Suzetrigine, a Selective Pain Signal Inhibitor of NaV1.8 Shows Proof-of-concept for Treatment of Painful Diabetic Peripheral Neuropathy
Roy Freeman1, Richard Rauck2, Charles Argoff3, Simon Tian4, Xiaopeng Miao4, Hannah Bouldin Olivet4, Carmen Bozic4, Robert Dworkin5
1Beth Israel Deaconess Medical Center, 2Carolinas Pain Institute, 3Albany Medical College, 4Vertex Pharmaceuticals, 5University of Rochester School of Medicine and Dentistry
Objective:
To evaluate suzetrigine for painful diabetic peripheral neuropathy (DPN) treatment.
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 NaV1.8. NaV1.8 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.
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 NaV1.8 inhibition with suzetrigine as an analgesic approach in DPN, supporting further evaluation of suzetrigine for DPN treatment in ph3.
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