SUMMARY: The new nucleoside reverse transcriptase inhibitor (NRTI) festinavir, or OBP-601, demonstrated good antiviral activity, lowering HIV viral load by more than 1 log over 10 days, researchers reported this week at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) in Boston. The new drug, which is related to stavudine (d4T, Zerit), was associated with few serious drug-related adverse events in this short-term study, but longer clinical trials are needed.

By Liz Highleyman

Festinavir, chemically known as or 4'-ethynyl-d4T, was previously shown to have activity against wild-type and several NRTI- and NNRTI-resistant HIV strains in laboratory studies. It also appears to have prolonged activity, which might allow less frequent dosing.

Festinavir's chemical cousin, d4T, can cause serious side effects, including mitochondrial toxicity that may manifest as lipoatrophy (fat loss in the face and limbs), peripheral neuropathy, or liver damage. In cell cultures, however, festinavir appears to be less toxic, being a weaker inhibitor of mitochondrial DNA synthesis. The drug was previously found to be safe and well-tolerated up to 900 mg in a single oral dose given to healthy HIV negative volunteers.

In the poster presented at ICAAC, researchers described a double-blind, placebo-controlled, dose-escalating study of festinavir in 32 treatment-experienced HIV positive patients who were currently not taking antiretroviral drugs. At study entry participants had an average viral load of about 4.4 logs and a mean baseline CD4 count of about 400 cells/mm3.

Four cohorts of 8 patients each were sequentially recruited and received festinavir monotherapy at doses of 100, 200, 300, and 600 mg once-daily for 10 days; 2 participants in each cohort were randomly assigned to receive placebo.

HIV RNA, CD4 cell count, and safety and tolerability parameters were assessed at baseline and after receiving therapy. A 24-hour pharmacokinetic analysis was done on days 1 and 10. HIV reverse transcriptase (RT) and protease genotyping were performed at baseline, day 10, and day 17 to look for drug resistance mutations.

Results

	HIV viral load decreased by -0.87 log in the 100 mg group, -0.98 log in the 200 mg group, -1.36 log in the 300 mg group, and -1.2 log in the 600 mg group, compared with -0.07 log among placebo recipients.
	27 out of 32 patients reported a total of 99 adverse events, of which 62 where considered unrelated to festinavir.
	Adverse events showed no clear pattern, being reported by 4, 2, 5, and 1 patients in the respective festinavir dose groups, and by 4 people receiving placebo.
	Moderate-to-severe adverse events were reported by 5, 3, 0, and 6 patients, respectively, in the escalating festinavir dose groups, and by 1 placebo recipient.
	2 grade 4 adverse events were reported in the 600 mg group, but both were considered unrelated to festinavir.
	A dose-dependent correlation was observed between festinavir dose and area under the curve (total drug exposure between doses).
	No new RT mutations emerged by day 10 or day 17.

"OBP-601 monotherapy for 10 days appears safe and well-tolerated up to 600 mg/day in HIV-infected, treatment-experienced patients," the investigators concluded. "Antiviral efficacy appears remarkable for a nucleoside [reverse transcriptase inhibitor] and deserves further studies."

Investigator affiliations: Hospices Civils de Lyon, Lyon, France; Université de Nice, Nice, France; Hotel-Dieu, Nantes, France; Ctr. Hosp. de Tourcoing, Tourcoing, France; Hosp. Saint Louis, Paris, France; Hosp. Antoine Beclère, Paris, France; ONCOLYS Biopharma, Tokyo, Japan.

9/14/10

Reference
L Cotte, P Dellamonica, F Raffi, and others. A Phase-Ib/IIa Dose-Escalation Study of OBP-601 (4'-ethynyl-d4T, Festinavir) in Treatment-Experienced, HIV-1-Infected Patients. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. (Abstract).