Laser 2L Phototherapy + Combo Agent(s) 3L+ Surgery Depigmentation Therapy Treat
Slide 13: Vitiligo – Epidemiology
Vitiligo – Epidemiology Large market with high unmet need and lack of approved prescription treatment options 13 3.2 M 1.9 M 0 1 2 3 4 U.S. Vitiligo Patients U.S. Diagnosed (Dx) Vitiligo Patients U.S. Addressable Patients Literature suggests ~60% of patients are diagnosed • Large U.S. market between
Slide 14: InhiBET BET Inhibitor Platform Panel
InhiBET ΠBET Inhibitor Platform Panel 14
Slide 15: Panelist biographies
2022 KOL Event: BET Inhibition for I&I Diseases & Clinical Development of VYN201 • Professor, Boston University School of Medicine - molecular oncologist with experience in chromatin control of transcription in cancer • Pioneered studies of the BET bromodomains proteins, a family comprised of BRD2 (
Slide 16: Exclusive Access to Library of NCE BET Inhibitors; Clinical Milestones through 2023
Target Candidate Selection Preclinical Clinical Trials Near - Term Catalysts FMX114 Mild - to - moderate Atopic Dermatitis Phase 1b: completed Phase 2a: TLR Q2 VYN201 Locally administered Pan - BD BET inhibitor 2H 2022: FPI Phase 1 for Vitiligo 2023: Clinic - ready VYN202 Oral BD2 BET inhibitor 1 20
Slide 17: BET proteins control transcription of cytokine genes
Gerald V. Denis, PhD Boston University School of Medicine Department of Pharmacology and Experimental Therapeutics BET proteins, through their bromodomain motifs, control transcription of cytokine genes critical for inflammatory diseases Boston University
Slide 18: Domain structure of human BET proteins
Shi & Vakoc , Mol. Cell 2014 Domain structure of human BET proteins • The bromodomain family (“ Brd ” or “BD”) is comprises of 4 members (BRD2 - 4, BRDT) and have two shared domains, bromodomain 1 and 2 (BD1 and BD2) with an extra - terminal domain • The Brd family is different from other BD domain
Slide 19: Domain structure of human BET proteins: BD1 and BD2
Shi & Vakoc , Mol. Cell 2014 Domain structure of human BET proteins • BD1 and BD2 primarily recognize acetylated lysines on histone termini of chromatin • Both BD1 and BD2 are recognized as druggable small molecule inhibitor targets • The difficulty in developing selective small molecule BET inhibit
Slide 20: Domain structure of human BET proteins: transcription factors
Shi & Vakoc , Mol. Cell 2014 Domain structure of human BET proteins • Remaining structure involved in recruiting/binding additional transcriptional factors that promote chromatin remodeling, which facilitates the initiation of gene transcription chromatin interaction chromatin interaction enzyme com
Slide 21: BET proteins bind histones and recruit co-regulator complexes
Cheung, … & Ming - Ming Zhou, Mol Cell 2017 BET proteins bind to histones in chromatin and recruit co - regulator complexes • Targeted loops is where all the “action” happens as transcription is a group effort among several recruited factors • Inhibiting BET proteins prevents transcriptional complex
Slide 22: The History/Evolution of BET Inhibition
The History/Evolution of BET Inhibition • JQ1, I - BET - 151 1 and other first generation BETi : all pan - BD BET inhibitors for hematological and solid tumor applications • Dose limiting toxicities have limited these first generation development programs (Gastro - intestinal stem cell, immuno - and
Slide 23: BRD2 and BRD4 bind to promoters of macrophage cytokine genes
1. Belkina , Nikolajczyk & Denis , J. Immunol . 2013. 2. https:// en.wikipedia.org /wiki/JQ1 BRD2 and BRD4 bind to promoters of macrophage inflammatory cytokine genes (JQ1) Chromatin immunoprecipitation shows pan - BET inhibitors displace BET protein from chromatin 1 • Example of how a BETi impacts
Slide 24: Knockdown of BET proteins reduces cytokine production
Knockdown of each BET protein in primary macrophages reduces cytokine production Belkina, Nikolajczyk & Denis , J. Immunol . 2013 CXCL1 CCL2 IL - 6 TNF α • Example shows that not all cytokines are regulated by BETis (CXCL1 is not regulated) • Disease applications have to be targetable by BETis and s
Slide 25: Pan-BET inhibition blocks Th17 differentiation in human naïve T cells
