'Impoyz Cream Final Slide Deck'.- clobetasol

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1. Topical Corticosteroids in the management of Psoriasis. The New and Evolved Clobetasol Propionate 0.025%

2. Outline Impact of psoriasis on quality of life Role of topical corticosteroids in the management of psoriasis Limitations of topical corticosteroid therapy Rationale behind developing clobetasol propionate 0.025% cream Clinical efficacy and safety of CP 0.025% cream in the management of psoriasis Key summary Formulation vehicle and its role in the safety of topical corticosteroids CP: Clobetasol propionate

3. Krueger G, et al . Arch Dermatol . 2001;137(3):280–284. 54% of patients with psoriasis were depressed. 79% of patients reported a negative impact of psoriasis on their lives. 79% 20% of psoriasis patients had contemplated suicide. 20% 54% Impact of Psoriasis on Quality of Life Survey by National Psoriasis Foundation

4. Patients with psoriasis have clinically significant prevalence of depression, anxiety and perceived stress. 1 Depression is the leading comorbidity of psoriasis. 2 The Link Between Stress and Psoriasis Cross-sectional Indian study 78.9% 76.7% Incidence of depression, anxiety and stress in psoriasis: 1 Depression Anxiety 57.6% Severe Stress Score Stress, anxiety and depression may trigger and worsen psoriasis . 3 1. Lakshmi S, et al . Indian J Psychol Med . 2015; 37(4): 434–440. 2. Depression by National Psoriasis Foundation. Available at: https://www.psoriasis.org/life-with-psoriasis/depression Accessed on: 04 June 2020. 3. Cunha Ferreira B, et al . J Clin Aesthet Dermatol . 2016; 9(6): 36–43.

5. Role of Topical Corticosteroids in the Management of Psoriasis Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. Uva L, et al . Int J Endocrinol . 2012; 2012: 561018. Cornerstone of most topical regimens for psoriasis. 1 Superpotent TCs, commonly utilized by dermatologists, demonstrate high levels of efficacy. 1 Demonstrate greater potential in clearing psoriatic plaque more effectively vs. other topical agents. 1 TCs: Topical corticosteroids

6. Global Guidelines: TCS for Psoriasis Topical corticosteroids, widely accepted as a first line topical therapy for mild psoriasis, are also used for recalcitrant lesions in more severe disease. 1 Journal of Dermatological Treatment 2019 In the treatment of psoriasis, topical therapies, such as corticosteroids , may be effective and sufficient for managing limited psoriasis. 2 2020 First-line therapy for psoriasis describes traditional topical therapies such as corticosteroids . 3 2011 For mild to moderate disease, first-line treatment involves topical corticosteroids and is considered as the cornerstone of topical treatment. 4 2017 1. Kleyn E, et al . J Dermatol Treat . 2019;30:4, 311–319. 2. Menter A, et al . J Am Acad Dermatol . 2020;82:1445–1486. 3. NICE Guideline, 2012. Available at: https://www.nice.org.uk/guidance/cg153/documents/psoriasis-nice-guideline2 Accessed on: 04 June 2020. 4. Kim W, et al . Can Fam Physician . 2017;63:278–285. TCs: Topical corticosteroids

7. Assessing the Need – Gap Current Limitations with Topical Corticosteroids

8. Limitations of TCS: Systemic Safety Profile - HPA Axis Suppression High-potency TCs have high systemic absorption and thus carry a higher risk of systemic AEs such as HPA axis suppression. 1,2 TC: Topical corticosteroids; HPA: Hypothalamic–pituitary–-adrenal; CRH: Corticotropin-releasing hormone; ACTH: Adrenocorticotropic hormone; AE: Adverse event . Decani S, et al . J Dermatol Treat. 2014;25(6):495-500. 2. Bartley P. The Australasian Journal of Dermatology. 1978;19(3):109–113. 3. Dhar S, et al . Indian J Dermatol . 2014;59(5): 460–464. Topical corticosteroids Prolonged use of TCs Use of TCs in CT Recovery Exhibit suppressive effects on hypothalamic CRH and pituitary ACTH. 3 May be associated with HPA axis suppression and adrenal insufficiency. 3 Sustained HPA suppression was observed. 3 Full recovery may take months following treatment discontinuation. 2 Topical steroid, even at lesser amount, can induce systemic adverse effects. 3

