Kattamis et al. 2025 — VITHAL trial (vamifeport Phase 2a in β-NTDT)
The VITHAL study (NCT04364269) is the first randomized placebo-controlled human trial of vamifeport (VIT-2763), an oral small-molecule inhibitor of ferroportin (SLC40A1), in patients with non-transfusion-dependent β-thalassemia (β-NTDT). Published in Orphanet Journal of Rare Diseases in November 2025, it is the lead clinical proof-of-concept that oral ferroportin inhibition produces rapid, sustained, and pharmacodynamically coherent iron restriction in humans — establishing the pharmacological viability of this target class.
Aging-wiki framing: β-thalassemia is not an aging disease. This page’s primary relevance to the aging_wiki is as pharmacological proof-of-concept that oral ferroportin inhibition is mechanistically productive in humans — the same receptor axis (hepcidin → ferroportin → systemic iron regulation) that the aging hallmarks context invokes. There is no aging-indication trial of vamifeport and no evidence that iron restriction via ferroportin inhibition benefits older adults outside disease contexts. The mechanistic read-across from this trial to iron-driven aging hallmarks (Fenton chemistry, ferroptosis, mitochondrial dysfunction, anemia of aging) remains hypothetical and is flagged as such below.
Trial design
| Parameter | Detail |
|---|---|
| Trial name | VITHAL |
| Registration | NCT04364269 (registered 2020-04-01) |
| Phase | Phase 2a |
| Design | Randomized, double-blind, placebo-controlled, multicenter, parallel-group |
| Blinding | Quadruple (participants, care providers, investigators, outcomes assessors) |
| Randomization | Centralized IWRS; ratio ~5:1 (active:placebo) |
| Sponsor | Vifor (International) Inc. |
| Sites | ~20 primary care sites across Greece, Israel, Italy, Lebanon, and Thailand |
| Enrollment window | June 2020 – November 2021 |
| Treatment duration | 12 weeks |
| Follow-up | Additional 4-week safety follow-up (to Week 16) |
Dose regimens (weight-stratified):
- Vamifeport QD arm (n=9): 60 mg once daily (body weight 40–59 kg) or 120 mg once daily (60–100 kg)
- Vamifeport BID arm (n=12): 60 mg twice daily (40–59 kg) or 120 mg twice daily (60–100 kg)
- Placebo arm (n=4): matched capsules, weight-stratified frequency
Screened → randomized: 35 screened; 25 randomized (71% enrollment rate). Two patients discontinued early: 1 QD-arm patient (treatment-related acute hemolytic TEAE) and 1 BID-arm patient (consent withdrawal). Both are included in the full analysis set (safety analysis); the per-protocol set excludes them plus patients with major protocol violations (QD PPS n=8, BID PPS n=11, placebo PPS n=2).
Patient population (β-NTDT)
Key inclusion criteria:
- Adults aged 12–65 years with diagnosed β-NTDT
- Non-transfusion-dependent: fewer than 5 RBC units transfused in the prior 24 weeks
- Baseline hemoglobin ≤11 g/dL
- Baseline transferrin saturation (TSAT) ≥30%
- Body weight 40–100 kg
- Liver iron concentration (LIC) ≤15 mg/g dry weight
Key exclusion criteria: Transfusion-dependent thalassemia; active iron chelation therapy within 4 weeks prior; body weight outside 40–100 kg; LIC >15 mg/g dry weight.
Rationale for ferroportin inhibition in β-NTDT: β-NTDT is characterized by pathological ineffective erythropoiesis, which suppresses hepatic hepcidin production via erythroferrone (ERFE) and GDF15 elevation; low hepcidin leaves ferroportin constitutively surface-expressed, causing iron overabsorption from the gut and progressive systemic iron loading despite no transfusions. Vamifeport mimics hepcidin’s action (blocking ferroportin) to restore iron-restricted erythropoiesis without requiring exogenous hepcidin.
