Intro
At the end of May, Eli Lilly announced a $1 billion deal with Site One Therapeutics, a company developing a Nav1.8 for the treatment of pain (Link).
With Vertex’s Journavx now on the market, what other companies are working in the pain space to develop novel therapies, and who might be interesting acquisition targets for big pharma looking to get involved?
In this deep dive, we’ll cover the burden of disease from pain, the history of sodium channel blocking to target pain, including recent developments, and then review three potential targets for pharma to partner or acquire.
Burden of disease(s) and unmet needs
Pain as a disease places a considerable burden on patients, the health care system, and the economy. For patients undergoing surgery,>80% suffer from acute pain, with ~75% reporting inadequate pain relief, which in 10-30% of cases risks transitioning into chronic pain or refractory pain lasting > 3 months post-surgery from operations such as Mastectomy, Thoracotomy, or hernia repair (Link, Link, Link).
Chronic Pain is also a considerable challenge, with ~51 million US adults experiencing it, and ~17 million of them being classified as suffering from high-impact chronic pain (Link). As well as the suffering for patients suffering disability and mental health comorbidities, it places a huge burden on the health system and results in lost productivity for the economy, estimated between $560-635 billion per year (Link).
Standard of care in treating pain pre-2025
Opioids, NSAIDs, Antidepressants, and Anticonvulsants have all been used for a long time now to treat pain, with limited innovation or novel drug classes being approved in the last 20 years.
When used appropriately, opioids are often suitable for addressing acute pain, following surgery or procedures. However, their associations with addiction and overdose have led to a crippling epidemic that is still impacting vulnerable populations across the world (Link).
As well as the addictive concerns, their use is associated with side effects, including an increased risk of vomiting, delirium, drowsiness, and constipation.
Their use in chronic pain conditions like neuropathic pain is also variable (Link). In a large meta-analysis of 96 randomised clinical trials in non-cancer chronic pain, their use was found to have a statistically significant but small impact versus placebo (Link). In a systematic review of studies between 4 and 12 weeks, some opioids provided a clinically relevant effect of 50% or greater reduction of disability compared to placebo. However, being on this class of medicines for more extended periods increases the potential for side effects and addiction.
NSAIDS, meanwhile, risk GI, renal, and cardiovascular complications, and they are of limited use in chronic neuropathic conditions (Link), whilst antidepressants and anticonvulsants have a low response rate, which is accompanied by cognitive and metabolic side effects.
Blocking sodium channels as a way to address pain
Given the many known issues with current pain medication, especially opioids, it’s unsurprising that companies have been looking for better options. One of the main routes that has been explored as an alternative to opioids is to block sodium channels selectively (Link).
The exploration of the science behind blocking sodium channels began in the middle of the 20th century, when Hodgkin and Huxley elucidated the role of sodium channels in action potential generation.
Throughout the rest of the 20th and early 21st centuries, researchers identified and studied the sodium subchannels, especially the importance that Nav1.7, 1.8, and 1.9 play in the transmission of pain signals and their attractiveness as drug development targets.
Older molecules like lidocaine (which was approved in 1948), a local anaesthetic, work by preventing the initiation and conduction of nerve impulses. It binds to sodium channels in a 1:1 fashion, controlling the flow of sodium ions (Link, Link).
However, its lack of selectivity impacts multiple sodium channel subtypes, which can cause cardiac issues, numbness, and motor impairment.
A quick break out of the channels will be of use when we look at some of the molecules that have been developed.
Nav1.7 is closely linked with various hereditary pain conditions. Some members of the population have congenital insensitivity to pain due to a loss-of-function mutation in this channel. It is a threshold channel that regulates the generation of action potentials, and its relatively selective expression in nociceptors means that blocking it could provide pain relief with a lower risk of adverse events seen in broader spectrum blockers (Link).
Nav1.8 is linked to inflammatory and neuropathic pain within the peripheral nervous system, with gain-of-function mutations found in Small fiber neuropathy and diabetic neuropathy. The fact that it does not involve the central nervous system has made it a popular target for non-addictive analgesics.
Nav1.9 is known to have significant involvement in cold pain sensing and small fiber neuropathy, although its mechanism of action still needs further investigation.
