SDC-1801 was generally well tolerated in healthy participants and produced biomarker changes consistent with tyrosine kinase–2 and Janus kinase–1 pathway inhibition in a first-in-human phase 1 trial.
Researchers evaluated the oral tyrosine kinase–2 (TYK2)/Janus kinase–1 (JAK1) inhibitor SDC-1801 in 95 healthy male and female participants enrolled in randomized single-ascending dose, multiple-ascending dose, and food-effect cohorts. The doses ranged from 5 mg to 150 mg. The study's primary objective was safety and tolerability, while secondary and exploratory objectives included pharmacokinetics, food effects, and pharmacodynamic biomarkers associated with TYK2 and JAK1 signaling.
No mortality or treatment-related serious adverse events were reported. All treatment-emergent adverse events were mild or moderate, with headache the most frequently reported adverse event in the single- and multiple-dose parts of the study. The researchers reported no safety-stopping criteria during dose escalation.
The researchers also observed evidence of pharmacologic activity. In the multiple-dose cohorts, SDC-1801 was associated with reductions in interferon-gamma–induced protein-10 (IP-10) and high-sensitivity C-reactive protein. At higher drug exposures, IP-10 concentrations were reduced prior to dosing on day 9 and rebounded following treatment discontinuation.
Flow cytometry analyses demonstrated increasing inhibition of signal transducer and activator of transcription 3 (STAT3) and STAT5 phosphorylation with increasing SDC-1801 exposure. According to the researchers, the findings indicated an exposure-response relationship consistent with TYK2/JAK1 inhibition.
Pharmacokinetic analyses showed peak plasma concentrations approximately 3 to 5 hours following administration. The geometric mean half-life ranged from approximately 15 to 27 hours across the study cohorts, supporting the potential for once- or twice-daily dosing. Drug exposure showed low-to-moderate variability.
The researchers did not demonstrate a consistent dose-exposure relationship. They attributed the findings largely to formulation-related differences in capsule strength and solubility. Exposure was lower than expected with 50-mg capsules compared with formulations composed of multiple 10-mg capsules, preventing confirmation of pharmacokinetic linearity across the tested dose range.
In the food-effect cohort, administration with food resulted in modestly higher exposure compared with administration in a fasted state. The researchers suggested that food may improve absorption by enhancing solubilization.
Renal elimination of SDC-1801 was limited, with less than 4% of the administered dose recovered unchanged in urine, suggesting that the drug may be cleared through metabolism
One participant receiving 100 mg once daily developed elevated creatine phosphokinase levels and treatment-related rhabdomyolysis with myalgia. The participant discontinued treatment, and laboratory values returned to the normal range during follow-up. The researchers reported no associated abnormalities in creatinine, hepatic transaminases, troponin T, bilirubin, or urine microscopy.
The findings should be interpreted within the context of several limitations, according to the researchers. The study was conducted in healthy participants rather than patients with inflammatory or autoimmune diseases and was designed to evaluate safety, pharmacokinetics, and pharmacodynamics rather than clinical efficacy. In addition, formulation-related differences in exposure limited the assessment of dose proportionality and pharmacokinetic linearity.
"The safety profile and positive biomarker effects reported in this paper indicate SDC-1801 could be a potent, more selective, TYK2/JAK1 inhibitor for patients with various inflammatory and autoimmune conditions, and further clinical development is warranted," wrote lead study author Chris Brearley, of tranScrip in the United Kingdom, and colleagues.
The study was funded by Sareum Limited. Co–study author John Reader reported share ownership in Sareum Holdings. The study authors reported no other conflicts of interest.