Pan - BET inhibition blocks Th17 differentiation in human naïve T cells (JQ1) Note: The canonical paper showing Th17 regulation by BET proteins: Mele et al, J. Exp Med. 2013 • Blocking Th17 with JQ1: this mechanism introduced the relevance of BETi for Th17 - mediated diseases • Th17 - relevant disea
Slide 26: Pan-BET inhibition protects mice from autoimmunity
Pan - BET inhibition protects mice from autoimmunity (JQ1) Mele et al , J. Exp Med . 2013 collagen - induced arthritis model experimental autoimmune encephalitis model Th17 cytokine • Potent anti - inflammatory effects seen in in vitro T cell differentiation studies was shown to translate in several
Slide 27: The Future of BETi's
The Future of BETi’s • Improved medicinal chemistry efforts have enabled gains on on - target potency, with differentiated BD1/2 selectivity profiles being achievable for new BETis • There is a greater (yet evolving) understanding of the role of bromodomain selectivity on both pharmacological/diseas
Slide 28: Evolving science of BET protein inhibition
• The science of BET protein inhibition in immuno - inflammatory and oncology applications continues to evolve • Work continues to elucidate the impact of BD selectivity on both oncogene and cytokine expression “signatures” • Broad inhibitory networks have value because many inflammatory cytokines f
Slide 29: InhiBET BET Inhibitor Platform
InhiBET ΠBET Inhibitor Platform Bromodomain & Extra - Terminal Domain (BET) Inhibition for Immunology and Inflammatory Diseases 29
Slide 30: InhiBET BET Inhibitor Platform Overview
InhiBET ΠBET Inhibitor Platform Overview Platform includes global rights to a library of NCEs for any indication 30 VYN201 Locally administered Pan - BD BET inhibitor VYN202 Oral BD2 - selective BET inhibitor BD1 BD2 Designed to selectively bind to BD2 and is being developed for major immuno - infl
Slide 31: BET Proteins Regulate Inflammatory and Oncogenic Genes
BET Proteins Play a Key Role in the Regulation of Inflammatory and Oncogenic Genes involved in Several Diseases Gene transcription stimulated Histones N - terminal of histones BRD4 Oncogenic genes, leading to: • Increased cell proliferation/survival • An increase in solid tumors and hematologic mali
Slide 32: How BET Proteins Fuel the Vicious Cycle of Cytokine Production
How BET Proteins Fuel the “Vicious Cycle” of Pro - Inflammatory Cytokine Production in Autoimmune Diseases Pro - inflammatory cytokines Cytokines bind to cytokine receptors 1 Activation of NF - kb kinase complex 2 Nuclear translocation 3 Recruitment of transcription factors 4 5 6 BRD4 active cytokin
Slide 33: BET Inhibitors Block BD1/BD2 Binding to Acetylated Lysines
cytokine transcription BET Inhibitors Block BD1/BD2 Binding to Acetylated Lysines and Stall Pro - inflammatory Protein Transcription BET INHIBITOR Binds BD1 and/or BD2 of BRD4 protein making it unable recognize acetylated histones, recruit transcription factors and release pro - inflammatory cytokin
Slide 34: VYN201 Locally administered pan-BET inhibitor
VYN201 Locally administered pan - BET inhibitor
Slide 35: VYN201 Pre-Clinical Efficacy Model Evaluations
VYN201 Pre - Clinical Efficacy Model Evaluations 35 Indication/area Model Administration Route Status Th17 autoimmune diseases IMI - induction mouse model Topical Complete Th2 autoimmune diseases DNCB - induction mouse model Topical Complete Fibrosis Wound healing outcomes mouse model Topical Comple
Slide 36: VYN201: Th17 autoimmune diseases
VYN201: Th17 autoimmune diseases
Slide 37: VYN201 reduces composite inflammation score in IMI model
IMI – Imiquimod. *Composite Inflammation Severity Score is a composite mean score of erythema and peeling severity scored on a 4 - point ordinal sc ale per domain (0=none, 1=mild, 2=moderate and 3=severe for a maximum score of 6), data expressed as a mean percentage change from initiation of treatme
Slide 38: VYN201 reduces pro-inflammatory biomarkers in IMI model
IMI – Imiquimod. Dorsal depilated BALB - C mice were dosed topically for 14 days with 100mg topical IMI cream (Day 1 - 7: induction phase, Day 8 - 14: treatment phase). N=4 animals were assigned to each treatment group with each group receiving 100mg of allocated treatment on Day 8 - 14 once daily •
