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Background <p>Uncoupling of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) axis and impaired cGMP synthesis are hallmarks of chronic kidney disease (CKD). While sGC has been a target of therapeutic interest for CKD, clinical progress has been limited.</p> Methods <p>In this single center, phase 1 study (NCT07021157), the pharmacokinetics (PK), pharmacodynamics (PD), and safety of SK-08, a novel, oral sGC activator, were evaluated. Healthy participants were randomized to SK-08 or placebo in the single-ascending-dose phase; in the food-effect phase, SK-08 10&#xa0;mg was administered under fasted and fed conditions. cGMP was the key PD biomarker, and exposure-response analyses were performed.</p> Results <p>Between 18th March 2025–17th June 2025, 16 participants were randomized and received SK-08 5&#xa0;mg (<i>n</i> = 3), 7.5&#xa0;mg (<i>n</i> = 3), or 10&#xa0;mg (<i>n</i> = 6), or placebo (<i>n</i> = 4). Adverse events (AEs) were mild/moderate and resolved spontaneously, those with an incidence &gt; 10% were hypotension (4/12, 33.3%) and dizziness (2/12, 16.7%). A higher C<sub>max</sub> was associated with an increased incidence of adverse drug reactions (ADRs) across all SK-08 doses. Under fasted conditions, the absorption and time to peak plasma concentration of SK-08 was fairly rapid (median T<sub>max</sub> 2.5–5.0&#xa0;h). Administration after a high-fat meal prolonged the median T<sub>max</sub> by 0.7&#xa0;h; C<sub>max</sub> and AUC were decreased by ~ 10%. Mean cGMP maximum percentage change (E<sub>max</sub>) increased dose dependently, from 5.99% at 5&#xa0;mg to 27.19% at 10&#xa0;mg, with a median time to E<sub>max of</sub> 2.75–6.00&#xa0;h.</p> Conclusions <p>SK-08 was well tolerated in healthy participants and induced dose-related sGC activation. A potential association between C<sub>max</sub> levels and the incidence of ADRs, and no clinically meaningful impact of food, was observed. These findings guide the optimization of a controlled-release formulation to maximize the therapeutic potential of SK-08.</p> Trial registration <p>Chinadrugtrials.org.cn (CTR20250337). Registered 20,250,126 Clinicaltrials.gov (NCT07021157). Registered 20,250,512.</p>

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Safety, pharmacokinetic, and pharmacodynamic characteristics of SK-08, a soluble guanylate cyclase activator, after oral administration in healthy participants: a randomized phase 1 trial

  • 期刊论文

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  • 发表日期：

    2026年7月9日

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  • Jian Liu,
  • Ying Du,
  • Hong Zhou,
  • Hanghuan Jia,
  • You Zhai,
  • Jie Ruan,
  • Caixia Yan,
  • Nana Xu,
  • Yijing Xin,
  • Liya Zheng,
  • Yingying Song,
  • Danna Jiang,
  • Jing Yang

摘要

Background

Uncoupling of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) axis and impaired cGMP synthesis are hallmarks of chronic kidney disease (CKD). While sGC has been a target of therapeutic interest for CKD, clinical progress has been limited.

Methods

In this single center, phase 1 study (NCT07021157), the pharmacokinetics (PK), pharmacodynamics (PD), and safety of SK-08, a novel, oral sGC activator, were evaluated. Healthy participants were randomized to SK-08 or placebo in the single-ascending-dose phase; in the food-effect phase, SK-08 10 mg was administered under fasted and fed conditions. cGMP was the key PD biomarker, and exposure-response analyses were performed.

Results

Between 18th March 2025–17th June 2025, 16 participants were randomized and received SK-08 5 mg (n = 3), 7.5 mg (n = 3), or 10 mg (n = 6), or placebo (n = 4). Adverse events (AEs) were mild/moderate and resolved spontaneously, those with an incidence > 10% were hypotension (4/12, 33.3%) and dizziness (2/12, 16.7%). A higher Cmax was associated with an increased incidence of adverse drug reactions (ADRs) across all SK-08 doses. Under fasted conditions, the absorption and time to peak plasma concentration of SK-08 was fairly rapid (median Tmax 2.5–5.0 h). Administration after a high-fat meal prolonged the median Tmax by 0.7 h; Cmax and AUC were decreased by ~ 10%. Mean cGMP maximum percentage change (Emax) increased dose dependently, from 5.99% at 5 mg to 27.19% at 10 mg, with a median time to Emax of 2.75–6.00 h.

Conclusions

SK-08 was well tolerated in healthy participants and induced dose-related sGC activation. A potential association between Cmax levels and the incidence of ADRs, and no clinically meaningful impact of food, was observed. These findings guide the optimization of a controlled-release formulation to maximize the therapeutic potential of SK-08.

Trial registration

Chinadrugtrials.org.cn (CTR20250337). Registered 20,250,126 Clinicaltrials.gov (NCT07021157). Registered 20,250,512.