Drug Development
Randomized, Placebo‐Controlled Single‐Ascending‐Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the HIV Nucleoside Reverse Transcriptase Inhibitor, BMS‐986001, in Healthy Subjects
The Journal of Clinical Pharmacology 54(6) 657–664 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.252
Y. Urata, MSc1, E. Paintsil, MD2, Y.‐C. Cheng, PhD3, T. Matsuda, MSc, RPh1, H. Sevinsky, MS4, D. Hawthorne, BS, MBA4, R. Bertz, PhD4, G.J. Hanna, MD4, D. Grasela, PharmD, PhD4, and C. Hwang, MD, PhD4
Abstract The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS‐986001 as a single oral dose in healthy male subjects. Sixty‐four healthy male subjects were randomized to receive a single dose of BMS‐986001 or placebo in this single‐blind, placebo‐controlled, sequential ascending‐dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900 mg fed; and 100 and 300 mg fasted) of eight subjects each (BMS‐986001 n ¼ 6/placebo n ¼ 2). BMS‐986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS‐986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS‐986001 was rapidly absorbed and exhibited a linear dose–exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS‐986001 as a single dose was generally safe and well tolerated. A linear dose–exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted.
Keywords human immunodeficiency virus type 1, nucleoside reverse transcriptase inhibitor, BMS‐986001, pharmacokinetics, safety
Introduction Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the backbone of combination antiretroviral therapy (cART) for HIV. Major HIV‐1 treatment guidelines recommend that cART be initiated with two NRTIs plus one other active agent, a non‐NRTI, a protease inhibitor or an integrase inhibitor.1–3 Although NRTIs are widely used in first‐line regimens, there are ongoing concerns regarding the potential long‐term toxicities and the evolution of cross‐resistance to members of this class. Some NRTIs are not routinely used due to their toxicities, which include mitochondrial toxicity, namely peripheral neuropathy,4,5 lipoatrophy,6,7 metabolic acidosis,8 and anemia and pancreatitis.2,9,10 The toxicity profiles of the cytidine analogs lamivudine (3TC) and emtricitabine (FTC) are favorable; however, their use in combination is not recommended due to their minimal additive antiviral activity and similar resistance profiles.2 FTC combined with tenofovir disoproxil fumarate (TDF) or 3TC combined with abacavir (ABC) is recommended by current treatment guidelines.1–3 Of these, TDF combined with FTC is preferred, based on its overall efficacy, safety, tolerability, and convenient dosing
regimen; however, there are concerns regarding nephrotoxicity, decreased bone mineral density, and increased risk of fractures with TDF.1–3,11,12 ABC is associated with hypersensitivity reaction in HLA‐B 5701‐positive patients and has been linked to an increased risk of myocardial infarction and cardiovascular disease.13,14
1
Oncolys BioPharma, Tokyo, Japan Department of Pediatrics and Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA 3 Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA 4 Bristol‐Myers Squibb, Research and Development, Princeton, NJ, USA 2
Submitted for publication 14 October 2013; accepted 18 December 2013. Corresponding Author: Carey Hwang, Bristol‐Myers Squibb, Research and Development, Princeton, NJ 08543‐4000, USA. Email: [email protected] This work has been presented in part at the 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 8–11, 2009 (poster 568).
658 With the duration of antiviral therapy increasing and convenience of treatment regimens becoming an important factor in improving adherence; long‐term toxicity and tolerability and pharmacokinetic (PK) profiles are important considerations for new antiretroviral agents. There is a need for an NRTI with potent anti‐HIV activity, a tolerability profile that is similar to or better than currently available antiretroviral agents, a favorable long‐ term safety profile in terms of bone mineral density and decline in renal function, with a high genetic barrier to HIV drug resistance/limited cross‐resistance to existing NRTIs. BMS‐986001 is a thymidine NRTI that has demonstrated greater in vitro potency, reduced in vitro mitochondrial toxicity and evidence of a higher genetic barrier to resistance compared with other thymidine analogs.15–17 BMS‐986001 displays significantly reduced inhibition of host DNA polymerases16 and minimal cytotoxicity or effect upon mitochondrial DNA (mtDNA) content was seen in cultures of human proximal tubule epithelium, skeletal muscle, or differentiated adipocytes.18 This is in contrast to stavudine, adefovir and ABC, which caused cytotoxicity and reductions in mtDNA.18 Preclinical studies have also demonstrated a favorable safety profile for BMS‐986001, with no evidence of renal or bone toxicity observed in rats and cynomolgus monkeys receiving chronic high‐ doses of BMS‐986001.19 This is in contrast to reports of renal and bone toxicity in monkeys, rats, and mice following treatment with high‐doses of tenofovir.20–25 BMS‐986001 has also demonstrated activity against some NRTI‐resistant HIV‐1 mutants, and a number of HIV‐1 subtypes.26,27 The objectives of this study were to determine the safety and tolerability, and PK of a single oral dose of BMS‐986001 administered to healthy male subjects.
