Lexicon Pharmaceuticals (LXRX) Study Update summary

Study background and unmet need

• Diabetic peripheral neuropathic pain (DPNP) affects about 25% of diabetes patients, with approximately 9 million in the U.S. as of 2024.

• No innovative DPNP treatments have been introduced in the past 20 years, and 60% of patients have tried multiple therapies.

• Pilavapadin (LX9211) is a novel, oral, non-opioid AAK1 inhibitor developed for neuropathic pain, with nearly 600 DPNP patients treated to date.

• Pilavapadin has received FDA Fast Track designation for DPNP.

Study design and objectives

• The phase IIb PROGRESS study enrolled 496 adults with type 1 or type 2 diabetes and moderate to severe DPNP, using a placebo-controlled design with three dosing regimens over eight weeks after a two-week placebo run-in.

• Patients could continue a stable non-opioid DPNP medication during the trial, reflecting real-world use, and enrollment exceeded targets.

• The primary goal was to identify a single dose for phase III with meaningful pain reduction and improved tolerability, eliminating the day-one loading dose used in prior studies.

• The primary endpoint was change from baseline to week 8 in average daily pain score (ADPS) compared to placebo; secondary endpoints included burning pain and pain interference on sleep.

• The statistical plan aimed to detect a dose-response signal, assuming all active arms would separate from placebo in pain reduction.

Key efficacy and safety results

• The 10 mg dose showed a 1.74-point reduction in ADPS from baseline at week 8, compared to 1.31 for placebo, demonstrating meaningful separation.

• The 10 mg dose demonstrated early and sustained separation from placebo throughout the study, with completion rates for 10 mg (87.8%) similar to placebo (87.9%).

• The 20 mg arm did not outperform placebo, likely due to higher dropout rates and lower adherence, leading to the primary endpoint not being met.

• Removal of the loading dose markedly improved tolerability, especially in the 10 mg arm, with overall discontinuation rates and TEAEs low and similar to placebo.

• Dizziness and nausea were the main adverse events causing discontinuation, most frequent in the 20 mg arm; nearly all adverse events were mild or moderate.