A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis

Scandinavian Journal of Pain - Tập 17 - Trang 134-143 - 2017
Arthur J. Mayorga1, Christopher M. Flores1, Jeremiah J. Trudeau1, John A. Moyer1, Kevin Shalayda1, Mark Dale2, Mary Ellen Frustaci1, Nathaniel Katz3,4, Prasarn Manitpisitkul1, Roi Treister3,4,5, Stuart Ratcliffe6, Gary Romano1
1Janssen Research & Development, LLC, Titusville, NJ, USA
2MAC Clinical Research, Manchester, UK
3Analgesic Solutions, Natick, MA, USA
4Tufts University School of Medicine, Boston, MA, USA
5Massachusetts General Hospital & Harvard Medical School, Department of Neurology, Nerve Injury Unit, Boston, MA, USA
6St Pancras Clinical Research, London, UK

Tóm tắt

AbstractBackground/AimsTransient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep.MethodsIn this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50 mg mavatrep, 500 mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed.ResultsOf 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53];p= 0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30];p= 0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p= 0.049] and 7 [p= 0.041], stiffness on day 7 [p= 0.075]), and function on day 7 [p= 0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred.ConclusionOverall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep’s safety profile was consistent with its mechanism of action as a TRPV1 antagonist.ImplicationsFurther studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception.Trial Registration2009-010961-21 (EudraCT Number).