Methods The study protocol, amendments and informed consent documents were approved by the Institutional Review Board. Written informed consent was obtained from all participants. The studies were performed in accordance with International Conference on Harmonization Good Clinical Practice Guidelines. Study Design A randomized, single‐blind (subjects were blinded, but the investigator was not), placebo‐controlled, sequential ascending, single oral‐dose study was conducted in healthy, male subjects between May and July 2008. Only male subjects were enrolled due to the limited availability of maternal and embryo‐fetal toxicity data. There were eight dose groups of eight subjects each. Within each dose group, subjects were randomized to receive a single dose of BMS‐986001 (n ¼ 6) or placebo
The Journal of Clinical Pharmacology / Vol 54 No 6 (2014)
(n ¼ 2) in a 3:1 ratio; group 1 (10 mg fed), group 2 (30 mg fed), group 3 (100 mg fed), group 4 (300 mg fed), group 5 (600 mg fed), group 6 (900 mg fed), group 7 (100 mg fasted), and group 8 (300 mg fasted). Doses in groups 1–6 were tested under fed conditions (subjects received standard, non‐calorie‐restricted US Food and Drug Administration [FDA] meals). Doses in groups 7–8 were tested under fasted conditions, to enable a comparison of the effect of food across cohorts. Doses of 100 and 300 mg were chosen for comparison because these doses were well tolerated in the fed state. In order to provide for the safety of subjects and to minimize the risk of adverse reactions throughout the dosing cohort, the first subject from groups 1 to 6 received a single dose of test drug on Day 1 of each study period, followed by an observation period of up to 1 day. The next seven subjects in groups 1–6 were then dosed, five received BMS‐986001 and two received placebo. Subjects in groups 7 and 8 (fasting groups) were all dosed on the same day. All subjects were under direct observation for at least 30 minutes after dosing. Study drug was administered as a single dose after a meal (or at the appointed time following rising, in the case of the fasted dose). No other food was allowed until 4 hours after study drug was administered. There was one protocol amendment to document the addition of two groups not included in the original protocol (groups 7 and 8). Study Population Subjects underwent screening evaluations up to 28 days prior to administration of study drug. Eligible subjects were healthy adult males (aged 18–45 years) with a body mass index of 18.5 and 50% of the BMS‐986001 dose was excreted unchanged in urine. There was no statistically significant difference in effect of BMS‐986001 on urinary excretion ratio across treatment groups (P ¼ 0.0828).
0 0 1 (16.7) 0 1 (16.7) 0 0 0 0 1 (6.3) 0 0
0 1 (16.7) 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
1 (16.7) 0 0 2 (33.3) 0 0
0 0 0 0 0 0
0 0 0 0 0 1 (16.7)
1 1 1 2 1 1
0 0 0 0 0 0 0 0 0
0
7 (14.6) 0 1 (16.7) 0 0 0 3 (50.0) 0 0 0 0 0 0 0 1 (16.7) 0 2 (33.3) 0 1 (6.3) 0
1 adverse event, n (%) 1 serious adverse event, n (%) Deaths Adverse events by disorder Diarrhea Vomiting Chest discomfort Fatigue Dizziness Pharyngolaryngeal pain
Placebo (n ¼ 16)
Table 2. Summary of Adverse Events
10 mg (n ¼ 6)
30 mg (n ¼ 6)
100 mg (n ¼ 6)
300 mg (n ¼ 6)
600 mg (n ¼ 6)
900 mg (n ¼ 6)
100 mg (fasted) (n ¼ 6)
300 mg (fasted) (n ¼ 6)
All subjects treated with BMS‐986001 (n ¼ 48)
Urata et al
Figure 1. Mean plasma log concentration–time profiles of doses of BMS‐986001.
