When Vertex Pharmaceuticals announced last month that its experimental pain pill had shown positive results in late-stage studies, it marked a major breakthrough in the hunt for new non-opioid pain medication.
Despite the market still being dominated by cheap opioid-based painkillers that are widely available, highly addictive, and firmly established, Vertex’s success in these trials has provided a reason to be hopeful. And it’s not just Vertex; other biotech companies are also attempting to develop new, non-addictive ways to fight pain.
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The opioid crisis
Opioids work by binding to opioid receptors in the brain, spinal cord, and other areas of the body, triggering the brain’s reward centers and reducing pain signals. They also mute other nerve cell functions, such as breathing, heart rate, and level of alertness. Over time, the body adapts to these medications, and the pain relief lessens. This is known as ‘tolerance,’ and means that more of the same medication is necessary to achieve the degree of pain relief that the person was feeling before their tolerance kicked in.
This tolerance, and ultimately addiction, is what led to the opioid crisis. According to the Centers for Disease Control and Prevention (CDC), the first wave of the crisis began with increased prescribing of opioids in the 1990s, with overdose deaths involving prescription opioids increasing since at least 1999. Then, the second wave began in 2010, with rapid increases in overdose deaths involving heroin. And, most recently, the third wave started in 2013, with significant increases in overdose deaths involving synthetic opioids, particularly illicitly manufactured fentanyl.
The crisis has not yet ended. In fact, as per the CDC, the figures now are even scarier: the number of people who died from a drug overdose in 2021 was over six times the number in 1999, and the number of drug overdose deaths increased more than 16% from 2020 to 2021, with more than 75% of the nearly 107,000 drug overdose deaths in 2021 involving an opioid. According to a report from the Stanford-Lancet Commission on the North American Opioid Crisis, without urgent intervention, 1.2 million people in the U.S. and Canada will die from opioid overdoses by the end of the decade.
Joseph Stauffer, chief medical officer (CMO) of Antibe Therapeutics, told Labiotech that the opioid crisis has “profoundly” impacted how biotech and pharmaceutical companies now approach the development of pain medication. “With widespread concerns about opioid misuse and addiction, there’s a notable shift towards prioritizing the creation of safer, non-addictive alternatives.”
He continued: “While there have been no novel oral painkillers introduced in the last 25 years, there has certainly been a lot of recent activity in the space, with Vertex recently reading out phase 3 data for its NaV1.8 inhibitor.”
Vertex Pharmaceuticals’ new non-opioid pain medication VX-548: a success in late-stage studies
On January 30, in what was a major milestone in the company’s decades-long efforts to bring a non-opioid pain medicine to market, Vertex announced positive results from its phase 3 program for the selective NaV1.8 pain signal inhibitor, called VX-548, in the treatment of moderate-to-severe acute pain.
In two phase 3 studies – each containing more than 1,000 participants – those who received VX-548 after surgery experienced a greater reduction in pain over two days compared to those who received placebo. Participants in one study had an abdominoplasty and participants in the second study had bunion surgery. Furthermore, reductions in pain scores were clinically meaningful (>3 points and close to 50% from baseline in each trial) and were rapid and sustained throughout the treatment period. Vertex also said that VX-548 was safe and well-tolerated, with common side effects including nausea and constipation.
In a comment to Labiotech, Vertex said that selectively inhibiting the NaV1.8 and NaV1.7 sodium channels found in peripheral sensory neurons has long been a heavily pursued area of drug discovery for pain relief, and Vertex is the first company to show phase 3 efficacy data on the NaV1.8 target – a voltage-gated sodium channel that plays a critical role in pain signaling in the peripheral nervous system.
Unlike opioids, VX-548 works by blocking pain signals at the source. Vertex’s approach is to selectively inhibit NaV1.8 using small molecules to create a new class of medicines that have the potential to provide effective relief of pain without the limitations of opioids, including their addictive potential.
Vertex’s two studies were also designed to test whether VX-548 could beat hydrocodone plus acetaminophen, which is a common pain treatment combo that is best known by the brand name Vicodin. Unfortunately, VX-548 ultimately failed to meet this secondary endpoint; however, it did show comparable efficacy over two days in the abdominoplasty study.
Stifel analyst Paul Matteis told Endpoints news: “This may complicate the prescribing decision in the acute setting, where patients often take a short course of treatment and efficacy is a primary consideration. The implications to chronic pain, however – which is more important commercially – may be less significant.”
Considering attempts to bring new opioid alternatives to market by drugmakers such as Eli Lilly and Regeneron Pharmaceuticals have failed in trials, this is still a big win for Vertex. According to a report in Reuters, analysts said the drug is likely to gain approval for the treatment of acute pain, offering a much-needed alternative to the opioid-based medications that have fueled a national crisis.
Moving forward, Vertex’s next steps are to submit a New Drug Application to the U.S. Food and Drug Administration (FDA) by mid-2024, with the goal of achieving a broad label in moderate-to-severe acute pain.
Latigo Biotherapeutics emerges from stealth to develop new non-opioid pain medications
Vertex is not alone in its quest to develop a NaV1.8 inhibitor. On February 14, Latigo Biotherapeutics emerged from stealth with $135 million in series A financing and a lead program targeting exactly the same channel.