9. - CP 0.05% Can decrease morning cortisol level after a few days. 2 May cause secondary adrenal failure. 4 Even when given within maximum dose limit of 50 g/week. 3 Exists between the amount of topical clobetasol applied and HPA axis suppression. 1 At 2g/day dose Can cause HPA axis suppression Application of >50g/week Linear relationship Limitations of TCS: Clobetasol Propionate 0.05% 1. Carruthers J, et al . Br Med J . 1975; 4(5990):203–204 . 2. Kelly A, et al . BMJ . 1972;14:114. 3. Pels R, et al . Drugs Today ( Barc ) . 2008;44(7):547–557. 4. Ohman E, et al . J R Soc Med . 1987; 80(7): 422–424. HPA: Hypothalamus–pituitary–adrenal.

10. Cutaneous Adverse Events Uva L, et al . Int J Endocrinol . 2012; 2012: 561018. Senyigit T, et al . Available at: https://www.intechopen.com/books/glucocorticoids-new-recognition-of-our-familiar-friend/corticosteroids-for-skin-delivery-challenges-and-new-formulation-opportunities Accessed on: 03 June 2020. TCs: Topical corticosteroids; AEs: Adverse events. Adapted from : Int J Endocrinol . 2012; 2012: 561018. Atrophy, allergic contact dermatitis, delayed wound healing, rosacea, erythema, telangiectasia, hypertrichosis. 1,2 Erythema and telangiectasia together with skin atrophy may lead to permanent rubeosis steroidica. 1

11. Limitations of TCS: Risk Factors TCs: Topical corticosteroids; AEs: Adverse events; PG: Propylene glycol. Dhar S, et al. Indian J Dermatol . 2014; 59(5): 460–464. Available from Senyigit T, et al. https://www.intechopen.com/books/glucocorticoids-new-recognition-of-our-familiar-friend/corticosteroids-for-skin-delivery-challenges-and-new-formulation-opportunities Accessed on 10 June 2020. Any novel TCS formulation offering advantages based on these factors, would be more beneficial. 2 Potency Strength/Amount Vehicle The higher the potency, the increased the chance of systemic side effects. 1 Solvents such as Propylene Glycol results in increased permeability after prolonged use. 1 Absorption is directly proportional to the amount of drug applied to the skin. 1

12. Need - Gap Can we have a better option that retains the efficacy but ensures better safety? Can we have a different formulation approach that may improve the risk–benefit ratio?

13. Therapeutic Rationale for HALF concentration clobetasol propionate 0.025%

14. Rationale Behind Reduced Concentration Approach Safety profile disadvantages of Conventional CP 0.05%: 1 Robust Clinical development: 9 clinical studies globally More than 1100 patients Similar efficacy as CP 0.05% Better systemic safety profile Rationale: To improved safety profile without compromising efficacy. Half the strength of Conventional CP 0.05% - NOVEL CP 0.025% formulation 1. Draelos Z, et al . Skin . 2018;2(6): 410–420. TCs: Topical corticosteroids; HPA: Hypothalamic–pituitary–adrenal; AEs: Adverse events; CP: Clobetasol.

