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Long-Acting Subcutaneous Lenacapavir Dosed Every 6 Months

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Long-Acting Subcutaneous Lenacapavir Dosed Every 6 Months Long-acting Subcutaneous Lenacapavir Dosed Every 6 Months as part of a Combination Regimen in Treatment-Naïve People with HIV: Interim 16-week Results of a Randomized, Open-label, Phase 2 Induction-Maintenance Study (CALIBRATE) Samir K. Gupta,1 Mezgebe Berhe,2 Gordon Crofoot,3 James Sims,4 Paul Benson,5 Moti Ramgopal,6 William E. Sanchez,7 Peter Ruane,8 Cheryl McDonald,9 Anita Scribner,10 Hui Wang,11 Laurie VanderVeen,11 Hadas Dvory-Sobol,11 Robert H. Hyland,11 Martin S. Rhee,11 Jared M. Baeten,11 Diana M. Brainard,11 Ellen Koenig12 1Indiana University School of Medicine, Indianapolis, USA; 2North Texas Infectious Diseases Consultants, Dallas, USA; 3The Crofoot Research Center, Inc., Houston, USA; 4St. Hope Foundation, Bellaire, USA; 5Be Well Medical Center, Berkley, USA; 6Midway Specialty Care Center, Fort Pierce, USA; 7Floridian Clinical Research, Hialeah, USA; 8Ruane Clinical Research Group, Los Angeles, USA; 9Texas Centers for Infectious Disease Associates, Fort Worth, USA; 10Diagnostic Clinic of Longview Center for Clinical Research, Longview, USA; 11Gilead Sciences Inc., Foster City, USA; 12Instituto Dominicano de Estudios Virológicos, Santo Domingo, Dominican Republic Disclosures SKG receives unrestricted research grant support from the NIH, Indiana University School of Medicine, and GSK/ViiV and receives advisory board fees from Gilead Sciences, Inc., and GSK/ViiV. 2 Acknowledgments We extend our thanks to: The study participants and their families Participating study investigators and staff: Dominican Republic: E Koenig United States: P Benson; DS Berger; M Berhe; C Brinson; P Cook; DR Coulston; GE Crofoot; FA Cruickshank; D Cunningham; E DeJesus; C Dietz; V Drelichman; E Gardner; A Gaur; D Goldstein; SK Gupta; D Hagins; R Hengel; T Hodge; C-B Hsiao; A Khalsa; CA Kinder; P Kumar; C McDonald; A Mills; JO Morales-Ramirez; C Newman; G Oguchi; O Osiyemi; MN Ramgopal; PJ Ruane; W Sanchez; JL Santana-Bagur; L Santiago; A Scribner; J Sims; GI Sinclair; JL Stephens; M Wohlfeiler; AK Wurapa This study was funded by Gilead Sciences, Inc. 3 LEN Targets Multiple Stages of HIV Replication Cycle Link JO, et al. Nature 2020;584:614-8; Bester SM, et al. Science 2020;370:360-4. 4 Introduction ♦ Lenacapavir (LEN, GS-6207) is a long-acting first-in-class inhibitor of HIV-1 capsid function – In clinical development for treatment and prevention of HIV-1 infection ♦ PK of SC LEN supports its use once every 6 months1 – Reduction of daily pill burden through less frequent dosing ♦ In viremic heavily treatment-experienced PWH (CAPELLA study) with multi-drug resistance2,3 – LEN demonstrated potent antiviral activity (1.9 log decline) at Day 15 when added to a failing regimen – LEN led to high rates of viral suppression (81%) at