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New HIV Drugs: NNRTI, PRO140, Maturation
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Reported by Jules Levin
CROI Feb 8-12 2009, Montreal
from Jules: At CROI there were posters on several apparently interesting new HIV drugs: PRO 140; new NNRTIs from Ardea (RDEA427/640); Myriad presented early data on their maturation inhibitor program after acquiring Bevirimat from Panacos. I spoke with Myriad officials and they said they are planning to start a Bevirimat study and develop their own maturation inhibitor as well. The HIV drug pipeline isn't as full as it was several years ago when etravirine, darunavir, raltegravir and maraviroc were emerging after tipranavir and of course Fuzeon but that was a very unique time. Now, GSK has an integrase program and so does Gilead with elvitegravir entering phase III with the hope of a 'quad' pill' once daily with boosted elvitegravir. The GSK integrase appears promising. Schering's CCR5 drug vicriviroc is in phase III. And CCR5 drugs have yet to be used much.. After the recent announcement just prior to CROI that the Idenix NNRTI was sold to GSK, yes GSK remains in HIV and is active in development, we see at CROI the Ardea NNRTI drug development program with 2 posters and 2 NNRTIs. Ardea has been presenting their NNRTIs at several conferences this year and they also hope these NNRTIs will have activity against NNRTI resistance just like the Idenix NNRTI appears to promise similar hope. So the pipeline is not empty although not as exciting as 3 years ago.. There are a lot of NNRTIs in the pipeline including TMC278 as well as several integrase inhibitors, all developers hope these will be active against resistance in their class. Firstline therapy choices I expect will soon be very crowded. So perhaps we shouldn't yet feel too discouraged about new HIV drug development...let's see. Very important is the issue of aging because it is not being adequately addressed. We appear faced with a situation where HIV accelerates the aging process by 15 years or more compared to HIV-negatives, this was the language in an oral at CROi and discussed by some at the meeting. For two years we have been discussing that non-AIDS events such as heart disease, kidney disease, and bone disease develop at accelerated pace in HIV+. At this CROI there was a heightened focus and further recognition that neurologic and cognitive problems are also accelerated in HIV-positive individuals. The "new frontier in HIV" and yet unaddressed nor recognized except for a few individuals is that the virus itself, HIV accelerates the aging process. A recent study reported that in vitro HIV accelerated the aging of HIV naive & memory cells to put them in a similar state as in aging HIV-negative individuals, so-called senesence, referred to the state of aging individuals in the general population. The study authors doubt HAART reverses this aging process. Mitochondrial toxicity results from both HIV and ART and accelerates aging. HIV accelerates bone disease and causes inflammation, which is a hot topic at this CROI. Inflammation is fairly well recognized as a cause of aging in the general population. SO, what our research community is NOT addressing is this question: do HIV changes in naive & memory cells to an aging state correlate with the development of comorbid conditions, and if the answer is yes then we have identified a problem we can work on. A second research question we should pursue is do inflammation markers correlate with cormorbid conditions developing. We must move these research questions ahead.
Phase 1, Single Ascending Oral Dose Study of the Safety, Tolerability, and Pharmacokinetics of a Novel HIV-1 Maturation Inhibitor in HIV- Healthy Volunteers
Andrew Beelen*1, J Otto1, M Fidler1, E Sanguinetti1, P Smiley1, A Balch1, M Medlock2, M Jackson1, and E Swabb1
1Myriad Pharmaceuticals Inc, Salt Lake City, UT, US and 2PPD, Austin, TX, US
Background: MPC-9055 is a potent, orally bioavailable, small molecule inhibitor of HIV-1 maturation. MPC-9055 targets a unique cleavage event in the HIV life cycle by inhibiting processing of the viral capsid protein p25 to p24. Inhibition of this final step in Gag processing leads to the noninfectious virion and thereby prevents subsequent rounds of HIV infection.
Methods: This was a first-in-human, single-dose, double-blind, placebo-controlled, sequential escalating design study to evaluate the safety, tolerability, and pharmacokinetic parameters of MPC-9055 under fasted and fed conditions. The fasted dose levels were 1, 2, 4, 8, 16, 32, and 48 mg/kg. The fed dose levels were 8 mg/kg (high fat) and 16 mg/kg (low fat). Safety measurements included physical exams, ECG, vital signs, laboratory parameters, and adverse event monitoring. Pharmacokinetic parameters were summarized and dose-proportionality was assessed using a log-log model.
