Author: Bob Kronemyer
The novel, water-soluble prodrug CA-008 (Concentric Analgesics), coupled with standard of care treatment that included a Mayo block with bupivacaine hydrochloride (HCl), was found to significantly reduce both pain and opioid reliance after bunionectomy surgery, according to two randomized, placebo-controlled studies.
“CA-008 is a prodrug of trans-capsaicin, the substance in chili peppers that produces the heat sensation,” said Mike Royal, MD, the chief medical officer for Concentric, which sponsored the study. Capsaicin is a TRPV1 (transient receptor potential channel) agonist. “Capsaicin … is known to provide a durable analgesic effect that lasts weeks to months after a single administration. With CA-008, we look to bring this long-lasting, pain-selective benefit to surgical patients.” The first bunionectomy study was designed as a first-in-human ascending-dose safety study, whereas the second trial, a phase 2, included efficacy, safety and pharmacokinetic end points.
In the larger phase 2 study (N=147), patients were randomly assigned to one of three dosing regimens of CA-008 (0.7, 2.1 or 4.2 mg) versus control, with 36 or more patients in each group.
The 4.2-mg dose demonstrated a 50% reduction in mean pain scores at 96 hours and a 48% reduction at 168 hours, compared with the standard of care treatment of a Mayo block with bupivacaine HCl alone.
Opioid-Free Recovery Enhanced
Both studies also showed a reduction in opioid consumption. In the second efficacy study, the 4.2-mg dose showed a 50% reduction over 96 hours compared with standard of care alone.
Furthermore, both studies demonstrated an increased likelihood of opioid-free recovery in patients receiving CA-008 plus standard of care as opposed to bupivacaine HCl standard of care alone.
In the efficacy study, 26% of patients in the CA-008 group required no opioids after surgery versus 5% in the control group over 96 hours, and for the period 24 hours after surgery to 28 days (39% vs. 8%, respectively).
“Not only was cumulative opioid use significantly less with the addition of CA-008, but no subject in the standard of care plus CA-008 group required opioids after day 5,” Dr. Royal said.
To increase the efficacy of CA-008, Dr. Royal recommended a multimodal standard of care that includes traditional local anesthetic and systemic nonopioid medications.
“This is the first time a single injectable product has demonstrated the potential to safely reduce pain for 96 hours or longer with milestone improvements through the first week,” Dr. Royal said. “Additionally, we saw a compelling fivefold improvement in the number of subjects who required no opioids whatsoever.”
Later this year, the company plans on demonstrating CA-008’s efficacy in other surgical models, including total knee replacement and complete abdominoplasty.
“With breakthrough therapy designation in hand, we are also committed to move as aggressively as possible through the regulatory process to make CA-008 available to physicians and patients,” Dr. Royal said.
Peter S. Staats, MD, an anesthesiologist and pain specialist and the chief medical officer of National Spine and Pain Centers, said the study represented “really great work in demonstrating that this novel drug performs under a regional block and is effective in improving postoperative pain, decreasing immediate post-op opioid use and decreasing opiates after 24 hours.”
Dr. Staats also was surprised and impressed with the long duration of action for CA-008, “which tracked so nicely with a dose–response curve,” he said. “In the era of great concern with opioid misuse, this type of novel approach that minimizes opioid use for a surgical procedure is highly appealing.”
Decades ago, Dr. Staats and his colleagues published on the use of topical capsaicin performed under regional anesthesia for neuropathic pain. “The strategy of using a prodrug takes that work to a new level,” he said.