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The Journal of Clinical Pharmacology / Vol 54 No 6 (2014)
Table 3a. Pharmacokinetic Parameters of BMS‐986001 Under Fed Conditions
Cmax, ng/mL, mean SD AUC0–24, ng·h/mL, mean SD AUC1, ng·h/mL, mean SD Tmax, h, median (range) T1/2, h, median (range) CL/F, mL/h, mean SD
10 mg (n ¼ 6)
30 mg (n ¼ 6)
100 mg (n ¼ 6)
300 mg (n ¼ 6)
600 mg (n ¼ 6)
900 mg (n ¼ 6)
154 51.4 604 151 627 159 2.00 (1.00–2.00) 2.4 (2.0–2.7) 16,753 3,947
435 85.0 1,890 358 1,929 359 1.50 (1.00–3.00) 2.3 (2.1–3.2) 16,003 2,911
1,475 243 6,263 502 6,306 518 2.00 (1.00–2.00) 3.4 (3.2–3.9) 15,950 1,363
4,003 695 16,452 2,109 16,546 2,166 1.00 (1.00–2.00) 3.3 (3.1–3.9) 18,380 2,281
7,178 1,441 32,141 3,990 32,364 4,048 1.50 (1.00–2.00) 3.7 (3.3–4.0) 18,828 2,784
10,398 1,560 50,193 12,890 50,593 13,186 2.00 (1.00–2.00) 3.4 (3.1–4.0) 18,573 3,659
Discussion With NRTIs remaining the cornerstone of cART for HIV, concerns over long‐term toxicities highlight a requirement for new NRTIs with potent anti‐HIV activity, improved tolerability and long‐term toxicity profiles, and minimal cross‐resistance to existing NRTIs. BMS‐986001 has demonstrated improved in vitro potency,15 activity against a variety of HIV‐1 subtypes and some NRTI‐resistant mutants,26,27 and a favorable preclinical safety and
Figure 2. (a) BMS‐986001 dose relationship for AUCINF under fed conditions. (b) BMS‐986001 dose relationship for Cmax under fed conditions.
toxicity profile.16,18,19 These results represent the first report of safety and PK analysis of the NRTI BMS‐986001 in healthy male subjects. BMS‐986001 was well tolerated in this study. There were no serious AEs or deaths and no AEs resulted in study discontinuation. All AEs were mild to moderate and considered unlikely to be related to the study drug. The number and severity of AEs did not increase in a dose‐dependent manner. In addition, no clinically meaningful changes, abnormalities, or trends in vital signs (including heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature), ECG results, physical examination results or clinical laboratory results were observed. BMS‐986001 was rapidly absorbed at all doses studied (10–900 mg), reaching a maximum concentration in approximately 1–2 hours. A strong linear dose–exposure relationship was observed across the dose range studied and the increases in Cmax and AUC were proportional to the increase in dose. There was no apparent effect of food on the PK of BMS‐986001 when assessed in subjects receiving the 100 and 300 mg doses; however, due to the limited number of subjects in this study, these data are not definitive. In addition, dose escalation had no effect on BMS‐986001 urinary excretion ratios. The high urinary excretion ratios reported in this study indicate that BMS‐986001 is excreted via the kidneys and not metabolized in the liver. BMS‐986001 is metabolized intracellularly to its active triphosphate form. Previous in vitro studies in CEM cells (CD4þ T‐cell line) have demonstrated an intracellular T1/2 of approximately 9.7 hours for the active triphosphate moiety of BMS‐986001.29 One limitation to our study is the lack of clinical data on the intracellular concentrations of the active triphosphate moiety in peripheral blood mononuclear cells and the resultant intracellular half‐life of the triphosphate. These data are being collected from ongoing clinical studies of BMS‐986001. An additional limitation is the enrollment of only male subjects into the study. However, it is likely that the results described herein are applicable to female subjects, and female subjects have been enrolled in subsequent studies. Subsequent to this study, a 10‐day multiple dose ascending monotherapy study was performed in order to investigate the safety, tolerability, antiviral activity, and
663
Urata et al Table 3b. Pharmacokinetic Parameters of BMS‐986001 Under Fed Compared With Fasted Conditions
Cmax (ng/mL) Mean SD Difference (95% CI) AUC0–24 (ng·h/mL) Mean SD Difference (95% CI) Tmax, h, median (range) T1/2, h, median (range) CL/F, mL/h, mean SD
100 mg fed (n ¼ 6)
100 mg fasted (n ¼ 6)
300 mg fed (n ¼ 6)
300 mg fasted (n ¼ 6)
1,475 243
1,572 370 96.7 (306 to 500)
4,003 695
3,842 905 162 (1,200 to 876)
6,263 502
6,374 822 111 (765 to 987) 1.00 (1.00–2.00) 3.3 (3.1–3.5) 15,812 1,919
16,452 2,109
17,819 3,284 1,366 (2,184 to 4,917) 2.00 (1.00–3.00) 3.4 (3.2–4.0) 17,208 3,214
2.00 (1.00–2.00) 3.4 (3.2–3.9) 15,950 1,363
PK of a narrower dose range of BMS‐986001 (100–600 mg once daily) in HIV‐1 infected, treatment‐experienced (not exposed to any antiretroviral therapy in the previous 3 months) subjects, both male and female.30 PK parameters were comparable to those observed in this study, with increases in Cmax and AUC being dose‐proportional across the range studied.30 Treatment with once‐daily doses of BMS‐986001 resulted in a median decrease in plasma HIV‐1 RNA ranging from 0.97 to 1.28 log10 copies/mL, comparing favorably to other NRTIs.30 The antiviral activity was roughly comparable across treatment arms, and exposure–response analysis showed that AUC values produced by BMS‐986001 doses of 100–600 mg were on the upper end of the exposure–response curve.30 Based on these data, once‐daily doses of 100, 200, and 400 mg BMS‐986001 are anticipated to result in BMS‐986001 exposures that fall within the range that has demonstrated antiviral activity (median decrease in HIV‐1 RNA 1 log10). These doses are being evaluated in a Phase 2b study (NCT01489046). In conclusion, BMS‐986001 administered as a single dose was generally safe and well tolerated. BMS‐986001 demonstrated a linear dose–exposure relationship across all doses studied, can be administered without regard to meals, and further clinical development is warranted. Acknowledgements Data management and statistical analysis for this study was performed by Iberica Clinical Research Center, Eatontown, NJ; the authors acknowledge J.S. Ross from Iberica Clinical Research Center. The authors also acknowledge Tandem Labs, a LabCorp Company, West Trenton, NJ, for the bioanalytical analysis of the plasma and urine samples. Editorial support during manuscript development was provided by Anna Shirazi of MediTech Media and was funded by Bristol‐Myers Squibb. Dr. Yung‐chi Cheng is a Fellow of the National Foundation for Cancer Research.
