Lodenosine belongs to the class of anti-HIV drugs known as nucleoside analogue reverse transcriptase inhibitors. Its development as an anti-HIV drug was discontinued in late 1999 following one drug-related death and serious liver and kidney damage among participants in early clinical trials. The phase II safety and dosing study had enrolled 176 people in three countries, including the UK. All participants have now ceased the drug and are being monitored for adverse events.

Lodenosine was discovered by the US National Cancer Institute, and was being developed by US Bioscience Inc. It is known by the chemical name 2'-beta-fluoro-2',3'-dideoxyadenosine or FddA, and the generic name lodenosine.

In test-tube studies, it seemed to be active against HIV strains resistant to ddI and all other nucleoside analogues. A six-week monotherapy study found a median viral load reduction of 0.42 log. In combination with d4T/nelfinavir in pre-treated people, lodenosine showed effectiveness in four of nine participants.

Key research

Young presented interim 12-week data on 66 participants in a 48-week dosing study of lodenosine (100 mg - 300mg twice daily) plus d4T/indinavir compared to 3TC/d4T/indinavir. Mean viral load reduction was -2.6 log for the lower doses and -2.5 log for the 300-mg dose. Common side-effects included hyperbilirubinaemia, nausea, vomiting, and taste perversion.

Little presented early data from a phase I study of lodenosine in adults and children. Group I studied 5 doses (0.2-3.2mg twice daily) of lodenosine monotherapy among 26 adults for 12 weeks. 20 had previously taken treatment for more than 6 months. The median viral load among 9 people on the two highest doses had a median viral load reduction of -0.42 log at week 6. The second group of adults was treated with monotherapy for 4 weeks, and then combination treatment with d4T and nelfinavir. 2 of 4 heavily pretreated adults achieved viral loads below 200 after week 12 of combination therapy. 13 children have been enrolled in a dosing study. Early data suggests the higher doses produce the greatest viral load reductions.

Welles reported that 22 HIV-positive people with a mean CD4 count of 164, who were not on anti-viral therapy, were allocated to one of 5 dosing levels of FddA ranging from 0.2mg-3.2mg twice daily. 6 people on the 1.6mg/kg dose all had viral load reductions at week 6 (ranging from -0.14 to -1.43 log). Trends towards viral load reductions occurred in the 0.4mg and 0.8mg/kg arms. Side-effects reported included transaminase elevations, neutropenia, hyperglycemia, hyperamylasemia.

Yarchoan conducted a phase I dosing study of lodenosine among 25 HIV-positive people. At week 6, 8 people on the 2 highest doses had viral load reductions of about half a log. 4 out of 9 people with extensive prior NRTI treatment achieved undetectable viral load (less than 200) after 24 weeks on a combination of lodenosine, nelfinavir and d4T.

References

Little RF et al. Phase I adult and pediatric studies of lodenosine (F-ddA) as monotherapy and combined with stavudine and nelfinavir. Sixth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 380, 1999.

Welles L et al. A phase I study of 2'-beta-fluoro-2',3'-dideoxyadenosine (FddA) in patients with symptomatic HIV infection. Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 651, 1998.

Yarchoan R et al. A phase I dose escalation study of 2'-B-fluoro-2',3'-dideoxyadenosine (F-ddA), lodenosine) in patients with symptomatic HIV infection. Twelfth World AIDS Conference, Geneva, abstract 22281, 1998.

Young B et al. Multi-center randomized phase II trial of multiple doses of lodenosine (FddA) in combination with stavudine and indinavir in antiretroviral naive HIV-infected adult patients. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 1975, 1999.