Cox 26/4/07 15:06 Page 61 Antiviral Chemistry & Chemotherapy 18:61–70 Review Apricitabine: a novel deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of nucleoside-resistant HIV infection Mark A Wainberg1, Pedro Cahn2, Richard C Bethell3, James Sawyer4* and Susan Cox5 1McGill University AIDS Center, Lady Davis Institute-Jewish General Hospital, Montreal, Canada 2Fundación Huesped, Buenos Aires, Argentina 3Shire Biochem Inc., Laval, Québec, Canada (presently Boehringer-Ingelheim [Canada] Ltd, Laval, Québec, Canada) 4Prism Ideas, Nantwich, Cheshire, UK 5Avexa Ltd, Richmond, Australia *Corresponding author: Tel: +44 (0) 1270 621 724; Fax: +44 (0) 1270 621 725: E-mail: [email protected] Existing nucleoside reverse transcriptase inhibitors co-administration of ATC together with these for HIV disease are limited by problems of resis- agents will not be possible. The drug is renally tance and, in some cases, long-term toxicity. eliminated, giving a low potential for hepatic drug Apricitabine (ATC; formerly BCH10618, SPD754 interactions. In a double-blind, randomized, and AVX754) is a deoxycytidine analogue nucleo- placebo-controlled Phase II monotherapy trial in side reverse transcriptase inhibitor in clinical antiretroviral-naive patients, ATC doses of development. ATC retains substantial in vitro 1,200 and 1,600 mg/day reduced plasma viral load activity against HIV-1 containing many mutations levels by 1.65 and 1.58 log10 HIV RNA copies/ml, associated with nucleoside reverse transcriptase respectively, after 10 days of treatment (P<0.0001 inhibitor resistance, showing a less than twofold versus placebo). ATC showed a low propensity to reduction in susceptibility in the presence of either select for resistance mutants in vitro and during up to five thymidine analogue mutations or the clinical monotherapy. ATC was well tolerated in M184V mutation. ATC showed a low potential for volunteers and in HIV-infected patients. This cellular or mitochondrial toxicity in vitro. ATC is promising profile suggests that ATC may be useful well absorbed orally, with a bioavailability of in treating patients who have failed previous 65–80%. Its plasma elimination half-life (approxi- lamivudine- or emtricitabine-containing regimens. mately 3 h), and the intracellular half-life of its Further studies to evaluate the long-term efficacy triphosphate (TP) metabolite (6–7 h) support and tolerability of ATC are underway. twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivu- Keywords: apricitabine, ATC, AVX754, HIV-1, dine or emtricitabine, indicating that clinical reverse transcriptase inhibitors Introduction Nucleoside reverse transcriptase inhibitors (NRTIs) remain resistance, including cross-resistance (Tamalet et al., 2003), central components of almost all the drug combinations used reduce the options for salvage therapy in patients who have in highly active antiretroviral therapy (HAART) for HIV experienced virological failure on their initial regimens disease (Gazzard, et al., 2005; Department of Health and (Deeks, 2004; Gallant, 2005; Wainberg et al., 2005b). Human Services Panel on Antiretroviral Guidelines for Thus, a need for new agents remains, especially for Adults and Adolescents, 2006; Hammer et al., 2006). HAART-experienced patients (Wainberg et al., 2005a). However, existing NRTIs confront two important problems. Apricitabine (ATC; formerly BCH10618, SPD754 First, several of the early NRTIs to be introduced are associ- and AVX754; Avexa, Richmond, Australia) is a single ated with poor long-term tolerability, including effects due to (–)-enantiomer deoxycytidine analogue NRTI in clinical mitochondrial toxicity (Kakuda, 2000; Anderson et al., 2004), development for patients with HIV disease. In common so the commonly used HAART regimens depend heavily with other NRTIs (Ray, 2005), ATC undergoes intracellular on a few, well-tolerated NRTIs. Second, rising levels of activation to the NRTI triphosphate (TP) form before ©2007 International Medical Press 0956-3202 61 Cox 26/4/07 15:06 Page 62 MA Wainberg et al. competing with endogenous deoxynucleotide triphosphates In vitro virological activity for binding to the viral reverse transcriptase (RT) enzyme (De Muys et al., 1999). The subsequent incorporation of the Antiretroviral activity NRTI monophosphate into the nascent viral DNA results ATC-TP has been shown to inhibit wild-type HIV-1 RT in the termination of chain elongation and inhibition of in vitro with an inhibitory constant (Ki) of 0.08 μM, reverse transcription. There are currently only two deoxycy- compared with 0.16 μM for 3TC-TP (De Muys et al., tidine analogue NRTIs approved for the treatment of HIV, 1999). In early studies of its antiretroviral activity, ATC lamivudine (3TC) and emtricitabine (FTC), both of which showed 50% inhibitory concentrations (IC50) against wild- are (–)-enantiomeric compounds. These two agents are type HIV-1 of 1.3 μM (Taylor