review - food and drug administration · 2020. 10. 8. · u.s. department of health and human...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

761136Orig2s000

STATISTICAL REVIEW(S)

U.S. Department of Health and Human ServicesFood and Drug Administration Center for Drug Evaluation and ResearchOffice of Translational SciencesOffice of Biostatistics

S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N

CLINICAL STUDIES

BLA Serial Number: 761136/00 Orig. 2

Drug Name: REBLOZYL (Luspatercept-aamt)

Indication(s): For adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS)-associated anemia who have ring sideroblasts and require red blood cell (RBC) transfusions

Applicant: Celgene Corporation

Receipt DatePDUFA Goal Date

04/04/201904/04/2020

Review Priority: Standard

Biometrics Division: IX

Statistical Reviewer: Weishi Yuan

Concurring Reviewers: Yu-te Wu, Team LeaderThomas Gwise, Division Director

Medical Division: Division of Hematology Malignancies 1

Clinical Team: Elizabeth Pulte, Clinical ReviewerDonna Przepiorka , Team LeaderAlbert Deisseroth, Associate Division Director

Project Manager: Rosa Lee-Alonzo

Keywords: Myelodysplastic Syndromes (MDS), Red Blood Cell Transfusion Independence, Stratified Cochran Mantel-Haenszel (CMH) Test

Reference ID: 4538554

Table of ContentsLIST OF TABLES..........................................................................................................................................3

LIST OF FIGURES........................................................................................................................................4

1. EXECUTIVE SUMMARY....................................................................................................................5

2. INTRODUCTION ..................................................................................................................................7

2.1 OVERVIEW ........................................................................................................................................72.1.1. Class and Indication.................................................................................................................72.1.2. Regulatory History ...................................................................................................................72.1.3. Study Reviewed.........................................................................................................................8

2.2 DATA SOURCES .................................................................................................................................9

3. STATISTICAL EVALUATION .........................................................................................................10

3.1 DATA AND ANALYSIS QUALITY ......................................................................................................103.2 EVALUATION OF EFFICACY .............................................................................................................10

3.2.1. Study Design and Endpoints...................................................................................................103.2.2. Efficacy Measures ..................................................................................................................123.2.3. Sample Size Consideration .....................................................................................................133.2.4. Statistical Methodologies .......................................................................................................133.2.5. Patient Disposition, Demographic and Baseline Characteristics..........................................143.2.6. Results and Conclusions.........................................................................................................18

3.3 EVALUATION OF SAFETY.................................................................................................................23

4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS...............................................................24

4.1 AGE, GENDER, RACE, AND GEOGRAPHIC REGION...........................................................................244.2 OTHER SUBGROUP ANALYSIS .........................................................................................................25

5. SUMMARY AND CONCLUSIONS...................................................................................................26

5.1 STATISTICAL ISSUES AND COLLECTIVE EVIDENCE..........................................................................265.2 CONCLUSIONS AND RECOMMENDATIONS........................................................................................265.3 LABELING RECOMMENDATIONS......................................................................................................27


LIST OF TABLES

Table 1. Patient Disposition ...........................................................................................................................15Table 2. Patient Demographics.......................................................................................................................16Table 3. Baseline Characteristics ...................................................................................................................17Table 4. Primary Efficacy Results..................................................................................................................18Table 5. Key Secondary Efficacy Results ......................................................................................................18Table 6. RBC TI Response Rate by Treatment Periods, Additional Analyses ..............................................19Table 7. Duration of RBC TI ≥ 8 Response, Weeks 1-24..............................................................................20Table 8. OS Analysis Results Based on Original Data Submission...............................................................20Table 9. Overall Survival with July 2019 Data Cutoff...................................................................................21Table 10. Subgroup Analyses of Response Rate by Age, Gender, Race and Region ....................................24Table 11. Subgroup Analysis Based on Baseline Characteristics ..................................................................25


LIST OF FIGURES

Figure 1. Overall Study Design Trial ACE-536-MDS-001..............................................................................9Figure 2. Kaplan-Meier Curves of OS in Original Submission .....................................................................21Figure 3. Kaplan-Meier Curves of OS Based on July 2019 Data Cutoff .......................................................22


1. EXECUTIVE SUMMARY

The applicant submitted data and final study reports of a randomized Phase 3 study to support approval for luspatercept indicated for the treatment of adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS)-associated anemia with ring sideroblasts (RS) and require red blood cell (RBC) transfusions. Luspatercept was approved for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions on November 8, 2019.

This application was based on a single trial, Study MDS-001, titled “A Phase 3, Double-Blind, Randomized Study To Compare The Efficacy And Safety Of Luspatercept (ACE-536) Versus Placebo For The Treatment Of Anemia Due To IPSS-R Very Low, Low, Or Intermediate Risk Myelodysplastic Syndromes In Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions ”.

