Lexicon Pharmaceuticals Advances Pilavapadin Towards Potential FDA Approval for Diabetic Peripheral Neuropathic Pain
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Pilavapadin, an investigational non-opioid treatment developed by Lexicon Pharmaceuticals, is one step closer to becoming a reality for the millions suffering from diabetic peripheral neuropathic pain (DPNP) after a productive End-of-Phase 2 meeting with the Food and Drug Administration (FDA). The agency indicated no major concerns regarding the proposed Phase 3 program, paving the way for pivotal trials to begin.
A New Hope for DPNP Sufferers
“People with DPNP are desperately in need of new treatment options,” stated a senior official at Lexicon Pharmaceuticals. “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.” DPNP, a debilitating condition affecting approximately half of all people with diabetes, currently lacks effective, non-addictive treatment options.
Promising Phase 2 Data Supports Advancement
The positive FDA feedback follows encouraging results from the Phase 2b PROGRESS study (NCT06203002), which involved nearly 500 participants with moderate to severe DPNP. Data revealed that pilavapadin treatment led to measurable reductions in pain compared to placebo. These findings, coupled with data from the earlier RELIEF-DPN-1 study (NCT04455633), solidified the selection of a 10-mg once-daily dose for the upcoming Phase 3 trials.
PROGRESS Study Details
The PROGRESS study evaluated three pilavapadin dosages – 10 mg, 20 mg, and 20 mg for a week followed by 10 mg – against a placebo control group. Over an eight-week period, patients receiving the 10 mg dose experienced an average reduction of 1.74 points on the change in average daily pain score (ADPS), a key metric for assessing pain relief. The 20 mg and 20 mg/10 mg arms showed reductions of 1.70 and 1.38 points, respectively, while the placebo group experienced a reduction of 1.31 points.
While the 20 mg dose arm showed a trend toward improvement, the difference in ADPS reduction did not reach statistical significance (P = .011). Researchers noted the trial was designed primarily to assess dose-response. The 10 mg dose, however, demonstrated a clear and sustained separation from the placebo group throughout the study duration.
Safety Profile and Tolerability
Although adverse events (AEs) were reported more frequently in the pilavapadin treatment groups compared to placebo, the incidence of these events was lower than observed in the RELIEF-DPN-1 study. Most AEs were mild to moderate in severity. The 20 mg dose was associated with a higher rate of AEs, while the 10 mg dose was generally well-tolerated. Dizziness and nausea were the most commonly reported AEs and the primary reasons for study discontinuation, particularly within the 20 mg dose group.
RELIEF-DPN-1: Laying the Groundwork
The decision to prioritize the 10 mg dose was initially informed by the results of the RELIEF-DPN-1 trial. This earlier study, conducted across 45 sites in the United States and involving 319 patients with DPNP, assessed two pilavapadin regimens against placebo. Patients receiving the lower dose of pilavapadin (100 mg initial dose followed by 10 mg daily) experienced a reduction of 1.39 points on the ADPS (P = .007 vs placebo), while those on the higher dose (200 mg initial dose followed by 20 mg daily) saw a reduction of 1.27 points (P = .030 vs placebo). The placebo group experienced a reduction of 0.72 points. A P-value of less than 0.028 was considered statistically significant for the study.
Notably, treatment benefit in RELIEF-DPN-1 was observed as early as week one and continued throughout the six-week treatment period. Similar to the PROGRESS study, dizziness, nausea, and headache were the most common AEs reported, and a higher proportion of participants receiving active treatment discontinued due to AEs compared to those receiving placebo.
Looking Ahead: Phase 3 Trials and Potential Market Impact
The upcoming Phase 3 program will consist of two 12-week, placebo-controlled studies, evaluating the 10-mg daily dose of pilavapadin against placebo, with change in ADPS serving as the primary endpoint. If successful, pilavapadin could represent a significant advancement in the treatment of DPNP, offering a much-needed non-opioid alternative for patients struggling with this chronic and debilitating condition. .
References
- 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
- 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
- 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
