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Antiviral activity and safety of 873140, a novel CCR5 antagonist, during short-term monotherapy in HIV-infected adults
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AIDS: Volume 19(14)
23 September 2005
Lalezari, Jacoba; Thompson, Melanieb; Kumar, Prinyc; Piliero, Peterd; Davey, Richarde; Patterson, Kristinef; Shachoy-Clark, Anneg; Adkison, Kimberlyg; Demarest, Jamesg; Lou, Yug; Berrey, Michelleg; Piscitelli, Stepheng
From the aQuest Clinical Research, San Francisco, California, USA
bARCA, Atlanta, Georgia, USA
cGeorgetown University, Washington D.C., USA
dAlbany Medical College, Albany, New York
eNational Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
fUniversity of North Carolina, Chapel Hill, North Carolina, USA
gGlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Efficacy
The median change in HIV RNA from baseline is shown in Fig. 1. The log10 decline at nadir and the percentage of subjects achieving a 1 log drop is shown in Table 2. A dose-dependent decrease in HIV RNA was observed with the greatest effect of a mean 1.66 log10 decline seen at the highest dose of 600 mg b.i.d. with all subjects in this cohort achieving at least a 1 log10 decline. The nadir HIV RNA most commonly occurred on day 12, but ranged between day 5 and 24 (14 days postdosing) for subjects receiving 873140. No differences were noted in antiviral response between subjects who were naive to therapy or those having previously received antiretroviral drugs. CD4 lymphocyte counts on day 11 were not significantly different from baseline. Subjects with 1 log or more reduction in VL: 62% (n=8) in 400 mg qd regimen; 75% (6/8) in 200 mg bid; placebo (n=9) 0/9; 1/7 16% in 200mg qd; 1005 8/8 in 600 mg bid regimen.
Introduction
The identification of new targets and novel agents against HIV infection remains a critical undertaking due to the widespread prevalence of drug resistant strains [1,2]. The cellular cc chemokine receptor 5 (CCR5) antagonists represent a new class of agents aimed at inhibiting viral entry. Following binding of gp120 to the CD4 receptor, CCR5 antagonists inhibit the interaction of gp120 to the co-receptor, an integral step in the fusion of HIV to the host cell [3,4].
873140 is a CCR5 antagonist of the spirodiketopiperazine class that is in late stage clinical development for the treatment of HIV infection. 873140 demonstrates potent in vitro antiviral activity with a 50% inhibitory concentration (IC50) against CCR5-tropic HIV-1 in the subnanomolar range and demonstrates a slow receptor offset rate with no appreciable dissociation over 150 h in vitro [5,6]. This study represents the first administration of this agent to HIV-infected subjects to compare the antiviral effect, safety, tolerability, and pharmacokinetics of 873140 versus placebo during 10 days of monotherapy.
Abstract
Objective: 873140 is a spirodiketopiperazine CCR5 antagonist with prolonged receptor binding and potent antiviral activity in vitro. This study evaluated plasma HIV RNA, safety, and pharmacokinetics following short-term monotherapy in HIV-infected adults.
Design: Double-blind, randomized, placebo-controlled multi-center trial.
Methods: Treatment-naive or experienced HIV-infected subjects with R5-tropic virus, CD4 cell count nadir > 200 x 106 cells/l, viral load > 5000 copies/ml and not receiving antiretroviral therapy for the preceding 12 weeks were enrolled. Forty subjects were randomized to one of four cohorts (200 mg QD, 200 mg BID, 400 mg QD, 600 mg BID) with 10 subjects (eight active, two placebo) in each cohort, and received treatment for 10 days. Serial HIV RNA, pharmacokinetics, and safety evaluations were performed through day 24.
Results:
Of the 40 subjects, 21 were treatment-experienced; 35 were male, 20 were non-white, and eight were coinfected with hepatitis C virus.
Median baseline HIV RNA ranged from 4.26log10 to 4.46 log10.
873140 was generally well tolerated with no drug-related discontinuations. The most common adverse events were grade 1 gastrointestinal complaints that generally resolved within 1-3 days on therapy.
No clinically significant abnormalities were observed on electrocardiogram or in laboratory parameters.
Mean log changes in HIV RNA at nadir, and the percentage of subjects with > 1 log10 decrease were -0.12 (0%) for placebo, -0.46 (17%) for 200 mg once daily, -1.23 (75%) for 200 mg twice daily, -1.03 (63%) for 400 mg once daily, and -1.66 (100%) for 600 mg twice daily.
An Emax relationship was observed between the area under the 873140 plasma concentration-time curve and change in HIV RNA.
Conclusions: 873140 demonstrated potent antiretroviral activity and was well tolerated. These results support further evaluation in Phase 2b/3 studies.