Results: Safety: A total of 55 subjects received active drug and 20 received placebo. No serious adverse events or clinically significant laboratory trends or ECG changes were observed. Overall, 33% of subjects who received active treatment experienced at least one treatment emergent adverse event compared to 15% who received placebo. The most common adverse events in the active treatment groups were gastrointestinal in nature and included nausea, diarrhea, and abdominal pain. All adverse events were of mild intensity with the exception of 1 adverse event of moderate intensity diarrhea. Pharmacokinetic: In the fasted cohorts, mean half-life ranged from 23 to 42 hours, Tmax ranged from 2 to 4 hours and Cmax and AUC values increased with increasing dose in a sublinear fashion. AUC increased approximately 2-fold following either a low-fat or high-fat meal relative to the fasted state. Cmax was also increased in both fed states and Tmax and apparent half-life were not significantly changed.
Conclusions: MPC-9055 had a favorable safety and pharmacokinetic profile following single dose administration to healthy volunteers. A multiple dose study in HIV-infected individuals is planned.
RDEA427 and RDEA640 Are Novel NNRTI with Potent Anti-HIV Activity against NNRTI-resistant Viruses
Anneke Raney*, R Hamatake, W Xu, J M Vernier, J L Girardet, P Weingarten, and B Quart
Ardea Biosci, Inc, San Diego, CA, US
Background: NNRTI constitute an important class of drugs used in HIV-1 therapy. Mutant viruses resistant to the most widely used NNRTI, efavirenz (EFV) and nevirapine, lead to treatment failure. The characterization of activities against a panel of NNRTI-resistant HIV-1 and in vitro toxicological studies suggest the novel NNRTI RDEA427 and RDEA640 have the potential to overcome the most prevalent of these resistant strains.
Methods: Antiviral activities of the NNRTI were determined using VSV-g pseudotyped HIV-1-containing wild type and NNRTI-resistant sequences. These assays were also performed with human serum and human serum albumin to assess the effect of protein binding on antiviral activity. Cytotoxicity was evaluated in primary human cells and cell lines. Non-linear regression analysis was used to calculate IC50 values. CYP3A4 induction was determined in vitro using a CYP3A4 promoter-driven luciferase reporter cell line carrying the pregnane X receptor.
Results: RDEA427 and RDEA640 are potent inhibitors of wild type HIV-1 with EC50 values of 0.9 nM and 0.8 nM, respectively, and CC50 values of >50 ƒÊM. The fold-changes in EC50 against the major NNRTI-resistant viruses found in patients failing EFV therapy are significantly lower than those of EFV. Fold-changes for both RDEA427 and RDEA640 against the K103N and G190S mutants are 0.9 and 0.3, respectively, vs 16 and 63 for EFV. While the K103N/L100I mutant caused a fold-change of 1700 for EFV, and 2.4 and 5.4 for TMC125 and TMC278, respectively, the fold-change of RDEA640 was 0.4 against this mutant. RDEA640 had a 6-fold EC50 shift in the presence of 40% human serum and RDEA427 and RDEA640 had 9-fold shifts in the presence of 45 mg/mL human serum albumin, values similar to the fold-changes for TMC125 and better than those for EFV and TMC278. At 6 ƒÊM, RDEA427 and RDEA640 caused 2.6-fold increases in CYP3A4 promoter-driven luciferase activity compared with 8.7-fold and 7.5-fold increases for TMC125 and TMC278, respectively.
Conclusions: RDEA427 and RDEA640 are superior to EFV against a panel of NNRTI-resistant viruses and are less affected by binding to serum proteins than EFV and TMC278. RDEA427 and RDEA640 also show a low potential for CYP induction and a large selectivity index. The in vitro characterization of these novel NNRTI shows strong potential for improved performance over current NNRTI and warrants evaluation in humans.
Resistance-selection Study in vitro and Favorable Human Pharmacokinetic Properties of RDEA427, a New HIV NNRTI
V Ong1, B Groschel1, Z Shen1, R Straney1, W Xu1, Anneke Raney*1, S Dueker2, J-L Girardet1, K Manhard1, and B Quart1
1Ardea Biosci, Inc, San Diego, CA, US and 2Vitalea Sci, Davis, CA, US
Background: The emergence of resistance to NNRTI limits the efficacy of these drugs. New NNRTI with a higher genetic barrier to resistance and activity against these drug-resistant viruses are needed. RDEA427 exhibits excellent in vitro potency against wild-type and resistant viruses. The results of an in vitro resistance selection study and the favorable human pharmacokinetic properties of RDEA427 are presented.
