Secukinumab in Moderate to Severe Hidradenitis Suppurativa: Primary Endpoint Analysis From the SUNSHINE and SUNRISE Phase 3 Trials Alexa B. Kimball,1 Afsaneh Alavi,2 Gregor B.E. Jemec,3 Alice Gottlieb,4 Xiaoling Wei,5 Magdalena B. Wozniak,6 Lorenz Uhlmann,7 Angela Llobet Martinez,7 Deborah Keefe,8 Ruvie Martin,8 Li Chen,8 Elisa Muscianisi8 1Harvard Medical School and Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Department of Dermatology, Mayo Clinic, Rochester, MN, USA; 3Department of Dermatology, Zeeland University Hospital, Health Sciences Faculty, University of Copenhagen, Roskilde, Denmark; 4Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 5Novartis Pharma Shanghai, China; 6Novartis Ireland Limited, Dublin, Ireland; 7Novartis Pharma AG, Basel, Switzerland; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA SYNOPSIS • Hidradenitis suppurativa (HS) is a chronic autoinflammatory keratinization disease of the skin involving the hair follicle characterized by nodules, abscesses and draining tunnels1 • HS is characterized by high patient burden and a recognized need for novel therapeutic options2 • The IL-17 pathway has been implicated as a key orchestrator of inflammation in HS3 • The SUNSHINE and SUNRISE studies investigated the efficacy and safety of secukinumab, an anti-IL-17A agent, in the treatment of moderate to severe HS OBJECTIVE • To describe the primary endpoint analysis (Week 16) results from SUNSHINE (NCT03713619) and SUNRISE (NCT03713632), two double-blind, identical, Phase 3 randomised controlled trials of secukinumab in patients with moderate to severe HS METHODS Study Design • SUNSHINE and SUNRISE were two randomised, double-blind, multicentre studies assessing short (16 weeks) and long-term (up to 1 year) efficacy, safety, and tolerability of two subcutaneous (s.c.) SEC dose regimens in adult patients with moderate to severe HS • A total of 1084 patients (mean age 36.2, 56.3% female) across 219 sites worldwide were randomized in SUNSHINE (n=541) and SUNRISE (n=543) • In each study, adult patients with moderate to severe HS were randomly assigned in a 1:1:1 fashion to receive s.c. secukinumab 300 mg every 2 (SECQ2W) or 4 weeks (SECQ4W), or placebo (Figure 1) Figure 1. Sunshine and Sunrise Study Design 1: 1: 1 al lo ca tio n 30 0m g Q 2W :3 00 m g Q 4W :P la ce bo Primary endpoint analysis Screening Treatment period 1 Week -4 BSL Week 4 8 12 16 SECQ4W SECQ2W PBO Treatment allocation SEC s.c PBO s.c SEC Induction phase Treatment period 2 20 24 28 32 36 40 44 48 52 60 F8 EOT2EOT1 SECQ4W SECQ2W SECQ4W SECQ2W 1:1 Follow-up Eligible patients will enter extension study (NCT04179175) BSL, baseline; EOT1/EOT2: end of treatment period 1/2; F8, end of 8-week follow-up period; PBO, placebo; PRO, patient-reported outcome; Q2W, every two weeks; Q4W, every four weeks; s.c., subcutaneous; SEC, secukinumab 300 mg. Endpoints/assessments • Primary endpoint (week 16): To demonstrate superiority of secukinumab versus placebo based on HiSCR (defined as at least a 50% decrease in AN count with no increase in the number of abscesses and/or in the number of draining fistulae relative to baseline). • Secondary endpoints (Week 16): Percentage change in AN count from baseline, flares, and achievement of NRS30 among patients with a baseline skin pain NRS ≥3 (defined as at least a 30% reduction and at least a 2-unit reduction in baseline patient’s global assessment of skin pain at worst) • Exploratory objectives: To evaluate long-term safety, efficacy, and