Slide 39: Normal Skin Physiology in Th17 Murine Model Suggests VYN201 Well Tolerated
VYN201 0.1% VYN201 Vehicle Clobetasol Cream 0.05% • No appreciable improvement in clinical signs • Substantial resolution of clinical signs • Skin presents with normal physiology with no evidence of striae rubrae or atrophy • No evidence suggestive of intolerance • Substantial resolution of clinical
Slide 40: VYN201 Reduced Pro-Inflammatory Proteins in Human Tissue
VYN201 Significantly Reduced Expression of Several Key Pro - Inflammatory Proteins Relevant to Th17 - mediated Autoimmune Diseases in Human Tissue 1 Interleukin 36 - gamma IL36 γ is implicated in upregulating IL - 17A signaling - related genes and so able to amplify keratinocyte inflammatory respons
Slide 41: VYN201: Dermal and Lung Fibrosis
VYN201: Dermal and Lung Fibrosis
Slide 42: VYN201 murine skin wound healing model
Female hairless mice (n=4/group) had two identical 10mm incisions made either side of the flank. Animals were topically dosed 1X daily with 100mg VYN201 vehicle, VYN201 1% or a Hydroalcoholic gel* until each wound had completely healed • Statistically significant difference (p<0.05) in composite glo
Slide 43: Little Evidence of Residual Swelling in Murine Skin Healing Model
VYN201 1% VYN201 Vehicle Hydroalcoholic gel • Still evidence of minor swelling around incision sites • Little evidence of residual swelling • Wound appears more macular in nature compared to VYN201 vehicle or the Hydroalcoholic gel • Incision sites appear less distinct and leave a more aesthetic out
Slide 44: Bleomycin-induced mouse model of IPF - Histology
VYN201: Bleomycin - induced mouse model of IPF - Histology Histology images indicate positive impact of VYN201 0.06mg/ml on fibrosis in lungs. Additional preclinical exploration planned 4 Healthy sham control Bleomycin control Bleomycin + 0.06mg/ml VYN201 A : N ormal lung parenchyma with open airway
Slide 45: VYN201: Rheumatoid Arthritis
VYN201: Rheumatoid Arthritis
Slide 46: CAIA Mouse Model of Arthritis – Paw Thickness
VYN201: CAIA Mouse Model of Arthritis – Paw Thickness Marked inhibition of paw thickening/swelling CAIA = Collagen Antibody Induced Arthritis; IA = Intra - articular; IP = Intraperitoneal 1.75 2.00 2.25 2.50 2.75 3.00 3.25 3.50 Baseline Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 10 Day 12 Paw thickness
Slide 47: CAIA Mouse Model of Arthritis – Arthritis Score
VYN201: CAIA Mouse Model of Arthritis – Arthritis Score Demonstrated dose dependent reduction in disease severity *Scoring based on a five - point composite severity scale of redness, swelling of the ankles and wrists, and paw thickness. Scorin g ranges from 0 (normal) to 4 (extensive signs and symp
Slide 48: CAIA Mouse Model of Arthritis – Systemic Impact
VYN201 1 & 10mg/kg results demonstrated the highest localized effect in the treated limb when compared to the untreated limbs (largest delta between treated and untreated limbs) Each animal treated with the intra - articular injections received the injection in the ankle of one rear paw. The untreat
Slide 49: VYN201: Vitiligo
VYN201: Vitiligo %VYNE
Slide 50: Human Tissue Model of Vitiligo – Inhibition of MMP9
10 • Stimulated and vehicle treated RHE demonstrated a significant upregulation of MMP9, relative to unstimulated and untreated control • VYN201 markedly reduced the expression of MMP9 in a dose - dependent manner with a maximal effect at the 1% concentration • VYN201 1% reduced the secretion of MMP
Slide 51: Human Tissue Model of Vitiligo – Reduction of Soluble E-cadherin
VYN201: Human Tissue Model of Vitiligo – Reduction of Soluble E - cadherin • Stimulated and vehicle - treated RHE demonstrated a significant upregulation of soluble E - cadherin, relative to unstimulated control • VYN201 affects a dose - dependent reduction in solubilized E - cadherin • VYN201 was n
Slide 52: Human Tissue Model of Vitiligo – Effect on Melanocyte Retention
