Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study.

ABSTRACT: Patients with hemophilia A require exogenous factor VIII (FVIII) or nonfactor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector-based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain-deleted human F8 gene. In the ongoing phase 1/2, dose-ranging Alta study, 4 sequential cohorts of male participants with severe hemophilia A received a single IV dose of giroctocogene fitelparvovec. The primary end points are safety and changes in circulating FVIII activity. Interim results up to 214 weeks after treatment for all participants are presented. Eleven participants were dosed. Increases in alanine and aspartate aminotransferases were the most common treatment-related adverse events (AEs), which resolved with corticosteroid administration. Two treatment-related serious AEs (hypotension and pyrexia) were reported in 1 participant within 6 hours of infusion and resolved within 24 hours after infusion. At the highest dose level (3 × 1013 vg/kg; n = 5), the mean circulating FVIII activity level at week 52 was 42.6% (range, 7.8%-122.3%), and at week 104 it was 25.4% (range, 0.9%-71.6%) based on a chromogenic assay. No liver masses, thrombotic events, or confirmed inhibitors were detected in any participant. These interim 104-week data suggest that giroctocogene fitelparvovec is generally well tolerated with appropriate clinical management and has the potential to provide clinically meaningful FVIII activity levels, as indicated by the low rate of bleeding events in the highest dose cohort. This trial was registered at www.clinicaltrials.gov as #NCT03061201.

Hepatic safety of maraviroc in patients with HIV-1 and hepatitis C and/or B virus: 144-week results from a randomized, placebo-controlled trial.

BACKGROUND: In the primary 48-week analysis of a hepatic safety trial in patients with HIV-1 coinfected with HBV and/or HCV, maraviroc-containing treatment regimens were not associated with increased hepatotoxicity. METHODS: In this randomized, double-blind, placebo-controlled, multicentre study, patients received maraviroc twice daily (n=70) or placebo (n=67) with concomitant antiretroviral therapy for 144 weeks (Clinicaltrials.gov identifier, NCT01327547). The primary end point was the proportion of patients with protocol-defined Grade 3/4 alanine aminotransferase (ALT) abnormalities through week 48. Key secondary end points included 144-week analysis of Grade 3/4 ALT abnormalities and liver fibrosis by enhanced liver fibrosis (ELF) testing, hepatic elastography and an optional biopsy substudy. RESULTS: Through 144 weeks of treatment, two (maraviroc) and three (placebo) patients met the protocol-defined Grade 3/4 ALT end point. Similar to the 48-week results, there were no statistically significant differences between groups in change from baseline in ELF or hepatic elastography. However, decreased elastography scores were noted in the maraviroc group. Blinded pathologist review suggested that 2 of 11 paired biopsies (both on maraviroc) showed signs of decreased fibrosis. One (maraviroc) and two (placebo) patients experienced treatment-related hepatobiliary adverse events (AEs). Five patients in the maraviroc group discontinued because of treatment-related AEs versus three in the placebo group. One death in the maraviroc group and two deaths in the placebo group were reported. CONCLUSIONS: Use of maraviroc did not increase hepatotoxicity in this population through 144 weeks. Further investigation regarding possible beneficial effects of maraviroc on liver fibrosis may be warranted.

Hepatic safety in subjects with HIV-1 and hepatitis C and/or B virus: a randomized, double-blind study of maraviroc versus placebo in combination with antiretroviral agents.

BACKGROUND: One of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents. OBJECTIVE: To evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1-infected subjects co-infected with HCV and/or HBV. METHODS: In this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (n = 70) or placebo (n = 67) in combination with other antiretroviral agents. PRIMARY ENDPOINT: the percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5 × upper limit of normal (ULN) if baseline ALT ≤ ULN or >3.5 × baseline if baseline ALT>ULN in the maraviroc versus the placebo arm. RESULTS: At week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hy's law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group. CONCLUSIONS: The use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48 weeks of treatment.