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Pipeline ART: maturation inhibitors and an attachment inhibitor

CROI logoSimon Collins, HIV i-Base

Several studies at CROI 2015 included tentative results using compounds from two new classes of drugs – maturation inhibitors and attachment inhibitors. These results will be especially important for people who already have reduced options due to drug resistance to existing classes.

Maturation inhibitors

Maturation inhibitors work at a late stage of viral replication, blocking protease cleavage and leading to the release of immature HIV that is not infectious.

Despite greater than 1.2 log reductions to the maturation inhibitor bevirimat in Phase 2 studies in responders, approximately 50% of participants had no repsonse due to common naturally occurring polymorphisms at and around the codon 370 region in gag. It is therefore exciting that other companies are developing molecules that overcome this problem.

At CROI 2015, this included results from the first part of a Phase 2b, 10-day monotherapy study using BMS-955176 – a new maturation inhibitor from Bristol-Myers Squibb. [1]

BMS-955176 has greater potency (IC50 2-13 nM) compared to bevirimat, with potential for once-daily dosing. This dose-finding study randomised 60 participants who were predominantly (92%) treatment-naive, to 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 120 mg (n=8 for each) or placebo (n=2, matched to each group).

Baseline characteristics across arms included median CD4 count of 437-539 cells/mm3 and low viral load – from 3.6 – 4.1 log copies/mL. Participants were men (apart from one woman) and white (apart from three non-white).

At each of the three higher doses, comparable reductions of -1.4 logs were reported at day 10, which were sustained for a further week after drug was discontinued. Maximum median reduction in viral load was -1.7 log copies/mL in the 40 mg arm. Results were broadly similar for each group, irrespective of baseline gag polymorphisms associated with reduced activity to bevirimat.

Side effects reported by >5% of participants included headache, abnormal dreams, night sweats and diarrhoea, but were broadly similar between active and placebo groups and there were no discontinuations. No serious side effects or laboratory abnormalities were reported, other than two single cases of transient grade 3 neutropenia (one in each of the 80 mg and 120 mg groups). Phase 2b clinical studies are already planned to start Q2 2015 but these were not yet listed at clinicaltrials.org when we went to press.

GSK also has maturation inhibitors in development. Although promising details on GSK 2578999 were presented at the Drug Resistance Workshop [2] this compound is not going forward [2] and preclinical information on a second compound, GSK 2828232 were presented in a poster at CROI 2015. [3]

GSK 2828232 had an IC50 of 0.8-4.3 nM against a broad spectrum of 26 isolates covering a range of genotypes, and is not affected by previous PI-experience. Multiple-dose Phase 1 studies in HIV negative volunteers looking at food and drug interactions and safety have either already been conducted or are ongoing.

Attachment inhibitor: fostemsavir

There are already two approved ARVs that support the efficacy of blocking viral entry: maraviroc which is a CCR5 coreceptor inhibitor and enfuvirtide (T-20) which blocks gp-41, but which is now rarely used.

At CROI 2015, 48-week results were presented from an ongoing Phase 2b dose-ranging study of fostemsavir (formerly BMS-663068), a gp-120 blocker from Bristol-Myers Squibb. [4]

Earlier reports from this study included approximate viral load reductions of 0.7 to 1.5 log copies/mL after 7 days of monotherapy (ten patients per arm), and broadly similar viral efficacy across arms for the week 24 primary endpoint (approximately 50 participants per arm).

The study randomised 251 treatment experienced participants to one of four doses of fostemsavir (groups 1-4: 400 mg or 800 mg twice-daily, or 600 mg or 1200 mg once-daily), with a control group taking atazanavir/ritonavir (300 mg /100 mg). All participants also received tenofovir DF (300 mg once-daily) and raltegravir (400 mg twice-daily).

Baseline characteristics were similar between groups. Median age was 39 years, 60% were male and 38% were white. Median CD4 and viral load was 230 cells/mm3 (with 38% <200) and 4.85 log copies/mL (with 43% >100,000), respectively. Approximately 50% of participants had virus with at least one major mutation associated with NRTI, NNRTI or PI resistance.

In the modified intent-to-treat (mITT) analysis (FDA Snapshot), the percentage of patients with viral load <50 copies/mL was 82%, 61%, 69% and 68% in groups 1-4 respectively, compared to 71% in the control. Using a cut-off of <400 copies/mL, the results were 86%, 76%, 84% and 80% vs 75%, respectively.

Response rates from people with baseline viral load above vs below 100,000 copies/mL were lower in all arms but similar to the atazanavir/r control group. There were no significant differences between active and control groups for CD4 responses or safety results other than those already associated with atazanavir/r.

Responses in the fostemsavir groups were not affected by baseline IC50 and this will not be an exclusion criterion in future studies.Two other posters at CROI 2015 included new results on this compound.

The first was a modeling study, supported by clinical and virological results from which BMS has selected the 600 mg twice-daily dose to go forward for further studies. [5]

The second poster reported that no dose adjustment was needed when fostemsavir was taken with both darunavir/ritonavir and etravirine together, because the approximately 50% increase in level of fostemsavir from the boosted-PI was roughly compensated by the 50% reduction caused by the NNRTI. [6]

References:

Unless stated otherwise, all references are to the Programme and Abstracts of the 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle, Washington, USA.

  1. Hwang C et al. Antiviral activity/safety of a second-generation HIV-1 maturation inhibitor. CROI, 23-26 February 2015, Seattle. Oral late breaker abstract 114LB.
    Abstract:
    http://www.croiconference.org/sessions/antiviral-activitysafety-second-generation-hiv-1-maturation-inhibitor
    Webcast:
    http://www.croiwebcasts.org/console/player/25756
  2. Tang J et al. GSK2578999, an HIV-1 maturation inhibitor with improved virology profile against Gag polymorphisms. XXIV International Drug Resistance Workshop, 21-22 February 2015, Seattle. Oral abstract 63.
  3. Jeffrey J et al. GSK2838232, a second generation HIV-1 maturation inhibitor with an optimized virology profile. CROI, 23-26 February 2015, Seattle. Poster abstract 538.
    http://www.croiconference.org/sessions/antiviral-activitysafety-second-generation-hiv-1-maturation-inhibitor
  4. Thompson M et al. Attachment inhibitor prodrug BMS–663068 in ARV-experienced subjects: week 48 analysis. CROI, 23-26 February 2015, Seattle. Poster abstract 545.
    Abstract:
    http://www.croiconference.org/sessions/attachment-inhibitor-prodrug-bms–663068-arv-experienced-subjects-week-48-analysis
    Poster:
    http://www.croiconference.org/sites/default/files/posters-2015/545.pdf (PDF)
  5. Savant Landry I et al. HIV-1 Attachment inhibitor prodrug BMS-663068: model-based dose selection. CROI, 23-26 February 2015, Seattle. Poster abstract 509.
  6. Savant Landry I et al. HIV-1 attachment inhibitor prodrug BMS-663068: interactions with DRV/r and/or ETR. CROI, 23-26 February 2015, Seattle. Poster abstract 523.