Targeting Ineffective Erythropoiesis and Iron Dysregulation

Many preclinical studies have provided evidence on the role of ruxolitinib (JAK1/JAK2 inhibitor) as a potential target to improve ineffective erythropoiesis. The inhibition of JAK2 in TDT and non-transfusion-dependent thalassaemia (NTDT) mouse models was shown to not only improve ineffective erythropoiesis but also to decrease splenomegaly (Casu et al., 2018). A phase 2a study assessed the efficacy and safety of ruxolitinib in TDT patients with spleen enlargement. Ruxolitinib was overall well tolerated in this study population, and the safety profile was consistent with the previous reports. However, because the major purpose of reducing spleen size in patients with TDT is to improve pre-transfusion haemoglobin and related reduction in transfusion needs where ruxolitinib had shown a limited effect, no further studies were conducted.

Sotatercept or ACE-011 has been also shown to correct ineffective erythropoiesis by acting as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor β (TGF-β) superfamily. A phase 2 study conducted on 16 TDT patients showed that the majority of TDT patients (66%) treated with higher doses of sotatercept (0.75-1.0 mg/kg) achieved reductions of ≥33% in red cell transfusion requirements. The increase in haemoglobin and reduction in red cell transfusion correlated with increased serum exposure to sotatercept (Cappellini et al., 2019). Sotatercept exhibited an overall good safety profile and was tolerated by most patients. Treatment discontinuation due to adverse events was rare, and the incidence of grade 3-4 adverse events was low. A decision, however, was made not to advance trials of sotatercept in β thalassaemia due to binding of sotatercept to activin A.

Preliminary data with sotatercept led to the initiation of similar trials in TDT patients using luspatercept. Luspatercept or ACE-536 is a recombinant fusion protein that binds to specific ligands of the TGF-β superfamily and enhances erythroid maturation. It is the most recently approved therapy (FDA and EMA) for the management of TDT. Pre-clinical data on murine models showed that treatment with RAP-536 reduced α globin chain aggregation and haemolysis, while increasing erythrocyte life span and improving iron overload (Suragani et al., 2014b). Additionally, RAP-536 increased haemoglobin concentration and red cell count (RBC), and reduced comorbidities associated with β thalassemia, such as decreased bone mineral density and splenomegaly (Suragani et al., 2014a). In the phase 1 study, 32 healthy volunteers were randomized 3:1 to receive 2 doses of luspatercept (0.0625–0.25 mg/kg) or placebo subcutaneously every 2 weeks (ClinicalTrials.gov number NCT01432717). Luspatercept was well-tolerated and dose-dependent and increases in haemoglobin concentration and RBC were observed after the first dose (Attie et al., 2014). A phase 2, open-label, nonrandomised, uncontrolled, dose-finding study was then conduced to evaluate the effects of luspatercept in β thalassaemia patients. The study enrolled 33 NTDT patients and 31 TDT patients (ClinicalTrials.gov number NCT01749540) (Piga et al., 2019). Luspatercept was administered subcutaneously every 21 days (0.2–1.25 mg/kg) in dose escalation and expansion cohorts. The primary endpoint of mean increase in haemoglobin concentration from baseline of ≥ 15 g/l for ≥2 weeks (in the absence of red cell transfusions) was achieved by 58% (95% confidence interval [CI] 39.1 to 75.5) of NTDT patients receiving the higher dose range of luspatercept (0.6–1.25 mg/kg). In TDT patients, the primary endpoint of a transfusion-burden reduction of ≥ 20% over any 12 weeks vs baseline was achieved by 81% (95% CI 63.6, 92.8) of patients receiving the higher dose range of luspatercept. These findings, including the achievement of secondary endpoints, prompted a randomised Phase 3 clinical trial (BELIEVE Trial) to assess efficacy and safety.

The approval of luspatercept was based on the results the BELIEVE trial, a phase 3, randomised, double-blind, placebo-controlled trial which showed that subcutaneous administration of luspatercept (n=224) at doses of 1-1.25 mg/kg led to a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24. Moreover, a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%) (Cappellini et al., 2020b). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). Parallel reductions in serum ferritin levels were also observed. Adverse events more commonly seen in the luspatercept group compared to placebo included bone pain, arthralgia, dizziness, hypertension and hyperuricaemia. Data on the long-term use of luspatercept, its real-life application and its use in the paediatric population are awaited.

