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The Antiretroviral Pipeline

September 2011

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BMS-663068: An Oral Entry Inhibitor

BMS-663068 (BMS-068) is an entry inhibitor in development from Bristol-Myers Squibb active against the gp120 binding site on the CD4 cell. After oral administration this prodrug rapidly converts to BMS-626529, which reaches steady state after 2-3 days.

Richard Nettles from BMS reported results from a randomized open-label proof-ofconcept study using BMS-068 in 50 people who were either antiretroviral treatment-naive (n = 34) or treatment-experienced but off treatment for the previous eight weeks (n = 16). Pharmacodynamic data were presented for 39 patients with an eligible IC50 <0.1 uM.49

The study included five dose combinations using BMS 068 1200mg once-daily and either 600 mg or 1200 mg twice-daily, with and without ritonavir boosting. Baseline demographics included median (range): CD4 432 cells/mm3 (206-921); viral load 4.4 log copies/mL (3.3-6.1); age 42 years (20-70).

After eight days most doses had reduced viral load by 1.6 logs (ranging from -1.22 to -1.78 in the intent-to-treat and -1.59 to -1.77 in the pharmacodynamic analysis). CD4 cell increases ranged from +28 to +106 after eight days. All patients with an eligible IC50 achieved viral load reductions of at least 1 log.

The pharmacokinetic data showed ritonavir to have a relatively modest impact on boosting BMS-068 and plasma levels of BMS-529 remaining 50-fold above median protein adjusted IC90 for twice-daily dosing and 9-fold above with the once-daily arm (with ritonavir).

All adverse events were grade 1 or 2 and were similar in each arm (though there was not a control arm). The most frequent side effects included headache (22/50, 44%) and rash (8/50, 16%), mostly mild. There were no drug discontinuations.

Detailed results were also available in a separate poster available online.50

A pharmacokinetic analysis of the dose response rate reported that the baseline EC90 as a marker for drug susceptibility has a stronger correlation to virological response that pharmacokinetic exposure and that EC90 values were wide in the monotherapy study (median 9.6 ng/mL, range 0.33 to >1860).51

Drug levels suggested that ritonavir boosting may not be needed, and phase IIb trials in treatment-experienced patients are planned to start later this year.

Dolutegravir: A New Integrase Inhibitor

Dolutegravir (previously GSK1349572) is in development by ViiV/Shionogi as a oncedaily integrase inhibitor but overcomes resistance to raltegravir with twice-daily dosing. This makes this a key pipeline compound for use in multidrug-resistant patients.


Results from a second open-label phase IIb study of dolutegravir in people with raltegravir resistance were presented at CROI 2011.52

The dose-response rates from the initial use of a 50 mg once-daily dose of dolutegravir supported increasing the dose to 50 mg twice daily for this second cohort of treatment-experienced patients.

Baseline demographics included median (IQR): CD4 202 cells/mm3 (19-384); viral load 4.3 log copies/mL (3.9-4.8); age 47 (33-68); 75% male; duration on raltegravir 29 months (10-63). At baseline the median (range) fold change in susceptibility was >128 (0.8 to >128) to raltegravir and 2.7 (0.9 to 9.5) to dolutegravir. Baseline patterns of integrase-associated mutations were: N155H (n = 6); Y143H (n = 6); Q148+1 (n = 8); Q148+2 (n = 2); mixture (n = 1); other (n = 1).

The 50 mg twice-daily results included 24 people who added dolutegravir to a failing combination for 11 days (and who dropped raltegravir if they were still taking it). To be included in the study people needed to have at least one additional drug that would be active, and this was added to dolutegravir on day 11 when the background combination was optimized, based on resistance test results.

Nearly all patients (23 out of 24) either reduced their viral load to less than 400 copies/mL or by at least 0.7 logs. The average (mean) drop in viral load at day 11 was -1.76 logs (SD 0.54) for the study as a whole and -1.57 for people with integrase mutations (Q148 + others). This compared to -1.45 logs seen in the initial 50 mg once-daily study.

