Abstract
Background and aims:
This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2).
Methods:
Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2–50 mg; part 2: 10–50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks).
Results:
Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%).
Conclusions:
JNJ-39439335 (doses 2–50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain.
Implications:
Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.
1 Introduction
Pharmacologic management of chronic pain is a global public health concern, as opioids and non-steroidal anti-inflammatory drugs (NSAIDS), such as COX2 inhibitors, which have been the mainstay of pain therapy for many decades, are variously effective and tolerated for short-term pain relief but are associated with serious safety issues with long-term use. Thus, the development of improved analgesic agents that can be used for treating chronic pain is warranted.
One promising class of drugs under investigation for the treatment of chronic pain includes the transient receptor potential vanilloid subtype 1 (TRPV1) channel antagonists [1]. JNJ-39439335 (mavatrep) is a potent, selective, competitive TRPV1 antagonist being developed for the treatment of pain [2]. JNJ-39439335 has demonstrated analgesic activity in established animal models of hyperalgesia, including carrageenan-evoked thermal hyperalgesia and complete Freund’s adjuvant-evoked thermal hyperalgesia in rats [3]. The compound also showed acceptable safety margins in both rat and monkey 4-week toxicology studies. Consistent with actions at TRPV1 receptors in vivo, JNJ-39439335 blocked capsaicin-induced flare in a concentration- and dose-dependent manner. An earlier first-in-human, phase 1 study that evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending oral doses of JNJ-39439335 (1–225 mg) in healthy men demonstrated significant dose- and concentration-related decreases in heat-induced pain perception and capsaicin-induced flare and increased heat pain tolerance; the results further suggested that even low doses of JNJ-39439335 elicit significant pharmacodynamic actions, which appear to last for several days consistent with its pharmacokinetic half-life [4].
The present phase 1 study was a two-part study that evaluated multiple-ascending oral doses of JNJ-39439335 in healthy men (part 1), and in men and women with osteoarthritis (OA) of the knee (part 2). The multiple daily dosing regimens evaluated in this study will potentially be used to assess efficacy in larger proof-of-concept and phase 2b studies.
2 Methods
2.1 Study design
This was a double-blind, randomized, placebo-controlled, sequential group, multiple-ascending dose study, consisting of two parts. part 1 (EudraCT Number: 2008-007463-16) was conducted at a single center in the UK in healthy men. part 2 (conducted under a country-specific amendment to the original protocol, EudraCT registration was not required by South Africa) was conducted at two clinical study units within a single clinical research organization in South Africa in otherwise healthy men and women with OA of the knee. The primary objectives of both parts of the study were to evaluate the safety, pharmacodynamic effects and PK of JNJ-39439335 following multiple oral dosing. Exploratory efficacy assessments (part 2 only) were also performed.
Participants were enrolled in multiple sequential cohorts of eight participants each. In each cohort, participants were randomly assigned to treatment with once-daily oral doses of either JNJ-39439335 (n=6) or placebo (n=2) for 21 days. JNJ-39439335 dose levels were 2, 10, 25 and 50 mg for part 1, and 10, 25 and 50 mg for part 2. All doses were administered in the morning after an overnight fast of at least 8 h. Participants were allowed free access to drinking water until 2 h prior to study drug administration and from 2 h after study drug administration. Otherwise water and other fluids (methylxanthine-free) were allowed ad libitum throughout the study. Both part 1 and part 2 consisted of three phases: eligibility screening (up to 21 days), double-blind treatment phase (21 days) and four follow-up visits (7, 14, 21 and 28 days after the last dose). The study duration for each participant in both parts 1 and 2 was approximately 10 weeks. Participants were resident in the unit from day-2 to day 22.
2.2 Study population
Thirty-two healthy adult men [non-smokers of age 18–45 years (inclusive) with body mass index (BMI) 18.5≤ 30 kg/m2 (inclusive)] were enrolled in part 1. For part 2, 24 otherwise healthy men and women [age 18–65 years (inclusive), BMI≤36 kg/m2] with OA of the knee [meeting ≥3 of the American College of Rheumatology clinical classification criteria for OA (age >50 years, morning stiffness <30 min, crepitus on active motion, bony tenderness, bony enlargement, no palpable warmth of synovium)] were enrolled. Women were post-menopausal or surgically non-reproducing. Eligible participants had continuing OA knee joint pain for ≥5 days per week for 3 months before screening, and were treated with benefit with a non-opioid analgesic for OA knee pain for ≥5 days before screening. All participants had a pain score of ≥4 on the 11-point numerical rating scale (NRS, 0–10 points where 0=no pain and 10=pain as bad as you can imagine) and a patient global impression of change score (PGIC, modified to specifically measure changes in stair-climbing-induced pain in the target knee) of 5 (minimally worse), 6 (much worse), or 7 (very much worse) following stair-climbing, before entering the study.
Participants with an oral temperature >37.5 °C, abnormal electrocardiogram (ECG) readings, history or current evidence of congenital short QT syndrome or other significant cardiac disease or other illness at screening or day 1 were excluded from the study. Participants who failed to correctly answer all 10 questions of a burn prevention measures questionnaire designed to increase participants’ awareness of the potential for thermal burns were excluded. In addition, participants who had occupations or hobbies in which they were routinely exposed to situations in which they could sustain thermal burns were also excluded from the study. Only participants who showed an adequate response to the capsaicin flare procedure at screening (at least 50% increase from baseline in flare intensity as measured by Laser Doppler) and able to tolerate the PD testing were included in part 1 of the study.
Participants were prohibited from strenuous exercise, alcohol consumption, and smoking during the study. Consumption of food and beverages containing methylxanthine and quinine was prohibited from 48 h before to 72 h after dosing, while consumption of grapefruit, grapefruit juice and Seville oranges was prohibited from 7 days before to 7 days after dosing. Participants were prohibited from using any prescription, over-the-counter (including NSAIDs), herbal medication (including herbal tea or garlic extract), vitamins or mineral supplements within 14 days prior to study drug administration and for the duration of the study. St. John’s Wort was prohibited within 30 days of study drug administration and during the study. However, pre-existing stable regimens of low-dose aspirin (75–80 mg daily), and topical, nasal or inhaled corticosteroids were allowed during the study.
The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practices and applicable regulatory requirements. The study protocols and informed consent forms for part 1 and part 2 were reviewed and approved by the respective Independent Ethics Committee at the clinical sites. All enrolled participants provided written informed consent for their participation in the study.
