Why Peripheral Nerve Block for Post-operative Pain?
Flexion is committed to advancing local therapies for patients confronting musculoskeletal conditions, like post-operative pain. In 2010, there were an estimated 48 million ambulatory surgery procedures performed in the United States.1 Over 80% of patients who undergo surgical procedures experience acute post-operative pain and ~75% of those patients report their pain severity as moderate, severe, or extreme.2 In more than 50% of cases, patients report not receiving adequate pain relief following their procedure.2 Inadequately controlled post-operative pain can have both short- and long-term effects, including negative effects on quality of life, function and functional recovery, the risk of post-operative complications, and the risk of persistent post-operative pain.
Orthopedic surgery generates the second-highest rates of opioid prescriptions among adults, with many patients using opioids after surgery, facilitating a path to potential addiction.3
There is a substantial unmet need in post-operative pain management for a sensory blockade with an extended regional analgesia effect that does not compromise motor function.
Flexion believes that a treatment that provides extended pain relief while retaining motor function could reduce the need for opioids, allow for earlier ambulation and physical therapy, and provide the ability for patients to leave the hospital or ambulatory surgical center sooner after surgery.
What is FX301?
FX301 is an investigational locally administered thermosensitive hydrogel formulation of the preferential NaV1.7 inhibitor, funapide. Initial development of FX301 is targeted as a peripheral nerve block for control of post-operative pain.
Flexion developed the proprietary formulation of the thermosensitive hydrogel in its Innovation Lab. Approximately one minute following injection, the formulation transitions from a liquid to a soft pliable gel, which then acts as a drug depot to provide local, sustained delivery of funapide near target nerves for up to a week.
Based on preclinical data, Flexion believes the formulation technology has many desired attributes for use as a peripheral nerve block. The formulation is easy to inject at room temperature, is hyper-echoic thus enabling visualization with ultrasound (see video), is capable of releasing drug for several days to maintain high local concentrations while limiting systemic exposure, and employs known, well-tolerated, biodegradable polymers.
Typical local anesthetics inhibit the activity of a broad panel of voltage-gated sodium channels (NaVs).4 The pharmacology profile of funapide, with its preferential affinity for the NaV1.7 isoform, has the potential to provide effective non-opioid pain relief for 3-5 days, while preserving extremity motor function. FX301 has the potential to enable ambulation, rapid discharge, and early rehabilitation following musculoskeletal surgery.
Why NaV1.7 as the Target for FX301 and Post-operative Pain?
Voltage-gated sodium channels (NaVs) are transmembrane proteins crucial for action potential generation and propagation in neurons, the key cell type for pain communication.
Nine NaV isoforms (NaV1.1-1.9) have been characterized in humans, and several of these (NaV1.3, NaV1.7, NaV1.8, and NaV1.9) have been implicated in pain.5,6 NaV1.7 in particular has received considerable attention since hereditary pain conditions were mapped to mutations in the SCN9A gene that encodes the channel: gain-of-function missense mutations cause hypersensitivity to pain in primary erythromelalgia and paroxysmal extreme pain disorder, whereas loss-of-function mutations lead to impaired nociception in congenital insensitivity to pain (CIP).7,8,9
Even with a global deficiency of NaV1.7, CIP patients appear otherwise healthy, displaying no motor, cognitive, sympathetic, or gastrointestinal issues.5,10,11 Taken together, these observations have made NaV1.7 inhibition a potentially attractive approach for treating pain.
However, while many pharmaceutical companies have pursued the development of systemically or topically delivered NaV1.7 inhibitors as analgesic agents, most programs to our knowledge have failed in clinical trials, likely due to insufficient target coverage or access – resulting in inadequate efficacy – or due to poor tolerability at clinically active dose levels – potentially arising from lack of appropriate NaV channel selectivity.
FX301 Nonclinical Efficacy and Safety Results
In a validated post-operative pain model in pigs, a single injection of FX301 administered as a peripheral nerve block demonstrated analgesic effect beginning at 1 hour post-dosing compared to placebo and significantly greater analgesic effect compared to liposomal bupivacaine at 36 hours post-dosing (see Figure 1).
In addition, treatment with FX301 did not significantly affect total walking distance in animals at 2 and 24 hours post-injection whereas animals treated with liposomal bupivacaine experienced a significant reduction in total walking distance compared with baseline at those time points.
Flexion also assessed the systemic and local pharmacokinetic profiles of funapide following FX301 administration as a nerve block. Importantly, as shown in Figure 2, low systemic concentrations and high local concentrations of funapide are observed after FX301 dosing. These data are indicative of controlled drug release from the thermosensitive hydrogel formulation at the site of administration and suggest maintenance of potentially efficacious local funapide concentrations for several days.
FX301 Clinical Development
The FDA cleared the Investigational New Drug (IND) application for FX301 in February 2021. Flexion initiated a Phase 1b proof of concept clinical trial (NCT04826328) of FX301 administered as a popliteal fossa block (a commonly used nerve block in foot and ankle-related surgeries) in patients undergoing bunionectomy in March 2021. Topline results from the trial are anticipated in late 2021.
- Chou R et al., 2016 Feb;17(2):131-57.
- Smith D et al., The American Journal of Managed Care, November 2018, Volume 24, Issue 11
- Yanagidate F, G R Strichartz, Handb Exp Pharmacol. 2007;(177):95-127
- Dib-Hajj SD et al., Nat Rev Neurosci. 2013 Jan;14(1):49-62.
- Emery EC et al., 2016 Aug;20(8):975-83.
- Yang Y et al., J Med Genet. 2004 Mar;41(3):171-4.
- Fertleman CR et al., Neuron. 2006 Dec 7;52(5):767-74
- Goldberg YP et al., Clinical Genetics. 2007 Apr 25
- Ahmad S et al., Hum Mol Genet. 2007 Sep 1;16(17):2114-21.
- Cox JJ et al., Nature. 2006 Dec 14;444(7121):894-8.