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GW640385X, new Protease Inhibitor
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Reported by Jules Levin
At the recent annual GSK-community meeting early study data for this new protease inhibitor was discussed. GSK discussed their new drug pipeline, which includes developing drugs for different HIV targets and for hepatitis C. In addition to their CCR5 drug GW873140, research includes drugs for integrase and CXCR4. As well, GSK has a program to develop drugs for HCV.
The new PI is being studied in patients and has received a Fast Track designation from the FDA. '385' has been studied in >350 subjects in phase I and II. It is dosed twice daily (300/100 mg) with ritonavir boosting. The study data in treatment-naives and experienced with PI resistance, and information and early study data was presented at the meeting last week. The study result to date show 385 to be safe and potent in both naives and experienced.
385 was designed and selected for clinical development on the basis of virologic potency:
--HIV PI: KI about 15fM
--In vitro anti-HIV activity: IC50=2.2 nM (MT4) / 0.2 nM (PBMC)
--50-250x more potent in-vitro than amprenavir and other marketed PIs
Ritonavir is required to boost 385 due to its low oral bioavailability (via CYP3A4 inhibition), similarly as other PIs are boosted by RTV. 385 is 87-98% bound in human plasma.
385 was tested in vitro (in the test tube) against HIV viruses from patients with drug resistance to the current PIs including lopinavir, IDV, NFV, and APV.Viruses were selected from Virologic panel based on the presence of protease mutations at codons 10, 32, 47, 50, 54, 84, and/or 90 (these are key PI mutations that lead to PI drug resistance). The average number of mutations for each patient blood sample was 8, range: 4-14. Using the Phenosense Assay the patient samples were highly resistant to current PIs and mostly susceptible to 385. The fold-change for 385 was very low for many viruses with the exception of only a few.
A combined safety analysis reported adverse events: no serious adverse events or drug-related grade 3-4 events. AEs were all mild (grade 1) except for grade 1-2 rash. AEs potentially related to 385: headache, nausea, abdominal cramps, soft stool/diarrhea, lightheadedness, and pruritis (severe itching). AEs necessitating discontinuation in healthy subjects (HPR10003): 3 healthy subjects receiving 385X alone and one on 385X/fosamprenavir had grade 1-2 rash.
Clinical laboratory tests: no clinically significant abnormal trends regarding LFTs, TFTs, or lipase, including >24 weeks in HIV+ patients. Modest increases were seen in cholesterol, triglycerides consistent with other boosted PIs.
CARDIAC CONDUCTION (preliminary data): No clinically significant ECG trends were seen in ECGs performed and stored in digital database in 6 studies. No clinically significant changes observed in >320 healthy volunteer studied or 31 HIV+ patients. Dedicated QTc study still planned.
HPR1006 study: antiviral activity in combination with NRTIs
This was an open-label, pilot study of 30 subjects. These are preliminary interim analysis 8-week data for a planned 48 week study. Study patients were both ART-naives and experienced. 385 was dosed 300/100 mg twice a day (100mg RTV boost). 385 was combined with any NRTIs except TDF+ ABC (I guess to avoid the possibility of an interaction). 31 patients were randomized, 2 withdrew prior to week 8. At baseline 25 patients had wild-type HIV, 6 patients had multi-drug resistance (MDR).
Safety through 8 weeks: no rash, no drug-related serious adverse events, or grade 3-4 toxicities; 1 withdrawal (SE), possibly related to 385; no clinically significant changes in LFTs; small increases in cholesterol/triglycerides (consistent with other boosted PIs).
VIRAL LOAD REDUCTIONS: a median -2.7 log HIV RNA reduction at week 8 in wild-type and -2.2 log in MDR patients. 21/31 patients at week 8 <400 copies/ml, 67%. The 6 MDR subjects had median 7 PI mutations with 2 primary PI mutations. These patients had median 385 IC50 fold change=1.03, in other words they were phenotypically sensitive to 385 although resistant to other PIs. The PK (extrapolated) was the same as in healthy subjects. 27 patients were on Combivir (AZT/3TC), and comparative data show no significant drug-interaction.
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