Abstract Details

Title Suzetrigine, a Selective Pain Signal Inhibitor of NaV1.8 Shows Proof-of-concept for Treatment of Painful Diabetic Peripheral Neuropathy

Topic Pain

Presentation(s) S11 - Pain (11:27 AM-11:39 AM)

Poster/Presentation
Number 002

Background Painful DPN, a peripheral neuropathic pain condition, has an unmet need for novel analgesics given limitations of standard-of-care (pregabalin, duloxetine), including inadequate pain relief and adverse effects (e.g., somnolence, dizziness, nausea). Suzetrigine is an oral, small molecule, non-opioid, highly selective pain signal inhibitor of Na_V1.8. Na_V1.8 is critical in transmitting nociceptive signals, is selectively expressed on peripheral nociceptors and within dorsal root ganglia and not expressed in the brain; based on mechanism-of-action, suzetrigine has no addictive potential.

Objective To evaluate suzetrigine for painful diabetic peripheral neuropathy (DPN) treatment.

Design/Methods This ph2, randomized, double-blind, active-controlled study enrolled adults (N=192) with painful DPN and weekly average of daily numeric pain rating scale ≥4 (NPRS; range, 0-10). Participants received suzetrigine once daily at 69mg (high-dose), 46mg (mid-dose), or 23mg (low-dose), or 100-mg pregabalin (active reference group) three times daily for 12wks, supporting the evaluation of suzetrigine’s treatment effect. The primary endpoint was change from baseline in the weekly average of daily pain intensity on NPRS at Wk12. Secondary endpoints included safety. P values are nominal.

Results

Suzetrigine treatment met the primary endpoint with statistically significant and clinically meaningful mean reductions from baseline in pain intensity on NPRS at Wk12: -2.26 (95%CI:-2.82,-1.70; P<0.0001), -2.11 (95%CI:-2.67,-1.55; P<0.0001) and -2.18 (95%CI:-2.94,-1.41; P<0.0001) in the high-, mid-, and low-dose groups. For context, mean change from baseline in NPRS at Wk12 with pregabalin was -2.09 (95%CI:-2.65,-1.52; P<0.0001). All suzetrigine dose groups had sustained mean reductions in pain from baseline starting at Wk1; pain continued to decrease until Wk5, which was maintained through Wk12. Suzetrigine was safe and well-tolerated with most AEs mild or moderate in severity; there were no serious AEs related to suzetrigine.

Conclusions These results provide proof-of-concept for selective Na_V1.8 inhibition with suzetrigine as an analgesic approach in DPN, supporting further evaluation of suzetrigine for DPN treatment in ph3.

Authors/Disclosures
Roy L. Freeman, MD (Beth Israel Deaconess Hosp) PRESENTER	Dr. Freeman has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regenacy. Dr. Freeman has received personal compensation in the range of $100,000-$499,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurobo. Dr. Freeman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Vertex. Dr. Freeman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli-Lilly. Dr. Freeman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Theravance. Dr. Freeman has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Inhibikase. Dr. Freeman has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Freeman has stock in Neurobo. Dr. Freeman has stock in Cutaneous NeuroDiagnostics. The institution of Dr. Freeman has received research support from NIH. The institution of Dr. Freeman has received research support from Theravance. The institution of Dr. Freeman has received research support from Biohaven. The institution of Dr. Freeman has received research support from Lundbeck.
Richard Rauck, MD	Dr. Rauck has nothing to disclose.
Charles E. Argoff, MD (Albany Medical Center)	Dr. Argoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nevro. Dr. Argoff has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for XGene. Dr. Argoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex. Dr. Argoff has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Scilex. Dr. Argoff has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Colllegium. Dr. Argoff has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Vertex. Dr. Argoff has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Allergan/Abbvie. Dr. Argoff has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Lundbeck. Dr. Argoff has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Scilex. Dr. Argoff has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Scilex. The institution of Dr. Argoff has received research support from Lilly. The institution of Dr. Argoff has received research support from Lundbeck. The institution of Dr. Argoff has received research support from Abbvie. The institution of Dr. Argoff has received research support from Vertex. Dr. Argoff has received publishing royalties from a publication relating to health care.
Simon Tian, MD	Dr. Tian has nothing to disclose.
Xiaopeng Miao, PhD	Dr. Miao has received personal compensation for serving as an employee of Vertex Pharmaceulticals. Dr. Miao has stock in Vertex Pharmaceulticals. Dr. Miao has stock in Biogen .
Hannah Bouldin Olivet, MD	Dr. Bouldin Olivet has received personal compensation for serving as an employee of Vertex. Dr. Bouldin Olivet has stock in Vertex.
Carmen Bozic, MD	Dr. Bozic has received personal compensation for serving as an employee of Vertex Pharmaceuticals. Dr. Bozic has stock in Vertex Pharmaceuticals.
Robert H. Dworkin, PhD (University of Rochester School of Medicine and Dentistry)	Robert H. Dworkin, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia, Akigai, Allay, AM-Pharma, Analgesic Solutions, Beckley, Biogen, Biosplice, Bsense, Cardialen, Chiesi, Clexio, Collegium, CombiGene, Confo, Contineum, Eccogene, Editas, Eli Lilly, Emmes, Endo, Epizon, Exicure, GlaxoSmithKline, Glenmark, Gloriana, JucaBio, Kriya, Mainstay, Merck, Mind Medicine, NeuroBo, Noema, OliPass, Orion, Oxford Cannabinoid Technologies, Pfizer, Q-State, Regenacy, Rho, Sangamo, Semnur, SIMR Biotech, Sinfonia, SK Biopharmaceuticals, Sparian, SPM Therapeutics, SPRIM Health, Tiefenbacher, Validae, Vertex, Viscera, and WCG.

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