Baricimiant Refreshment Session - Immunology Line 17-9 PDF

Barcimiant AA- Refreshment session Immunology line - Egypt cluster Ahmed Elrashedy Medical Science Liaison 1 Corporate Slides / EVA Pharma...

Barcimiant AA- Refreshment session Immunology line - Egypt cluster Ahmed Elrashedy Medical Science Liaison 1 Corporate Slides / EVA Pharma 2 Pathogenesis of inflammatory dermatoses (an overview): The whole triad must be present for the disease to develop. This can be simplified in the following equation: Genetic predisposition + Environmental triggers (antigens) + Immunological disturbance Clinical picture September 25, 2024 2  Corporate Slides / EVA Pharma 3 Normal hair follicle growth cycle SG Hair papilla Bulge (contains stem Germinative cells) epithelium Hair bulb Anagen Catagen Telogen Exogen Growth Regressing Resting Shedding phase1,2 phase1,2 phase1,2 phase3 SG=sebaceous gland September 25, 2024 1. Waters JM et al. Semin Cell Dev Biol 2007;18(2):245-54; 2. Juárez-Rendón KJ et al. Arch Argent Pediatr 2017;115(6):e404-11; 3. Santos Z et al. Expert Opin Drug Discov 2015;10(3):269-92; immune privilege in AA Company Confidential © 2021 Eli EVA and Company Loss of immune privilege in AA Olayinka, Jadesola (Jadé) Temitope, and Jillian M. Richmond. “Immunopathogenesis of Alopecia Areata.” Current Research in Immunology, vol. 2, 2021, pp. 7–11, https://doi.org/10.1016/j.crimmu.2021.02.001. Company Confidential © 2021 Eli EVA and Company  Corporate Slides / EVA Pharma 6 Hair Follicle (HF) Cycle in AA Inflammatory cells in AA specifically attack the anagen HF1,2 SG The activated T-cells produce IFN-γ which binds IL-15 to HF cells, inducing a premature transition to IFN-γ catagen and production of IL-151,2 IL-15 subsequently binds to IL-2/15R on T-cells, further inducing IFN-γ production1,2 IL-15Rα After exogen (shedding), HFs enter kenogen, or Hair IL-15 empty telogen, where they remain dormant and bulb do not enter back into anagen growth3 Anagen Catagen Continuous IFN-γ production is facilitated Regressing via a positive feedback loop involving Growth phase4 Kenogen phase4 2-6 years5 Empty telogen3 IFN-γ and IL-15 signaling8,9 ~93% of hairs6,7 2-4 weeks5 1-2% of hairs6 AA=Alopecia Areata; IFN=Interferon; IL=Interleukin; SG=Sebaceous Gland. 1. Paus R, et al. J Investig Dermatol Symp Proc. 2018;19:S12-S17. 2. Pratt CH, et al. Nat Rev Dis Primers. 2017; 3:17011. 3. Vogt A, et al. Hair Growth and Disorders (1st Ed), 2008. 4. Waters JM, et al. Semin Cell Dev Biol. 2007;18(2):245-254. 5. Juárez-Rendón KJ, et al. Arch Argent Pediatr. 2017;115(6):e404-e411. 6. Santos Z, et al.September 25, 2024 Expert Opin Drug Discov. 2015;10(3):269-292. 7. Cotsarelis G and Botchkarev V. Fitzpatrick’s Dermatology (9th edition). 8. Divito SJ, et al. Nat Med. 2014;20(9):989-990. 9. Fukuyama M, et al. J Corporate Slides / EVA Pharma 7 Loss of immune privilege in AA The exact cause of immune privilege loss in AA is unclear1 There are two main hypotheses to explain the initial loss of immune privilege: 1. Local defects in hair follicles caused by oxidative stress1,2 2. Systemic immune system dysregulation1 IP loss Normal hair follicle1 AA hair follicle3 Protected through Immune cells such as several IP mechanisms CD8+ and CD4+ T cells that prevent immune cell infiltrate, representing a infiltration “swarm of bees” September 25, 2024 AA=alopecia areata; CD=cluster of differentiation; IP=immune privilege 1. Rajabi et al. Br J Dermatol 2018;179(5):1033-48; 2. Prie BE et al. J Med Life 2015;8(Spec Issue):43-6; 3. Strazzulla LC et al. J Am Acad Dermatol 2018;78(1):1-12 Loss of immune privilege in AA Company Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 9 Supporting features of AA Signs1,2 - Body hair loss in patches, or loss of eyebrows/eyelashes - Nail involvement - Exclamation mark hairs: Dystrophic hairs with fractured tips Exclamation mark hair Yellow dots Dermoscopy (trichoscopy)1,2 - Yellow dots in areas of active disease: correspond to empty hair follicles filled with sebum and/or keratotic material - Cadaverized hairs: Black dots; hair is fractured before Cadaverized hairs emergence from scalp September 25, 2024 Company Confidential © 2021 Eli EVA and Company Exter JAK - STAT pathway Company Confidential © 2021 Eli EVA and Company  Role of JAK-STAT pathway, immune cells, and related cytokines in the immune-pathogenesis of alopecia areata. Sardana, Kabir, et al. “Which Is the Ideal JAK Inhibitor for Alopecia Areata – Baricitinib, Tofacitinib, Ritlecitinib or Ifidancitinib - Revisiting the Immunomechanisms of the JAK Pathway. Company Confidential © 2021 Eli EVA and Company ” Indian Dermatology Online Journal, vol. 14, no. 4, 1 July 2023, p. 465, journals.lww.com/idoj/Fulltext/2023/14040/Which_is_the_Ideal_JAK_Inhibitor_for_Alopecia.3.aspx, https://doi.org/10.4103/idoj.idoj_452_22.  