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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 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- 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 , both in schedules, and minimal . To pro- to with emtricitabine,” commented Dr. combination with (Zerit) and vide prn with a glimpse of drugs current- Gulick. “We’ll soon be in a position to offer either (Sustiva) or 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 • ( )* few years. A summary of his presenta- New Classes (Partial List) • * dmp-450 tion—along with data presented at the • ( ) tmc 114* 9th Conference on Retroviruses and Op- • hiv tmc 126 portunistic (croi), held in Feb- • tmc 15 ruary in Seattle—is provided here. Inhibitors • Nucleoside Analogues hiv Entry Inhibitors** • emtricitabine (ftc)* dapd Attachment Inhibitors • ( )* • pro 542 • d4C I. New Nucleoside/Nucleotide Analogues • ach-126,443 Co-Receptor Inhibitors bch-10618 cxcr4 Emtricitabine (Coviracil) • • inhibitors • bch-13520 • 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 • (Ag1549) compound lamivudine (Epivir) in human • dpc 083* Fusion Inhibitors cell lines (Hazen, 2001). Unfortunately, • dpc 961 • T-20 () the M184V mutation associated with lamivu- • tmc 125* • T-1249 dine resistance also confers decreased • tmc 120 • d-peptides sensitivity to emtricitabine. • • 5-helix Results from an open-label dose-ranging • dabo trial were published last year (Rousseau, • sj-3366 hiv Integrase Inhibitors 2001). Lamivudine- and -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- 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 , 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 (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 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-, 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 that had a combination of zi- exception of some episodes of grade 3/4 extended-release didanosine and efavirenz. dovudine and lamivudine resistance muta- in study FTC-302. In this tions and nnrti resistance mutations. All the study, severe 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 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 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. tmc 125: Activity Against nnrti-Resistant Clinical Isolates (n=1,081) trials—one involving antiretroviral-naive patients and another involving antiretro- 100% viral-experienced volunteers—were pre- sented at the 9th croi in Seattle. In the first 80% study, patients received zidovudine and lamivudine and one of three DPC 083 doses 60% (50 mg, 100 mg, or 200 mg qd) or efavirenz (Ruiz, 2002). Each of the four 40% groups had between 29 and 38 patients. Approximately 60% to 70% of patients in 20% each group had hiv-rna levels below 50 copies/mL after 16 weeks of treatment. In the second study enrolling patients 0% who had experienced virologic failure while Nevirapine Efavirenz tmc125 on a previous nnrti-based regimen, once- daily doses of 100 mg and 200 mg DPC 083 ec50> 100 nm ec50> 10 nm ec50< 10 nm were used, in combination with two NRTIs (Ruiz, 2002a). At baseline, mutations con- Source: Sanne, 2001. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Abstract 667. sistent with nnrti resistance were present in 94% of the study population. Approxi- ther 25 mg, 100 mg, 200 mg, 300 mg, or multiple nnrti-related mutations in re- mately 70% of patients had hiv containing 500 mg, all twice a day). After 15 days of verse transcriptase. either the K103N or Y181C mutations. Of the follow-up, hiv-rna levels dropped in a dose- DPC 083 is less highly bound to plasma 10 patients who did not switch NRTIs at dependent manner, ranging from 0.5 log in proteins than efavirenz, which results in baseline, four (40%) had hiv-rna <50 the 25 mg group to 1.6 log in the 500 mg higher levels of free drug at equivalent to- copies/mL after eight weeks of treatment. group. tal plasma concentrations and a signifi- Better yet were the results in patients who Unsatisfied with these results, Dr. cant (10- to 20-fold) improvement in an- switched at least one nrti upon entering the Eron’s group conducted a second study tiviral activity relative to efavirenz. To ex- study: 13/18 (72%) who switched one of looking at the addition of amdoxovir (500 amine the of DPC 083, their NRTIs had hiv-rna levels below 50 mg bid) to the failing regimens of five ad- researchers conducted a study in which copies/mL and 10/15 (67%) who switched ditional patients. After 15 days of adjunc- five groups of hiv-negative male volun- both of their NRTIs at entry had hiv-rna tive therapy with amdoxovir, hiv-rna lev- teers were given varying doses of DPC 083, levels below 50 copies/mL at week 8. els decreased, on