Pipeline ARVs at IAS 2015: doravirine, BMS-955176 and BMS-663068

1 August 2015. Related: Conference reports, Antiretrovirals, IAS 8th Vancouver 2015.

Simon Collins

Several presentations at IAS 2015 included new drugs in development, principally an NNRTI and an attachment inhibitor.

New results for tenofovir alafenamide fumerate (TAF) – which has already been submitted to the US FDA for approval as part of three separate fixed dose combinations – will be covered in a separate HTB report.

A comprehensive review of all pipeline antiretrovirals in advanced development is included in the i-Base/TAG 2015 Pipeline Report. [1]

Doravirine (NNRTI)

Jose Gatell from University of Barcelona presented results from a Phase II study of the NNRTI doravirine being developed by Merck. [2]

This was a randomised, double blind, placebo controlled two part study in treatment naive participants. Part one was a 5-arm 24-week dose-finding study compared to efavirenz with all participants (approximately 40 per arm) using tenofovir/FTC as backbone NRTIs. In part two, the doravirine arms rolled over to the 100 mg selected dose and 132 additional participants were included, randomised to either doravirine 100 mg or efavirenz. [3]

The selected analysis at IAS 2015 combined 24-week results from the 42 people from part one who started at the 100 mg dose together with 24-week results from new participants in part two. Primary endpoints included viral suppression to <40 copies/mL at week 24 and CNS-related side effects at week 8.

Baseline characteristics included approximately 80% white, 92% male, median age 35 (range 20 to >60), with median CD4 and viral load of approximately 400 cells/mm3 (range 100 to 1100) and 4.6 log copies/mL (range 2.6 to 6.7).

At 24 weeks, viral suppression <40 copies/mL was similar in both groups: 72% vs 73% in the doravirine vs efavirenz groups respectively, difference: -1.2 (95%CI: -13.0 to 10.5), see Table 1. Using the <200 copy cut-off, rates were just under 90% in each group. Median CD4 increases were similar at approximately +150 cells/mm3.

In the prespecified analysis stratified by baseline viral load above 100,000 copies/mL, suppression to <40 was lower for both groups (~60% vs 56%) compared to 92% vs 95% from those starting < 100,000 copies/mL.

Doravirine had significantly fewer drug-related side effects (28% vs 56%; difference -27.8, 95%CI: -39.9 to -14.8), mostly related to CNS events, see Table 1. Laboratory abnormalities were broadly similar.

BMS-955176 (BMS-176, maturation inhibitor)

Results from a phase 2a study of the second-generation maturation inhibitor BMS-176 were presented as a late-breaker oral abstract by Carey Hwang from BMS. [4]

This was a randomised, placebo controlled, multi-part study. Part one was a 10-day monotherapy dose finding study (20 to 120 mg doses) that selected a 40 mg dose, based on a median maximum viral load decline of 1.6 log copies/mL. [5]

Results from part two, presented at IAS 2015, were from 28 new participants (protease and maturation inhibitor naive), randomised 2:2:2:1 to one of four once-daily groups for 28 days: 40 mg BMS-176 plus either atazanavir/ritonavir 300/100 mg or atazanavir 400 mg, 80 mg BMS-176 plus atazanavir 400 mg or to a control arm of atazanavir/ritonavir plus tenofovir/FTC. All doses of BMS-176 used an oral solution. All participants discontinued all drugs on day 29.

Baseline characteristics included median age 32, male (100%), white (90%) with median CD4 and viral load that ranged from 430 to 580 cells/mm3 and 4.0 to 4.4 log copies/mL across arms. No IQR or range values were given for each arm or for the overall study population, but CD4 was > 500 cells/mm3 for the majority of patients and viral load was low. The primary endpoint was viral suppression at day 29.

Median viral load decline at day 29 ranged from 1.6 to 2.2 logs for the BMS-176 arms vs -2.2 for the control arm. Maximum median viral load change at 42 weeks (study discharge) was similar between arms, see Table 2.

Safety and tolerability appeared broadly similar between groups with perhaps the non-ritonavir arms having fewer laboratory abnormalities including lower median bilirubin elevations. There were no serious adverse events or discontinuations.