2.3 Dose selection
In part 1, the first dose level of 2 mg (administered once daily for 21 days) was selected based on the safety, tolerability, and pharmacokinetic results from the previous single-ascending dose study [4]. The second and subsequent dose levels were chosen based on the safety, tolerability, and pharmacokinetic profile of the respective previous dose levels. The daily exposure (mean AUC24 h) associated with the highest dose administered in this study did not exceed the exposure associated with the NOAEL in rat (AUC24 h=10,700 ng·h/mL). Doses in part 2 were selected based on the results of part 1.
2.4 Pharmacokinetic assessments
2.4.1 Sample collections, handling and analyses
Venous blood samples for the measurement of JNJ-39439335 were collected on days 1, 14 and 21 at predose (within 30 min) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 h postdose; and at predose on days 3 through 13 days 16 through 20. Additional blood samples were taken on day 22 and at the follow up visits 7, 14, 21 and 28 days after the last dose. Urine samples were collected during the following intervals: −18 to −14 h (predose, day-1), and on days 1, 14 and 21 from 0 to 4, 4 to 8, 8 to 12, 12 to 24 h postdose. The entire amount of urine voided in these intervals was collected; the total volume was measured and recorded for each collection interval.
Plasma and urine samples were analyzed to determine concentrations of JNJ-39439335 using validated and qualified liquid chromatography-mass spectrometry assays, respectively. The range of quantitation for plasma samples was 1.0–1,000 ng/mL and the lower limit of quantitation (LLOQ) was 1.0 ng/mL. The range of quantitation for urine samples was 1.0–1,000 ng/mL and the LLOQ was 1.0 ng/mL. Only urine samples from the 50-mg JNJ-39439335 dose group in part 1 were analyzed; urine samples from other dose groups were not analyzed as concentrations from the 50-mg dose group were generally below the limit of quantification. Plasma and urine concentrations were subjected to pharmacokinetic analyses using non-compartmental methods by WinNonlin Enterprise Version 5.2.1 (Pharsight Corporation, Mountain View, CA, USA) and EXCEL® software, Version 2007 (Microsoft Corporation).
The following PK parameters were estimated from plasma in all participants receiving ≥1 dose of JNJ-39439335: Cmax (maximum observed concentration, determined by visual inspection of the data); tmax (time of maximum observed concentration, determined by visual inspection of the data); AUC24 h (area under the concentration-time curve from 0 to 24 h postdose); t1/2 (elimination half-life); CLss/F [total clearance (CL) after extravascular administration, corrected for absolute bioavailability (F), calculated as dose/AUC24 h (steady state)]; Vdss/F (apparent volume of distribution after extravascular administration, corrected for absolute bioavailability, calculated as dose/(λz×AUC24 h) for steady state), and accumulation ratio.
Based on the urinary excretion data, the following parameters were calculated: Ae (amount of unchanged drug excreted into the urine, calculated by multiplying the urinary volume with the urinary concentration); Ae, % dose (amount of unchanged drug excreted in urine, expressed as percent of dose, calculated as Ae/dose×100); CLR [Renal clearance calculated as the cumulative amount excreted in the urine (Aet)/AUCt, where t is time].
2.5 Pharmacodynamic assessments
2.5.1 Sensory testing and capsaicin-induced flare (part 1)
In part 1, heat pain perception threshold assessments were performed at screening, day 1 (predose and 4 h postdose), day 2 (predose), day 3 (predose), day 5 (predose), day 7 (predose), day 14 (predose and 4 h postdose), day 21 (predose and 4 h postdose), day 22 (24 h after last dose). Additional heat pain perception threshold assessments were performed at the discretion of the investigator in participants with ongoing heat pain perception changes at day 22. Capsaicin flare, mechanical pain perception threshold, cold pain perception threshold, and heat pain latency tests were performed during part 1 at screening, day 1 (predose and 4 h postdose) day 21 (predose and 4 h postdose). All part 1 pharmacodynamic assessments used methodology that was identical to that described previously [4].
Briefly, the heat pain perception was assessed using a computer-controlled 9×9 mm Peltier device (MSA Thermotest, Somedic, Sweden). The device was positioned on the volar aspect of the forearm, approximately 20 cm from the wrist crease, and within approximately 1 cm of the midline, avoiding the area intended for capsaicin administration. The baseline temperature of the probe was 32 °C and gradually increased at a rate of 1 °C/s. The test was stopped, and the temperature threshold was returned to baseline by the participant by pushing a button on the response unit when the first sensation of heat pain was reached. The maximum cut-off temperature was 52 °C to avoid skin injury.
For the heat pain latency test, participants were asked to place the tip of their ring finger on the tip of the 9×9 mm Peltier device preheated to 52 °C and to withdraw their hand when the heat pain was no longer tolerable; a maximum latency of 10 s was used to prevent skin injury. A similar method was used for cold pain detection, except that the probe temperature was gradually decreased at a rate of 1 °C/s, with the cut-off temperature set at 0 °C. For mechanical pain detection threshold, mechanical stimuli of increasing intensity were applied to the dorsal skin fold between the index finger and middle finger using von Frey hairs that exerted forces of 78, 256 and 588 mN, respectively, with a 1-min interval between the presentation of successively increasing calibers of von Frey hairs. The first von Frey hair that the participant reported as painful was recorded as the mechanical pain threshold, and the pain intensity was rated on a numerical rating scale (0–11), with 0 being no pain at all and 11 being the worst pain imaginable.
A laser Doppler imager was used to obtain a scan of dermal blood flow on an area of the forearm before and after application of capsaicin (Axsain®, 0.075% capsaicin w/w). Capsaicin was kept on the skin for 30 min. The flare area (in cm2) was calculated from all pixels around the stimulation site in which flux values exceeded the 95% percentile (mean +2 SD) of the baseline distribution. The flare intensity was calculated using relative flux (arbitrary units).
2.5.2 Meal tolerance test (part 2)
To explore the potential effects of TRPV1 antagonism on glucose homeostasis, the effects of multiple dosing of JNJ-39439335 for 21 days on plasma glucose excursion were assessed using a meal tolerance test (MTT). The MTT was performed on days – 1 and 21 (at 4 h after administration of the daily dose or at the corresponding time on day-1). Blood samples were collected for the determination of plasma glucose, serum insulin, serum C-peptide, and serum free fatty acid levels prior to study drug administration, 30 min before a standard meal, immediately before a standard meal, and at 15, 30, 60 and 120 min after the meal on day 21 and at the corresponding times on day-1.
