AIDS
Maturation Inhibitors : A New Class for Drug Resistant HIV
By Akanksha, Pharmacology Correspondent
Mar 1, 2005, 11:14

Panacos Pharmaceuticals, Inc., today announced that it has provided detailed results from a positive Phase I/II clinical trial of its HIV drug candidate PA-457 at the 12th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, MA.

PA-457 is the first in a new class of HIV drugs called Maturation Inhibitors, with broad activity against HIV, including strains resistant to currently approved drugs.

In the Phase I/II study, PA-457 was administered as a single oral dose to HIV-infected patients who were not on other therapy, in order to determine the pharmacokinetics and antiviral activity of the compound.

Single doses of up to 250 mg were tested and the level of HIV in the plasma, known as the viral load, was measured before and at intervals after treatment in each patient. Following dosing, patients in the highest dose groups had reductions in viral load of up to approximately 0.7 log10 and mean reductions compared to the placebo group of approximately 0.4 log10 that were statistically significant.

Of particular interest were two subjects with pre-existing drug-resistance mutations in the highest dose groups, who both exhibited greater than 0.5 log10 reductions from baseline following PA-457 treatment. PA-457 was very well tolerated at all dose levels in the Phase I/II study.

"PA-457 exhibited an impressive antiviral effect in this study after only a single dose, providing clear proof-of-concept for the drug and strongly supporting its further development," commented Dr. David E. Martin, Senior VP, Drug Development at Panacos. "Few HIV drugs have been tested for antiviral potency following a single dose in HIV-infected patients. In this Phase I/II study, PA-457 exhibited a similar effect on viral load to that previously seen with single doses of potent HIV drugs such as the approved drug, tenofovir."

Also at the Conference, Dr. Martin presented the results of a multiple dose Phase I clinical trial to study the safety and pharmacokinetics of PA-457 in uninfected volunteers.

In this study, PA-457 was administered orally once a day for 10 days at dose levels of up to 200 mg/day. PA-457 was well tolerated at all dose levels. Following 10 days of dosing, PA-457 trough plasma concentrations at all dose levels exceeded the target trough concentration that has been predicted to provide a therapeutic effect in HIV- infected people, by up to 17 fold.

Dr. Carl Wild, Panacos' Chief Science Officer presented the latest findings on PA-457's molecular target at CROI.

Panacos scientists and collaborators previously demonstrated that PA-457 works by a novel mechanism, involving blocking release of the HIV-1 capsid protein (CA or p24) from its precursor (CA-SP1 or p25) resulting in the release of non-infectious immature virus.

In the new study, Panacos scientists further defined the region of CA- SP1 targeted by PA-457 by showing that the transfer of 14 amino acids spanning the HIV-1 CA-SP1 junction into simian immunodeficiency virus rendered that virus sensitive to the drug.

PA-457 is a small molecule, orally bioavailable HIV drug candidate. Preclinical studies have shown that PA-457 retains full activity against drug- resistant virus and is effective in an animal model of HIV infection. In December 2004, the Company initiated a Phase IIa study of PA-457.

The study, currently ongoing at several sites in the U.S., is designed to demonstrate the antiviral potency of PA-457 following once-daily oral dosing for 10 days in HIV-infected subjects who are not on other antiretroviral therapy. Results of the Phase IIa clinical trial are expected in Q2, 2005. During the second half of 2005, Panacos intends to initiate a Phase IIb study of PA-457 designed to pave the way for pivotal Phase III studies.

FDA recently granted Fast Track designation to PA-457. Fast Track is a process designed to expedite development and approval of new drugs that may have the potential to improve treatment for serious or life-threatening diseases. Developers of Fast Tracked products have greater access to FDA resources as well as eligibility for rolling NDA submissions. In addition, Fast Track designation may enable priority FDA review and accelerated approval.

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