CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

suggesting the effect is likely attributable to changes in anti-HIV immune function. The figure, table, or graphic for this abstract has been removed. A Randomized, Adaptive Phase I Study to Determine the Phase II Dose of VIR-7832: AGILE CST5 Richard J FitzGerald 1 , Chris Edwards 2 , Jimstan Periselneris 3 , Geoff Saunders 4 , Nicky Downs 4 , Rebecca Lyon 5 , Danny Pratt 2 , Helen Reynolds 1 , Lauren Walker 1 , Gareth Griffiths 4 , Saye Khoo 1 , Thomas Fletcher 6 , for AGILE CST 5 1 University of Liverpool, Liverpool, United Kingdom, 2 NIHR Southampton Clinical Research Facility, Southampton, United Kingdom, 3 King's College Hospital NHS Foundation Trust, London, United Kingdom, 4 University of Southampton, Southampton, United Kingdom, 5 NIHR Liverpool Clinical Research Facility, Liverpool, United Kingdom, 6 Liverpool School of Tropical Medicine, Liverpool, United Kingdom Background: Despite widespread COVID-19 vaccination, anti-virals remain important for COVID-19 treatment. Early treatment is crucial to avoid progression and severe disease, with monoclonal antibodies (mAb) offering possible advantages in single dosing and duration of effect. VIR-7832 is a novel mAb derived from the same parental antibody as sotrovimab with addition of an Fc domain XX2 modification to enhance effector function and modulate immune response. Here we report data from the First-in-Human (FIH) trial of VIR-7832 in mild-moderate COVID-19 patients (AGILE CST5, NCT04746183). Methods: Participants with PCR-confirmed mild-moderate COVID-19 infection, within 7 days of onset, were randomised (3:1, double-blind) to single dose VIR-7832 or placebo. Three cohorts of 8 participants were recruited, with dose escalation in between (Cohort 1-50mg, Cohort 2-150mg, Cohort 3-500mg) supported by a Bayesian dose-toxicity model. Participants were followed to day 253 post-dose, with assessments performed for safety (laboratory samples, electrocardiograms, vital signs), VIR-7832 pharmacokinetics (PK), patient reported outcomes (FLU-PRO PLUS) and viral swabs. The primary endpoint was safety & tolerability to day 8 (AEs, SAEs and dose-limiting toxicities (DLT, defined as CTCAE >/= grade 3)) with secondary endpoint of VIR-7832 PK and exploratory endpoint of SARS-CoV-2 viral dynamics (PCR swab at day 1,3,5,8,11,15,22,29). Results: 24 individuals (8 female) were recruited. Median (range) age, BMI, number of days with Covid symptoms were 23.5 years (19-52), 22.9 Kg/m 2 (17.8-32.9), 5 days (2-7) respectively. For the primary endpoint, to day 8, 1 participant receiving 150mg VIR-7832 reported a DLT (syncope); beyond day 8, 2 more DLTs were reported in placebo group (diarrhoea, neutropenia). One SAE (dyspnoea, considered unrelated) was reported in a participant receiving 50mg VIR-7832. Skin rashes were reported by 2 participants receiving 150mg VIR-7832 (lichenoid reaction & maculopapular rash). Time to negative SARS-CoV-2 PCR in all participants in each cohort was 15 days for those receiving 50mg VIR-7832, 8 days for 150mg VIR-7832, 8 days for 500mg VIR-7832 and 22 days for placebo. Conclusion: This is the first report of the safety, tolerability and viral outcomes for VIR-7832, a novel mAb for treating SARS-CoV-2. These data suggest VIR-7832 is safe and well tolerated at doses up to 500mg. SARS-CoV-2 PCR data are presented for each cohort; however, these data are limited by the small number of participants. Gendered Inclusion in Studies Evaluating Injectable HIV Treatment and PrEP: A Scoping Review Alexa L. Elias, Isabelle Whelan, Melanie Smuk, Nuala A. Pepper, Nishat Halim, Vanessa Apea, Chloe M Orkin Queen Mary University of London, London, United Kingdom Background: Globally, 54% of people living with HIV (PLWH) are female (UNAIDS). Therapies containing long-acting injectable (LA-I) agents are included in treatment guidelines and licensed for pre-exposure prophylaxis (PrEP). In female participants, LA-I cabotegravir (CAB) is superior to oral PrEP. However, cisgender and transgender women are historically underrepresented in wider HIV research. Methods: We report an ongoing scoping review to evaluate inclusion of women (cis/trans) and non-binary people (NBP) in Phase I-III clinical trials, implementation and real-world studies evaluating any LA-I agent for HIV treatment or PrEP. We searched electronic databases (PubMed, MEDLINE, Embase) and peer reviewed abstracts excluding studies with no report of sex or gender. Statistics were descriptive. Results: We included 41 studies, 14 evaluated PrEP (34%) and 27 (66%) evaluated treatment. We included 27 clinical trials [Phase I (n=8); Phase II (n=12); Phase III (n=7)], 6 implementation and 8 real-world studies. 38 studies included sites in high-income countries and 13 included sites in low- and