2.6 Efficacy assessments (part 2)
Efficacy was evaluated in participants with OA (part 2) as an exploratory endpoint by using the 11-point NRS score. Participants completed the NRS at rest and immediately after stair-climbing (within 2 min) on days – 1, 8, 15 and 22, at approximately 4 h postdose (or corresponding time point on day-1). The stair-climbing-induced pain model was developed by Nathaniel Katz, MD and colleagues (Analgesic Solutions, Natick, MA, USA) and consisted of walking up and down a set of eight stairs twice. Knee pain and joint stiffness were also evaluated using a modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire (Version LK 3.1, 5-point Likert format) in which participants self-assessed pain as none, mild, moderate, severe, or extreme) on days – 1, 15 and 21, at approximately 4 h postdose (or corresponding timepoint on day-1). The WOMAC questionnaire was modified for this study such that only 2 of 3 WOMAC domains (pain and stiffness) were used. The third domain, difficulty performing daily activities, was not used, because several of the questions in this domain were considered irrelevant for an in-patient study. The recall period for completion of the WOMAC was 48 h.
2.7 Safety assessments
Safety was assessed by the type and incidence of reported adverse events (AEs) and changes from baseline in clinical safety laboratory values (hematology, coagulation, serum chemistry and urinalysis), oral temperature, vital signs (pulse, blood pressure), 12-lead ECG, and physical examination. Oral temperature was measured within 1 h before and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 16 h after the daily dose of JNJ-39439335 or placebo (or corresponding timepoints on day-1), and 24 h following the day 21 dose.
2.8 Statistical analyses
No formal statistical power calculations of sample size were conducted for this study. The planned sample size (n=6 active and n=2 placebo per cohort) was in accordance with sample sizes used in early development trials, and was large enough to permit clinical judgment of safety and tolerability as well as PK and PD assessments. After completion of Cohort 2, unblinded interim summaries of the efficacy data at a treatment group level were generated by the sponsor for Cohorts 1 and 2; after completion of Cohort 3, the unblinded efficacy data from all three cohorts for part 2 were combined and summarized so that strategic decisions could be made by the sponsor about future protocol development. Unblinded analyses were not shared with the investigators until completion of the study and database closure.
The PK parameters for JNJ-39439335 were summarized and descriptive statistics were generated for each dose group. Dose-normalized AUC24 h and Cmax data were summarized and evaluated for dose proportionality. Drug accumulation and steady state were assessed through descriptive summary statistics and graphical approaches.
The PD measures (heat pain perception threshold, mechanical pain perception threshold, cold pain perception threshold, heat pain latency, and capsaicin-induced flare) were exploratory and were compared between placebo and JNJ-39439335 treatment groups using analysis of covariance (ANCOVA). Pre-capsaicin corrected data were used for flare analysis and the model was fitted separately for the area and intensity of flare. For each PD parameter, point estimates and 90% confidence intervals (CIs) for the difference between JNJ-39439335 and placebo were constructed using the appropriate variance term.
The analyses of the post-MTT incremental and total AUC4−6 h for glucose, insulin, C-peptide, and free fatty acids were also exploratory. These measures were log-transformed and analyzed using a linear model with the PD endpoint as dependent variable and a fixed effect for treatment group, and the results were back transformed. Additionally, an ANCOVA model was used with day-1 (AUC4−6 h) values as a covariate. The geometric means (GMs) and the associated 95% CIs for the post-MTT total and incremental AUC4−6 h at each dose level were provided for day 21. The GM ratios for JNJ-39439335 versus placebo and their associated 90% CIs for each PD parameter were also provided for day 21. Potential relationships between plasma drug concentrations and corresponding PD endpoints were plotted.
The efficacy analyses (NRS and WOMAC) were also exploratory, and statistical significance at the p<0.05 level are reported without correction for multiple comparisons, as is appropriate for a signal-finding proof of concept study. An ANCOVA model was used to compare the on-treatment assessment value of treated versus placebo. For each comparison, point estimates and 90% CIs for the difference between active treatment(s) and placebo were constructed using the appropriate variance term. The NRS score was analyzed separately for pain at rest, pain following stair-climbing, and the change from pre- to post-stair-climbing. Safety data were summarized.
3 Results
3.1 Participant disposition
Part 1 of the study was conducted from February 2009 to October 2009 followed by part 2 from October 2009 to March 2011. Of 32 participants enrolled, 31 participants completed part 1; one participant treated with JNJ-39439335 (10-mg dose group) withdrew from the study early due to AEs (pyrexia and pharyngitis). All 24 participants enrolled and randomized in part 2 completed the study (Supplemental Fig. 1).
3.2 Demographics and baseline characteristics
Demographic and baseline characteristics were similar across all treatment groups in both part 1 and part 2 (Table 1). Mean age of participants in part 1 ranged from 24.9 to 34.0 years with mean BMI ranging from 22.0 to 25.7 kg/m2. Mean age of participants in part 2 ranged from 46.5 to 52.0 years with mean BMI ranging from 27.3 to 30.6 kg/m2. The majority of participants in both part 1 and 2 were white.
Demographic and baseline characteristics.
| Part 1 | Part 2 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Placebo (n=8) |
2 mg (n=6) |
10 mg (n=6) |
25 mg (n=6) |
50 mg (n=6) |
Placebo (n=6) |
10 mg (n=6) |
25 mg (n=6) |
50 mg (n=6) |
|
| Sex, n (%) | |||||||||
| Men | 8 (100) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 2 (33) | 2 (33) | 3 (50) | 2 (33) |
| Women | |||||||||
| Race, n (%) | |||||||||
| White | 3 (38) | 5 (83) | 5 (83) | 6 (100) | 2 (33) | 5 (83) | 4 (67) | 4 (67) | 2 (33) |
| Black/African American | 3 (38) | 0 | 0 | 0 | 2 (33) | ||||
| Asian | 2 (25) | 0 | 1 (17) | 0 | 2 (33) | ||||
| Other | 0 | 1 (17) | 0 | 0 | 0 | 1 (17) | 2 (33) | 2 (33) | 4 (67) |
| Age (years) | |||||||||
| Mean | 24.9 | 34.0 | 25.7 | 31.5 | 30.0 | 51.0 | 52.0 | 46.5 | 48.2 |
| SD | 3.36 | 7.97 | 6.98 | 5.47 | 6.48 | 6.07 | 8.17 | 7.45 | 7.00 |
| Weight | |||||||||
| Mean | 68.7 | 76.1 | 83.3 | 69.7 | 73.6 | 77.9 | 89.7 | 77.1 | 74.9 |
| SD | 9.93 | 7.87 | 4.42 | 12.02 | 3.96 | 14.77 | 9.40 | 12.93 | 15.50 |
| BMI (kg/m2) | |||||||||
| Mean | 22.0 | 24.9 | 25.7 | 23.6 | 23.7 | 28.3 | 30.6 | 27.3 | 27.4 |
| SD | 1.35 | 3.18 | 1.54 | 2.83 | 2.02 | 3.81 | 3.70 | 4.96 | 5.81 |
-
BMI=body mass index; SD=standard deviation.
