Pilavapadin

Lexicon Pharmaceuticals’ non-opioid drug has failed a mid-stage test in a chronic pain indication — but the company says there’s still a path forward and even potential partnership opportunities for the lower dose. The biotech’s AAK1 inhibitor, dubbed pilavapadin, did not meet the primary endpoint of change from baseline in average daily pain score (ADPS) at eight weeks in the Phase 2b PROGRESS trial in moderate to severe diabetic peripheral neuropathic pain (DPNP). The condition develops when high blood sugar levels damage nerves throughout the body, causing pain and numbness. The primary endpoint miss was driven by a “lack of separation” between the 20 mg dose and placebo, according to a Monday release. The 10 mg pilavapadin dose, meanwhile, demonstrated “early and clinically meaningful separation from placebo” in ADPS, which was maintained throughout the trial, Lexicon said. But the trial technically still failed because its primary endpoint was designed to detect a “dose-response signal” that assumed separation from placebo across all treatment cohorts. Detailed results from PROGRESS will be presented at an upcoming medical meeting. Lexicon’s share price $LXRX plummeted around 29% premarket Monday. The Texas biotech still plans to advance the 10 mg dose into Phase 3 based on PROGRESS as well as a previous mid-stage study called RELIEF-DPN-1. The RELIEF-DPN-1 trial tested 10 mg and 20 mg of pilavapadin given after initial loading doses of 100 mg and 200 mg, respectively. By contrast, the PROGRESS trial did not feature a loading dose. In RELIEF-DPN-1, the 10 mg arm met the ADPS primary endpoint at six weeks versus placebo but the 20 mg arm “narrowly missed statistical significance.” In RELIEF-DPN-1, both treatment arms were also negatively impacted by tolerability issues due to the high-loading doses. But in PROGRESS, the 10 mg dose was well tolerated with most side effects being mild or moderate. “The enormous potential of [pilavapadin] has generated significant interest from potential partners, and we intend to accelerate these discussions while we plan for Phase 3 development,” Lexicon CEO Mike Exton said in the Monday release. He added that the neuropathic pain market represents a “multibillion dollar opportunity.” Pilavapadin took center stage for Lexicon in November when the company got rid of its commercial team and switched tack to focus on clinical development. That decision came on the heels of regulatory setbacks for its type 1 diabetes and chronic kidney disease drug sotagliflozin, which faced two rejections from the FDA in the span of five years. In 2022, pilavapadin failed a Phase 2 study in patients with postherpetic neuralgia, a rare side effect of shingles. Editor’s Note: This article was updated to add information about Lexicon’s share price.

Shares in Lexicon Pharmaceuticals crashed over 58% on Monday after its diabetes pain drug candidate pilavapadin (LX9211) missed statistical targets in a mid-stage trial, despite showing a better side-effect profile than in an earlier study. However, the company still plans to advance the drug's lowest dose into final-stage testing.The PROGRESS study tested the oral non-opioid AAK1 inhibitor in 496 adults with diabetic peripheral neuropathic (DPN) pain, evaluating doses of 10 mg, 20 mg, and a 20 mg/10 mg step-down regimen. The treatments led to reductions in average daily pain scores (ADPS) of 1.74, 1.38, and 1.70, respectively, compared to 1.31 for placebo.The study's statistical analysis plan was designed to detect a dose-response signal across all treatment arms from baseline to week eight, but the 20-mg arm's underperformance caused the study to miss statistical significance on its primary endpoint.Removal of loading doseBut unlike the earlier Phase II RELIEF-DPN-1 study, which included problematic 10-fold loading doses on day 1, PROGRESS eliminated the loading dose strategy that had contributed to tolerability problems. Specifically, the loading dose had led to higher rates of dizziness, nausea and headache in RELIEF-DPN-1 that appeared to be related to both dose and treatment duration. The majority of events occurred early in treatment."The tolerability concerns observed in the RELIEF study can now be conclusively ascribed to the loading dose administered on day one," said CEO Mike Exton during Monday's investor call."In both studies [PROGRESS and RELIEF-DPN-1], there is a rapid early separation from placebo with the 10-mg arm that continues throughout the treatment duration," noted Chief Medical Officer Craig Granowitz. "This is particularly notable in PROGRESS, where the placebo response was nearly double that of RELIEF, and yet there is still a rapid and clinically meaningful separation from placebo in progress."Nearly all adverse events in PROGRESS were reported as mild or moderate. Although Granowitz suggested that the "likely explanation" for the lack of separation in the 20-mg arm "is that side effects, such as dizziness, led to a higher dropout rate, and potentially also a lower treatment adherence in those who remained in the study."Scouting for partnersThe setback follows Lexicon's recent struggles to get type 1 diabetes drug Zynquista (sotagliflozin) off the ground, adding pressure on its pipeline. During the investor call, Exton pointed out that pilavapadin's "enormous potential" has generated significant interest from potential partners and that the company is "in active partnership discussions" while preparing for Phase III development.Meanwhile, the company faces competition from Vertex Pharmaceuticals, which recently received FDA approval for the oral NaV1.8 inhibitor Journavx (suzetrigine) in acute pain and is currently enrolling a 1100-patient Phase III study of the drug in DPN pain. The FDA nod marks the first step towards Vertex's goal of making pain medications its next multi-billion-dollar franchise.A January note from Jefferies analysts highlighted that Vertex's separate Phase II DPN pain study of VX-993, a next-generation NaV1.8 inhibitor, has enrolled 192 patients.