Baseline characteristics:
| Parameter | QD (n=9) | BID (n=12) | Placebo (n=4) |
|---|---|---|---|
| Median age (range), years | 42.0 (26–61) | 31.0 (18–40) | 40.5 (34–58) |
| Male sex, n (%) | 3 (33.3%) | 10 (83.3%) | 3 (75.0%) |
| Mean body weight (SD), kg | 54.7 (8.5) | 64.4 (13.0) | 56.1 (4.5) |
| Weight <60 kg, n (%) | 6 (66.7%) | 5 (41.7%) | 3 (75.0%) |
| Prior splenectomy, n (%) | 1 (11.1%) | 3 (25.0%) | 3 (75.0%) |
| Mean serum Hb (SD), g/L | 88.2 (17.5) | 88.5 (14.7) | 92.3 (9.8) |
| Mean serum iron (SD), µmol/L | 23.8 (13.4) | 28.4 (9.8) | 30.9 (13.3) |
| Mean TSAT (SD), % | 69.3 (31.2) | 79.0 (24.1) | 83.3 (33.5) |
| Mean serum ferritin (SD), µg/L | 426.9 (239.6) | 1133.2 (2119.1) | 440.0 (321.5) |
| Mean hepcidin (SD), nmol/L | 5.7 (4.1) | 5.8 (6.4) | 2.3 (3.1) |
| Mean MCV (SD), fL | 77.3 (15.7) | 69.1 (9.8) | 75.3 (10.6) |
| Mean LDH (SD), U/L | 244.3 (89.8) | 332.7 (165.0) | 230.3 (88.9) |
Baseline imbalances: The trial arms were notably heterogeneous. The placebo arm (n=4) had higher rates of prior splenectomy (75%), prior transfusion (100%), and hydroxyurea use (50%) relative to vamifeport arms, reflecting the small sample size and absence of stratified randomization for these covariates. Baseline ferritin in the BID arm was highly variable (mean 1133 µg/L vs ~440 in the others), driven by a few outlier patients with higher iron burden. The authors note this imbalance as a study limitation. Baseline hepcidin was low across all arms (reflecting NTDT pathophysiology), but numerically lower in the placebo arm (2.3 vs 5.7–5.8 nmol/L).
Primary endpoints: safety and tolerability
The co-primary objectives were: (1) treatment-emergent adverse events (TEAEs) through Week 16, and (2) changes in vital signs (blood pressure, heart rate) and ECG parameters (PR, QRS, QT, QTcF intervals) through Week 12. Both were assessed as evidence of pharmacological safety of oral ferroportin inhibition at these doses.
TEAE summary:
| Category | Vamifeport QD (n=9) | Vamifeport BID (n=12) | Placebo (n=4) |
|---|---|---|---|
| Any TEAE | 6 (66.7%) | 7 (58.3%) | 3 (75.0%) |
| Severe TEAE | 0 | 0 | 0 |
| Treatment-related TEAE | 2 (22.2%) | 4 (33.3%) | 2 (50.0%) |
| TEAE leading to discontinuation | 1 (11.1%) | 0 | 0 |
| Serious TEAE | 0 | 0 | 0 |
| Death | 0 | 0 | 0 |
Treatment-related TEAEs by type (selected; n per arm):
| Event | QD | BID | Placebo |
|---|---|---|---|
| Anemia | 1 (11.1%) | 1 (8.3%) | 0 |
| Hemolysis | 1 (11.1%) | 0 | 0 |
| Nausea | 0 | 1 (8.3%) | 0 |
| Vomiting | 0 | 1 (8.3%) | 0 |
| Gastrointestinal disorders (any TEAE, all grades) | — | 4 (33.3%) | — |
| Fatigue | 0 | 1 (8.3%) | 0 |
| Pyrexia | 0 | 1 (8.3%) | 0 |
| Discolored feces | 0 | 1 (8.3%) | 0 |
| Increased ALT/AST | 0 | 1 (8.3%) each | 0 |
| Headache | 0 | 1 (8.3%) | 1 (25.0%) |
Note: The GI disorders row reflects any-grade any-cause GI TEAEs from the text (the most common TEAE system organ class by body system in BID); individual treatment-related GI events are captured in the rows above (nausea, vomiting, discolored feces). The text states 17% (2/12) of BID patients had a GI TEAE considered treatment-related.
Two discontinuations: One patient in the vamifeport QD arm discontinued due to a treatment-related acute hemolytic event (the only TEAE-related discontinuation). One patient in the vamifeport BID arm withdrew consent (not safety-related). No serious adverse events occurred in any group.
Safety conclusion (authors): “In this 12-week Phase 2a study…oral vamifeport at doses up to 120 mg BID had a favorable safety and tolerability profile.” Vital signs and ECG parameters showed no clinically meaningful drug-related changes.
gap/long-term-unknown — 12-week duration is insufficient to characterize hepatic, cardiac, or long-term hematologic safety of sustained ferroportin inhibition. Anemia and hemolysis signals at low frequency (1/9 QD each) require monitoring in larger trials.
Secondary endpoints: pharmacodynamic results
Secondary objectives were iron-related pharmacodynamic (PD) markers as a first signal of target engagement and potential efficacy in normalizing iron-restricted erythropoiesis.