Further details on the profile of BMS-176 were also presented as a poster, including in vitro activity against Gag polymorphisms associated with lack of activity to the first-generation maturation inhibitor bevirimat. [6]

BMS-663068 (BMS-068, attachment inhibitor)

BMS-068 is an attachment inhibitor in development at BMS, that binds to gp-120 to block entry. As with the BMS maturation inhibitor reported above this compound has great potential to help people with multidrug resistance to currently approved ARVs.

Two posters were included at IAS 2015. The first presented details on the development of drug resistance in a 48 week phase 2 dose-finding study that compared BMS-068 to atazanavir/r (300/100 mg), each in combination with tenofovir DF and raltegravir, and selected 1200 mg QD dose for further development. [7]

A drug interaction poster reported that a BMS-068 600 mg twice-daily (BID) dose can be used with atazanaivr/ritonavir, darunavir/ritaonavir and ritonavir. Even though these combination results in creased drug exposure to BMS-068, no dose adjustments are judged necessary.

With etravirine, even though exposure to BMS-068 was reduced by approximately 50% (for Cmax, AUC and Cmin), no dose adjustment was judged necessary using the 600 mg BID dose of BMS-068.

No significant interactions were reported when used with raltegravir/tenofovir.

However, the once-daily 1200 mg dose of BMS-068 is contraindicated with rifampin 600 mg QD due to significant reduced levels of BMS-068 (approximately 80% reductions). [8]

References:

Unless stated otherwise, references are to the Programme and Abstracts of the 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015), 19 – 22 July 2015, Vancouver.

http://pag.ias2015.org

1. Collins S, Horn T. The antiretroviral pipeline. i-Base/TAG 2015 Pipeline Report. (July 2015)
   https://i-base.info/htb/28460
2. Gatell J et al. Efficacy and safety of doravirine 100mg QD vs efavirenz 600mg QD with TDF/FTC in ART-naive HIV-infected patients: week 24 results. IAS 2015, 19-22 July 2015, Vancouver. Oral abstract TUAB0104. No webcast or slides on IAS site.
3. A dose-ranging study to compare doravirine (MK-1439) plus Truvada versus efavirenz plus Truvada in human immunodeficiency virus (HIV)-1 Infected participants (MK-1439-007). ClinicalTrials.gov Identifier: NCT01632345.
   https://clinicaltrials.gov/ct2/show/NCT01632345
4. Hwang C et al. Second-generation HIV-1 maturation inhibitor BMS-955176: antiviral activity and safety with atazanavir +/- ritonavir. IAS 2015, 19-22 July 2015, Vancouver. Late breaker oral abstract TUAB106LB. (No webcast, slide online).
   http://pag.ias2015.org/PAGMaterial/PPT/2234_13087/Hwang%20et%20al_POC_Part%20B_IAS%20Presentation%20FINAL.pptx
5. Study to Evaluate a HIV Drug for the Treatment of HIV Infection. NCT01803074.
   https://clinicaltrials.gov/ct2/show/NCT01803074
6. Nowicka-Sans B et al. BMS-955176: characterisation of a 2nd-generation HIV-1 maturation inhibitor. IAS 2015, 19-22 July 2015, Vancouver. Poster abstract TUPEA078.
   http://pag.ias2015.org/PAGMaterial/eposters/1723.pdf
7. Lataillade N et al. HIV-1 attachment inhibitor prodrug BMS-663068 in antiretroviral-experienced subjects: analysis of emergent viral drug resistance through 48 weeks of follow-up. IAS 2015, 19-22 July 2015, Vancouver. Poster abstract TUPEB284.
   http://pag.ias2015.org/PAGMaterial/eposters/1753.pdf (PDF)
8. Adamczyk R et al. HIV-1 attachment inhibitor prodrug BMS-663068: interactions with rifabutin, with or without ritonavir, in healthy subjects. IAS 2015, 19-22 July 2015, Vancouver. Poster abstract TUPEB277.
   http://pag.ias2015.org/PAGMaterial/eposters/1774.pdf (PDF)