The primary endpoint of the study was the proportion of patients who were RBC transfusion-free over any consecutive 56-day period (8 weeks) (TI-8) within Weeks 1 - 24 of the study (e.g., the TI period started and ended within Weeks 1 - 24). Key secondary endpoints included the proportions of patients who were RBC transfusion-free over any consecutive 84-day period (12 weeks) (TI-12) within Weeks 1 - 24 and within Weeks 1 - 48 of the study. A total of 229 patients were randomized in a 2:1 allocation with 153 in the luspatercept arm and 76 in the placebo arm.

The data and analyses from current submission showed that the response rates of patients in the luspatercept arm was higher than that of patients in the placebo arm. The primary endpoint, response rate of RBC-TI ≥ 8 weeks from Week 1 through Week 24, was 37.9% with 95% confidence interval (CI) (30.2%, 46.1%) in the luspatercept arm compared with 13.2% with 95% CI (6.5%, 22.9%) in the placebo arm. The difference between the two arms was 24.6% with 95% CI (14.5%, 34.6%). The p-value from a stratified Cochran Mantel-Haenszel (CMH) test was < 0.0001.

For the two key secondary endpoints, the response rates of patients in the luspatercept arm was higher than that of patients in the placebo arm. The response rate of RBC-TI ≥ 12 weeks from Week 1 through Week 24 was 28.1% with 95% CI (21.1%, 35.9%) in the luspatercept arm compared with 7.9% with 95% CI (3.0%, 16.4%) in the placebo arm, and the difference between the two arms was 20.0% with 95% CI (10.9%, 29.1%), with a p-value of 0.0002 from a stratified CMH test. The response rate of RBC-TI ≥ 12 weeks from Week 1 through Week 48 was 33.3% with 95% CI (25.9%, 41.4%) in the luspatercept arm compared with 11.8% with 95% CI (5.6%, 21.3%) in the placebo arm, and the difference between the two arms was 21.4% with 95% CI (11.2%, 31.5%), with a p-value of 0.0003 from a stratified CMH test.

The overall survival (OS) was not mature at the time of data cut-off. With a total of 21 deaths, the median survivals in the two study arms were not estimable. There were 12 deaths (7.8% of patients) in the luspatercept arm and 9 deaths (11.8% of patients) in the placebo arm.


Based on the data and protocol defined analyses, the study results showed a higher response rate in the luspatercept arm compared with placebo. Whether the data and analyses provided in this submission showed a favorable benefit/risk profile in supporting a regulatory approval will be a clinical decision.


2. INTRODUCTION

The applicant submitted data and final study reports of a Phase 3 study to seek approval for luspatercept. This application was based on Study MDS-001, a randomized, double-blind, placebo-controlled trial in patients with anemia requiring red blood cell (RBC) transfusions in the setting of very low- to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS). .

2.1 Overview

2.1.1. Class and Indication

Luspatercept is a recombinant fusion protein consisting of a modified form of theextracellular domain of the human activin receptor type IIB (ActRIIB) receptor linked to the human immunoglobulin G1 (IgG1) fragment crystallizable (Fc) domain. TheActRIIB receptor and its ligands are members of the transforming growth factor-β (TGF-β) superfamily. The TGF-β superfamily participate in the proliferation and differentiation of erythroid progenitors. It has been proposed that members of the TGF-β ligands,through their binding to activin receptors, are involved in modulating the differentiation of latestage erythrocyte precursors (normoblasts) in the bone marrow.

The indication sought for luspatercept was treatment for adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS)-associated anemia who have ring sideroblasts and require red blood cell (RBC) transfusions.

2.1.2. Regulatory History

Luspatercept was submitted simultaneously for indications in the treatment of anemia in MDS and reduction of transfusion burden in patients with transfusion dependent beta-thalassemia. The application in beta-thalassemia was approved on November 8, 2019. The pre-submission regulatory history for the MDS indication is summarized below.

Jun. 16, 2010: A type B pre-IND meeting was held with the initial Sponsor (Acceleron Pharma)

Jul. 14, 2011: IND 112562 became active under Acceleron Nov. 7, 2011: Full clinical hold placed on IND 112562 due to CMC issues Feb. 15, 2012: Full hold removed Jun. 29, 2012 and Sep. 26, 2012: Fast track requests denied due to lack of adequate

evidence of clinical activity in the treatment of the conditions for which the designation was requested (MDS and beta-thalassemia)

Mar. 18, 2013: Orphan designation for MDS granted Apr. 3, 2015: IND transferred to Celgene Jul. 29, 2015: A type B pre-phase 3 meeting held to discuss the clinical

development program with respect to use of luspatercept in treatment of anemia due to very low to intermediate risk MDS with ring sideroblasts

Dec. 3, 2015: fast track status for treatment of anemia in persons with IPSS-R lower risk (very low, low, intermediate risk) myelodysplastic syndrome granted


Sep. 5, 2018: A type B pre-BLA CMC meeting held Oct. 4, 2018: A type B pre-BLA meeting was held to discuss the luspatercept

clinical developmental programs for MDS and beta-thalassemia to support a BLA submission

2.1.3. Study Reviewed

ACE-536-MDS-001 is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts who require RBC transfusions.

