The FDA has approved Vertex’s suzetrigine (Journavx), an oral inhibitor of voltage-gated sodium channel 1.8 (NaV1.8), for the treatment of moderate to severe acute pain. The decision provides a much-needed new treatment option for acute pain management, which has been dominated for decades by addictive opioids.

“Having a non-opioid that selectively blocks pain transmission, it's exciting,” says May Chin, a retired anaesthesiologist who worked at the George Washington University Hospital and was not involved in the development of suzetrigine.

Pain-associated NaV channels conduct electrical signals known as action potentials in peripheral pain-sensing neurons, playing a key role in the transmission of pain signals. These channels have long been on the radar of drug developers looking to provide cleaner pain relief.

Initially, researchers focused on developing NaV1.7 inhibitors, owing to compelling genetic validation in humans for both loss- and gain-of-function NaV1.7 variants. But the need for subtype selectivity among the nine closely related NaV channels, which are involved in various physiological functions, proved a stumbling block. Several NaV1.7-targeted candidates have failed in mid-late-stage clinical trials.

NaV1.8 has proven to be more amenable to selective small-molecule inhibitors.

In Vertex’s pivotal trials in over 2,000 patients with moderate to severe pain after bunionectomy or abdominoplasty, suzetrigine provided comparable pain relief to an acetaminophen–opioid combination. The treatment was safe and well-tolerated.

“This is a new era that separates us from the millennia before, where we treated pain with non-selective agents,” says Paul Negulescu, senior vice president of research at Vertex. “This is the first step in a journey.”

Other NaV1.8 inhibitors, from Vertex and others, are in early-mid-stage clinical development (Table 1).

Drug

Company

Target

Indication

Status

NaV1.8

Suzetrigine

Vertex

NaV1.8 inhibitor

Acute pain

Approved

VX-993

Vertex

NaV1.8 inhibitor

Pain

Phase I/II

JMKX-000623

Shanghai Jemincare

NaV1.8 inhibitor

DPN

Phase II

ATZ01

AlgoTherapeutix

NaV1.7, 1.8 and 1.9 inhibitor, topical

CIPN and erythromelalgia

Phase II

LTG-305

Latigo Bio

NaV1.8 inhibitor

Pain

Phase I

HBW-004285

Hyperway

NaV1.8 inhibitor

Pain

Phase I

NaV1.7

OLP-1002

Olipass

NaV1.7 ASO

OA pain

Phase II

ST-2427

SiteOne

NaV1.7 inhibitor

Pain

Phase I

iN1011-N17

iN Therapeutics

NaV1.7 inhibitor

OA pain

Phase I

Other targets

Resiniferatoxin

Grunenthal

TRPV1 agonist

OA pain

Phase III

Cemdomespib

Biogen

HSP90 modulator

DPN

Phase II

Mazisotine

Lilly

SSTR4 agonist

Pain

Phase II

LY3857210

Lilly

P2X7 inhibitor

Chronic pain

Phase II

LY3848575

Lilly

Anti-epiregulin mAb

Chronic pain

Phase II

NA

Lilly

AT2R antagonist

Pain

Phase I

EC5026

EicOsis

sEH inhibitor

Pain

Phase I

Suzetrigine could achieve blockbuster sales in the acute setting, analysts forecast. However, it will still have to compete with cheap and effective — if addictive and adverse-effect-prone — opioids.

Vertex is also testing the drug in chronic pain indications, a much larger market with long-term treatment needs. Phase III studies in painful diabetic neuropathy are ongoing. But in a recent phase II trial in lumbrosacral radiculopathy, a form of nerve compression that causes sciatica, suzetrigine did not seem to outperform placebo — dealing a blow to the company’s chronic pain ambitions.

Multiple therapeutic targets are needed in any case to address chronic pain indications, says Michael Oshinsky, director of the National Institute of Neurological Disorders and Stroke’s office of preclinical pain research. “The idea of a single drug being a silver bullet is not taking into consideration all the variety of pathways that lead to pain,” he adds.

Success for suzetrigine could boost interest and investment in the notoriously challenging field of analgesic drug development. Several other targets are currently under investigation (Table 1).