First-in-human evaluation of safety and pharmacokinetics of intravenous or subcutaneous infusions of PGT121.141.LS, an anti-V3 HIV-1 broadly neutralizing antibody in healthy volunteers without HIV

Title

First-in-human evaluation of safety and pharmacokinetics of intravenous or subcutaneous infusions of PGT121.141.LS, an anti-V3 HIV-1 broadly neutralizing antibody in healthy volunteers without HIV

Presenter

Srilatha Edupuganti

Authors

S. Edupuganti * (1), C. Hurt (2), K. Stephenson (3), Y. Huang (4), C. Paez (4), T. Gamble (5), C. Yu (4), C. Yen (6), S. Regenold (6), W. Chege (6), R.J. Landovitz (7), K.H. Mayer (8), M. Siegel (9), M.E. Sobieszczyk (10), S.R. Walsh (11), J. Heptinstall (12), K. Seaton (12), D. Montefiori (1), G. Tomaras (12)

Institutions

(1) Emory University, Medicine, Atlanta, United States, (2) University of North Carolina at Chapel Hill, Medicine, Chapel Hill, United States, (3) Beth Israel Deaconess Medical Center, Harvard Medical School, Center for Virology and Vaccine Research, Boston, United States, (4) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, United States, (5) FHI 360, Durham, United States, (6) National Institute of Allergy and Infectious Diseases, Rockville, United States, (7) UCLA Center for Clinical AIDS Research & Education, Los Angeles, United States, (8) Boston-Fenway Health, Harvard Medical School, Boston, United States, (9) George Washington Medical Faculty Associates, Washington, DC, United States, (10) Columbia University Irving Medical Center, New York, United States, (11) Brigham and Women's Hospital, Harvard Medical School, Boston, United States, (12) Duke University, Durham, United States

BACKGROUND: Multiple broadly neutralizing antibodies (bnAbs) targeting domains of gp120 are in development for prevention of HIV-1. PGT121.414.LS, a modification of the anti-V3 glycan bnAb PGT121, potently neutralizes multiple HIV-1 clades in vitro.
METHODS: The ongoing, phase 1 HVTN 136/HPTN 092 trial assesses the safety, tolerability, and pharmacokinetics (PK) of PGT121.414.LS in 13 healthy adults without HIV. We evaluated IV dose-escalation and SC infusion in four groups: 3 mg/kg IV (group T1, n=3), 10 mg/kg IV (T2, n=4), 30 mg/kg IV (T3, n=3) and 5 mg/kg SC (T4, n=3). Serum concentrations of PGT121.414.LS were measured on days 0, 1, 2, 3, 6, 14, 28, 56 and 112 after a single infusion. Non-compartmental PK analyses were performed.
RESULTS: The median participant age was 30 years; 77% were assigned female sex at birth; 15% Black and 85% White. IV and SC infusions were safe and well-tolerated, with no related serious adverse events or dose-limiting toxicities. Peak concentrations after IV infusions were observed on day 1, increasing linearly with higher doses (median = 525.8 in T3 vs 164.7 Âµg/mL in T2). Peak concentrations after SC infusion occurred on day 14. On day 112 (trough visit), T1 and T4 concentrations were similar (12.1 and 13.7 Âµg/mL); T2 concentrations (31.3 Âµg/mL) were lower than those predicted for T3 (78.8 Âµg/mL). Day 112 concentrations for T3 are in progress. PGT121.414.LS estimated clearance was 0.06-0.12 liter/day in T1-T4. PGT121.414.LS estimated elimination half-lives were 3 times longer than its precursor, PGT121, with medians of 53.6 -74.3 days in T1-T4. The estimated bioavailability of SC PGT121.414.LS was 70%, twice the bioavailability of its precursor.
CONCLUSIONS: PGT121.414.LS was safe and well-tolerated following IV or SC infusion in healthy US adults. These preliminary safety and pharmacokinetic findings support further development of PGT121.414.LS in combination with other bnAbs for global HIV-1 prevention.

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