Eligible subjects were randomized at a 2:1 ratio to either:

Experimental Arm - Luspatercept (ACE-536): Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) OR

Control Arm: Placebo (volume equivalent to experimental arm) subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).

After randomization, no crossover between the treatment arms was permitted at any point during the study.

Best supportive care may be used in combination with study treatment in both arms when clinically indicated per investigator discretion.

Randomization was stratified by: RBC Transfusion burden at baseline (mean of the two consecutive 8-week periods

immediately prior to randomization): o ≥ 6 RBC units/8 weeks vs. o < 6 RBC units/8 weeks

IPSS-R at baseline: o Very low, low vs. o Intermediate


Figure 1. Overall Study Design Trial ACE-536-MDS-001*

*Source: Celgene CSR

2.2 Data Sources

The original data package used for review is from the electronic submission received on 04/04/2019. Additional data were received throughout the review cycle. The network paths for the submissions are:

\\CDSESUB1\evsprod\BLA761136\0001, \\CDSESUB1\evsprod\BLA761136\0032, \\CDSESUB1\evsprod\BLA761136\0033, \\CDSESUB1\evsprod\BLA761136\0058, \\CDSESUB1\evsprod\BLA761136\0069.


3. STATISTICAL EVALUATION

3.1 Data and Analysis Quality

Data and reports of this submission were submitted electronically. The applicant submitted data as well as the related SAS programs for analysis. The data were properly organized and adequate documentations were provided.

The reviewer was able to perform the analyses using the submitted data.

3.2 Evaluation of Efficacy

3.2.1. Study Design and Endpoints

The study was divided into the Screening Period, a double-blind Treatment Period (Primary Phase and Extension Phase) and a Post-treatment Follow-up Period.

In the Primary Phase of the Treatment Period (Weeks 1-24), subjects received investigational product (IP) through at least the first 24 calendar weeks unless the subject experienced unacceptable toxicities, withdrew consent, or met any other discontinuation criteria.

The Week 25 Visit was the MDS Disease Assessment, which was completed 24 calendar weeks after the date of first dose, regardless of dose delays. Based on the outcome of the Week 25 Visit MDS Disease Assessment, subjects were either discontinued from treatment with IP and entered the Posttreatment Follow-up Period or continued double-blind treatment with IP in the Extension Phase of the Treatment Period. In order for subjects to remain on double-blind treatment beyond the first 24 calendar weeks, the following criteria must be confirmed upon the completion of the MDS Disease Assessment by the investigator at the Week 25 Visit:

• Evidence of clinical benefit (e.g., decrease in RBC transfusion requirement compared to baseline requirement or hemoglobin increase compared to baseline) AND

• Absence of disease progression per IWG criteria for altering natural history of MDS.

Subjects who met the criteria for remaining on double-blind treatment with IP in the Extension Phase might continue dosing on Day 1 of each 21-day treatment cycle until the subject experienced unacceptable toxicities, disease progression per IWG criteria for altering natural history of MDS or withdrew consent or met any other discontinuation criteria. MDS Disease Assessment was repeated by the investigator at Extension Cycle 8, Day 1, and Day 1 of every eighth Extension cycle thereafter (i.e., Extension Cycle 8, 16, 24+, or every 24 weeks in the event of dose delays) until the subject was discontinued from IP.


In the posttreatment follow-up period, all subjects discontinued from protocol-prescribed therapy for any reason would be followed for adverse event (AE)/serious adverse event (SAE) reporting for a period of 42 days after the last dose of IP, as well as for SAEs made known to the Investigator at any time thereafter that are suspected of being related to IP. For subjects who did not complete the Primary Treatment Phase or participate in the Extension Phase or subjects who terminated the Extension Phase with less than 1-year of ADA monitoring, ADA and PK samples would be collected at End of Treatment (EOT) and then every 12 weeks for up to 1 year from the first dose in the Primary Treatment Phase. Transfusion data collection continued up until 16 weeks from the date of last dose of IP or the EOT Visit (whichever is later).

Continuation of monitoring for progression to AML and other malignancies/pre-malignancies would occur in the Posttreatment Follow-up Period along with collection of information related to subsequent MDS therapies, and overall survival for at least 3 years from the date of last dose of IP unless the subject withdraws consent from the study, dies, or is lost to follow-up.

The expected duration of the study was approximately 5 years with approximately 2 years of enrollment, approximately 1 additional year of blinded luspatercept or placebo treatment after the last subject is randomized, and at least an additional 3 years to complete the posttreatment follow-up period.