3.3 Pharmacokinetic results
3.3.1 Part 1: healthy participants
Figure 1 illustrates mean plasma concentration-time profiles of JNJ-39439335 on all days (Fig. 1A), day 1 (Fig. 1B), day 14 (Fig. 1C), day 21 (Fig. 1D). Following oral administration, JNJ-39439335 was absorbed rapidly into the systemic circulation with median tmax ranging from 2 to 5 h on day 1 (Fig. 1B), 3 to 10 h on day 14 (Fig. 1C), and 2 to 3.5 h on day 21 (Fig. 1D). Due to secondary peaks in the plasma concentration time profiles, wide variability was observed within the individual tmax values ranging from 1 to 24 h for day 14, and 1 to 16 h for day 21 (Table 2). Following tmax, JNJ-39439335 plasma concentrations declined in a multiexponential manner, with mean t1/2 on day 21 ranging from 81 to 111 h (Table 2). All participants receiving JNJ-39439335 showed systemic exposure to JNJ 39439335, and the exposures (Cmax and AUC24 h) increased with increasing doses from 2-mg to 50-mg once-daily over 21 days (Fig. 2A and B).
Mean (SD) plasma concentration-time profiles of JNJ-39439335 in healthy participants (A) from day 1 to day 21 (B) day 1 (C) day 14 (D) day 21.
Mean (%CV) plasma pharmacokinetic parameters forJNJ-39439335 after multiple oral dosing in healthy participants (part 1).
| Cmax (ng/mL) | tmaxa (h) | AUC24 h (h⋅ng/mL) | t½ (h) | Vdss/F (L) | CLss/F (L/h) | Acc. ratiob |
||
|---|---|---|---|---|---|---|---|---|
| Cmax | AUC24 h | |||||||
| Part 1 | ||||||||
| Day 1 | ||||||||
| 2 mg qd | 7.55 | 4.96 | 97.7 | NAs | NAs | NAs | NAs | NAs |
| n=6 | (21.9) | (2.00–5.05) | (22.6) | |||||
| 10 mg qd | 38.2 | 2.03 | 388 | NAs | NAs | NAs | NAs | NAs |
| n=6 | (30.9) | (2.00–4.98) | (24.6) | |||||
| 25 mg qd | 77 | 2.02 | 967 | NAs | NAs | NAs | NAs | NAs |
| n=6 | (23.5) | (1.95–3.03) | (23.7) | |||||
| 50 mg qd | 268 | 4.48 | 3,390 | NAs | NAs | NAs | NAs | NAs |
| n=6 | (24.6) | (1.97–5.00) | (37.2) | |||||
| Day 14 | ||||||||
| 2 mg qd | 24.2 | 3.97 | 457 | NAs | 766 | 4.57 | 3.24 | 4.69 |
| n=6 | (21.3) | (1.98–15.98) | (25.3) | (49.0)c | (21.3) | (14.7) | (11.8) | |
| 10 mg qd | 164 | 10.00 | 2,731 | NAs | 363 | 3.78 | 4.75 | 7.45 |
| n=6 | (11.6) | (2.98–23.85) | (21.4) | (37.8)d | (18.3) | (34.7) | (24.9) | |
| 25 mg qd | 420 | 2.99 | 7,741 | NAs | 285 | 3.44 | 5.59 | 8.28 |
| n=6 | (25.6) | (0.98–10.07) | (26.7) | (49.9) | (27.4) | (24.8) | (27.1) | |
| 50 mg qd | 1,177 | 8.93 | 21,493 | NAs | 194 | 2.71 | 4.54 | 6.83 |
| n=6 | (33.3) | (2.00–10.05) | (31.7) | (44.9) | (54.7) | (36.9) | (40.4) | |
| Day 21 | ||||||||
| 2 mg qd | 31.9 | 3.52 | 556 | 80.9 | 435 | 3.79 | 4.25 | 5.79 |
| n=6 | (29.1) | (0.98–16.00) | (26.4) | (31.6) | (33.6) | (23.7) | (20.9) | (23.6) |
| 10 mg qd | 201 | 2.00 | 3,218 | 97.1 | 441 | 3.32 | 5.66 | 8.62 |
| n=6 | (33.9) | (0.98–3.90) | (31.6) | (44.2) | (34.4) | (26.5) | (34.3) | (26.6) |
| 25 mg qd | 518 | 2.00 | 9,597 | 96.6 | 374 | 2.71 | 6.99 | 10.5 |
| n=6 | (22.4) | (1.00–10.02) | (21.8) | (45.2) | (52.7) | (22.1) | (25.7) | (31.5) |
| 50 mg qd | 1,348 | 2.04 | 26,270 | 110.8 | 313 | 2.28 | 5.18 | 8.39 |
| n=6 | (31.1) | (2.00–9.93) | (33.3) | (40.8) | (28.3) | (60.8) | (36.4) | (43.7) |
-
aData presented as median (min-max); baccumulation ratio calculated as day 14/day 1 day 21/day 1 on day 14 day 21, respectively; cn=5; dn=4.
-
CV=coefficient of variation; n=size of subsample; NAs=not assessed; qd=daily.
(A) Relationship between Cmax versus dose of JNJ-39439335 in healthy participants on day 1, day 14 day 21. (B) Relationship between AUC24 h versus dose of JNJ-39439335 in healthy participants on day 1, day 14 day 21.
