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UK-427,857 (HIV attachment inhibitor)
Reported by Jules Levin
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Effect of Short-Term Monotherapy with UK-427,857 on Viral Load in HIV-Infected Patients
In Sunday’s first slide session on HIV, Fatkentheuer and colleagues (abstract H-443) reported results from a 10-day study of monotherapy of the first HIV co-receptor inhibitor to show efficacy and no safety issues in patients. The study was conducted in 24 HIV-infected patients of whom 8 received UK-427,857. The study results are promising in showing UK-427 to be potent and safe and tolerable. The drug will be studied with once and twice a day administration and further studies are planned.
Technically, attachment of HIV to the CD4 cell is first made to the CD4 receptor and the second step is attachment to the co-receptor so UK-427 is considered a co-receptor anagonist or inhibitor. UK-427,857 is being developed by Pfizer Pharmaceuticals.
After HIV binds to the CD4 receptor on the CD4 cell, HIV binds to a co-receptor, CCR5 or CXCR4 are the two co-receptors used for HIV to attach itself to the CD4 cell for entry into the CD4 cell where HIV reproduces itself.
It appears that patients will have to be tested to see whether they are R5, dual, or X4 tropic (explained further below). If patients are not R5 tropic it may not be worthwhile for them to be treated with UK-427. Some patients may revert from dual tropism, R5/X4, to R5 on HAART, but if patients don’t revert they may not need to take 427. Patients who are X4 tropic may not be as likely to respond to the inhibitor. You can see this area is complicated and a lot of research will have to be conducted to understand this.
The drug is active against HIV resistant to current HIV drugs. Efficacy against HIV with T-20 resistance has not been tested yet but it will be studied.
Summary of Healthy Volunteer Data Prior to this study 427 was tested in >320 healthy volunteers who received single or multiple doses. For up to 28 days 427 was safe and well tolerated in single doses up to 900 mg and multiple doses up to 300 mg BID. Most frequent adverse events after multiple dosing were headache, flatulence, dizziness, nausea, and postural hypotension (feeling lightheaded when standing after being in prone position). There was no evidence of QTc prolongation following single doses of 900 mg or multiple doses of up to 300 mg BID. QTc prolongation was observed in study of a Schering-Plough co-receptor inhibitor, SCH-C, and they are now developing SCH-D instead. QTc is a measure of the time it takes an electrical impulse to pass through the heart. QTc prolongation can increase the risk of serious heart rhythm disturbances. Dose of 100 mg BID should achieve 24 hour plasma concentration in excess of IC90 at steady state.
This study looked at monotherapy of 427 in patients infected with CCR5 virus because the drug as monotherapy is not effective against CXCR4 tropic HIV; that is, HIV that uses the CXCR4 co-receptor. After HIV progresses to a certain point patients can switch from CCR5 tropic (HIV uses this co-receptor) to CXCR4 (HIV uses this co-receptor). A small number of patients may be dual R5/X4 tropic. Results from studies find, however, that patients who are X4 tropic can revert to R5 after starting HAART. So HAART plus 427 will be studied by Pfizer for patients who are CXCR4 tropic.
CD4 counts were >250 and viral load was >5000 copies/ml for patients in this study. Patients were treatment naïve or off treatment for 8 weeks for the study.
There were 8 patients in each study arm (placebo, 25 mg once daily, 100 mg twice daily; both oral administration). Drug was dosed for 10 days with a 40-day follow-up.
RESULTS
Plasma concentrations were similar to those seen in healthy volunteers under similar food restrictions, with all patients receiving 100mg BID reaching trough concentrations in excess of the mean antiviral IC90 in PBMC. Mean CCR5 receptor saturation at 100mg BID was in excess of 90% throughout the dosing period, but at 25mg QD mean saturation fell to <80% by day 10. There is a food effect. The PK (drug levels) profile following a single dose of UK-427,857 was reported. These data show the drug uptakes quickly as levels were similar on day 1 as day 10. Plasma concentrations were similar at day one vs day 10. Drug levels were higher in the fasting state compared to the fed state.
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7 of 7 patients with CCR5 tropic virus at baseline had at least a 1 log reduction in viral load. One patient receiving 100 mg BID was found to be dual tropic at baseline and was excluded from the analysis. Mistakenly the patient was initially tested as being CCR5 tropic. There was some evidence of response at 25 mg once daily, with 4/8 patients achieving a viral load decline of >0.5 log. The mean viral load decrease was –1.41 log for patients receiving 100 mg BID excluding the 1 patient who was dual tropic. The mean viral load reduction was –0.43 log for patients receiving 25 mg QD, and –0.02 log for patients receiving placebo.
After stopping 427 viral load declines slowly back to baseline because apparently some drug remains for a time attached to the co-receptor.
Effect of UK-427,857 in R5/X4-tropic Patient
There was no response to UK-427,857 100 mg BID. Screening virus tropism indicated presence of R5 virus, but data from day 1, 11, and 40 indicates R5/X4 (sample error was confirmed).
There was an apparent increase in X4 from day 1 to day 11 (with decrease in R5), and values returned to baseline by day 40:
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*RFU-relative fluoresence units
The change in viral load appears not to be significant. The important data is that when the selective pressure of an r5 inhibitor was removed the patient’s virus population reverted back to predominantly being r5 tropic.
SAFETY & TOLERABILITY. 427 was reported to be well tolerated in patients with no serious adverse events reported. Asthenia, headache, and dizziness was reported in all 3 study arms. There were no discontinuations due to adverse events or lack of toleration, There were no clinically significant laboratory abnormalities. There was no evidence of QTc prlongation or other ECG abnormalities.
In sum, 427 appeared safe and exhibited potent antiviral activity when given as short-term monotherapy. Further study evaluation is planned and both once and twice daily oral administration is being explored for use in Phase III studies.
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