Takeda Announces Compelling Data from the Phase 2 Trial of Pevonedistat Plus Azacitidine in Patients with Higher-Risk MDS

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced the results of the Phase 2 Pevonedistat-2001 trial will be presented during oral sessions at the virtual 56^thAmerican Society of Clinical Oncology (ASCO) Annual Meeting and the virtual 25^thEuropean Hematology Association (EHA) Annual Meeting. The study evaluated pevonedistat plus azacitidine versus azacitidine alone in patients with rare leukemias, including higher-risk myelodysplastic syndromes (HR-MDS). These results show that the combination of pevonedistat and azacitidine is a highly active, promising therapeutic approach and suggest benefit in the HR-MDS subgroup across multiple clinically meaningful endpoints, including overall survival (OS), event-free survival (EFS), complete remission (CR) and transfusion independence, with a safety profile similar to azacitidine alone.

The Pevonedistat-2001 trial was designed as a proof-of-concept study in patients with HR-MDS, higher-risk chronic myelomonocytic leukemia (HR-CMML) and low-blast acute myeloid leukemia (LB-AML). Though it did not achieve pre-defined statistical significance for the primary endpoint of OS, treatment with the pevonedistat combination demonstrated a numerically longer OS compared with azacitidine alone and a trend towards benefit in EFS, defined as death or transformation to AML.

“We are very optimistic about pevonedistat based on these Phase 2 results, particularly in the higher-risk MDS subgroup, which showed that the combination of pevonedistat and azacitidine provided benefit to patients at the level of several key endpoints, without introducing additional safety concerns. Not only did the combination demonstrate longer survival, but patients in the higher-risk MDS subgroup also achieved higher response rates and increased transfusion independence,” said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda. “We are looking forward to building on this dataset with our Phase 3 PANTHER trial, which completed enrollment last fall, and will support registration for pevonedistat globally.”

There have been no treatment advancements for HR-MDS in more than a decade and current treatment options provide limited benefit. Pevonedistat could be the first new treatment option for these patients.

“It’s exciting to see such encouraging results in the Pevonedistat-2001 trial, particularly in higher-risk MDS, an aggressive type of MDS associated with poor prognosis, diminished quality of life, and higher chance of transformation to AML,” said Lionel Adès, MD, PhD, Hôpital Saint-Louis, and a primary investigator of the Pevonedistat-2001 study. “Adding pevonedistat to the current standard of care in higher-risk MDS doubled complete remission rates, increased the duration of response and improved long-term outcomes with a safety profile similar to azacitidine alone, which may address a significant need for people living with this disease.”

Primary Results from the Phase 2 Pevonedistat-2001 Trial of Pevonedistat Plus Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS), Higher-Risk Chronic Myelomonocytic Leukemia (HR-CMML) and Low-Blast Acute Myeloid Leukemia (LB-AML).

Key findings, to be presented by Dr. Lionel Adès, include:

• Intent to treat population (n=120):
  • Median OS was 21.8 months (mos.) in the pevonedistat combination arm, vs. 19.0 mos. with azacitidine alone (HR 0.802; p = 0.334).
  • EFS trended longer in the pevonedistat combination arm vs. azacitidine alone with a median of 21.0 mos. vs. 16.6 mos.
• HR-MDS Subgroup (n=67):
  • Median OS in the pevonedistat combination arm alone was 23.9 mos. vs. 19.1 mos. with azacitidine alone.
  • Median EFS in the pevonedistat combination arm was 20.2 mos. vs. 14.8 mos. with azacitidine alone.
  • Overall response rate (ORR) in the pevonedistat combination arm was 79.3% vs. 56.7% with azacitidine alone.
  • CR rate in the pevonedistat combination arm was 51.7% vs. 26.7% with azacitidine alone.
  • Median duration of response (DoR) in the pevonedistat combination arm was 34.6 months vs. 13.1 mos. with azacitidine alone.
  • Of the patients who were red blood cell (RBC) transfusion dependent at baseline, 69.2% receiving pevonedistat plus azacitidine vs. 50.0% receiving azacitidine alone became transfusion independent.
• LB-AML (n=36) & HR-CMML (n=17) Subgroups:
  • Median OS in LB-AML was 23.6 mos. in the pevonedistat combination arm vs. 16.0 mos. with azacitidine alone.
  • Median OS and EFS in HR-CMML favored the azacitidine alone arm, which may be due to low sample size and/or greater patient heterogeneity.
• Safety data includes:
  • The safety profile of pevonedistat combined with azacitidine was similar to azacitidine alone, and did not lead to increased myelosuppression.
  • The most common grade ≥3 AEs across both arms were neutropenia (33% vs. 27%), febrile neutropenia (26% vs. 29%), decreased neutrophil count (21% vs. 10%), anemia (19% vs. 27%), thrombocytopenia (19% vs. 23%), and pneumonia (12% vs. 10%).
  • On-study deaths occurred in 9% of patients in the pevonedistat combination arm versus 16% with azacitidine alone.

About the Pevonedistat-2001 Trial

Pevonedistat-2001 (NCT02610777) is a global, randomized, controlled, open-label, multi-center, Phase 2 clinical trial designed to evaluate the safety and efficacy of pevonedistat in combination with azacitidine versus single-agent azacitidine in patients with higher-risk MDS or CMML, or low-blast AML, who were ineligible for stem cell transplant and have not received prior therapies. Approximately 120 participants were enrolled worldwide. The primary endpoint of the trial is OS.

About Pevonedistat

Pevonedistat is a first in class NEDD8-activating enzyme (NAE) inhibitor, which blocks modifications of select proteins. Pevonedistat treatment disrupts cell cycle progression and cell survival, leading to cell death in cancers including leukemias. Pevonedistat in combination with azacitidine demonstrated antitumor activity in preclinical studies and was well tolerated, with promising clinical activity, in a Phase 1 study of patients with AML. Pevonedistat is currently being evaluated in Phase 3 studies as a first-line treatment for patients with HR-MDS, HR-CMML, and AML, who are ineligible (unfit) for transplant or intensive induction chemotherapy and is also being explored in a Phase 2 study in unfit AML in a triple combination with azacitidine and venetoclax.

About MDS, CMML and AML

MDS, CMML and AML are rare forms of bone marrow-related cancer caused by irregular blood cell production within the bone marrow. These cancers most commonly affect older patients, with the median age of diagnosis ranging from 60 to 74 years. As a result of this irregular production, a person with MDS, CMML or AML does not have enough normal red blood cells, white blood cells and/or platelets in circulation. Symptoms for MDS, CMML and AML are often vague and related to low blood counts, and may include fatigue, shortness of breath, easy bruising or bleeding, loss of appetite, weakness, pale skin, fever and frequent or severe infections.

There are several classifications of MDS – very low risk to very high risk – determined by blood counts, blast counts, mutations and cytogenetics. Higher-risk disease is defined as intermediate, high or very high risk on the International Prognostic Scoring System – Revised (IPSS-R), and these patients have a poorer prognosis. Approximately 40% of patients with HR-MDS transform to AML, an aggressive form of acute leukemia in adults, with poor outcomes.

Takeda’s Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Rare Diseases, Neuroscience, and Gastroenterology (GI). We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries.

For more information, visit https://www.takeda.com

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