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New HIV Drug & New Class of HIV Drugs: BMS-488043, an attachment Inhibitor
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Reported by Jules Levin
NATAP UPDATE FROM the 2004 RETROVIRUS CONFERENCE
Saturday, March 13, 2004, from 8:30am to 1pm, at NYU Medical Center, 550 1st Ave (between 31st & 32nd Sts, Alumni Auditorium F (downstairs) Contact NATAP for registration & info: 212 21-0106; 888-26-NATAP. Speakers include:
--Judith Aberg, MD, Principal Investigator at NYU ACTU, Director of HIV at Bellevue Hospital Center (lipodystrophy, metabolics, Womens Issues);
--Graeme Moyle, MD, Associate Director of HIV Research, Chelsea & Westminster Hospital, London, UK (new drugs and ART);
--Stuart Ray, MD Assistant Professor of Medicine, Viral Hepatitis Center, Johns Hopkins University School of Medicine (hepatitis C)
On the final day of the conference new study results were reported on 5 new drugs for HIV, 3 entry inhibitors. George Hanna from Bristol Myers Squibb presented at the Retrovirus Conference results from testing BMS-488043, an HIV attachment inhibitor, in a phase IIa study in HIV+ patients. Patients received monotherapy with BMS-488043 for 7 days. Immediately below are the results from testing the drug for 8 days with monotherapy in HIV-infected patients in a Phase II. In this preliminary, proof-of-concept study the drug showed potency by reducing viral load on average by 1 to 2 logs, increased CD4 counts, and appeared safe. The study report is followed by additional information on 043, including new information presented by Hanna on the pharmacokinetics of the drug.
The patients did not have a medical indication for antiretroviral therapy (both naïve or those off therapy for greater than 16 weeks), had a CD4 cell count of greater than 250 cells/mm3, and a plasma viral load of 5,000 to 500,000 copies/mL. Two groups of 15 HIV-1 infected adults (12 active/three placebo per group) received 800 or 1800 mg doses of BMS-488043 or placebo every 12 hours for seven days and in the morning of day eight with a high-fat meal. 043 was administered with 200 mg capsules and BMS is addressing formulation issues. Viral load was assessed daily. The high fat meal was anticipated to provide higher drug levels.
Mean age of patients was 39-41 years and were mostly men. Mean HIV RNA was 16,000 copies/ml to 58,000 copies/ml. Mean CD4 count was 372-413. Previously patients had taken 4-7 ART drugs in the two treatment arms in the study where patients received BMS-488043.
The mean day 8 change in HIV-RNA was --0.72 log for the 12 patients receiving 800 mg twice daily (range --1.37 to +0.34). For the 12 patients receiving the 1800 mg dose twice daily the mean day 8 change in HIV viral load was --0.96 log (range --1.95 to +0.03). Patients receiving placebo did not see any change in viral load.
The mean maximal change in viral load was --1.01 log (range: -1.69 log to --0.33 log) for patients receiving 800 mg dose, and --1.23 log (range: -2.05 log to --0.24) for patients receiving the 1800 mg dose. The CD4 changes at day 8 was +106 for the 800 mg dose and +48 for the 1800 mg dose. Several patients had significant viral load reductuions, as great as 2 logs.
The majority of BMS-488043-treated patients in both treatment arms (7/12 in the 800 mg arm and 8/12 in the 1800 mg arm) experienced at least a 1.0 log10 copies/mL decline in viral load (with some achieving reductions of up to 2.0 log10 copies/mL) with 8 days of monotherapy. 75% of patients receiving 1800 mg dose and 67% receiving 800 mg dose had >0.5 log viral load reductions; 67% receiving 1800 mg dose and 58% receiving the 800 mg dose had >1 log reductions; 42% receiving 1800 mg dose and 25% receiving 800 mg dose had >1.5 log reductions.
SAFTEY: there were no serious adverse eventsa reported, no discontinuations, 24 mild adverse events for all the patients, 3 moderate adverse events (fatigue, abscesses, diarrhea); no grade 3 or 4 lab abnormalities or adverse events. 4 patients on 800 mg dose experienced fatigue, 2 headache, 2 insomnia, 0 diarrhea, 0 nausea. On the 1800 mg dose, 0 experienced fatigue, 0 headache, 0 insomnia, 2 diarrhea, 0 nausea. Hanna summarized that BMS-488043 taken for 8 days was safe and well tolerated.
Hanna concluded that this proof of concept study validates this novel class of inhibitors that target gp120. Potent antiviral activity was demonstrated by this orally bioavailable attachment inhibitor in HIV-infected individuals. Understanding and optimization of the exposure-response relationship (dosing and the amount of drug in each capsule, pill count) is ongoing. Further development of 043 and this series of compounds is warranted.