Alopecia Areata and Atopic Dermatitis AD is more common in patients with AA, compared with the general population1 Mechanisms of association between AD and AA are still unclear, but they have overlapping biological pathways and similar genetic backgrounds2 A pooled analysis of four studies found higher odds of AD in patients with AT/AU, compared with those with patchy AA (p=0.04)3 AA=alopecia areata; AD=atopic dermatitis; AT=alopecia totalis; AU=alopecia universalis 1. Lee S et al. J Am Acad Dermatol 2019;80(2):466-77; 2. https://www.slideshare.net/NationalAlopeciaAreataFoundation/the-atopic-dermatitis-pathogenesis-and-implications-for-alopecia-areata; Company Confidential © 2021 Eli EVA and Company 3. Mohan GC and Silverberg JI. JAMA Dermatol 2015;151(5):522-8 Corporate Slides / EVA Pharma 13 European expert consensus statement on the systemic treatment of alopecia areata - 2024 September 25, 2024 L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. ” JEADV. Journal of the European AcademyCompany Confidential of Dermatology © 22021 and Venereology, Eli EVA Jan. 2024, and Company https://doi.org/10.1111/jdv.19768. Corporate Slides / EVA Pharma 14 FDA approved treatment for Alopecia Areata September 25, 2024 “Approved Treatment FAQs - National Alopecia Areata Foundation Company | NAAF.” Confidential © National 2021 Eli Alopecia Areata Foundation | NAAF, 30 July 2024, EVA and Company Corporate Slides / EVA Pharma 15 Therapeutic options – Systemic therapy - JAKis Ritlecitinib (JAK 3/TEC inhibitor) o Ritlecitinib is approved by the FDA and EMA for the treatment of severe alopecia areata in adults and adolescents 12 years of age or older. o It is a selective dual inhibitor that blocks JAK 3 and TEC. o With 200 mg/day ritlecitinib loading dose (four weeks) and continued therapy with 50 mg/day. o The EMA-approved dose of ritlecitinib is 50 mg/day. o Consideration should be given to discontinuing ritlecitinib in patients who show no evidence of therapeutic benefit after 36 weeks. o These observations may indicate that in patients who have a good therapeutic effect, treatment should not be discontinued too early. o EMA general safety measures for JAK inhibitors do not include ritlecitinib as of DecemberL. Rudnicka, 2023. et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. September 25, 2024 ” JEADV. Journal of the European Academy of Company Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 16 Therapeutic options – Systemic therapy - JAKis Ritlecitinib (JAK 3/TEC inhibitor) L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. September 25, 2024 ” JEADV. Journal of the European Academy of Company Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 17 Therapeutic options – Systemic therapy - JAKis FDA Approves JAK Inhibitor Deuruxolitinib for Alopecia Areata o Announced in a July 25, 2024, news release from the drug's manufacturer Sun Pharma, is based on data from two pivotal randomized, double-blind, placebo- controlled phase 3 clinical trials: THRIVE-AA1 and THRIVE-AA2, o Deuruxolitinib, which comes in 8-mg tablets, is an oral selective inhibitor of JAK1 and JAK2 and is administered twice a day L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. September 25, 2024 ” JEADV. Journal of the European Academy of Company Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 18 Key cytokines involved in AA IFN-γ3 IL-23 IL-73 IL-153 IL-213 Baricitinib Exter The FIRST JAKi approved by the FDA for the treatment of AA September 25, 2024 Company Confidential © 2021 Eli EVA and Company Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2) ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. 