FDA Clears Pilavapadin for Phase 3 Development in Diabetic Peripheral Neuropathic Pain

According to a recent company update, Lexicon Pharmaceuticals completed an End-of-Phase 2 meeting with the FDA to advance pilavapadin, an investigational agent, as a potential treatment for diabetic peripheral neuropathic pain (DPNP). The agency had no concerns over the phase 3 program, which will include two 12-week, placebo-controlled studies evaluating a 10-mg daily dose versus placebo, using change in average daily pain score (ADPS) over a 12-week period as the primary end point.¹

“People with DPNP are desperately in need of new treatment options. This progress puts Lexicon one step further toward making pilavapadin the first non-opioid DPNP medicine available to patients in over two decades. That’s why we are very pleased that the End-of-Phase 2 meeting with FDA was productive and provided us with the insights needed to design a robust Phase 3 program,” Craig Granowitz, MD, PhD, senior vice president and chief medical officer at Lexicon, told NeurologyLive^®.

Previously reported topline data from the phase 2b PROGRESS study (NCT06203002), a large-scale study of nearly 500 participants, demonstrated that treatment with pilavapadin led to reductions in pain compared with placebo in adults with moderate to severe DPNP.² Along with findings from the earlier RELIEF-DPN-1 study (NCT04455633), these results supported selecting a 10-mg once-daily dose for advancement into phase 3 trials.

PROGRESS included 496 patients with a diagnosis of diabetes and moderate to severe DPNP who received once daily pilavapadin doses of 10 mg, 20 mg, or 20 mg for 7 days followed by 10 mg thereafter. On the primary end point of change in ADPS, patients in the 10 mg, 20 mg/10 mg, and 20 mg dose arms achieved reductions of 1.74, 1.70, and 1.38, respectively, over the 8-week treatment period. In comparison, those on placebo demonstrated reductions of 1.31 in ADPS.

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In the study, the difference in ADPS reduction between the 20 mg dose arm and placebo did not reach statistical significance (P = .011); however, the trial was primarily conducted to detect a dose-response signal. In contrast, the 10 mg dose arm displayed clear evidence of effect by achieving early and clinically meaningful separation from placebo on ADPS that was maintained throughout the study duration.

In terms of safety, adverse events (AEs) occurred more frequently in the pilavapadin treatment arms compared to the control, though their incidence improved notably across all doses compared with the RELIEF-DPN-1 study. The majority of AEs were categorized as mild or moderate, with the 20 mg dose showing the highest rate of AEs, and the 10 mg dose considered well-tolerated. Dizziness and nausea were the most commonly reported AEs and were the leading reasons for patient discontinuation, primarily observed in the 20 mg dose group.

The decision to move forward with the 10 mg dose was finalized based on findings from PROGRESS; however, the initial idea first came from the previously conducted RELIEF DPN-1 trial. This double-blind, placebo-controlled, parallel-group study enrolled 319 patients with DPNP across 45 sites in the United States, assessing 2 dosing regimens of pilavapadin (an initial single dose of 100 mg followed by once-daily doses of 10 mg or an initial single dose of 200 mg followed by once-daily doses of 20 mg) against matching placebo (n = 107).

Over the 6-week treatment period, patients in the low- and high-dose arms of pilavapadin demonstrated reductions of 1.39 (P = .007 vs placebo) and 1.27 points (P = .030 vs placebo) on the primary end point of ADPS, compared with reductions of 0.72 points in the placebo arm. Under the statistical analysis plan for the study, a P-value of less than 0.028 was considered statistically significant.³

In RELIEF-DPN1, treatment benefit was observed beginning at week 1 and maintained thereafter. Most common AEs affiliated with pilavapadin were dizziness, nausea and headache. Notably, more participants who received active treatment (20 mg: 26.4%; 10 mg: 16.0%) than placebo (2.8%) discontinued study drug prematurely because of AEs. Serious AEs were uncommon, occurring in 2 patients in the 20 mg group, 0 patients in the 10 mg group, and 1 in the placebo group.

REFERENCES
1. Lexicon Pharmaceuticals Announces Successful End-of-Phase 2 Meeting with FDA For Pilavapadin in the Treatment of Diabetic Peripheral Neuropathic Pain. News release. Lexicon Pharmaceuticals. January 21, 2026. Accessed January 26, 2026. https://investors.lexpharma.com/news-releases/news-release-details/lexicon-pharmaceuticals-announces-successful-end-phase-2-meeting
2. Lexicon Pharmaceuticals Announces Topline Results from Phase 2b PROGRESS Study Evaluating Pilavapadin (LX9211) in Adults with Diabetic Peripheral Neuropathic Pain. News release. Lexicon Pharmaceuticals. March 3, 2025. Accessed January 26, 2026. https://investors.lexpharma.com/news-releases/news-release-details/lexicon-pharmaceuticals-announces-topline-results-phase-2b
3. Pop-Busui R, Patel A, Sang C, et al. Efficacy and Safety of LX9211 for Relief of Diabetic Peripheral Neuropathic Pain (RELIEF-DPN 1): Results of a Double-Blind, Randomized, Placebo-Controlled, Proof-of-Concept Study. Diabetes Care. 2024;47(8):1325-1332. doi:10.2337/dc24-0188