15. Clobetasol Propionate Cream 0.025% Similar efficacy as conventional CP 0.05% Superior safety profile

16. Robust clinical development process A multi - center, multi – nation clinical study drug development process comprising of 9 clinical trials involving 1144 patients

17. Investigator's Global Assessment (IGA) scoring for TCS clinical studies IGA is the most valued endpoint for the USFDA for almost all dermatological study indications, including acne and eczema. The IGA is typically the primary endpoint for topical psoriasis treatments. For a treatment to be considered successful, the affected area must receive a score of 0 or 1 and experience a two-point improvement from baseline. Journal of Dermatological Treatment, 26:1, 23-31

18. Clinical Efficacy of CP 0.05% vs. CP 0.025% in Patients With Psoriasis Draelos Z, et al . Skin . 2018;2(6): 410–420. CP: Clobetasol propionate; IGA: Investigator Global Assessment. % of patients Baseline IGA scores

19. Similar efficacy of CP 0.025% compared with conventional CP 0.05% Draelos Z, et al . Skin . 2018;2(6): 410–420. CP: Clobetasol propionate; IGA: Investigator Global Assessment. Based on IGA score, the efficacy results were similar between both the groups. % of patients IGA scores Day 15 of treatment 50% of the subjects in each treatment group had an IGA score of 2 (mild). 16.7% of subjects in the CP 0.025% and 18.1% in the CP 0.05% group had an IGA score of 0 or 1. Similar Efficacy

20. Superior Systemic Safety Profile: HPA Axis Suppression (1/2) Lower proportion in the CP 0.025% group showed TEAEs, i.e., HPA axis suppression than the CP 0.05% group. Draelos Z, et al . Skin . 2018;2(6): 410–420. HPA: Hypothalamus-pituitary-adrenal; ACTH: Adrenocorticotropic hormone; TEAEs: Treatment-emergent adverse events. Superior Systemic Safety profile compared to CP 0.05% CP 0.025% group demonstrated 3-fold lower proportion of subjects with abnormal ACTH stimulation test, indicative of HPA axis suppression. Percentage of study participants with abnormal ACTH test at day 15

21. Superior Systemic Safety Profile: HPA Axis Suppression (2/2) CP 0.025% group demonstrated ~2-fold lower percentage reduction in serum DHEA concentration on day 15 vs. CP 0.05% group. Lower proportion in the CP 0.025% group showed decreased DHEA vs. CP 0.05% group. Draelos Z, et al . Skin . 2018;2(6): 410–420. HPA: Hypothalamus-pituitary-adrenal; DHEA: Dehydroepiandrosterone; TEAEs: Treatment-emergent adverse events. Percent reduction in serum DHEAs concentration at day 15 Superior Systemic Safety profile compared to CP 0.05%

22. >2.5x Mean post-treatment plasma concentrations of clobetasol propionate (pg/mL) Mean CP concentration(pg/mL) Superior Systemic Safety Profile: Mean Plasma Concentration of CP p=0.014 The CP 0.025% group demonstrated >2.5 fold lower mean post-treatment CP plasma concentrations vs. CP 0.05% cream group (p=0.014). Lower Systemic Absorption Draelos Z, et al . Skin . 2018;2(6): 410–420. CP: Clobetasol propionate. Superior Systemic Safety profile compared to CP 0.05%

23. Two separately performed, identically designed, randomized, double-blind, vehicle-controlled, parallel group, phase III trials. 532 adult patients (mean age: 49.6 years old) with moderate-to–severe plaque psoriasis (IGA score 3 or 4 at baseline) Clinical diagnosis of stable (at least 3 months) plaque-type psoriasis BSA - 3% or more of the body surface area, not including the face, scalp, groin, axillae, and other intertriginous areas Randomization Efficacy assessment Percent of subjects achieving Clear (IGA score rating of 0) or Almost clear (IGA score 1) More than a two-grade improvement from baseline was considered as efficacy. Safety assessment Skin tolerability Safety Study Design Clobetasol propionate 0.025% cream N=354 Vehicle N =178 Twice-daily application for 14 days Intervention and Duration Parameters Evaluated Phase III Trials – Design, Duration and End points Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. CP: Clobetasol propionate; IGA: Investigator Global Assessment; BSA: Body surface area.

