Preliminary results from a phase 1b double-blind study to assess the safety, tolerability and efficacy of intra-articular administration of resiniferatoxin or placebo for the treatment of moderate to severe pain due to osteoarthritis of the knee

Leiman, David; Minkowitz, Harold S.; Levitt, Roy C.; Solanki, Daneshvari R.; Horn, Danielle Bodzin; Janfaza, David; Sarno, Danielle L.; Albores-Ibarra, N.; Xu, Bo; Takeshita, Kenzo; Zhao, Tian; Lu, Chia‐Wen; Bharathi, P; Ahern, Jo Ann; Klincewicz, Stephen L.; Nedeljković, Srdjan S.

doi:10.1016/j.joca.2020.02.228

Cited by 14 publications

(10 citation statements)

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“…Resiniferatoxin (RTX), a potent TRPV1 agonist, that specifically targets and ablates the nociceptive nerve fibers is pending phase 3 trials for knee OA pain and shows promising outcome in terms of long-term efficacy. 36 If the drug lives up to its promise, it could become a viable alternative to surgery and supportive therapy for patients in need of a pain-controlled deferment of their surgical procedure. Similarly, NaV 1.8 blocker VX-150 has efficacy in treating acute pain in multiple pain conditions, with pending phase 2a results with OA in the knee.…”

Section: Effects Of Delayed Surgical Repair On Morbidities Associamentioning

confidence: 99%

Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery

Cisternas

Ramachandran

Yaksh

et al. 2020

PR9

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Section: Effects Of Delayed Surgical Repair On Morbidities Associamentioning

confidence: 99%

Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery

Cisternas

Ramachandran

Yaksh

et al. 2020

PR9

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“…[ 32 ], and injected s.c. into the neck skin on three consecutive days with increasing doses (30, 70, 100 μg/kg) to desensitize TRPV1-expressing fibers. All injections were performed under isoflurane anesthesia, as injection of RTX evokes a temporary burning pain due to massive stimulation of the TRPV1-receptor, which is described by humans as mild to moderate [ 33 ]. As the TRPV1-expressing neurons desensitize very quickly and permanently, short anesthesia, which is also the protocol for intra-articular RTX injection in arthritic dogs [ 34 ], should be sufficient to prevent pain and stress for the rats.…”

Section: Methodsmentioning

confidence: 99%

Imaging the influence of peripheral TRPV1-signaling on cerebral nociceptive processing applying fMRI-based graph theory in a resiniferatoxin rat model

et al. 2022

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Resiniferatoxin (RTX), an extract from the spurge plant Euphorbia resinifera, is a potent agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1), mainly expressed on peripheral nociceptors—a prerequisite for nociceptive heat perception. Systemic overdosing of RTX can be used to desensitize specifically TRPV1-expressing neurons, and was therefore utilized here to selectively characterize the influence of TRPV1-signaling on central nervous system (CNS) temperature processing. Resting state and CNS temperature processing of male rats were assessed via functional magnetic resonance imaging before and after RTX injection. General linear model-based and graph-theoretical network analyses disentangled the underlying distinct CNS circuitries. At baseline, rats displayed an increase of nociception-related response amplitude and activated brain volume that correlated highly with increasing stimulation temperatures. In contrast, RTX-treated rats showed a clear disruption of thermal nociception, reflected in a missing increase of CNS responses to temperatures above 48°C. Graph-theoretical analyses revealed two distinct brain subnetworks affected by RTX: one subcortical (brainstem, lateral and medial thalamus, hippocampus, basal ganglia and amygdala), and one cortical (primary sensory, motor and association cortices). Resting state analysis revealed first, that peripheral desensitization of TRPV1-expressing neurons did not disrupt the basic resting-state-network of the brain. Second, only at baseline, but not after RTX, noxious stimulation modulated the RS-network in regions associated with memory formation (e.g. hippocampus). Altogether, the combination of whole-brain functional magnetic resonance imaging and RTX-mediated desensitization of TRPV1-signaling provided further detailed insight into cerebral processing of noxious temperatures.

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“…After the IND milestone was reached, a double-blind placebocontrolled phase I trial was designed and conducted in humans (Leiman et al, 2020). The starting doses (between 3 and 30 µg delivered in five or 10 mls of saline) were justified from the dog studies, although the volume is considerably larger in this human study than in the initial companion work (Figure 4E).…”

Section: Treatment Of Human Osteoarthritis Pain By Intraarticular Rtxmentioning

confidence: 99%

“…In both species RTX was delivered intraarticularly (fore or hind limb in the dog and into the knee joint in the human). The canine work is from reference 37, the human clinical data are adapted from a published abstract (Leiman et al, 2020). Note the duration of the 5 ml placebo injection which only begins to wane after 14 days despite the fact that only one injection of either vehicle or RTX was delivered reducing the opportunities for reinforcement such as daily oral medication which are absent with this interventional single injection treatment.…”

Section: Treatment Of Human Osteoarthritis Pain By Intraarticular Rtxmentioning

confidence: 99%

Pain Treatment in the Companion Canine Model to Validate Rodent Results and Incentivize the Transition to Human Clinical Trials

Iadarola

Brown

Nahama³

et al. 2021

Front. Pharmacol.

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One of the biggest challenges for analgesic drug development is how to decide if a potential analgesic candidate will work in humans. What preclinical data are the most convincing, incentivizing and most predictive of success? Such a predicament is not unique to analgesics, and the pain field has certain advantages over drug development efforts in areas like neuropsychiatry where the etiological origins are either unknown or difficult to ascertain. For pain, the origin of the problem frequently is known, and the causative peripheral tissue insult might be observable. The main conundrum centers around evaluation of translational cell- and rodent-based results. While cell and rodent models are undeniably important first steps for screening, probing mechanism of action, and understanding factors of adsorption, distribution metabolism and excretion, two questions arise from such studies. First, are they reliable indicators of analgesic performance of a candidate drug in human acute and chronic pain? Second, what additional model systems might be capable of increasing translational confidence? We address this second question by assessing, primarily, the companion canine model, which can provide particularly strong predictive information for candidate analgesic agents in humans. This statement is mainly derived from our studies with resiniferatoxin (RTX) a potent TRPV1 agonist but also from protein therapeutics using a conjugate of Substance P and saporin. Our experience, to date, is that rodent models might be very well suited for acute pain translation, but companion canine models, and other large animal studies, can augment initial discovery research using rodent models for neuropathic or chronic pain. The larger animal models also provide strong translational predictive capacity for analgesic performance in humans, better predict dosing parameters for human trials and provide insight into behavior changes (bladder, bowel, mood, etc.) that are not readily assessed in laboratory animals. They are, however, not without problems that can be encountered with any experimental drug treatment or clinical trial. It also is important to recognize that pain treatment is a major veterinary concern and is an intrinsically worthwhile endeavor for animals as well as humans.

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Preliminary results from a phase 1b double-blind study to assess the safety, tolerability and efficacy of intra-articular administration of resiniferatoxin or placebo for the treatment of moderate to severe pain due to osteoarthritis of the knee

Cited by 14 publications

References 0 publications

Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery

Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery

Imaging the influence of peripheral TRPV1-signaling on cerebral nociceptive processing applying fMRI-based graph theory in a resiniferatoxin rat model

Pain Treatment in the Companion Canine Model to Validate Rodent Results and Incentivize the Transition to Human Clinical Trials

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