Amitriptyline Hydrochloride

AlgoTherapeutix’s topical non-opioid drug has flunked a mid-stage trial in chemotherapy-induced pain due to a stronger-than-expected placebo arm, but the company is still determined to find a path forward. The Paris-based biotech’s ATX01 did not significantly reduce pain versus placebo in the Phase 2 ACT study of 276 patients with chemotherapy-induced peripheral neuropathy. The drug achieved an improvement of around 1.5 points from baseline on the numerical pain rating scale, which was “completely comparable” to placebo, CEO Stéphane Thiroloix told Endpoints News in an interview. Algo was aiming for a delta of around one point between treatment and placebo but an overperforming placebo arm prevented that from transpiring, Thiroloix said. It’s unclear exactly what drove the strong placebo results at certain trial sites, he added. “It may have to do with how patients interact with the site; it may be that it could be random, but then it’s very surprising that you don’t have a mirror effect between low [performing] and high [performing] placebo sites,” Thiroloix said. Even so, the company believes it still has a case for further development of ATX01. In a post hoc analysis that only included low-performing placebo sites, the 15% concentration of the drug demonstrated “statistically significant superiority to placebo” in most primary and secondary endpoints, according to a Tuesday release . The candidate was also well tolerated with most side effects being local, transient and reversible dermatological events. Algo plans to conduct another double-blind study in the same population focusing on the 15% concentration of ATX01 and featuring design elements to “help minimize the background noise of placebo effect,” Thiroloix said. This could include a placebo run-in phase or an enrichment design. “Whether [the trial] is a Phase 2 or Phase 3 study will really be a matter of debate with FDA going forward,” Thiroloix added. The company closed a €20M Series B raise two years ago to fund the Phase 2 study. Algo will discuss the Phase 2 data with “potential partners” whom it has been in discussions with for two years, Thiroloix said. Based on the outcomes of these talks, Algo will decide whether to “team up” for further development or potentially raise more cash and go it alone, he added. ATX01 is a topical formulation of the tricyclic antidepressant amitriptyline, which inhibits the activity of sodium channels. In January, Vertex’s sodium channel blocker Journavx won FDA approval for moderate-to-severe acute pain.

iStock, ALLVISIONN AlgoTherapeutix blames a “strong placebo effect” for the mid-stage failure for its pain gel ATX01, but the company still believes in the promise of its candidate as Vertex Pharmaceuticals’ first-in-class drug Journavx opens up the non-opioid space. Just over a week after the landmark approval of Vertex Pharmaceuticals’ non-opioid pain drug Journavx, AlgoTherapeutix has suffered a setback in the space, with its investigational topical analgesic therapy ATX01 failing to significantly ease pain in patients suffering from chemotherapy-induced peripheral neuropathy. The Paris-based biotech said Tuesday that ATX01 showed “encouraging” efficacy signals, especially when given at the higher, 15% concentration dose. However, several study sites documented what CEO Stéphane Thiroloix in a statement called a “strong placebo effect,” which in turn prevented ATX01’s benefit from hitting statistical significance. Posthoc analyses of the study’s data showed that in trial centers with low placebo effect, 15% ATX01 elicited significantly better pain relief than placebo. Despite the lack of a significant response, Thiroloix called Tuesday’s readout “a significant step forward” for ATX01, pointing to promising signals of efficacy, such as the 1.6-point pain improvement, as measured by the Numerical Pain Rating Scale. ATX01 was also superior to placebo in terms of key secondary endpoints in posthoc analyses. Designed to be applied topically, ATX01 is a proprietary formulation of amitriptyline , an antidepressant that has been approved by the FDA in a tablet form to treat depression. AlgoTx’s version, however, leverages the non-systemic application of amitriptyline, which potentially dampens or blocks pain signaling locally, focusing on nerve fibers in the skin. Though it did not specifically spell out its future plans for ATX01, AlgoTx in its news release on Tuesday seemed to still believe in the promise of its candidate in chemotherapy-induced peripheral neuropathy. The company “sees a strong rationale to further explore the development of ATX01 15%,” AlgoTx noted, adding that it can look at other trial designs to minimize or even eliminate the placebo effect, such as enrichment/withdrawal strategies or a placebo run-in period. “There is the potential to design a new study, with additional mitigation strategies in place, to evaluate ATX01’s efficacy . . . without ambiguity,” Thiroloix said. BioSpace has reached out to AlgoTx for more clarity on ATX01’s path forward and will update this story accordingly. AlgoTx was previously testing ATX01 for erythromelalgia—a rare vascular condition that affects the extremities and causes intense pain—but according to the biotech’s website , a readout last year returned underwhelming data, forcing the biotech to discontinue the asset’s development in this indication. AlgoTx is also running early studies for ATX01 in painful diabetic peripheral neuropathy, COVID-induced neuropathy and phantom limb pain. AlgoTx’s mid-stage stumble on Tuesday comes after Vertex earlier this month won the FDA’s approval for Journavx, an inhibitor of the NaV1.8 voltage-gated sodium channel that marks the first new mechanism for analgesia in over 20 years—and potentially offering the U.S. a way out of its opioid crisis. According to data from the National Institute on Drug Abuse, nearly 74,000 people died from an overdose of synthetic opioids in 2022. Meanwhile, the Centers for Disease Control and Prevention estimated that the cost of opioid use disorder and related fatalities reached over $1 trillion in 2017. And Journavx may be only the beginning for this new class of pain medicines as several other biotechs seek to follow in Vertex’s footsteps. Lexicon, Algiax, Xgene and Tris Pharma are among those with non-opioid candidates in mid- to late-stage trials, for example. Meanwhile, newcomer Latigo Bio, which launched in February 2024 with $135 million in starting funds to advance its own oral NaV1.8 blocker LTG-001 and is now launching a Phase II trial , said in Friday SEC filing stated that it is now targeting up to $150 million in new funding.