Serum iron — rapid and sustained reduction
Vamifeport produced rapid, acute serum iron reductions within 2 hours of the first dose:
- QD arm: −12.2 (SD 6.5) µmol/L at 2h
- BID arm: −14.5 (SD 12.1) µmol/L at 2h
- Placebo: no clinically meaningful change
By Week 12, serum iron reductions were sustained across all vamifeport-treated patients (Fig. 2 box plots; exact group means are reported in Supplemental Table 1, not the main text). The placebo group showed no clinically meaningful change. The specific means “−10.5 to −16.2 µmol/L vs +0.03 µmol/L placebo” derive from the ClinicalTrials.gov results posting (NCT04364269), not the main publication; they are flagged here as gap/unverifiable-from-main-text until the supplemental tables are independently confirmed. gap/needs-replication
The 2-hour serum iron drop is mechanistically interpretable: vamifeport blocks ferroportin-mediated iron export from gut enterocytes and macrophages within the absorption timescale, directly reducing plasma iron. The sustained Week-12 reduction reflects ongoing daily iron re-restriction.
Transferrin saturation (TSAT) — large acute and sustained decline
- QD arm: −33.6% (SD 18.9) at 2h; −32.6% (SD 19.6) at Week 1
- BID arm: −37.2% (SD 27.6) at 2h; −44.8% (SD 24.6) at Week 1
- Placebo: no clinically meaningful change
By Week 12: TSAT remained below baseline at each subsequent visit in the vamifeport groups (Fig. 3 box plots; exact group means are in Supplemental Table 2, not the main text). The placebo group showed no clinically meaningful change. The specific Week-12 values “−27.6% to −46.8% vs −1.3% placebo” derive from the ClinicalTrials.gov results posting (NCT04364269), not the main publication body; flagged as gap/unverifiable-from-main-text until supplemental tables are independently confirmed. The scale of TSAT reduction is consistent with vamifeport driving iron-restricted erythropoiesis — bringing TSAT from the supranormal β-NTDT range (baseline mean 69–83%) toward a more physiological range. The main text describes the reduction as “nearly one-third within 2 h of vamifeport QD or BID administration.”
Hemoglobin — stable, no clinically meaningful change
No patient experienced a hemoglobin change of ≥1.0 g/dL (the pre-specified clinical meaningful threshold) during the 12-week study, except two patients who required transfusions (both tracked as expected in the β-NTDT population). A downward trend was observed in the vamifeport arms but did not reach the clinical threshold.
The authors note the 12-week duration may be insufficient to observe hemoglobin improvement from restricted ineffective erythropoiesis. Mouse model data (from Townes HbSS and Hbbth3/+ β-thalassemia models) showed hemoglobin improvement at 6 weeks, but the authors caution that “observations in animal models of this disease have not consistently been reproduced in patients with β-thalassemia.” gap/needs-human-replication — no human hemoglobin efficacy signal was demonstrated in this Phase 2a.
Mean corpuscular volume (MCV) — downward trend
MCV showed a downward trend in both vamifeport QD and BID patients, persisting up to two weeks after the last dose (Week 12 / end of treatment). Dunnett’s multiple comparisons test found p<0.01 at Week 12/EoT specifically in the BID arm (Fig. 6 asterisk); the QD arm showed a numerical trend that did not reach the p<0.01 threshold in the main paper’s figure. The text states the trend “persisted up to two weeks (Week 12, EoT) after the last dose (p<0.01)” — the p-value applies to BID. Decreasing MCV is consistent with more iron-restricted erythropoiesis: red cells produced under iron restriction are smaller (microcytic). This is an on-target PD effect confirming ferroportin inhibition is reaching the bone marrow compartment.
Hepcidin — no meaningful change
Serum hepcidin did not change meaningfully in any group during the 12-week study. This is expected: vamifeport acts downstream of hepcidin (directly on ferroportin), and the trial was not expected to change the upstream hepatic hepcidin synthesis. The persistently low hepcidin at baseline (2.3–5.8 nmol/L, consistent with β-NTDT pathophysiology driven by erythroferrone-mediated hepcidin suppression) was not altered by the drug.