tolerability of secukinumab and its effect on patient reported outcomes (PROs) and biomarkers RESULTS Patient demographics and baseline characteristics • N=541 (SUNSHINE) and N=543 (SUNRISE) randomized; 509 (94.1%) and 506 (93.2%) patients completed Treatment Period 1 (Week 16), respectively • Discontinuation rate of treatment up to Week 16 was very low and balanced despite COVID-19 pandemic (Table 1) Table 1. SUNSHINE and SUNRISE: Patient Disposition Disposition/ reason, n (%) SUNSHINE SUNRISE SECQ2W N=181 SECQ4W N=180 Placebo N=180 Total N=541 SECQ2W N=180 SECQ4W N=180 Placebo N=183 Total N=543 Completed Week 16 168 (92.8) 169 (93.9) 172 (95.6) 509 (94.1) 170 (94.4) 169 (93.9) 167 (91.3) 506 (93.2) Discontinued treatment 13 (7.2) 11 (6.1) 8 (4.4) 32 (5.9) 10 (5.6) 11 (6.1) 16 (8.7) 37 (6.8) Primary reason for discontinuing treatment up to Week 16 Patient decision 4 (2.2) 9 (5.0) 5 (2.8) 18 (3.3) 6 (3.3) 6 (3.3) 8 (4.4) 20 (3.7) Adverse event 4 (2.2) 0 (0.0) 1 (0.6) 5 (0.9) 1 (0.6) 4 (2.2) 4 (2.2) 9 (1.7) Other* 5 (2.8) 2 (1.2) 2 (1.2) 9 (1.7) 3 (1.7) 1 (0.6) 4 (2.2) 8 (1.5) *Other includes the following reasons: lost to follow-up, physician decision, technical problems, lack of efficacy and pregnancy. COVID-19, coronavirus disease 2019; N, number of patients in group; n, number of patients with characteristic; Q2W, every two weeks; Q4W, every four weeks; SEC, secukinumab 300 mg. • 59% of participants were categorized as Hurley stage II and 37% as Hurley stage III (Table 2) • About one quarter of participants had received previous systemic biologic therapy (mostly anti-TNFs) Efficacy: Primary endpoints • The primary endpoint was met in both the SUNSHINE and SUNRISE studies • Greater response rates for secukinumab compared to placebo were seen at all time-points from Week 2 to Week 16, with a rapid onset of action by Week 2 (Figure 2) Table 2. SUNSHINE and SUNRISE Results: Baseline Characteristics Characteristic SUNSHINE SUNRISE SECQ2W N=181 SECQ4W N=180 Placebo N=180 Total N=541 SECQ2W N=180 SECQ4W N=180 Placebo N=183 Total N=543 Age group in years, n (%) <30 58 (32.0) 69 (38.3) 51 (28.3) 178 (32.9) 52 (28.9) 60 (33.3) 57 (31.1) 169 (31.1) 30‒<40 56 (30.9) 45 (25.0) 70 (38.9) 171 (31.6) 48 (26.7) 61 (33.9) 65 (35.5) 174 (32.0) 40‒<65 64 (35.4) 63 (35.0) 58 (32.2) 185 (34.2) 77 (42.8) 57 (31.7) 59 (32.2) 193 (35.5) ≥65 3 (1.7) 3 (1.7) 1 (0.6) 7 (1.3) 3 (1.7) 2 (1.1) 2 (1.1) 7 (1.3) Sex, n (%) Female 102 (56.4) 100 (55.6) 102 (56.7) 304 (56.2) 98 (54.4) 103 (57.2) 105 (57.4) 306 (56.4) Weight groups (kg), n (%) ≥90 99 (54.7) 100 (55.6) 97 (53.9) 296 (54.7) 94 (52.2) 91 (50.6) 91 (49.7) 276 (50.8) Time since diagnosis of HS, mean±SD Years 7.4±7.98 6.6±6.73 7.5±7.00 7.1±7.25 7.1±7.04 8.2±8.42 7.0±6.65 7.4±7.41 Baseline Hurley stage, n (%) II 104 (57.5) 107 (59.4) 121 (67.2) 332 (61.4) 92 (51.1) 106 (58.9) 110 (60.1) 308 (56.7) III 70 (38.7) 63 (35.0) 51 (28.3) 184 (34.0) 82 (45.6) 68 (37.8) 70 (38.3) 220 (40.5) Previous exposure to systemic biologic therapy, n (%) Yes 44 (24.3) 39 (21.7) 46 (25.6) 129 (23.8) 36 (20.0) 42 (23.3) 48 (26.2) 126 (23.2) Current systemic antibiotic use (i.e., antibiotic strata), n (%) Yes 26 (14.4) 25 (13.9) 18 (10.0) 69 (12.8) 18 (10.0) 21 (11.7) 19 (10.4) 58 (10.7) HS, hidradenitis suppurativa; N, number of patients in group; n, number of patients with characteristic; Q2W, every two weeks; Q4W, every four weeks; SD, standard deviation; SEC, secukinumab 300 mg. Figure 2. Primary Efficacy Endpoint: HiSCR up to Week 