et al., 2000), 1.45 μM (De cross resistant and cannot be used sequentially following Muys et al., 1999) and 25 μM (Gu et al., 2006). selection of the M184V mutation in RT. ATC might there- The activity of ATC in vitro is maintained in the presence fore represent a new therapeutic option within this subclass of many nucleoside analogue mutations (NAMs) associated for the treatment of experienced patients who have failed with resistance to other NRTIs (De Muys et al., 1999; 3TC or FTC, and also for treatment-naive patients. Taylor et al., 2000; Bethell et al., 2005; Gu et al., 2006). This paper reviews the biochemical, virological and Gu et al. (2006) tested the activity of ATC against 50 clin- pharmacokinetic properties of ATC, together with its clinical ical HIV-1 isolates, of which 45 were NRTI-resistant, efficacy and tolerability in HIV-infected patients. using the Antivirogram™ assay (Monogram Biosciences, Inc., San Francisco, CA, USA). ATC susceptibility was Chemical structure reduced 1.2–2.2-fold against isolates resistant to zidovu- dine (AZT) owing to the presence of the M41L and ATC is the (–)-enantiomer of 2′-deoxy-3′-oxa-4′- T215Y/F thymidine analogue mutations (TAMs), plus a thiocytidine (de Muys et al., 1999; Taylor et al., 2000) median of three additional TAMs, and/or resistant to 3TC (Figure 1). Both the (+)- and (–)-enantiomers of this owing to the M184V mutation. ATC activity was reduced compound have anti-HIV activity in vitro (De Muys et al., 1.3–2.8-fold against isolates resistant to abacavir (ABC; 1999; Taylor et al., 2000; Bethell et al., 2005; Gu et al., that is, L74V, Y115F and M184V plus one other NAM) or 2006) and in HIV-infected patients (Wood et al., 1999; stavudine (d4T; that is, V75T/M, M41L, T215F/Y, and Cahn et al., 2006). However, the racemic mixture exhibited four other NAMs). Insertions at amino acid position 69 significant toxicity in preclinical studies, which was not and viruses containing the Q151M cluster of mutations seen with the single (–)-enantiomer, ATC (Locas C, Ching S (with or without M184V) gave respective reductions in & Damment S [2004] Safety profile of SPD754 in apricitabine activity of 5.2-fold and 14–16-fold, similar or cynomolgus monkeys treated for 52 weeks. 11th Conference lower than the reductions seen with other NRTIs. ATC on Retroviruses and Opportunistic Infections. San Francisco, showed similar activity (IC50: 10–50 µM) against isolates of CA, USA, 8–11 February 2004, Abstract I-17). The (–)- various group M HIV-1 clades, including A/G, B, C, D, enantiomer shows no racemization to the corresponding A(E), D/F, F and H (Gu et al., 2006). As in previous (+)-enantiomer in vivo (Holdich et al., 2006). studies (Taylor et al., 2000), ATC showed additive virolog- ical effects in vitro in combination with other NRTIs (AZT, 3TC, d4T, didanosine [ddI] and ABC), tenofovir (TDF), nevirapine or saquinavir (Gu et al., 2006). Figure 1. Molecular formula structure of apricitabine Subsequently, in response to the observation of a competi- NH2 tive interaction between 3TC and ATC for intracellular phosphorylation (Bethell RC, Adams J, De Muys J, Lippens J, Richard A, Hamelin B, Ren C, Collins P, N Struthers-Semple C, Holdich T & Sawyer J [2004] Pharmacological evaluation of a dual deoxycytidine analogue combination: 3TC and SPD754 [ATC]. 11th O N Conference on Retroviruses and Opportunistic Infections;San Francisco, CA, USA, 8–11 February 2004. Abstract 138), a HO further combination study was undertaken with ATC and S 3TC against a virus bearing the M184V mutation in RT. This modified study design revealed the antagonistic effect of 3TC with regard to the antiviral activity of ATC (Bethell RC, O Collins P,Holdich T & Sawyer J [2004] In vitro and in vivo Molecular weight = 229.26, 1μM = 0.229 μg/ml. antiviral activity of SPD754 [ATC] against wild-type 62 ©2007 International Medical Press Cox 26/4/07 15:06 Page 63 Apricitabine: a new NRTI for HIV-1 disease Figure 2. Fold changes in apricitabine susceptibility in HIV-1 containing according to presence of thymidine analogue mutations in HIV-1 reverse transcriptase A 7.00 3TC 6.00 ABC 5.00 e c ddl 4.00 3.00 TDF resistan d 2.00 ATC Fol 1.00 0.00 Wild-type 41, 215 41, 210, 41, 67, 41, 67, 210, 215 210, 215 215, 219 Location of mutations in reverse transcriptase B 7.00 6.00 5.00 e c 4.00 3.00 resistan d 2.00 Fol 1.00 0.00 Wild-type 67, 70 67, 70, 67, 70, 41, 67, 70, 219 215, 219 215, 219 Location of mutations in reverse transcriptase Apricitabine susceptibility was tested using the PhenoSenseTM HIV assay against wild-type HIV-1 and HIV-1 containing varying patterns of thymidine analogue mutations: accumulated via (A) the 41, 215 pathway (reverse transcriptase codons 41, 67, 210, 215, and 219), and (B) the 67, 70, 219 pathway (codons 41, 67, 70, 215 and 219) (Bethell et al., 2005). ABC, abacavir; ATC, apricitabine; ddl, didanosine; TDF, tenofovir; 3TC, lamivudine.