Upon multiple dosing, a steady state condition seemed to be approached by day 17 based on predose concentrations collected on days 2–21 (Fig. 1A). The mean Cmax and AUC24 h values on day 21 were only slightly greater than those for day 14 with LS mean ratios for Cmax and AUC24 h ranging from 114.1% to 129.7% and 115.6% to 125.3%, respectively, thus suggesting that a steady state condition was approaching by day 14. Mean accumulation ratio values on day 21 (relative to day 1) ranged from 4.25 to 6.99 for Cmax and 5.79 to 10.5 for AUC24 h (Table 2). Both Vdss/F and CLss/F decreased with increasing doses on days 14 and 21 (Table 2). The decrease in Vdss/F could be attributed to an increase in oral bioavailability since volume of distribution is normally independent of dose. The renal excretion of JNJ-39439335 was negligible. Concentrations in the majority of urine samples at the highest dose of 50 mg were below the limit of quantification (1 ng/mL) and thus indicated that JNJ-39439335 was mainly eliminated via non-renal clearance.
3.3.2 Part 2: participants with OA of the knee
Similar to healthy participants in part 1, the oral absorption of JNJ-39439335 in participants with OA of the knee occurred rapidly with a median tmax ranging from 2 to 3.5 h on day 1, 2 to 6 h on day 14, and 4 to 7 h day 21 (Table 3). Wide individual variability was also observed for tmax values ranging from 1 to 24 h for day 14 and 0 to 24 h for day 21; thereby suggesting enterohepatic recirculation of JNJ-39439335. Following tmax, JNJ-39439335 plasma concentrations declined in a multiexponential manner, with mean t1/2 ranging from 147 to 182 h on day 21 (Table 3). All participants receiving JNJ-39439335 showed systemic exposure to JNJ-39439335 and the exposures increased with increasing doses from 10 to 50 mg. Mean accumulation ratio values on day 21 (relative to day 1) ranged from 4.99 to 9.01 for Cmax and 8.72 to 11.7 for AUC24 h. Both Vdss/F and Clss/F decreased with increasing dose on days 14 and 21 (Table 3).
Mean (%CV) plasma pharmacokinetic parameters forJNJ-39439335 after multiple oral dosing in participants with osteoarthritis of the knee (part 2).
| Cmax (ng/mL) | tmaxa (h) | AUC24 h (h⋅ng/mL) | t½ (h) | Vdss/F (L) | CLss/F (L/h) | Acc. ratiob |
||
|---|---|---|---|---|---|---|---|---|
| Cmax | AUC24 h | |||||||
| Day 1 | ||||||||
| 10 mg qd (n=6) | 23.3 (43.1) | 2.02 (2.00–6.10) | 247 (32.7) | NAs | NAs | NAs | NAs | NAs |
| 25 mg qd (n=6) | 93.4 (34.1) | 3.50 (2.00–10.00) | 1,081 (17.5) | NAs | NAs | NAs | NAs | NAs |
| 50 mg qd (n=6) | 257 (19.6) | 2.00 (2.00–2.00) | 2,476 (31.1) | NAs | NAs | NAs | NAs | NAs |
| Day 14 | ||||||||
| 10 mg qd | 119 | 2.02 | 1,850 | NAs | 782 | 5.70 | 6.53 | 8.19 |
| n=6 | (22.6) | (1.00–23.87) | (24.4) | (70.0)c | (25.7) | (70.0) | (35.5) | |
| 25 mg qd | 592 | 2.00 | 9,161 | NAs | 288 | 2.76 | 6.75 | 8.57 |
| n=6 | (8.8) | (1.00–2.00) | (11.8) | (32.4)c | (11.7) | (23.0) | (11.7) | |
| 50 mg qd | 996 | 6.00 | 16,668 | NAs | 528 | 3.29 | 3.95 | 6.86 |
| n=6 | (22.1) | (1.03–23.83) | (28.3) | (38.0)d | (38.8) | (26.5) | (14.7) | |
| Day 21 | ||||||||
| 10 mg qd | 178 | 7.00 | 2,631 | 178.0 | 987 | 3.97 | 9.01 | 11.7 |
| n=6 | (28.9) | (0–24.13) | (22.0) | (43.1) | (37.5) | (23.9) | (48.9) | (35.3) |
| 25 mg qd | 663 | 4.00 | 10,735 | 182.5 | 587 | 2.39 | 7.48 | 10.1 |
| n=6 | (24.2) | (2.00–24.00) | (17.3) | (69.1) | (59.2) | (18.7) | (29.8) | (22.7) |
| 50 mg qd | 1,244 | 4.00 | 20,947 | 147.3 | 605 | 2.56 | 4.99 | 8.72 |
| n=6 | (20.1) | (3.00–24.00) | (26.4) | (45.3) | (77.1) | (31.5) | (29.4) | (17.5) |
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aData presented as median (min-max); baccumulation ratio calculated as day 14/day 1 day 21/day 1 on day 14 day 21, respectively; cn=5; dn=4.
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CV=coefficient of variation; n=size of subsample; NAs=not assessed; qd=daily.
3.4 Pharmacodynamic results
3.4.1 Part 1: sensory testing and Capsaicin-induced flare
Heat pain perception threshold: Increases in heat pain perception threshold were observed in all JNJ-39439335 dose groups relative to placebo, and were maintained throughout dosing period with no signs of tolerance with repeated dosing. Most participants receiving JNJ-39439335 reached the maximum heat pain perception temperature allowed in this study (52 °C) by day 3 or day 5 and continued to not perceive the 52 °C heat stimulus as painful at all timepoints thereafter. In contrast, no participant receiving placebo reached the maximum heat pain perception of 52 °C. Figure 3A shows that heat pain perception temperature (threshold) values increased with increasing plasma concentrations of JNJ-39439335, and reached a plateau level at the maximum heat pain temperature allowed in this study (52 °C) at JNJ-39439335 concentrations of approximately 100 ng/mL.
Individual heat pain detection temperatures (A) and heat pain latency (B) versus plasma JNJ-39439335 concentrations in healthy participants on days 1, 14 and 21.
Heat pain latency: Increases in heat pain latency were observed in all JNJ-39439335 dose groups. A clear difference versus placebo for the change from baseline was evident on day 21 at all dose levels with no signs of tolerance with repeated dosing. Most participants receiving JNJ-39439335 were able to tolerate a temperature of 52 °C for the maximum 10-s limit applied in this study at 4 h after the day 21 dosing. Figure 3B shows that majority of the participants reached the 10-s limit for heat pain latency used in this study following exposure to JNJ-39439335, reaching a plateau level at approximately 100 ng/mL.
Cold pain detection threshold: There were no clear dose-related effects in cold pain detection threshold across the JNJ-39439335 2- to 50-mg dose groups. No participant reached the minimum cold pain detection temperature allowed in this study (0 °C). There was no obvious relationship between cold pain detection temperatures or individual changes from baseline in cold pain detection threshold and increasing plasma concentrations of JNJ-39439335.
