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V116517) in Healthy Volunteers and Comparison with Preclinical Profile Lars Arendt-Nielsena,B,*, Steve Harrisc, Garth T

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V116517) in Healthy Volunteers and Comparison with Preclinical Profile Lars Arendt-Nielsena,B,*, Steve Harrisc, Garth T Research Paper A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile Lars Arendt-Nielsena,b,*, Steve Harrisc, Garth T. Whitesidec, Michele Hummelc, Terri Knappenbergerc, Sarah O’Keefec, Ram Kapilc, Don Kylec Abstract This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B- induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus–response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P , 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P 5 0.004 and P , 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P 5 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P , 0.0001) reduced by celecoxib. Stimulus–response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue. Keywords: Experimental pain, Sensitization, UV-B, Capsaicin, Pain thresholds, TRPV1 antagonist, Phase I, Proof-of-concept, Preclinical 1. Introduction failed in clinical trials.33,38,50 One clinical study showed analgesia after third molar tooth extraction.44 An unwanted side effect of The unmistakable pungency of capsaicin has led to substantial TRPV1 antagonists has been hyperthermia42 although new research into TRPV1 (transient receptor potential vanilloid sub- 32 family, member 1) function and an appreciation of this ion channel “modality-specific” molecules seem to show less of this effect. on pain signaling pathways. The TRPV1 channel is distributed in The discussion concerning clinical potency and safety of TRPV1 antagonists has been intense,31 and hence other TRPV channels the peripheral and central nervous system and shown in 24,29 preclinical studies to play a role in nociceptive pathways.34 Direct such TRPV3 have been targeted for pain relief. Because only blockade of this channel interrupts initiation of various sensory one clinical study has confirmed analgesic actions of TRPV1 receptor signals as it is activated by a range of mechanical, antagonists in humans, the use of human mechanistic quantita- thermal, or chemical stimuli.28 tive sensory testing may help profiling the TPRV1 antagonist in proof-of-concept studies to target the most optimal patient The TRPV1 expression on sensory neurons is known to be 2 increased in persistent inflammation and has been a target for population for later clinical trials. drug development20,47 although most TRPV1 antagonists have As TRPV1 receptors are involved in pain and sensitization associated with tissue injury and inflammation, human pain models should incorporate those phenomena in an efficacy test Sponsorships or competing interests that may be relevant to content are disclosed platform. Chizh et al.11 investigated the antihyperalgesic activity at the end of this article. a of a TRPV1 receptor antagonist (SB-705498). The compound SMI, Department of Health Science and Technology, Faculty of Medicine, Aalborg showed significant effects on heat-evoked pain, cutaneous University, Aalborg, Denmark, b C4Pain, Aalborg, Denmark, c Purdue Pharma, Stamford, CT, USA hyperalgesia, and neurogenic inflammation induced by capsaicin *Corresponding author. Address: SMI, Department of Health Science and or UV-B irradiation. Similarly, laser-evoked pain from UV-B- Technology, Faculty of Medicine, Aalborg University, Fredrik Bajersvej 7D3, DK- sensitized skin has shown to be modulated by a TRPV1 receptor 9220 Aalborg, Denmark. Tel.: 145 9940 8837; fax 145 98154008. E-mail address: antagonist (ABT-102).48 [email protected] (L. Arendt-Nielsen). These findings support the many preclinical studies of novel PAIN 157 (2016) 2057–2067 TRPV1 antagonists showing significant antihyperalgesia against © 2016 International Association for the Study of Pain thermal and mechanical end points in standard models of pain- http://dx.doi.org/10.1097/j.pain.0000000000000610 like behavior in rodents. Furthermore, this underlines the September 2016· Volume 157· Number 9 www.painjournalonline.com 2057 Copyright Ó 2016 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. 2058 L. Arendt-Nielsen et al.·157 (2016) 2057–2067 PAIN® suggestion that translational experimental quantitative pain The production and packaging of the study medication were assessment tools, representing isolated pain mechanisms, may performed as follows: V116517 was produced by Purdue be useful for proof-of-concept studies4 although a direct Pharmaceuticals L.P. and GMP packed by HB- Medical ApS, correlation between rodent models and human experimental Hvidovre, Denmark. Placebo for V116517 was produced by pain has not been ascertained. A possible side effect of TRPV1 Purdue Pharmaceuticals L.P. and GMP packed by HB-Medical antagonists could be burn injuries by an elevated intraoral heat ApS, Hvidovre, Denmark. Celebrex was produced by Pfizer and pain threshold (HPT). Therefore, a human experimental pain GMP packed by HB-Medical ApS, Hvidovre, Denmark. Placebo study on the TRPV1 antagonist ABT-102 evaluated changes in for Celebrex was produced and GMP packed by HB-Medical intraoral HPTs and found an elevation of 4.4˚C.46 ApS, Hvidovre, Denmark. This healthy volunteer, proof-of-concept, randomized study aimed to investigate mechanistically the antihyperalgesic profile of 4. Experimental study drug a new-generation TRPV1 antagonist (V116517) in comparison with a COX-2 inhibitor (celecoxib) in healthy subjects and to compare V116517 was demonstrated to be a potent TRPV1 antagonist of the effects with the preclinical profile from analogous rodent both pH- and capsaicin-activated recombinant human TRPV1 53 models. Cutaneous sensitizations were provoked with capsaicin receptor in vitro (IC50 5 39.6 nM and 35.1 nM, respectively). In and UV-B, and thermal and/or mechanical stimuli were used for a specificity profile run against 65 total enzymes, cell surface pharmacodynamic assessments in humans and rats together with receptors, ion channels, and other proteins (NovaScreen Profile), recordings of neurogenic inflammation in humans. The hypothesis V116517 showed more than 50% inhibition against only the was that the different sensitization models, based on the adenosine transporter target (actual value 5 51.09%). However, mechanisms involved, responded differently to the 2 drugs. the IC50 for this transporter (8.68 mM) was more than 200-fold greater than the IC50 values for blockade of capsaicin- or pH-activated TRPV1 channels. Evaluation of the specificity toward TRPV1 vs other 2. Material and methods members of the TRPV family also showed that V116517 is not Healthy male subjects aged 18 to 45, inclusive, with no clinically a potent blocker of heat-induced activation of recombinant human significant medical history, who were deemed suitable to take part in TRPV3 channels, or 4alpha-PDD-induced activation of recombinant this clinical study by the investigator, were screened in consecutive human TRPV4 channels. The in vivo efficacy of V116517 has been order after signing the informed consent form when visiting the clinic. demonstrated in a series of preclinical studies with standard rodent The sample size was estimated to 32 based on previous TRPV1 and models of capsaicin- and Freund’s complete adjuvant (FCA)- COX-2 studies, and hence a total of 63 were screened and 37 induced inflammatory pain, FCA-induced arthritis pain, postsurgical volunteers were included as some drop-outs were to be expected. pain, and neuropathic pain. In these models, V116517 demonstrated Volunteers were recruited from the databases of C4Pain, a high potency and a broad-spectrum efficacy that was similar to, or Aalborg, Denmark, the study was conducted in the C4Pain clinic, better than, the standard comparators such as indomethacin, and all study files were kept at these premises. The study was celecoxib, morphine, and gabapentin, in the respective models. approved by the ethics committee, the Danish Medicine Agency (reg. no. 2011-0714-56) with the attributed EudraCT No. 2011- 5. Inclusion and exclusion criteria 002399-18, and registered at ClinicalTrials.gov (Identifier: NCT02695745). Because the study was registered as a phase I During the first visit, demographic information was obtained from trial, it was not made public in the EU Clinical Trials Register.
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