Declaration of Conflicting Interests Y.‐C. Cheng is a co‐inventor of 40 Ed4T (BMS‐986001), reports institutional patents, royalties, and stock options in association with Yale University and previously received consultancy fees
1.00 (1.00–2.00) 3.3 (3.1–3.9) 18,380 2,281
from Oncolys BioPharma. E. Paintsil received grants from the National Institutes of Health. T. Matsuda is an employee of AbbVie GK and holds stock/stock options. H. Sevinsky, D. Hawthorne, R. Bertz, G.J. Hanna, D. Grasela, and C. Hwang are all employees of Bristol‐Myers Squibb and obtain stock as partial compensation.
Funding This work was supported by Oncolys Pharma and Bristol‐Myers Squibb. The authors had full access to all of the data and take full responsibility for the accuracy of the data analysis. The authors received no financial support or compensation for this publication.
References 1. European AIDS Clinical Society. Guidelines version 6.1. Available from: ; 2012 Accessed 01.04.13. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV‐1‐infected adults and adolescents 2012 update. Available from: ; 2012 Accessed 05.18.12. 3. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2010 revision. Available from: ; 2010 Accessed 08.02.12. 4. Cherry CL, Skolasky RL, Lal L, et al. Antiretroviral use and other risks for HIV‐associated neuropathies in an international cohort. Neurology. 2006;66(6):867–873. 5. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV‐infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS. 2000;14(3):273–278. 6. Hendrickson SL, Kingsley LA, Ruiz‐Pesini E, et al. Mitochondrial DNA haplogroups influence lipoatrophy after highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2009;51(2): 111–116. 7. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor‐sparing regimens for initial HIV treatment. AIDS. 2009; 23(9):1109–1118. 8. Lactic Acidosis International Study Group. Risk factors for lactic acidosis and severe hyperlactataemia in HIV‐1‐infected adults exposed to antiretroviral therapy. AIDS. 2007;21(18):2455– 2464.
664 9. Moreno A, Quereda C, Moreno L, et al. High rate of didanosine‐ related mitochondrial toxicity in HIV/HCV‐coinfected patients receiving ribavirin. Antivir Ther. 2004;9(1):133–138. 10. Reisler RB, Murphy RL, Redfield RR, Parker RA. Incidence of pancreatitis in HIV‐1‐infected individuals enrolled in 20 adult AIDS clinical trials group studies: lessons learned. J Acquir Immune Defic Syndr. 2005;39(2):159–166. 11. Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS. 2012;26(7):825–831. 12. Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26(7):867– 875. 13. Strategies for Management of Anti‐Retroviral Therapy/INSIGHT, DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV‐infected patients. AIDS. 2008;22(14):F17–F24. 14. Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV‐ infected patients enrolled in the D:A:D study: a multi‐cohort collaboration. Lancet. 2008;371(9622):1417–1426. 15. Dutschman GE, Grill SP, Gullen EA, et al. Novel 40 ‐substituted stavudine analog with improved anti‐human immunodeficiency virus activity and decreased cytotoxicity. Antimicrob Agents Chemother. 2004;48(5):1640–1646. 16. Yang G, Dutschman GE, Wang CJ, et al. Highly selective action of triphosphate metabolite of 40 ‐ethynyl D4T: a novel anti‐HIV compound against HIV‐1 RT. Antiviral Res. 2007;73(3):185–191. 17. Yang G, Paintsil E, Dutschman GE, et al. Impact of novel human immunodeficiency virus type 1 reverse transcriptase mutations P119S and T165A on 40 ‐ethynylthymidine analog resistance profile. Antimicrob Agents Chemother. 2009;53(11):4640–4646. 18. Wang F, Flint OP. BMS‐986001, an HIV nucleoside reverse transcriptase inhibitor, does not degrade mitochondrial DNA in long‐ term primary cultures of cells isolated from human kidney, muscle and adipose tissue. Antimicrob Agents Chemother. 2013;57(12):6205–6212. 19. Guha M, Pilcher G, Moehlenkamp J, et al. Absence of renal and bone toxicity in non‐clinical studies of BMS‐986001, a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus (HIV). In: 19th International AIDS Conference. Washington, USA; July 22, 2012. Abstract TUPE041. 20. Castillo AB, Tarantal AF, Watnik MR, Martin RB. Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta). J Orthop Res. 2002; 20(6):1185–1189.
