Peripheral Sodium Channel: the holy grail?
Myron Yaster MD, Mark Schreiner MD, and Vidya Chidambaran MD
Today’s PAAD and its accompanying editorial and physiology review1-3 are the culmination of years of hypothesis, trial, error and until recently complete failure. As many of you know, this isn’t unusual. New drug discovery and development is a very long, inefficient, and incredibly costly process that only rarely results in the successful launch of a new drug into the marketplace.4 Indeed, on average it takes 13 years for a new drug to be approved by the FDA or EMA for marketing, which makes the rapid development of Covid-19 vaccines fairly miraculous.
For more than 2 decades, a search for specific peripheral sodium (Na) channel blockers as analgesic alternatives to opioids has been one of the holy grails of pharmaceutical research. As anesthesiologists we use non-specific Na channel blockers, otherwise known as local anesthetics, to block action potentials and nerve conduction on a daily basis. The non-specific voltage gated Na channel is required to produce action potentials in muscle cells, cardiac myocytes and neurons. The widespread distribution of Na channels makes drugs that block these channels so potentially dangerous (think the myocardial effects of local anesthetic toxicity). A specific afferent and efferent Na channel subtype blocker that works only on the peripheral sensory neurons that transmit pain would theoretically produce analgesia without systemic toxicity. Could such a drug be found? In today’s PAAD, Jones et al.3 report that the quest for such a compound may have been accomplished. Although this discovery is exciting, only time will tell if this new peripheral Na channel blocker will actually reach the market. Nevertheless, conceptually this new class of analgesics is so important I thought it would be worth alerting all of you to this new development. I’ve asked Drs. Vidya Chidambaran and Mark Schreiner to assist in this review. Myron Yaster MD
Editorial
Wallace, M. S. (2023). Trials for Managing Acute Pain — A Clinically Meaningful Small Effect Size? New England Journal of Medicine, 389(5), 464-465. https://doi.org/10.1056/NEJMe2305480
Physiology review
Waxman, S. G. (2023). Targeting a Peripheral Sodium Channel to Treat Pain. New England Journal of Medicine, 389(5), 466-469. https://doi.org/10.1056/NEJMe2305708
Original article
Jones, J., Correll, D. J., Lechner, S. M., Jazic, I., Miao, X., Shaw, D., Simard, C., Osteen, J. D., Hare, B., Beaton, A., Bertoch, T., Buvanendran, A., Habib, A. S., Pizzi, L. J., Pollak, R. A., Weiner, S. G., Bozic, C., Neg Waxman SG. Targeting a Peripheral Sodium Channel to Treat Pain. New England Journal of Medicine. 2023;389(5):466-469. doi:10.1056/NEJMe2305708ulescu, P., & White, P. F. (2023). Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. New England Journal of Medicine, 389(5), 393-405. https://doi.org/10.1056/NEJMoa2209870
The current analgesic tool kit consists of opioids, local anesthetics, NSAIDs, acetaminophen, ketamine, and maybe the gabapentenoids. All have problems balancing safety and efficacy; searching for safer alternatives with equal or superior analgesia to these drugs has driven pharmaceutical research for decades. One research approach has been to block action potential generation in sensory neurons. As you recall from medical school physiology, the key first step in action potential production is entry of Na into the neuron through specific voltage gated sodium channels. There are multiple voltage gated Na channel subtypes. For example, NaV1.5 channel is found in cardiac myocytes, NaV1.7 (coded by SCN9A) in sympathetic and peripheral neurons, and the NaV1.8 (encoded by SCN10A) and NaV1.9 (encoded by SCN11A) are expressed only in peripheral sensory neurons (Figure). Targeting just the peripheral sensory specific Na channel subtypes would theoretically alleviate pain without central or cardiac side effects. The magic bullet! It might be worth mentioning that Nav1.8 may directly affect the cardiomyocyte’s electrical function, in the diseased, remodeled heart. This was aptly captured in the concluding statement of an editorial by Odening - “The role of SCN10A/Nav1.8 in cardiac electrical function is thus not a matter of the heart or the nerve but rather of both—depending on the heart’s state”.5
Jones et al. and the pharmaceutical company Vertex (vrtx.com) targeted the NaV1.8 channel because it is highly specific to peripheral sensory neurons making it a potentially wonderful analgesic. The new drug, VX-548 inhibits NaV1.8 approximately 30,000 times more potently than other sodium channels and would therefore be expected to have limited off-target actions on other sodium channels.1, 3
OK but does it work? Before discussing the results of the Jones et al. study, how one determines efficacy and safety in pain studies is the basis of an accompanying editorial by Wallace.2 For those of you who do pain research or read the results of pain research articles this is a must read. Indeed, it so important that I’ve asked Dr. Mark Schreiner to review it and summarize it for the PAAD. It will be posted in the next week or two.
There are certain commonly used models for testing new analgesics for acute postoperative pain in adults including: 3d molar extraction, bunionectomy, and abdominoplasty. Jones et al. conducted “two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate–acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo.”3
OK, what did they find? The highest VX-548 dose significantly reduced acute pain (the lower doses were no better than placebo). Side effects - headache and constipation were mild. One major limitation of the study is that each dose of VX-548 was compared to placebo and not to hydrocodone-acetaminophen. Why didn’t the investigators do that? It is important to understand that these trials were Phase II trials which are usually dose-finding studies not typically powered to demonstrate efficacy. Adequately powered efficacy trials are ongoing.
Other limitations of the study as pointed out in the accompanying editorial by Wallace were the lack of data of rescue medication use (in this case, ibuprofen was allowed), and unclear clinical relevance of SPID48. Of note, there was no data safety monitoring board but the study had a double dummy design for blinding, was conducted at several sites and confidentiality agreements were in place so publication of the results could not be influenced by the sponsor (company).
Since these were just Phase II trials, this is just the middle of the journey. Will VX-548 demonstrate efficacy and then make it through the regulatory process and then make it to market? If approved, what will the labelled indications be? Would other specific peripheral Na channel blockers working alone or in combination produce more analgesia? Will this new class of drugs be effective in neuropathic or inflammatory pain? Only time and additional clinical trials will be needed to fully understand the role of these agents in clinical practice. In the meantime, keep your eyes open as we enter this new world. Let us know what you think and Myron will post in a Friday Reader response
PS from Myron: my wife Dr. Pamela Zeitlin is a world-famous pediatric pulmonologist and CF researcher who has worked extensively with Vertex in the development of their CF drugs. For obvious conflict of interest reasons, we do not own individual stock in this company, although mutual funds that we do own do.
References
1. Waxman SG. Targeting a Peripheral Sodium Channel to Treat Pain. New England Journal of Medicine. 2023;389(5):466-469. doi:10.1056/NEJMe2305708
2. Wallace MS. Trials for Managing Acute Pain — A Clinically Meaningful Small Effect Size? New England Journal of Medicine. 2023;389(5):464-465. doi:10.1056/NEJMe2305480
3. Jones J, Correll DJ, Lechner SM, et al. Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. New England Journal of Medicine. 2023;389(5):393-405. doi:10.1056/NEJMoa2209870
4. Brodniewicz T, Grynkiewicz G. Preclinical drug development. Acta Pol Pharm. Nov-Dec 2010;67(6):578-85.
5. Odening KE. The Role of Nav1.8 in Cardiac Electrophysiology-a Matter of the Heart or the Nerve? Cardiovasc Drugs Ther. Dec 2019;33(6):645-647. doi:10.1007/s10557-019-06931-8
Figure reproduced from ref 1 Waxman SG NEJM