16 SUNSHINE SUNRISE SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 45.0% (p=0.0070) 41.8% (p=0.0418) 33.7% SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 42.3% (p=0.0149) 46.1% (p=0.0022) 31.2% 45.0 41.8 33.7 0 10 20 30 40 50 60 0 2 4 6 8 10 12 14 16 H iS C R r es po nd er s (% ) Week SECQ2W (N=181) SECQ4W (N=180) Placebo (N=180) SECQ2W (N=180) SECQ4W (N=180) Placebo (N=183) 42.3 46.1 31.2 0 10 20 30 40 50 60 0 2 4 6 8 10 12 14 16 H iS C R r es po nd er s (% ) Week End of induction phase End of induction phase One-sided nominal p-values are based on a logistic regression model, the primary estimand, and multiple imputation. Error bars represent 95% CI. Green represents statistical significance and red represents non-significance compared with placebo. CI, confidence intervals; HiSCR, hidradenitis suppurativa clinical response; N, number of patients in group; Q2W, every two weeks; Q4W, every four weeks; SEC, secukinumab 300 mg; Wk, week. Efficacy: Secondary endpoints • In both studies, secukinumab reduced the abscess and inflammatory nodule count in patients with moderate to severe HS (Figure 3) – A decrease in AN count with secukinumab appeared as early as Week 2, and further improved up to Week 16 in both studies Figure 3. Percent change From Baseline in AN Count End of induction phase End of induction phase -46.8 -42.4 -24.3 ˗60 ˗50 ˗40 ˗30 ˗20 ˗10 0 0 2 4 6 8 10 12 14 16 C ha ng e fr om B as el in e (% ) i n A N c ou nt SUNSHINE SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 -46.8% (p<0.0001) -42.4% (p=0.0004) -24.3% Week SECQ2W (N=181) SECQ4W (N=180) Placebo (N=180) -39.3 -45.5 -22.4 ˗60 ˗50 ˗40 ˗30 ˗20 ˗10 0 0 2 4 6 8 10 12 14 16 C ha ng e fr om B as el in e (% ) i n A N c ou nt SUNRISE SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 -39.3% (p=0.0051) -45.5 % (p=0.0001) -22.4% SECQ2W (N=180) SECQ4W (N=180) Placebo (N=183) Week One-sided nominal p-values are based on an ANCOVA, the secondary estimand, and multiple imputation. Error bars represent SE. Green represents statistical significance and red represents non-significance compared with placebo. AN, abscess and inflammatory nodule; ANCOVA, analysis of covariance; HS, hidradenitis suppurativa; N, number of patients in group; Q2W, every two weeks; Q4W, every four weeks; SE, standard error; SEC, secukinumab 300 mg; Wk, week. • The proportion of patients experiencing flares was lower with secukinumab compared to placebo at all timepoints from Week 2 to Week 16, with a rapid onset of action starting at Week 2 in both studies (Figure 4) Figure 4. Proportion of Patients Experiencing Flares (%)* End of induction phase End of induction phase 15.4 23.2 29.0 0 10 20 30 40 0 0 10 20 30 40 2 4 6 8 10 12 14 16 20 4 6 8 10 12 14 16 P ro po rt io n of p at ie nt s ex pe ri en ci ng fl ar es (% ) P ro po rt io n of p at ie nt s ex pe ri en ci ng fl ar es (% ) 20.1 15.6 27.0 SUNSHINE SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 15.4% (p=0.0010) 23.2% (p=0.0926) 29.0% SECQ2W (N=181) SECQ4W (N=180) Placebo (N=180) SUNRISE SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 20.1% (p=0.0732) 15.6% (p=0.0049) 27.0% SECQ2W (N=180) SECQ4W (N=180) Placebo (N=183) *Flares are defined as as at least a 25% increase in AN count with a minimum increase of 2 AN relative to baseline. One-sided nominal p-values are based on a logistic regression model, the secondary estimand, and multiple imputation. Error bars represent 95% CI. Green represents statistical significance and red