Tài liệu tham khảo

Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med 2010;26:355–69, http://dx.doi.org/10.1016/jxger.2010.03.001. Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet Lond Engl 2005;365:965–73, http://dx.doi.org/10.1016/S0140-6736(05)71086-2. Harris H, Crawford A. Recognizing and managing osteoarthritis. Nursing (Lond) 2015;45:36–42, http://dx.doi.org/10.1097/01.NURSE.0000458918.87973.15,quiz42–3. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 2007;15:981–1000, http://dx.doi.org/10.1016/jjoca.2007.06.014. Parsons WH, Calvo RR, Cheung W, Lee YK, Patel S, Liu J, Youngman MA, Dax SL, Stone D, Qin N, Hutchinson T, Lubin ML, Zhang SP, Finley M, Liu Y, Brandt MR, Flores CM, Player MR. Benzo[d]imidazole transient receptor potential vanilloid 1 antagonists for the treatment of pain: discovery of trans-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (mavatrep). J Med Chem 2015;58:3859–74, http://dx.doi.org/10.1021/acs.jmedchem.5b00132. Bolcskei K, Helyes Z, Szabo A, Sandor K, Elekes K, Nemeth J, Almasi R, Pinter E, Petho G, Szolcsanyi J. Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice. Pain 2005;117:368–76, http://dx.doi.org/10.1016/j.pain.2005.06.024. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000;288:306–13. Chizh BA, O’Donnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bullman JN, Gray EJ, Lai RY, Williams PM, Appleby JM. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 2007;132:132–41, http://dx.doi.org/10.1016Zj.pain.2007.06.006. Honore P, Wismer CT, Mikusa J, Zhu CZ, Zhong C, Gauvin DM, Gomtsyan A, El Kouhen R, Lee C-H, Marsh K, Sullivan JP, Faltynek CR, Jarvis MF. A-425619[1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats. J Pharmacol Exp Ther 2005;314:410–21, http://dx.doi.org/10.1124/jpet.105.083915. Trudeau J, Katz N, Eaton T, Gracely R, Raymond S, Jensen M, Baird J, Bhat G, Ng D, Tan K, Osgood E. Predicting variability in pain reporting by psychological and psychophysical assessment. Glasgow, Scotland, UK; 2008. Pogatzki-Zahn EM, Shimizu I, Caterina M, Raja SN. Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. Pain 2005;115:296–307, http://dx.doi.org/10.1016/j.pain.2005.03.010. Quiding H, Jonzon B, Svensson O, Webster L, Reimfelt A, Karin A, Karlsten R, Segerdahl M. TRPV1 antagonistic analgesic effect: a randomized study of AZD1386 in pain after third molar extraction. Pain 2013;154:808–12, http://dx.doi.org/10.1016/j.pain.2013.02.004. Remadevi R, Szallisi A. Adlea (ALGRX-4975), an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief. lDrugs lnvestig Drugs J 2008;11:120–32. Svensson O, Thorne C, Miller F, Bjornsson M, Reimfelt A, Karlsten R. A phase ll randomized controlled trial evaluating efficacy and safety of the TRPV1 antagonist AZD1386 in osteoarthritis of the knee, Montreal, Canada; 2010. Joshi SK, Honore P, Hernandez G, Schmidt R, Gomtsyan A, Scanio M, Kort M, Jarvis MF. Additive antinociceptive effects of the selective Nav1. 8 blocker A-803467 and selective TRPV1 antagonists in rat inflammatory and neuropathic pain models. J Pain Off J Am Pain Soc 2009;10:306–15, http://dx.doi.org/10.1016/jjpain.2008.09.007. Walker KM, Urban L, Medhurst SJ, Patel S, Panesar M, Fox AJ, Mclntyre P. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003;304:56–62, http://dx.doi.org/10.1124/jpet.102.042010. Kanai Y, Nakazato E, Fujiuchi A, Hara T, lmai A. lnvolvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCl rats. Neuropharmacology 2005;49:977–84, http://dx.doi.org/10.1016/j.neuropharm.2005.05.003. Christoph T, Gillen C, Mika J, Grunweller A, Schafer MK, Schiene K, Frank R, Jostock R, Bahrenberg G, Weihe E, Erdmann VA, Kurreck J. Antinociceptive effect of antisense oligonucleotides against the vanilloid receptor VR1/TRPV1. Neurochem lnt 2007;50:281–90, http://dx.doi.org/10.1016/j.neuint.2006.8.017. Pomonis J, Harrison J, Mark L, Bristol D, Valenzano K, Walker K. N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-Yl) tetrahydropyrazine-1 (2 h)-carbox-amide (BCTC), a novel, orally effective vanilloid receptor 1 antagonist with analgesic properties: ll, in vivo characterization in rat models ofinflammatory and neuropathic pain. J Pharmacol Exp Ther 2003;306:387–93, http://dx.doi.org/10.1124/jpet.102.046268. Manitpisitkul P, Brandt M, Flores CM, Kenigs V, Moyer JA, Romano G, Shalayda K, Mayorga AJ. TRPV1 antagonistJNJ-39439335 (mavatrep) demonstrates proof of pharmacology in healthy men: a first-in-human, double-blind, placebo-controlled, randomized, sequential group study. PAlN Rep 2016;1:e576, http://dx.doi.org/10.1097/PR9.0000000000000576. Gavva NR. Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1. Trends Pharmacol Sci 2008;29:550–7, http://dx.doi.org/10.1016Zj.tips.2008.08.003. Treister R, Eaton TA, Trudeau JJ, Elder H, Katz NP. Development and preliminary validation of the focused analgesia selection test to identify accurate pain reporters. J Pain Res 2017;2017:319–26, http://dx.doi.org/10.2147/JPR.S121455. Bieleman HJ, Oosterveld FGJ, Oostveen JCM, Reneman MF, Groothoff JW. Work participation and health status in early osteoarthritis of the hip and/or knee: a comparison between the cohort hip and cohort knee and the osteoarthritis initiative. Arthritis Care Res 2010;62:683–9, http://dx.doi.org/10.1002/acr.20112. Bellamy N, Campbell J, Hill J, Band P. A comparative study of telephone versus onsite completion of the WOMAC 3. 0 osteoarthritis index. J Rheumatol 2002;29:783–6. Littell R, Stroup W, Freund R. SAS® for Linear Models.4th ed. Cary, NC, USA: SAS lnstitute; 2002. Luo Z, Ma L, Zhao Z, He H, Yang D, Feng X, Ma S, Chen X, Zhu T, Cao T, Liu D, Nilius B, Huang Y, Yan Z, Zhu Z. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1a upregulation in mice. Cell Res 2012;22:551–64, http://dx.doi.org/10.1038/cr.2011205. Puttfarcken PS, Han P, Joshi SK, Neelands TR, Gauvin DM, Baker SJ, Lewis LGR, Bianchi BR, Mikusa JP, Koenig JR, Perner RJ, Kort ME, Honore P, Faltynek CR, Kym PR, Reilly RM. A-995662 [(R)-8-(4-methyl-5-(4-(trifluoromethyl) phenyl) oxazol-2-ylamino)-1, 2, 3, 4-tetrahydronaphthalen-2-ol], a novel, selective TRPV1 receptor antagonist, reduces spinal release of glutamate and CGRP in a rat knee joint pain model. Pain 2010;150:319–26, http://dx.doi.org/10.1016/j.pain.2010.05.015. Round P, Priestley A, Robinson J. An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects. Br J Clin Pharmacol 2011;72:921–31, http://dx.doi.org/10.1111/j.1365-2125.2011.04040.x. Schaffler K, Reeh P, Duan WR, Best AE, Othman AA, Faltynek CR, Locke C, Nothaft W. An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV (B)-inflamed and normal skin. Br J Clin Pharmacol 2013;75:404–14, http://dx.doi.org/10.1111/j.1365-2125.2012.04377.x. Medler KF. Multiple roles for TRPs in the taste system: not your typical TRPs. Adv Exp Med Biol 2011;704:831–46, http://dx.doi.org/10.1007/978-94-007-0265-3_43. Crutchlow M. Pharmacological in hibition of TRPV1 impairs sensation of potentially injurious heat in healthy subjects. United States: National Harbor; 2009. Rowbotham MC1, Nothaft W, Duan WR, Wang Y, Faltynek C, McGaraughty S, Chu KL, Svensson P. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 2011;152:1192–200, http://dx.doi.org/10.1016/j.pain.2011.01.051.
Thông tin
Thông tin xuất bản

Scandinavian Journal of Pain

Tập 17

134-143

Thông tin tác giả