average, by 1.9 log in ranging from 50 mg to 400 mg per day Rash was the most common side ef- these five patients. (Fiske, 2000). One group of female volun- fect in these two trials. In the antiretrovi- teers received 100 mg per day. Two doses ral-naive study, grade 3 rash—which re- were administered on the first day, fol- quired discontinuation of study drug—oc- lowed by single daily doses for the fol- curred in 14% of patients in the 200 mg lowing eight days, for a total of ten doses. DPC 083 group, 8% in the 100 mg group, 4% According to preliminary data presented at in the 50 mg group, and 9% in the II. New Non-Nucleoside Reverse the 7th croi, held in San Francsico in efavirenz group. In the study involving 2000, DPC 083 had a very long terminal antiretroviral-experienced patients, rash Transcriptase Inhibitors half-life, ranging from 143 to 175 hours. occurred more frequently in the 100 mg Interestingly, the half-life was longer, on DPC 083 group than in the 200 mg group. dpc 083 average, in women than in men. After 10 The other side effect described most com- DPC 083 is the lead candidate of four doses of >100 mg DPC 083, the average monly was central nervous system effects quinazolinone NNRTIs being developed by trough concentration exceeded the calcu- (e.g., somnolence, ). Bristol-Myers Squibb (DPC 082, DPC 961, and lated protein-binding-adjusted concentra- DPC 963 are the other three). In vitro, DPC 083 tion needed for 90% inhibition of wild demonstrates activity against wild-type hiv type viruses by >172-fold, of K103N virus by equivalent to efavirenz. The drug is also ac- >11-fold, of K103N + P225H by >1.9-fold, or tmc125 tive against hiv strains containing single re- K103N + V108I by >2.9-fold, and of K103N + one of the more promising experimental verse transcriptase mutations that typi- Y181C by >1.6-fold. antiretrovirals discussed at the 9th croi cally confer high-level resistance to cur- “Essentially, we’re looking at a half- was TMC125, Tibotec-Virco’s potent nnrti. rent NNRTIs, such as L100I and K103N, and life of more than 90 hours with DPC 083,” In vitro, it is active against hiv strains against some double-substitution variants Dr. Gulick pointed out. “This definitely harboring the K103N mutation, as well as including K103N/Y181C, K103N/V108I, and support once-daily dosing. Less frequent those containing the L100I, Y181C, Y188L and K103N/P225H). It is still not known how active dosing might also be possible, perhaps the G190A/S mutations (see Figure 2). the drug is against hiv variants containing twice or three times a week.” In antiretroviral-naive patients, seven

18 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG days of TMC125 monotherapy resulted in a tion in the protease gene appeared first regimen, although 85% took prior protease 1.99 log reduction in hiv-rna (Gruzdev, during the selection process in two of the inhibitors) (Haas, 2002). The median base- 2001). In fact, data presented at the 9th three strains. An I84V change appeared to line viral load among the three groups was Conference on Retroviruses and Oppor- be an important substitution in the third approximately 4.3 log and the median CD4+ tunistic Infections (croi) suggest that the strain used. Mutations were also observed count was approximately 310 cells/mm.3 drug—as monotherapy—results in a sim- at the protease cleavage sites following There were more discontinuations because ilar initial rate of decline of hiv-rna during drug selection. Of note, the evolution to re- of adverse events in the / the first week of treatment as a five-drug, sistance seemed distinct for each of the group (30%) compared to 9% in the low- pi- and nnrti-containing regimen (Sankas- three strains used, suggesting multiple path- dose atazanavir group and 11% in the high- ing, 2002). ways to resistance and the importance of dose atazanavir group. Virologic responses Also presented in Seattle were the short- the viral genetic background. were comparable among all three groups. term effects of TMC125 in nnrti-experienced A cross-resistance study involving five At 48 weeks, the mean change from base- patients with high levels of drug resistance other protease inhibitors indicated that line in hiv-rna was –1.44 log in the 400 mg to currently available NNRTIs (Gazzard, atazanavir-resistant virus remained sen- atazanavir group, –1.19 log in the 600 mg 2002). Sixteen patients, most of whom had sitive to saquinavir (Fortovase), while it atazanavir group, and –1.66 log in the ri- greater than 100-fold resistance to either showed various levels—0.1- to 71-fold de- tonavir/saquinavir group. The mean in- efavirenz (Sustiva) or nevirapine (Vira- crease in susceptibility—of cross-resis- creases from baseline in CD4+ counts were mune), received TMC125 900 mg bid for tance to , , ritonavir, 109 cells/mm,3 55 cells/mm,3 and 149 seven days. The median decrease in hiv- and . In reciprocal experi- cells/mm,3 respectively. rna—again, as monotherapy—was 0.9 log. ments, the atazanavir susceptibility of hiv Beyond atazanavir’s potential efficacy Twelve patients had a decrease in viral variants selected in the presence of each of for antiretroviral-experienced patients, load of at least 0.5 log; in seven patients a the currently approved protease inhibitors there has been a great deal of interest in decrease in excess of 1 log was observed. showed that the nelfinavir-, saquinavir-, the drug’s minimal impact on lipid levels in As for side effects, occurred in and amprenavir-resistant strains of hiv clinical trials conducted thus far. In study approximately 30% of patients; remained sensitive to atazanavir, while 009, mean baseline fasting triglycerides occurred in 25%, and , flat- indinavir- and ritonavir-resistant viruses levels were between 177 mg/dL and 223 ulence, , and musculoskeletal pain displayed six- to ninefold changes in mg/dL, and levels were be- occurred in 6% of patients. atazanavir sensitivity. tween 181 mg/dL and 202 mg/dL (Piliero, One clinical trial discussed by Dr. Gulick 2002). After 48 weeks of treatment, total was bms-ai424-008, which compared two cholesterol increased 11% in the riton- doses of atazanavir (400 mg or 600 mg) to avir/saquinavir group (fasting ldl in- nelfinavir, both in combination with stavu- creased by 23%), compared to a 5% de- III. Protease Inhibitors dine (Zerit) and lamivudine (Sanne, 2001). crease in the 600 mg atazanavir group At baseline, the 467 antiretroviral-naive (fasting ldl decreased by 7%). In the 400 Atazanavir patients had viral loads of approximately mg atazanavir group, total cholesterol and bristol-myers squibb’s atazanavir (BMS- 4.77 log. Using an intent-to-treat analysis, ldl cholesterol remained roughly the same 232,632) is a semi-symmetrical azapeptide 64% in the 400 mg atazanavir group, 67% throughout the 48 weeks of study. Fasting agent with an IC50 of 2.6 to 5.3 nM, thus in the 600 mg atazanavir group, and 53% triglycerides increased 94% in the riton- more potent in vitro than the currently in the nelfinavir group had hiv-rna levels avir/saquinavir group and decreased ap- approved protease inhibitors. In dose- below 400 copies/mL at 48 weeks. Ap- proximately 5% in the 400 mg atazanavir ranging studies involving hiv-negative vol- proximately 35% in all three groups had group and 27% in the 600 mg atazanavir unteers, single doses of 100 mg up to hiv-rna levels below 50 copies/mL. Com- groups. Similar results were reported in 1,200 mg appeared to be well tolerated parable increases in CD4+ counts—between 48-week analyses of studies 007 and 008. (O’Mara, 1999). The drug was well ab- 210 and 240 cells above baseline—were —due to increased indirect sorbed and had a half-life ranging be- seen in three groups. These data, along , similar to that seen with indi- tween 2.9 and 6.5 hours. Atazanavir dos- with the preliminary results of a similar navir treatment—was reported in study es of 400 mg or higher resulted in plasma study in antiretroviral-naive patients (BMS- 009 and has been seen in other clinical tri- concentrations above the necessary IC50 AI424-007), indicate that atazanavir is at least als of atazanavir. Approximately 13% and for more than 24 hours. Based on these re- comparable to nelfinavir in efficacy when 19% of patients in the 400 mg and 600 mg sults, a dose of 400 mg—two 200 mg used as part of a combination regimen. atazanavir groups, respectively, experi- tablets—once a day with food has been Another important study is BMS-A1424- enced symptomatic hyperbilirubinemia in selected for continued development. 009, a 48-week safety and efficacy study this study. However, Dr. Gulick pointed In vitro passage of hiv in the presence of comparing dual-protease inhibitor combi- out that other liver enzymes were not el- inhibitors showed that atazanavir selected nations: atazanavir (400 mg or 600 mg qd) evated in these patients and that jaundice for resistant variants more slowly than nel- combined with saquinavir (1200 mg qd), or resolved in all cases upon discontinuation finavir (Viracept) or ritonavir (Norvir) (Gong, ritonavir (400 mg bid) combined with of atazanavir. 2000). Genotypic and phenotypic analysis of saquinavir (400 mg bid) in patients who An expanded access program for three different hiv strains resistant to had failed an earlier antiretroviral regimen atazanavir was recently opened by Bristol- atazanavir indicated that an N88S substitu- (not necessarily a protease inhibitor-based Myers Squibb (see sidebar on page 21).

THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG 19 tions per sample—95 At baseline, 40/41 (97%) clinical isolates Table 2. Investigational Drugs 2002: Future Classes (90%) were susceptible to were considered to be susceptible to • Budding inhibitors: interferon tipranavir; eight (8%) had tipranavir—defined as a less than tenfold • dc-sign inhibitors four- to tenfold resistance reduction in IC50—despite decreases in to tipranavir, and only two susceptibility to a mean average of 2.9 • Regulatory protein (e.g., nef, vif, ) inhibitors (2%) had more than ten- currently available protease inhibitors. • Uncoating inhibitors fold resistance. There was no association between the • rnaase H inhibitors At the 41st Inter- number of protease mutations at baseline science Conference on and the magnitude of viral load reduc- • Zinc finger (dna complex) inhibitors Antimicrobial Agents and tion. For example, in the 500 mg • Capsid protein polymerization inhibitors Chemotherapy (icaac), tipranavir group, individuals with < 5 • Assembly inhibitors held late last year in baseline protease mutations experienced Chicago, data from study reductions in viral load of -2.39 log at • Adjunctive therapy: bi 1182.4 were reported, a week 48, compared to a reduction of –2.24 –Hydroxyurea (ribonucleotide reductase inhibitor) clinical trial comparing in patients with >5 protease mutations at –Mycophenolic acid (imp dehydrogenase inhibitor) tipranavir (500 mg or baseline. Decreased tipranavir suscepti- • Immunomodulators 1250 mg bid) and bility was associated with a mean of 16 saquinavir, both in com- mutations including two or three muta- bination with ritonavir tions at positions 82, 84, and 90. Five of Tipranavir and two new NRTIs (Slater, 2001). Sixty- the six hiv isolates with decreased tipranavir is a nonpeptidic dihydropy- three patients, all of whom had viral load tipranavir susceptibility had protease mu- rone, a new class of protease inhibitors be- levels above 1,000 copies/mL while re- tations at position V82T, and 4/6 had either lieved to have greater flexibility in conform- ceiving their first protease inhibitor-based L33I, V, or F. ing to enzyme variants resistant to current regimen, were randomized evenly among The optimal dose of tipranavir has not protease inhibitors. The compound was orig- the three groups. In an intent-to-treat yet been defined, and its pharmacokinet- inally developed by Pharmacia & Upjohn analysis, the proportion of patients with ic interactions with other protease in- and has since been sold to Boehringer In- hiv-rna below 400 copies/mL was equiv- hibitors—aside from ritonavir—and the gelheim. alent in the lower-dose tipranavir/ritonavir NNRTIs have not been elucidated. As with its unique mechanism of action, and the saquinavir/ritonavir arms (39% tipranavir also differs from other currently and 40%, respectively), and somewhat available protease inhibitors in its metab- greater in the higher-dose tipranavir/ri- tmc114 olism. The drug induces the cytochrome tonavir arm (55%) at 16 weeks. MUCH LIKE ITS NNRTI CONTENDER TMC 125 (DIS- P450 pathway, whereas current protease in- Only 28/63 (44%) of patients partici- cussed above), Tibotec-Virco dubs hibitors either inhibit or both inhibit and pating in bi 1182.4 had hiv protease muta- TMC114—its lead protease inhibitor candi- induce this enzyme system. In early phase tions at baseline. This, in turn, limited the date—a “resistant-repellant” compound. II studies, a whopping 1500 mg of research team’s ability to match key pat- More specifically, TMC114 has been de- tipranavir, taken three times daily, was terns of mutations with virologic outcomes signed not only to bind to typical active required to achieve the necessary trough using tipranavir in a protease inhibitor- sites of the protease enzyme with high concentration. To circumvent this hurdle, experienced