Mechanical pain threshold: The arithmetic mean mechanical pain ratings for all participants both before and after dosing were very low (ranging from 0.0 to 0.8) at a pressure level of 78, 256 and 588 mN, and no clear trend of change from baseline in the arithmetic means or LS means was observed in any dose group.
Capsaicin-induced flare: Capsaicin-induced flare area and flare intensity were blocked by a single (day 1, 4 h postdose, greatest reductions observed in the 50-mg dose group) and multiple doses (day 21, 4 h postdose) of JNJ-39439335 at all dose levels (2-, 10-, 25-, and 50-mg) (Fig. 4). The reduction in the capsaicin-induced flare area corresponded with increasing JNJ-39439335 concentrations in plasma before leveling out with flare area values below 5 cm2 at concentrations >100 ng/mL. On day-1 (4 h postdose), the maximum effect was observed at concentrations of approximately 100–170 ng/mL; at trough concentration during steady-state condition on day 21 (predose), the maximum effect was observed at concentrations >25 ng/mL. After multiple oral dosing for 21 days, all dose levels were maximally effective at blocking flare area and intensity. Similarly, capsaicin-induced flare intensity values decreased with increasing doses before leveling out with flare intensity values below 50 flux units at plasma concentrations >100 ng/mL.
Capsaicin-induced flare area in healthy participants receiving once-daily dosing with JNJ-39439335 or placebo for 21 days. Data are mean ±1 standard error. One participant (10-mg dose group) was withdrawn from the study after dosing on day 1 and was excluded from day 3 onward.
3.4.2 Part 2: meal tolerance test
Two participants who had a protocol deviation of having not received the 75 mg glucose drink with their standardized meal on day 21 (placebo: n=1; 50-mg JNJ-39439335 group: n=1) were excluded from the primary MTT analyses. There were no clinically relevant changes from baseline in mean total and incremental AUC4−6 h on day 21 for glucose, insulin, C-peptide, and free fatty acids observed in the JNJ-39439335 treatment groups compared with placebo. No obvious trends were observed with increasing doses of JNJ-39439335.
3.5 Exploratory efficacy (part 2)
3.5.1 Pain assessment using 11−point numerical rating scale scores
Pain intensity at rest: The mean reductions from baseline on day 22 for JNJ-39439335 25-mg and 50-mg dose groups were statistically significantly greater than for the placebo group (p<0.05) (Fig. 5A).
Knee pain at rest (A) and after stair-climbing (B): mean change from baseline, based on the 11-point numerical rating scale. (A) Knee pain at rest. LS mean difference (95% CI) between JNJ-39439335 25 mg and placebo on day 22: −2.4 (−3.77, −0.99); p=0.008; LS mean difference (95% CI) between JNJ-39439335 50 mg and placebo on day 22: −2.8 (−4.24, −1.29); p=0.004. (B) Knee pain after stair-climbing. LS mean difference (95% CI) between JNJ-39439335 50 mg and placebo on day 8: −3.5 (−6.22, −0.78); p=0.038; LS mean difference (95% CI) between JNJ-39439335 25 mg and placebo on day 22: −3.8 (−6.10, −1.57); p=0.009; LS mean difference (95% CI) between JNJ-39439335 50 mg and placebo on day 22: −3.7 (−5.92, −1.41); p=0.011.
Pain intensity after stair-climbing: The mean reductions from baseline on day 22 for JNJ-39439335 25-mg and 50-mg dose groups were significantly greater than for the placebo group (p<0.05). For the 50 mg dose group, a significant difference versus placebo was also observed on day 8 (p<0.05) (Fig. 5B).
Results of responder analysis (Fig. 6) revealed that 67% of the participants in the JNJ-39439335 10-mg dose group, and all participants (100%) in the JNJ-39439335 25-mg and 50-mg dose groups showed at least a 30% reduction in stair-climbing-induced pain intensity scores at the end of the dosing period compared with 50% of participants in the placebo group. Fifty percent of participants in the 10-mg dose group, 83% of participants in the 25-mg dose group, and all participants in the 50-mg dose group showed at least a 50% reduction in stair-climbing-induced pain intensity at the end of the dosing period compared with 33% of participants in the placebo group.
Responder analysis: percentage of participants achieving a 30% or 50% improvement in pain after stair-climbing placebo or JNJ-39439335 once-daily for 21 days.
Pain and joint stiffness using the modified WOMAC questionnaire: Numerical differences in the change from baseline for the WOMAC assessment of pain for JNJ-39439335 treatment relative to placebo were observed (ranging from −0.4 to −0.8 points); however, these differences were not statistically significant. In the joint stiffness subscale, statistically significant differences compared with placebo were observed for the JNJ-39439335 10-mg and 25-mg dose groups for the change from baseline at day 15, but not at day 21. On day 21 the differences for the JNJ-39439335 10-mg (−1.0 points) and 25-mg (−0.7 points) dose groups were not statistically significant compared with placebo.
3.6 Safety
All participants receiving JNJ-39439335 and five participants receiving placebo reported at least 1 TEAE in both part 1 and part 2 (Table 4). For part 1, the most common TEAEs in JNJ-39439335-treated participants were feeling hot (n=19, 79%), thermohypoesthesia (n=17, 71%), paresthesia (n=14, 58%), feeling cold (n=12, 50%), pyrexia (n=9, 38%), thermal burns (n=6, 25%), headache (n=6, 25%), and burning sensation (n=5, 21%), consistent with the PD profile of JNJ-39439335. For part 2, the most common (>20% incidence) TEAEs following JNJ-39439335 exposure were thermal burn (n=9, 50%), and headache, paresthesia, dysgeusia, thermohypoesthesia, feeling hot, and hot flush (n=8, 44% each), followed by feeling cold, and pruritis (n=6, 33% each) (Table 4).
