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Week-48 Subgroup Responses to Attachment Inhibitor in Phase 2b Trial
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IDWeek 2015, October 7-11, San Diego
Mark Mascolini
Virologic or CD4 response rates to the HIV-1 attachment inhibitor BMS-663068 did not vary substantially by age, gender, or race in a subgroup analysis of week-48 results from a phase 2b trial in antiretroviral-experienced people [1]. The sub-50-copy response rate was somewhat higher in people who began treatment with a viral load below versus above 100,000 copies, and CD4 responses were marginally higher in people who started treatment with a higher viral load; but these analyses were not powered to detect statistically significant differences between subgroups.
BMS-663068 is a prodrug of BMS-626529, an investigational antiretroviral that binds directly to the HIV-1 envelope protein gp120 and so thwarts viral entry to CD4 cells. The attachment inhibitor is active against virus resistant to the entry inhibitor maraviroc or to other antiretroviral classes.
A phase 2b trial that randomized treatment-experienced people to BMS-663068 or atazanavir/ritonavir, both plus raltegravir and tenofovir, found similar 48-week virologic and CD4 results across BMS-663068 dosage groups and the atazanavir/ritonavir group [2]. With 50 participants per dosage arm, BMS-663068 doses were 400 or 800 mg twice daily (BID) or 600 or 1200 mg once daily (QD). Everyone received standard doses of raltegravir, tenofovir, and atazanavir/ritonavir. And everyone began the phase 2b trial with a viral load at or above 1000 copies, a CD4 count above 50, and susceptibility to all study drugs (50% inhibitory concentration less than 100 nM for BMS-626529).
At week 48 proportions of people reaching a viral load below 50 copies in a modified intention-to-treatment analysis were 82% with 400 mg of BMS-663068 BID, 61% with 800 mg BID, 69% with 600 mg QD, 68% with 1200 mg QD, and 71% with atazanavir/ritonavir. The post hoc subgroup analysis determined on-treatment virologic and CD4 responses at week 48 by gender, age (below 40 versus 40 or older), race (black, white, or other), baseline viral load (below 100,000 copies or higher), and baseline CD4 count (below 200 or higher).
Demographics and disease characteristics were similar across the five study arms. Median age stood at 39, 60% were men, 38% white, 30% black, and 32% another race or ethnicity. Median baseline viral load measured 4.85 log (about 71,000 copies), and median CD4 count 229.5.
Sub-50-copy response rates generally proved moderately higher across treatment arms in people who began with a viral load below 100,000 copies or a CD4 count above 200. In the combined BMS-663068 arms 48-week virologic response rates were 87.8% in people with a baseline load below 100,000 copies and 76.1% in those with a higher baseline load. Respective response rates in the atazanavir/ritonavir arm were 96.3% and 71.4%. In the combined BMS-663068 arms, virologic response rates were 85.5% in those starting with more than 200 CD4 cells and 77.6% in those starting with fewer. Respective response rates with atazanavir/ritonavir were 95.5% and 78.9%.
Among study participants younger than 40 years old, 48-week sub-50-copy response rates were 84.7% in the pooled BMS-663068 arms and 85.7% with atazanavir/ritonavir. Respective rates for older people were 81% and 90%. Virologic response rates among men were 81.4% with BMS-663068 and 95.7% with atazanavir/ritonavir, and among women 85.1% with BMS-663068 and 77.8% with atazanavir/ritonavir. In the pooled BMS-663068 arms, 48-week virologic response rates were 86.3% in blacks, 81.8% in whites, and 80.8% in others. Respective rates among people randomized to atazanavir/ritonavir were 90%, 83.3%, and 92.3%. In all subgroup analyses, virologic response rates to BMS-663068 were slightly higher in the 400-mg BID groups than in other dosage groups.
CD4-cell responses through 48 weeks did not vary substantially by gender, age, or race in the BMS-663068 arms or the atazanavir/ritonavir arm. CD4 gains averaged about 150 through 48 weeks in all groups. In both the BMS-663068 groups and the atazanavir group, people who began treatment with a viral load above 100,000 copies tended to gain more CD4 cells than people who started with a lower viral load. Among people starting treatment with a viral load above 100,000 copies, those randomized to atazanavir/ritonavir gained between 200 and 250 CD4s through 48 weeks compared with about 150 CD4s in the BMS-663068 arms.
A phase 3 placebo-controlled trial currently recruiting antiretroviral-experienced participants with multidrug-resistant HIV will test 600 mg of BMS-663068 twice daily plus an optimized background regimen [3].
References
1. Feinberg J, Lalezari J, Martins M, et al. HIV-1 attachment inhibitor prodrug BMS-663068 in antiretroviral-experienced subjects: week 48 subgroup analysis. IDWeek 2015, October 7-11, San Diego. Abstract 1075. https://idsa.confex.com/idsa/2015/webprogram/Paper51890.html
2. Thompson M, Lalezari J, Kaplan R, et al. Attachment inhibitor prodrug BMS-663068 in ARV-experienced subjects: week 48 analysis. CROI 2015. Seattle. Abstract 545. www.croiconference.org/sites/default/files/posters-2015/545.pdf
3. ClinicalTrials.gov. Attachment inhibitor comparison in heavily treatment experienced patients. ClinicalTrials.gov identifier NCT02362503. https://clinicaltrials.gov/ct2/show/NCT02362503
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