Fostemsavir demonstrates good antiviral activity

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Bristol-Myers Squibb’s HIV attachment inhibitor BMS-663068 (fostemsavir), which prevents the virus from binding to T-cells, demonstrated good antiviral activity and was well-tolerated at 24 weeks, according to study results published recently. Findings from a subgroup analysis at 48 weeks, presented at IDWeek 2015, showed that response rates were similar regardless of demographics or baseline viral load or CD4 cell count.

Combination antiretroviral therapy (ART) consists of drugs that target different steps of the HIV lifecycle. None of the currently approved drugs blockthe first step, initial attachment of the virus to a host cell; fusion inhibitors like enfuvirtide (Fuzeon) affect a slightly later step. Drugs that work in novel ways are particularly beneficial for people with HIV who are highly treatment-experienced and have extensively resistant virus.

BMS-663068 – the first drug in its class – is a pro-drug or precursor of BMS-626529, which binds directly to the gp120 protein that makes up part of the “spikes” on HIV’s outer surface, thereby preventing viral attachment to CD4 T-cells. Unlike maraviroc (Selzentry), BMS-663068 binds to the virus not the cell itself, and it is active against HIV that uses either CCR5 or CXCR4 co-receptors. Study AI438011 (NCT01384734) looked at the safety, efficacy, and dose-response characteristics of BMS-663068 in previously treated people with HIV.

Trial participants were randomised to receive either BMS-663068 or ritonavir-boosted atazanavir (Reyataz) as part of a combination regimen. Jay Lalezari from Quest Clinical Research in San Francisco and colleagues have published 24-week primary results from this ongoing trial. The study enrolled 254 participants at 53 hospitals and outpatient clinics in 10 countries in North and South America, Europe, and Africa between July 2011 and July 2012. A majority (60%) were men, 38% were white, 30% were black, and the median age was 39 years.

Overall, participants had relatively advanced disease, with a mean CD4 count of 230 cells/mm3, nearly 40% having less than 200 cells/mm3, and just over 40% having high baseline viral load. Many had failed first- or second-line ART and about half had at least 1 major mutation conferring resistance to at least 1 widely used antiretroviral drug class; however, they were required to still be sensitive to BMS-626529 and other drugs used in the study according to resistance tests.

Participants were randomly allocated to 5 treatment arms receiving BMS-663068 at doses of 400 mg or 800 mg twice-daily, 600 mg or 1200 mg once-daily, or 300/100 mg atazanavir/ritonavir. Everyone also took 400 mg raltegravir (Isentress) and 300 mg tenofovir disoproxil fumarate (Viread). Participants receiving BMS-663068 had a higher daily pill burden, which could have an effect on adherence.

Virological response rates, or the proportion of participants with viral load

Mean CD4 cell gains at 48 were also similar across treatment arms. BMS-663068 was generally safe and well-tolerated at all doses tested. At 24 weeks 7% of patients in all BMS-663068 groups combined experienced serious adverse events, compared with 10% in the boosted atazanavir group. 2% of BMS-663068 recipients and 4% of boosted atazanavir recipients discontinued treatment early due to adverse events. None of the serious adverse events or adverse events leading to treatment discontinuation were considered related to BMS-663068. No notable trends in laboratory abnormalities were seen in the BMS-663068 groups, while boosted atazanavir was more likely to cause elevated bilirubin.

“In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a Phase 3 trial in heavily treatment-experienced individuals,” study authors concluded.

In a poster presented at IDWeek, Judith Feinberg from the University of Cincinnati and colleagues reported findings from a post hoc subgroup analysis of virological and immunological response through week 48 according to sex, age (above or below 40 years), race/ethnicity (white, black, or other), baseline viral load (above or below 100,000 copies/mL), and baseline CD4 T-cell count (above or below 200 cells/mm3).

48-week viral suppression rates were statistically similar regardless of sex, age, race/ethnicity, baseline viral load, or CD4 count: Men: 81% in combined BMS-663068 groups vs 96% on atazanavir/ritonavir; women: 85% vs 78%, respectively; age 40: 81% vs 90%, respectively; white: 82% vs 83%; black: 86% vs 90%; other race/ethnicity: 81% vs 92%; low baseline viral load: 88% vs 96%; high baseline viral load: 76% vs 71%; baseline CD4 count >200 cells/mm3: 86% vs 96%; and baseline CD4 count

Mean CD4 cell gains were similar with BMS-663068 and boosted atazanavir regardless of sex, age, race/ethnicity, or baseline CD4 count, but in both arms people starting with high viral loads saw larger increases.
“At Week 48, virologic responses were generally similar across the BMS-663068 and atazanavir/ritonavir arms in treatment-experienced subjects, regardless of gender, race, age, baseline viral load, or baseline CD4+ T-cell count,” the researchers concluded.

