REBLOZYL Powder for solution for injection / infusion Ref.[10138] Active ingredients: Luspatercept

Increases in Hemoglobin in Patients with Low RBC Transfusion Burden

In patients having received <4 units of RBC transfusion within 8 weeks prior to study, hemoglobin increased within 7 days of initiating REBLOZYL and correlated with the time to luspatercept-aamt maximum serum concentration (C_max). The greatest Hgb increase occurred after the first dose; approximately 0.75 g/dL at a dose of 0.6 to 1.25 times the recommended starting dose for beta thalassemia, or approximately 1 g/dL at a dose of 0.75 to 1.75 times the recommended starting dose for MDS. Additional smaller increases were observed after subsequent doses. Hemoglobin levels returned to baseline approximately 6 to 8 weeks from the last dose following administration of luspatercept-aamt (0.6 to 1.75 mg/kg).

Increasing luspatercept-aamt serum exposure (AUC) was associated with greater Hgb increase in patients with beta thalassemia or MDS who had a baseline transfusion burden <4 units/8 weeks. Increasing luspatercept-aamt serum exposure (time-averaged AUC) was associated with greater probability of achieving transfusion independence for at least 8 consecutive weeks in patients with MDS requiring transfusions (≥2 units of RBC transfusion within 8 weeks).

Luspatercept-aamt exhibited linear pharmacokinetics (PK) over the dose range of 0.2 to 1.25 mg/kg (0.2 to 1.25 times the recommended starting dosage) in patients with beta thalassemia, and from 0.125 mg/kg to 1.75 mg/kg in patients with MDS. The mean (% coefficient of variation [CV]) steady-state AUC at the starting dose of 1 mg/kg was 126 (35.9) day∙µg/mL for patients with beta thalassemia and 145 (38.3%) day∙µg/mL for patients with MDS. Luspatercept-aamt serum concentration reached steady state after 3 doses when administered every 3 weeks. The accumulation ratio of luspatercept-aamt was approximately 1.5.

Absorption

The median (range) time to maximum concentration (T_max) of luspatercept-aamt was observed at approximately 7 [6 to 10] days post-dose in adult patients with beta thalassemia or 7 [5 to 21] days post-dose in adult patients with MDS. The absorption of luspatercept-aamt was not significantly affected by the subcutaneous injection sites (upper arm, thigh, or abdomen).

Distribution

The mean (CV) apparent volume of distribution (V_d/F) of luspatercept-aamt was 7.1 (26.7) L for patients with beta thalassemia, and 9.7 (26.5%) for patients with MDS.

Elimination

The mean (CV) half-life (t_1/2) of luspatercept-aamt was approximately 11 (25.7) days and the mean (CV) apparent total clearance (CL/F) was 0.44 (38.5) L/day in patients with beta thalassemia. The mean (CV) t_1/2 of luspatercept-aamt was approximately 13 (31.6) days and the mean (CV) CL/F was 0.52 (41.2) L/day in patients with MDS.

Metabolism

Luspatercept-aamt is expected to be catabolized into amino acids by general protein degradation processes in multiple tissues.

Specific Populations

No clinically significant differences in the luspatercept-aamt PK was observed based on age (18 to 95 years), sex, race/ethnicity (Asian, White), mild to severe hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransaminase [AST] or alanine transaminase [ALT] > ULN, or total bilirubin > ULN and any AST or ALT), mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73 m²), baseline albumin (30 to 56 g/L), baseline serum erythropoietin (2.4 to 2450 U/L), red blood cell (RBC) transfusion burden (0 to 43 units/24 weeks), beta thalassemia genotype (β0/β0 vs. non-β0/β0), splenectomy, and ring sideroblasts status in MDS (negative vs. positive). The effect of AST or ALT >3 × ULN and the effect of severe renal impairment (eGFR <30 mL/min/1.73 m²) on luspatercept-aamt PK is unknown.

Body Weight

The apparent CL/F and V_d/F of luspatercept-aamt increased with increasing body weight in patients with beta thalassemia (34 to 97 kg) and in patients with MDS (46 to 124 kg).

Drug Interaction Studies

Effect of Iron-chelating Agents on Luspatercept-aamt

No clinically significant differences in luspatercept-aamt PK were observed when used concomitantly with iron-chelating agents.

No carcinogenicity or mutagenicity studies have been conducted with luspatercept-aamt.

In a repeat-dose toxicity study, juvenile rats were administered luspatercept-aamt subcutaneously at 1, 3, or 10 mg/kg once every 2 weeks from postnatal day 7 to 91. Hematologic malignancies (granulocytic leukemia, lymphocytic leukemia, malignant lymphoma) were observed at 10 mg/kg resulting in exposures (based on area under the curve [AUC]) approximately 4.4 times the maximum recommended human dose (MRHD) of 1.75 mg/kg.

In a combined male and female fertility and early embryonic development study in rats, luspatercept-aamt was administered subcutaneously to animals at doses of 1 to 15 mg/kg. There were significant reductions in the average numbers of corpora lutea, implantations, and viable embryos in luspatercept-aamt-treated females. Effects on female fertility were observed at the highest dose with exposures (based on AUC) approximately 7-times the MRHD of 1.75 mg/kg. Adverse effects on fertility in female rats were reversible after a 14-week recovery period. No adverse effects were noted in male rats.

