New Antiretrovirals in Development: Reprinted from The PRN Notebook,™ june 2002. Dr. James F. Braun, Editor-in-Chief. Tim Horn, Executive Editor. Published in New York City by the Physicians’ Research Network, Inc.,® John Graham Brown, Executive Director. For further information and other articles The View in 2002 available online, visit http://www.PRN.org All rights reserved. © june 2002. Roy “Trip” Gulick, md, mph Associate Professor of Medicine, Weill Medical College of Cornell University Director, Cornell Clinical Trials Unit, New York, New York Summary by Tim Horn Edited by Scott Hammer, md espite the fact that 16 antiretro- tiviral activity of emtricitabine was estab- Preliminary results from two random- virals are approved for use in the lished, with total daily doses of 200 mg or ized studies—FTC-302 and FTC-303—were United States, there is an indis- more producing the greatest median viral reported by Dr. Charles van der Horst and putable need for new anti-hiv com- load suppression: 1.72-1.92 log. Based on his colleagues at the 8th croi, held in Feb- pounds that have potent and these data, a once-daily dose of 200 mg ruary 2001 in Chicago (van der Horst, durable efficacy profiles, unique re- was selected for further long-term clinical 2001). FTC-302 was a blinded comparison sistance patterns, patient-friendly dosing study. “This is what we’re looking forward of emtricitabine and lamivudine, both in schedules, and minimal toxicities. To pro- to with emtricitabine,” commented Dr. combination with stavudine (Zerit) and vide prn with a glimpse of drugs current- Gulick. “We’ll soon be in a position to offer either efavirenz (Sustiva) or nevirapine ly snaking their way through the develop- patients once-daily regimens.” (Viramune). Four hundred sixty-eight an- ment pipeline, Dr. Roy “Trip” Gulick re- turned to the podium at the February 2002 prn meeting to discuss his obser- Table 1. Investigational Drugs Protease Inhibitors bms 232,632 vations of data presented over the past 2002: Existing and • atazanavir ( )* few years. A summary of his presenta- New Classes (Partial List) • tipranavir* dmp-450 tion—along with data presented at the • mozenavir ( ) tmc 114* 9th Conference on Retroviruses and Op- • hiv tmc 126 portunistic Infections (croi), held in Feb- Reverse Transcriptase • tmc 15 ruary in Seattle—is provided here. Inhibitors • Nucleoside Analogues hiv Entry Inhibitors** • emtricitabine (ftc)* dapd Attachment Inhibitors • amdoxovir ( )* • pro 542 • d4C I. New Nucleoside/Nucleotide Analogues • ach-126,443 Co-Receptor Inhibitors bch-10618 cxcr4 Emtricitabine (Coviracil) • • inhibitors • bch-13520 • ccr5 inhibitors emtricitabine (coviracil), formerly • dpc 817 sc-351125 (sch-c) known as ftc, is a thiacytidine nucleo- pro 140 side analogue being developed by Triangle Non-Nucleoside Reverse sch-d Pharmaceuticals. The drug has in vitro Transcriptase Inhibitors uk-427,857 anti-hiv activity comparable to its sister • capravirine (Ag1549) compound lamivudine (Epivir) in human • dpc 083* Fusion Inhibitors cell lines (Hazen, 2001). Unfortunately, • dpc 961 • T-20 (enfuvirtide) the M184V mutation associated with lamivu- • tmc 125* • T-1249 dine resistance also confers decreased • tmc 120 • d-peptides sensitivity to emtricitabine. • calanolide A • 5-helix Results from an open-label dose-ranging • dabo trial were published last year (Rousseau, • sj-3366 hiv Integrase Inhibitors 2001). Lamivudine- and abacavir-naive pa- • hby 1293 • compound C (diketo acid)* tients received 25 mg bid, 100 mg qd, 100 • miv-150 • s-1360* mg bid, 200 mg qd, or 200 mg bid of emtricitabine as a single agent for 14 days. * Reviewed in this article. ** Reviewed in the March 2002 issue of The PRN Notebook. A dose-response relationship for the an- 16 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG tiretroviral-naive South Africans were en- viral load less than 50 Figure 1. Proportion of Patients with rolled in this study. After 24 weeks of copies/mL (see Figure 1). hiv-rna <50 copies/mL: Emtricitabine treatment, approximately 61% to 65% of Additionally, 8/9 (89%) pa- the study volunteers had hiv-rna levels tients with baseline viral 100 below 50 copies/mL, irrespective of which loads greater than 100,000 regimen they received. However, viral re- copies/mL had hiv-rna be- bound after initial suppression below 400 low 400 copies/mL for the 75 copies occurred in 12% of the emtricitabine same time period. The me- recipients compared to 6% of lamivudine dian increase in CD4 cell recipients (p<0.05). The cause of this dis- count observed at week 96 50 hiv-rna < 50 (itt: m = f) parity may have been the result of less was 272 cells/mm.3 than optimal adherence to the experi- In addition to these stud- hiv-rna < 50 (%) 25 mental regimen, since 60% of those who ies, Triangle is currently experienced viral load rebound receiving conducting FTC-301, a phase 0 emtricitabine had wild-type virus, com- III, 48-week, double-blind, pared to 23% of those in the lamivudine placebo-controlled trial 8 16 24 32 40 48 60 64 72 80 88 96 group, and only 15% had the 184V muta- planned for 100 clinical weeks tion in the emtricitabine group compared sites in the United States, to 54% of the 3TC group (p=0.03). Europe and Latin America. 