The primary objective is to evaluate red blood cell transfusion independence (RBC-TI) ofluspatercept compared with placebo.

The secondary objectives are as follows:

To assess the safety and tolerability of luspatercept compared to placebo To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in

hemoglobin, duration of RBC-TI, improvement in health-related quality of life (HRQoL) (i.e. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in platelets, decrease in serum ferritin, decrease in iron chelation therapy use, and time to RBC-TI compared with placebo

To evaluate population pharmacokinetics and exposure-response relationships for luspatercept in MDS subjects

Reviewer’s Comments:

The trial is described as a double-blind trial. However, the Sponsor did not provide the placebo, but rather placebo was supplied by the individual site. In addition, the investigational product is described as “clear to slightly opalescent” and thus the active product could be differentiated from the placebo visually. Masking procedures are not defined.


3.2.2. Efficacy Measures

In the applicant’s analysis plan, the primary efficacy endpoint was red blood cell transfusion independence (RBC-TI) ≥ 8 weeks, Week 1 through Week 24. Key secondary efficacy endpoints were RBC-TI ≥ 12 weeks, Week 1 through Week 24; and Week 1 through Week 48.

The primary efficacy endpoint of transfusion independence response was defined as the absence of any RBC transfusion during any consecutive 56-day period during the Primary Phase of the Treatment Period (first 24 weeks of double-blind treatment) i.e. days 1 to 56, days 2 to 57, days 3 to 58, etc. Subjects had to have at least 56 days of transfusion independence prior to (and including) Week 24 cutoff date to qualify as a responder. Subjects who failed to achieve at least 56 days prior to or on cutoff date were counted as non-responders.

The key secondary endpoint, proportion of subjects achieving RBC-TI with duration ≥ 12 weeks was the absence of any RBC transfusion during any consecutive 84-day period during the Treatment Period (Week 1-48, or Week 1-24), i.e., days 1 to 84, days 2 to 85, days 3 to 86, etc. Subjects discontinued from the Treatment Period without achieving at least 84 consecutive days of RBC transfusion independence were counted as non-responders.

Other secondary endpoints included: Reduction in RBC units transfused over 16 weeks: Mean change in total RBC units

transfused over a fixed 16 week period, weeks 9-24 or 33-48 mHI-E per IWG: Proportion of patients who achieved mHI-E over any consecutive

56-day period in weeks 1-24 or weeks 1-48 Mean Hgb ≥1.0 g/dl: Proportion of subjects who achieved mHI-E over any

consecutive 56-day period in weeks 1-24 or weeks 1-48 Duration of RBC-TI: Maximum duration of RBC-TI for subjects who achieved

RBC-TI of ≥8 weeks in weeks 1-24 and week 1 through EOT HRQoL: Change in EORTC QLQ-C30 score in weeks 1-48 or baseline through

EOT HI-N per IWG: Proportion of subjects who achieved HI-N over any consecutive

56-day period weeks 1-24 or weeks 1-48 HI-P per IWG: Proportion of subjects who achieved HI-P over any consecutive 56-

day period weeks 1-24 or weeks 1-48 Mean decrease in serum ferritin: Change in serum ferritin in weeks 9-24 or weeks

33-48 Mean decrease in ICT use: Change in mean daily dose of ICT in weeks 9-24 or 33-

48 Progression to AML: Number and percentage of subjects progressing to AML; time

to AML progression from randomization through at least 3 years post-last dose or weeks 1-48

OS: Time from date of randomization to death due to any cause in weeks 1-48 and randomization through at least 3 years post last dose


Safety: Type, frequency, severity of AEs, and relationship of AEs to luspatercept/placebo in screening through 42 days post last dose, weeks 1-48

Population PK Model: A population PK model that described the PK exposure data of luspactercept and associated variability from randomization through 1 year post-first dose

Exposure-response relationship: Exposure-response relationship for primary efficacy endpoint, AEs of interest, and selected secondary endpoints from randomization through 1 year post-first dose

ADAs: Frequency of ADAs and the effect on efficacy or safety or PK from randomization through 1 year post-first dose

3.2.3. Sample Size Consideration

Assuming a response rate of 0.30 in the luspatercept arm and a response rate of 0.10 in the placebo arm, a total sample size of 210 (140 in the luspatercept arm, and 70 in the placebo arm) would have 90% power to detect the difference, based on an one-sided alpha of 0.025, test statistics on difference of proportions using pooled estimate of variance and 10% dropout rate.

A total of 229 patients were randomized with 153 in the luspatercept arm and 76 in the placebo arm.

3.2.4. Statistical Methodologies

The Intent-to-Treat (ITT) population was used for the efficacy analysis. The ITT population comprises all randomized patients regardless of whether or not treatment was administered. The Cochran–Mantel–Haenszel (CMH) test was used to test the difference between the 2 response rates at a 1-sided significance level of 0.025 with randomization factors as strata.

