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Novel Pain Therapy Addresses the Complex Pathway of Painful Diabetic Neuropathy

Dr. Craig Granowitz of Lexicon Pharmaceuticals details the success of the LX9211 clinical trial for painful diabetic neuropathy and the unique study design.

Data which assessed a novel painkiller LX9211 has gained traction throughout September with presentations at PAINWeek 2022 National Conference on Pain Management and IASP World Congress on Pain. The therapeutic cadidate has displayed promising results for the treatment of neuropathic pain without any involvement in the opioid pathway.

The clinical trial (RELIEF-DPN 1) utilized a unique study design while investigators evaluating its impact on patients with painful diabetic neuropathy. The full framework and analysis of the resutls will also be presented at Arrowhead's Annual Pain Therapeutics Summit in Washington DC on November 14.

Craig Granowitz, MD, Chief Medical Officer and Senior Vice President of Lexicon Pharmaceuticals was excited to discuss the potential that LX9211 has on pain management, an area of medicine that has been impeded by various obstacles for decades.

"Most of the other agents had been identified through serendipity—these were agents that had already been established for other uses and then were identified in a post marketing, or in a later stage of development, as potentially having an impact on pain," Granowitz explained in an interview with HCPLive.

Part of what differentiates the drug candidate from current treatments is the intentional approach of its development and the 15-year journey which has showed a distinct pain state separating LX9211 from other approved neuropathic pain agents.

"If you look at the story of LX9211, that actually started based on a knockout mouse model that identified a phenotype of pain resistance, and then developing an understanding of that knockout gene, the mechanism of that gene, and then developing a specific oral inhibitor of that gene that mimicked the phenotype initially seen in mice," he continued. "Then bringing that forward into humans, demonstrating that this particular drug candidate can be delivered safely and effectively."

The pathway of neuropathic pain is very complex, and while current treatments like gabapentin and tricyclic antidepressants provide relief, Granowitz said that they come with a liability of adverse events. Furthermore, the complications associated with opioid use has been apparent in long-term opioid patients and on a societal level, as well.

"We found in that, that this alpha adrenergic, what's called the off adrenergic neuron pathway, which sort of runs from the periphery of your body into the spinal cord, was specifically inhibited by this LX9211 compound through a gene target called AAK1," he said. "Now, this is the first and most advanced AAK1 that's in development."

Adaptor-associated protein kinase 1 (AAK1) inhibitors have been investigated before, but Granowitz explained that LX9211 is the only one active at this time. He's hopeful that the promising results demonstrated by this research "re-energizes" other neuropathic pain programs that were previously done, to take a closer look at the neuropathic pathway of pain

"Nothing creates change in a field like having a successful drug," he said. "We see that over and over again, is that one innovation breaks a dam open, and that there's a lot of additional innovation, and then there's significant movement forward in a field."