14.1 Beta Thalassemia

The efficacy of REBLOZYL was evaluated in adult patients with beta thalassemia in the BELIEVE trial (NCT02604433). BELIEVE was a multicenter, randomized, double-blind, placebo-controlled trial in which (n=336) patients with beta thalassemia requiring regular red blood cell transfusions (6-20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during that period were randomized 2:1 to REBLOZYL (n=224) or placebo (n=112). In BELIEVE, REBLOZYL was administered subcutaneously once every 3 weeks as long as a reduction in transfusion requirement was observed or until unacceptable toxicity. All patients were eligible to receive best supportive care, which included RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed.

The BELIEVE trial excluded patients with a diagnosis of Hemoglobin S/β-thalassemia or isolated alpha (α)-thalassemia (e.g., Hemoglobin H) or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Patients with recent deep vein thrombosis or stroke or recent use of ESA, immunosuppressant, or hydroxyurea therapy were also excluded. The median age was 30 years (range: 18-66). The trial was comprised of patients who were 42% male, 54.2% White, 34.8% Asian, and 0.3% Black or African American. The percent of patients reporting their race as “other” was 7.7%, and race was not collected or reported for 3% of patients.

Table 10 summarizes the baseline disease-related characteristics in the BELIEVE study.

Table 10. Baseline Disease Characteristics of Patients with Beta Thalassemia in BELIEVE:

HbE=hemoglobin E.
* “Missing” category includes patients in the population who had no result for the parameter listed.

The efficacy of REBLOZYL in adult patients with beta thalassemia was established based upon the proportion of patients achieving RBC transfusion burden reduction (≥33% reduction from baseline) with a reduction of at least 2 units from Week 13 to Week 24.

Efficacy results are shown in Table 11.

Table 11. Efficacy Results in Beta Thalassemia – BELIEVE:

14.2 Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic / Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia

The efficacy of REBLOZYL was evaluated in the MEDALIST trial (NCT02631070), a multi-center, randomized, double-blind, placebo-controlled trial in patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who have ring sideroblasts and require red blood cell transfusions (2 or more RBC units over 8 weeks). For eligibility, patients were required to have had an inadequate response to prior treatment with an erythropoiesis-stimulating agent (ESA), be intolerant of ESAs, or have a serum erythropoietin >200 U/L. The MEDALIST trial excluded patients with deletion 5q (del 5q), white blood cell count >13 Gi/L, neutrophils <0.5 Gi/L, platelets <50 Gi/L, or with prior use of a disease modifying agent for treatment of MDS.

The MEDALIST trial included 229 patients randomized 2:1 to REBLOZYL (n=153) or placebo (n=76). Randomization was stratified by baseline RBC transfusion burden and baseline IPSS-R. Treatment was started at 1 mg/kg subcutaneously every 3 weeks; the dose could be increased after completion of the first 2 cycles if the patient had at least one RBC transfusion in the prior 6 weeks. Two dose level increases were allowed (to 1.33 mg/kg and to 1.75 mg/kg). Doses were held and subsequently reduced for adverse reactions, reduced if the hemoglobin increased by ≥2 g/dL from the prior cycle, and held if the predose hemoglobin was ≥11.5 g/dL.

All patients received best supportive care, which included RBC transfusions as needed. The primary efficacy assessment was conducted after completion of 24 weeks on study drug. Patients with a decrease in transfusion requirement or increase in hemoglobin could continue on blinded study drug thereafter until unacceptable toxicity, loss of efficacy, or disease progression. The median age of the 229 study participants was 71 years (range: 26, 95 years). The trial population was 63% male and 69% White. Table 12 summarizes the baseline disease-related characteristics in the MEDALIST study.

Table 12. Baseline Disease Characteristics of Patients in MEDALIST:

EPO=erythropoietin; IPSS R=International Prognostic Scoring System-Revised; ITT=intent-to-treat; MDS=myelodysplastic syndromes; RARS=refractory anemia with ring sideroblasts; RBC=red blood cell; RCMD=refractory cytopenia with multilineage dysplasia; SD=standard deviation; WHO=World Health Organization.
* Time since original MDS diagnosis was defined as the number of years from the date of original diagnosis to the date of informed consent.
^† Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug.
^‡ Includes MDS-RS-MLD and MDS-RS-SLD.
^§ Includes MDS-EB-1, MDS-EB-2, and MDS-U.

The efficacy of REBLOZYL in adult patients with MDS-RS and MDS-RS-T was established based upon the proportion of patients who were red blood cell transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period occurring entirely within Weeks 1 through 24.

The efficacy results are shown in Tables 13 and 14.

Table 13. Efficacy Results in MEDALIST:

* The median (range) duration of treatment was 4 9 weeks (6 to 114 weeks) on the REBLOZYL arm and 24 weeks (7 to 89 weeks) on the placebo arm.

Table 14 shows the proportion of patients who achieved RBC-TI ≥ 8 weeks during Weeks 1-24 by diagnosis and baseline transfusion requirement.

Table 14. RBC-TI ≥8 weeks during Weeks 1-24 By Diagnosis and Baseline Transfusion Burden in MEDALIST:

* Includes MDS-EB-1, MDS-EB-2, and MDS-U.
^† Includes patients who received 3.5 units.
^‡ Includes patients who received 5.5 units.