The Journal of Clinical Pharmacology / Vol 54 No 6 (2014) 21. Kohler JJ, Hosseini SH. Subcellular renal proximal tubular mitochondrial toxicity with tenofovir treatment. Methods Mol Biol. 2011;755:267–277. 22. Lebrecht D, Venhoff AC, Kirschner J, et al. Mitochondrial tubulopathy in tenofovir disoproxil fumarate‐treated rats. J Acquir Immune Defic Syndr. 2009;51(3):258–263. 23. Tarantal AF, Marthas ML, Shaw JP, Cundy K, Bischofberger N. Administration of 9‐[2‐(R)‐(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety and efficacy studies. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20(4):323–333. 24. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short‐term or prolonged administration of 9‐[2‐(phosphonomethoxy) propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother. 2004;48(5):1469–1487. 25. Van Rompay KK, Durand‐Gasselin L, Brignolo LL, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Chemother. 2008;52(9):3144–3160. 26. Bristol‐Myers Squibb. Data on file. J Clin Pharm, unpublished data, 2011. 27. Li Z, Terry B, Olds W, et al. In vitro cross‐resistance profile of nucleoside reverse transcriptase inhibitor (NRTI) BMS‐986001 against known NRTI resistance mutations. Antimicrob Agents Chemother 2013;57(11):5500–5508. 28. US Food and Drug Administration. Guidance for Industry, Bioanalytical Method Validation. Available from: ; 2013 Accessed 07.24.13. 29. Wang X, Tanaka H, Baba M, Cheng YC. Retention of metabolites of 20 ,30 ‐didehydro‐30 ‐deoxy‐40 ‐ethynylthymidine, a novel anti‐human immunodeficiency virus type 1 thymidine analog, in cells. Antimicrob Agents Chemother. 2009;53(8):3317–3324. 30. Cotte L, Dellamonica P, Raffi F, et al. Randomized, placebo‐ controlled study of the safety, tolerability, antiviral activity and pharmacokinetics of 10‐day monotherapy with BMS‐986001, a novel HIV NRTI, in treatment‐experienced HIV‐1‐infected subjects. J Acquir Immune Defic Syndr. 2013;63(3):346–354.
Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web‐site.
Randomized, Placebo‐Controlled Single‐Ascending‐Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the HIV Nucleoside Reverse Transcriptase Inhibitor, BMS‐986001, in Healthy Subjects
The Journal of Clinical Pharmacology 54(6) 657–664 © 2014, The American College of Clinical Pharmacology DOI: 10.1002/jcph.252
Y. Urata, MSc1, E. Paintsil, MD2, Y.‐C. Cheng, PhD3, T. Matsuda, MSc, RPh1, H. Sevinsky, MS4, D. Hawthorne, BS, MBA4, R. Bertz, PhD4, G.J. Hanna, MD4, D. Grasela, PharmD, PhD4, and C. Hwang, MD, PhD4
Abstract The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS‐986001 as a single oral dose in healthy male subjects. Sixty‐four healthy male subjects were randomized to receive a single dose of BMS‐986001 or placebo in this single‐blind, placebo‐controlled, sequential ascending‐dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900 mg fed; and 100 and 300 mg fasted) of eight subjects each (BMS‐986001 n ¼ 6/placebo n ¼ 2). BMS‐986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS‐986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS‐986001 was rapidly absorbed and exhibited a linear dose–exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS‐986001 as a single dose was generally safe and well tolerated. A linear dose–exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted.