Treatment-emergent adverse events occurring in two or more participants receiving multiple oral doses of JNJ-39439335.
| Part 1 |
Part 2 |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| Placebo (n=8) n (%) |
2 mg (n=6) n (%) |
10 mg (n=6) n (%) |
25 mg (n=6) n (%) |
50 mg (n=6) n (%) |
Placebo (n=6) n (%) |
10 mg (n=6) n (%) |
25 mg (n=6) n (%) |
50 mg (n=6) n (%) |
|
| Total no. participants with AEs | 5 (63) | 6 (100) | 6 (100) | 6 (100) | 6 (100) | 5 (83) | 6 (100) | 6 (100) | 6 (100) |
| Thermohypoesthesia | 1 (13) | 1 (17) | 5 (83) | 6 (100) | 5 (83) | 0 | 4 (67) | 4 (67) | 0 |
| Paresthesia | 0 | 3 (50) | 3 (50) | 4 (67) | 4 (67) | 1 (17) | 3 (50) | 4 (67) | 1 (17) |
| Headache | 2 (25) | 0 | 4 (67) | 1 (17) | 1 (17) | 2 (33) | 3 (50) | 4 (67) | 1 (17) |
| Burning sensation | 0 | 0 | 0 | 3 (50) | 2 (33) | ||||
| Dysgeusia | 0 | 0 | 1 (17) | 1 (17) | 2 (33) | 0 | 2 (33) | 4 (67) | 2 (33) |
| Dizziness postural | 1 (13) | 0 | 0 | 2 (33) | 0 | ||||
| Dizziness | 0 | 0 | 2 (33) | 0 | 0 | ||||
| Lethargy | 0 | 0 | 2 (33) | 0 | 0 | ||||
| Thermohyperesthesia | 0 | 1 (17) | 0 | 1 (17) | 0 | ||||
| Hypogesia | 0 | 2 (33) | 2 (33) | 0 | |||||
| Hypoesthesia | 1 (17) | 0 | 0 | 2 (33) | |||||
| Hyperesthesia | 0 | 0 | 0 | 2 (33) | |||||
| Feeling hot | 1 (13) | 6 (100) | 4 (67) | 6 (100) | 3 (50) | 1 (17) | 5 (83) | 1 (17) | 2 (33) |
| Feeling cold | 0 | 4 (67) | 5 (83) | 2 (33) | 1 (17) | 1 (17) | 2 (33) | 3 (50) | 1 (17) |
| Pyrexia | 0 | 1 (17) | 3 (50) | 2 (33) | 3 (50) | ||||
| Thermal burn | 0 | 1 (17) | 1 (17) | 3 (50) | 1 (17) | 0 | 3 (50) | 3 (50) | 3 (50) |
| Hyperhidrosis | 0 | 1 (17) | 2 (33) | 2 (33) | 0 | ||||
| Pruritus | 1 (17) | 0 | 3 (50) | 3 (50) | |||||
| Dermatitis contact | 0 | 0 | 2 (33) | 0 | |||||
| Dry throat | 0 | 0 | 2 (33) | 0 | 0 | ||||
| Nasopharyngitis | 0 | 0 | 2 (33) | 1 (17) | 0 | ||||
| Nausea | 2 (33) | 2 (33) | 1 (17) | 0 | |||||
| Aphthous stomatitis | 0 | 0 | 1 (17) | 2 (33) | |||||
| Vomiting | 0 | 0 | 2 (33) | 0 | |||||
| Hot flush | 0 | 4 (67) | 4 (67) | 0 | |||||
| Muscle spasms | 1 (17) | 0 | 2 (33) | 0 | |||||
Some participants experienced minor thermal burns on the fingers/hand or mouth due to touching hot objects or eating/drinking hot foods/beverages; these events resolved without clinical consequences. Six (25%) participants receiving JNJ-39439335 in part 1 (mild severity: n=5; moderate severity: n=1) and nine participants (50%) receiving JNJ-39439335 in part 2 (mild severity: n=6; moderate severity: n=3) experienced minor thermal burns without clinical consequences.
No deaths or serious adverse events were reported during the study. One participant (10-mg dose group, part 1) was withdrawn from the study after the first dose due to treatment-emergent pyrexia (maximum body temperature was 39.6 °C, on day 3) and accompanying pharyngitis (not related to treatment); the events resolved without further clinical sequelae. Ten participants (placebo: n=2; JNJ-39439335: n=8) received concomitant medication, consisting largely of occasional paracetamol for headache.
One participant in part 2 had increased levels of gamma-glutamyl transferase (moderate in severity); the gamma-glutamyl transferase values in this participant were elevated on day 4 (148 U/L, normal range: 5–40 U/L) and returned to normal by day 28 (24 U/L). Another participant had presence of crystals in urine (mild in severity) detected on day 4. No other clinically significant abnormalities were reported for other laboratory investigations, ECG and vital signs (blood pressure and pulse rate) during both part 1 and part 2 of the study.
3.7 Pharmacokinetic-safety relationship
Individual body temperature and QTcF values were correlated with JNJ-39439335 plasma concentrations.
3.7.1 Body temperature
Part 1 and part 2 combined: On day 1, the relationship between body temperature and plasma concentrations could be fitted to an Emax (maximum effect) model with an initial effect at zero concentration (E0) and the plasma concentration of JNJ-39439335 at 50% of the maximum effect (EC50); the estimated value was 36.7 °C for E0, 37.2 °C for Emax and 3.43 ng/mL for EC50. When fitted to the same Emax model as day 1, the estimated value on day 21 was 36.7 °C for E0, 36.9 °C for Emax, and 3.74 ng/mL for EC50. The model did not show a strong correlation between temperature increases and plasma concentrations of JNJ-39439335 at either day 1 or day 21.
3.7.2 QTcF
Part 1 and part 2 combined: QTcF values appeared to decrease with increasing JNJ-39439335 plasma concentrations on day 21. The relationship between the decrease in QTcF and JNJ-39439335 plasma concentrations could be fitted to a simple Emax model; the estimated value was 2.96 ms for Emax and 0.00208 ng/mL EC50. The model did not show a strong correlation between decreases in QTcF and plasma concentrations of JNJ-39439335 at day 21.
4 Discussion
In this DB, randomized, placebo-controlled, sequential group, multiple- ascending dose, 2-part, phase 1 study, safety, PK, PD, and exploratory efficacy of JNJ-39439335 were evaluated following once daily oral dosing for 21 days. Part 1 was conducted in healthy men (2–50 mg); while, part 2 was conducted in men and women with OA of knee (10–50 mg).