The challenge for drug developers has been to find an approach that selectively binds a single channel.
The development of targeted therapies – Nav1.7
Early development efforts by pharma saw Pfizer working on developing PF-05089771, a selective, peripherally restricted Nav1.7 sodium channel blocker for pain due to diabetic peripheral neuropathy (Link).
In a randomized trial, it failed to show statistical significance compared to a placebo at week 4. In comparison, pregabalin did cause a statistically significant difference compared to placebo. As the efficacy criteria were not met, the study did not proceed (Link, Link).
In 2016, development was discontinued as Pfizer focused its efforts on other parts of its portfolio.
Xenon Pharmaceuticals was one of the other early innovators in this space, partnering with Teva in the development of XEN402/ TV-45070, a topical Nav1.7 (and to a lesser extent Nav1.8) inhibitor (Link).
In July 2015, it failed in a Phase 2b Osteoarthritis trial. Neither of the two strengths tested (4% or 8%) demonstrated a statistically significant difference from placebo in the efficacy endpoint of reductions in pain due to OA.
It also failed in a Phase 2 trial in Postherpetic Neuralgia in June 2017, when the investigator saw no difference in analgesia measured between TV-45070 and a placebo. One of the commentaries on the results suggested the mean duration of pain in the cohort was longer than usual (5 years), meaning they were more refractory to treatment(Link).
In 2018, Teva and Xenon terminated the development agreement, with Xenon out-licensing XEN402 to Flexion Therapeutics in 2019 (Link), and according to Adisinsight, development was discontinued in 2022 (Link).
Biogen’s attempts to target Nav1.7
Biogen had one of the most extensive development programs for a Nav1.7 drug, vixotrigine, for several pain indications from 2015 to 2022. It acquired vixotrigine as part of the acquisition of Convergence Pharmaceuticals in 2015 (Link).
In a Phase 2 clinical trial treating 82 patients with neuropathic pain as a result of lumbosacral radiculopathy, the primary endpoint was met, which was to reduce daily neuropathic pain compared with baseline. However, in a confirmatory Phase 2, with 502 persons with lumbosacral radiculopathy, neither primary nor secondary endpoints were met (Link).
A Phase 2 study in trigeminal neuralgia tested treatment failure, defined as 50% increase in frequency or intensity of pain or paroxysms. Participants receiving vixotrigine experienced less treatment failure than placebo (33.3% vs 64.3%); however, the result did not reach statistical significance. The secondary endpoint was met.
It then ran a sizable Phase 2 trial in small fiber neuropathy, called CONVEY. It tested two doses (200 and 350 mg) versus placebo; strangely, the lower dose met statistical significance for the primary endpoint of mean average daily pain, but not for the higher dose. The secondary endpoint, which was patient-reported outcomes, however, did reach statistical significance (Link).
Although it had these mixed results from Ph2 trials, Biogen was planning two larger Ph3 trials, where it hoped that a larger population might show a more significant effect (Link). These were listed on CT.gov with trial design presented at pain conferences and published in journals. However, the program was then axed as part of a strategic review in 2022, with these trials never truly initiating (Link).
Several other Nav1.7 inhibitors were in Ph1 testing, including AstraZeneca’s AZD-3161 (Link), Genentech’s GDC-0276 (Link), and Sumitomo Dainippon Pharma’s DSP-2230 (Link), but these were removed quietly from their respective pipelines.
Targeting Nav1.8
Vertex, on the other hand, achieved clinical development success at the start of this year with the approval of Journavx (suzetrigine) in moderate pain (Link).
Vertex was initially developing a molecule, VX-150 (Link), which had multiple positive proof-of-concept studies. A Phase 2 trial in Small Fiber Neuropathy achieved a statistically significant reduction in pain at Week 6, with the molecule being well tolerated. It also showed significant relief of acute pain versus placebo in patients following bunionectomy surgery, and in chronic pain caused by osteoarthritis of the knee.
Vertex then dropped VX-150 due to the low potency requiring high doses, and moved on to developing suzetrigine (VX-548) due to its greater selectivity. Due to the similarities between the sodium channels, Vertex focused on achieving a roughly 10,000-fold selectivity, with it reaching a 30-40,000-fold selectivity for suzetrigine (Link).
