Luspatercept

Luspatercept is a recombinant fusion protein made in Chinese Hamster Ovary cells: a modified extracellular domain of human activin receptor type IIB fused to the Fc portion of human IgG1. It is classed as an erythroid maturation agent. In myelodysplastic syndromes (MDS), a group of bone-marrow disorders, and in beta-thalassaemia, an inherited red-cell disorder caused by mutations in the β-globin gene, red cells mature poorly in the bone marrow (ineffective erythropoiesis) and anaemia follows. Luspatercept acts on this late stage of red-cell development.

Mechanism of Action

• Ligand trap: it binds selected TGF-β superfamily ligands (for example GDF-11 and activin B), which otherwise restrain late-stage red-cell maturation, and so inhibits Smad2/3 signalling.
• Erythroid maturation: this leads to expansion and differentiation of late-stage erythroid precursors (normoblasts) in the bone marrow, restoring effective erythropoiesis.
• Rationale: Smad2/3 signalling is abnormally high in disease models with ineffective erythropoiesis (MDS and beta-thalassaemia) and in the bone marrow of MDS patients.
• Haemoglobin response: in patients who had received fewer than 4 units of red cells in the 8 weeks before the study, haemoglobin rose within 7 days of starting, in step with the time to peak concentration. The largest mean rise followed the first dose, with smaller further rises after later doses, and haemoglobin returned to baseline about 6 to 8 weeks after the last dose (0.6 to 1.75 mg/kg).

Pharmacokinetics

• Absorption: slowly absorbed after subcutaneous injection, with the peak serum concentration often seen about 7 days after the dose. Absorption is linear over the doses studied and is not significantly affected by the injection site (upper arm, thigh or abdomen). Variability between individuals in AUC is about 37%.
• Distribution: the geometric mean apparent volume of distribution is 9.56 L in MDS and 7.26 L in beta-thalassaemia, indicating that luspatercept stays mainly in extracellular fluid.
• Metabolism: expected to be broken down into amino acids by general protein degradation.
• Elimination: not expected to be excreted in urine because the molecule is too large to be filtered. The geometric mean apparent clearance is 0.47 L/day in MDS and 0.44 L/day in beta-thalassaemia; the geometric mean half-life in serum is about 14.1 days in MDS and 11 days in beta-thalassaemia.
• Dose proportionality: Cmax and AUC rise roughly in proportion to dose from 0.125 to 1.75 mg/kg, and clearance is independent of dose and time. With dosing every 3 weeks, steady state is reached after 3 doses, with an accumulation ratio of about 1.5.
• Special populations: patients with renal impairment at baseline have higher exposure. Iron-chelating agents taken at the same time did not change luspatercept pharmacokinetics.

Reblozyl is indicated in adults for:

• Myelodysplastic syndromes (MDS): treatment of transfusion-dependent anaemia due to very low-, low- and intermediate-risk MDS.
• Beta-thalassaemia: treatment of anaemia associated with transfusion-dependent and non-transfusion-dependent beta-thalassaemia.

• Hypersensitivity to the active substance or to any of the excipients.
• Pregnancy.
• Patients who need treatment to control the growth of extramedullary haemopoiesis (EMH) masses.

The most frequent reactions (at least 15% of patients) were: in MDS, fatigue, diarrhoea, nausea, asthenia, dizziness, peripheral oedema and back pain; in transfusion-dependent beta-thalassaemia, headache, bone pain and arthralgia; in non-transfusion-dependent beta-thalassaemia, bone pain, headache, arthralgia, back pain, prehypertension and hypertension. Treatment was stopped because of an adverse event in 10.1% of MDS patients (the most common reason was progression of the underlying MDS), and because of an adverse reaction in 2.6% of transfusion-dependent and 3.1% of non-transfusion-dependent beta-thalassaemia patients. The frequencies below are the highest seen in the pivotal and long-term studies.

