Phase 1 trial shows NHE3 blocker JMKX003002 raises stool sodium excretion
A randomized, placebo-controlled Phase I study in healthy Chinese participants found the oral gut-restricted NHE3 inhibitor well tolerated with minimal systemic absorption and a consistent shift of sodium and phosphorus excretion from urine to stool.
Executive Summary
- A randomized, double-blind, placebo-controlled Phase I trial evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of an oral NHE3 inhibitor in healthy Chinese participants, using single-ascending-dose, multiple-ascending-dose, and food-effect designs.
- The drug was well tolerated across all dosing cohorts, with mostly mild adverse events, no serious adverse events, and no discontinuations due to treatment.
- Blocking the target transporter in the gut shifted sodium and phosphorus excretion from urine into stool, with minimal drug absorbed into the bloodstream, the intended gut-restricted profile.
- The finding supports moving the compound into patient populations where reducing sodium or phosphorus retention is a treatment goal, though the healthy-volunteer design does not establish a clinical benefit.
The study's purpose
NHE3 is a transporter in the gut lining that normally helps the body reabsorb sodium; blocking it keeps sodium in the intestine instead of letting it pass into the bloodstream. The trial set out to test whether an oral NHE3 inhibitor, JMKX003002, could do this safely in humans and whether it produced the expected pharmacodynamic effect of pushing sodium and phosphorus excretion from urine into stool. That mechanism has downstream relevance to conditions marked by sodium or phosphorus retention, since a drug that works locally in the gut without extensive systemic absorption could limit off-target effects elsewhere in the body. SafetySafety, tolerability, pharmacokinetics, and pharmacodynamics of oral JMKX003002 in Chinese healthy participants: a randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food-effect phase I clinical trial.Jul 19, 2026
How it was done
The randomized, double-blind, placebo-controlled Phase I program combined three sub-studies in healthy Chinese participants: a single-ascending-dose study with seven cohorts spanning 1 mg (n=4) up to 125 mg (n=8), a food-effect study using six sequence groups at 25 mg twice daily (n=4), and a multiple-ascending-dose study with two cohorts at 10 mg or 20 mg twice daily (n=10). The trial measured safety and tolerability, pharmacokinetics (drug levels in plasma, urine, and stool), and pharmacodynamics (urinary and stool sodium and phosphorus excretion). A mixed-effects model was used to test for a food interaction on stool electrolyte excretion in the food-effect cohort. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2300070473). SafetySafety, tolerability, pharmacokinetics, and pharmacodynamics of oral JMKX003002 in Chinese healthy participants: a randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food-effect phase I clinical trial.Jul 19, 2026
The safety result
JMKX003002 was well tolerated, with mostly mild treatment-related adverse events and no serious adverse events reported. One Grade 3 diarrhea event occurred in the 50 mg single-ascending-dose group and one in the 125 mg group, but no participant discontinued or withdrew because of a treatment-emergent adverse event. Most plasma samples fell below the limit of quantification (0.2 ng/mL), with only transient detection of low concentrations, indicating minimal systemic exposure. The drug was recovered primarily in stool, at 79.9%, and was undetectable in urine, consistent with a gut-restricted mechanism rather than one that circulates through the bloodstream. SafetySafety, tolerability, pharmacokinetics, and pharmacodynamics of oral JMKX003002 in Chinese healthy participants: a randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food-effect phase I clinical trial.Jul 19, 2026
The pharmacodynamic result
Across the single-dose, multiple-dose, and food-effect studies, JMKX003002 consistently decreased urinary sodium and phosphorus while increasing stool sodium and phosphorus compared to baseline. In the multiple-ascending-dose study, elevated stool sodium and phosphorus persisted one day after the last dose was given. The food-effect study additionally found an interaction between food intake and stool sodium and phosphorus excretion using a mixed-effects model, indicating that meal timing or content measurably altered the drug's electrolyte effect. That food interaction is itself a result with practical bearing on how any future dosing regimen would need to account for meals, distinct from the core safety and pharmacodynamic findings but derived from the same design. SafetySafety, tolerability, pharmacokinetics, and pharmacodynamics of oral JMKX003002 in Chinese healthy participants: a randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food-effect phase I clinical trial.Jul 19, 2026
What the design does and does not establish
As a healthy-volunteer, dose-ranging Phase I study, the trial is built to establish safety, tolerability, and the pharmacodynamic signature of the mechanism, not clinical benefit in a patient population with sodium or phosphorus overload. The consistent shift in excretion across three independent sub-studies supports that the mechanism performs as intended at the doses tested, but translating that shift into a treatment effect requires testing in patients whose condition the excretion change is meant to address. SafetySafety, tolerability, pharmacokinetics, and pharmacodynamics of oral JMKX003002 in Chinese healthy participants: a randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food-effect phase I clinical trial.Jul 19, 2026
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