Keywords human immunodeficiency virus type 1, nucleoside reverse transcriptase inhibitor, BMS‐986001, pharmacokinetics, safety
Introduction Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the backbone of combination antiretroviral therapy (cART) for HIV. Major HIV‐1 treatment guidelines recommend that cART be initiated with two NRTIs plus one other active agent, a non‐NRTI, a protease inhibitor or an integrase inhibitor.1–3 Although NRTIs are widely used in first‐line regimens, there are ongoing concerns regarding the potential long‐term toxicities and the evolution of cross‐resistance to members of this class. Some NRTIs are not routinely used due to their toxicities, which include mitochondrial toxicity, namely peripheral neuropathy,4,5 lipoatrophy,6,7 metabolic acidosis,8 and anemia and pancreatitis.2,9,10 The toxicity profiles of the cytidine analogs lamivudine (3TC) and emtricitabine (FTC) are favorable; however, their use in combination is not recommended due to their minimal additive antiviral activity and similar resistance profiles.2 FTC combined with tenofovir disoproxil fumarate (TDF) or 3TC combined with abacavir (ABC) is recommended by current treatment guidelines.1–3 Of these, TDF combined with FTC is preferred, based on its overall efficacy, safety, tolerability, and convenient dosing
regimen; however, there are concerns regarding nephrotoxicity, decreased bone mineral density, and increased risk of fractures with TDF.1–3,11,12 ABC is associated with hypersensitivity reaction in HLA‐B 5701‐positive patients and has been linked to an increased risk of myocardial infarction and cardiovascular disease.13,14
1
Oncolys BioPharma, Tokyo, Japan Department of Pediatrics and Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA 3 Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA 4 Bristol‐Myers Squibb, Research and Development, Princeton, NJ, USA 2
Submitted for publication 14 October 2013; accepted 18 December 2013. Corresponding Author: Carey Hwang, Bristol‐Myers Squibb, Research and Development, Princeton, NJ 08543‐4000, USA. Email: [email protected] This work has been presented in part at the 16th Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, February 8–11, 2009 (poster 568).
658 With the duration of antiviral therapy increasing and convenience of treatment regimens becoming an important factor in improving adherence; long‐term toxicity and tolerability and pharmacokinetic (PK) profiles are important considerations for new antiretroviral agents. There is a need for an NRTI with potent anti‐HIV activity, a tolerability profile that is similar to or better than currently available antiretroviral agents, a favorable long‐ term safety profile in terms of bone mineral density and decline in renal function, with a high genetic barrier to HIV drug resistance/limited cross‐resistance to existing NRTIs. BMS‐986001 is a thymidine NRTI that has demonstrated greater in vitro potency, reduced in vitro mitochondrial toxicity and evidence of a higher genetic barrier to resistance compared with other thymidine analogs.15–17 BMS‐986001 displays significantly reduced inhibition of host DNA polymerases16 and minimal cytotoxicity or effect upon mitochondrial DNA (mtDNA) content was seen in cultures of human proximal tubule epithelium, skeletal muscle, or differentiated adipocytes.18 This is in contrast to stavudine, adefovir and ABC, which caused cytotoxicity and reductions in mtDNA.18 Preclinical studies have also demonstrated a favorable safety profile for BMS‐986001, with no evidence of renal or bone toxicity observed in rats and cynomolgus monkeys receiving chronic high‐ doses of BMS‐986001.19 This is in contrast to reports of renal and bone toxicity in monkeys, rats, and mice following treatment with high‐doses of tenofovir.20–25 BMS‐986001 has also demonstrated activity against some NRTI‐resistant HIV‐1 mutants, and a number of HIV‐1 subtypes.26,27 The objectives of this study were to determine the safety and tolerability, and PK of a single oral dose of BMS‐986001 administered to healthy male subjects.
Methods The study protocol, amendments and informed consent documents were approved by the Institutional Review Board. Written informed consent was obtained from all participants. The studies were performed in accordance with International Conference on Harmonization Good Clinical Practice Guidelines. Study Design A randomized, single‐blind (subjects were blinded, but the investigator was not), placebo‐controlled, sequential ascending, single oral‐dose study was conducted in healthy, male subjects between May and July 2008. Only male subjects were enrolled due to the limited availability of maternal and embryo‐fetal toxicity data. There were eight dose groups of eight subjects each. Within each dose group, subjects were randomized to receive a single dose of BMS‐986001 (n ¼ 6) or placebo
The Journal of Clinical Pharmacology / Vol 54 No 6 (2014)
(n ¼ 2) in a 3:1 ratio; group 1 (10 mg fed), group 2 (30 mg fed), group 3 (100 mg fed), group 4 (300 mg fed), group 5 (600 mg fed), group 6 (900 mg fed), group 7 (100 mg fasted), and group 8 (300 mg fasted). Doses in groups 1–6 were tested under fed conditions (subjects received standard, non‐calorie‐restricted US Food and Drug Administration [FDA] meals). Doses in groups 7–8 were tested under fasted conditions, to enable a comparison of the effect of food across cohorts. Doses of 100 and 300 mg were chosen for comparison because these doses were well tolerated in the fed state. In order to provide for the safety of subjects and to minimize the risk of adverse reactions throughout the dosing cohort, the first subject from groups 1 to 6 received a single dose of test drug on Day 1 of each study period, followed by an observation period of up to 1 day. The next seven subjects in groups 1–6 were then dosed, five received BMS‐986001 and two received placebo. Subjects in groups 7 and 8 (fasting groups) were all dosed on the same day. All subjects were under direct observation for at least 30 minutes after dosing. Study drug was administered as a single dose after a meal (or at the appointed time following rising, in the case of the fasted dose). No other food was allowed until 4 hours after study drug was administered. There was one protocol amendment to document the addition of two groups not included in the original protocol (groups 7 and 8). Study Population Subjects underwent screening evaluations up to 28 days prior to administration of study drug. Eligible subjects were healthy adult males (aged 18–45 years) with a body mass index of 18.5 and 50% of the BMS‐986001 dose was excreted unchanged in urine. There was no statistically significant difference in effect of BMS‐986001 on urinary excretion ratio across treatment groups (P ¼ 0.0828).