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Effect of Broadly Neutralizing Antibody Exposure on HIV Rebound Following Combination Immunotherapy Amelia N Deitchman 1 , Leonid Serebryannyy 2 , Rowena Johnston 3 , Lucio Gama 2 , Marina Caskey 4 , Elena Vendrame 5 , Devi SenGupta 5 , Romas Geleziunas 5 , Jackie Reeves 6 , Christos Petropoulos 6 , Michel Nussenzweig 4 , Rachel Rutishauser 1 , Steven G. Deeks 1 , Michael J. Peluso 1 , for the UCSF-amfAR Study Team 1 University of California San Francisco, San Francisco, CA, USA, 2 National Institutes of Health, Bethesda, MD, USA, 3 amfAR, New York, NY, USA, 4 The Rockefeller University, New York, NY, USA, 5 Gilead Sciences, Inc, Foster City, CA, USA, 6 Monogram BioSciences, San Francisco, CA, USA Background: Waning broadly neutralizing antibody (bNAb) levels and emergence of resistance have been associated with viral rebound during analytic treatment interruption (ATI) studies. In this pharmacokinetic/ pharmacodynamic (PK/PD) analysis, we evaluated the impact of bNAb exposure, susceptibility, and antidrug antibody (ADA) formation on rebound kinetics following combination immunotherapy with a boosted DNA vaccine, lefitolimod, and bNAbs (10-1074 and VRC07-523LS) (NCT04357821), in which 7/10 individuals exhibited altered post-intervention rebound dynamics. Methods: We described plasma bNAb PK using population PK modeling approaches in Monolix software. We performed Spearman correlations or Wilcox's test to determine the relationship between bnAb AUC, peak concentration (C max ), and bNAb level at time of rebound and rebound kinetics (time to rebound, post ATI setpoint). We evaluated susceptibility (IC 90 ) relative to bNAb level (i.e., IQ 90 : bNAb level/IC 90 ). We performed competitive and functional ADA assays for both bNAbs. Results: Time to Rebound: Greater bNAb exposure for 10 participants (9 cis men, 1 trans woman) was associated with later rebound (VRC07-523LS AUC ρ=0.76, p=0.04; 10-1074 C max ρ =0.7, p=0.04). In those who rebounded later (>15 weeks), VRC07-523LS and 10-1074 levels were lower at the time of rebound (both p=0.01), with a similar trend observed for IQ 90 (p=0.01 and p=0.03, for each bNAb). There was no association between IC 90 and time to rebound. Post intervention setpoints: Although there was no association between VRC07-523LS IC 90 and setpoint, higher VRC07-523LS IQ 90 at the time of rebound was associated with higher post-intervention setpoint (ρ = 0.85, p=0.006). No association between 10-1074 IQ 90 or IC 90 and setpoint were observed. Antidrug antibody: While ADA was detected for two participants for competitive assays for both bNAbs, no functional ADA impacting PK was observed. Conclusion: Higher bNAb exposure (e.g., AUC, C max ) was consistently associated with delayed viral rebound. Our results suggest that post-treatment setpoint was not driven by bNAb susceptibility and that the association of IQ 90 and setpoint is driven by higher VRC07-523LS levels at the time of rebound in those who rebounded earlier and had higher setpoints. Overall, bNAb PK-PD is likely not responsible for lower observed post-treatment setpoints during this trial,

Poster Abstracts

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CROI 2024 174