Safety data were available for a median 96 days (range 30-172) mainly included common grade 1 or 2 gastrointestinal events not related to dolutegravir. Grade 3 laboratory abnormalities were reported in 4 people (17%) with no discontinuations. One participant had two serious events judged unrelated to the study drug (demyelinating polyneuropathy and diabetes mellitus). No grade 4 events were reported.

The 50mg twice-daily dose has now been selected for phase III studies in people who have integrase inhibitor resistance to raltegravir or elvitegravir. Phase III studies are also ongoing in integrase-naive patients.53

Forty-eight-week results from ViiV's phase II dose-ranging study of dolutegravir compared to efavirenz in treatment-naive patients were presented at the 2011 IAS in Rome.54 These results were broadly similar to the 16-week virological and safety results presented at the IAS conference in Vienna in 2010. Dolutegravir and efavirenz achieved similar virological efficacy with differences between the two arms driven by slightly higher discontinuations related to efavirenz side effects.

Dolutegravir is also being coformulated in a fixed dose combination with GSK/ViiV nucleosides abacavir and 3TC. A phase III study in treatment-naive patients began recruitment in April 2011.55

Lersivirine: An NNRTI

Lersivirine (formally UK-453061) is an NNRTI previously in development at Pfizer and amalgamated into the ViiV antiretroviral portfolio, where development has not been prioritized over GSK's pipeline compounds.

A review of lersivirine was presented at the 10th International HIV Congress held in Glasgow in November 2010 focusing on the resistance profile.56

Viral load reductions of 1.6-1.8 logs were previously reported at the three higher doses of a 7 day monotherapy study in treatment-naive patients.

Lersivirine retained in vitro susceptibility (defined as <10-fold change in the IC50 of lersivirine) to 11 out of 19 viruses with multiple NNRTI resistance mutations that had significant loss of sensitivity to etravirine (>2.9-fold change; the lower clinical cutoff for etravirine) and to 5 out of 10 viruses (with >10-fold increase in IC50 for etravirine). Sensitivity to lersivirine was retained for many of the multiple mutations including Y181C. Additionally, the lack of correlation between resistance patterns for lersivirine and etravirine was reported to be consistent with their distinct mechanisms of action.

Forty-eight-week results were presented at the IAS for a dose-finding study comparing lersivirine to efavirenz in treatment-naive patients. The percentage of patients with viral load <50 copies/mL was 79%, 79% and 86% in the 500mg, 750mg and EFV groups respectively. Although the study was not powered to detect between arm efficacy the lersivirine arms suggested a poorer response compared to efavirenz (500 mg: -9% difference; 80%CI -18.1, 0.8 and 750 mg: -8% difference; 80%CI -17.0, 1.2). Overall, the combined safety analyisis reported a similar incidence of side effects in each group but fewer grade 3/4 events in the lersivirine groups (n= 2 and n=3) compared to efavirenz (n=8).57

Cenicriviroc: CCR5 and CCR2 Inhibitor (Formerly TBR-652 and TA K-652)

Cenicriviroc is a CCR5 inhibitor with CCR2 activity in development with Tobira. CCR2 is associated with and studied in association with diseases related to immune activation.

Results from a 10 day dose-ranging monotherapy study in 54 treatment-experienced but CCR5-receptor blocker-naive patients were presented at the 18th International AIDS Society Conference in July 2010. Participants were randomized to 25, 50, 75, 100, or 150 mg cenicriviroc, all once daily, or to a placebo group. Inflammatory markers (MCP-1, hsCRP, and IL-6) were measured at days 1 and 10.58

Baseline median viral load was 4.5 log copies/mL (range 3.1-6.0), approximately 30,000 copies/mL, but this presumably limited the ability to detect maximum changes for patents starting with low viremia.

At day 10, viral load reductions of 1.4-1.8 log copies/mLwere seen in the 50-150 mg groups. Side effects were generally mild but were dose-related, and were higher in the 100 and 150 mg groups.

Although MCP-1 (a cytokine involved in immune inflammation) increased in all groups except placebo (significantly compared to placebo in the 50, 100, and 150 mg groups) this was only markedly higher for the 150 mg arm (by approximately 350 pg/mL).

Phase IIb studies of the compound are expected to start early in 2011.20

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
See Also
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HIV Drugs in Development

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