Very common (≥1/10): dizziness, headache, hypertension, nausea, diarrhoea, back pain, fatigue and asthenia in both indications. In MDS also urinary tract infection, electrolyte imbalance, cough, dyspnoea and peripheral oedema. In beta-thalassaemia also upper respiratory tract infection, influenza, insomnia, prehypertension, abdominal pain, arthralgia, bone pain, and raised aspartate aminotransferase and blood bilirubin (laboratory values of any grade).

Common (≥1/100 to <1/10): bronchitis, hypersensitivity, hyperuricaemia, anxiety, syncope or presyncope, vertigo (including positional vertigo), thromboembolic events, epistaxis, injection site reactions and raised alanine aminotransferase in both indications. In MDS also respiratory tract infection, upper respiratory tract infection, influenza, thrombocytopenia, dehydration, decreased appetite, insomnia, confusional state, atrial fibrillation, cardiac failure, tachycardia, abdominal pain, abdominal discomfort, hyperhidrosis, arthralgia, bone pain, myalgia, muscular weakness, kidney injury, non-cardiac chest pain, influenza-like illness, and raised aspartate aminotransferase, blood bilirubin and γ-glutamyltransferase. In beta-thalassaemia also urinary tract infection, dyspnoea, extramedullary haemopoiesis, irritability, migraine, spinal cord compression, proteinuria, albuminuria and traumatic fracture.

Not known: extramedullary haemopoiesis in MDS (reported only after marketing).

Important serious reactions:

• Thromboembolic events: 3.9% in MDS, 3.6% in transfusion-dependent beta-thalassaemia.
• EMH masses: 3.2% in transfusion-dependent and 6.3% in non-transfusion-dependent beta-thalassaemia, with spinal cord compression in 1.9% and 1.0% respectively.
• Hypertension: grade 3 events in 7.5% of MDS patients.
• Traumatic fracture: 8.3% in non-transfusion-dependent beta-thalassaemia.
• Antibodies: treatment-emergent anti-luspatercept antibodies appeared in 9.1% of MDS patients and 1.84% of beta-thalassaemia patients; serum concentration tended to fall in their presence.

MDS patients without ring sideroblasts, or with non-mutated SF3B1, were more likely to have serious adverse events.

• No formal clinical interaction studies have been performed.
• Iron-chelating agents: concurrent use had no effect on luspatercept pharmacokinetics.

Treatment should be started by a physician experienced in the treatment of haematological diseases. The haemoglobin level is assessed before each administration; if a red blood cell transfusion was given before dosing, the pre-transfusion haemoglobin is used for dosing. Reblozyl is for subcutaneous use. Section 4.2 of the SmPC does not state who gives each injection; it describes how the dose is prepared and injected (reconstitution is covered in section 6.6 of the SmPC).

Injection

• After reconstitution, the solution is injected subcutaneously into the upper arm, thigh or abdomen. The exact total volume for the patient is calculated and slowly drawn from the single-dose vial(s) into a syringe.
• The recommended maximum volume per injection site is 1.2 mL. If more is needed, the total volume is divided into separate injections of similar volume, given at separate sites in the same anatomical location on opposite sides of the body.
• A new syringe and needle are used for each subcutaneous injection, and no more than one dose is taken from a vial.
• If the reconstituted solution has been refrigerated, it is taken out 15 to 30 minutes before injection to reach room temperature, which makes the injection more comfortable.

Starting Dose

• 1 mg/kg once every 3 weeks.

Myelodysplastic Syndromes

• The desired haemoglobin range is 10–12 g/dL.
• If, after at least 2 consecutive doses at 1 mg/kg, the patient is not transfusion-free, or does not reach a haemoglobin of 10 g/dL or more and the rise is below 1 g/dL, increase to 1.33 mg/kg. The same criteria after at least 2 doses at 1.33 mg/kg lead to 1.75 mg/kg, the maximum every 3 weeks.
• A dose increase should not come more often than every 6 weeks (2 administrations) and not straight after a dose delay. If the pre-dose haemoglobin is above 9 g/dL and transfusion independence has not been reached, an increase may be needed at the physician’s discretion; a haemoglobin rise above target with concomitant transfusion cannot be excluded.
• Dose levels: 0.8, 1, 1.33 and 1.75 mg/kg. A patient who loses response moves up one level.