represents non-significance compared with placebo. AN, abscess and inflammatory nodule; CI, confidence intervals; HS, hidradenitis suppurativa; N, number of patients in group; Q2W, every two weeks; Q4W, every four weeks; SEC, secukinumab 300 mg; Wk, week. Scan to download a copy of this poster To download a copy of this poster, visit the web at: http://novartis.medicalcongressposters.com/Default.aspx?doc=2cf04 Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without written permission of the authors • Secukinumab reduced skin pain in patients with moderate to severe HS (Figure 5) – NRS30 was defined as ≥30% reduction and a ≥2-unit reduction from baseline in Patient’s Global Assessment of Skin Pain. Only patients with a baseline NRS≥3 were included in the analysis of skin pain – Pooled CRP levels demonstrate numerical reductions from placebo group • A larger treatment effect was achieved with secukinumab compared with the placebo regimen as early as Week 4 and sustained up to Week 16 Figure 5. Patients’ Reduction in Pain End of induction phase End of induction phase38.9 35.8 26.9 0 10 20 30 40 50 60 0 2 4 6 8 10 12 14 16P at ie nt s ac hi ev in g N R S 30 (% ) Week 12.8 11.5 14.7 0 5 10 15 20 25 0 2 4 6 8 10 12 14 16 C R P (m g/ L) Week SUNSHINE and SUNRISE NRS30 (pooled) SUNSHINE and SUNRISE CRP (pooled) SECQ2W Wk 16 SECQ4W Wk 16 Placebo Wk 16 38.9% (p=0.0031) 35.8% (p=0.0249) 26.9% SECQ2W (N=233) SECQ4W (N=222) Placebo (N=230) SECQ2W (N=361) SECQ4W (N=360) Placebo (N=363) One-sided nominal p-values are based on a logistic regression model, the secondary estimand, and multiple imputation. Error bars represent 95% CI (NRS30) or SE (CRP). Green represents statistical significance and red represents non-significance compared with placebo. CI, confidence intervals; CRP, C-reactive protein; HS, hidradenitis suppurativa; N, number of patients in group; NRS, numerical rating score; Q2W, every two weeks; Q4W, every four weeks; SE, standard error; SEC, secukinumab 300 mg; Wk, week. Safety • Secukinumab was well tolerated, consistent with the known safety profile in other approved indications (Table 3) Table 3. Summary of Secukinumab Safety Through Week 16 Outcome, n (%) SUNSHINE SUNRISE SECQ2W N=181 SECQ4W N=180 Placebo N=180 SECQ2W N=180 SECQ4W N=180 Placebo N=183 Safety overview Any AEs 122 (67.4) 118 (65.6) 120 (66.7) 113 (62.8) 114 (63.3) 116 (63.4) All non-fatal SAEs 3 (1.7) 3 (1.7) 6 (3.3) 6 (3.3) 6 (3.3) 5 (2.7) Deaths 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Discontinued study treatment due to AEs 5 (2.8) 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.2) 4 (2.2) AEs of special interest Infections and infestations (SOC) 59 (32.6) 51 (28.3) 53 (29.4) 52 (28.9) 59 (32.8) 62 (33.9) URTI (HLT) 33 (18.2) 26 (14.4) 22 (12.2) 27 (15.0) 21 (11.7) 29 (15.8) Fungal infectious disorders (HLGT) 12 (6.6) 1 (0.6) 7 (3.9) 7 (3.9) 13 (7.2) 3 (1.6) Candida infections (HLT) 2 (1.1) 1 (0.6) 4 (2.2) 5 (2.8) 5 (2.8) 2 (1.1) Hypersensitivity (SMQ, narrow) 12 (6.6) 9 (5.0) 9 (5.0) 7 (3.9) 5 (2.8) 7 (3.8) Malignant or unspecified tumours* (SMQ) 0 (0.0) 0 (0.0) 1 (0.6) 0 (0.0) 1 (0.6) 1 (0.5) MACE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) IBD† 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.6) 1 (0.6) 0 (0.0) *Excludes non-melanoma skin cancers; †one case of IBD and one case of ulcerative colitis was reported. AE, adverse event; AESI, adverse event of special interest; HLGT, high-level group terms; HLT, high-level term; IBD, inflammatory