population of patients—a key affinity, but also to remain flexible in the the manufacturer has developing a self- factor that must be addressed if the drug is event of mutations that arise during ther- emulsifying drug delivery system (sedds) to be used correctly as a component of apy with other protease inhibitors. for the compound. Tipranavir will likely salvage therapy. Fortunately, new data pre- In vitro, the drug is active against wild- need to be combined with low doses of sented at the 9th croi have helped shed type and protease inhibitor-resistant hiv ritonavir (100 mg) to reverse the rapid light on this situation (Schwartz, 2002). In (De Bethune, 2001). Of 261 randomly se- metabolism of the drug by cytochrome this analysis, the genotypic patterns of 41 lected recent recombinant clinical isolates, P450 and to allow for twice-daily dosing protease inhibitor-experienced patients 32% showed a greater than tenfold increase with food (McCallister, 2002). participating in a dose-finding study of in the ec50 for at least one protease in- An initial glimpse into the in vitro ac- tipranavir (BI 1182.2) were analyzed. At the hibitor. What’s more, there was no greater tivity of tipranavir against multiple-pro- start of the study, all patients had hiv-rna than a fivefold increase in ec50 when test- tease inhibitor-resistant hiv strains was levels above 5,000 and had failed two pre- ed against a panel of 20 hiv variants resis- published by Dr. Brendan Larder and his vious protease inhibitor-based regimens. tant to current protease inhibitors. colleagues two years ago in AIDS (Larder, Patients initially received a hard capsule A dose-escalating study of TMC114 has 2000). Studied by Dr. Larder’s team were formulation of tipranavir and were later been conducted (Van der Geest, 2001). 134 clinical viral isolates documented to be switched to the sedds formulation. The Two groups of nine hiv-negative volun- highly cross-resistant to currently avail- first study group of patients received 500 teers (six active, three placebo) received al- able protease inhibitors. Of 105 isolates mg tipranavir bid in combination with ternating doses of 100 mg, 200 mg, 400 with more than tenfold resistance to three 100 mg of ritonavir bid. The second group mg, 800 mg, 1200 mg, or 1600 mg. Be- or four protease inhibitors—with an av- received 1,000 mg tipranavir bid in com- cause the maximum tolerated dose was erage of 6.1 key protease inhibitors muta- bination with 200 mg ritonavir bid. not reached, an additional panel was

20 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG added to receive 2400, 3200 and 4000 cDNA forms inactive and unstable circu- able pharmacokinetic profiles, but it’s like- mg. Initially, plasma concentrations in- lar structures, and the virus is unable to ly that derivatives of these compounds creased more than proportionally with replicate. Two earlier enzymatic functions could serve as precursors to potent inte- the dose. No further increases were ob- of the integrase gene—assembly of pre-in- grase inhibitors for future development. served between 2400 mg and 3200 mg. tegration complexes and 3’ processing of

The mean Cmax was 14.4 – 15.3 mg/ml at the viral dna ends—are not inhibited by these dose levels. The elimination half- diketo acids. They specifically inhibit the s-1360 (gw810781) life was approximately ten hours, irre- third step—strand transfer of viral dna to CURRENTLY IN PHASE I CLINICAL TRIALS IS S-1360, spective of dose. For 800 mg doses and cellular dna. an being developed by higher, plasma levels at eight to 12 hours Using a specific assay for the inhibi- Shinogi & Company, Ltd., in collaboration post-dose exceeded protein-adjusted IC50’s tion of integrase, researchers at Merck with GlaxoSmithKline Pharmaceuticals. for isolates resistant to currently approved have discovered a series of diketo acids In