Panacos, a biotechnology company pioneering new classes of HIV drugs, says that it has found the first fusion inhibitors that could be administered orally, and is already working to develop second and third generation maturation inhibitors to bring to market alongside its lead maturation inhibitor, bevirimat.
New drug classes continue to be needed for patients who cannot tolerate existing therapies or who develop cross-class resistance. Although several promising products are on the horizon, including Merck’s first-in-class integrase inhibitor, the hunt for new drug targets and new agents that can bypass the limitations of existing products is a potentially lucrative one for any company that might be lucky enough to develop a well-tolerated and highly effective new agent.
Bevirimat is the first drug to target a stage in the HIV lifecycle called maturation. Maturation inhibitors interfere with the production of the HIV capsid protein, one of the final stages in the viral lifecycle within an infected human cell. Maturation inhibitors prevent the cleavage of the viral capsid protein, which is necessary for the production of a mature internal structural protein called p24. Without this protein, any HIV particles that are released from the infected cell are non-infectious.
“Frankly it was rather a surprising mechanism of action and no one had considered it a druggable target,” Dr Graham Allaway of Panacos told aidsmap.
“Bevirimat has some very nice properties,” he went on. “It’s a once-daily drug, it’s not metabolised by the cytochrome p450 system so it doesn’t have most of the drug interaction issues [that affect protease inhibitors], and there are no adverse events that we believe are related to the drug after treating more than 300 patients.”
Panacos announced last week that bevirimat is non-teratogenic in animal studies, and a phase IIB dose escalation study in patients failing current therapy is now recruiting volunteers in the United States. The study is using a 14-day introductory phase, during which bevirimat is added to current failing treatment in order to measure initial viral load response, followed by twelve weeks of optimised background therapy.
The study will escalate dosing from 400mg to 500 and 600mg, and Panacos will release data from each dosing group before escalating to the next dose.
A second generation analogue of bevirimat is already undergoing preclinical studies and should begin a phase I study in humans in 2007, while a third generation maturation inhibitor, chemically unrelated to bevirimat, is already in the pipeline.
At last week’s International AIDS Conference in Toronto Panacos also unveiled details of their new discovery – three- candidate fusion inhibitors that can be taken orally, unlike their first-in-class companion enfuvirtide (Fuzeon), which must be injected subcutaneously.
“There are significant limitations, both of cost and mode of administration derived from the fact that [enfuvirtide] is a peptide,” said Dr Allaway. Panacos’s compounds are chemicals that can be synthesised by standard drug manufacturing processes rather than the complex peptide manufacturing system that Roche had to develop for enfuvirtide.
It also works at a slightly earlier stage of the fusion process, although it’s unclear at this time whether this will create any advantages in terms of the development of resistance or synergy with other types of entry inhibitors.
However, Panacos’s compounds are far from the clinic at this point; human studies will be needed to define the dosing interval and potential toxicities.
But the company is clearly excited by the potential of its drug pipeline at the moment.
“One of the things we’re looking at is which novel fixed dose combinations we might look at which offer new treatment paradigms.”
The company is also signalling that it may be in the market for the long haul, rather than selling on its products to a larger company as soon as it reaches the phase III development stage, a tactic which has invariably delayed the progress of new drugs to market.
“We’re strongly considering building the infrastructure to take our products to market ourselves. The size of a sales and marketing team for an HIV drug [in North America] is much smaller than for other indications, maybe less than 100,” Dr Allaway told aidsmap.
Meanwhile Roche and Trimeris, the partners who developed enfuvirtide, continue to search for easier-to-take peptide fusion inhibitors. At last week’s AIDS conference they reported on two compounds, TRI-1144 and TRI-999, that have the potential for once-weekly dosing at much lower volumes than Fuzeon. This approach could make a peptide fusion inhibitor more affordable and attractive to a much wider range of patients than those needing a salvage agent.