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Synergistic effect of the active components in HTX-011, a novel fixed-ratio formulation of bupivacaine and meloxicam, across multiple doses and surgical models
Session: MP-02a
Thurs, April 19, 10:15-11:45 am
Shubert (Shubert Complex), 6th floor

Please note, medically challenging cases are removed three months after the meeting and scientific abstracts after three years.

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Synergistic Effect of the Active Components in HTX-011, a Novel Fixed-ratio Formulation of

Bupivacaine and Meloxicam, Across Multiple Doses and Surgical Models

Eugene Viscusi, MD1; Harold S. Minkowitz, MD2; Erol Onel, MD3; Alice Chu, MA3; Sanjay S. Patel, PhD3; Thomas Ottoboni, PhD3; Clynn Wilker, PhD3; Barry Quart, PharmD3

1Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA; 2HD Research Corp., Houston, TX; 3Heron Therapeutics, Inc, San Diego, CA

INTRODUCTION

• The most severe pain after a surgery occurs within the first 72 hours

• Adequate non-opioid postoperative pain management during this period is crucial to preventing adverse outcomes

and reducing over-reliance on systemic opioids, which are contributing to the opioid epidemic in the United States

• Bupivacaine is a common local anesthetic used for surgical pain relief6; however, available formulations including extended-release (ER) formulations of bupivacaine alone have limited efficacy beyond 12-24 hours after surgery

• The normal inflammatory process after acute injury (eg, surgical incision) creates an acidic environment that may impair the ability of local anesthetics to block nociception,8,9 possibly explaining the lack of efficacy of available local anesthetics beyond 12-24 hours

• HTX-011 is a novel, extended-release (ER), non-opioid, fixed-ratio formulation of bupivacaine and meloxicam in proprietary Biochronomer® technology that is designed to overcome the challenges of the local inflammatory process, with meloxicam potentiating the analgesic effect of bupivacaine for 72 hours

• HTX-011 is a viscous solution administered as a single-dose application via needle-free syringe to directly coat the affected tissue within the surgical site prior to suturing

METHODS

Study Designs

  • These analyses included 2 randomized, multicenter, double-blind, placebo-controlled, institutional review board–approved phase 2 trials involving subjects undergoing bunionectomy (NCT02762929) or herniorrhaphy (NCT02504580)

• Each analysis included subjects who were randomly assigned to receive one of the treatments described in Table 1; doses used in the efficacy study are being carried forward into phase 3 studies

• After eligible subjects provided informed consent and underwent surgery, each was kept in the hospital for 72 hours for assessments of postoperative pain and opioid rescue medication use (Table 2)

 

RESULTS

Baseline Population Characteristics

• These analyses included 234 bunionectomy and 179 herniorrhaphy subjects; demographic characteristics were comparable across cohorts for each study (Table 3)

SYNERGY

Synergy of HTX-011 Is Demonstrated Across Surgical Models

• HTX-011 exhibited a synergistic effect compared with bupivacaine ER and meloxicam ER given individually, or the sum of the two components after bunionectomy or herniorrhaphy (Figure 1)

• HTX-011’s synergistic combination demonstrated greater pain relief, despite exhibiting a similar release profile to bupivacaine ER (Figure 2)

–– The release rate of bupivacaine from HTX-011 was calculated from the plasma concentration-time profile using deconvolution analysis

EFFICACY

Postoperative Pain Relief

• HTX-011 provided significantly better pain relief than either bupivacaine HCl or saline placebo after bunionectomy (60 mg) or herniorrhaphy (300 mg) through 72 hours (Figure 3)

• Mean pain scores after surgery remained below the severe pain threshold after treatment with HTX-011, whereas scores after treatment with bupivacaine and saline placebo (bunionectomy only) both crossed the threshold for severe pain (Figure 3)

Postoperative Opioid Rescue Medication

• HTX-011 subjects required significantly less opioid rescue medication (21.73 intravenous morphine milligram equivalents [MMEs]) than subjects receiving bupivacaine HCl (32.28 MMEs, p = 0.0382) or saline placebo (32.65 MMEs, p = 0.0047) after bunionectomy through 72 hours (Figure 4)

• Total opioid rescue medication consumption was numerically lower after herniorrhaphy with HTX-011 (18.38 MMEs) compared with bupivacaine HCl (25.09 MMEs, p = 0.3324) and saline placebo (28.94 MMEs, p = 0.0815) through 72 hours (Figure 4)

• A greater proportion of herniorrhaphy (H) and bunionectomy (B) subjects were opioid-free through 72 hours with HTX-011 treatment than with bupivacaine HCl (H: 50.0% vs 12.5%, p = 0.0108; B: 17.3% vs 8.0%, p = 0.4877) or saline placebo (H: 50.0% vs 7.2%, p = 0.0001; B: 17.3% vs 3.9%, p = 0.0106)

Safety

• The adverse event profile of HTX-011 was not clinically meaningfully different from the adverse event profile of the comparators in either study

• The mean bupivacaine plasma concentration after needle-free application of HTX-011 reached a Cmax of 271 ng/mL after a 300-mg dose in herniorrhaphy and 53.6 ng/mL after a 60-mg dose in bunionectomy

 

CONCLUSIONS

• Across multiple clinical studies, HTX-011 provided a synergistic analgesic effect that was greater than that of either bupivacaine ER or meloxicam ER administered alone or the sum of the two individual components, and than saline placebo through 72 hours

• HTX-011 reduced pain intensity through the first 72 hours after surgery compared with bupivacaine ER, bupivacaine HCl, or saline placebo in both surgical models

–– The mean pain intensity for HTX-011 subjects also remained well below the threshold for severe pain throughout the 72-hour study period

• HTX-011 significantly reduced the amount of opioid rescue medication used after bunionectomy and significantly increased the number of subjects that remained opioid free through 72 hours after herniorrhaphy compared with bupivacaine or saline placebo

• The non-opioid formulation in HTX-011, applied into the surgical site, may represent a significant advance in prevention and treatment of postoperative pain

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