078: Pharmacokinetics, Pharmacodynamics & Safety of Rusfertide, A Hepcidin Mimetic, in Subjects With Hepatic Impairment & in Subjects With Renal Impairment

Statement of Purpose, Innovation or Hypothesis: Rusfertide is a synthetic peptide mimetic of the natural peptide hormone hepcidin and binds to the ferroportin receptor. Rusfertide is currently in clinical investigation for the treatment of polycythemia vera. The purpose of this study was to evaluate the pharmacokinetics, pharmacodynamics, and safety of rusfertide in subjects with severe renal impairment and in subjects with moderate hepatic impairment compared to healthy subjects.

Description of Methods & Materials: This open-label, reduced design, Phase 1 study was conducted at 3 sites. Eight subjects with severe renal impairment and 8 with moderate hepatic impairment were enrolled. Demographics were matched to healthy controls (n=8). Subjects received a single 20 mg subcutaneous dose of rusfertide. Blood samples were collected for measurement of rusfertide and its 2 major metabolites, M4 and M9 for up to 216 hours following dose administration. Blood samples for measurement of unbound fraction of rusfertide were collected. Pharmacodynamic assessments included measurement of serum iron and transferrin-iron saturation (TSAT). PK parameters were estimated using Phoenix WinNonlin (Certara, NJ).

Data & Results: Mean age was 60.0±8.9 years overall and did not differ by more than ±10 years and mean BMI did not differ by more than ±20% in either the renal or hepatic impairment group versus healthy subjects. Most subjects were male (79.2%) and White (91.7%). Rusfertide pharmacokinetics are summarized in Table 1. In subjects with severe renal impairment, the Cmax and AUCinf for rusfertide were higher than in healthy subjects. In patients with moderate hepatic impairment, the Cmax and AUCinf for rusfertide were lower than in healthy subjects. The terminal elimination half-life (t1/2) for rusfertide was comparable in all 3 groups. No significant associations were seen between rusfertide AUCinf or Cmax and estimated GFR for renal impairment, and albumin and bilirubin for hepatic impairment subjects. Similar reductions from baseline in mean serum iron concentrations (7-9 μmol/L) and TSAT (10%-12%) were seen in all 3 groups. A single 20 mg subcutaneous dose of rusfertide was well tolerated. Five subjects (20.8%) reported at least one treatment-emergent adverse event: 1 healthy subject (12.5%) and 4 subjects with hepatic impairment (50.0%). All but one were mild in severity; a moderate sprained ankle considered not treatment-related. Two subjects had an injection-site reaction: one erythema, and the other pain. No serious adverse events were reported, and no tolerability or safety issues were identified.

Interpretation, Conclusion or Significance: Overall differences of < 2-fold in Cmax and AUCinf were noted in severe renal or moderate hepatic impairment compared to subjects with normal organ function, and dosing is titrated to effect based on hematocrit response, suggesting no dose adjustments are required for rusfertide in patients with severe renal impairment or with moderate hepatic impairment. Pharmacodynamic effects on serum iron and TSAT were similar in all three groups. Rusfertide was generally well tolerated in all 3 groups of subjects.

Disclosures: Protagonist Therapeutics, Inc sponsored this study. NM and PD are employees of and own stock in Protagonist Therapeutics, Inc.

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