Approval was based on two Phase 3 studies of patients with moderate to severe pain post-surgery (either abdominoplasty or bunionectomy). The primary endpoint, the time-weighted sum of the pain intensity difference as recorded on the NPRS from 0 to 48 hours (SPID48) compared to placebo, was significantly met in both trials.
As of January 2025, Vertex was aiming to expand the number of indications for suzetrigine, with an ongoing Phase 3 in Painful diabetic peripheral neuropathy (with primary completion in May 2027) and plans to start a Phase 3 in painful lumbosacral radiculopathy pending discussion with regulators (Link).
Analysts expect sales to hit roughly $1.6 billion in peak sales in 2033, representing a 15% penetration rate (Link).
Eli Lilly enters the targeted space with an acquisition
Lilly’s ~$1 billion acquisition of Siteone Therapeutics brings it a Ph2-ready Nav1.8 inhibitor (Link).
With Journavx already in the market, we now move into that common pharma scenario of similar drugs differentiating on small dosing or convenience benefits. STC-004 was dosed once daily in the Ph1 trial, which brings it a convenience advantage vs Journavx, which is taken once every 12 hours.
Siteone’s leadership also messaged hope to ensure STC-004 is safe to take with other drugs. As this is generally the case for all medicines, it’s unclear what Siteone is doing to ensure this. Might its subsequent trial include an arm for patients on a common type of medication that these patients would be using, and investigate side effects?
Now, with Lilly’s clinical and commercial support, the team working on STC-004 is likely to accelerate development, and we can anticipate the next set of trials in the coming months.
Potential acquisition targets – Other companies working in this space
Lilly snapped up one of the biotech companies in this space, but several others might be targets for big pharma looking to get in on developing therapies for pain. We’ll look at three, and then discuss the merits of acquisition (or partnering).
Dogwood Therapeutics
Initially founded in 2012 as Virios Therapeutics, Dogwood was formed as part of a merger with Wex Pharmaceuticals in 2024, whose lead program, Halneuron(R), is in development for Chemotherapy-induced neuropathic pain (Link).
Halneuron is tetrodotoxin, a potent small molecule found in puffer fish and other marine animals. It inhibits Nav1.7, reducing pain signal transmissions. It is delivered as a subcutaneous injection, and in preclinical paw withdrawal models, it had a comparable efficacy to suzetrigine.
It has run several Phase 2 trials; in the first, 165 patients with cancer-related pain were randomized in a double-blind, placebo-controlled multicentre trial. Patients received eight injections over 4 days and were followed up every 15 days after the primary endpoint. A statistically significant effect was seen: 51% of patients on Halneuron(R) experienced a >30% reduction in pain vs. 35% on placebo.
The mean pain response for Halneuron responders was 57.7 days vs. 10.5 days for placebo responders, showing a long duration of response.
Dogwood used a Phase 2a in 125 patients with Chemotherapy Induced Neuropathic Pain (CINP) as a dose finding study, testing three dose levels and two dosing regimens (once daily vs twice daily), as well as determining the treatment effect size needed to power the study. The safety profile was acceptable in these patients, similar to the CRP study.
It is currently running a Ph2b in CINP, with a target enrolment of 200 patients. The patients will receive 8 Halneuron® injections over 2 weeks, and have the primary endpoint, weekly average of daily 24-hour recall pain intensity scores, measured in week 4. An interim analysis is planned in Q4 2025 (Link).
The company has an executive team with experience in brand development and commercialization from multiple large brands, including Lyrica, Zoloft, Lipitor, and Viagra. The merger helped recapitalize the company; however, its limited runway of $17.5 Mn leaves it operational funding through Q1 2026, and so it has a high need for a partner or additional funding to continue development of Halneuron (and its two antiviral molecules in fibromyalgia and long-covid).
Latigo Biotherapeutics
Latigo was incubated by venture firm Westlake Village BioPartners, which led a $135 million series A funding in February 2024, followed by a $150 million series B in March 2025 (Link). Following Journavx’s approval, there was significant interest from four investors, with an additional eight funds supporting the financing.
