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Nonopioid Analgesic Pilavapadin Advances to Phase 3 for Diabetic Neuropathy
The investigational once-daily oral analgesic, a potent inhibitor of a novel target for neuropathic pain, achieved meaningful pain reduction vs placebo.
The investigational nonopioid analgesic pilavapadin (LX9211) demonstrated meaningful pain reduction and favorable tolerability at a 10 mg dose in adults with moderate to severe pain from diabetic peripheral neuropathic pain (DPNP) in the the phase 2b PROGRESS trial, according to topline results announced by Lexicon Pharmaceuticals.1
The 10 mg dose achieved an average daily pain score (ADPS) reduction of 1.74 points from baseline to week 8, compared with 1.31 points in the placebo group. Based on these findings and prior data from the phase 2 RELIEF-DPN-1 study, Lexicon will advance the 10 mg dose into phase 3 development for DPNP.
While the study’s statistical analysis plan required all treatment arms to show separation from placebo, the 20 mg dose arm failed to meet this threshold (P =.11). However, the 10 mg dose demonstrated early and sustained pain reduction, supporting its progression to late-stage trials, the company stated.1
The US FDA previously granted granted fast-track status to the therapy for development in treating DPNP.2
PROGRESS. The study enrolled 496 adults with a diagnosis of type 1 or type 2 diabetes experiencing moderate to severe DPNP, with patients remaining on stable doses of existing neuropathic pain therapies such as gabapentin, pregabalin, or duloxetine. Investigators evaluated 3 dosing regimens: 10 mg once daily, 20 mg once daily, or 20 mg for 1 week followed by 10 mg daily. An initial loading dose, used in the RELIEF-DPN-1 study, was removed to improve tolerability, according to Lexicon.1
Pilavapadin, an oral inhibitor of adaptor-associated kinase 1 (AAK1), was generally well tolerated, with improved safety over the prior RELIEF-DPN-1 study. Adverse events, predominantly dizziness and nausea, were mostly mild to moderate and occurred more frequently at the 20 mg dose.
RELIEF-DPN. The efficacy, safety, and pharmacokinetics of pilavapadin in DPNP were evaluated in the phase 2a proof of concept RELIEF-DPN study (n = 319), which evaluated 2 dosing regimens – the initial loading dose of 100 mg followed by 10 mg daily or a loading dose of 200 mg followed by 20 mg daily, the company detailed. The lower-dose arm achieved a significant reduction in average daily pain score from baseline as did the higher dose; the loading dose, however, led to tolerability issues, leading to the decision to remove it from the PROGRESS study.1
“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,” Rodica Pop-Busui, MD, PhD, lead investigator of the PROGRESS study, said in the Lexicon news release. “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.”1
“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,” Mike Exton, PhD, CEO of Lexicon, stated.
The full PROGRESS study results will be submitted for presentation at an upcoming medical conference and for publication in a peer-reviewed journal.1