Methods: Antiviral activities were determined using HIV-1 viruses containing wild-type or NNRTI-resistant sequences. HIV-1 virus resistant to RDEA427 was selected by serial passage in SupT1 cells. At each virus breakthrough, the drug concentration was doubled and the RT region was sequenced for genotypic analysis. Animal pharmacokinetic data were obtained following intravenous administration of RDEA427 and facilitated allometric scaling to predict its half-life in humans. Exposure and urinary excretion in humans were evaluated following intravenous administration of a micro-dose of [14C]RDEA427. Quantitative analysis of [14C]RDEA427 was performed using accelerator mass spectrometry.
Results: RDEA427 had an EC50 value of ~1 nM and retained potent antiviral activity against NNRTI-resistant mutations such as K103N, Y188L, Y181C, K101E, K103N-Y181C, Y181C-G190A, and K103N-P225H. In an in vitro resistance-selection study, K103N virus was controlled by the initial RDEA427 concentration for at least 30 passages. Allometric scaling of clearance data from rat, dog, and monkey intravenous pharmacokinetic studies suggest that RDEA427 possesses potential for once-a-day dosing. This was confirmed in humans, where RDEA427 displayed a mean half-life of ~41 hours and clearance of 0.24 L/h/kg. The presence of an active metabolite, with antiviral activity equivalent to the parent and a half-life of ~50 hours, was also identified and quantified. Mean 24-hour urinary recovery of total radioactivity was 3.8% of the radioactive dose.
Conclusions: RDEA427 has shown potent in vitro activity against wild-type and NNRTI-resistant viruses. In a resistance-selection study, RDEA427 controlled K103N HIV-1 infection for >100 days, suggesting that RDEA427 may provide a high barrier to resistance. Favorable pharmacokinetics of RDEA427 following intravenous micro-dosing in healthy volunteers supports the development of RDEA427, and the long half-life may mitigate the risk of a missed dose.
Anti-viral Characterization in vitro of a Novel Maturation Inhibitor, MPC-9055
Vijay Baichwal*, H Austin, B Brown, R McKinnon, K Yager, V Kumar, D Gerrish, M Anderson, and R Carlson
Myriad Pharmaceuticals, Salt Lake City, UT, US
Background: There is a continuing need for anti-HIV drugs with novel mechanisms because of development of resistance to existing therapies. MPC-9055 was discovered in a medicinal chemistry program as a potent, broad-acting small molecule inhibitor of HIV-1 maturation and is now in phase I clinical development.
Methods: Antiviral replication assays in human peripheral blood mononuclear cells (PBMC) were used to determine the potency, range of action and activity of MPC-9055 against clinical drug-resistant isolates. Cytoprotection assays were used to analyze the mode of action and to isolate virus resistant to MPC-9055. Western blot with a p24 antibody was used to investigate effects of MPC-9055 on Gag processing.
Results: MPC-9055 had potent antiviral activity against the IIIB strain of HIV in a PBMC assay (IC50 7 nM) and against the NL4-3 and RF strains in cytoprotection assays with MT-4 and CEM-SS cells, respectively (EC50 10 and 13 nM). MPC-9055 exhibited efficacy against a broad range of clinical isolates from groups M, N, and O, subtypes A to G, and receptor tropisms (X4, R5, and R5/X4). Importantly, it was also active against RT- and PI-resistant isolates and MDR strains with IC50 values ranging from 8 to 170 nM. Mode of action studies indicate that MPC-9055 acts at a late step in the viral life cycle with selective inhibition of Gag processing and HIV maturation. MPC-9055 specifically blocked processing of CA-SP1 Gag intermediate to mature CA and reduced infectivity of virions produced from 293T cells transfected with a pro-viral genome. Treatment of latently infected ACH-2 cells with MPC-9055 resulted in production of non-infectious virus. Engineered mutations at the CA-SP1 cleavage sites L363F and A364V were 60- and 395-fold less active, respectively, against MPC-9055 in a cytoprotection assay in MT-4 cells. In an analogous manner, virus selected for resistance to MPC-9055 by serial passage in vitro had the single amino acid change A364V at the CA-SP1 junction.
Conclusions: MPC-9055 is a potent anti-HIV agent with a broad range of action. It has a novel mechanism of action and targets the last step in Gag processing, cleavage of CA-SP1 to CA. MPC-9055 is also active against RT- and PI-resistant strains. Based upon this efficacy profile and novel mechanism of action, MPC-9055 is a promising new HIV therapeutic.
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