Background/Purpose: CNTX-4975, a highly purified, synthetic trans-capsaicin and long-acting, non-opioid analgesic in phase 3 trials for moderate to severe OA knee pain, has demonstrated safety and efficacy in a randomized, phase 2 study. CNTX-4975 targets the transient receptor potential vanilloid 1, producing analgesia via reversible desensitization of end terminals of primary afferent pain fibers. We report pharmacologic and pharmacokinetic (PK) data from preclinical and human studies of CNTX-4975.

Methods: An in vitro pharmacologic study, using human and rat cells, assessed the activity of 10 μM CNTX-4975 at 113 receptors and 42 enzymes to identify potential off-target effects. In an in vivo rat model, the analgesic efficacy of a single intra-operative instillation of CNTX-4975 (0.075–7.5 mg/mL) in incised rat paws was evaluated by assessing response to thermal stimuli after surgery compared with subcutaneous buprenorphine (50 μg/kg, 1 hour before test). Tolerability of IA or intra-tendon injections of CNTX-4975 was evaluated in 11 local tolerance studies conducted in rabbits, rats, and dogs using doses (0.12–0.60 mg/mL) that resulted in considerably higher systemic exposures than those investigated in human trials. Phase 1 and 2 human studies assessed efficacy, safety, and PK of CNTX-4975 (0.01–15 mg) across multiple indications, including moderate to severe OA knee pain. PK parameters included peak plasma concentration (C_max), systemic exposure (mean area under the curve to last measured time point [AUC_0-last]), half-life (t_1/2), and time to C_max (T_max).

Results: In the in vitro pharmacology study, CNTX-4975 10 μM demonstrated activity at 1 benzodiazepine and 1 melatonin receptor. The 10 μM concentration was up to 2000 times higher than that detected in plasma following the highest dose administered in human studies (15 mg intra-operatively; 2 mg IA). No pharmacologic effects from activity at these receptors are expected with clinical doses of CNTX-4975. In the postsurgical rat pain model, a single intraoperative dose of CNTX-4975 0.25 mg/mL substantially relieved thermal hyperalgesia, and 7.5 mg/mL demonstrated efficacy comparable to buprenorphine; efficacy was sustained for several days to 1 week, depending on the dose. In local tolerance studies, CNTX-4975 was well tolerated, and no local toxicity was observed following a single IA injection of CNTX-4975 into rat knees. In human trials, PK analyses demonstrated rapid absorption of CNTX-4975 following IA knee injection. C_max and AUC_0-last for CNTX-4975 were linearly related to dose over the range studied and across indications (0.1–15 mg); approximate T_max <1 hour was not dose-dependent. Mean t_1/2 was 0.3–3.6 hours. C_max and AUC_0-last did not exceed mean values of 2.6 ng/mL and 4 ng•h/mL, respectively.

Conclusion: A single IA injection of CNTX-4975 demonstrated rapid absorption in humans, and was associated with substantial, prolonged efficacy and no local toxicities in preclinical studies. These findings are consistent with the mechanism of action of CNTX-4975 and safety and tolerability results from open-label and randomized, phase 2 clinical trials.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-the-pharmacology-and-pharmacokinetics-of-cntx-4975-a-high-purity-synthetic-trans-capsaicin-in-clinical-development-for-the-treatment-of-moderate-to-severe-oa-knee-pain/