0 0 1 (16.7) 0 1 (16.7) 0 0 0 0 1 (6.3) 0 0
0 1 (16.7) 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
0 0 0 0 0 0
1 (16.7) 0 0 2 (33.3) 0 0
0 0 0 0 0 0
0 0 0 0 0 1 (16.7)
1 1 1 2 1 1
0 0 0 0 0 0 0 0 0
0
7 (14.6) 0 1 (16.7) 0 0 0 3 (50.0) 0 0 0 0 0 0 0 1 (16.7) 0 2 (33.3) 0 1 (6.3) 0
1 adverse event, n (%) 1 serious adverse event, n (%) Deaths Adverse events by disorder Diarrhea Vomiting Chest discomfort Fatigue Dizziness Pharyngolaryngeal pain
Placebo (n ¼ 16)
Table 2. Summary of Adverse Events
10 mg (n ¼ 6)
30 mg (n ¼ 6)
100 mg (n ¼ 6)
300 mg (n ¼ 6)
600 mg (n ¼ 6)
900 mg (n ¼ 6)
100 mg (fasted) (n ¼ 6)
300 mg (fasted) (n ¼ 6)
All subjects treated with BMS‐986001 (n ¼ 48)
Urata et al
Figure 1. Mean plasma log concentration–time profiles of doses of BMS‐986001.
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Table 3a. Pharmacokinetic Parameters of BMS‐986001 Under Fed Conditions
Cmax, ng/mL, mean SD AUC0–24, ng·h/mL, mean SD AUC1, ng·h/mL, mean SD Tmax, h, median (range) T1/2, h, median (range) CL/F, mL/h, mean SD
10 mg (n ¼ 6)
30 mg (n ¼ 6)
100 mg (n ¼ 6)
300 mg (n ¼ 6)
600 mg (n ¼ 6)
900 mg (n ¼ 6)
154 51.4 604 151 627 159 2.00 (1.00–2.00) 2.4 (2.0–2.7) 16,753 3,947
435 85.0 1,890 358 1,929 359 1.50 (1.00–3.00) 2.3 (2.1–3.2) 16,003 2,911
1,475 243 6,263 502 6,306 518 2.00 (1.00–2.00) 3.4 (3.2–3.9) 15,950 1,363
4,003 695 16,452 2,109 16,546 2,166 1.00 (1.00–2.00) 3.3 (3.1–3.9) 18,380 2,281
7,178 1,441 32,141 3,990 32,364 4,048 1.50 (1.00–2.00) 3.7 (3.3–4.0) 18,828 2,784
10,398 1,560 50,193 12,890 50,593 13,186 2.00 (1.00–2.00) 3.4 (3.1–4.0) 18,573 3,659
Discussion With NRTIs remaining the cornerstone of cART for HIV, concerns over long‐term toxicities highlight a requirement for new NRTIs with potent anti‐HIV activity, improved tolerability and long‐term toxicity profiles, and minimal cross‐resistance to existing NRTIs. BMS‐986001 has demonstrated improved in vitro potency,15 activity against a variety of HIV‐1 subtypes and some NRTI‐resistant mutants,26,27 and a favorable preclinical safety and
Figure 2. (a) BMS‐986001 dose relationship for AUCINF under fed conditions. (b) BMS‐986001 dose relationship for Cmax under fed conditions.
