Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial

Abstract

Objective: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. Design: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0e100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. Results: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P ¼ 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ! 27.5 kg/m 2 , N ¼ 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12e18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. Conclusions: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. Clinical trial registration number: EudraCT 2015-001136-37.

CR4056, a powerful analgesic imidazoline‐2 receptor ligand, inhibits the inflammation‐induced PKCε phosphorylation and membrane translocation in sensory neurons

“…CR4056 is an ideal candidate for such analysis: It specifically binds I 2 receptors with no or negligible interactions with over 60 pharmacologically relevant targets (in either binding or functional assays, Rottapharm Biotech, data on file). Moreover, this is the first I 2 ligand able to control pain in humans (Rovati et al, ).…”

“…This drug displays strong in vivo analgesic properties in several animal models of inflammatory, chronic, and neuropathic pain (Comi et al, ; Ferrari et al, ; Lanza, Ferrari, Menghetti, Tremolada, & Caselli, ; Meregalli et al, ; Siemian, Wang, Zhang, & Li, ). A recent phase II clinical trial of CR4056 in patients with knee osteoarthritis chronic pain demonstrated for the first time the efficacy of an I 2 ligand in humans (Rovati et al, ). The understanding of its pharmacological and molecular mechanisms of action leading to analgesia is therefore highly relevant to evaluate its potential use in human therapies and to clarify the functional pathways activated by I 2 ligands.…”

Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models

“…Overall, the results of this study point towards a selective synergism between CR4056 and morphine for their analgesic activity, thus providing a strong rationale for use of CR4056 as an opioid‐sparing drug in multimodal analgesia. CR4056 is the first I 2 receptor ligand to show analgesic activity in humans (Rovati et al, 2020), which supports clinical development as a non‐opioid analgesic across a broad range of pain indications. Our present findings open a novel development path for CR4056 at low doses.…”

“…; CR4056 was suspended in 0.5% hydroxypropylmethyl cellulose (HPMC) and administered orally. The oral route was chosen because CR4056 has good oral availability and is formulated for oral administration in humans (Rovati et al, 2020). Volumes of administration were 5 mlÁkg −1 for CR4056 and naloxone and 2 mlÁkg −1 for morphine.…”

Effectiveness of drugs with delayed-release structurally modified action depending on the phenotype of osteoarthritis

“…была показана высокая эффективность фиксированных комбинаций хондроитина и глюкозамина, превосходящая таковую при мототерапии [7]. Учитывая несогласованность мнений экспертов и результатов исследований относительно эффективности SYSADOA, особую актуальность приобретает тезис о том, что когорта больных ОА является фенотипически гетерогенной [8,9]. При этом неоднородность когорты больных реализуется на клиническом, молекулярном и структурном уровнях [10,11,12,13].…”