VYN201: Human Tissue Model of Vitiligo – Effect on Melanocyte Retention 12 • Stimulated and vehicle - treated RHE demonstrated a significant loss in melanin content, relative to unstimulated control • VYN201 substantially prevents the loss of melanin pigment in the basal layers of skin in a dose dep
Slide 53: Human Tissue Model of Vitiligo - Histology
TRV: tyrosinase - related protein 1 (important enabler of melanogenesis) Keratinocytes (blue), melanocytes (green) Basal layer Melanocyte migration Retention of melanocytes at the basal layer Stimulated and Vehicle treated Unstimulated and untreated control Stimulated and VYN201 1% treated Melanocyt
Slide 54: Human Tissue Model of Vitiligo – Gene regulation
Stimulated control Stimulated and VYN201 1% treated Preliminary data suggest that VYN201 regulates genes relevant to Vitiligo including impacting WNT pathway which is believed to play a key role in melanocyte regeneration Significant upregulation of cytokines IL6, IL1A and IL1B and TNF Melanocyte mi
Slide 55: Planned Phase 1 Study Design in Vitiligo
Phase 1b Portion (n=up to 20) Treatment on the face and target lesion(s) on trunk of vitiligo patients for 8 weeks of once - daily treatment with planned extension. Primary objective: Evaluation of the safety and pharmacokinetics of VYN201 in vitiligo patients • Dose level(s) will be selected based
Slide 56: VYN202: BD2 selective BET inhibitor
VYN202: BD2 selective BET inhibitor
Slide 57: VYN202 Program Highlights & Molecular Profile
Potential Target Market 1 : • Immuno - inflammatory indications such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis/Crohn's and multiple sclerosis; additional potential in myeloproliferative neoplastic disorders 2 Focused activity: • Highly selective inhibition of BD2 doma
Slide 58: Thierry Passeron: New therapeutic approaches in vitiligo
Thierry Passeron, MD, PhD Department of Dermatology & INSERM U1065, C3M CHU Nice, France How addressing the pathophysiology of vitiligo is providing new therapeutic approaches 18
Slide 59: Disclosures
Disclosures • Almirall • Abbvie • Amgen • Astellas • BMS • Celgene • Galderma • GSK • Incyte • Janssen • LEO Pharma • Lilly • MSD • Novartis • Pfizer • Sanofi - Genzyme • SUN pharma • UCB pharma • Vyne therapeutics 19
Slide 60: Vitiligo
Vitiligo • Acquired depigmentation of the skin and the hair • Acquired loss of melanocytes • 0.5 to 2% of worldwide population • (Non segmental) vitiligo : 85 to 95% of vitiligo cases Vitiligo Segmental vitiligo Mixed vitiligo 20 Image credit T . Passeron . Bergqvist C, Ezzedine K, 2020;236;571 - 59
Slide 61: Major impact on affected patients
• Affect social, sexual and professional life (comparable at least to depression or even some cancers) • Difficulty to find a job • Major impact in some countries due to resemblance with leprosy • In Western countries more than half of the affected patients are willing to pay more than 5000 euros to
Slide 62: Immune-related genes and diseases associated with vitiligo
Rheumatoid arthritis Type 1 diabetes Celiac disease AutoImmune Thyroiditis Inflammatory bowel disease Alopecia Areata Multiple sclerosis Myasthenia gravis Auto - Immune Hepatitis Psoriasis Pigmentation phenotypes Melanoma Immune - related genes associated with vitiligo 1 – 4 * * Genes involved in im
Slide 63: Skin intrinsic abnormalities in vitiligo
Skin intrinsic abnormalities in vitiligo 1 • Involvement of melanocytes, keratinocytes and fibroblasts • Increased susceptibility to oxidative stress • Increased production of ROS • SAPS secretion • Mitochondrial alteration • Increase ECM protein release 23 α - SMA, alpha smooth muscle actin; ECM, e
Slide 64: Melanocytorragy
Melanocytorragy • Detachment of melanocytes in vitiligo skin 1 • Altered e - cadherin levels and distribution precede clinical manifestation of vitiligo 2,3 • IFN g and TNF a induce melanocyte detachment through E - cadherin disruption by the increase of MMP9 4 MMP9 immuno - staining 24 MMP9: metall
Slide 65: Innate and adaptive immunity
Innate and adaptive immunity Innate response is the link between stressors and the adaptive anti - melanocytic response 25 1. Boniface K, et al. Front Immunol . 2021; 12:613056.
