PA-457, new kind of antiretroviral: ten-day clinical trial results.

On August 22 Panacos, a pharmaceutical company. released results of a small, 10-day human trial of the maturation inhibitor PA-457, the first time more than a single dose of this compound has been tested in HIV-positive people. The largest of the four doses tested reduced viral load by a median of one log (ten fold) for the six patients in that group. No dose-limiting toxicity was found.

PA-457 is important because it works by a new mechanism of action, different from any approved drug: therefore patients already resistant to other antiretrovirals will probably not be resistant to PA-457 (although resistance to it can develop, as it has with every anti-HIV drug). PA-457 is taken orally, and has a long half-life in the body (two to three day's); therefore it can be taken once a day', and unlike some new drugs, does not need to be used with ritonavir. And just in case this particular compound turns out not to be safe and effective, the company has other potential maturation inhibitors ready, to take its place.

The U.S. FDA granted fast-track status to PA-457 in January 2005--allowing the drug to move more rapidly through the approval process because of its potentially great importance to patients. (But on the other hand, the political fallout from Vioxx and other drug problems could slow all approvals at the FDA. A key structural problem has always been that in balancing y risks and benefits, an error in approval has a high public profile, and consequences for the agency, while an error in excess caution does not, even if more people are harmed.)

How does this drug's mechanism differ from that of protease inhibitors? Both maturation inhibitors and protease inhibitors block viral maturation and cause new virus particles to be non-infectious. The difference is that protease inhibitors target the protease enzyme, while PA-457 uses other mechanisms (in technical language, it blocks release of the capsid protein). [1] So the two kinds of drugs are not cross-resistant.

PA-457 is synthetic derivative of a natural product, betulinic acid, which is found in the bark of many trees. including birch and the European plane tree.

Future Development Plans

The next step in the development of PA-457 will be a larger, phase 2b study in about 150 patients. It is expected to start in the first half of 2006. After that, phase III trials will be necessary before approval.

Meanwhile, more information about the ten-day study might be presented at the ICAAC conference, originally scheduled for September 21-24 in New Orleans, changed to December 16-19 in Washington DC due to the flood disaster. The trial results were not ready until long after the regular deadline, so it was submitted as a "late breaker"--a particularly important result that was not ready by the standard deadline. Only a few late breakers are accepted.

Note on Panacos: In early 2005, Panacos Pharmaceuticals Inc. merged with V.I. Technologies Inc. and the combined company was known as V.I. Technologies, or Vitex. Recently the combined company changed its name to Panacos.

Besides maturation inhibitors for HIV, Panacos is also developing small-molecule fusion inhibitors for HIV and possibly some other viruses. For HIV, these would work like FUZEON (T-20), but would be easier to use because they could be taken orally like other antiretrovirals, instead of by injection.

Comment: Doses in the Ten-Day PA-457 Study

The ten-day results, so far available only in a press release from the company, suggest to us that the most effective dose might be higher than any used in that study. Huge differences were found between the four doses tested (25, 50, 100, and 200 mg, each taken once per day by six volunteers; there was also a placebo group). 200 mg gave a 1.03 log median viral load reduction; but 100 mg gave only' 0.48, 50 gave 0.17, and 25 mg showed no reduction at all in this study.

While the 200 mg results were certainly good, they might have been better. The three 200 mg patients who started with a viral load of less than 100,000 had a 1.52 log reduction: possibly a higher dose could have helped others achieve greater than a one-log reduction. Also. barely enough drug is not good enough for anti-infectives--because of individual variations among patients, because adherence is almost never 100%, and because drug regimens that do not almost completely block viral replication are likely to result in resistance. Hopefully experts will look closely at the dosing issue, and the possibility of testing one or more doses above 200 mg. A larger dose, if it is safe, could give a greater margin above a minimal effective dose, allowing the drug to work better, longer, and for more patients.

References

The earlier one-dose trial was reported at the 2005 Retrovirus conference [2], which also had two other presentations on PA-457.

(1.) Li F, Goila-Gaur R, Salzwedel K, and others. PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proceedings of the National Academy of Sciences. 2003: volume 100, pages 13555-13560 (available without charge at www.pnas.org--search for "PA-457".

(2.) Martin D, Jacobson J, Schurmann D, Osswald E, Doto J, Wild C, and Allaway G. PA-457, the first-in-class maturation inhibitor, exhibits antiviral activity following a single oral dose in HIV-1-infected patients. 12th Conference on Retroviruses and Opportunistic Infections, February 22-25, 2005, Boston [abstract 1591. Also see abstracts number 256 and 551.