In preclinical studies, the investigational CXCR1/2 inhibitor ladarixin was shown to prevent and reverse diabetes in NOD mice. On this basis, a multicenter clinical trial in adult patients with new onset type 1 diabetes (T1D) was conducted (NCT02814838).
Patients (Table 1) were randomized 2:1 to ladarixin (LDX) 400 mg BID or placebo (PLA) and randomized within 100 days from first insulin administration.
Patients received 3 treatment cycles, each consisting of 14 days on and 14 days off drug, and were then followed up for 12 months. The difference between LDX and PLA in mixed meal tolerance test (MMTT) AUC of C peptide was statistically significant neither at week 13 (primary endpoint, p=0.330) nor at week 26 (p=0.404). Conversely, at week 26 patients having HbA1c<7% and daily insulin requirements <0.50 IU/kg were 76.6% and 45.8% in LDX and PLA, respectively (p=0.0095).
In patients with baseline fasting C-peptide below the median value of trial population (prespecified subgroup analysis), the difference between LDX and PLA in MMTT AUC of C peptide trended at week 13 (p=0.111) and reached statistical significance at week 26 (p=0.041).
Adverse Reactions occurring in ≥10% of patients included dyspepsia (16% LDX vs. 0% PLA) and headache (16% LDX vs. 15.4% PLA).
Although primary endpoint was not met, secondary and subgroup analyses suggest further investigation of LDX in new onset T1D may be warranted.
E. Bosi: Consultant; Self; Abbott, Eli Lilly and Company, Medtronic, Novartis AG, Roche Diabetes Care, Sanofi. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd. E. Cossu: None. T. Linn: Advisory Panel; Self; Dompe Pharmaceuticals. L. Rose: None. B. Keymeulen: None. P. Gillard: None. L. Daffonchio: Employee; Self; Domp farmaceutici S.p.A. P.A. Ruffini: Employee; Self; Domp farmaceutici S.p.A., Domp farmaceutici S.p.A. M. Allegretti: Employee; Self; Domp Farmaceutici spa. L. Piemonti: Advisory Panel; Self; AstraZeneca, Roche Diabetes Care, Semma Therapeutics, Inc.