Slide 66: Melanocyte Regeneration: Key Role of The WNT Pathway
Healthy skin Vitiligo lesional skin WNT LEF Epidermis Dermis Differentiation & migration Keratinocyte Melanocyte Stem cell Oxidative stress Immune system Melanocyte detachment and melanocyte death LEF WNT Decreased renewal of melanocyte Differentiation & migration Keratinocyte Melanocyte Normal rene
Slide 67: Three Objectives in Vitiligo Treatment
Three Objectives in Vitiligo Treatment To halt the melanocytic loss To induce the differentiation and the proliferation of melanocytes (long process that usually takes 6 to 24 months) To prevent relapses 27
Slide 68: To Halt the Depigmentation
To Halt the Depigmentation 28
Slide 69: Evolution of Vitiligo
Evolution of Vitiligo • The course of vitiligo is unpredictable • Lack of prognosis factors except clinical signs • Hypochromic borders under Wood’s lamp examination 1,3 • Confetti - like depigmentation 2 • Development of Vitiligo Signs of Activity Score (VSAS) 3 When vitiligo is active, it must be
Slide 70: How To Treat an Active Form of Vitiligo
How To Treat an Active Form of Vitiligo • Data strongly suggest the usefulness of Oral Mini - Pulse therapy (OMP) for halting vitiligo progression • MTX, cyclosporine and minocycline also seem to be effective (not indicated for treatment) • But Nb - UVB appears more important for halting disease pro
Slide 71: To Induce Repigmentation
To Induce Repigmentation 31
Slide 72: Combination of Phototherapy and Topical Treatments
Combination of Phototherapy and Topical Treatments • Interest of combining topical calcineurin inhibitors (off - label use) or potent topical steroids with sun exposure or Nb - UVB 1,2 • Confirmed by meta - analyses • Combination approaches are today the gold standard treatment for vitiligo • Better
Slide 73: To Prevent The Relapses
To Prevent The Relapses 33
Slide 74: Preventing Vitiligo Relapses
• >40% of lesions have new depigmentation in the year following the treatments » For localized vitiligo : » Tacrolimus 0.1% 2/ wk » Decreases the risk of relapse from 40% to 9.7% 1 » Potent topical steroids appears as effective but no demonstration in prospective randomized trials » For widespread v
Slide 75: Perspectives
Adapted from Passeron T. Lancet 2020 ; 396(10244):74 - 5 and JEADV 2021, 35, 2305 – 2307 . Perspectives 35
Slide 76: What the market needs from new Vitiligo therapies
Treatments today: • Cumbersome, poly - pharmacy regimen involving both Rx and Dx • Onset of efficacy can take quite some time to meaningfully develop • Some new treatments in development e.g. JAK inhibitors, anti - IL15 and WNT agonists (preclinical stage) but many more needed to provide treatment o
Slide 77: Thank you for your attention!
Thank you for your attention! 37
Slide 78: Targeted Clinical Milestones through 2023
Target Candidate Selection Preclinical Clinical Trials Near - Term Catalysts FMX114 Mild - to - moderate Atopic Dermatitis Phase 1b: completed Phase 2a: TLR Q2 VYN201 Locally administered Pan - BD BET inhibitor 2H 2022: FPI Phase 1 for Vitiligo 2023: Clinic - ready VYN202 Oral BD2 BET inhibitor 1 20