Week 26 when combined with an optimized background regimen – LEN was well tolerated with no AEs leading to discontinuation through Week 26 – Late breaker oral presentation on Tues (20th) by Molina J-M et al3 ♦ CALIBRATE study was designed to generate clinical data that will support the future development of oral and injectable LEN-containing long-acting regimens F/TAF, emtricitabine/tenofovir alafenamide; PWH, people with HIV; SC, subcutaneous. 1. Begley R, et al. AIDS 2020, PEB0265; 2. Segal-Maurer S, et al. CROI 2021, oral 2228; 3. Molina J-M, et al. IAS 2021, A-LB-IAS2021-02605. 5 Study Design Induction Maintenance BL Wk 28 54 80 Treatment Group 1* LEN SC Q6M* n=52 F/TAF oral QD TAF oral QD† Treatment naïve N=182 Treatment Group 2* LEN SC Q6M* n=53 † Key eligibility criteria: Open label F/TAF oral QD BIC oral QD . ARV naïve Randomized ‡ . HIV-1 RNA ≥200 copies/mL Treatment Group 3 LEN oral QD . CD4+ cell count ≥200 cells/µL n=52 F/TAF oral QD Treatment Group 4§ n=25 B/F/TAF oral QD 2◦ Endpoint 1◦ Endpoint ♦ DMC recommended continuation of study, based on Week 16 results (i.e. abstract data) *LEN oral lead-in (600 mg on Days 1 and 2, 300 mg on Day 8) followed by LEN SC 927 mg on Day 15; F/TAF 200/25 mg; †Participants in TG 1 and 2 will need HIV-1 RNA results <50 copies/mL at Wks 16 and 22 to initiate either TAF 25 mg or BIC 75 mg at Wk 28; those with HIV-1 RNA ≥50 copies/mL will discontinue study at Wk 28; ‡LEN 600 mg on Days 1 and 2, followed by LEN 50 mg from Day 3; F/TAF 200/25 mg; §B/F/TAF 50/200/25 mg. ARV, antiretroviral; BIC, B, bictegravir; BL, baseline; DMC, data monitoring committee; QD, once daily; Q6M, every 6 months; TG, treatment group; Wk, Week. 6 TG 1: LEN SC + F/TAF (→TAF) Baseline Characteristics TG 2: LEN SC + F/TAF (→BIC) TG 3: LEN QD + F/TAF TG 4: B/F/TAF LEN Total B/F/TAF TG 1 TG 2 TG 3 TG 4 Overall n=52 n=53 n=52 n=25 N=182 Age, median (range), years 31 (19, 61) 28 (19, 56) 28 (19, 72) 29 (21, 61) 29 (19, 72) Sex, % female at birth 10 2 12 0 7 Race, % Black 46 45 60 64 52 Ethnicity, % Hispanic/Latinx 48 40 46 48 45 HIV-1 RNA, median log10 copies/mL 4.27 4.32 4.53 4.37 4.37 Q1, Q3 3.77, 4.63 3.96, 4.74 3.82, 4.83 4.09, 4.77 3.86, 4.74 >100,000 copies/mL, % 10 17 17 16 15 CD4 count, median cells/μL 404 450 409 482 437 Q1, Q3 320, 599 332, 599 301, 600 393, 527 332, 599 <200 cells/μL, % 0 2 6 0 2 7 TG 1: LEN SC + F/TAF (→TAF) FDA Snapshot Outcome (ITT) at Week 28 TG 2: LEN SC + F/TAF (→BIC) TG 3: LEN QD + F/TAF TG 4: B/F/TAF 100 100 94 92 94 80 60 40 Participants, % 20 4 6 4 6 0 0 0 0 0 HIV-1 RNA <50 copies/mL HIV-1 RNA ≥50 copies/mL No HIV-1 RNA Data n= 49/52 49/53 49/52 25/25 0/52 2/53* 0/52 0/25 3/52 2/53 3/52 0/25 ♦ In the pooled LEN group (receiving either SC [TG 1+2] or oral [TG 3] LEN in combination with F/TAF), 94% (147/157) achieved HIV-1 RNA <50 copies/mL at Week 28 *1 participant discontinued due to not meeting the protocol criteria of having HIV-1 RNA <50 copies/mL prior to Week 28; 1 participant discontinued on Day 2. 