A sequential gate-keeping approach was used to control the overall type I error rate in multiplicity. Two endpoints, the primary efficacy endpoint of RBC transfusion independence (RBC-TI) ≥ 8 weeks and the key secondary endpoint of RBC-TI ≥ 12 weeks (week 1-48 & week 1-24), were tested sequentially in the pre-specified order. The primary efficacy endpoint was tested first at the one-sided 0.025 significance level. The test for the RBC-TI ≥ 12 weeks analysis (first tested for week 1-48, then week 1-24) can only be made if superiority of luspatercept is demonstrated for the primary efficacy endpoint, RBC-TI ≥ 8 weeks, at the one-sided 0.025 significance level.

An interim analysis for futility on the primary and key secondary endpoint were to be performed when approximately 105 subjects completed the Primary Phase of the Treatment Period (first 24 weeks of double-blind treatment) or discontinued before reaching 24 weeks of double-blind treatment (50% information for primary endpoint). There was no plan to claim luspatercept superiority at the interim analysis.


The health-related quality of life was measured by the EORTC QLQ-C30 and QoLE questionnaires. Changes from baseline in overall score and sub-scores were analyzed and compared between treatment groups using repeated measures of Analysis of Variance (ANOVA)/ANCOVA using the screening scores and stratification factors as covariates..

Reviewer’s Comments:Control of Type I error probability was addressed for the primary and two key secondary endpoints.. Results from other endpoints are considered to be exploratory.

3.2.5. Patient Disposition, Demographic and Baseline Characteristics

A total of 290 patients were screened, and 229 were randomized to one of two treatment arms using a 2:1 randomization ratio with 153 patients in the luspatercept arm and 76 in the placebo arm. A total of 65 study centers enrolled patients, with 6 in Belgium, 4 in Canada, 10 in France, 5 in Germany, 7 in Italy, 2 in the Netherlands, 8 in Spain, 4 in Sweden, 2 in Turkey, 6 in United Kingdom, and 11 in the United States.

The study was initiated on February 9th, 2016 and primary analysis data cut-off date was May 8th, 2018. The median follow-up time was ??? months.

As of the primary analysis cut-off date, 33.2% of patients were still continuing treatment in the study, with 45.8% in luspatercept arm, and 7.9% in the placebo arm. Approximately 20% of subjects in the luspatercept group, and 25% of subjects in the placebo group, discontinued from the study, primarily due to withdrawal by subject (8.5% and 10.5%,respectively) or death (7.8% and 11.8%, respectively). The patient disposition is summarized in Table 1.


Table 1. Patient DispositionNumber (%) of Subjects

Luspatercept

(N = 153)Placebo(N = 76)

Total(N = 229)

Subjects Completed 24 Weeks of Treatment

128 (83.7) 68 (89.5) 196 (85.6)

Subjects Completed 48 Weeks of Treatment

78 (51.0) 12 (15.8) 90 (39.3)

Subjects Remaining on Treatment as of the Data Cutoff Date

70 (45.8) 6 (7.9) 76 (33.2)

Subjects Discontinued IP 83 (54.2) 70 (92.1) 153 (66.8)Lack of Efficacy 51 (33.3) 50 (65.8) 101 (44.1)Withdrawal by Subject 14 (9.2) 10 (13.2) 24 (10.5)Adverse Event 10 (6.5) 4 (5.3) 14 (6.1)Progressive Disease 3 (2.0) 2 (2.6) 5 (2.2)Protocol Violation 1 (0.7) 0 1 (0.4)Other 4 (2.6) 4 (5.3) 8 (3.5)

Subjects Discontinued From the Study 30 (19.6) 19 (25.0) 49 (21.4)Withdrawal by Subject 13 (8.5) 8 (10.5) 21 (9.2)Death 12 (7.8) 9 (11.8) 21 (9.2)Lost to Follow-up 2 (1.3) 0 2 (0.9)Other 3 (2.0) 2 (2.6) 5 (2.2)


3.2.6. Results and Conclusions

Primary Endpoint Analysis:

A statistically significantly greater proportion of luspatercept-treated subjects achieved RBC-TI ≥ 8 weeks from Week 1 through Week 24 compared with placebo with the response rates being 37.91% and 13.16%, respectively. The difference between response rates was statistically significant based on a stratified CMH test with p < 0.0001. The results are summarized in the following table.

Table 4. Primary Efficacy ResultsLuspatercept (N = 153) Placebo (N = 76)

RBC-TI ≥ 8 weeks from Week 1 to Week 24Number of Responders 58 10Response Rate (%) (95% CI) 37.91 (30.20, 46.10) 13.16 (6.49, 22.87)Difference (%) (95% CI) 24.56 (14.48, 34.64)p-value < 0.0001

Reviewer’s comments:

For subgroup analyses of the primary endpoint, please refer to Section 4.

