Presentation Abstract

Session: 086-Antiretrovirals: Safety and Tolerability
Wednesday, Sep 11, 2013, 11:00 AM - 1:00 PM
Presentation Title: H-672 - Meta-Analysis of Safety Data from 8 Clinical Studies with GSK1265744, an HIV Integrase Inhibitor, Dosed Orally or as Injection of Long-Acting Parenteral Nanosuspension
Location: Exhibit Hall A
Presentation Number: H-672
Pres. Time: Wednesday, Sep 11, 2013, 11:00 AM - 1:00 PM
Category: H2
Keywords: GSK1265744; Long-Acting Parenteral Injection; Meta-analysis
Author(s): Y. Lou, E. Gould, S. Chen, D. Wilfret, W. Spreen, S. Piscitelli, D. Margolis;
GlaxoSmithKline, Durham, NC
Financial Disclosures:  Y. Lou, None..
E. Gould, None..
S. Chen, None..
D. Wilfret, None..
W. Spreen, None..
S. Piscitelli, None..
D. Margolis, None.
Abstract: Background: GSK1265744 (GSK744) is an investigational integrase inhibitor with robust antiviral activity dosed in clinical trials as a once daily oral tablet (t½~40hrs) or long-acting parenteral (LAP) injection at intramuscular (IM) or subcutaneous (SC) sites (t ½~30-40days). Safety was evaluated from Phase 1 and 2a studies across various dosing routes and treatment durations. Methods: Safety analysis included 6 short-term healthy or HIV-infected subject oral dosing studies and 2 healthy subject LAP studies dosed as single or repeat monthly (x4) or quarterly (x2) injections with relevant clinical exposures exceeding 6 months. Oral GSK744 5-50mg was administered up to 14 days (n=187) and LAP as 100mg-800mg IM or 100mg-400mg SC injections in single (n=58) or repeat doses (n=40). Adverse events (AEs), labs and ECGs were pooled across studies and summarized. Results: GSK744 was administered to 245 subjects across all studies. There were no drug-related SAEs. The most frequent (>5%) non-injection site reaction (ISR) related AEs were headache (22%) and nausea (5%). Two Grade 3 AEs (CK, BIL) and two grade 4 AEs (CK, osteomyelitis) were reported as unrelated to GSK744. Treatment emergent ≥Grade 2 lab abnormalities were infrequent: total cholesterol (5%), lipase (4%), bilirubin(2%), glucose (2%) and CK (2%). 2540 post-dose ECGs were evaluated; the difference in mean change in QTcF from baseline between GSK744 and PBO groups was -2.9 msec. No relationship was observed between dose and non-ISR AE rate, ECG change from baseline and lab test abnormalities. ISRs related to GSK744 LAP injection were largely mild (93%) with no Grade 3 ISR-AEs. The most frequent ISRs for IM and SC dosing were pain (71% and 24%), erythema (9% and 23%) and nodules (7% and 23%). Median IM ISR durations were ~5 days for both pain and erythema and ~22 days for nodules. There were no ISR related withdrawals. Conclusion: GSK744 as single and repeat oral doses up to 50mg and SC/IM LAP injections up to 800mg were well tolerated. All ISRs were self-limited and predominantly Grade 1. Safety analyses support continued development of both oral and parenteral GSK744 formulations.

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