14   A 14-Day Assessment of the Safety, Pharmacokinetics, and Antiviral Activity of T-1249, a Peptide Inhibitor of Membrane Fusion.

J. Eron*¹, T. Merigan², M. Kilby³, B. Yangco⁴, J. Gleavy⁶, P. Rusnak⁶, B. Dimassimo⁶, R. Smith⁶, B. Baker⁶, F. Duff⁵, J. Drucker⁶, T. Matthews⁶, and S. Hopkins⁶for the T1249-101 Study Group.
¹Univ. of North Carolina at Chapel Hill;²Stanford Univ., Palo Alto, CA;³Univ. of Alabama at Birmingham;⁴IFDI, Tampa, FL;⁵Roche, Inc., Nutley, NJ; and⁶Trimeris, Inc., Durham, NC.

Background:T-1249 is a peptide fusion inhibitor developed as a follow on compound to T-20. In laboratory and animal studies, T-1249 has demonstrated unique potency against a broad range of HIV-1, HIV-2, and SIV isolates, favorable PK characteristics, and a non-overlapping resistance profile with respect to T-20. We evaluated the safety, PK and antiviral activity of T-1249 in a phase I/II dose escalation study.

Methods:We enrolled 72 HIV-1 positive, treatment experienced adults with no concomitant ARV therapy and plasma HIV RNA >5,000 c/mL. Patients received T-1249 monotherapy by SC injection for 14 days at doses ranging from 6.25 mg/day to 50 mg/day, on a once or twice daily regimen. PK were assessed after a single IV dose (day -7) and during SC dosing (days 0 and 7).

Results:Dose-dependent decreases in HIV RNA were observed. On day 14, the median change from baseline ranged from -0.10 (6.25 mg/day) to -1.40 (50 mg/day) log₁₀c/mL. The plasma half-life and bioavailability support once-daily dosing. AUC, C_maxand C_minwere dose dependent. Two serious AEs, possibly related to study drug, occurred: hypersensitivity reaction (oral ulcers, maculopapular rash, fever) and grade 4 neutropenia. Otherwise, no treatment-related, clinically important laboratory abnormalities occurred. Injection site reactions (pain, induration, erythema) were mild and reported in 40% of patients. No dose-limiting toxicity was identified; therefore, evaluation of higher doses is warranted.

Conclusions:These results indicate that 14-day T-1249 monotherapy is well tolerated, has PK characteristics that support once daily dosing, and confers potent, dose-related suppression of plasma HIV RNA.