19 Corporate Slides / EVA Pharma 20 BRAVE-AA Phase 3 trial program Global Global Phase 2/3 Phase 3 Estimated N=725 1,2 Estimated N=4761,3 PBO PBO BARI 2-mg BARI 2-mg BARI 4-mg BARI 4-mg Primary outcome 36 36 (week) End of treatment duration 200a 200b (week) September 25, 2024 Randomized withdrawal study from Week 52; bridging extension from Week a 104 to Confidential Company Week 200; Randomized b downtitration © 2021 Eli EVA and study Week 52; bridging extension Week 104; AA=alopecia areata Company  Study background BRAVE-AA1 and BRAVE-AA2 are ongoing, independent, randomized, double-blind, parallel-group, placebo-controlled studies Objective of the study The aim of this study was to evaluate the efficacy and safety of baricitinib for AA in adults with ≥50% scalp hair loss through 52 weeks of continuous therapy in two phase III trials (BRAVE-AA1 and BRAVE- AA2). Study endpoint Efficacy outcomes at 52 weeks included the proportion of patients achieving SALT score ≤ 20 (≤ 20% scalp hair loss), which is considered a clinically meaningful outcome for patients with ≥ 50% scalp hair loss at baseline. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Disposition of patients randomized to baricitinib in BRAVE-AA1 and BRAVEAA2 through 52 weeks Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Proportions of patients achieving SALT score ≤20 through Week 52 BRAVE-AA1 and BRAVE-AA2 The proportions of patients achieving SALT score ≤ 20 continuously increased over the treatment period, with response rates for patients treated with baricitinib 4 mg and 2 mg, respectively, reaching 40.9% and 21.2% in BRAVE-AA1 and 36.8% and 24.4% in BRAVE-AA2 at Week 52 SALT, Severity of Alopecia Tool. A SALT score ≤20 indicates ≤20% scalp hair loss. Bars represent 95% confidence intervals. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Patients achieving ClinRO Measure for Eyebrow Hair Loss 0 or 1 with ≥2-point improvement from baseline through Week 52 Among patients with a score of ≥2 at baseline in a) BRAVE-AA1 and b) BRAVE-AA2 Eyebrow and eyelash response rates also increased over the 52-week period. ClinRO, Clinician-Reported Outcome A ClinRO score of 0 indicates full coverage, and a score of 1 indicates minimal gaps in eyebrows or eyelashes. Bars represent 95% confidence intervals. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Patients achieving ClinRO Measure for Eyelash Hair Loss 0 or 1 with ≥2-point improvement from baseline through Week 52 Among patients with a score of ≥2 at baseline in a) BRAVE-AA1 and b) BRAVE-AA2 Eyebrow and eyelash response rates also increased over the 52-week period. ClinRO, Clinician-Reported Outcome A ClinRO score of 0 indicates full coverage, and a score of 1 indicates minimal gaps in eyebrows or eyelashes. Bars represent 95% confidence intervals. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Clinical photographs of patients with alopecia areata at baseline and after 36 weeks and 52 weeks of treatment with baricitinib 4 mg in BRAVE-AA1. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Summary of serious adverse events Most TEAEs were mild or moderate in severity. The most frequently reported TEAEs were upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, increased blood creatinine phosphokinase (CPK), and COVID-19 infection The frequency of discontinuations Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). due to AEs was low ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Summary of serious adverse events Newly reported herpes zoster infections that occurred after the placebo- controlled period were localized; all patients recovered, and none discontinued. Herpes simplex infections were all mild or moderate and there were no discontinuations. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  Potential for baricitinib in the treatment of severe AA across 52 weeks In BRAVE-AA1 and BRAVE-AA2, response rates in 1 scalp hair regrowth increased over 52 weeks of baricitinib treatment in adults with severe AA. In addition to Eyebrow and eyelash 2 Clinical response was O S O numerically greater with N N baricitinib 4 mg than 2 mg. N N Response rates for most endpoints did not plateau over the study period, indicating that maximum N N N H 3 benefit in scalp, eyebrow, and eyelash hair regrowth may require more than 52 weeks of treatment, in particular for patients with more extensive disease. Safety findings were consistent 3 with the known safety profile of baricitinib. Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company  The present analysis demonstrates the benefits of continuous baricitinib treatment over 1 year for severe AA Kwon, Ohsang, et al. “Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2). ” American Journal of Clinical Dermatology, 1 Mar. 2023, https://doi.org/10.1007/s40257-023-00764-w. Company Confidential © 2021 Eli EVA and Company Long-term efficacy and safety of baricitinib in patients with severe alopecia areata: 104-weeks results from BRAVE-AA1 and BRAVE-AA2 Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. 33  Study background BRAVE-AA1 and BRAVE-AA2 are ongoing, independent, randomized, double-blind, parallel-group, placebo-controlled studies Objective of the study To evaluate the efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy. Study endpoint Efficacy outcomes at 104 weeks included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Patient-reported outcomes (PROs) ClinRO Measure for Eyebrow & Eyelashes Safety assessments included adverse events (AEs), serious AEs (SAEs) and clinical laboratory tests. ---. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2.” Journal of the European Academy of Dermatology and Venereology,Companyvol. 38, no. Confidential 3, 23 Feb. 2024, © pp. 583–593, 2021 Elihttps://doi.org/10.1111/jdv.19665. EVA and Company Study design and description of efficacy analysis population BARI, baricitinib; PBO=placebo; QD=once daily; R=randomization; W=Week a Figure is not the full BRAVE-AA1 and BRAVE-AA2 program. b Baricitinib-4-mg–treated and 2-mg–treated patients with SALT score ≤20 at Week 52 c Baricitinib-4-mg–treated patients who had SALT score >20 at Week 52 but had reached SALT score ≤20 at prior visit(s) and/or patients with Clinician-Reported Outcome (ClinRO) Measure for Eyebrow Hair Loss or ClinRO Measure for Eyelash Hair Loss scores ≥2 at baseline who had achieved a ClinRO Eyebrow/Eyelash ≥2-point improvement from baseline at Week 52 ---. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2.” Journal of the European Academy of Dermatology and Venereology,Companyvol. 38, no. Confidential 3, 23 Feb. 2024, © pp. 583–593, 2021 Elihttps://doi.org/10.1111/jdv.19665. EVA and Company Study design and description of efficacy analysis population Among patients with SALT score >20 at Week 52 who were continuously treated with baricitinib 4 mg, 39.1% achieved SALT score ≤20 and 25.5% achieved SALT ---. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2.” score ≤10 by Week Journal of the European Academy of Dermatology and Venereology,Companyvol. 38, no. Confidential 3, 23 Feb. 2024, © pp. 583–593, 2021 Elihttps://doi.org/10.1111/jdv.19665. EVA and Company 104  Clinically Meaningful Scalp Hair Regrowth Was Maintained Through Week 104 in ~90% of Patients Treated With BARI 4-mg or 2-mg Who Responded at Week 52 Proportion of Week 52 Respondersa Who Achieved SALT Score ≤20 Through Week 104 a Patients who achieved SALT score ≤20 at Week 52 Note: Data were summarized with mLOCF imputation BARI=baricitinib; CI=confidence interval; mLOCF=modified last observation carried forward; SALT=Severity of Alopecia Tool ---. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2.” Journal of the European Academy of Dermatology and Venereology,Companyvol. 38, no. Confidential 3, 23 Feb. 2024, © pp. 583–593, 2021 Elihttps://doi.org/10.1111/jdv.19665. EVA and Company Corporate Slides / EVA Pharma 38 Proportion of patients achieving Scalp Hair Assessment PRO™ score 0 or 1 with ≥2-point improvement from baseline from Week 52 through Week 104 in Week-52 responders and mixed responders. Hair Assessment PRO™ score 0 or 1 with Hair Assessment PRO™ score 0 or 1 with (a) Week-52 Responders (b) Week-52 Mixed Responders Proportion of patients achieving Scalp Proportion of patients achieving Scalp ≥2-point improvement from baseline ≥2-point improvement from baseline 100 100 90 85.5% 86.3% 90 80 80 70 72.4% 75.9% 70 60 60 50 50 40 40 30 28.0% 30 20 Baricitinib 4 mg (N=124) 20 11.2% 10 Baricitinib 2 mg (N=58) 10 Baricitinib 4 mg (N=107) 0 52 56 60 64 68 72 76 80 84 88 92 96 100 104 0 52 56 60 64 68 72 76 80 84 88 92 96 100 104 Week Week Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp.Confidential