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UK-427,857, a new CCR5 (entry) Inhibitor: viral load, safety QTc interval, tolerability, food effect in 10 day monotherapy study
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Reported by Jules Levin
--first CCR5 (entry) inhibitor to enter large Phase III studies
--10-day monotherapy study shows –1.3 to –1.6 log viral load reductions
Genetic evidence indicates blocking of the CCR5 receptor on cells should have a profound effect on viral replication and HIV disease progression in patients who carry R5 HIV variants. UK-427,857 is being developed by Pfizer and is the first CCR5 inhibitor to enter phase III studies. Three large international Phase III studies are expected to begin by the end of 2004. UK-427,857 is a selective CCR5 antagonist with potent anti-HIV activity in vitro (in the test tube). To date, studies in healthy volunteers have demonstrated that the drug is safe and well tolerated with plasma concentrations in excess of the antiviral IC90 obtained at doses >=100 mg BID (twice daily). At the Intl XV AIDS Conference in Bangkok (July 2004), researchers (Fatkenheuer et al) reported short-term monotherapy study results in HIV patients to evaluate the effect of this drug on viral load, and the relationship between viral load reduction and PK/PD parameters, the effect of food, and to explore the effect of various doses on viral load reduction. As well th study examined safety and tolerability. Here is the author's report.
BRIEF SUMMARY: UK-427,857 at doses up to 300 mg (bid) was safe and well tolerated in this study. HIV viral load was reduced by 1.3 to 1.6 log after 10 days of this monotherapy study. by doses that will be used in Phase III studies. Doses of >=100 mg BID and QD (once daily) resulted in viral load reductions of >1 log when given as short-term monotherapy. Dosing with food did not have a significant effect on the antiviral efficacy. Comparison of the 150 mg bid fed and fasted data suggests that food reduces the Cmax and AUC by about 60% and 50%, respectively. But, viral load reductions in this study (on day 11) were not effected by food, patients taking the drug fed or fasted had similar viral load reductions. For Phase III studies, 150 mg once daily and twice daily are being examined.
The poster at Bangkok reported results from two studies (A4001007 and A4001015), which were randomized, double-blind, placebo-controlled studies in asymptomatic HIV-infected patients. Patients were therapy-naïve, or off therapy for at least 8 weeks prior to study start. Patient's CD4 counts were >250 and viral load >5000 copies/ml. Patients had CCR5 tropic virus only. The Virologic Phenosense entry assay was used to screen for the patient's tropism: either CCR5 or CXR4: screening with this assay was conducted on days 1, 11 and 40.
80 patients with CD4 count >250 and plasma viral load >5000 received UK-427,857or placebo for 10 days and were followed up until day 40. In order to evaluate qd versus bid dosing regimens, doses of 25, 100, and 300 mg qd and 50, 100, 150, and 300 mg bid were evaluated. Additionally, a dose of 150 mg bid following a high-fat meal was evaluated in order to assess the effect of food on antiviral efficacy. Patients were pre-screened for the presence ofCCR5-tropic virus only. Viral load, UK-427,857 plasma concentration, and CCR5recepyor saturation were evaluated regularly throughout the study. Clinical safety evaluations, including ECGs and laboratory safety tests were performed.
RESULTS
There was no significant difference between the antiviral effects of 150mg bid and 300 mg qd with decreases of 1.45 log and 1.35 log, respectively. In addition, the antiviral effect of 150mg bid of UK-427,857 appeared to be independent of food intake, with reductions of 1.34 log and 1.45 log for the fed and fasted groups, respectively. For the patients taking 150 mg doses or greater, after dosing stopped on day 10 viral load reductions were sustained for 5 days without an increase in viral load at which point viral loads started to increase but it took another 10 days before they returned to baseline.
MEAN VIRAL LOAD DECREASES FROM BASELINE to DAY 11 BY DOSE GROUP
| N | Log decline | Min/Max | | 25mg qd | 8 | -0.43 | 0.016/-1.07 | | 50mg bid | 8 | -0.66 | 0.40/-1.36 | | 100mg qd | 8 | -1.13 | -0.43/-1.69 | | 100mg bid | 7 | -1.419 | -1.04/-1.84 | | 150mg bid | 8 | -1.44 | -0.89/-1.71 | | 150mg bid(fed) | 8 | -1.343 | -0.51/-1.78 | | 300mg qd | 8 | -1.34 | -0.95/-1.62 | | placebo (07) | 12 | 0.02 | 0.56/-0.44 | | placebo (15) | 4 | 0.085 | 0.27/-0.19 |
CCR5 SATURATION
Using an experimental assay CCR5 saturation was evaluated predose and 4 hours postdose on day 1, predose on days 5 and 10, and on days 11, 13, 15, 19, and 40. Mean CCR5 receptor saturation in patients receiving all doses of UK-427,857 was equal to or in excess of 85% on days 5 and 10 predose, except for subjects receiving 25 mg qd whose mean receptor saturation fell <80% by day 10 predose (steady state). Saturation remained above 60% for 5 or more days after drug was stopped at day 10 for the higher dose regimens. This may be related to the delay in viral load rebound after dosing was stopped on day 10. Saturation slowly declined from 60% to 40% from day 20 to day 40.
