Leon Jiang, MD, PhD
Chief Medical Officer &SVP
Xgene Pharmaceutical Inc.
Lexington, Massachusetts
J. Richard Evanson, DO
Orthopedic Surgeon
Legent Orthopedic Hospital
Carrollton, Texas
Daneshvari Solanki, MD
Physician
First Surgical Hospital
Bellaire, Texas
Dominick D’Aunno, MD
Physician
HD Research
Houston, Texas
Emanuel DeNoia, MD
Physician
Endeavor Clinical Trials
San Antonio, Texas
Juan Carlos Rondon, MD
Physician
Clinical pharmacology of Miami
Miami, Florida
Alina Beaton, MD
Physician
Pacific Research Network
San Diego, California
Louise Taber, MD
Physician
Arizona Research Center
Phoenix, Arizona
We aimed to test XG005, a novel, non-opioid chemical entity, simultaneously targeting both nociceptive and neuropathic pain pathways, which often are activated in surgical trauma or other acute pain conditions. XG005 is a single molecule conjugating naproxen and pregabalin, which is not active in gastrointestinal tract and thus minimizes naproxen side effects compared with administering naproxen directly. Phase 1 trials demonstrated that pregabalin and naproxen derived from XG005 had synchronized Tmax values. Their Ctrough levels increased by approximately 73% and 27%, respectively, compared to bioequivalent doses of pregabalin and naproxen administered in combination. We hypothesized that the synchronized multimodal approach and pharmacokinetics advantages would yield strong analgesic effects in acute post-operative pain.
Methods: A phase 2b, multicenter, double-blind, placebo-controlled, randomized trial was conducted in subjects undergoing bunionectomy at eight sites across the USA (ClinicalTrials.gov, NCT06017999). Qualified subjects were randomized (1:1:1) to receive either 1250 mg or 750 mg of XG005 tablets, or placebo. The study drug was administered one hour before surgery and every 12 hours for 72 hours in domiciled centers. The primary efficacy endpoint was summed pain intensity over a 48-hour period (SPI48) for the 1250 mg XG005 versus placebo, measured with the Numeric Pain Rating Scale (NPRS, 0–10, higher score indicates greater pain) at 16 time points post-surgery. The key secondary efficacy endpoint was SPI48 for the 750 mg XG005 versus placebo. Rescue analgesics use, sleep interference and safety were monitored. Serial gatekeeping multiple adjustments were used for the analysis of the primary and the key secondary efficacy endpoints.
Results:
This trial randomized 450 participants (median age, 48 years; 80% female) with comparable demographic and baseline characteristics across groups. The least-squares mean (LSM) (SE) of SPI48 for the 1250 mg XG005 group (n=152) vs placebo (n=149) was 132.6 (8.0) vs 286.0 (8.2) (P< 0.0001, Cohen’s d=1.55), reflecting an average of 54% pain relief. For the 750 mg group (n=149) vs placebo, the LSM (SE) of SPI48 was 157.9 (8.3) vs 289.5 (8.5) (P< 0.0001, Cohen’s d=1.28), representing an average of 45% improvement in pain. SPIs at each nominal timepoint from 2 to 72 hours were significantly better in the XG005 groups compared to the placebo group (P< 0.0001). The LSM differences of SPIs between 1250 mg and 750 mg XG005 were statistically significant at each nominal timepoint from 16 to 54 hours, with the 1250 mg group showing a greater benefit (P< 0.05). The pain intensity score was statistically lower in both active arms than placebo from hour 1 to hour 72 post-surgery (P< 0.0001); the maximum pain was mild (mean NPRS=3.8) in severity in the high dose arm, in contrast to severe pain (mean NPRS= 7.2) in the placebo arm. Rescue medication was spared by 42.8% (65/152), 33.6% (50/149), and 2.7% (4/149) participants in the 1250 mg, 750 mg, and placebo groups, respectively. Hazard ratios (95% CI) for time to initiate rescue medication were 0.18 (0.14-0.25, P< 0.0001) for 1250 mg and 0.24 (0.18-0.31, P< 0.0001) for 750 mg vs placebo. The median time to first use of rescue medications was delayed 8-fold or 3-fold for the high or low dose XG005 compared with the placebo. Tramadol consumption in the placebo group was 4.1- or 3.0-fold more than in the 1250 mg or 750 mg groups over 72 hours, and those were 3- or 2.5-fold in acetaminophen consumption. Sleep was moderately disturbed in the placebo group for the first 24 hours post-surgery, while XG005 groups were spared. Mild somnolence, dizziness and constipation were more common in active groups. Eight (2.7%) participants in active groups and one (0.7%) in placebo discontinued treatment due to adverse events.
Conclusions/Implications for future research and/or clinical care:
XG005 as a non-opioid analgesic dose-dependently reduced acute post-operative pain with a large effect size, dramatically cut down opioid consumption and spared post-operative sleep disturbance. In comparison with other analgesics to treat acute pain using the same bunionectomy model with the same efficacy endpoint (SPI48) or Summed Pain Intensity Difference at 48 hours (SPID48), the pooled mean effect sizes are: 0.59 with various NSAIDs, 0.52 with various opioids combination with either acetaminophen or NSAIDs, 0.88 with tapentadol (an opioid) and 0.36 with a Nav1.8 antagonist. Thus, XG005 demonstrated more than 3-fold stronger analgesic effects than opioid combination products, along with favorable safety profile. XG005 has the potential to replace opioids for perioperative and other acute pain management, change the treatment algorithm for acute pain and modify policy on opioid use. Immediate future trials will include testing the molecule in other acute pain models with head-to-head comparisons to existing analgesics including opioids.