Company 583–593, https://doi.org/10.1111/jdv.19665. © 2021 Eli EVA and Company Accessed 20 Mar. 2024. Confidentia September 25, 2024 Corporate Slides / EVA Pharma 39 The proportion of patients achieving PRO Measure for Eyebrows™ score 0 or 1 with ≥2-point improvement from baseline from Week 52 through Week 104 in (a) Week-52 responders and (b) Week-52 mixed responders. Measure for Eyebrows™ score 0 or 1 with Measure for Eyebrows™ score 0 or 1 with (a) Week-52 Responders (b) Week-52 Mixed Responders Proportion of patients achieving PRO Proportion of patients achieving PRO ≥2-point improvement from baseline ≥2-point improvement from baseline 100 100 90 90 80 75.3% 80 64.2% 67.4% 70 70 60 66.7% 60 50 50 56.4% 51.1% 40 40 30 30 20 Baricitinib 4 mg (N=81) 20 10 Baricitinib 2 mg (N=39) 10 Baricitinib 4 mg (N=92) 0 0 52 56 60 64 68 72 76 80 84 88 92 96 100 104 52 56 60 64 68 72 76 80 84 88 92 96 100 104 Week Week Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp.Confidential Company 583–593, https://doi.org/10.1111/jdv.19665. © 2021 Eli EVA and Company Accessed 20 Mar. 2024. September 25, 2024 Confidentia Corporate Slides / EVA Pharma 40 Proportion of patients achieving PRO Measure for Eyelashes™ score 0 or 1 with ≥2-point improvement from baseline from Week 52 through Week 104 in (a) Week-52 responders and (b) Week-52 mixed responders. Measure for Eyelashes™ score 0 or 1 with Measure for Eyelashes™ score 0 or 1 with (a) Week-52 Responders (b) Week-52 Mixed Responders Proportion of patients achieving PRO Proportion of patients achieving PRO ≥2-point improvement from baseline ≥2-point improvement from baseline 100 100 90 90 80 74.2% 80 67.9% 70 70 56.1% 70.4% 58.0% 60 60 50 51.9% 50 40 40 30 30 20 Baricitinib 4 mg (N=66) 20 10 Baricitinib 2 mg (N=27) 10 Baricitinib 4 mg (N=81) 0 0 52 56 60 64 68 72 76 80 84 88 92 96 100 104 52 56 60 64 68 72 76 80 84 88 92 96 100 104 Week Week Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp.Confidential Company 583–593, https://doi.org/10.1111/jdv.19665. © 2021 Eli EVA and Company Accessed 20 Mar. 2024. September 25, 2024 Confidentia Corporate Slides / EVA Pharma 43 Most TEAEs were mild or moderate in severity. Summary of safety outcomes. The frequency and IR of study drug discontinuation due to AEs was low and similar across groups No deaths were reported. Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. Accessed 20 Mar. 2024. Confidentia September 25, 2024 Corporate Slides / EVA Pharma 44 Summary of safety outcomes. The most common TEAEs (occurring in ≥5% of patients in All-Bari-AA) were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine Mostphosphokinase cases of herpes(CPK) simplex were oral herpes; increase. there were no cases associated with study discontinuation. Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. Accessed 20 Mar. 2024. Confidentia September 25, 2024 Corporate Slides / EVA Pharma 45 Summary of safety outcomes. Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. Accessed 20 Mar. 2024. Confidentia September 25, 2024 Corporate Slides / EVA Pharma 46 Laboratory summary. Changes in laboratory analytes were consistent with those previously reported for baricitinib Overall, clinically relevant hematological changes were reported in a few patients over the long- term observation period. Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. Accessed 20 Mar. 2024. Confidentia September 25, 2024 Corporate Slides / EVA Pharma 47 Maintenance of efficacy in Week-52 RESPONDERS 90.7% 89.2% 81.4% 73.8% 83.8% 67.6% 4 mg 2 mg 4 mg 2 mg 4 mg 2 mg Maintained a SALT score ≤20 Achieved SALT score ≤10 ClinRO improving ≥2 at Week 104 points from baseline for Eyebrow Both 4-mg and 2-mg responders had mean 80.9% 73.3% 85.5% 72.4% changes from baseline of −1.4 points for HADS-Anxiety and −0.9 points for HADS- Depression at Week 52; these improvements 4 mg 2 mg 4 mg 2 mg were maintained through Week 104 ClinRO improving ≥2 Self-reported Scalp Hair Both dose groups saw continuous points Assessment PRO 0 or 1 improvements in Skindex-16 for AA from baseline for Eyelash symptoms, emotions, and functioning scores. Senna, M, et al. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. Accessed 20 Mar. 2024. Confidentia September 25, 2024 Corporate Slides / EVA Pharma 48 Improved efficacy in Week-52 MIXED RESPONDERS Among patients with SALT score >20 at Week 52 who were continuously treated with baricitinib 4 mg 39.1% 56.4% 41.8% 72.4% 72.2% 4 mg 4 mg 4 mg 4 mg 4 mg Achieved SALT score ≤20 Achieving SALT50 and ClinRO responses for SALT75 eyebrow and eyelash increased from remained stable over time 40.9% and 4.5% at Week 52 The proportions of patients achieving PROs for scalp hair, eyebrow and eyelash regrowth increased over time HADS-Anxiety and HADS-Depression scores decreased −0.7 and −0.6 points at Week 104, respectively. Emotion scores decreased −18.2 points and functioning scores dropped −14.8 points by Week 104. Though mean Skindex-16 for AA symptoms score did not improve relative to Senna, M, et al. “Long‐baseline. Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results from BRAVE ‐AA1 and BRAVE ‐AA2. September 25, 2024 ” Journal of the European Academy of Dermatology and Venereology, vol. 38, no. 3, 23 Feb. 2024, pp. 583–593, https://doi.org/10.1111/jdv.19665. Accessed 20 Mar. 2024. Confidentia Baricitinib across 104 weeks of treatment ≥50% improvements from baseline in SALT score were maintained in all patients continuously treated with baricitinib 2 mg and 98.4% of patients treated with baricitinib 4 mg. Baricitinib demonstrated a high 1 level of maintenance of efficacy over 104 weeks in patients with severe AA. increased in Week-52 mixed Efficacy responders, These results suggest that long- 2 O S O term therapy may be especially important for N N patients with extensive disease at baseline, N N as it may take longer to respond to treatment. Long-term treatment is necessary to 3 N N observe maximum benefit in some N H patients. for both patients with and without clinical response at Week 52. 3 No new safety signals were observed. Company ---. “Long‐Term Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: 104 ‐Week Results Confidential from BRAVE ‐AA1 and BRAVE ‐AA2.” © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 50 Safety profile of systemic JAK inhibitors in alopecia areata Recent systematic reviews show that the safety profile of JAK inhibitors in alopecia areata in both adults and children is good. The most common side effects of JAK inhibitors in patients with alopecia EMA recommended in 2023 that JAK areata are headache and acne. inhibitors (tofacitinib, baricitinib, The odds ratio for upper respiratory tract upadacitinib, abrocitinib, filgotinib) should infections varies from over 7-fold increased to be used in the following patients only comparable to placebo depending on the JAK if no suitable treatment alternatives inhibitor. are available: those aged 65 years or The risk of serious adverse events is not above, those at increased risk of major increased. cardiovascular problems (such as heart  Available data show that in patients with alopecia attack or stroke), those who smoke or have areata adverse effects are usually mild and transient done so for a long time in the past, and those at increased risk of cancer. and that there is no increased risk of severe adverse effects compared to placebo. L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. September 25, 2024 ” JEADV. Journal of the European Academy of Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Corporate Slides / EVA Pharma 51 Safety profile of systemic JAK inhibitors in alopecia areata Patients with alopecia areata are generally younger and healthier, without comorbidities that increase the risk of side effects, as they were observed in patients with rheumatoid arthritis in the ORAL Surveillance study. L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. September 25, 2024 ” JEADV. Journal of the European Academy of Company Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 52 Safety profile of systemic JAK inhibitors in alopecia areata An earlier recommendation by the FDA required warnings (‘black box warning’) about an increased risk for serious heart- related events, cancer, blood clots and death for JAK1 inhibitors (tofacitinib, baricitinib and upadacitinib). The above announcements were based on the results obtained in One study one disease One group of patients (50+ patients (Rheumatoid Arthritis) with cardiac risk factors) and compared to TNF inhibitors, which have a cardioprotective