Vertex Submits NDA for VX-548 (Suzetrigine), a First-in-Class Non-Opioid Treatment for Moderate-to-Severe Acute Pain

On July 30 local time, Vertex announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for suzetrigine (VX-548), a NaV1.8 inhibitor. VX-548 is an oral, selective NaV1.8 pain signal inhibitor indicated for the treatment of moderate-to-severe acute pain. Notably, VX-548 could become the first drug with a novel mechanism of action for acute pain in more than two decades, filling a gap in the non-opioid acute pain medication market.

Currently, the FDA has granted Priority Review status to VX-548, with a Prescription Drug User Fee Act (PDUFA) target date of January 30, 2025.Previously, VX-548 had received FDA Fast Track designation and Breakthrough Therapy designation for the treatment of moderate-to-severe acute pain.

According to Mordor Intelligence’s 2023 market research report, the global pain management market was valued at an estimated $75.4 billion in 2023 and is projected to reach $90 billion by 2028. Despite this substantial market potential, the field has faced a two-decade drought in new drug approvals, leaving opioids as a common therapeutic choice. The challenge with opioids lies not in their efficacy, but in safety concerns, tolerance development, and addiction risks.

A 2022 report by the U.S. Congressional Joint Economic Committee stated that opioid misuse cost the United States nearly $1.5 trillion, accounting for approximately 7% of the nation’s gross domestic product (GDP) that year. The Lancet has predicted that, with the rise in co-use of xylazine and opioids, approximately 1.22 million Americans will die from opioid overdoses cumulatively between 2020 and 2029 if no new measures are taken.

Faced with a vast market opportunity and clear industry pain points, many pharmaceutical companies are actively developing next-generation analgesic products. Vertex’s VX-548 is poised to become the world’s first NaV1.8 inhibitor, breaking the two-decade drought in non-opioid drugs for acute pain and emerging as the pharmaceutical industry’s new blockbuster category after the multibillion-dollar GLP-1 market.

VX-548 is an oral selective NaV1.8 inhibitor that exhibits high selectivity for NaV1.8 over other NaV channels. In August 2023, VX-548 was featured in The New England Journal of Medicine, demonstrating a 30,000-fold selectivity for NaV1.8.

Furthermore, NaV1.8 is a voltage-gated sodium channel that plays a pivotal role in pain signal transmission within the peripheral nervous system. This mechanism of action differs fundamentally from that of opioids; rather than acting on the brain, it directly blocks pain signals in the peripheral nervous system. Consequently, VX-548 does not pose a risk of addiction. In clinical studies, the incidence of common adverse events such as nausea, headache, constipation, and dizziness was lower in patients treated with VX-548 compared to those receiving placebo or opioids.

The New Drug Application (NDA) for VX-548 is primarily based on the positive results from the pivotal Phase 3 clinical trials of this therapy for the treatment of acute pain, which Vertex announced in January this year. Trial data demonstrated that, within the first 48 hours following abdominoplasty and bunionectomy, VX-548 significantly reduced postoperative pain compared with placebo. Single-arm study results indicated that VX-548 was effective for various surgical and non-surgical pain conditions, with effects lasting up to 14 days. VX-548 exhibited a favorable safety profile and was well tolerated across all three studies.

In a review article published by the industry media Evaluate, VX-548 was listed as a potential blockbuster therapy. An analyst from Leerink Partners noted that the current pain market bears similarities to the obesity market two years ago, projecting that annual sales of VX-548 could reach $5.1 billion by 2030. Other analysts forecast that VX-548 will generate $4.4 billion in sales for acute pain indications and $7 billion in sales for neuropathic pain indications by 2032.

Although major analytical firms have provided inconsistent forecasts for the future market sales of VX-548, they have all expressed optimism and high expectations for this pipeline. A Leerink analyst stated, “We continue to believe that the investment community significantly underestimates the unmet needs in acute and neuropathic pain, as well as Vertex’s sustained innovation capability.”

Perhaps a new generation of “GLP-1” blockbuster drugs is also on the horizon in the acute pain sector.

As the leading enterprise in the field of cystic fibrosis (CF) therapeutics, Vertex has currently launched four CF drugs: Kalydeco, Orkambi, Symdeko, and Trikafta. The first three of these medications are suitable for treating approximately 40,000 patients worldwide. At present, Vertex faces virtually no competition in the CF drug market, resulting in high profit margins. Having accumulated tens of billions of dollars in wealth through its CF portfolio, Vertex is poised to introduce its next blockbuster product at the peak of its success, thereby sustaining its remarkable momentum.

It is reported that VX-548 is currently Vertex’s most advanced investigational asset and the fastest-developing NaV1.8 inhibitor globally.

Vertex has higher expectations for VX-548. Previously, VX-548 achieved positive results in Phase II studies for pain associated with diabetic peripheral neuropathy, and Vertex has already planned to initiate pivotal clinical trials. Furthermore, Phase II clinical studies of VX-548 are also underway in the field of lumbosacral radiculopathy.

In addition to VX-548, Vertex is also advancing a broader pipeline of non-opioid small-molecule analgesics. Currently, two candidate drugs targeting NaV1.8, namely VX-993 and VX-973, have entered clinical trials, while other investigational agents targeting NaV1.8 or NaV1.7 for intravenous administration are in the preclinical stage.

It is worth noting that Vertex is also advancing its pipeline of third-generation NaV1.8 inhibitors. In the future, we may have greater expectations for Vertex’s NaV1.8 inhibitor program.

In addition to Vertex, multinational corporations (MNCs) such as Merck & Co. and GSK are also developing NaV1.8-targeted therapies, all of which are currently in the preclinical stage.

In China, numerous companies have also laid out strategies targeting NaV1.8, with multiple drug candidates having entered clinical stages, including HRS-4800 from Jiangsu Hengrui Pharmaceuticals, JMKX000623 from Shanghai Jiyu, HBW-004285 from Haibowei Pharmaceutical, and FZ008-145 from Fermion (for which Regeneron has obtained exclusive rights in Greater China). Other companies, such as Minghui Pharmaceutical and Pengji Kaifeng, also have pipelines in the preclinical stage.

Among them, Hengrui Medicine has made the most rapid progress. As early as 2021, Hengrui Medicine’s NaV1.8 blocker, HRS-4800, received approval in China to initiate clinical trials for research on postoperative analgesia following impacted tooth extraction, and it is currently in Phase II clinical development. In February this year, Hengrui publicly disclosed its new patent for a NaV1.8 inhibitor, becoming the first globally announced fast-follow project targeting VX-548. We look forward to more Chinese enterprises demonstrating “China speed” and bringing new opportunities to the analgesic drug market.

References:

1. CPhI Pharma Online, “New Drug | Positive Results from VX-548 Study, Breakthrough in Opioid Crisis Imminent”

2. Lanjingling No. 1, “How Much Do Vertex Painkillers Cost”