The effects of luspatercept on iron loading over time and the impact of baseline iron parameters on response to luspatercept was also evaluated and showed that luspatercept treatment resulted in clinically meaningful and maintained reductions in serum ferritin levels (Porter et al., 2019). Baseline iron overload did not seem to affect response rates with luspatercept. Treatment with luspatercept resulted in clinically meaningful reductions in red cell transfusion burden regardless of baseline serum ferritin level. There was a trend for decrease in liver iron concentration (LIC) with longer follow up at 96 weeks; among responders, the decrease was more pronounced compared with non-responders (Porter et al., 2019). In a sub-analysis on long-term efficacy and safety of luspatercept, it was shown that luspatercept treatment was associated with prolonged periods of clinically meaningful reductions in transfusion burden, including in patients who crossed over from the placebo arm (Taher et al., 2020). The safety profile of crossover patients was consistent with that reported in the luspatercept arm. Another sub-analysis study explored the association between β globin genotype and response to luspatercept in adult patients with β thalassaemia in the BELIEVE trial (Cappellini et al., 2020a). It was found that although response rates were lower in patients with the most severe disease (β⁰/β⁰), clinically meaningful reductions in transfusion burden were observed across all genotypes (Cappellini et al., 2020a).

Other agents targeting ineffective erythropoiesis and iron dysregulation also exist. These include VIT-2763 (an oral ferroportin inhibitor), TMPRSS6-LRx (anti-sense oligonucleotides downregulating TMPRSS6), and Mitapivat (AG-348) (an oral, small molecule, allosteric activator of the red cell-specific form of pyruvate kinase). Ongoing clinical trials on the use of these agents are currently underway in NTDT patients only.

Box

Summary and Recommendations.

References

1. Attie K.M., Allison M.J., McClure T., Boyd I.E., et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. American Journal of Hematology. [Online] 2014;89(7):766–770. Available from: doi: [PMC free article: PMC4173124] [PubMed: 24715706] [CrossRef]
2. Bou-Fakhredin R., Tabbikha R., Daadaa H., Taher A.T. Emerging therapies in β-thalassemia: toward a new era in management. Expert Opinion on Emerging Drugs. [Online] 2020;25(2):113–122. Available from: doi: [PubMed: 32249632] [CrossRef]
3. Cappellini D., Hermine O., Piga A., Viprakasit V., et al. Assessment of response to Luspatercept by β-globin genotype in adult patients with β-thalassemia in the BELIEVE trial. [Online]. 12 June 2020 EHA Library. 2020a. p. Available from: https://library​.ehaweb​.org/eha/2020/eha25th/295114/maria​.domenica​.cappellini.assessment​.of.response.to​.luspatercept.by.-globin​.html?f=listing​%3D0%2Abrowseby%3D8​%2Asortby%3D1%2Asearch%3Ds295 [Accessed: 12 February 2021]
4. Cappellini M.D., Porter J., Origa R., Forni G.L., et al. Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study. Haematologica. [Online] 2019;104(3):477–484. Available from: doi: [PMC free article: PMC6395345] [PubMed: 30337358] [CrossRef]
5. Cappellini M.D., Viprakasit V., Taher A.T., Georgiev P., et al. A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia. The New England Journal of Medicine. [Online] 2020b;382(13):1219–1231. Available from: doi: [PubMed: 32212518] [CrossRef]
6. Casu C., Presti V.L., Oikonomidou P.R., Melchiori L., et al. Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of β-thalassemia intermedia and major. Haematologica. [Online] 2018;103(2):e46–e49. Available from: doi: [PMC free article: PMC5792284] [PubMed: 29097498] [CrossRef]
7. EMA. European Medicines Agency. [Online]. 2021. European Medicines Agency; 2021. Available from: https://www​.ema.europa.eu/en [Accessed: 4 March 2021]
8. Hanna E., Rémuzat C., Auquier P., Toumi M. Gene therapies development: slow progress and promising prospect. Journal of Market Access & Health Policy. [Online] 2017;5(1) Available from: doi: [Accessed: 11 February 2021] [PMC free article: PMC5328344] [PubMed: 28265348] [CrossRef]
9. Motta I., Bou-Fakhredin R., Taher A.T., Cappellini M.D. Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation. Drugs. [Online] 2020;80(11):1053–1063. Available from: doi: [PMC free article: PMC7299245] [PubMed: 32557398] [CrossRef]
10. Piga A., Perrotta S., Gamberini M.R., Voskaridou E., et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. [Online] 2019;133(12):1279–1289. Available from: doi: [PMC free article: PMC6440118] [PubMed: 30617198] [CrossRef]
11. Porter J., Cappellini M.D., Coates T., Hermine O., et al. Effects of Luspatercept on Iron Overload and Impact on Responders to Luspatercept: Results from the BELIEVE Trial. Blood. [Online] 2019;134 Supplement_1:2245–2245. Available from: doi: [CrossRef]
12. Suragani R.N.V.S., Cadena S.M., Cawley S.M., Sako D., et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nature Medicine. [Online] 2014a;20(4):408–414. Available from: doi: [PubMed: 24658078] [CrossRef]
13. Suragani R.N.V.S., Cawley S.M., Li R., Wallner S., et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia. Blood. [Online] 2014b;123(25):3864–3872. Available from: doi: [PMC free article: PMC4064330] [PubMed: 24795345] [CrossRef]
14. Taher A., Cappellini M.D., Viprakasit V., Hermine O., et al. Assessment of longer-term efficacy and safety in the phase 3 BELIEVE trial of Luspatercept to treat anemia in patients (pts) with β-Thalassemia. [Online]. 12 June 2020 EHA library. 2020. p. Available from: https://library.ehaweb.org/eha/2020/eha25th/294032/ali.taher.assessment.of.longer-term.efficacy.and.safety.in.the.phase.3.believe.html?f=listing%3D 3%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D1 [Accessed: 12 February 2021]
15. U.S. FDA. U.S. Food and Drug Administration. [Online]. 2021. FDA; 2021. Available from: https://www​.fda.gov/home [Accessed: 4 March 2021]