toxicity profile.16,18,19 These results represent the first report of safety and PK analysis of the NRTI BMS‐986001 in healthy male subjects. BMS‐986001 was well tolerated in this study. There were no serious AEs or deaths and no AEs resulted in study discontinuation. All AEs were mild to moderate and considered unlikely to be related to the study drug. The number and severity of AEs did not increase in a dose‐dependent manner. In addition, no clinically meaningful changes, abnormalities, or trends in vital signs (including heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature), ECG results, physical examination results or clinical laboratory results were observed. BMS‐986001 was rapidly absorbed at all doses studied (10–900 mg), reaching a maximum concentration in approximately 1–2 hours. A strong linear dose–exposure relationship was observed across the dose range studied and the increases in Cmax and AUC were proportional to the increase in dose. There was no apparent effect of food on the PK of BMS‐986001 when assessed in subjects receiving the 100 and 300 mg doses; however, due to the limited number of subjects in this study, these data are not definitive. In addition, dose escalation had no effect on BMS‐986001 urinary excretion ratios. The high urinary excretion ratios reported in this study indicate that BMS‐986001 is excreted via the kidneys and not metabolized in the liver. BMS‐986001 is metabolized intracellularly to its active triphosphate form. Previous in vitro studies in CEM cells (CD4þ T‐cell line) have demonstrated an intracellular T1/2 of approximately 9.7 hours for the active triphosphate moiety of BMS‐986001.29 One limitation to our study is the lack of clinical data on the intracellular concentrations of the active triphosphate moiety in peripheral blood mononuclear cells and the resultant intracellular half‐life of the triphosphate. These data are being collected from ongoing clinical studies of BMS‐986001. An additional limitation is the enrollment of only male subjects into the study. However, it is likely that the results described herein are applicable to female subjects, and female subjects have been enrolled in subsequent studies. Subsequent to this study, a 10‐day multiple dose ascending monotherapy study was performed in order to investigate the safety, tolerability, antiviral activity, and
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Urata et al Table 3b. Pharmacokinetic Parameters of BMS‐986001 Under Fed Compared With Fasted Conditions
Cmax (ng/mL) Mean SD Difference (95% CI) AUC0–24 (ng·h/mL) Mean SD Difference (95% CI) Tmax, h, median (range) T1/2, h, median (range) CL/F, mL/h, mean SD
100 mg fed (n ¼ 6)
100 mg fasted (n ¼ 6)
300 mg fed (n ¼ 6)
300 mg fasted (n ¼ 6)
1,475 243
1,572 370 96.7 (306 to 500)
4,003 695
3,842 905 162 (1,200 to 876)
6,263 502
6,374 822 111 (765 to 987) 1.00 (1.00–2.00) 3.3 (3.1–3.5) 15,812 1,919
16,452 2,109
17,819 3,284 1,366 (2,184 to 4,917) 2.00 (1.00–3.00) 3.4 (3.2–4.0) 17,208 3,214
2.00 (1.00–2.00) 3.4 (3.2–3.9) 15,950 1,363
PK of a narrower dose range of BMS‐986001 (100–600 mg once daily) in HIV‐1 infected, treatment‐experienced (not exposed to any antiretroviral therapy in the previous 3 months) subjects, both male and female.30 PK parameters were comparable to those observed in this study, with increases in Cmax and AUC being dose‐proportional across the range studied.30 Treatment with once‐daily doses of BMS‐986001 resulted in a median decrease in plasma HIV‐1 RNA ranging from 0.97 to 1.28 log10 copies/mL, comparing favorably to other NRTIs.30 The antiviral activity was roughly comparable across treatment arms, and exposure–response analysis showed that AUC values produced by BMS‐986001 doses of 100–600 mg were on the upper end of the exposure–response curve.30 Based on these data, once‐daily doses of 100, 200, and 400 mg BMS‐986001 are anticipated to result in BMS‐986001 exposures that fall within the range that has demonstrated antiviral activity (median decrease in HIV‐1 RNA 1 log10). These doses are being evaluated in a Phase 2b study (NCT01489046). In conclusion, BMS‐986001 administered as a single dose was generally safe and well tolerated. BMS‐986001 demonstrated a linear dose–exposure relationship across all doses studied, can be administered without regard to meals, and further clinical development is warranted. Acknowledgements Data management and statistical analysis for this study was performed by Iberica Clinical Research Center, Eatontown, NJ; the authors acknowledge J.S. Ross from Iberica Clinical Research Center. The authors also acknowledge Tandem Labs, a LabCorp Company, West Trenton, NJ, for the bioanalytical analysis of the plasma and urine samples. Editorial support during manuscript development was provided by Anna Shirazi of MediTech Media and was funded by Bristol‐Myers Squibb. Dr. Yung‐chi Cheng is a Fellow of the National Foundation for Cancer Research.
Declaration of Conflicting Interests Y.‐C. Cheng is a co‐inventor of 40 Ed4T (BMS‐986001), reports institutional patents, royalties, and stock options in association with Yale University and previously received consultancy fees
1.00 (1.00–2.00) 3.3 (3.1–3.9) 18,380 2,281
from Oncolys BioPharma. E. Paintsil received grants from the National Institutes of Health. T. Matsuda is an employee of AbbVie GK and holds stock/stock options. H. Sevinsky, D. Hawthorne, R. Bertz, G.J. Hanna, D. Grasela, and C. Hwang are all employees of Bristol‐Myers Squibb and obtain stock as partial compensation.
Funding This work was supported by Oncolys Pharma and Bristol‐Myers Squibb. The authors had full access to all of the data and take full responsibility for the accuracy of the data analysis. The authors received no financial support or compensation for this publication.
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Supporting Information Additional supporting information may be found in the online version of this article at the publisher’s web‐site.
