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Cabotegravir(CAB) Safety Meta-analysis Update from 14 Phase I/IIa Studies

Year: 2016

Type: article

Abstract: Background. CAB is an investigational integrase inhibitor being developed for the treatment and prevention of HIV-1 infection. CAB has been dosed as a once-daily oral tablet (5–150 mg once a day administered up to 28 days) or as a long-acting parenteral (LA) injection, either as 100–800 mg intramuscular (IM) or 100–400 mg subcutaneous (SC), in 14 completed phase I/IIa studies. These studies included single- and repeat-dose escalation, relative bioavailability, QTc, drug-drug interaction, and mass balance studies in healthy volunteers, and two cohorts of HIV-infected subjects for proof of concept (POC). Methods. Fourteen Phase I/IIa studies were pooled across studies. Adverse events were described and summarized separately as injection site reaction (ISR) or non-ISR events. Lab data was summarized by the toxicity grade. Results. CAB was administered to 423 subjects, including 408 healthy subjects and 15 HIV-infected subjects, in 14 Phase I/IIa studies. Oral CAB was given to 365 subjects, while LA CAB was administered to 136 subjects. Four non-drug related SAEs (osteomyelitis, uterine fibroids, appendicitis, seizure) were reported, all occurring in the LA studies. Nine subjects withdrew due to non-drug related AEs. The most frequent (>= 4%) non–ISR AEs were headache (16%), upper respiratory tract infection (6%), and nausea (4%). Six Grade 3 AEs (elevated creatine kinase [CK], hyperbilirubinemia, joint dislocation) and four Grade 4 AEs (elevated CK, hyperbilirubinemia, osteomyelitis) were reported in LA dosing studies, and were assessed by investigators as unrelated to CAB. ISR AEs (n =4 58) related to CAB LA injection were ≤ Grade 2 and were largely mild (93%). The most frequent ISR AEs for IM and SC dosing, respectively, were pain (67% and 24%), erythema (7% and 23%), and nodules (10% and 22%). For pain and erythema, median ISR AE durations for IM and SC dosing were no more than 5 days and 7 days, respectively; for nodule, the respective medians were 19 and 53 days. Overall treatment-emergent ≥ Grade 2 laboratory abnormalities were infrequent and included elevations in total cholesterol (7%), lipase (4%), bilirubin (2%), and CK (2%). QTc study demonstrated no QT prolongation. Conclusion. CAB given orally, intramuscularly or subcutaneously was well tolerated, and supports continued development of both oral and parenteral CAB formulations. Disclosures. Y. Lou, PAREXEL International: Employee, Salary E. Gould, PPD: Employee, Salary C. Fu, PAREXEL International: Employee, Salary A. Tenorio, ViiV Healthcare: Employee, Salary W. Spreen, ViiV Healthcare: Employee, Salary P. Patel, ViiV Healthcare: Employee, Salary D. Margolis, ViiV Healthcare: Employee, Salary

Source: Open Forum Infectious Diseases

DOI: 10.1093/ofid/ofw172.1215