ANNEX I

Product characteristics of Reblozyl^®. Extracts from EMA (European Medicines Agency) and the FDA (Food and Drug Administration) summaries.

NAME OF THE MEDICINAL PRODUCT

Reblozyl 25 mg powder for solution for injection Reblozyl 75 mg powder for solution for injection (EMA)

Figure

• This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions (EMA)

POSOLOGY

Prior to each Reblozyl administration, the haemoglobin (Hb) level of patients should be assessed. In case of a red blood cell (RBC) transfusion occurring prior to dosing, the pre-transfusion Hb level must be considered for dosing purposes. (EMA)

Figure

Figure

Missed doses

In case of a missed or delayed scheduled treatment administration, the patient should be administered Reblozyl as soon as possible and dosing continued as prescribed with at least 3 weeks between doses. (EMA)

Patients experiencing a loss of response

If patients experience a loss of response to Reblozyl, causative factors (e.g. a bleeding event) should be assessed. If typical causes for a loss of haematological response are excluded, dose increase should be considered as described above for the respective indication being treated (EMA)

Discontinuation

Reblozyl should be discontinued if patients do not experience a reduction in transfusion burden after 9 weeks of treatment (3 doses) at the maximum dose level if no alternative explanations for response failure are found (e.g. bleeding, surgery, other concomitant illnesses) or if unacceptable toxicity occurs at any time. (EMA)

WARNINGS AND PRECAUTIONS (FDA)

 

5.1 Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. Reported TEEs included deep vein thromboses, pulmonary embolus, portal vein thrombosis, and ischemic strokes. Patients with known risk factors for

Reference ID: 4586176 8 thromboembolism, e.g. splenectomy or concomitant use of hormone replacement therapy, may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients with beta thalassemia at increased risk of TEE. Monitor patients receiving REBLOZYLfor signs and symptoms of thromboembolic events and institute treatment promptly.

5.2 Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of grade 3-4 hypertension ranged from 1.8% to 8.6%. In adult patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg.

Monitor blood pressure prior to each administration. Manage new-onset hypertension or exacerbations of preexisting hypertension using anti-hypertensive agents.

5.3 Embryo-Fetal Toxicity

Based on findings from animal reproductive studies, Reblozyl^® may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes including increased embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures (based on area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD) of 1.75 mg/kg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with REBLOZYL and for at least 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

Tabulated list of adverse reactions

The highest frequency for each adverse reaction that was observed and reported in the two pivotal studies in MDS and β-thalassaemia is shown in Table 3 below. The adverse reactions are listed below by body system organ class and preferred term. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). (EMA)

Figure