HSK16149 (crisugabalin): Phase 2 to 3 clinical trial results for the treatment of painful diabetic neuropathy

Aims: This phase 2 to 3 randomized clinical trial aimed to evaluate the efficacy and safety of different doses of HSK16149 (crisugabalin), a selective α2δ ligand, in the treatment of diabetic peripheral neuropathic pain in Chinese individuals compared with placebo including a pregabalin treatment arm to compare dose selection.

Methods: Conducted at 53 study sites, 725 randomly assigned participants received crisugabalin (40, 80, 120, or 160 mg/d), pregabalin (300 mg/d), or placebo. The primary endpoint was the change in average daily pain score (ADPS) at week 13.

Results: At week 13, mean (SD) changes from baseline ADPS were -2.24 (1.55), -2.16 (1.79), -2.03 (1.69), and -2.15 (1.79) in the crisugabalin 40, 80, 120, and 160 mg/d groups, respectively, -1.23 (1.68) in the placebo group, and -2.09 (1.57) in the pregabalin group. The reduction in ADPS was greater in the crisugabalin 40 and 80 mg/d groups compared to placebo. Responder rates for ≥30% pain reduction in these groups ranged from 51 to 57% and for ≥50% pain reduction from 32 to 36%. The most common treatment-associated adverse events in these groups were dizziness and somnolence.

Conclusions: Crisugabalin 40 and 80 mg/d was superior to placebo and was well tolerated and safe for the treatment of neuropathic pain in Chinese individuals with diabetic neuropathy.

Comments. In this clinical trial, pain reduction under treatment with crisugabalin 40 or 80 mg/d was comparable to that with pregabalin 300 mg/d. Responder rates for pregabalin were not reported in this study and therefore not compared with crisugabalin. Numerically, the responder rates for crisugabalin 40 or 80 mg/d were between those reported for pregabalin 300 and 600 mg/d in a recent Cochran review. The overall safety profile of crisugabalin was comparable to that of pregabalin, while dizziness and drowsiness appeared to be dose-dependent. While this trial does not appear to place much emphasis on comparing between crisugabalin and pregabalin, it may have been interesting to compare the efficacy and safety with pregabalin at the maximum dose of 600 mg/d. A potential advantage of crisugabalin over established α2δ ligand drugs is that it was administered and recommended without the need for a dose titration period.

Gidon J Bönhof

Reference. Guo X, Zhang T, Yuan G, Zeng W, Hu Q, Ma J, Li Y, Li H, Zhang Y, Liu J, Bian F, Zhang W, Zhang F, Pang S, Li Y, Wu X, Tang X, Zhang K, Pan T, Hu H, Cheng Z, Wang Y, Gao J, Sun J. GABA Analogue HSK16149 in Chinese Patients With Diabetic Peripheral Neuropathic Pain: A Phase 3 Randomized Clinical Trial. JAMA Netw Open. 2024 Aug 1;7(8):e2425614. doi: 10.1001/jamanetworkopen.2024.25614. PMID: 39158916; PMCID: PMC11333976.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2822403