Safety
There were no deaths, serious adverse events, or grade 4 AE reported. Twenty-eight of 40 subjects (70%) experienced 69 AE that were considered by the investigator to be related to the study drug. The most commonly reported drug-related AE were gastrointestinal in nature. Diarrhea was reported more frequently in subjects receiving 873140 (25-57%) compared to placebo (0%). The incidence of loose stools was similar in subjects taking 873140 (13-38%) and in those taking placebo (33%). Nausea and abdominal pain occurred in 13-38% of subjects in the 873140 groups and 11% in subjects receiving placebo. The incidence of gastrointestinal AE was 57% at 200 mg q.d., 50% at 200 mg b.i.d., 75% in the 400 mg q.d. and 600 mg b.i.d. groups, and 44% in the placebo group. Gastrointestinal AE usually occurred on day 1 and generally resolved within 1-3 days while subjects continued on therapy. Two subjects received supportive medications for gastrointestinal AE: one received a single dose of loperamide and one received two doses of promethazine. Other AE included minor central nervous system complaints such as headache and dizziness and occurred with low frequency in only one or two subjects in both the active treatments and placebo groups. One subject experienced grade 3 fatigue 4 days after his first dose of 873140 (200 mg b.i.d.) which resolved 14 days after onset. All other drug-related AE were mild or moderate in intensity. There were no clinically significant changes in vital signs or ECG interval in subjects treated with 873140. In eight subjects with hepatitis C virus (HCV) coinfection, serum HCV RNA was not significantly altered between day 1 and day 11.
Tropism and phenotype
One subject randomized to the 200 mg q.d. group had a transient detection of both CCR5 and CxCR4-using viruses on day 10 of the study. CCR5-using virus only was detected in this subject at other timepoints on therapy (day 1 and 5) and at follow-up on day 24. This subject had a 0.5 log10 decrease in HIV RNA during the study, consistent with the mean decrease for this dosing group. A preliminary analysis of this subject demonstrated that CCR5- and CxCR4-using virus was pre-existing prior to therapy but that is was below the assay detection limit. In all other subjects only CCR5-using virus was detected during the trial and at follow-up.
Pharmacokinetics
Pharmacokinetic parameters of 873140 on day 10 are shown in Table 3. 873140 was readily absorbed with a median tmax of 1.75-2.5 h on day 10 of dosing. AUC(0-:) and AUC(0-t) increased with total daily dose; the increase was slightly greater than dose-proportional on day 10. Some accumulation was observed with AUC(0-t) values on day 10 that were 41%, 79%, and 80% higher than the AUC(0-t) on day 1 for the 200 mg q.d., 200 mg b.i.d., and 600 mg b.i.d. regimens, respectively. This increase in AUC over time was not seen at 400 mg q.d.
Cmin (ng/ml)
200 qd 0.80-2.54 (n=2)
200 bid 6.27 (2.42-16.25
400 qd 1.65 (0.53-5.07) (n=7)
600 bid 4.12 (1.55-10.97)
Discussion
CCR5 represents a novel target for development of new antiretroviral drugs. This trial demonstrated that 873140 possesses potent activity against R5-tropic HIV strains during short-term monotherapy. The antiviral effect was similar between treatment naive and experienced subjects, which is expected for a compound directed toward a new target. The mean 1.6 copies/ml log10 decline in HIV RNA is similar to other investigational drugs in this class, as well as to that seen with nucleoside reverse transcriptase inhibitors and protease inhibitors, further validating CCR5 as an important target for further drug development [7-10].
Of note, the HIV-RNA levels continued to decline after 873140 was discontinued with the nadir generally occurring on day 12, approximately 48 h after treatment was stopped (Fig. 1). This extended antiviral effect may be a consequence of the prolonged binding of 873140 to CCR5. In an in vitro assay using membrane preparations, various CCR5 antagonists were shown to have extended binding to the receptor [6]. 873140 demonstrated a half-life of receptor occupancy estimated to be in excess of 150 h [6]. This delay in achieving viral load nadir has also been observed in short-term clinical studies of other investigational CCR5 antagonists and in SIV-infected macaques receiving a CCR5 inhibitor [7,8,11]. Ongoing clinical trials including 873140 in combination with other antiretrovirals will determine both the activity and durability of 873140-based antiretroviral regimens.
A range of doses (200-1200 mg/day) was studied to allow examination of exposure-response relationships. In addition, the dose of 400 mg/day was administered either once daily or in divided doses twice daily to explore the effect of dosing frequency on the antiviral activity of 873140. PK/PD modeling of the relationship between various plasma PK parameters (total daily AUC, maximum and minimum concentrations-Cmax, and Cmin) and antiviral activity (HIV RNA day 11 or nadir change from baseline) demonstrated that overall exposure, as described by plasma AUC, provided the best fit of the PK/PD model shown in Fig. 2. A comparison of the 400 mg q.d. and 200 mg b.i.d. regimens supported the notion that plasma AUC and not Cmax was the better PK parameter linked to efficacy in this study. An evaluation of the plasma Cmin-antiviral effect relationship was limited because many Cmin values were below the assay limit of detection for the q.d. regimens. The AUC-antiviral effect relationship was used to select doses for future studies, which will continue to explore the exposure-response relationship of various 873140 regimens in combination with other antiretrovirals.
873140 was well tolerated during this short term study with gastrointestinal complaints reported as the most common adverse event. When these events did occur, they generally began on day 1 and resolved in the majority of patients over 1-3 days. Adverse events were generally mild and supportive medications for nausea or diarrhea were only given to two subjects in the trial.
873140 has now progressed into larger late stage clinical trials. The availability of a new, potent class of drugs to the HIV clinician has numerous implications. The successful development of the CCR5 antagonist class will lead to new treatment options for HIV-infected subjects.
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