Overview

This is a Phase 2, randomized, double-blind, active-controlled, dose-escalation study evaluating the safety, pharmacokinetics, efficacy, and pharmacodynamics of ALX006, an extended-release bupivacaine formulation, administered as a single-dose sciatic nerve block in the popliteal fossa in adult subjects undergoing primary unilateral bunionectomy. Approximately 60 subjects will be enrolled across 3 sequential dose cohorts (100 mg, 150 mg, 200 mg ALX006), with each cohort comparing ALX006 against MARCAINE 0.25% (bupivacaine HCl 50 mg) as the active comparator at a 3:1 randomization ratio. Dose escalation between cohorts is governed by an Independent Data Monitoring Committee.

Eligibility

Inclusion Criteria:

• Male or female, ages 18 or older at screening
• American Society of Anesthesiologists (ASA) physical status 1, 2, or 3 (see Appendix 5)
• Able to provide informed consent, adhere to the study schedule, and complete all study assessments
• Primary surgical indication is related to a bunion deformity (i.e., hallux valgus) and subject is scheduled to undergo a primary unilateral distal metaphyseal osteotomy procedure (i.e., Austin procedure)
• Indicated to undergo elective (i.e., not emergency) bunionectomy
• Body Mass Index (BMI) ≥18 and \<40 kg/m2

Exclusion Criteria:

• Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, opioids, bupivacaine HCl, NSAIDs)
• Concurrent painful physical condition (e.g. arthritis, fibromyalgia, cancer) that may require analgesic treatment with NSAIDs or opioids in the post dosing period for pain that is not strictly related to the surgery and which, in the Investigator's opinion, may confound the post dosing assessments
• Inadequate sensory function of the foot/ankle as assessed by the Investigator
• History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past two (2) years
• Administration of an investigational drug within thirty (30) days or five (5) elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration, or planned administration of another investigational product or procedure during the subject's participation in this study
• Administration of any local anesthetic within 72 hours prior to administration of study drug, other than for pretreatment prior to a needle placement
• Require additional local anesthetic other than study drug or lidocaine used for the Mayo field block or for pretreatment prior to a needle placement during the study period
• Uncontrolled anxiety, psychiatric, or neurological disorder that, in the opinion of the Investigator, could interfere with study assessments or compliance
• Currently pregnant, nursing, or planning to become pregnant during the study
• Clinically significant medical disease that, in the opinion of the Investigator would make participation in a clinical study inappropriate. This includes diabetic neuropathy, coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, hepatic dysfunction, glucose-6-phosphate dehydrogenase deficiency or other conditions that would constitute a contraindication to participation in the study
• Confirmed clinically significant vital sign or ECG abnormality, including QTcF \> 450 msec at Screening
• Has any of the following laboratory abnormalities during Screening (1 retest permitted):
  1. History of liver cirrhosis, having an aspartate aminotransferase \>3x the upper limit of normal (ULN), or having an alanine aminotransferase \> 3x ULN.
  2. Severe kidney function impairment as defined by estimated glomerular filtration rate (eGFR) by CKD-EPI 2021 equation \<30 mL/min/1.73 m²or on dialysis.
  3. Platelet count \< 100,000/uL, hemoglobin \< 12 g/dL, or hematocrit \< 35%.
• Currently on a gabapentinoid (e.g., gabapentin, pregabalin \[Lyrica\]) or a serotonin-norepinephrine reuptake inhibitor (SNRI) with recognized analgesic properties (e.g., duloxetine \[Cymbalta\]) that cannot be discontinued within 30 days before surgery. Other agents with documented efficacy in modulating acute or chronic pain may be excluded at the discretion of the Investigator in consultation with the Sponsor Medical Monitor. Selective serotonin reuptake inhibitors (SSRIs) are not excluded under this criterion.
• Current use of systemic glucocorticoids within thirty (30) days of randomization in this study
• Use of dexmedetomidine HCl or clonidine within three (3) days of study drug administration
• Any use of marijuana (including tetrahydrocannabinol (THC) and cannabidiol (CBD)) within thirty (30) days prior to randomization, or planned use during the study.
• Chronic opioid use within thirty (30) days prior to randomization (average ≥30 oral morphine mg equivalents/day)