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Background: The NaV1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV1.8, on control of acute pain is being studied.
Results: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548.
BOSTON--(BUSINESS WIRE)--Aug. 3, 2023--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced publication in the New England Journal of Medicine (NEJM) of preclinical data and the results from its Phase 2 proof-of-concept trials evaluating treatment with the selective, oral NaV1.8 inhibitor VX-548 for acute pain following abdominoplasty and bunionectomy surgeries.
Vertex expects to complete the pivotal program in late 2023 and share results from these studies in late 2023 or early 2024. VX-548 has been granted Breakthrough Therapy and Fast Track designations in the U.S. for moderate to severe acute pain. In addition, Vertex has initiated a Phase 2 dose-ranging study of VX-548 in neuropathic pain.
SOUTH SAN FRANCISCO, Calif., May 18, 2023 /PRNewswire/ -- SiteOne Therapeutics, Inc., a clinical-stage biopharmaceutical company developing isoform-selective inhibitors of the voltage gated sodium channel (NaV) for the treatments of pain, cough, and other conditions involving hypersensitivity of the nervous system, today announced that it has received a grant (UG3DA058552) for up to $15 million from the National Institute on Drug Abuse (NIDA) for the development of STC-004, an investigational, non-opioid treatment for acute and chronic pain conditions. The grant was awarded through the National Institutes of Health (NIH) Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, a trans-agency effort to accelerate the development of scientific solutions to the national opioid public health crisis.
The award, titled "Development of a Potent and Selective Nav1.8 inhibitor for the Treatment of Acute and Chronic Pain with the Goal of Reducing Opioid Use and Preventing Opioid Use Disorders," is a UG3/UH3 Phase Innovation Awards Cooperative Agreement involving two phases. The UG3 phase is to support a project with specific milestones to be accomplished by the end of a two-year period. The UH3 phase will provide funding for a further three years to a project that successfully completed the milestones set in the UG3 phase. Application budgets are limited to $3 million direct costs per year and UG3 projects that have met their milestones will be considered by NIDA and prioritized for transition to the UH3 phase, with the total funding currently expected to be available under both the UG3 and UH3 phases to be a maximum of $15 million in direct costs.
"SiteOne Therapeutics is honored to receive funding from the National Institute on Drug Abuse to develop innovative solutions for the treatment of pain and aim to reduce our health care system's reliance on opioids," commented John Mulcahy, President and Chief Executive Officer of SiteOne Therapeutics. "This award validates our approach to addressing pain by targeting individual sodium channel isoforms, NaV1.7 and NaV1.8, that are predominantly expressed in pain-sensing nerve fibers."
"The perception of pain is a complex neurological process, and the key to providing solutions to address both acute and chronic pain is to selectively target pathways that lead to this sensation. Both opioids and over-the-counter NSAIDs can sometimes pose major health risks to patients and are ineffective in blocking certain types of pain, particularly neuropathic pain," noted John Hunter, Chief Scientific Officer of SiteOne Therapeutics. "Our therapeutic approach of inhibiting sodium channel function aims to limit the hypersensitivity reaction to pain by regulating the misfiring of peripheral nerves that transmit the perceived pain to the central nervous system. This grant is essential in funding the clinical development of our NaV1.8 inhibitors with the goal to provide relief to patients across a variety of pain conditions."
This research is supported by the National Institute on Drug Abuse of the National Institutes of Health and the NIH Helping to End Addiction Long-term Initiative under award number UG3DA058552. The content presented in this release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
SiteOne Therapeutics is a clinical-stage biopharmaceutical company advancing a novel class of highly selective small molecule inhibitors targeting NaV1.7, NaV1.8, and other voltage-gated sodium ion channels to treat peripheral hypersensitivity disorders such as chronic cough, itch, and pain. Since its inception, SiteOne has been dedicated to the development of safe and effective pain therapeutics without the significant addiction potential and side effects of opioids. The company is also advancing additional novel drug candidates that exhibit precise selectivity for individual sodium channel subtypes to treat other hypersensitivity disorders such as chronic cough and chronic ocular surface pain. For more information, visit www.siteonetherapeutics.com.