The day 1 safety, PK and PD results in healthy participants were consistent with those of a single-dose study of JNJ-39439335 published earlier [4]. With repeated daily dosing, plasma concentrations and systemic exposure of JNJ-39439335 increased with increasing doses in a slightly higher than dose-proportional fashion. However, the formulation used in this study was an early formulation and not optimized, and multiple dose strengths (1-mg, 5-mg and 25-mg tablets) were used in combination for different dose levels. Further studies on dose proportionality are warranted using the final formulation at a therapeutic dose range. Consistent with the long plasma half-life (81–111 h) of JNJ-39439335, accumulation occurred upon multiple daily dosing. Steady-state condition was reached by day 14. Renal excretion of JNJ-39439335 was negligible, indicating that JNJ-39439335 was eliminated exclusively via non-renal clearance (metabolism, bile and/or feces). There were age differences between participants in part 1 and part 2. Ages of participants in part 2 (range 46.5–51.0 years) were greater than those for part 1 (range 24.9–34.0 years) which may account for the slightly prolonged mean t1/2 in part 2 compared to that in part 1.
Consistent with earlier findings [4], single and multiple oral doses of JNJ-39439335 produced a marked dose-related increase in heat pain perception threshold and heat pain latency in all participants; these presumably mechanism-related pharmacodynamic effects persisted throughout the 21-day treatment period with no signs of tolerance with repeated dosing of JNJ-39439335. Consistent with its single-dose profile in humans, daily dosing with JNJ-39439335 for 21 days had no analgesic effect on cold pain detection threshold or mean mechanical pain ratings. Effects on capsaicin-induced flare area and flare intensity compared with placebo treatment were also consistent with effects observed with a single dose and did not demonstrate tolerance with multiple dosing [4]. These findings do not represent new information regarding the TRPV1 antagonist class, in that several other TRPV1 antagonists have shown pharmacodynamic effects on measures of heat perception and/or capsaicin flare [1, 5, 6, 7]. The novel information provided by the study are the exploratory OA pain assessments. The results do however suggest target engagement of the TRPV1 receptor with JNJ-39439335 with multiple dosing. A limitation of the heat perception methodology used was that superficial skin temperature was not assessed and included as a covariate in the statistical analysis, therefore it is possible that the findings may be artefacts not caused by the effect of the drug on the peripheral TRPV1 receptors, but simply a change in superficial temperature due to TRPV1 interaction with thermoregulatory mechanisms.
JNJ-39439335-treated participants with knee OA demonstrated statistically significant improvements in pain intensity compared with placebo in a stair-climbing-induced pain model, with a dose-related increase in the responder rates. This efficacy signal was consistent with that observed with JNJ-39439335 following a single dose in OA patients [8]. To our knowledge, this is the first analgesic efficacy signal in an OA pain model utilizing multiple daily dosing of a TRPV1 antagonist. However, given the exploratory nature and small sample size associated with the efficacy assessment, these results would need to be confirmed in larger proof-of-concept studies in OA patients. A further limitation of this study was the lack of an active comparator, which should be included in future phase 2 studies. The WOMAC pain assessments were numerically consistent with the NRS pain results, but did not show statistically significant differences between JNJ-39439335 and placebo. The cellular and molecular pathways underlying OA pain are not completely understood, and neither is it fully known what are the endogenous mediators of TRPV1 activation [9]. To the extent that in the present study the highly selective TRPV1 antagonist JNJ-39439335 demonstrated analgesic efficacy in OA patients, it is reasonable to hypothesize that TRPV1 is a driver of pain in this population and is being activated by some intrinsic factor that most probably is not heat. Also, preclinical data have demonstrated that TRPV1 is expressed on both the peripheral and central (i.e. spinal) terminals of primary nociceptors, as well as in the brain, and that the antinociceptive effects of TRPV1 antagonists may result from actions at multiple levels of the neuraxis [3]. However, these aspects have not been systematically evaluated in humans. In adult, male rats, concentrations of JNJ-39439335 following a dose of 2 mg/kg i.v. were approximately equivalent in brain, spinal cord and plasma at 0.5 and 2 h (data not shown), indicating that the compound readily crosses the blood-brain barrier and suggesting that mavatrep would likely penetrate the central nervous system following oral administration in humans. Therefore, we cannot rule out the possibility that some of the analgesic effects of mavatrep reported here may occur via the antagonism of TRPV1 channels localized to the central nervous system, direct evidence for which will require further investigation.
JNJ-39439335 administration was associated with minimal discontinuation of participants over a dose range of 2–50 mg daily for 21 days. The most common adverse events were related to changes in body temperature, heat perception and other sensory events likely related to its mechanism of action as a TRPV1 antagonist. Although the changes in body temperature were minimized with repeated dosing, no tolerance developed to the decreased heat perception observed with JNJ-39439335 treatment. The decreased heat perception has been reported for other TRPV1 antagonists [1, 5, 6, 7] and requires further confirmation. Larger clinical trials with a longer treatment period are needed with additional implementation and evaluation of patient counseling methods to determine whether the incidence of the minor thermal burns observed with JNJ-39439335 treatment can be reduced. In addition, this unique safety profile needs to be evaluated in light of whether the potential analgesic benefit is observed in larger studies. Consistent with preclinical studies in dogs [10], the increased body temperature seen with JNJ-39439335 was associated with a decreased QTcF interval, but this was not associated with any cardiac adverse events; further larger studies are warranted to confirm this.
In conclusion, JNJ-39439335 was associated with a multiple-dose PK profile amenable to further development and produced sustained PD effects on sensory tests (heat pain perception, heat pain latency) and capsaicin-induced flare, suggesting target engagement at the TRPV1 receptor. Moreover, JNJ-39439335 treatment was associated with improvement versus placebo in a stair-climbing-induced model in participants with OA of the knee. Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Still to be explored is whether lower doses administered over a longer period of time can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counseling techniques to reduce the minor thermal burns related to decreased heat perception.
Acknowledgments
The authors thank Dr. Shruti Shah and Dr. Rishabh Pandey (SIRO Clinpharm) for writing assistance, and Dr. Ellen Baum (Janssen Research & Development, LLC) for additional editorial assistance. The authors also thank the study participants, without whom this study would not have been accomplished, as well as the investigators for their participation in this study.
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Authors’ statements
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Resarch Funding: The study was sponsored by Janssen Research and Development, LLC, USA. The sponsor also supported development of this manuscript.
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Conflict of Interest: All authors are employees of Johnson and Johnson. Drs. Manitpisitkul and Hutchison were employees of Johnson and Johnson at the time of the study. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to publish these data.
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Informed consent: All enrolled participants provided written informed consent for their participation in the study.
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Ethical approval: The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent with Good Clinical Practices and applicable regulatory requirements. The study protocols and informed consent forms for part 1 and part 2 were reviewed and approved by the respective Independent Ethics Committee at the clinical sites.
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Supplementary Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/sjpain-2017-0184).
©2018 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.
