Pilavapadin Heads for Phase 3 Trial Following Positive PROGRESS Study of Neuropathic Pain

Rodica Pop-Busui, MD, PhD

Newly announced data from the phase 2b PROGRESS study (NCT06203002) showed that treatment with investigational pilavapadin (Lexicon Pharmaceuticals) resulted in noticeable reductions in pain relative to placebo in adults with moderate to severe diabetic peripheral neuropathic pain (DPNP). These findings, coupled with data from the previously conducted RELIEF-DPN-1 study (NCT04455633), identified 10 mg once daily as an appropriate dose to advance into phase 3 development for DPNP.¹

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 average daily pain score (ADPS), patients in the 10 mg, 20mg/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.

Overall, the difference in ADPS reduction between the 20 mg dose arm and placebo did not reach statistical significance (P = .011); however, the study 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.

"DPNP is a complex and highly prevalent complication of diabetes which severely impacts quality of life. People with DPNP often cycle through multiple treatments without adequate relief, and they and their health care providers are in dire need of new, non-opioid treatment options," principal investigator Rodica Pop-Busui, MD, PhD, Jordan Schnitzer Chair in Diabetes and clinical nutrition director of the Harold Schnitzer Diabetes Center, Oregon Health & Science University, said in a statement. "The results of the PROGRESS 2b study provide further evidence that AAK1 inhibition may provide an alternative treatment option to opioid use, offering clinically meaningful reductions in pain and the potential for pilavapadin to fill a critical gap in DPNP care."

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 to the RELIEF-DPN-1 study. The majority of AEs were categorized as mild or moderate. The 20 mg dose showed the highest rate of AEs, while the 10 mg dose was generally 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.

"We are very encouraged by the topline results from the PROGRESS Phase 2b study, which give us great confidence in Phase 3 development of the 10 mg dose for DPNP," Mike Exton, PhD, chief executive officer and director at Lexicon, said in a statement. "The neuropathic pain market represents a multibillion-dollar opportunity that is primed for innovative treatments. With these results, we firmly believe that pilavapadin has the opportunity to become the first oral non-opioid treatment approved in neuropathic pain in 20 years. The enormous potential of this investigational medicine has generated significant interest from potential partners, and we intend to accelerate these discussions while we plan for Phase 3 development."

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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.²

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 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 March 5, 2025. https://www.globenewswire.com/news-release/2025/03/03/3035469/0/en/Lexicon-Pharmaceuticals-Announces-Topline-Results-from-Phase-2b-PROGRESS-Study-Evaluating-Pilavapadin-LX9211-in-Adults-with-Diabetic-Peripheral-Neuropathic-Pain.html
2. 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