8 Participants with HIV-1 RNA <50 copies/mL by Visit TG 1: LEN SC + F/TAF (→TAF) TG 2: LEN SC + F/TAF (→BIC) Missing = Failure (On Treatment) TG 3: LEN QD + F/TAF TG 4: B/F/TAF 100 94% (49/52) 80 92% (49/53) 1 RNA 1RNA - TG 1 83% (43/52) 94% (49/52) TG 2 79% (42/53) 60 100% (25/25) TG 3 87% (45/52) TG 4 84% (21/25) 40 <50 <50 % copies/mL, Participants with HIV Participants 20 0 D1 1 2 4 10 16 22 28 Week 9 Confidential – Not for distribution Resistance Analysis* ♦ One participant in TG 2 had emergent resistance mutations at Week 10 Oral SC LEN AZT+3TC, F/TAF TDF, DTG 1000000 – CA: Q67H+K70R 100000 (LEN fold change=20) 10000 – RT: M184M/I ♦ 1000 Plasma LEN concentrations were HIV-1 copies/mL RNA, Emergent resistance † consistently in target range 100 mutations in CA and RT 50 copies/mL -4 0 4 8 12 16 20 24 28 Week *Resistance testing performed for participants with confirmed HIV-1 RNA ≥50 copies/mL and <1 log10 reduction from Day 1 at Week 10 or at rebound to HIV-1 ≥50 copies/mL or >1 log10 increase from nadir. †Lower bound of confidence interval above IQ of 4 based on paEC95 from MT-4 cells; 3.87 ng/mL = IQ1. 3TC, lamivudine; AZT, zidovudine; CA, HIV capsid protein; DTG, dolutegravir; IQ, inhibitory quotient; paEC95, protein-adjusted 95% effective concentration; RT, reverse transcriptase. 10 Confidential – Not for distribution Adverse Events (excluding ISRs) LEN vs B/F/TAF LEN Total B/F/TAF TG 1+2+3 TG 4 ≥5% Participants in LEN total, % n=157 n=25 Headache 11 8 Nausea 11 4 Lymphadenopathy 8 4 COVID-19 7 4 Back pain 6 8 Diarrhea 6 4 Depression 6 0 Syphilis 5 12 ♦ No SAEs related to study drug ♦ No Grade 4 AEs related to study drug ♦ Gastrointestinal AEs: SC LEN (TG 1+2) vs oral LEN (TG 3) – Nausea: 12% vs 8% – Diarrhea: 6% vs 8% ISR, injection site reaction; SAE, serious adverse event. 11 Injection Site Reactions: Incidence 100 Cumulative Median ≥10% Incidence incidence* (%) duration (days) 80 Swelling 18 10 ♦ No ISRs reported in 61% (63/103) Erythema 17 5 ♦ 83% (33/40) of ISRs were Grade 1 and Pain 16 4 resolved within days 60 Nodule 11 189 ♦ 1 Grade 3 ISR (nodule), no Grade 4 ISRs 11 143 Induration ♦ All nodules but 1 were Grade 1 40 ♦ Only 2 participants discontinued due to Participants, % AEs (both due to Grade 1 injection site induration) 20 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Week n*= 105 105 105 102 102 102 101 101 *TG 1+ 2 (i.e. those who received at least one dose of SC LEN and still on study or last study date in 2-week interval) 12 Laboratory Abnormalities LEN Total B/F/TAF TG 1+2+3 TG 4 ≥3% Participants in LEN total, % n=157 n=25 Any Grade 3 or 4 lab abnormality 17 12 Low creatinine clearance/eGFR 4 8 High creatine kinase 5 0 Nonfasting/fasting hyperglycemia* 3 0 ♦ No Grade 3 or 4 lab abnormalities were clinically relevant – No discontinuations associated with Grade 3 or 4 lab abnormalities – Alternative explanation (e.g.
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