The development of the CCR5 antagonist aplaviroc (GW873140) by GlaxoSmithKline (Glaxo) was prematurely discontinued due to several cases of treatment-associated hepatotoxicity1 -- mercifully, none fatal. The agent also appears to be associated with diarrhea. In contrast, both of these adverse events are not associated with maraviroc (UK-427,857) or vicriviroc (SCH 417690, SCH-D), two other CCR5 antagonists currently in development.
At the time Glaxo terminated aplaviroc development, several studies in both treatment-naive and treatment-experienced patients were ongoing. Of particular interest was the EPIC study evaluating aplaviroc + lopinavir/ritonavir (LPV/r, Kaletra) -- a regimen sparing the nucleoside reverse transcriptase inhibitor (NRTI) class -- against a standard regimen of zidovudine/lamivudine (ZDV/3TC, Combivir) + lopinavir/ritonavir in treatment-naive individuals.2 Patients assigned to the aplaviroc arm received one of three aplaviroc doses: 200 mg twice daily (BID), 400 mg twice daily or 800 mg once daily. NRTI-sparing regimens are of considerable interest for persons who cannot take NRTIs due to toxicity, transmitted resistance, or other contraindications.
The multicenter, randomized, open-label, parallel-group, repeat-dose, phase IIb EPIC study included 193 individuals harboring CCR5-tropic or CCR5/CXCR4-tropic virus who were enrolled at 36 centers in the United States, five centers in Canada and 38 sites in the European Union. Of these individuals, 191 received at least one dose of study medication, hence comprising the safety population, and 141 initiated treatment early enough to complete 12 weeks of treatment before the study was terminated on September 15, 2005. A total of 133 of the 141 individuals (94%) who could have completed 12 weeks of treatment actually did so.
The proportion of patients achieving a viral load below 400 copies/mL by week 12 is shown in the figure. The data suggest a delayed or diminished response with aplaviroc treatment, since only 49% to 54% of aplaviroc-treated patients had a viral load below 400 copies/mL compared with 72% of zidovudine/lamivudine-treatment patients. Virologic failure was infrequent in this study (6%) and was not associated with the development of resistance to aplaviroc or a change in tropism.3
Changes in CD4+ cell count did not differ significantly between arms, although aplaviroc recipients showed trends toward greater CD4+ cell count increases -- an observation also suggested from clinical data with other CCR5 antagonists. Changes at week 12 were +144 cells/mm3 in the zidovudine/lamivudine arm relative to +169, +170, and +198 cells/mm3 in the aplaviroc 200 mg twice daily, 400 mg twice daily and 800 mg once daily arms, respectively.
Is the hint of a poor virologic response with aplaviroc based on the EPIC data corroborated by other studies? Indeed, it appears to be so.
The ASCENT study was a multicenter, randomized, partially double-blind, parallel-group, phase IIb study conducted in treatment-naive individuals using different oral doses of aplaviroc in combination with zidovudine/lamivudine relative to efavirenz (EFV, Sustiva, Stocrin) + zidovudine/lamivudine.4 Only individuals with CCR5-tropic HIV and no baseline reverse transcriptase resistance mutations were eligible for the study. Patients were randomized 2:2:1 to aplaviroc 600 mg twice daily, aplaviroc 800 mg twice daily or efavirenz, each in combination with zidovudine/lamivudine. Unlike the disastrous vicriviroc study conducted in treatment-naive patients that had to be stopped for high rates of virologic failure,5 participants in ASCENT started all drugs simultaneously.
A total of 145 individuals enrolled at 61 sites in the United States, Canada and Europe were randomized to one of the three treatment arms. The demographic and baseline characteristics were similar across treatment groups. Moreover, a comparable proportion of individuals had a baseline plasma HIV-1 RNA below and above 100,000 copies/mL (48% and 52%, respectively). The majority of patients had stable tropism readouts, with 140 of 145 individuals testing CCR5-tropic at screening and remaining so at baseline.
Prior to Glaxo's abandon of aplaviroc development, 115 of the 145 individuals included in ASCENT completed 12 weeks of treatment. Treatment efficacy through week 12 according to baseline viral load is shown below. The overall proportion of individuals with HIV-1 RNA below 400 copies/mL at week 12 according to intent-to-treat analysis was 53% (95% confidence interval [CI]: 40%, 67%) with aplaviroc 600 mg twice daily, 50% (95% CI: 37%, 63%) with aplaviroc 800 mg twice daily and 66% (95% CI: 46%, 82%) with efavirenz. So, again, the aplaviroc arms demonstrated a moderately diminished virologic response in comparison with the control regimen.
There was greater variability in the change in HIV-1 RNA from baseline in the two aplaviroc treatment arms relative to the control arm based on the range of responses observed. However, this variable efficacy was not explained by the pharmacokinetic data, as the mean plasma aplaviroc area under the curve values for the two aplaviroc treatment arms met or exceeded the target aplaviroc area under the curve value. Similar CD4+ cell count increases were seen across all groups.
Overall, the data suggest that aplaviroc's development, although allegedly discontinued for reasons of toxicity, may have also been discontinued based on insufficient efficacy. Since the pharmacokinetic data do not indicate that insufficient aplaviroc concentrations were the cause of poor efficacy, the data suggest that aplaviroc has an intrinsic problem in its ability to interact with its CCR5 receptor target. The development of aplaviroc has shed little light on the potential of CCR5 antagonists in treatment-naive individuals and, in particular, in novel NRTI-sparing regimens. It has, however, illuminated the various challenges of drug development.
Ryan CT. Trials of aplaviroc halted in treatment-naive patients. AIDS Clin Care. November 2005;17(11):107-108.
Yeni P, Rockstroh J, LaMarca A, et al. Safety and Antiviral Activity of the Novel CCR5 Antagonist Aplaviroc in Combination with Lopinavir/ritonavir in HIV-Infected Therapy Naive Subjects. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV; November 12-16, 2006; Glasgow, United Kingdom. Abstract P394.
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Kitrinos KM, Irlbeck DM, LaBranche CC, Madsen HA, Demarest JF. Virologic characterization of treatment naive subjects failing an aplaviroc-based regimen with either lamivudine/zidovudine or lopinavir/ritonavir. In: Program and abstracts of the XV International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 21.
Currier J, Lazzarin A, Kleim JP, Steel H, Millard J, Bonny T. Safety and antiviral activity of the novel CCR5 antagonist aplaviroc in combination with zidovudine + lamivudine in HIV-infected therapy naive subjects. In: Program and abstracts of the 8th International Congress on Drug Therapy in HIV; November 12-16, 2006; Glasgow, United Kingdom. Abstract P392.
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Greaves W, Landovitz R, Fatkenheuer G, et al. Late virologic breakthrough in treatment-naive patients on a regimen of Combivir + vicriviroc. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 161LB.