Corgentech Inc. reported positive, top-line clinical data from a phase 2 clinical trial in total knee replacement surgeries showing that 4975, the company's novel, long-acting, non-opioid drug candidate being developed for site-specific, moderate-to-severe pain, demonstrated pain reduction at all pre-specified time intervals in the study, including statistically significant pain relief at day one (p=0.0273) and at day 14 (p=0.0071).
The difference in average daily pain scores between the 4975-treated group (n=25) and the placebo group (n=25) on day one was statistically significant and showed a relative difference in pain on first ambulation of 24 per cent. On a numerical rating scale of zero to 10, the average pain score for the treated group was 5.4 compared with the placebo group's average of 7.1. It is noteworthy that 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 Brief Pain Inventory form showed a relative difference of 34 per cent with the average pain scores being 3.9 and 5.9 for the treated group and placebo group, respectively.
The analysis of additional exploratory efficacy endpoints favoured the 4975 group over the placebo group including average daily pain scores at multiple time points: day 1, day 2, days 1-2, days 3-7, days 8-14, days 1-14 and days 3-14. In addition, the measure of pain interference with activities favoured the 4975 group over the placebo group at most of the time points measured. The preliminary data showed that 4975 was safe and well tolerated.
Total knee replacement (also known as total knee arthroplasty) is performed in patients with end-stage osteoarthritis of the knee. These patients have disabling pain which imposes severe limitations on their mobility, and knee replacement is performed with the goal of restoring or improving patients' quality of life. There were an estimated 470,000 total knee replacement procedures performed in the United States in 2005, and the number of replacements will continue to grow as the average age of the US population increases and as these individuals conduct more active lives. The American Academy of Orthopedic Surgery projects that approximately 3.5 million of these procedures will be done each year by 2030.
"4975 has demonstrated its ability to provide relief of acute and chronic pain to patients experiencing post-surgical, neuropathic and musculoskeletal pain for weeks to months after only a single, local administration. Unlike opioids, which have systemic side effects including nausea, vomiting, constipation and respiratory depression, 4975 appears to have a more favourable safety profile," said Daniel J. Gennevois, M.D., vice president of medical affairs at Corgentech. "Leveraging the positive data from the knee replacement trial in conjunction with the large body of 4975 clinical data collected to date, we look forward to discussing the data with regulators as we advance the clinical development of 4975."
The phase 2 study involved 50 knee replacement surgery patients who were randomized to receive either a single dose of 4975 or placebo, which was dripped by syringe into the wound prior to closure. Post-operatively, patients self-administered intravenous morphine via patient controlled analgesia (PCA) pump to achieve satisfactory analgesia. Additionally, after PCA was discontinued, patients could receive supplemental hydrocodone/acetaminophen as needed to manage their pain.
The company also reported that in a phase 2 trial of 4975 in 44 patients undergoing cholecystectomy (gall bladder removal) surgeries, the trial did not show a difference in pain scores between those receiving 4975 and those receiving placebo. The patients were randomized to receive either a single dose of 4975 or placebo, which was dripped by syringe into the surgical wound prior to closure, and both treatment groups received concomitant pain medications. Preliminary data show that 4975 was safe and well tolerated in this study. While both the knee and cholecystectomy trials were in surgical settings and included similar concentrations of 4975, it is possible that the extent of contact between the drug and the relevant tissues in the cholecystectomy surgeries may not have been maintained at a level sufficient to provide therapeutic benefit. In future trials, the company will continue to explore additional routes of administration that will enable optimal drug distribution, including direct injection into the relevant tissues.
4975 is long-acting, with the potential to provide pain relief for weeks or months after just a single treatment. It is a non-opioid TRPV1 agonist based on capsaicin. Its unique mechanism of action provides a long-lasting, localized effect on C-fibers, and blocks the transmission of aching, throbbing pain caused by major surgical procedures. Because it selectively acts on nerve endings, 4975 does not affect other nerve fibers necessary for sensory or motor sensations, such as those needed to sense temperature or pressure.
In clinical studies to date, 4975 has not had the side effects often associated with other pain medications and has been shown to be well tolerated. Opioid drugs, such as morphine, which are commonly used agents to relieve pain in post-surgical and musculoskeletal pain conditions, have significant side effects including sedation, respiratory depression, euphoria, and nausea and vomiting during acute use, and constipation and physical dependence during chronic use.