bowel disease; MACE, major adverse cardiovascular events; MedDRA, medical dictionary for regulatory activities; n, number of patients with outcome; N, number of patients in group; Q2W, every two weeks; Q4W, every four weeks; SAE, serious adverse event; SEC, secukinumab; SMQ, standardised MedDRA queries; SOC, system organ class; URTI, upper respiratory tract infection. CONCLUSIONS • The SUNSHINE and SUNRISE Phase 3 trials both met their primary endpoint (HiSCR) demonstrating superiority of secukinumab over placebo with rapid symptom relief in patients with moderate to severe HS • Secukinumab achieved the majority of its secondary endpoints of AN count, flares and pain while demonstrating positive numeric trends in safety and efficacy in DLQI and CRP • Secukinumab was well tolerated in patients with moderate to severe HS, consistent with the known favorable safety profile in other approved indications REFERENCES 1. Frew J. JAAD Int. 2020;1(1):62-72. 2. Ingram JR, et al. Eur Acad Dermatol Venereol. 2022;36(9):1597-1605. 3. Zouboulis CC, et al. Exp Dermatol. 2021;30(Suppl 1):8-17. FINANCIAL DISCLOSURES ABK is a consultant and investigator for Abbvie, Bristol Meyers Squibb, Janssen, Eli Lilly, Novartis, Pfizer, and UCB; investigator for Incyte and AnaptysBio; consultant for Bayer, Boehringer Ingelheim, Ventyx, Moonlake, Lilly, Concert, EvoImmune, Sonoma Bio, Sanofi, receives fellowship funding from Janssen; and serves on the Board of Directors for Almirall. AA has received honoraria as a consultant or advisory board participant from AbbVie, Janssen, Novartis, Boehringer-Ingelheim, InflaRx, and UCB and is an investigator for Processa and Boehringer-Ingelheim. GBEJ has served as a consultant for AbbVie, Coloplast, Leo Pharma, Novartis, UCB, and InflaRX; as an investigator for AbbVie, Leo Pharma, Novartis, Regeneron, UCB, and InflaRX; has received unrestricted grants from AbbVie, Leo Pharma, and Novartis; has served on Adboards for AbbVie, Janssen-Pharma, MSD, and Novartis; and as a speaker for AbbVie, Coloplast, Leo Pharma, and Galderma. AG has received honoraria as an advisory board member, non-promotional speaker or consultant for: Amgen, AnaptysBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, Sun Pharmaceutical Industries, UCB, and Xbiotech (stock options for an RA project). AG has also received research/educational grants from: AnaptysBio, Janssen, Novartis, Ortho Dermatologics, Sun Pharmaceutical Industries, Bristol-Myers Squibb and UCB; all funds go to Icahn School of Medicine at Mount Sinai. XW is an employee at Novartis Pharma Shanghai, China. MBW is an employee and stockholder at Novartis Ireland Limited, Dublin. LU, and ALM are employees and stockholders at Novartis Pharma AG, Basel, Switzerland. DK, RM, LC, and EM are employees and stockholders at Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. ACKNOWLEDGEMENTS All authors participated in the development of poster for the presentation. The authors thank Swati Shrivastava and Nivedita Jangale of Novartis Healthcare Pvt Ltd, Hyderabad for editorial and medical writing support, which was funded by Novartis Pharma AG, Basel, Switzerland in accordance with the Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) This investigation was sponsored by Novartis Pharma AG, Basel, Switzerland. Originally presented as an oral presentation at the 31st EADV Congress, September 7−10, 2022; Milan Italy. Poster presented at: Winter Clinical Dermatology Conference, January 13 - 18, 2023, Hawaii