Efficacy and Safety of Vamifeport in Adult Participants With Homeostatic Iron Regulator Gene (HFE)-Related Hereditary Hemochromatosis

• Vamifeport (Drug): Vamifeport capsule administered orally.
• Placebo (Drug): Placebo capsule matching IP administered orally.

Primary outcomes

• Change from baseline in magnetic resonance imaging (MRI)-based liver iron concentration (LIC) [At Baseline and Day 360]

Secondary outcomes

• Number of participants with treatment-emergent adverse events (TEAEs) [Up to Day 390]
• Percentage of participants with TEAEs [Up to Day 390]
• Number of participants with treatment-emergent serious adverse events (SAEs) [Up to Day 390]
• Percentage of participants with treatment-emergent SAEs [Up to Day 390]
• Number of participants with clinically significant change from baseline in clinical safety laboratory tests and 12-lead electrocardiogram (ECG) [From Baseline to Day 390]: Clinical safety laboratory tests will include hematology, biochemistry and coagulation.
• Percentage of participants with clinically significant change from baseline in clinical safety laboratory tests and 12-lead ECG [From Baseline to Day 390]: Clinical safety laboratory tests will include hematology, biochemistry and coagulation.
• Change from baseline in transferrin saturation (TSAT) (measured at trough) [From Baseline to Day 360]
• Number of participants with TSAT less than or equal to (<=) 45% (measured at trough) [From Baseline to Day 360]
• Percentage of participants with TSAT <= 45% (measured at trough) [From Baseline to Day 360]
• Number of participants with 25% reduction in MRI-based LIC [At Day 180 and 360]
• Number of participants with 50% reduction in MRI-based LIC [At Day 180 and Day 360]
• Number of participants with TSAT ≤ 45% or MRI-based LIC < 5 milligrams per gram (mg/g) [At Day 360]
• Number of participants with TSAT ≤ 45% or MRI-based LIC < 2 mg/g [At Day 360]
• Change from baseline in joint pain score in a visual analog scale (VAS) [From Baseline to Day 360]: The VAS is a single-item questionnaire. Participants will be asked to record their joint pain at its worst over the previous week, from 0 (No pain) to 10 (Worst possible pain).
• Change from baseline in modified fatigue impact scale (MFIS) total score [From Baseline to Day 360]: Participants will be asked to read a list of 21 statements and assess how often fatigue has affected them in terms of physical, cognitive, and psychosocial functioning, over the previous 4 weeks, using a 5-point scale from 0 (Never) to 4 (Almost always). The total score is obtained by summing the scores of all the 21 items. Higher scores indicate a greater impact of fatigue on a participant's activities.
• Change from baseline in health-related quality of life: EuroQoL 5-dimension 5-level instrument (EQ-5D-5L) [From Baseline to Days 180, 360, and 390]: The EQ-5D-5L is a standardized measure of health status that provides a simple, generic measure of health for clinical and economic appraisal. Participants will complete the questionnaire based on their health on that day. The EQ-5D-5L descriptive profile includes 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Participants will rate each dimension based on 5 levels of severity: no problems, slight problems, moderate problems, severe problems, and extreme problems. A higher score indicates a more severe outcome than a lower score.
• Change from baseline in health-related quality of life: VAS (Arthralgia) [From Baseline to Day 180, 360, and 390]: The VAS is a single-item questionnaire. Participants will be asked to record their joint pain at its worst over the previous week, from 0 (No pain) to 10 (Worst possible pain).
• Change from baseline in health-related quality of life: Patient global impression of change in clinical status [From Baseline to Day 180, 360, and 390]: The PGI - Change (PGI-C) instrument is a self-reported measure that reflects belief about the efficacy of treatment. Participants will be asked to rate the change in their overall symptoms since they started taking investigational product (IP) on a 5-point scale, ranging from 1 (Much improved) to 5 (Much worse). A lower score reflects an improvement in clinical status.
• Change from baseline in health-related quality of life: Patient global impression of severity [From Baseline to Day 180, 360, and 390]: The PGI - Severity (PGI-S) instrument is a self-reported questionnaire and consists of 1 item that measures disease severity. Participants will be asked to rate the severity of their overall symptoms over the previous week on a 5-point scale from 1 (None) to 5 (Very severe). A higher score reflects a more severe outcome than a lower score.
• Change from baseline in health-related quality of life: MFIS physical, cognitive, and psychosocial subscales [From Baseline to Day 180, 360, and 390]: Participants will be asked to read a list of 21 statements and assess how often fatigue has affected them in terms of physical, cognitive, and psychosocial functioning, over the previous 4 weeks, using a 5-point scale from 0 (Never) to 4 (Almost always). Items on the MFIS will be aggregated into 3 subscales (Physical, Cognitive, or Psychosocial). Higher scores indicate a greater impact of fatigue on a participant's activities.
• Vamifeport plasma concentrations after a single dose [At Day 1]
• Vamifeport plasma concentrations at steady state [At Days 15, 180, and 360]
• Change from baseline in total serum iron (measured at trough) [From Baseline to Day 360]
• Change from baseline in serum ferritin (measured at trough) [From Baseline to Day 360]
• Frequency of rescue therapy use [Up to Day 390]: For assessment of this outcome measure, data will be collected retrospectively from 1 year before baseline as well as during the study (up to Day 390).
• Duration of rescue therapy use [Up to Day 390]: For assessment of this outcome measure, data will be collected retrospectively from 1 year before baseline as well as during the study (up to Day 390).
• Time to first use of rescue therapy [Up to Day 360]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adult (≥ 18 years) and has provided written informed consent.
* Confirmed diagnosis of HFE-HH in medical history.
* Evidence of iron overload as shown by:

  * TSAT > 45% (confirmed at 2 visits, at least 14 days apart) at Screening; and
  * Serum ferritin ≥ 200 nanogram per milliliter (ng/mL) and < 5000 ng/mL (confirmed at 2 visits, at least 14 days apart) at Screening; and
  * MRI-based LIC between 2.4 and 16 mg/g (43.0 and 286.5 mmol/kg) dry weight (dw) at Screening.
* Body mass index between 18.5 and 34.9 kilograms per meter squared (kg/m\^2).

Exclusion Criteria:

* Clinically relevant laboratory abnormalities, 12-lead electrocardiogram (ECG) findings, or medical history.

NIH grants: 2025