Secondary Endpoints Analyses:

The key secondary endpoints, response rates of RBC-TI ≥ 12 weeks from Week 1 to Week 24, and from Week 1 to Week 48, also showed statistically significant difference between the two arms based on a stratified CMH test. The results are summarized in the following table.

Table 5. Key Secondary Efficacy ResultsEndpoint Luspatercept (N = 153) Placebo (N = 76)RBC-TI ≥ 12 weeks from Week 1 to Week 24Number of Responders 43 6Response Rate (%) (95% CI) 28.10 (21.14, 35.93) 7.89 (2.95, 16.40)Difference (%) (95% CI) 20.00 (10.92, 29.08)p-value 0.0002RBC-TI ≥ 12 weeks from Week 1 to Week 48Number of Responders 51 9Response Rate (%) (95% CI) 33.33 (25.93, 41.40) 11.84 (5.56, 21.29)Difference (%) (95% CI) 21.37 (11.23, 31.51)p-value 0.0003



The results from the key secondary endpoints analyses are consistent with those of the primary endpoint.

FDA also requested Celgene to submit data and analyses results of data cutoff for the 3-Month Safety Update Report of 07 Jan 2019 in the ITT Population. The following endpoints were analyzed:

Weeks 1-24: The response rate displayed for the period Weeks 1-24 represents the proportion of subjects with RBC TI 8, 12, and 16 weeks within the first 24 weeks of therapy.

Weeks 24-48: The response rate displayed for the period Weeks 24-48 represents the proportion of subjects with RBC TI 8, 12, and 16 weeks within this period (Weeks 24-48), days of RBC-TI obtained prior to Week 24 were excluded for the calculation of the response in that period.

Weeks 48-72: The response rate displayed for the period Weeks 48-72 represents the proportion of subjects with RBC TI 8, 12, and 16 weeks within this period Weeks (48-72), days of RBC-TI obtained prior to Week 48 were excluded for the calculation of the response in that period.

The table below summarizes the analyses results. Table 6. RBC TI Response Rate by Treatment Periods, Additional Analyses

n (%) Occurring during Study PeriodWeeks 1 - 24 Weeks 24 - 48 Weeks 48 - 72 Any Time During

Treatment PeriodLuspatercept (N=153)≥ 8 weeks TI 58 (37.9) 54 (35.3) 47 (30.7) 72 (47.1)≥ 12 weeks TI 43 (28.1) 42 (27.5) 37 (24.2) 54 (35.3)≥ 16 weeks TI 29 (19.0) 31 (20.3) 31 (20.3) 47 (30.7)Placebo (N=76)≥ 8 weeks TI 10 (13.2) - - 12 (15.8)≥ 12 weeks TI 6 (7.9) - - 9 (11.8)≥ 16 weeks TI 3 (3.9) - - 6 (7.9)

The results of these analyses are consistent with the primary and key secondary endpoints. These analyses are post-hoc and considered to be exploratory.


Other Secondary Endpoint: Duration of Response

Duration of RBC-TI was defined as the longest duration of response for subjects who achieved RBC-TI of ≥ 8 weeks during the Treatment Period (Week 1 through Week 24 and Week 1 through Week 48).

The median durations of longest single episode of RBC-TI ≥ 8 weeks based on Kaplan-Meier estimates were 30.6 and 13.6 weeks in the luspatercept arm and the placebo arm, respectively. Among the subjects who achieved RBC-TI of ≥ 8 weeks from Week 1 through Week 24, 34.5% (20/58) of subjects in the luspatercept arm and 20.0% (2/10) of subjects in the placebo arm maintained response as of the cutoff date. The following tables summarizes the analyses results.

Table 7. Duration of RBC TI ≥ 8 Response, Weeks 1-24DOR RBC TI8 Luspatercept PlaceboNumber of Responders 58 10Median (95% CI) (weeks) 30.6 (20.6, 40.6) 13.6 (9.1, 54.9)Ongoing Response, n (%) 20 (34.5) 2 (20.0)

Reviewer’s Comment:The results were consistent with the corresponding primary and secondary efficacy endpoints.

Other Secondary Endpoint: OS

Overall survival (OS) data was provided in the original submission with less than 10% information. The analyses of the OS data is summarized in the following table.

Table 8. OS Analysis Results Based on Original Data SubmissionLuspatercept (N = 153) Placebo (N = 76)

Number of Deaths 12 9Median (95% CI) NE (NE, NE) NE (NE, NE)HR (95% CI) 0.76 (0.32, 1.83)


The following figure is the Kaplan-Meier curve for the original OS data.

