Yupelri
Yupelri
Generic Name
Yupelri
Mechanism
- Selective TGF‑β superfamily ligand trap: Binds and neutralizes α‑chain ligands such as activin A, GDF‑11, and others that signal through the SMAD 2/3 pathway.
- Enhances erythroid progenitor differentiation: By inhibiting SMAD‑dependent inhibition, it restores the maturation of late-stage erythroblasts, increasing endogenous erythropoiesis and reducing transfusion requirements.
- Reduces ineffective erythropoiesis: Decreases erythrocyte destruction in the marrow and improves hemoglobin levels.
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Pharmacokinetics
| Parameter | Value | Clinical Notes |
| Absorption | Subcutaneous (SC) administration | Peak serum concentrations within 3–5 days post‑dose. |
| Distribution | Protein‑bound (~95 %); volume of distribution ≈ 300 mL/kg | Limited ocular or CNS penetration. |
| Metabolism | Cleaved by proteases into active domain; no significant CYP involvement | Low drug‑drug interaction potential via metabolic enzymes. |
| Elimination | Renal and hepatobiliary clearance; half‑life ~13–16 days | Dose adjustments not required for mild‑to‑moderate renal/hepatic impairment. |
| Loading Dose | 3 mg/kg SC on day 0, followed by maintenance every 3 weeks | Weight‑based dosing optimizes therapeutic exposure. |
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Indications
- Transfusion‑dependent anemia in adults with MDS containing ring sideroblasts (RiMDS), not otherwise fit for or refractory to standard therapies.
- Transfusion‑dependent β‑thalassemia (adult patients); reduces transfusion burden and improves hemoglobin maintenance.
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Contraindications
- Contraindications
- Hypersensitivity to any component of the formulation (e.g., recombinant proteins).
- Active, uncontrolled infection at the injection site.
- Warnings
- Iron overload: Monitor iron status; concurrent chelation therapy may be necessary.
- Cardiovascular events: Hypertension and thromboembolic events have been reported; monitor BP and assess cardiovascular history.
- Bone marrow fibrosis: Rare reports of new‑onset fibrosis; monitor marrow adequacy.
- Precautions
- Pregnancy and lactation: Limited data; consider risk–benefit balance.
- Elderly: Monitor with caution; no evidence of altered PK.
- Comorbid cancers: Evaluate for potential impact on disease progression.
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Dosing
| Condition | Initial Dose | Maintenance | Administration |
| RiMDS | 3 mg/kg SC (max 35 mg) | Every 3 weeks | Subcutaneous injection (anterolateral thigh or upper arm). |
| β‑thalassemia | 3 mg/kg SC (max 35 mg) | Every 3 weeks | Same as above. |
• SC Technique: Rotate injection sites, hold the needle for 30 s post‑injection to reduce intra‑vascular leakage.
• Premedication: Not routinely required; antihistamines may be used if mild infusion reaction occurs.
• Storage: Reconstituted product (1 mg/mL) stored at 2–8 °C; use within 24 h.
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Monitoring
| Parameter | Frequency | Rationale |
| CBC (Hb, RBC, WBC, Platelets) | At baseline, weekly for first 6 weeks, then every 3 weeks | Evaluate efficacy and detect bone‑marrow suppression. |
| Ferritin & Transferrin Saturation | Baseline, monthly | Assess iron overload risk. |
| Blood Pressure | Baseline, every visit | Detect hypertension. |
| Liver Function Tests | Baseline, q3 weeks | Monitor hepatotoxicity. |
| Reticulocyte count | Every visit | Gauge erythropoietic response. |
| Injections site exam | Every visit | Identify local reactions. |
| Contraception status (women of childbearing potential) | Baseline, q3 weeks | Due to limited fetal safety data. |
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Clinical Pearls
- Efficacy Horizon: Response is typically seen after 4–6 treatment cycles; optimize follow‑up by documenting a 1.5–2 g/dL Hb increase or ≥2-unit reduction in transfusion requirement.
- Weight‑Based Dosing: Adhering to a 3 mg/kg schedule rather than a flat dose enhances response in heavier patients and reduces overtreatment in lighter ones.
- Iron Management: Begin or intensify iron‑chelation therapy when ferritin >1,200 ng/mL or if FERRITIN/P. Accept that iron overload can mask efficacy data; keep ferritin 30 mL/min), but caution in severe CKD–consider close monitoring for potential delayed clearance of metabolites.
- Injection Etiquette: Using a 27‑gauge needle, avoid rapid injection to prevent post‑injection migratory pain; hold the site for 30 s.
- Pregnancy & Lactation: Insufficient human data; counsel patients on no-oral‑concurrency; otherwise, benefit‑risk must be thoroughly discussed.
- Switching Strategy: For patients failing first‑line erythropoiesis‑stimulating agents, a switch to Yupelri can be considered if they possess a high transfusion burden and no contraindications.
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• Key Takeaway
Yupelri offers a unique, ligand‐trap strategy to restore erythropoiesis by dampening the TGF‑β/SMAD 2/3 over‑inhibition loop. Its subcutaneous, weight‑based regimen, coupled with robust monitoring of hematologic and iron parameters, makes it a powerful tool in managing transfusion‑dependent anemia in RiMDS and β‑thalassemia.