The Helping to End Addiction Long-term Initiative, or NIH HEAL Initiative, is an aggressive, trans-NIH effort to speed scientific solutions to stem the national opioid public health crisis. Launched in April 2018, the initiative is focused on improving prevention and treatment strategies for opioid misuse and addiction, and enhancing pain management. For more information, visit:
The primary endpoint was the time-weighted sum of the pain-intensity difference (SPID) over 48 hours (SPID48), calculated from Numeric Pain Rating Scale (NPRS) scores (which range from 0 to 10, with higher scores indicating greater pain) at 19 time points after the first dose of VX-548 or placebo.
"Attempts to use systemic nonselective sodium channel blockers have not succeeded because of dose-limiting side effects," Wallace pointed out. "Now, years of research on sodium channel blockers that are specific to the subtypes located on structures of the peripheral nervous system have come to fruition."
"It is perhaps disappointing that the effect size of this very original selective peripheral sodium channel blocker was small, and limited conclusions can be made about its effectiveness as compared with other agents because it was not directly compared with hydrocodone bitartrate-acetaminophen, which is a standard drug for the treatment of acute pain," he added. "However, these trials represent an early foray into an exciting new class of drugs in a difficult field."
Opioids are used to treat acute pain, but come with safety concerns about the possibility of misuse and addiction. Non-opioid pain treatments include nonselective sodium-channel inhibitors like lidocaine, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. Most approved analgesic drugs either act on the opioid-receptor system or are NSAIDs, Jones and co-authors noted.
"The voltage-gated sodium channel NaV1.8 is a therapeutic target for pain because of its role in transmitting nociceptive signals and its selective expression in peripheral nociceptive neurons of the dorsal-root ganglia," they wrote.
Jones and colleagues randomized 303 participants in the abdominoplasty study and 274 in the bunionectomy trial. Baseline mean NPRS scores were 7.2 to 7.4 in the abdominoplasty trial and 6.6 to 6.9 in the bunionectomy trial.
"Abdominoplasty, which is considered to be a model of soft-tissue pain, and bunionectomy, which is considered to be a model of bone pain, are common surgical procedures resulting in moderate-to-severe postoperative acute pain that is generally treated with analgesic medicines, including opioids, NSAIDs, and acetaminophen," the researchers noted.
Most adverse events were mild or moderate, and headache and constipation were common. In the abdominoplasty trial, three participants had serious adverse events, including one in the middle-dose VX-548 group; none were considered treatment-related. No serious adverse events occurred in the bunionectomy trial.
In both trials, fewer participants discontinued high-dose VX-548 than placebo or hydrocodone bitartrate-acetaminophen. Both studies appeared to show a treatment effect with VX-548 compared with hydrocodone bitartrate-acetaminophen, Jones and co-authors said.
"Sodium channel modulation is one of many mechanisms involved in pain transmission, and it is perhaps unlikely that modulating just one mechanism will lead to large effects on pain," observed Wallace. "At the moment, postoperative pain is still best managed by multimodal therapies, such as those that combine drugs with different mechanisms."
VX-548 (suzetrigine) is an experimental analgesic (pain-relieving medicine) that works by selectively blocking an ion channel called Nav1.8. It is currently undergoing investigational trials to assess its ability to relieve moderate to severe acute pain or peripheral neuropathic pain.
Advances in understanding the physiology behind pain has led to a better appreciation of the role ion channels play in this process. There are many different types of ion channels including transient receptor potential (TRP) channels, voltage-gated ion channels (Nav) channels, calcium channels (CaV), Acid-sensing ion channels (ASICs), Piezo channels, and Purinergic receptor ion channels (P2X).
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