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195 Efficacy and Safety of Roxadustat for Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndrome (LR-MDS) with Low Red Blood Cell (RBC) Transfusion Burden: Results of Phase III Matterhorn Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Treatment Options and Decision Making in Low Risk MDS
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Clinical Research, Therapies, Transfusion
Saturday, December 9, 2023: 2:30 PM

Moshe Mittelman, MD1, David H. Henry2, John Glaspy3*, Anil Tombak4*, Rosemary Anne Harrup5*, Krzysztof Madry, MD, PhD6*, Barbara Grabowska7*, Uwe Platzbecker, MD8, Tyson Lee9* and Katharina Modelska9*

1Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv, Israel
2Hospitals of the University of Pennsylvania‒Penn Presbyterian, Philadelphia
3University of California‒Los Angeles, Los Angeles
4Mersin University Medical Faculty, Mersin, Turkey
5Royal Hobart Hospital, Tasmania, Australia
6Medical University of Warsaw, Warsaw, Poland
7Centrum Medyczne PROMED, Krakow, Poland
8University Hospital of Leipzig, Leipzig, Germany
9FibroGen, Inc., San Francisco, CA

Presented on behalf of all MATTERHORN (FGCL-4592-082) study investigators

Introduction: For patients (pts) with LR-MDS, anemia poses a major clinical challenge, with limited response to first-line erythropoietin (EPO)-stimulating agents (ESAs) and a median duration of response ≤2 years. Further, pts with RBC transfusion dependence (≥2 packed RBC [pRBC] units every 8 weeks [Q8W]) are less likely to respond to ESAs. Anemia treatments with novel mechanisms of action enabling transfusion independence (TI) are needed to reduce frequent RBC transfusion burden. Roxadustat is a first-in-class, hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia with chronic kidney disease. In the MATTERHORN (NCT03263091) dose-selection stage, roxadustat was well-tolerated, and 37.5% of pts (9/24) with LR-MDS and low RBC transfusion burden ([LTB] 1 pRBC unit Q8W for two consecutive 8-week periods or 2–4 pRBC units Q8W) achieved TI. In the MATTERHORN double-blind stage, TI response rate and safety of roxadustat were further assessed.

Methods: MATTERHORN is an ongoing, double-blind, Phase III, randomized, placebo (PBO)-controlled trial. Eligible adult pts (≥18 years of age) had very low-, low-, or intermediate-risk primary MDS per Revised International Prognostic Scoring System (IPSS-R) classification (<5% bone marrow blasts); hemoglobin (Hb) ≤10.0 g/dL at baseline (BL); and LTB. Prior ESA use (>8 weeks before randomization) was permitted. Pts were randomized 3:2 to roxadustat or PBO, then stratified by serum EPO concentration (≤200 or 200–400 mIU/mL), IPSS-R risk, and transfusion burden. Pts received oral roxadustat (starting dosage: 2.5 mg/kg three times weekly based on the dose-selection stage) or PBO with best supportive care (BSC; per institutional criteria, including RBC transfusion) for a 52-week treatment period, followed by a 4-week follow-up period. Primary efficacy endpoint was percentage of pts with TI (the absence of RBC transfusion) for ≥56 consecutive days during the first 28 treatment weeks (TI responder). The percentage of pts with TI and mean Hb increase of ≥1.0 and ≥1.5 g/dL (averaged over 8 weeks) compared with BL pretransfusion Hb was also assessed (to be reported separately). Safety (including treatment-emergent adverse events [TEAEs] and serious TEAEs) was evaluated throughout the study.

Results: As of the final 28-week interim analysis of the double-blind stage (data cutoff: April 24, 2023), 140 pts (82 roxadustat, 58 PBO) were randomized and treated. Across arms, median age was 71.5 years (range, 26–96), 59.3% (83/140) were male, and 80.0% (112/140) were white. Most pts (72.1% [101/140]) had IPSS-R low-risk disease and a transfusion burden of 2–4 pRBC units Q8W (92.1% [129/140]). Median (range) BL transfusion burden was 2.5 (1–10) pRBC units. Seventy pts (50.0%) received prior ESAs (98.6% [69/70] were ESA-refractory). Eighty-four pts (41/82 [50.0%] roxadustat, 43/58 [74.1%] PBO) completed 28 weeks of treatment, and 15 pts (6/82 [7.3%] roxadustat, 9/58 [15.5%] PBO) were continuing treatment. Median (range) treatment duration was 24.1 (1.1–28.0) weeks for the roxadustat arm and 28.0 (0.1–28.0) weeks for the PBO arm.

A greater percentage of pts in the roxadustat arm compared with the PBO arm were TI responders (47.5% vs. 33.3%). However, this difference did not reach statistical significance (p=0.22; figure). Percentages of pts with TEAEs of any grade, serious TEAEs, and TEAEs leading to treatment discontinuation were similar across arms (table). Six deaths occurred on study (roxadustat: pneumonia [n=2], acute myocardial infarction and ischemic stroke [n=1], multiorgan failure [n=1]; PBO: urosepsis [n=1], disease progression [n=1]). Three pts (all in roxadustat arm) progressed to acute myeloid leukemia.

The study was terminated by the sponsor and is currently being completed.

Conclusions: Despite not meeting the primary endpoint, roxadustat plus BSC was well-tolerated, and a high percentage of pts with LR-MDS and LTB were TI responders. The high TI response rate in the PBO arm, historically poor outcomes in pts with ESA-refractory disease, and the inclusion of pts who were not transfusion-dependent (1 pRBC unit Q8W) may have contributed to the lack of a statistically significant difference in TI response rates between arms. MATTERHORN outcomes highlight the continued unmet need for effective and safe therapies that reduce RBC transfusion burden in LR-MDS.

Disclosures: Mittelman: Silence: Other: advisory boards; Astellas: Other: advisory boards; Janssen: Research Funding; Onconova: Other: advisory boards; Roche: Research Funding; Medison/Amgen: Research Funding; Novartis: Other: participated in clinical trials, advisory boards, Research Funding, Speakers Bureau; Celgene/BMS: Other: participated in clinical trials, Research Funding, Speakers Bureau; MDS HUB: Consultancy; Media Digital: Speakers Bureau; Geron: Other: participated in clinical trials; FibroGen: Other: participated in clinical trials; Takeda: Other: participated in clinical trials, advisory boards; Gilead: Consultancy, Research Funding; AbbVie: Other: participated in clinical trials, Research Funding. Henry: FibroGen: Research Funding. Glaspy: FibroGen: Research Funding. Tombak: GSK: Other: institution received research funding; Dr. Reddy’s: Other: institution received research funding; BeiGene: Other: institution received research funding; FibroGen: Other: institution received research funding. Harrup: F. Hoffmann-La Roche Ltd, Beigene: Research Funding; F. Hoffmann-La Roche Ltd, Takeda: Current equity holder in publicly-traded company; FibroGen: Research Funding. Madry: AbbVie: Other: advisory boards, lecture fees; BMS: Other: advisory boards, lecture fees; Teva: Other: lecture fees. Grabowska: FibroGen: Research Funding. Platzbecker: Jazz: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Research Funding; Merck: Research Funding; Janssen Biotech: Consultancy, Research Funding; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Curis: Consultancy, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Fibrogen: Research Funding; Amgen: Consultancy, Research Funding; Roche: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; BeiGene: Research Funding; BMS: Research Funding. Lee: FibroGen, Inc.: Current Employment, Current holder of stock options in a privately-held company, Other: stock. Modelska: FibroGen, Inc.: Current Employment, Current holder of stock options in a privately-held company, Other: stock.

*signifies non-member of ASH