Latigo is working on several Nav1.8 inhibitors; 1 has completed a Phase 1 trial, whilst another is ready to start Phase 1 (Link). The molecules are orally administered, although at this stage it is not clear if Latigo plans to administer daily like STC-004 or twice daily like Journavx. LTG-001 has been awarded Fast Track Designation by the FDA (Link)
A Phase 2 study in patients with pain after the removal of the third molar by surgery is currently recruiting (Link). However, given its long time active, multiple pushbacks on completion time (originally intended for 31 May 2024), and lack of discussion in investor articles, it is unclear how the trial is progressing.
Instead, in more recent releases, the company has focused its messaging on LTG-305, which it claims is a “potential best-in-class”. It does not elaborate on what might make it a best-in-class, and with a lack of published data, it is hard to substantiate this beyond marketing hype. I may be proven wrong, and Latigo may have compelling preclinical data showing superiority over suzetrigine, but we’ll have to see!
AlgoTherapeutix
AlgoTherapeutix is a French-based biotech that was formed in 2018 (Link). It raised €2.6 million in seed capital in 2019 and €12 million in a Series A round in 2020 (Link). The company is led by founder/CEO Stéphane Thiroloix, who brings executive vice president experience from Ipsen alongside roles at other med tech and biotech companies.
Algo is developing a topical sodium inhibitor that combines the active ingredient amitriptyline with a bespoke proprietary topical formulation (Link). This blocks Nav1.7, Nav1.8, and Nav1.9, providing a broader effect than the mono channel targeting products.
The topical formulation is chosen due to the limited efficacy of oral AMT on peripheral neuropathic pain and the rate-limiting side effects. Algo hopes that by applying topically, it can reach the peripheral sensory neurons in the skin.
In February of this year, AlgoTx announced Ph2 results from its CIPN trial in 276 patients, ‘ACT’. Encouraging signals were seen for the 15% concentration formulation. However, a strong placebo effect occurred in the trial at specific sites, which meant the primary endpoint was not met. A post-hoc analysis in “low-placebo” sites did show statistical significance for a 15% concentration dose, which Stéphane Thiroloix claimed will be used to inform future trial design (Link).
As of June 2025, there has been no update on next steps for the molecule.
Who is the most promising?
These three companies provide slightly different options to commercial pharmaceutical companies interested in partnering on development or outright acquisition.
Latigo is treading a similar path to Journavx with its Nav1.8 molecules. Still, by the time it reaches the market, it will likely also have Lilly as a competitor who will have benefited from Vertex’s groundwork, and bring a slight convenience advantage with its once-daily dose. This would see Latigo’s molecules 3rd to market, needing to differentiate on efficacy or by targeting indications that the other molecules have not expanded into. For the more risk-averse executive that is happy launching a 3rd or 4th to market and taking a slice of the competitors’ pie, Latigo is probably the safest bet, with the ability to conduct Phase 2 trials in similar populations to Vertex, and/or identify niche pain indications it has not yet received approval in.
Dogwood and AlgoTx are differentiated from Journavx in terms of target and method of administration. Still, given the historic attrition of targeting Nav1.7 and the muddy Ph2 results for ATX01, both are riskier bets. However, given their lower levels of funding, it may be easier to get a good deal on either of these companies, with the upside being a well-differentiated molecule in CIPN, an indication with a large unmet need that Vertex has not yet expanded into.
Overall, all 3 provide compelling pros and cons, and deeper discussions will be needed with leadership to see proprietary data (especially any info from Latigo on superiority vs Journavx in animal models).
Wrap up
With conditions like nociplastic pain, mixed neuropathic and central pain, post-stroke, and neurological lesion pain, there are still plenty of unmet needs to address with new therapeutics in pain. Understanding the complexities of these conditions and how they can be potentially treated will require continued research and trials, but with a valuable outcome at the end.
We hope to see some of the therapies above continue to progress to provide more options to patients suffering from different types of pain and lessen the burden of opioids.
This was a slightly longer deep dive than I usually write, so if you found it helpful or interesting, it would be great to hear your feedback at sv@sivan-consulting.com or by connecting with me on LinkedIn.