Figure 2. Kaplan-Meier Curves of OS in Original Submission


Updated OS data was submitted on Nov. 1, 2019 with a July 1st, 2019 data cutoff date. The analyses of the OS data with July 2019 cutoff is summarized in the following table.

Table 9. Overall Survival with July 2019 Data CutoffOS Luspatercept (N = 153) Placebo (N = 76)Number of Deaths 27 18Median (95% CI) NE (NE, NE) NE (NE, NE)HR (95% CI) 0.75 (0.41, 1.38)

The following figure is the Kaplan-Meier curve for the updated OS data.


Figure 3. Kaplan-Meier Curves of OS Based on July 2019 Data Cutoff

The results from the OS analysis are not considered robust due to the small number of deaths. The OS data is not mature.

Other Secondary Endpoint: PRO

Health-related quality of life (HRQoL) compliance rates over time for the EORTC QLQ-C30 questionnaire are summarized for all scheduled visits during the primary treatment phase. Compliance rates for each treatment group were estimated using the number of subjects expected to complete an HRQoL assessment at a given scheduled visit as the denominator. Compliance rates at baseline were 98% or higher and were > 79% at all visits up to the Week 25 visit. Compliance rates were similar between treatment groups across visits.

The primary HRQoL analyses were performed based on the HRQoL-evaluable population, defined as the ITT population who completed the EORTC QLQ-C30 assessment at baseline and at least 1 postbaseline assessment visit. Four subjects (1.7%) of the ITT population were not eligible for inclusion in the HRQoL-evaluable population, all from the luspatercept treatment group. Demographic and disease characteristics at baseline were similar between treatment groups among the HRQoL-evaluable population.

The patients reported similar results of the HRQoL analyses in the two arms. No difference were of large magnitude. There were no prespecified statistical hypotheses in regard to


comparison of HRQoL endpoints. This study was not powered to detect a difference between luspatercept and placebo in either HRQoL assessment, EORTC QLQ-C30 and QoL-E and therefore all of the analyses are descriptive.

3.3 Evaluation of Safety

Please refer to the clinical review of this application for details of safety evaluations.


4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

4.1 Age, Gender, Race, and Geographic Region

The following table summarizes the subgroup analysis of RBC-TI ≥ 8 response rate by age, gender, race and region.

Table 10. Subgroup Analyses of Response Rate by Age, Gender, Race and Region Responders / N RBC-TI ≥ 8 (95% CI) Placebo Luspatercept Placebo LuspaterceptPrimary Analysis 10 / 76 58 / 153 13.2 (6.5, 22.9) 37.9 (30.2, 46.1)Age<65 3 / 16 17 / 29 18.8 (4.0, 45.6) 58.6 (38.9, 76.5)>=65 7 / 60 41 / 124 11.7 (4.8, 22.6) 33.1 (24.9, 42.1)SexMale 4 / 50 32 / 94 8.0 (2.2, 19.2) 34.0 (24.6, 44.5)Female 6 / 26 26 / 59 23.1 (9.0, 43.6) 44.1 (31.2, 57.6)RaceWhite 8 / 51 40 / 107 15.7 (7.0, 28.6) 37.4 (28.2, 47.3)Other race/Not reported 2 / 25 18 / 46 8.0 (1.0, 26.0) 39.1 (25.1, 54.6)RegionNorth America 4 / 19 17 / 31 21.1 (6.1, 45.6) 54.8 (36.0, 72.7)EU 6 / 57 41 / 122 10.5 (4.0, 21.5) 33.6 (25.3, 42.7)


The analyses showed that the treatment effect of luspatercept over placebo was consistent across subgroups.


4.2 Other Subgroup Analysis The follow tables summarize subgroup analysis of RBC-TI ≥ 8 response rate by other baseline characteristics.