96-week follow-up data from anrs 091, an open-label study FTC-303 was an open-label switch study Patients will receive di- evaluating a once-daily regimen consisting of emtricitabine that enrolled 440 hiv-positive individuals danosine and efavirenz in (Coviracil), efavirenz (Sustiva), and didanosine (Videx) in who had hiv-rna levels below 400 combination with either 40 antiretroviral-naive hiv-positive patients. Median viral copies/mL for at least 12 weeks while re- emtricitabine or stavudine. load at baseline was 4.77 log and the median cd4 cell ceiving a lamivudine-containing regimen. The ANRS is completing en- count was 373 cells/mm.3 After 96 weeks of treatment, Patients were randomized in a 2:1 fashion rollment in its alize study, 34/40 (85%) patients maintained viral suppression below to switch to emtricitabine or remain on an open-label study in 400 copies/mL; 80% had a viral load less than 50 lamivudine. After 48 weeks of follow-up, France. In this study, pa- copies/mL (intent-to-treat analysis). The median cd4+ viral load rebound rates were similar in tients with hiv-rna levels count increase, above baseline, was 272 cells/mm.3 both groups (8%). below the level of de- Source: Katlama, 2001. 8th European Conference on Clinical Aspects and Treatment Both emtricitabine and lamivudine tectability while receiving a of hiv-Infection, Athens, Abstract 221. were generally well tolerated by the ma- lamivudine-containing jority of patients in both FTC-302 and FTC- haart regimen will be ran- 303. Adverse reactions were predominantly domized to continue the regimen or switch firmed by phenotypic analysis of recombi- mild to moderate in both groups with the to a once-a-day regimen of emtricitabine, nant viruses that had a combination of zi- exception of some episodes of grade 3/4 extended-release didanosine and efavirenz. dovudine and lamivudine resistance muta- hepatotoxicity in study FTC-302. In this tions and nnrti resistance mutations. All the study, severe liver toxicity was seen in viruses were susceptible to inhibition by 17% of the patients receiving nevirapine amodoxovir. As for reverse transcriptase (14% in the emtricitabine arm and 19% in Amdoxovir mutations that typically confer multi-nrti the lamivudine arm), whereas none of the dapd, which now carries the generic resistance, clinical isolates containing only patients receiving efavirenz concomitant- name amdoxovir, is a second nrti being K65R were said to be moderately resistant to ly with 3TC or ftc developed such hepato- developed by Triangle Pharmaceuticals. amdoxovir (5.6-fold increase in IC50). The toxicity. The overall rate of liver toxicity ob- It is a novel dioxolane purine analogue presence of the Q151M mutation, alone, also served in study FTC-302 is consistent with that is rapidly converted intracellularly by produced virus that was moderately resis- that observed in other published studies adenosine deaminase into D-dioxolane tant to amdoxovir (9.6-fold increase in IC50), with nevirapine, including those where guanine (dxg), a metabolite that has potent whereas virus containing the combination neither emtricitabine nor lamivudine was activity against hiv and hbv. of K65R and Q151M was highly resistant to part of the regimen. According to in vitro data published amdoxovir (>20-fold increase in ic50). In Also discussed by Dr. Gulick were data earlier this year in the Journal of Acquired contrast to findings from earlier reports, from ANRS 091, an open-label study evalu- Immune Deficiency Syndromes, amdoxovir viruses containing the L74V mutation alone ating a once-daily regimen consisting of demonstrated anti-hiv activity comparable remained susceptible to amdoxovir. emtricitabine, buffered didanosine (Videx), to that of lamivudine and abacavir (Zia- As for phase I clinical trial results, Dr. and efavirenz in 40 antiretroviral-naive gen) (Mewshaw, 2002). The drug had less Joseph Eron and his colleagues treated six French patients (Katlama, 2001). Median vi- activity than zidovudine and emtricitabine patients who had failed prior regimens ral load at baseline was 4.77 log copies/mL, against wild-type laboratory strains, but containing either zidovudine/ lamivudine or and the median CD4 cell count was 373 had greater activity than stavudine, di- stavudine/lamivudine with amdoxovir cells/mL. After 96 weeks of treatment, danosine, and adefovir. The activity of am- monotherapy (Eron, 2000). The patients 34/40 (85%) patients maintained viral sup- doxovir against zidovudine-, lamivudine-, underwent a seven-day washout prior to re- pression below 400 copies/mL; 80% had a and nnrti-resistant viruses was also con- ceiving their first dose of amdoxovir (ei- THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG 17 Preliminary results from two clinical Figure 2.