24. Primary efficacy endpoint results for CP 0.025% cream vs. vehicle cream twice daily for 14 days in adults with moderate-to–severe plaque psoriasis At day 15, a significantly higher proportion of patients in CP 0.025% group achieved endpoint success vs. vehicle group in both the phase III trials. Phase III Trials: Efficacy Results Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. CP: Clobetasol propionate.

25. Phase III Local Safety Results: Adverse Events (<1.2%) CP 0.025% (n=178) Vehicle (n=89) At Least One AE 24 (13.5%) 17 (19.1%) Administrative Site Conditions 17 (9.6%) 16 (18.0%) Application Site Atrophy 2 (1.1%) 0 (0.0%) Application Site Discoloration 3 (1.7%) 2 (2.2%) Application Site Fissure 2 (1.1%) 3 (3.4%) Application Site Pain 8 (4.5%) 7 (7.9%) Application Site Pruritus 5 (2.8%) 8 (9.0%) Application Site Telangiectasia 2 (1.1%) 0 (0.0%) Infections and Infestations 2 (1.1%) 0 (0.0%) Treatment emergent adverse events were comparable in both treatment Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29.

26. Individual Patient Outcome in the Phase III Trial (1/2) A 53-year–old woman with plaque psoriasis demonstrated progressive clinical improvement following 14 days of active treatment with CP 0.025% cream. The Investigator Global Assessment scale improved by 1 point. Baseline; IGA: 3; BSA: 3% Day 3; IGA: 3 Day 10; IGA: 2 Day 15; IGA: 2; BSA: 3% Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. CP: Clobetasol propionate; IGA: Investigator Global Assessment; BSA: Body surface area.

27. Baseline; IGA: 3; BSA: 5% Day 3; IGA: 3 Day 9; IGA: 2 Day 13; IGA: 2; BSA: 5% A 26-year–old woman with plaque psoriasis on the right elbow demonstrated progressive clinical improvement following 14 days of active treatment with CP 0.025% cream. The Investigator Global Assessment score improved by 1 point. Individual Patient Outcome in the Phase III Trial (2/2) Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. CP: Clobetasol propionate; IGA: Investigator Global Assessment; BSA: Body surface area.

28. Patient Outcome in Real World Experience (1/2) Baseline Post-treatment Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. CP: Clobetasol propionate; IGA: Investigator Global Assessment; BSA: Body surface area. A 47-year–old man with plaque psoriasis on the left forearm demonstrated clearance of psoriatic lesion following 14 days of active treatment with CP 0.025% cream.

29. Patient Outcome in Real World Experience (2/2) 14-day therapy of CP 0.025% cream demonstrated clearance of psoriatic lesion in a 49-year–old man with plaque psoriasis on the left elbow. Del Rosso J. J Clin Aesthet Dermatol . 2020;13(2):22–29. CP: Clobetasol propionate. Baseline Post-treatment 14-day therapy of CP 0.025% cream demonstrated clearance of psoriatic lesion in a 49-year–old man with plaque psoriasis on the left elbow.

30. Clobetasol Propionate 0.025% Patented Formulation Technology and Its Role in Efficacy and Safety

31. Conventional CP 0.05% formulations: Propylene Glycol Data on file. PG: Propylene glycol; CP: Clobetasol propionate. * Chlorocresoll , Wax, Cetostearyl alcohol, PEG100 Stearate, glyceryl monostearate. Upon application, excipients* partition into the skin PG and clobetasol partitions into skin. 1 2 3 PG moves through the water channel of the lipid bilayer 4 PG enhances skin permeability of CP and pulls a large amount of CP. 5 Thus, a high quantity of CP is available for systemic absorption Formulation partitioning of CP 0.05% cream formulation Propylene glycol pulls a substantial amount of clobetasol through the skin into systemic circulation.