Latigo’s NaV1.8 pain inhibitor is known as LTG-001. It is currently in a phase 1 trial in healthy volunteers and is intended to treat acute and chronic pain. It has the potential to be best-in-class with a rapid onset, meaningful efficacy, and superior safety to standard of care with no central nervous system (CNS) effects.
In an article in Fierce Biotech, Sean Harper, co-founding managing director of Westlake Village BioPartners, which founded and incubated Latigo beginning in 2020, said that beating opioids is a “tough bar”. He commented: “I think a goal in an acute pain setting to beat that type of comparator handsomely…would have to be [an] aspiration”.
Harper believes Latigo’s molecule will differentiate from Vertex’s by mitigating off-target effects in the brain and by tackling chronic pain. “We have every reason to believe that our NaV1.8 inhibitor will be effective in both acute and chronic pain. But obviously, that remains to be proven.”
Latigo now hopes to initiate a phase 2 study for patients with acute pain later this year.
Antibe Therapeutics’ mission to develop a safer nonsteroidal anti-inflammatory drug (NSAID)
Stauffer’s Antibe Therapeutics is also looking to develop a new non-opioid pain medication. This time, though, the drug the company is developing is a type of nonsteroidal anti-inflammatory drug (NSAID).
The drug is called otenaproxesul, and is specifically a hydrogen sulfide-releasing NSAID. Stauffer explained that hydrogen sulfide (H2S) – which has long been viewed as a poisonous gas – actually has several crucial physiological roles, including a range of anti-inflammatory effects, as well as antioxidant, vasodilatory, analgesic, cellular repair, and cellular protection functions.
“Upon absorption in the upper GI tract, one of H2S’s actions is to suppress white blood cell adhesion to the lining of blood vessels – the first part of the inflammatory cascade,” Stauffer continued to explain. “This action was discovered by our founder, Dr. John L. Wallace, and colleagues in the mid-2000s. Earlier, in 1990, Dr. Wallace had been the first to elucidate how NSAIDs damage the digestive tract; in the early 2000s, he had identified H2S’s key role as an inflammation mediator.”
By developing otenaproxesul, Antibe wants to create a best-in-class NSAID that is safer for the digestive tract, while also leveraging a favorable cardiovascular profile. Stauffer said that, while traditional NSAIDs have long been the go-to for managing inflammation and pain, these drugs pose a considerable risk of gastrointestinal damage and increased cardiovascular complications, in turn creating a dilemma for both patients and healthcare providers.
“A range of studies have shown that 23% of subjects develop ulcers in a 7-day course of treatment,” he said. “NSAIDs carry triple the risk of serious gastrointestinal outcomes in a 14-day course of treatment. Antibe scientists have published phase 2b data in the British Journal of Pharmacology indicating that naproxen is sixteen times more likely to cause gastric ulcers in a 14-day treatment period vs. otenaproxesul.”
According to Stauffer, otenaproxesul is slated to begin its phase 2 trial this spring, with topline results expected in Q3 2024.
Are there any challenges in bringing new non-opioid pain medications to market?
As mentioned previously, the pain management market is still dominated by cheap, highly effective opioid medications that are easy to access. According to an article in Endpoints News, if Vertex’s drug is approved, it is likely to be more expensive than opioids. Therefore, the challenge for Vertex here will be to persuade insurers (which will particularly be the case in the U.S.) that VX-548 will save on healthcare costs and benefit patients in the long run.
But when it comes to the efficacy of non-opioid medications compared to opioids, a study in the Journal of the American Medical Association suggests that opioid drugs are no more effective than a combination of non-opioid painkillers in treating acute pain. This is good news for biotechs trying to develop non-opioid painkillers that are just as effective as opioids.
When looking specifically at NSAIDs, according to Stauffer, several studies and meta-analyses have shown that NSAIDs and opioids can deliver similar analgesic pain relief efficacy in both acute and chronic pain settings. “Drawing on my experience as a former FDA medical review officer for anti-inflammatory and analgesic drugs (painkillers), the difficulties of developing novel analgesics are the typical hurdles for any drug developer – time, money, risk.”
However, he said that the withdrawal from the market of two COX-2 inhibiting NSAIDs in the early 2000s may have dampened interest in pursuing novel pain therapies – a potential setback for the non-opioid pain treatment market.
Non-opioid pain treatment market expected to show growth
Having said that, according to Grand View Research, the global non-opioid pain treatment market size was valued at $38.64 billion in 2021, and is expected to expand at a compound annual growth rate (CAGR) of 8.3% from 2022 to 2030. This expected growth can be attributed to the increasing R&D investments by the key players for developing novel non-opioid drugs, and government and private organizations for introducing favorable initiatives and creating awareness about available treatments.
While this is good news, Stauffer pointed out that many of the research efforts being put into novel mechanisms and non-opioid pathways are still in the preclinical stage, meaning it could take some time before we see an array of new non-opioid pain medications reach the market.
Ultimately, the pain drug market as a whole is in need of an overhaul; one that phases out addictive opioid pain pills and brings in effective new non-opioid medications. Vertex’s recent trial success could soon see the first step towards creating this vital change if the FDA decides to approve VX-548, making it the first new class of pain medicine to reach the market in more than two decades.
New technologies related to pain addiction:
- Selective Kappa Opioid Receptor Antagonists as a Novel Treatment Approach for Neuropathic Pain and Addiction – Texas Tech University System