Table 11. Subgroup Analysis Based on Baseline Characteristics Responders / N RBC-TI ≥ 8 (95% CI) Placebo Luspatercept Placebo LuspaterceptPrimary Analysis 10 / 76 58 / 153 13.2 (6.5, 22.9) 37.9 (30.2, 46.1)ECOG status0 5 / 33 17 / 54 15.2 (5.1, 31.9) 31.5 (19.5, 45.6) 1 4 / 32 38 / 91 12.5 (3.5, 29.0) 41.8 (31.5, 52.6) 2 1 / 11 3 / 8 9.1 (0.2, 41.3) 37.5 (8.5, 75.5)Hemoglobin level <7.5 1 / 25 18 / 57 4.0 (0.1, 20.4) 31.6 (19.9, 45.2)7.5- <8.5 7 / 41 32 / 69 17.1 (7.2, 32.1) 46.4 (34.3, 58.8) 8.5- <10 2 / 10 7 / 26 20.0 (2.5, 55.6) 26.9 (11.6, 47.8) >=10 0 1 / 1 NE 100 (5, 100)Erythropoietin level<100 7 / 31 23 / 51 22.6 (9.6, 41.1) 45.1 (31.1, 59.7)100- <400 3 / 32 29 / 75 9.4 (2.0, 25.0) 38.7 (27.6, 50.6)>=400 0 / 13 5 / 26 0.0 (0.0, 24.7) 19.2 (6.6, 39.4)<=500 10 / 65 54 / 131 15.4 (7.6, 26.5) 41.2 (32.7, 50.2)>500 0 / 11 3 / 21 0.0 (0.0, 28.5) 14.3 (3.0, 36.3)RBC units/8 weeks<4 8 / 20 37 / 46 40.0 (19.1, 63.9) 80.4 (66.1, 90.6)4-6 1 / 23 15 / 41 4.3 (0.1, 21.9) 36.6 (22.1, 53.1)>= 6 1 / 33 6 / 66 3.0 (0.1, 15.8) 9.1 (3.4, 18.7)Baseline Platelet < 100 1 / 6 2 / 8 16.7 (0.4, 64.1) 25.0 (3.2, 65.1) 100-400 8 / 61 42 / 128 13.1 (5.8, 24.2) 32.8 (24.8, 41.7) > 400 1 / 9 14 / 17 11.1 (0.3, 48.2) 82.4 (56.6, 96.2)WHO 2016 DiagnosisRST 2 / 9 9 / 14 22.2 (2.8, 60.0) 64.3 (35.1, 87.2)MLD/SLD 8 / 65 46 / 135 12.3 (5.5, 22.8) 34.1 (26.1, 42.7)Others 0 / 2 3 / 4 0.0 (0.0, 84.2) 0.75 (19.4, 99.4)

Reviewer’s comments:In general, efficacy statements made about specific subgroups are viewed as exploratory as the sample size can be small in certain subgroups


5. SUMMARY AND CONCLUSIONS

5.1 Statistical Issues and Collective Evidence

The major review issue of this application is the lack of clinical relevance based on the protocol defined primary endpoint. Though the primary and key secondary endpoints showed statistically significant improvement of luspatercept over placebo, the absolute response rates were rather low and the effect may not be clinically meaningful.

The primary endpoint of the study was the proportion of patients who were RBC transfusion-free over any consecutive 56-day period (8 weeks) (TI-8) within Weeks 1 - 24 of the study (e.g., the TI period started and ended within Weeks 1 - 24). Key secondary endpoints included the proportions of patients RBC transfusion-free over any consecutive 84-day period (12 weeks) (TI-12) within Weeks 1 - 24 and within Weeks 1 - 48 of the study. A total of 229 patients were randomized in a 2:1 allocation with 153 in the luspatercept arm and 76 in the placebo arm.

The data and analyses from current submission showed that the response rates of patients in the luspatercept arm was higher than that of patients in the placebo arm. The primary endpoint, response rate of RBC-TI ≥ 8 weeks from Week 1 through Week 24, was 37.9% with 95% confidence interval (CI) (30.2%, 46.1%) in the luspatercept arm compared with 13.2% with 95% CI (6.5%, 22.9%) in the placebo arm. The difference between the two arms was 24.6% with 95% CI (14.5%, 34.6%). The p-value from a stratified Cochran Mantel-Haenszel (CMH) test was < 0.0001.

For the two key secondary endpoints, the response rates of patients in the luspatercept arm was higher than that of patients in the placebo arm. The response rate of RBC-TI ≥ 12 weeks from Week 1 through Week 24 was 28.1% with 95% CI (21.1%, 35.9%) in the luspatercept arm compared with 7.9% with 95% CI (3.0%, 16.4%) in the placebo arm, and the difference between the two arms was 20.0% with 95% CI (10.9%, 29.1%), with a p-value of 0.0002 from a stratified CMH test. The response rate of RBC-TI ≥ 12 weeks from Week 1 through Week 48 was 33.3% with 95% CI (25.9%, 41.4%) in the luspatercept arm compared with 11.8% with 95% CI (5.6%, 21.3%) in the placebo arm, and the difference between the two arms was 21.4% with 95% CI (11.2%, 31.5%), with a p-value of 0.0003 from a stratified CMH test.

The overall survival (OS) was not mature at time of data cut-off. With a total of 21 deaths, the median survivals in the two study arms were not estimable. There were 12 deaths (7.8% of patients) in the luspatercept arm and 9 deaths (11.8% of patients) in the placebo arm.

5.2 Conclusions and Recommendations

Based on the data and protocol defined analyses, the study results showed a higher response rate in the luspatercept arm compared with placebo. Whether the data and analyses provided in this submission showed a favorable benefit/risk profile in supporting a regulatory approval will be a clinical decision.


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WEISHI YUAN12/23/2019 11:34:24 AM

YU-TE WU12/23/2019 11:44:58 AM

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review - food and drug administration · 2020. 10. 8. · u.s. department of health and human...

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