Diabetic peripheral neuropathy (DPN) is a common complication in individuals with diabetes with high morbidity and mortality. Painful DPN impacts quality of life and is very challenging to treat. The efficacy and safety of LX9211, a potent, non-opioid inhibitor of a novel target, AP2-associated protein kinase 1 (AAK1) was evaluated in a Phase 2 randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical study (RELIEF-DPN 1). The baseline characteristics [mean (SD)] of 319 adults were age 62.2 (9.94) years, A1C 7.7 (1.28) %, BMI 32.07 (4.45) kg/m2, and average daily pain score (ADPS) after placebo run-in period 6.55 (1.089). Patients were randomized to either placebo, LX9211 100 mg/10 mg (100 mg Day 1, 10 mg thereafter-Low Dose arm), or LX9211 200 mg/20 mg (200 mg Day 1, 20 mg thereafter-High Dose arm) for 6 weeks followed by 5-week safety follow-up period. At Week 6, LX9211 was associated with significant improvement in Neuropathic Pain Symptom Inventory (NPSI) total score (Low Dose: -5.18, p=0.064; High Dose: -7.22, p=0.008), burning pain (Low Dose: -1.40; p<0.001; High Dose: -0.89, p=0.017), pain interference on sleep (Low Dose: -0.96, p=0.005; High Dose: -1.04, p=0.002) and Patient Global Impression of Change score (Low Dose: -0.35, p=0.031; High Dose: -0.15, p=0.351) compared to placebo while achieving the primary endpoint (change from placebo in ADPS) in the low dose arm. LX9211 was safe (no treatment-related SAEs or deaths) and did not affect key cardiometabolic parameters (body weight, blood pressure, glucose control, cholesterol levels). RELIEF-DPN 1 demonstrated significant improvements in validated neuropathic pain instruments and in other patient reported outcomes suggesting that LX9211 is a promising, opioid independent new avenue to treat people with painful DPN. Confirmation of these positive results are planned in future Phase 3 trials. Disclosure R.Busui: Board Member; American Diabetes Association, Consultant; Averitas Pharma, Inc., Lexicon Pharmaceuticals, Inc., Nevro Corp., Novo Nordisk, Roche Diagnostics, Procter & Gamble, Research Support; Novo Nordisk, Medtronic, National Institutes of Health. A.Patel: Other Relationship; Lexicon Pharmaceuticals, Inc. C.N.Sang: Consultant; Arena Pharmaceuticals, Inc., Covance, SOLVD, Other Relationship; Kolon, Research Support; AbbVie Inc., Merck & Co., Inc., Tonix, Lexicon Pharmaceuticals, Inc., Vivozon, Helixmith. C.B.Granowitz: None. P.L.Banks: Employee; Lexicon Pharmaceuticals, Inc. P.Pierce: Employee; Lexicon Pharmaceuticals, Inc. F.W.Sun: Employee; Lexicon Pharmaceuticals, Inc. S.Gopinathan: Employee; Lexicon Pharmaceuticals, Inc. Funding Lexicon Pharmaceuticals, Inc.