Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial

Lalezari, Jacob; Latiff, Gulam H; Brinson, Cynthia; Echevarría, Juan; Treviño-Pérez, Sandra; Bogner, Johannes R.; Thompson, Melanie; Fourie, Jan; Pena, Otto A Sussmann; Urbina, Fernando C Mendo; Martins, Marcelo; Diaconescu, Iulian; Stock, David A.; Joshi, Samit R; Hanna, George J.; Lataillade, Max

doi:10.1016/s2352-3018(15)00177-0

Cited by 60 publications

(66 citation statements)

References 16 publications

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“…Second, on the basis of clinical data from the AI438011 study (7), the 400-mg BID dose led to a decline in the HIV-1 RNA level of Ͻ1 log 10 copies/ml, whereas a total daily dose of BMS-663068 at 1,200 mg (1,200 mg QD) had an efficacy and safety profile similar to that of a total daily dose of 1,600 mg (800 mg BID) when administered as cART for 24 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…Subjects in the AI438011 study received an ER wet granulation formulation of BMS-663068 at a dose of 400 mg BID, 600 mg QD, 800 mg BID, or 1,200 mg QD, all with a backbone of RAL at 400 mg BID and TDF at 300 mg QD, for up to 48 weeks (and the subjects were followed up to 96 weeks); a subset also participated in an elective 7-day monotherapy substudy prior to the main study. Only subjects with a baseline BMS-626529 half-maximal (50%) inhibitory concentration (IC 50 ) of Ͻ100 nM were included in the AI438011 study (7); the baseline BMS-626529 IC 50 was not an exclusion criterion for the AI438006 study. Plasma samples were analyzed for BMS-626529 concentrations by a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) assay as previously described (6).…”

Section: Methodsmentioning

confidence: 99%

“…In a subsequent phase 2b dose-finding study (the AI438011 study; ClinicalTrials.gov registration number NCT01384734) with HIV-1-infected, treatment-experienced subjects who were screened for sensitivity to BMS-626529 (measured with the Monogram Biosciences PhenoSense Entry assay) prior to enrollment on the basis of the findings of the phase 2a study, 7 days of BMS-663068 monotherapy in a lead-in substudy resulted in a median decline in the HIV-1 RNA level of 0.69 log 10 copies/ml with a dose of 400 mg twice daily (BID) and 1.28 to 1.44 log 10 copies/ml with BMS-663068 doses of 600 mg once daily (QD), 800 mg BID, and 1,200 mg QD (7). BMS-663068 also had efficacy similar to that of the comparator treatment, ATV/r, following 24 weeks of cART with raltegravir (RAL) and tenofovir disoproxil fumarate (TDF) as backbone treatments in all arms: 69 to 80% of subjects across the BMS-663068 arms and 75% of subjects in the ATV/r arm achieved HIV-1 RNA levels of Ͻ50 copies/ml through week 24 (modified intent-to-treat population) (7). Furthermore, all doses were generally well tolerated, and there were no BMS-663068-related adverse events (AEs) leading to discontinuation (7).…”

mentioning

confidence: 93%

“…BMS-663068 also had efficacy similar to that of the comparator treatment, ATV/r, following 24 weeks of cART with raltegravir (RAL) and tenofovir disoproxil fumarate (TDF) as backbone treatments in all arms: 69 to 80% of subjects across the BMS-663068 arms and 75% of subjects in the ATV/r arm achieved HIV-1 RNA levels of Ͻ50 copies/ml through week 24 (modified intent-to-treat population) (7). Furthermore, all doses were generally well tolerated, and there were no BMS-663068-related adverse events (AEs) leading to discontinuation (7).…”

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confidence: 93%

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Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

Landry

Zhu

Tarif

et al. 2016

Antimicrob Agents Chemother

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BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4؉ T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n ‫؍‬ 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8؉ T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the log e -transformed concentration at the end of a dosing interval (C tau ) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC 50 ) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log 10 copies/ml as a function of the log e -transformed PBAIC 50 -adjusted C tau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600-and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.) A s the management of HIV-1 infection requires lifelong treatment with sequential combination antiretroviral therapy (cART), antiretrovirals with a novel mechanism of action that can be used in combination with other agents to form active regimens following virologic failure are needed. This is particularly relevant for heavily treatment-experienced patients who, by definition, have limited remaining treatment options due to viral drug resistance, toxicity, and drug-drug interactions (1). For such patients, treatment guidelines recommend construction of a new regimen containing two or, ideally, three fully active agents where possible, on the basis of treatment history, viral drug resistance, and/or a new mechanism of action (1, 2).BMS-663068 is an oral prodrug of the first-in-class HIV-1 attachment inhibitor BMS-626529, which prevents initial viral attachment to the host CD4 ϩ T cell by binding to the viral envelope protein gp120 (3). BMS-663068 is administered as an extendedrelease (ER) formulation, which...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 93%

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Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

Landry

Zhu

Tarif

et al. 2016

Antimicrob Agents Chemother

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“…In phase 2b studies TMR showed similar efficacy to a ritonavir-boosted atazanavir (ATV/r) using tenofovir disoproxil fumarate (TDF) and raltegravir (RAL) as companions (42,57). Specifically, Thompson et al showed that, through week 48, the proportion of fostemsavir subjects with a VL <50 copies/ml was 77-95% versus 88% for ATV/r subjects (42).…”

Section: Gp120 Antagonistmentioning

confidence: 98%

Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (Review)

et al. 2019

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Despite the profound changes and improvements reached in the field of HIV treatment, tolerability and adherence to highly active antiretroviral therapy remains a challenge. Furthermore, multi-experienced patients could take advantage of drugs with different mechanisms of action to combat the spread of resistance to actual therapy. For these reasons identification of new HIV drugs is crucial. Among all the molecules that at present are under investigation, entry and fusion inhibitors pose an interesting class owing to their peculiar characteristics, including prevention of entry of the virus into the human cells. In this study, we reviewed articles, clinical trials, and conference communications about all the drugs under investigation belonging to the class of entry and fusion inhibitors that are at least in phase I clinical trials.

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Consensus recommendations for the use of novel antiretrovirals in persons with HIV who are heavily treatment‐experienced and/or have multidrug‐resistant HIV‐1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy

Cluck,

Chastain,

Murray

et al. 2024

Pharmacotherapy

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Treatment options are currently limited for persons with HIV‐1 (PWH) who are heavily treatment‐experienced and/or have multidrug‐resistant HIV‐1. Three agents have been approved by the U.S. Food and Drug Administration (FDA) since 2018, representing a significant advancement for this population: ibalizumab, fostemsavir, and lenacapavir. However, there is a paucity of recommendations endorsed by national and international guidelines describing the optimal use (e.g., selection and monitoring after initiation) of these novel antiretrovirals in this population. To address this gap, a modified Delphi technique was used to develop these consensus recommendations that establish a framework for initiating and managing ibalizumab, fostemsavir, or lenacapavir in PWH who are heavily treatment‐experienced and/or have multidrug‐resistant HIV‐1. In addition, future areas of research are also identified and discussed.

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Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial

Cited by 60 publications

References 16 publications

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (Review)

Consensus recommendations for the use of novel antiretrovirals in persons with HIV who are heavily treatment‐experienced and/or have multidrug‐resistant HIV‐1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy

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