vitro studies have demonstrated that protease inhibitors. All doses were con- that have activity in vitro and in vivo (L- S-1360 has potent integrase inhibition with sidered safe. Diarrhea—because of poly- 708,906 and L-731,988) (Hazuda, 2000). In- an ic50 of 20 nM (Yoshinaga, 2002). The ethylene glycol (peg) in the formulation— terestingly, when viruses were repeatedly drug had potent antiviral activity against a occurred at high dose levels and limited passaged in the presence of these com- variety of clinical isolates. The mean ec50 further escalation. Short-term localized pounds and mutations conferring resis- and ec90 values were 140 nM and 990 oral and peripheral paresthesias were ob- tance emerged, the replicative capacity of nM, respectively. S-1360 was active against served in 3/6 (50%) volunteers receiving hiv became significantly impaired. both X4 tropic and R5 tropic strains, and the 3200 mg tmc114 dose. Neither of these compounds will be against known nrti, nnrti, and pi drug-re- Tibotec-Virco’s next step will be to con- studied further by Merck, given unfavor- sistant variants. S-1360 was also synergis- duct proof-of-concept studies using a non- peg formulation of TMC114 to examine its safety and efficacy in hiv-positive patients. “This drug, much like tipranavir, will like- ly be studied in combination with riton- Atazanavir (BMS-232632) avir to boost its pharmacokinetics,” Dr. Gulick added. “Ritonavir has a profound effect on TMC114 concentrations, which Expanded Access Program should make for easier dosing and greater potency.” Now Open

Bristol-Myers Squibb has started en- cells/mm3) and who are in need of IV. Integrase Inhibitors rolling patients in an early access pro- atazanavir in order to construct a vi- gram (eap) to provide their protease in- able alternative treatment regimen. This the hiv integrase gene is essential for hibitor atazanavir to eligible patients stage of the program will also provide hiv replication and facilitates the integra- who are in need of an investigational atazanavir to patients who have severe tion of proviral hiv-dna into the host cell antiretroviral agent. haart-associated hyperlipidemia de- genome. Unfortunately, it has not been The initial phase of this program, spite lipid-lowering therapy, defined as easy to develop integrase inhibitors, de- which began May 15, provides atazana- a triglyceride level >750 mg/dL or a spite the intense efforts of many investi- vir to patients worldwide who need cholesterol level meeting ncep guide- gators and many pharmaceutical compa- atazanavir and meet specified entry cri- lines for use of a lipid-lowering agent. nies. Challenges to development have in- teria. As Bristol-Myers Squibb compiles The aforementioned viral load and CD4+ cluded the lack of correlation of some in- safety data from its ongoing phase III cell count restrictions do not apply to tegration inhibition assays with inhibition clinical trials, the eap and data on in- this latter group of patients. of whole virus replication, and nonselec- teractions between atazanavir and oth- Some restrictions will apply during tivity, adverse pharmacokinetic proper- er drugs, the company expects to mod- the initial phase of the eap, regarding ties, and toxicity of many of the candidate ify some of the protocol restrictions combined use of atazanavir with some compounds described to date. which currently apply. This could allow of the other available for a greater number of patients to access the treatment of hiv, until more is atazanavir. known about drug interactions between Diketo Acids The initial stage of the eap will pro- these agents and atazanavir. diketo acids work by sequestering the vide atazanavir to patients who are fail- To find out more about the active divalent cation (Mg++) that is bound ing their current antiretroviral therapy atazanavir eap, clinicians can call 1-877- in the active site of the integrase gene by (defined as an hiv-rna level >5000 7BMSEAP (1-877-726-7327). three acidic residues of the protein chain. copies/mL and a CD4+ count of < 300 Once the gene has been inhibited, the hiv

THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG 21 tic in combination with various NRTIs, NNR- Gruzdev B, Rakhmanova A, De Dier K, et al. daily doses of the NNRTI DPC 083 vs 600 mg TIs and PIs. S-1360 resistant mutants were TMC125 is a highly potent non-nucleoside re- efavirenz (EFV) in combination with 2 NRTIs in isolated, also in vitro, and the amino acid verse transcriptase inhibitor (NNRTI) in an- HIV anti-retroviral (ARV) treatment-naive pa- tiretroviral therapy (ART)-naive, HIV-1 in- tients [Abstract 7]. 9th Conference on Retro- substitutions responsible for drug resis- fected subjects [Abstract 668]. 41st Inter- viruses and Opportunistic Infections, Seattle, tance were in close proximity to the inte- science Conference on Antimicrobial Agents 2002. grase active site. The role of the mutation and Chemotherapy, Chicago, 2001. Ruiz N, Nusrat R, Lauenroth-Mai E, et al. Study at position 66 and others conferring S- Haas D, Zala C, Schrader S, et al. Atazanavir DPC 083-203, a phase II comparison of 100 and 1360 resistance was confirmed by site-di- plus saquinavir once daily favorably af- 200 mg once-daily DPC 083 and 2 NRTIs in pa- rected mutagenesis. fects total cholesterol (TC), fasting triglyc- tients failing a NNRTI-containing regimen [Ab- “S-1360 is not metabolized by CYP3A4, eride (TG), and fasting LDL cholesterol (LDL) stract 6]. 9th Conference on Retroviruses and which is good news in terms of drug-drug profiles in patients failing prior therapy Opportunistic Infections, Seattle, 2002a. (Trial AI424-009, week 48) [Abstract 42]. 9th interactions,” Dr. Gulick added. “We’re Conference on Retroviruses and Opportunis- Sankasing S, Weverling G, van Klooster G, et al. now looking at this drug in treatment-ex- tic Infections, Seattle, 2002. TMC125 monotherapy for 1 week results in a perienced hiv-positive patients.” similar initial rate of decline of HIV-1 RNA as Hazuda DJ, Felock P, Witmer M, et al. In- therapy with a 5-drug regimen [Abstract 5]. hibitors of strand transfer that prevent in- 9th Conference on Retroviruses and Oppor- tegration and inhibit HIV-1 replication in tunistic Infections, Seattle, 2002. Conclusion cells. Science 287:646-650, 2000. in summation, dr. gulick stressed that Sanne I, Cahn P, Percival L, et al. Comparative Katlama C. Once-daily combination thera- Results (Phase II 48-Week): BMS-232632, there is an urgent need to continue de- py with emtricitabine, didanosine and Stavudine, Lamivudine as HAART for Treat- veloping compounds that are unique, par- efavirenz in treatment-naive HIV-infected ment-Naive HIV-Positive Patients (AI424-008) ticularly with respect to their resistance adults: 24-month follow-up of the ANRS 091 [Abstract 667]. 41st Interscience Conference on profiles, and that a number of promising trial [Abstract 221]. 8th European Conference Antimicrobial Agents and Chemotherapy, candidates are in development in both ex- on Clinical Aspects and Treatment of hiv-In- Chicago, 2001. fection, Athens, 2001. isting classes and new classes. Clinical Schwartz R, Kazanjian P, Slater L, et al. Re- development of any new drug is a chal- Larder BA, Hertogs K, Bloor S, et al. Tipra- sistance to tipranavir is uncommon in a ran- lenge, but a continued sense of cautious navir inhibits broadly protease inhibitor- domized trial of tipranavir/ritonavir (TPV/RTV) resistant HIV-1 clinical samples. AIDS in multiple PI-failure patients (BI 1182.2) [Ab- optimism that the therapeutic options will 14(13):1943-8, 2000. stract 562]. 