Transfusion-Dependent Beta-Thalassaemia

• If the transfusion burden has not fallen by at least a third after at least 2 consecutive doses (6 weeks) at 1 mg/kg, increase to 1.25 mg/kg, the maximum every 3 weeks. A patient who loses response moves up one dose level (0.8, 1, 1.25 mg/kg).

Non-Transfusion-Dependent Beta-Thalassaemia

• If the pre-dose haemoglobin has not risen by at least 1 g/dL from baseline (at least 3 weeks after the last transfusion) after at least 2 consecutive doses (6 weeks) at the same level, or the response is not kept, increase by one dose level (0.6, 0.8, 1, 1.25 mg/kg). The maximum is 1.25 mg/kg every 3 weeks.

Dose Reduction, Delay and Modification

• A haemoglobin rise of more than 2 g/dL within 3 weeks without transfusion: reduce by one dose level (MDS: 1.75 to 1.33 to 1 to 0.8 mg/kg; beta-thalassaemia: 1.25 to 1 to 0.8 to 0.6 mg/kg, the last only in non-transfusion-dependent disease). The dose is not reduced below 0.8 mg/kg (MDS and transfusion-dependent beta-thalassaemia) or 0.6 mg/kg (non-transfusion-dependent).
• Haemoglobin of 12 g/dL or more for at least 3 weeks without transfusion: delay the dose until haemoglobin is 11 g/dL or less; if there was also a rapid rise, consider one step down after the delay.
• Grade 2 adverse reactions, including grade 2 hypertension: interrupt, and restart at the previous dose once improved or back to baseline.
• Grade 3 or higher hypertension: interrupt, and restart at a reduced dose once blood pressure is controlled.
• Other persistent grade 3 or higher reactions: interrupt, and restart at the previous or a reduced dose once improved or back to baseline.
• EMH masses causing serious complications: discontinue.

Loss of Response and Discontinuation

If response is lost, causes such as a bleeding event should be assessed first. Reblozyl should be discontinued if, after 9 weeks (3 doses) at the maximum dose level, there is no reduction in transfusion burden (transfusion-dependent beta-thalassaemia), no rise in haemoglobin from baseline without transfusion (non-transfusion-dependent beta-thalassaemia) or no fall in transfusion burden (MDS), and no other explanation is found, or if toxicity becomes unacceptable.

Missed Dose

A missed or delayed dose is given as soon as possible, and dosing then continues as prescribed with at least 3 weeks between doses.

Special Populations

• Elderly: no starting dose adjustment; data are limited in beta-thalassaemia patients aged 60 years or over.
• Hepatic impairment: no starting dose adjustment for bilirubin above the upper limit of normal and/or ALT or AST below 3 times the upper limit. No dose can be recommended for ALT or AST at 3 times the upper limit or more, or for liver injury of grade 3 or higher, because of lack of data.
• Renal impairment: no starting dose adjustment for mild or moderate impairment (eGFR 30 to 89 mL/min). No dose can be recommended for severe impairment (eGFR below 30 mL/min). Exposure is higher at baseline in renal impairment, so these patients should be monitored closely for adverse reactions and the dose adjusted accordingly.
• Children: no relevant use in MDS, or in beta-thalassaemia below 6 years. Safety and efficacy in beta-thalassaemia from 6 to under 18 years have not been established.

Traceability

Because Reblozyl is a biological medicinal product, its name and batch number should be clearly recorded for each patient.