Based on results from the Phase 2b study, a Phase 3 trial of BMS-663068 (NCT02362503) opened earlier this year. This study is recruiting treatment-experienced people who are currently on a failing regimen and are resistant to or unable to take at least 3 classes of antiretrovirals. Those who still have at least 1 fully active drug will be randomised to receive 600 mg twice-daily BMS-663068 or placebo with an optimized background regimen, while those with no fully active antiretrovirals will be enrolled in a non-randomised cohort.

Summary
Background
BMS-663068 is an oral prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 cells. AI438011 is an ongoing trial investigating the efficacy, safety, and dose–response of BMS-663068 in treatment-experienced, HIV-1-infected patients. Herein we present the results of the primary analysis.
Methods
AI438011 is a phase 2b, randomised, active-controlled trial, at 53 hospitals and outpatient clinics across ten countries in North and South America, Europe, and Africa. Individuals with an HIV-1 RNA viral load of at least 1000 copies per mL and a BMS-626529 half-maximum inhibitory concentration lower than 100 nmol/L were randomly assigned (1:1:1:1:1) to receive either BMS-663068 at 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily or ritonavir-boosted atazanavir (300 mg of atazanavir and 100 mg of ritonavir once daily), each with 400 mg of raltegravir twice daily and 300 mg of tenofovir disoproxil fumarate once daily as a backbone. The sponsor, participants, and investigators were masked for BMS-663068 dose but not for allocation. Primary endpoints were the proportion of patients with an HIV-1 RNA viral load less than 50 copies per mL (response rate) at week 24 and the frequency of serious adverse events and adverse events leading to discontinuation, up to the week 24 analysis. The primary analyses included all patients who received at least one dose of study drug (modified intention-to-treat population). This study is registered at ClinicalTrials.gov, NCT01384734.
Findings
Between July 26, 2011, and July 16, 2012, 581 participants were assessed for eligibility. Of these, 254 patients were randomly assigned to receive either BMS-663068 (n=52 for the 400 mg twice daily group, n=50 for the 800 mg twice daily group, n=51 for the 600 mg once daily group, and n=50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n=51). 200 patients received at least one dose of BMS-663068, and 51 patients received at least one dose of ritonavir-boosted atazanavir. At week 24, 40 (80%) of 50 patients in the BMS-663068 400 mg twice daily group, 34 (69%) of 49 patients in the 800 mg twice daily group, 39 (76%) of 51 patients in the 600 mg once daily group, and 36 (72%) of 50 patients in the 1200 mg once daily group had an HIV-1 RNA viral load less than 50 copies per mL, compared with 38 (75%) of 51 patients in the ritonavir-boosted atazanavir group. Serious adverse events were noted in 13 (7%) of 200 patients in the BMS-663068 groups and five (10%) of the 51 patients in the ritonavir-boosted atazanavir group. Four (2%) of the 200 patients in the BMS-663068 groups and two (4%) of the 51 patients in the ritonavir-boosted atazanavir group discontinued because of adverse events. No serious adverse events or adverse events leading to discontinuation were BMS-663068-related. Grade 2–4 adverse events related to study drug(s) occurred in 17 (9%) of 200 patients across the BMS-663068 groups and 14 (27%) of 51 patients in the ritonavir-boosted atazanavir group. For the BMS-663068 groups these events were mostly single instances with no dose relation and for the ritonavir-boosted atazanavir group these were mostly gastrointestinal or hepatobiliary disorders associated with hyperbilirubinaemia.
Interpretation
In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals.

Abstract
Background:
BMS-663068 is a prodrug of BMS-626529, an attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into the host CD4+ T-cell. AI438011 is an ongoing Phase IIb, randomized, controlled trial investigating the safety, efficacy and dose–response of BMS-663068 versus atazanavir/ritonavir (ATV/r), both given with raltegravir (RAL)+ tenofovir disoproxil fumarate (TDF), in treatment-experienced (TE), HIV-1-infected subjects. Through 48 weeks, BMS-663068 showed similar efficacy to ATV/r. We present here a subgroup analysis of viral efficacy and immunologic response through Week 48.

Methods:
TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs and BMS-626529 IC50 100,000 c/mL) and median CD4+ T-cell count 230 cells/mm3 (38% Conclusion:
At Week 48, virologic response was generally similar across the BMS-663068 arms and the ATV/r arm in TE subjects, regardless of gender, race, age, BL VL, or BL CD4+ T-cell count. Mean increases in CD4+ T-cell count from BL to Week 48 were similar in the BMS-663068 arms regardless of age, gender, race, and BL CD4+ T-cell count. These results are mostly in agreement with those reported at Week 24 and support the ongoing Phase III trial evaluating BMS-663068 for use in heavily treatment-experienced adults with limited therapeutic options (NCT02362503).

HIV and Hepatitis material
The Lancet article summary
ID Week 2015 abstract


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