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CNTX-4975 injection improves OA-associated knee pain
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A single 1-mg injection of trans-capsaicin, a synthetic treatment based on the extract that gives chili peppers their signature spice, significantly reduced osteoarthritis-associated knee pain through 24 weeks, with a safety profile similar to placebo, according to data published in Arthritis & Rheumatology.
“CNTX-4975, or trans-capsaicin, works in a way that is different to existing therapies — it does not have to be continuously present in the joint to produce a significant, long lasting analgesic effect,” Randall M. Stevens, MD, of Centrexion Therapeutics, told Healio Rheumatology. “The intra-articular doses of CNTX-4975 used in this study were able to deliver sufficient trans-capsaicin locally to do this before leaving the joint. We know that after intra-articular injection of CNTX-4975, it is rapidly cleared from the body with systemic levels of drug being detectible for less than 24 hours.”
To analyze the safety and efficacy of a single dose of CNTX-4975 in patients with chronic moderate-to-severe knee pain linked to OA, Stevens and colleagues conducted the phase 2b, double-blind TRIUMPH study. The researchers recruited participants from 22 sites in the United States, including adults aged 45 to 80 years with stable OA-associated knee pain for at least 2 months. Participants were randomly selected, in a 2:1:2 ratio, to receive a single, intraarticular injection of either 0.5 mg of CNTX-4975, 1 mg of CNTX-4975 or placebo.
The primary endpoint was area under the curve for change in daily pain, measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Question A1 (QA1), with a walking score ranging from zero to 10, from baseline through week 12. A total of 175 participants were included in the safety analysis, including 70 who received placebo, 34 treated with 0.5 mg of CNTX-4975 and 71 who received 1 mg.
The efficacy analysis included 172 participants, of whom 69 received placebo, 33 received 0.5 mg of CNTX-4975 and 70 received 1 mg.
According to the researchers, by week 12, there were greater decreases in area-under-curve pain in patients treated with either dose of CNTX4975 than in those who received placebo. Least squares mean differences were –0.79 for participants who received 0.5 mg of the treatment (P = .074) and –1.6 for those treated with 1 mg (P < .0001). Participants who received 1 mg of CNTX-4975 demonstrated significant improvements that were maintained at week 24, with a least squares mean difference of –1.4 (P = .0002). Adverse events associated with the treatment were similar among patients in the placebo and 1mg groups.
“Patients with moderate to severe pain from knee OA, including moderate to severe radiographic damage, with a BMI up to 45kg/m2 and have failed prior treatment, can, from a single 1-mg CNTX-4975 intra-articular injection, have substantial reduction in pain and 49% to 60% improvement in knee stiffness and function,” Stevens said. “This has onset by the second day and a duration of benefit of up to 6 months, all while having a side effect profile that is similar to placebo.” – by Jason Laday
Disclosure: Stevens reports employment with Centrexion Therapeutics, which sponsored this study. Please see the study for all other relevant financial disclosures.
Perspective
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Andrew L. Concoff, MD, FACR, CAQSM
Despite the staggering social and economic impact of symptomatic osteoarthritis of the knee, which affects approximately 14 million Americans and costs over $27 million dollars per year, an agonizing gap exists in the armamentarium clinicians use to confront the disease. No treatments have been proven to delay or prevent progression in knee OA and nonoperative interventions often fail to control patients’ pain long before they become appropriate candidates for total knee arthroplasty (TKA).
Indeed, recent research paints an even bleaker picture than previously appreciated, suggesting little relief from acetaminophen; little lasting relief with early risk for toxicity from non-steroidal anti-inflammatory medications; increased mortality when initiating tramadol and acetaminophen with codeine; uncertain long-term safety of repeated corticosteroid injections is uncertain, and; efficacy for only a prospectively-unidentifiable subset of knee OA patients following hyaluronic acid injections. Thus, patients with knee OA often suffer significant pain and disability for many years after having exhausted available therapeutic options but prior to considering definitive treatment via TKA.
The news has been sobering even for those who choose to undergo TKA. The effectiveness of TKA has been revised with the recognition that more than 20% of those who undergo TKA are dissatisfied by the level of ongoing pain from which they chronically suffer upon reaching their best recovery.
A number of novel approaches specifically directed at treating the pain generated by knee OA have been proposed to fill this gap, including: biologic, cytokine-directed treatments; cryoneurolysis, and: small molecules directed at G-protein coupled receptors or ion channels approaches. Among the ion channels of interest is transient receptor potential cation channel subfamily V member 1 (TRPV1) which is expressed on the terminals of pain sensory fibers. The best characterized ligand of TRPV1 is capsaicin (8-methly-N-Vanillyl-noneamid). Capsaicin, the chemical source of the “fire” in chili peppers, has been recommended for topical use as an established treatment for knee OA for many years.
In their study in Arthritis & Rheumatology, Stevens and colleagues have presented the results of the TRIUMPH study, a phase 2b, randomized, double-blind, placebo-controlled trial of CNTX-4975, an injectable form of highly purified trans-capsaicin in moderate-severe knee OA. The results demonstrate a dose-dependent improvement in knee OA pain from a single intra-articular injection of CNTX-4975 as assessed by the primary outcome, AUC for change from baseline through week 12 of daily responses to WOMAC question A1 (“Pain with walking on a flat surface”) when comparing CNTX-4975 versus placebo.
While the robust results of the TRIUMPH study are cause for enthusiasm, such excitement should be restrained by several factors. First, 20% of patients experienced moderately-severe to severe pain from the injection despite co-administration with 2% lidocaine, as opposed to just 7% for the placebo-lidocaine injections. Secondly, some caution should be reserved for the long-term safety of nerve-directed interventions in knee OA. Although the authors cite evidence that capsaicin affects nociceptive nerves rather than “other sensory function,” the only evidence provided is from an intradermal, rather than an intraarticular, study.
Other nerve-directed knee OA treatments have been limited by the development of Charcot-like, rapid progression of knee OA in some patients, which may only be resolved by the safety assessments in larger phase 3 trials. Speaking of which, there is additional cause for skepticism of this study as it is in phase 3 trials that ‘novel medications’ in rheumatology studies go to die —the step from phase 2 trial to 3 trials has been recognized to be particularly steep climb. Nonetheless, hope springs eternal and the results of the TRIUMPH study, place injection of CNTX-4975 on the list of molecules to watch in the growing competition to spice up the lives of those mired in the treatment gap of knee OA treatment.
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