SF AIDS Fdn: BETA 10/98 -- DRUG WATCH: FddA -- Antiretroviral in Development

Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

October 1998 Table of Contents

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DRUG WATCH: FddA -- Antiretroviral in Development

Leslie Hanna

A nucleoside analog drug currently in development that looks interesting thus far is FddA or lodenosine, manufactured by U.S. Bioscience. FddA was originally developed at the National Cancer Institute (NCI).

A reverse transcriptase inhibitor, FddA is structurally similar to ddI. FddA appears to have little in vitro cross-resistance with other drugs in its class, including AZT (Retrovir), ddI (Videx), and d4T (Zerit). Laboratory studies have shown that FddA has activity against strains of HIV that are resistant to AZT, ddI, and ddC, and even some activity against multidrug-resistant HIV. In addition, FddA resistance appears to develop very slowly. FddA’s metabolite, FddI, has anti-HIV activity equivalent to FddA.

To date, there are relatively few data on FddA. The most significant study completed thus far is a Phase I trial of FddA as monotherapy. The trial was conducted at the NCI. This was a small, dose-ranging study that enrolled 25 previously treated HIV positive subjects with a baseline average of 164 CD4 cells/mm³. Of the 22 participants, 19 had more than six months of previous antiretroviral therapy.

For 12 weeks, participants took the drug twice a day at doses ranging from 0.2 mg/kg to 3.2 mg/kg. At six weeks, decreases in viral load were noted in people taking the two highest doses, 1.6 mg/kg and 3.2 mg/kg. The average decrease was approximately half a log, or 68%. There was a trend towards a concomitant increase in CD4 counts at the two highest doses.

Thus far FddA appears to have some significant advantages. One is the drug’s stability in an acid environment, which means that the drug can be taken with food (unlike its cousin, ddI). The drug appears to have good bioavailability, both with food (65%) and without food (75%). Another attractive feature of the drug is that it has a long intracellular half-life, which means that it will probably only need to be taken once daily. FddA also appears to cause little or no bone marrow suppression. It also is thought to be less likely than ddI or ddC to cause peripheral neuropathy.

Currently, Phase I/II trials are being designed, which also will be conducted at the NCI. FddA will be taken once daily at 3.2 mg/kg, the highest level studied in the Phase I trial, or at 4.5 or 6.4 mg/kg. Participants will likely take FddA alone for four weeks, at the end of which time d4T and nelfinavir (Viracept) may be added. For more information, call the NCI at 301-496-8959. Pediatric trials with a liquid formulation of FddA are also being planned; call 301-402-1391.

U.S. Bioscience is planning a Phase II trial to look at two doses of FddA in combination with a protease inhibitor plus a nucleoside analog in people who have never before taken any antiretroviral medications. For more information on U.S. Bioscience trials, call 800-200-8070.

Since combination antiretroviral treatment is the standard today, and since this has led to concerns that strains of HIV that are resistant to multiple drugs will increasingly occur, the identification of FddA and other candidate antiretrovirals that do not share the same resistance profiles is significant. Researchers are beginning to stress the importance of early evaluation of candidate drugs, i.e., in preclinical stages, for their activity against highly drug-resistant clinical strains of HIV.

Leslie Hanna is Acting Editor of BETA.

Kelley, J.A. and others. The pharmcokinetics and oral bioavailability of lodenosine (F-ddA), a uniquely stable anti-HIV drug, in adults with symptomatic HIV infection. 12th World AIDS Conference. Geneva Switzerland. 28 June-3 July, 1998. Abstract 42263.

Palmer, S. and others. Highly drug-resistant HIV-I isolates are cross-resistant to many of the current anti-HIV compounds in clinical development. 5th Conference on Retroviruses and Opportunistic Infections. Chicago, IL. February 1998. Abstract 405.

Yarchoan, R. and others. A Phase I study of 2’-beta-fluoro-2’,3’-dideoxyadenosine (FddA) in patients with symptomatic HIV infection. 5th Conference on Retroviruses and Opportunistic Infections. Chicago, IL. February 1998. Abstract 651.

Yarchoan, R. and others. A Phase I study escalation study 2’-beta-fluoro-2’,3’ dideosyadenosine (F-ddA, lodenosine) in patients with symptomatic HIV infection. 12th World AIDS Conference. Geneva Switzerland. 28 June-3 July, 1998.Abstract 22281.

Page last updated 6 October 1998