Markers of ineffective erythropoiesis (erythroferrone, sTfR)
The paper’s exploratory erythropoietic endpoints were limited to fetal hemoglobin (HbF) and broad hemolytic markers (LDH, bilirubin, haptoglobin). The discussion states “Vamifeport treatment did not meaningfully improve markers of ineffective erythropoiesis in the present study.” Erythroferrone (ERFE) and soluble transferrin receptor (sTfR) — the primary ineffective-erythropoiesis markers in β-thalassemia — are not explicitly mentioned in the paper as having been measured or as planned future endpoints; the limitation discussion calls for “inclusion of additional time points for biomarker assessment” and future NTBI evaluation but does not name ERFE or sTfR specifically. Their absence from the reported results is a limitation of this Phase 2a. gap/long-term-unknown
LDH and unconjugated bilirubin (hemolysis markers)
Slight downward trends were observed in LDH and unconjugated bilirubin in some vamifeport BID patients, consistent with modest reduction in intravascular and extravascular hemolysis. These trends were not statistically significant given the small sample size and high baseline variability. gap/needs-replication
Pharmacokinetics
Formal pharmacokinetic parameters were not reported in the primary publication; PK data are stated to be reported separately. The weight-stratified dosing regimen (60 mg vs 120 mg based on <60 kg vs ≥60 kg weight band) reflects preclinical PK modeling to achieve target exposure across the body-weight range.
Authors’ conclusions
“In summary, in this 12-week Phase 2a study in adults with β-NTDT, oral vamifeport at doses up to 120 mg BID had a favorable safety and tolerability profile and showed promising target engagement and pharmacodynamic effects on total serum iron and TSAT levels versus placebo.”
The authors explicitly call for: larger, more extended studies in more homogeneous β-NTDT populations; evaluation of NTBI (non-transferrin-bound iron) in future studies; additional biomarker assessment time points; and investigation in sickle cell disease, polycythemia vera, and hemochromatosis contexts. The Conclusions section does not specifically name ERFE or sTfR as future endpoints.
Study limitations (per authors)
- Very small sample size (n=25; placebo n=4) — all reported within-arm trends are exploratory only; no formal between-group statistical tests on efficacy endpoints are powered.
- Unequal baseline characteristics — placebo arm had more prior splenectomy, transfusion, and hydroxyurea use; confounds interpretation of any comparative PD trends.
- 12-week duration — insufficient to observe hemoglobin improvement or assess long-term safety of sustained iron restriction; mouse model showed hemoglobin benefit at 6 weeks but human translation is uncertain.
- Limited biomarker time points — the authors call for “inclusion of additional time points for biomarker assessment” to better characterize the pharmacodynamic time course. The exploratory erythropoietic marker panel was restricted to fetal hemoglobin; ERFE and sTfR were not explicitly listed as endpoints and are not discussed as measured or unmeasured in the paper’s limitations section.
- Non-transferrin-bound iron (NTBI) — not assessed; NTBI is the form of iron most directly linked to organ toxicity in thalassemia.
- High heterogeneity — patients varied considerably in baseline ferritin, spleen status, fetal Hb fraction; some had near-100% HbF, limiting interpretation.
Aging-context extrapolation note
The hepcidin–ferroportin axis is central to aging iron physiology in both directions:
- In anemia of aging (ACI): inflammaging-driven IL-6 → excess hepatic hepcidin → pathological ferroportin degradation → functional iron deficiency → restricted erythropoiesis. In this context, preserving ferroportin is the therapeutic goal.
- In β-NTDT: erythroferrone suppresses hepcidin → constitutively surface-expressed ferroportin → iron overabsorption → iron overload. In this context, blocking ferroportin (vamifeport’s mechanism) is the goal.
These are opposite indications. Vamifeport, a ferroportin blocker, would worsen anemia of aging by further reducing the already-suppressed ferroportin activity in aged macrophages and enterocytes. There is no aging-indication rationale for ferroportin inhibition as of 2026.
The aging-wiki value of this trial is purely pharmacological: it establishes that oral ferroportin inhibition produces target-engaged, dose-dependent iron restriction in humans — confirming the druggability and mechanism of this receptor. The future aging-relevant pharmacology would run in the opposite direction: ferroportin-stabilizing or hepcidin-antagonizing strategies that protect ferroportin from inflammaging-driven degradation.
| Dimension | Status |
|---|---|
| Pathway conserved in humans? | yes — ferroportin inhibition → iron restriction confirmed in humans |
| Phenotype conserved in humans? | partial — β-NTDT iron dynamics confirmed; aging-ACI direction not tested |
| Replicated in humans? | single Phase 2a only; no independent replication gap/needs-replication |
Cross-references
- ferroportin — the drug target; this trial is the primary human PD proof-of-concept for vamifeport cited on that page
- hepcidin — the endogenous regulator of ferroportin; vamifeport pharmacologically mimics hepcidin action
- iron — systemic iron homeostasis context; serum iron, TSAT, ferritin dynamics
- anemia-of-aging — the aging-context direction (ferroportin preservation, not inhibition)
- chronic-inflammation — the upstream driver of pathological ferroportin loss in aging
- vamifeport stub — compound page for vamifeport (VIT-2763); not yet seeded