32. PARTITION DIFFUSION ABSORPTION Clobetasol 0.025% Vehicle Stage 1: Partition Clobetasol gets separated from the vehicle when it touches SC. Permeation Enhancer 2: Both lipophilic & Hydrophilic nature Permeation Enhancer 1 Stage 2.1: Diffusion Permeation enhancer 1 disrupts the lipid layer and creates void (space) for clobetasol and permeation enhancer 2 in the lipid layer. Stage 2.2: Diffusion Permeation enhancer 2 carries & holds clobetasol in the void created by permeation enhancer 1. This restricts the motion of clobetasol & allows more clobetasol to be available at the site of action. Stage 3: Absorption Very less proportion of clobetasol gets absorbed into the dermal blood supply. Novel Formulation of CP 0.025%: Novel Vehicles SC: Stratum corneum; CP: Clobetasol propionate. * Chlorocresoll , Wax, Cetostearyl alcohol, PEG100 Stearate, glyceryl monostearate. Data on file.

33. What Makes CP 0.025% Formulation Unique? Partitioning due to PG leads to faster penetration of clobetasol in the blood supply due to low lipophilic binding property of PG. More systemic absorption of CP due to faster passage through the layers. CP 0.05% Cream Formulation Superior partitioning with vehicle formulation that presents both hydrophilic and lipophilic properties; hence, clobetasol is available at the site of action with slower penetration. Less systemic absorption of CP due to delayed passage of clobetasol through the layers. CP 0.025% Cream Formulation Osborne D , et al. AAPS PharmSciTech . 2018;19(8):3512–3533. 2. Data on file. Adapted from: Osborne D , et al. AAPS PharmSciTech . 2018;19(8):3512–3533. Novel Permeation Enhancers in 0.025% CP formulation: Better permeation, increases cutaneous clobetasol propionate retention under the skin and enable delayed passage through the layers  thereby lower amounts are absorbed into systemic circulation. PG: Propylene glycol; CP: Clobetasol propionate.

34. Regulatory Status and Approved Indication of CP 0.025% Cream 2017 Approved by US FDA 1 Approved by India DCGI 2 2019 CP: Clobetasol propionate; US FDA: United States Food and Drug Administration; DCGI: Drug controller general of India. US FDA . Available at : https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209483Orig1s000TOC.cfm Accessed on: 17 June 2020. List of drugs approved from SND Division from 01.01.2019 to 31.12.2019. Available at: file:///C:/Users/Bipasha/Downloads/16.%20December2019sndee.pdf Accessed on: 17 June 2020.

35. Usage Recommendations INDICATIONS AND USAGE CP 0.025% Cream is indicated for the treatment of moderate to severe plaque psoriasis in patients 18 years of age and older. DOSAGE AND ADMINISTRATION Apply a thin layer of CP 0.025% Cream to the affected skin areas twice daily and rub in gently and completely. Use CP 0.025% Cream for up to 2 consecutive weeks of treatment. Treatment beyond 2 consecutive weeks is not recommended Instruct patients to avoid bandaging, wrapping or otherwise occluding the treatment area(s), unless directed by physician. Advise patients to avoid use on the face, scalp, groin, or axillae For external use only. Patients should wash their hands after applying the medication

36. Summary: When Half Serves the Purpose Novel vehicles in 0.025% CP formulation: Better permeation, increases cutaneous clobetasol propionate retention under the skin and enable delayed passage through the layers  thereby lowers the amounts of CP absorbed into systemic circulation. CP 0.025% is considered high potency Based on IGA score, similar efficacy was seen at day -8 and day -15 as compared with conventional CP 0.05% Local AEs were comparable with control Superior Systemic Safety Profile compared with CP 0.05% arm : 3 fold reduction in percentage of participants with abnormal ACTH test at day 15 2 fold reduction in percentage of participants with low serum DHEAs concentration at day 15 2.5 fold reduction in percentage of participants with mean higher post-treatment plasma concentrations of clobetasol propionate ( pg /mL)

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