 |
|
|
| |
Tolerance and Potent AntiHIV Activity of Reverset Following 10 Days of Monotherapy in Treatment Naïve Individuals
|
| |
| |
Reported by Jules Levin
Reverset is a cytidine analog inhibitor of HIV-RT (NRTI). Rob Murphy reported preliminary study results on Reverset at the 11th Retrovirus Conference in San Francisco on Feb 11, 2004. Reverset is being developed by Incyte and Pharmasset, small drug discovery & development companies focusing on anticancer & antiviral drugs. Reverset is Incyte’s most advanced product. Murphy reported that preclinical studies demonstrate activity against wild-type HIV-1, HIV-2, and mutants resistant to 3TC, AZT, TDF, and other NRTIs, NNRTIs, and protease inhibitors. The drug has a long intracellular half life of the triphosphate (17 hrs). No mitochondrial toxicity or lactic acid increase in vitro, but Murphy & the company did not present this data. A single-dose clinical study showed excellent bioavailability and Reverset (RVT) had potent anti-HIV activity after a single dose (0.4 log decrease, p<0.001).
Reverset is currently in Phase II clinical trials for the treatment of HIV infections under an approved United States Food and Drug Administration Investigational New Drug application.
Apparently resistance to RVT does not develop easily. Murphy reported on the selection of HIV-1 resistance to RVT in vitro. In several cell types 18-37 virus passages resulted in 8-13 fold RVT resistance with these mutation profiles occurring: K70N, V90I, R172K; K65R, V179D; K65R, K122E, F214L. In a PBMCs with 20 virus passages no RVT resistance was detected.
RVT-202 is a dose-escalation, multiple dose, placebo controlled, doible-blind study exploring the safety, tolerability, pharmacokinetics and virological effect of escalating doses of 50, 100, and 200 mg in HIV-infected subjects; 30 HIV-treatment naïve subjects; HIV viral load >5,000 copies/ml; CD4 count >50; 10 subjects per cohrt (8 on active & 2 on placebo); oral doses of 50, 100, or 200 mg once daily (QD) for 10 days; HIV plasma RNA and CD4 count were monitored. Patient followup was for 30 days after 10 day dosing period.
BASELINE CHARACTERISTICS (median): 6-8 subjects in each dose arm; 5-7 males in each dose arm; 1-2 females; HIV RNA 4.24-4.81 log; CD4 353-645. All genotypes were wild-type.
The mean reduction in viral load at the end of the treatment phase ranged from 1.67 log10 copies/mL to 1.77 log10 copies/mL across all 3 dose groups, with placebo asrm showing no viral load reduction. After 6 days, mean viral load reductions were –1.20 to –1.33 log, after 8 days –1.41 to –1.54, and after 10 days –1.67 to –1.77 log (200 mg), -1.74 (100mg), -1.67 (50 mg). After 10 days on drug mean CD4 counts were over 800 in 100mg dose arm and 420 in 50mg arm.
There were no serious adverse events; no drug or dose related clinical or lab toxicities; no drug discontinuations; 46% of 24 study patients reported cold su=ymptoms, 33% headache and 17 fatigue, but Murphy said the study took place during winter & patients may have had colds. 17&-33% of patients onplacebo had same adverse events. (ed note: this drug has a history of adverse events observed in previous development. The drug has been around for a while and adverse events were observed in earlier years. Redevelopment of thisdrug is emerging now).
There was a dose-proportional PK response. Cmax for RVT increased from 2.3 uM for 50 mg dose to 5.4 uM for 100 mg dose to 9.8 uM for 200 mg dose. AUC (uM*h) increased from 11.9 for 50 mg dose, to 31.7 for 100 mg dose and 74.6 for 200 mg dose. Half life (h) increased from 4.0 for 50mg dose to 5.2 for 100mg dose & 5.2 for 200 mg dose.
Murphy reported that RVT was active against a series of mutant HIV strains of HIV in vitro (fold change): 3.2 fold change for virus with K65R; L74V (ddI mutation) 0.6 fold; M184V 0.2 fold change; T215Y , no fold change; against several strains with multiple NRTI mutations there was no resistance. However, there was resistance against virus strain with Q151MDR (23 fold), multidrug resistant mutation, and against the D69 serine insertions (18 fold). Average wild type EC50=1.6 uM. Cmax at 200 mg dose=6.2 fold WT (9.8 uM).
Murphy summarized the Cmax at the 200 mg dose exceeds the EC90 of wild type, K65R, M18$V, and multiple TAMs. Once daily dosing supported by the in vitro intracellular RVT-TP half life (17 hrs), the plasma half life (5.2 hrs), and clinical antiviral activity. No changes were noted in genotype following 10 days of monotherapy in treatment-naïve patients. All subjects at all doses responded to treatment. CD4 counts increased in all dose groups during treatment. RVT is well tolerated with no significant clinical or lab adverse events observed (in this study). Recruitment of sites for an international phase 2B study in treatment experienced patients is underway.
|
|
| |
| |
|
| |
|
|
|
|
|