L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. effect. September 25, 2024 ” JEADV. Journal of the European Academy of Company Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Confidential © 2021 Eli EVA and Company Corporate Slides / EVA Pharma 53 Therapeutic strategies o Systemic JAK inhibitors are the only group of officially approved medications for alopecia areata and their efficacy and safety in this condition are well documented in several randomized, placebo-controlled, clinical trials. o This group of medications should be considered the first-choice therapeutic option in alopecia areata. o No preference in adults for either baricitinib or ritlecitinib. o In children (aged ≥12 years) ritlecitinib is currently the only EMA-approved treatment. L. Rudnicka, et al. “European Expert Consensus Statement on the Systemic Treatment of Alopecia Areata. September 25, 2024 ” JEADV. Journal of the European Academy of Dermatology and Venereology, 2 Jan. 2024, https://doi.org/10.1111/jdv.19768. Common TEAEsa in the All-BARI-AD and All-BARI-AA Populations Safety of Baricitinib Across Dermatology Indications: Atopic Dermatitis and Alopecia Areata  Common TEAEs in AD and AA largely overlapped  Differences were reported for some AEs, such as acne for AA and herpes simplex for AD a Events selected by occurrence ≥3% in the All-BARI-AD and All-BARI-AA datasets AA=alopecia areata; AD=atopic dermatitis; AE=adverse event; BARI=baricitinib; COVID-19=coronavirus disease 2019; CPK=creatine phosphokinase; IR=incidence rate; PYE=patient-years of exposure; TEAE=treatment-emergent AE; URTI=upper respiratory tract infection; UTI=urinary tract infection Company Confidential © 2021 Eli EVA and Company  Summary of key findings AA=alopecia areata; AD=atopic dermatitis; BARI=baricitinib; LTE=Long-Term Extension; PYE=patient-years of exposure World Congress of Dermatology (WCD); Singapore; 3-8 July 2023 Company Confidential © 2021 Eli EVA and Company  Summary of key findings  IRs of serious infections, MACE, VTE, and malignancies were within or below the background rates of AD and AA a Values represent the range of IRs from the PBO arms of JAK inhibitor trials for BARI and abrocitinib and 1 population-based cohort study of patients with AD; b Rates are from Korean and Taiwanese registry studies and include myocardial infarction and stroke endpoints rather than MACE AA=alopecia areata; AD=atopic dermatitis; BARI=baricitinib; DVT=deep vein thrombosis; IR=incidence rate; JAK=Janus kinase; MACE=major adverse cardiovascular event; NA=not available; NMSC=non-melanoma skin cancer; PBO=placebo; PE=pulmonary embolism; PYE=patient-years of exposure; VTE=venous thromboembolism World Congress of Dermatology (WCD); Singapore; 3-8 July 2023 Company Confidential © 2021 Eli EVA and Company How to start prescribing Baricitinib? 73 Baricitinib initiation Treatment should not be initiated in patients with: Absolute Lymphocyte Count (ALC) less than 0.5 x 109 cells/L Absolute Neutrophil Count (ANC) less than 1 x 109 cells/L, or Haemoglobin value less than 8 g/dL Treatment with Baricitinib is not recommended with: Creatinine clearance < 30 mL/min Severe hepatic impairment Live attenuated vaccines (or immediately prior to) Active DVT Pregnancy & Breast Feeding Active TB infection or any severe active infection Other biologic DMARDs or other Janus kinase (JAK) inhibitors Baricitinib EUPSC- 2024 Company Confidential © 2021 Eli EVA and Company Once-daily dosing Recommended dose 4-mg once daily 2-mg once daily Is appropriate for patients aged ≥65 years Patients at higher risk of VTE, MACE and malignancy Is recommended for patients with a creatinine clearance of 30-60 mL/min Is recommended for patients taking OAT3 inhibitors with strong inhibition potential, such as probenecid May be appropriate for patients with a history of chronic or recurrent infections May be considered for patients who have achieved sustained control of disease activity with 4-mg once daily and are eligible for dose tapering Pill is not representative of actual size OAT=organic anion transporter Company Confidential © 2021 Eli EVA and Company Baricitinib – Lab monitoring Baricitinib EUPSC- 2024 Company Confidential © 2021 Eli EVA and Company Patient Support Program Company Confidential © 2021 Eli EVA and Company Thank you 78