CD4 RESPONSES
There were small increases in mean CD4 count at day 11 in all of the UK-427,857 dose groups, but there was no correlation between the cd4 count and viral load response or dose. CD4 counts at baseline in the various dose groups ranged from 380 to 650.
VIRAL TROPISM
61/63 patients with CCR5 tropic virus at baseline and who received UK-427,857 for 10 days remained CCR5 tropic throughout the study.
Viral tropism changes were seen in 2 patients receiving 100mg qd who responded well, with viral load declines of 0.71 and 1.26, respectively.
One patient had a transient emergence of dual tropic virus at day 11, but reverted to being CCR5 tropic at day 40.
Dual tropic virus was detected at day 11 in the second patient, and has been detectable at all timepoints since.
Detailed clonal analysis of the virus at different timepoints, and followup of this patient is ongoing.
The patient remains clinically well, with viral load, and cd4 counts not significantly different from previous values, >6 months post-study.
QTc INTERVAL INHEALTHY SUBJECTS
In a separate poster Davis et al presented in a poster results from a study designed to estimate the effect of single doses of UK-427,857 on the QTc interval in healthy subjects. Single doses of UK-427,857 (100, 300, and 900mg) and moxifloxacin 400 mg were given in a randomized, placebo-controlled, 5-period crossover study. 61 subjects entered the study. Healthy male and female subjects aged 19 to 44 and weight between 60 and 85 kg (males) or 50 and 80 kg (females) and with Quetelet's Index --weight (kg)/height2 (m) between 18 and 28. Thirty male and 31 female subjects were assigned to treatment. The QT:RR relationship was evaluated from 12-lead ECGs recorded pre-dose and on a run-in day in period 3. A nonlinear mixed effect model was used to estimate a correction factor for each subject (b). QTcI was calculated per subject as QTcIs=QT/(RR)b. The primary endpoints analyzed were (1) QTcI at median T max (assumed to be 2 hrs for moxifloxacin); (2) Maximum increase from baseline in QtcI from 1-4 hr postdose; (3) Average QTcI from 1-4 h postdose. Comparisons against placebo were carried out for all primary endpoints using ANOVA. The ANOVA for each pair-wise comparison allowed for variation due to sequence, subject within sequence (random effect), period, and treatment. Baseline was used as a covariate.
RESULTS. Mean plasma concentrations-time profiles were similar in male & female subjects. UK-427,857 was rapidly absorbed with Tmax occurring in 1.0 to 4.0 hours. The mean difference in QtcI from placebo for all primary endpoints was <4 ms for UK-427,857 (100, 300, and 900mg). The upper limit of the 90% confidence interval was below 7 ms for all primary endpoints. There were no UK-427,857 treated subjects showing maximum QTcI values >450 ms (males) and 470 ms (females), or maximum increases from baseline in QtcI >60 ms. Moxifloxacin caused a mean increase in QTcI of 12-14 ms for all 3 primary endpoints. Geometric mean Cmax and AUC following the 900mg dose were 1.15 mg/L and 5.26 mg/L, respectively. No serious adverse events were reported. The most commonly reported AE was dizziness, following UK-427,857 900mg. Other reported adverse events included headache, postural hypotension, nausea, and cystitis. The authors concluded that single UK-427,857 doses up to and including 900 mg have no clinically significant effect on the QTc interval in healthy subjects.
SAFETY & TOLERABILITY
UK-427,857 was safe and well tolerated in HIV+ patients, with an AE profile similar to that seen in volunteers. All adverse events, except for 1 episode of diarrhea, were graded as being mild or moderate. Two patients discontinued treatment, 1 receiving 25 mg qd withdrew his consent on day 3, and another receiving 100 mg qd discontinued on day 3 due to a nontreatment-related adverse event. There were no clinically significant lab abnormalities or effects on QTc interval observed during dosing with UK-427,857.Adverse events, the types and number of events, were not dose related. The events reported were asthenia, dizziness, gingivitis, headache, nausea.
CONCLUSION. The authors concluded the drug was safe and well tolerated at doses up to 300 mg bid in this patient group. Mean viral load reductions were –1.3 to –1.6 in the 150 mg bid and 300 mg qd doses. Dosing with food did not have a significant effect on the antiviral efficacy, although food reduced Cmax and AUC by about 60% and 50%, respectively. Phase III studies are planned for the end of 2004.
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