9th Conference on Retroviruses meaningfully expand is warranted. and Opportunistic Infections, Seattle, 2002. McCallister S, Sabo J, Galitz L, et al. An open- label steady state investigation of the phar- Slater L, Farthing C, Jayaweera J, et al. Safe- macokinetics (PK) of tipranavir (TPV) and ri- ty and efficacy of tipranavir (TPV), a novel tonavir (RTV) and their effects on cytochrome non-peptidic protease inhibitor, plus ritonavir References P-450 (3A4) activity in normal healthy volun- (RTV), in PI-failure patients [Abstract LB-15]. De Bethune M, Wigerinck P, Jonckheere H, et teers (BI 1182.5) [Abstract 434]. 9th Confer- 41st Interscience Conference on Antimicrobial al. TMC114, a highly potent protease inhibitor ence on Retroviruses and Opportunistic Infec- Agents and Chemotherapy, Chicago, 2001. (PI) with an excellent profile against HIV tions, Seattle, 2002. variants highly resistant to current PIs [Ab- Van der Geest R, Van der Sandt I, Gille D, et al. stract F-1677]. 41st Interscience Conference on Mewshaw JP, Myrick FT, Wakefield DA, et al. Safety, tolerability and pharmacokinetics of Antimicrobial Agents and Chemotherapy, Dioxolane guanosine, the active form of the escalating single oral doses of TMC114, a nov- Chicago, 2001. diaminopurine dioxolane, is a po- el protease inhibitor (PI) highly active tent inhibitor of drug-resistant HIV-1 isolates against HIV-1 variants resistant to other PIs Eron J, Kessler H, Thompson M, et al. Clinical from patients for whom standard nucleo- [Abstract I-1934]. 41st Interscience Confer- HIV suppression after short-term monother- side therapy fails. J Acquir Immune Defic ence on Antimicrobial Agents and Chemother- apy with DAPD [Abstract 690]. 40th Inter- Syndr 29(1):11-20, 2002. apy, Chicago, 2002. science Conference on Antimicrobial Agents and Chemotherapy, Toronto, 2000. O’Mara EM, Smith J, Olsen SJ, et al. BMS-232632: Van der Horst C, Benson C, Rodriquez A, et al. single and multiple oral dose safety and phar- Long-term efficacy and safety of emtric- Fiske WD, Brennan JM, Harrison RR, et al. macokinetic study in healthy volunteers [Ab- itabine (FTC) in HIV-positive adults switching Pharmacokinetics of a second-generation stract 604]. 6th Conference on Retroviruses from a lamivudine (3TC)-containing HAART NNRTI, DPC 083, after multiple oral doses in and Opportunistic Infections, Chicago, 1999. regimen [Abstract 1932]. 8th Conference on healthy volunteers [Abstract 99]. 7th Con- Retroviruses and Opportunistic Infections, ference on Retroviruses and Opportunistic In- Piliero P, Cahn P, Pantaleo G, et al. Atazanavir: Chicago, 2001. fections, San Francisco, 2000. a once-daily protease inhibitor with a su- perior lipid profile—results of clinical tri- Yoshinaga T, Sato A, Fujishita F, et al. S-1360: in Gazzard B, Pozniak A, Arasteh K, et al. TMC125, als beyond week 48 [Abstract 706]. 9th Con- vitro activity of a new HIV-1 integrase in- a next-generation NNRTI, demonstrates high ference on Retroviruses and Opportunistic In- hibitor in clinical development [Abstract 8]. potency after 7 days therapy in treatment- fections, Seattle, 2002. 9th Conference on Retroviruses and Oppor- experienced HIV-1-infected individuals with tunistic Infections, Seattle, 2002. phenotypic NNRTI resistance [Abstract 4]. 9th Rousseau FS, Kahn JO, Thompson M, et al. Conference on Retroviruses and Opportunistic Prototype trial design for rapid dose selec- Infections, Seattle, 2002. tion of antiretroviral drugs: an example us- ing emtricitabine (Coviracil). J Antimicrob Gong YF, Robinson BS, Rose RE, et al. In vit- Chemother 48(4):507-13, 2001. ro resistance profile of the human immun- odeficiency virus type 1 protease inhibitor Ruiz N, Nusrat R, Lazzarin A, et al., for the DPC BMS-232632. Antimicrob Agents Chemother 083-201 Study Team. Study DPC 083-201: a phase 44(9):2319-26, 2000. II double-blind (DB) comparison of 3 once

22 THE PRN NOTEBOOK™ • VOLUME 7, NUMBER 2 • JUNE 2002 • WWW.PRN.ORG

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