At Wednesday morning's oral session the final 5 presentations reported new information on 5 new drugs for HIV. All the drugs are in early phases of development but are encouraging. There were two NRTIs that the speakers said appear preliminarily to be effective against NRTI resistance. Although the drugs appear to have antiviral efficacy, of course future studies will examine and have to establish safety, tolerability, and dosing. Presenters for these two drugs said no mitochondrial toxicity has been observed but they did not report the actual studies or data supporting this, so this remains a question. Three new entry inhibitors were presented by researchers from Bristol Myers Squibb, GlaxoSmith Kline and Schering Plough. For a number of years entry inhibitors have b in development. You have been hearing and reading reports of these from previous conferences. In addition to these entry inhibitors Pfizer is developing one that is in phase II development. Finally, it appears as though clinical advancement for these drugs is occurring, but they are still in early stages of development and as you know safety and other types of issues can present challenges and barriers to development. In this report I'll describe the data reported on the BMS attachment called BMS-488043. Soon forthcoming NATAP reports will describe the other new drugs and entry inhibitors. As well NATAP researchers/doctors who are also covering the conference for NATAP are preparing reports that will present their observations on these new drugs and these reports are soon forthcoming. All NATAP reports are archived on the NATAP website: http://www.natap.org
As you know we have 3 classes of drugs for treating HIV: protease inhibitors, NRTIs, and NNRTIs. These drugs prevent HIV from replication but do so by intervening in the reproduction process that occurs inside cells, particularly the CD4 cell. Entry inhibitors prevent HIV from entering the CD4 cell. There are attachment inhibitors that block viral entry by binding of the viral protein gp120 to cellular CD4 receptors. CCR5 inhibitors block binding to the CCR5 coreceptor which must also occur after attachment to facilitate viral entry. And of course fusion is the third step of viral entry and Fuzeon, the fusion inhibitor, is an approved HIV drug available in the pharmacy as the FDA approved it in 2003.
You may recall that BMS researchers have been presenting at key HIV conferences including the 9th and 10th Retrovirus Conferences on their program to develop an attachment inhibitor. They have a number of compounds that are in the pipeline. The first candidate is on hold as they develop 488043 for which you will see the data presented by them here. So progress is being made in developing a therapy.
Hanna presented data Wednesday from study AI430-003 on BMS-488043, one of the compounds from its series of experimental HIV-1 attachment inhibitors -- a potential new class of antiretrovirals. The study investigated the antiviral activity, safety, and tolerability of BMS-488043—a novel, oral small-molecule attachment inhibitor of HIV-1 that blocks viral entry by binding to the viral envelope protein gp120 and preventing it from binding to cellular CD4 receptors. The data demonstrate that the experimental attachment inhibitor compound has antiviral activity in HIV-1 infected patients, achieving proof of concept for this type of HIV inhibitors and warranting further development of BMS-488043 and this series of compounds.
BMS-488043 is a novel, oral small-molecule attachment inhibitor of HIV-1 that blocks viral entry by preventing the binding of the viral envelope protein gp120 to cellular CD4 receptors. Potent and selective inhibition is observed in vitro against macrophage-, T-, and dual-tropic HIV-1. Hanna reports that activity is co-receptor independent and maintained against macrophage-, T-, and dual tropic HIV-1. Susceptibility is retained against variant viruses resistant to other classes of antiretrovirals. Safety appears clean in vitro and in animal studies. 043 binds to a single binding site, one molecule is bound per gp120 protein. There is the potential for combining 043 with CCR5 inhibitors and fusion inhibitors in one regimen. Phase I studies in healthy subjects have demonstrated promising oral bioavailability and a good safety profile.
Clinical study of the previous compound BMS-378806 indicated that target exposure (Cmin) was not achieved so development was stopped. The median EC90 was 61.5 nM. For BMS-488043 the median EC90 is 38.5 nM, and the half-life is longer in animal studies compared to BMS-378806. Hanna reported also that the plasma concentrations in humans are 10-fold higher than BMS-478806.
Hanna reported pharmacokinetics of 043 in poster 535 at the conference. The antiviral activity, safety, and tolerability of BMS-488043 were evaluated in a placebo-controlled ascending multiple-dose study in HIV-1-infected adults. Inclusion criteria included being antiretroviral naive or off any antiretrovirals for >16 weeks, CD4+ cell count >250 cells/mL, and plasma viral load 5000-500,000 copies/mL. Two groups of 15 subjects (12 active/3 placebo per group) received 800- or 1800-mg doses of BMS-488043 or placebo every 12 hours for 8 days with a high fat meal. Viral load was assessed daily.
After single doses of 043 capsules under fasted conditions, median Tmax was 1 to 2 hours and mean Cmax was 662 to 1790 ng/mL for 200- to 2400-mg groups. Cmax and AUC appeared to be dose related, but less than dose proportional, for doses of 200 to 800 mg with no significant increase in exposure at higher doses. Ritonavir pretreatment increased 043 exposure by 43%. Compared with the capsule under fasted condition, administration of the solution resulted in 3-fold increased exposure, and administration with food showed 3- to 5-fold increased exposure. On day 14 of dosing 400 to 1800 mg 043 every 12 hours with a high fat meal, median Tmax was 3 to 4 hours after the morning dose, and mean Cmax was 2494-7136 ng/mL; AUC (0 to 12 hours) was 10,643 to 34,986 ngxh/mL; and Cmin was 139 to 745 ng/mL. Accumulation indices (day 14:day 1) ranged from 1.1 to 1.6. Exposures were generally higher with high fat meal compared to light meal, were generally dose proportional over the dose range of 400 to 1200 mg (high fat meal) and 400 to 800 mg (light meal), but exposure did not significantly increase above these doses. 043 appeared generally safe and well-tolerated with no serious adverse events.
Hanna concluded that BMS-488043 demonstrated promising safety, tolerability and pharmacokinetics when administered to healthy adults for up to 14 days. A dose of 800 mg twice daily is expected to provide Cmin levels adequate to suppress subtype B HIV-1 isolates.
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