Thromboembolic Events

In beta-thalassaemia, thromboembolic events occurred in 3.6% (8/223) of transfusion-dependent patients in the double-blind phase and in 0.7% (1/134) of non-transfusion-dependent patients in the open-label phase: deep vein thrombosis, portal vein thrombosis, pulmonary embolism, ischaemic stroke and superficial thrombophlebitis. All affected patients had had a splenectomy and at least one other risk factor (such as a history of thrombocytosis or hormone replacement therapy), and events did not follow raised haemoglobin. Benefit should be weighed against this risk in splenectomised patients with other risk factors, and thromboprophylaxis according to current guidelines considered in higher-risk patients. In MDS, thromboembolic events occurred in 3.9% (13/335), including cerebral ischaemia and cerebrovascular accident in 1.2%; all had significant risk factors (atrial fibrillation, stroke or heart failure, peripheral vascular disease).

Extramedullary Haemopoiesis Masses

In transfusion-dependent beta-thalassaemia, EMH masses occurred in 3.2% (10/315) of patients and spinal cord compression symptoms in 1.9% (6/315). In non-transfusion-dependent beta-thalassaemia, EMH masses occurred in 6.3% (6/96) and spinal cord compression in 1.0% (1/96). Patients with EMH masses may see them worsen. Patients should be monitored at the start and during treatment for symptoms and complications, treated according to clinical guidelines, and treatment must be discontinued for serious complications.

Increased Blood Pressure

Systolic and diastolic blood pressure rose by an average of up to 5 mmHg from baseline, and hypertension was more frequent during the first 12 months in non-transfusion-dependent beta-thalassaemia. Treatment must be started only when blood pressure is adequately controlled. Blood pressure should be monitored before each administration, the dose adjusted or delayed as needed, and hypertension treated per current guidelines. The benefit of Reblozyl should be re-evaluated if hypertension persists or worsens.

Traumatic Fracture

Traumatic fractures occurred in 0.4% (1/223) of transfusion-dependent and 8.3% (8/96) of non-transfusion-dependent beta-thalassaemia patients. Patients should be informed of the risk.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy: contraindicated. There are no human data, and animal studies showed reproductive toxicity. Treatment must not be started in a pregnant woman and must be discontinued if a patient becomes pregnant.
• Before starting: women of childbearing potential need a pregnancy test and the patient card has to be provided. They must use effective contraception during treatment and for at least 3 months after the last dose.
• Breastfeeding: it is unknown whether luspatercept or its metabolites pass into human milk; it was detected in the milk of lactating rats. A decision must be made whether to stop breastfeeding during therapy and for 3 months after the last dose, or to stop Reblozyl.
• Fertility: the effect in humans is unknown; animal findings suggest it may compromise female fertility.

Polysorbate 80 and Sodium

Each 25 mg vial contains 0.1 mg and each 75 mg vial 0.3 mg of polysorbate 80 (0.2 mg/mL), which may cause allergic reactions. The medicine contains less than 1 mmol (23 mg) sodium per dose, so it is essentially sodium-free.

Effect on Driving

Reblozyl has a minor influence on the ability to drive and use machines. Fatigue, vertigo, dizziness or syncope may impair reactions, so patients should take care until they know how the medicine affects them.

Store unopened vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the original carton to protect it from light. As a refrigerated product, it should be transported and stored in an unbroken cold chain. Storage after reconstitution is described under Shelf Life.

• Unopened vial: 5 years.
• After reconstitution: in the original vial, chemical and physical in-use stability has been shown for up to 8 hours at room temperature (up to 25 °C) or up to 24 hours at 2–8 °C. From a microbiological point of view the solution should be used immediately; if it is not, in-use storage is the user’s responsibility and should not exceed 24 hours at 2–8 °C. Do not freeze the reconstituted solution.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation); treatment is started by a physician experienced in the treatment of haematological diseases. Reblozyl is a powder that is reconstituted and injected subcutaneously every 3 weeks after a haemoglobin check, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.