Anesiva, Inc (SOUTH SAN FRANCISCO, California), a publicly-held, late-stage biopharmaceutical company focused on the development and commercialization of novel therapeutic treatments for pain management, announced that it has initiated a new phase II study of Adleaâ„¢, a long-acting, nonopiate TRPV1 (transient receptor potential vanilloid 1, formerly known as vanilloid receptor 1 or VR1) agonist, for the relief of postoperative pain in patients undergoing total knee arthroplasty (TKA). Adlea is designed to provide pain relief, without opiate-like side effects, for weeks to months after a single local injection during the surgical procedure. The new trial will evaluate a higher dose of Adlea, 15 mg relative to 5 mg and placebo in a double-blind, multicenter study of approximately 80 TKA patients. This 15 mg dose is equal to a higher drug concentration that has shown significant analgesic efficacy in other clinical settings.

Earlier results from a phase II clinical trial of 5 mg Adlea in TKA surgeries demonstrated that treatment with the agent resulted in significant reduction in pain on ambulation on first day postsurgery (P = .0273) and reduction in "pain right now" as well as "worst pain in past 24 hours" on Brief Pain Inventory (BPI) at 2 weeks postsurgery (P = .0071). The difference in average daily pain scores between the Adlea-treated group (n = 25) and the placebo group (n = 25) on day 1 was statistically significant and showed a relative difference in pain on first ambulation of 24%. On a numerical rating scale of 0 to 10, the average pain score for the treated group was 5.4 compared with the placebo group's average of 7.1. This difference was detected despite all patients being on concomitant morphine. On day 14, the patients' "worst pain in the previous 24-hour period" using the BPI form showed a relative difference of 34% with the average pain scores being 3.9 and 5.9 for the treated group and placebo group, respectively. Additionally, results showed a trend toward lower concomitant morphine usage in the Adlea-treated group over the placebo group, one of the exploratory endpoints. The preliminary data showed that Adlea was safe and well tolerated.

In clinical studies to date, the prolonged analgesic effect of Adlea does not seem to be associated with the systemic side effects commonly associated with NSAIDs (gastrointestinal and renal toxicities and impaired clotting), COX-2 inhibitors (cardiovascular risks and renal toxicity), or opiates (respiratory depression, nausea/vomiting, sedation, disorientation, physical dependence, and the risk of addiction).

Pharmacokinetic studies showed that when Adlea is locally administered to the site of pain, there appears to be limited systemic exposure. Its short duration of systemic exposure (hours) relative to the long duration of analgesia (12 weeks) resulting from a single treatment course of Adlea may potentially offer a safer treatment option in the management of chronic osteoarthritis (OA) pain.

Anesiva's goal is to initiate other clinical trials of the agent for two lead indications in the coming months: management of acute postoperative pain associated with orthopaedic surgeries and management of OA pain in the knee. These include phase II trials in total hip arthroplasty and arthroscopic shoulder surgery, a phase II /III trial in OA of the knee, and a phase III trial in TKA.

Adlea is a ligand-gated ion channel activated by agonists such as capsaicin and other factors such as heat and acidosis and provides a long-lasting, localized effect on C-fibers and blocks the transmission of aching, throbbing pain caused by major surgical procedures and end-stage OA. Because it selectively acts on pain-sensing nerve endings, the agent does not affect other nerve fibers necessary for sensory or motor sensations, such as those needed to sense temperature or pressure.