Background: Leronlimab is a humanized κ-IgG4 monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). We investigated leronlimab as a treatment option for people living with multidrug-resistant HIV-1. Setting and Methods: In a phase 2b/3, multicenter, randomized, double-blind, placebo-controlled study conducted in 21 hospital centers in the United States, treatment-experienced people living with HIV (PLWH) with documented drug resistance were randomly assigned once weekly leronlimab (350 mg subcutaneously) or matching placebo for one week overlapping existing failing antiretroviral treatment (ART), followed by a 24-week single-arm extension with weekly leronlimab combined with a new optimized background treatment (OBT). The primary endpoint was achieving ≥0.5 log 10 reduction in plasma HIV-1 RNA from baseline at the end of the one-week double-blinded treatment period. Results: 52 participants were enrolled (25 leronlimab and 27 placebo). After the one-week randomized phase, by the intent-to-treat analysis 64.0% (16/25) receiving leronlimab achieved ≥0.5 log 10 reduction in plasma HIV-1 RNA versus 23.1% (6/26) receiving placebo (p=0.0032), while by per protocol analysis 72.7% (16/22) receiving leronlimab achieved ≥0.5 log 10 reduction in plasma HIV-1 RNA versus 24.0% (6/25) receiving placebo (p=0.0008). Leronlimab was generally well tolerated with no drug-related SAEs reported. Overall, 175 adverse events were reported by 34/52 participants, with 120 (68.6%) adverse events categorized as mild. Conclusions: Leronlimab resulted in significantly reduced plasma HIV-1 within one week after addition to failing ART. After 24 weeks combined with an OBT, most participants had plasma HIV-1 RNA levels <50 copies per mL plasma, suggesting utility of leronlimab as a component of salvage therapy.

Background Lenacapavir is a long-acting human immunodeficiency virus type 1 (HIV-1) capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1. Methods This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase. Results At Week 104, 44 of 71 participants (62%, 95% confidence interval [CI]: 50; 73) had HIV-1 RNA <50 copies/mL via US Food and Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/mu L (95% CI: 80; 165), and the proportion of participants with CD4 cell count <200 cells/L decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; 7 resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction. Conclusions Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.

Background Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV. Methods In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (& LE;100 000 or > 100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA < 50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594. Findings Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2middot6%, 95% CI -18middot4 to 13middot2), 85% (45 of 53) for group 2 (-7middot1%, -23middot4 to 9middot3), 85% (44 of 52) for group 3 (-7middot2%, -23middot5 to 9middot1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling). Interpretation Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs. Copyright 2022 Elsevier Ltd. All rights reserved.

Abstract Background Lenacapavir (LEN) is a highly potent, long-acting, first-in-class inhibitor of HIV-1 capsid protein for the treatment of HIV-1 infection in adults with multidrug resistance (MDR) in combination with other antiretrovirals. Methods CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced people with HIV-1 with multidrug-resistance. Participants received oral LEN for loading followed by subcutaneous LEN Q6M in addition to an investigator-selected optimized background regimen (OBR). After reporting the efficacy and safety data through 52 weeks (W), the protocol was amended to allow longer follow up; we report W104 results. Results Of 72 participants enrolled (36 in each cohort), 25% were female, 38% were Black, median age was 52 years, 64% had CD4 <200 cells/µL, and 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI). One participant (of 72) decided not to continue in the post-W52 extension. At W104, 62% (44/71) had HIV-1 RNA <50 c/mL via FDA Snapshot algorithm, and 14% (10/71) had HIV-1 RNA >50 c/mL; 24% discontinued for reasons other than lack of efficacy (13/71) or had missing data but were on study drug (4/71). When analyzed as missing=excluded, 81% (44/54) had HIV-1 RNA <50 c/mL. CD4 count increased by a median 97 cells/µL (Q1 to Q3: 18 to 224) and the proportion of participants with CD4 count ≥200 cells/µL increased from 36% (26/72) at baseline to 71% (39/55) at W104. Fourteen participants had emergent LEN resistance (9 previously reported), 6 of whom subsequently suppressed while continuing LEN. The median (Q1–Q3) duration of follow-up on LEN was 125 (111–140) weeks. One participant discontinued due to injection site nodule at W52 (Grade 1, previously reported); no participant discontinued due to an AE after W52. Most common AEs (excluding injection site reactions [ISRs] and COVID-19) were diarrhea and nausea (19% each, +5% each since W52, respectively). LEN-related ISRs were mostly mild-to-moderate. Conclusion In people with MDR HIV-1 and limited treatment options, LEN in combination with an OBR was well tolerated and maintained virologic suppression at W104. These data support the use of LEN for treatment of people with MDR HIV-1. Disclosures Onyema Ogbuagu, MD, Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Janssen: Advisor/Consultant|Viiv: Advisor/Consultant Edwin DeJesus, MD, Gilead Sciences, Inc: Advisor/Consultant|Theratechnology: Advisor/Consultant|Theratechnology: Honoraria Mezgebe Berhe, MD, MPH, Gilead Sciences, Inc: Clinical Trial Investigator Gary J Richmond, MD, Gilead Sciences, Inc: Grant/Research Support|Glaxo Smith Kline: Grant/Research Support|Insmed: Grant/Research Support|TaiMed: Grant/Research Support Peter J Ruane, MD, Gilead Sciences, Inc: Advisor/Consultant|Viiv: Advisor/Consultant|Viiv: Honoraria Gary I. Sinclair, MD, Abbvie: Grant/Research Support|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Thera: Advisor/Consultant|Thera: Grant/Research Support|Thera: Honoraria|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria Moti N Ramgopal, MD, Abbvie: Honoraria|Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|Merck: Advisor/Consultant|Viiv: Advisor/Consultant|Viiv: Honoraria William Sanchez, MD, Gilead Sciences, Inc: Grant/Research Support|GSK: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support Gordon E Crofoot, MD, Gilead Sciences, Inc: Clinical Trial Investigator Nicolas A Margot, MA, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Hui Wang, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Hadas Dvory-Sobol, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Martin Rhee, MD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences, Inc: Employee|Gilead Sciences, Inc: Stocks/Bonds Sorana Segal-Maurer, MD, Gilead Sciences, Inc: Advisor/Consultant|Gilead Sciences, Inc: Honoraria|Janssen: Advisor/Consultant|Janssen: Honoraria|Theratechnologies: Advisor/Consultant|Theratechnologies: Honoraria|Viiv: Advisor/Consultant|Viiv: Honoraria

Background Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis.Methods HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site stall, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing.Findings Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54 center dot 7 years [SD 10 center dot 4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2 center dot 3 [95% CI 1 center dot 1-4 center dot 8]; p=0 center dot 025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2 center dot 2 [1 center dot 0-5 center dot 0]; p=0 center dot 036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2 center dot 2 [95% CI 1 center dot 0-4 center dot 8]; p=0 center dot 033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1 center dot 9 [0 center dot 8-4 center dot 3]; p=0 center dot 123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastroosophageal reflux disease). No deaths occurred. Interpretation Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials.