A maturation inhibitor, bevirimat, aims to prove its bark is as good as its bite
by Chael Needle
LifeGuide
[Treatment Horizons]
A maturation inhibitor candidate, bevirimat (BVM, formerly known as PA-457), in development at Panacos Pharmaceuticals, is in need of a tweak. While ten-day monotherapy studies have shown BVM to be a highly potent inhibitor of HIV replication, and continues to enjoy a solid safety and tolerability profile, recent Phase IIb study results from its first cohort showed lower than expected concentrations of the drug in patients’ blood. Higher concentrations typically translate into more potent efficacy. A Phase IIa study of BVM in drug-resistant patients, for example, showed a 1 log reduction of viral load at the study’s highest dose level.
In that study, says Dr. Graham Allaway, PhD, Panacos’s president and COO, investigators dosed with a 200 mg oral solution of BVM; in the Phase IIb optimization study, which in part is measuring the efficacy of BVM in combination with approved drugs in patients who have failed therapy due to resistance, investigators dosed with 400 mg (eight 50 mg tablets). This version of the solid form may account for the results. While these fourteen-day results showed similar levels of anti-HIV activity as in the earlier study at the same plasma concentrations, those plasma concentrations were about half what the investigators had anticipated and therefore viral load reductions did not meet expectations.
“Nevertheless we did see several patients with a greater than 1 log reduction [in viral load] and actually two out of twelve patients that we treated went to undetectable in two weeks following treatment with bevirimat,” says Allaway, noting that some patients have continued on with the drug. “One of our goals in Phase IIb is to dose-escalate to higher concentrations until we get the top of the dose response curve, where we would anticipate getting even greater viral load changes than we’ve seen in the past.” Pending approval from the FDA, Panacos hopes to modify the formulation in its currently ongoing dose-escalation and optimization trials.
In terms of anti-HIV drug development, BVM is a prime example of Panacos’s focus on novel mechanisms of action as well as improved resistance profiles. The biotech is targeting different points in HIV’s life cycle—aiming to block the beginning of infection (with fusion inhibitors) and the end (with maturation inhibitors). While fusion inhibitor research is in a preclinical phase at Panacos, maturation inhibitor research is well along in clinical development. BVM might be considered the leading inaugural candidate of all maturation inhibitors. Also, Panacos recently filed an IND application for a second-generation maturation inhibitor. Zeroing in on small molecule drugs that can be dosed orally, rather than drugs based on proteins or peptides that require injection, Panacos hopes to deliver “the kind of drug that is easiest to take and have the broadest utility among HIV patients,” says Allaway, “including both treatment-naive and treatment-experienced.”
BVM, which Panacos aims to introduce as a once-daily compound, metabolizes differently than most drugs, which may bode well for its inclusion in combination therapy, where different metabolic pathways may mean fewer negative drug interactions. Its novel mechanism of action—blocking the final step of the processing of the HIV Gag protein in end-stage viral replication—takes place “at the same point in replication as protease inhibitors,” Dr. Allaway points out, “but with a completely different target [and] as a result of that completely different target, there’s no cross-resistance between protease inhibitors and maturation inhibitors. They’re quite distinct, and therefore could potentially be used advantageously in combination.”
Panacos discovered bevirimat, and its novel mechanism of action, along with its academic collaborators, in particular, Professor K.H. Lee at the University of North Carolina at Chapel Hill. BVM is a potent synthetic derivative of betulinic acid, which can be extracted from tree bark, that has been found to be synergistic with approved drugs in cell culture assays as well as active against drug-resistant HIV strains. The wide availability of betulinic acid-containing tree bark and the simplicity of its manufacturing process makes BVM stand apart from some other HIV drugs that have difficult and expensive synthetic routes, notes Allaway.
Dr. Allaway is steadfastly excited about BVM as a “breakthrough” drug, as well as the push for anti-HIV drugs with new targets and novel mechanisms of action such as integrase inhibitors and CCR5 antagonists (he was involved in the discovery of CCR5 as one of the HIV coreceptors back in the nineties when he worked at Progenics). As the limitations and possibilities of these drugs are discovered, “one of the things we’re interested in, as well as many physicians,” says Dr. Allaway, “is the possibility of not only combining bevirimat with currently approved drugs but thinking about how we might create new paradigms, perhaps combining bevirimat with an integrase inhibitor down the road....I think there will be a few changes in treatment when bevirimat and some of these other drugs reach the market.”
Chael Needle wrote about new advances in microbicides, drug-resistance testing, and CCR5 antagonists in the January issue.
February 2007
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