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High Risk Myelodysplastic syndromes (HR-MDS) –Takeda, Gilead, Onconova Therapeutics & MEI Pharma

High Risk Myelodysplastic syndromes (MDS)-KEY DEVELOPMENTS

Myelodysplastic syndromes (MDS) is a rare form of bone marrow-related cancer caused by mutation of one or more genes that control development of blood cells. This cancer most commonly affects older patients, with the median age of diagnosis ranging from 60 to 74 years. However, MDS condition can occur at any age and more frequently in men than in women with 30% of MDS cases advancing to acute myeloid leukemia (AML).

Guillermo Garcia-Manero, MD,

MDS refers to a very heterogeneous group of patients, so there are patients with lower-risk and higher-risk disease. In 2020, we divide these patients based on their age, comorbidities, cytogenetic alterations, and molecular alterations, so this is very different than 20 years ago when we had no compounds for patients with MDS. In general, the majority of patients with intermediate- to high-risk MDS, globally, not only in the United States, are treated with a hypomethylating agent (HMA), and there are 2 of these compounds. One is called decitabine, and the other one is called azacitidine.

Competitive Space –High Risk Myelodysplastic syndromes (HR-MDS)

Ticker – Company Name

Drug Name



Key developments to note

ONTX -Onconova Therapeutics Inc.

Oral Rigosertib and azacitidine

First-line HR-MDS (high risk myelodysplastic syndromes)

Phase 3

Phase 3 Special Protocol Assessment (SPA) submission announced January 2, 2019.

ONTX -Onconova Therapeutics Inc.

IV Rigosertib – INSPIRE

2nd-line HR-MDS (high risk myelodysplastic syndromes)

Phase 3

Phase 3 data due by the end of 3Q 2020.

TAK -Takeda Pharmaceutical Company Limited

Pevonedistat (TAK-924)

Higher-risk myelodysplastic syndromes (HR-MDS)

Phase 3

Phase 3 data due 4Q 2020 / 1Q 2021.

MEIP -MEI Pharma Inc.

Pracinostat in combination with Vidaza

High-risk Myelodysplastic Syndrome (MDS)

Phase 2

Phase 2 data presented at ASCO May 29, 2020.

GILD -Gilead Sciences Inc

Magrolimab + Azacitidine

Higher risk-Myelodysplastic Syndrome (MDS)

Phase 1b

Phase 3 trial to be initiated 2H 2020.

Takeda’s Pevonedistat eyes to become first Novel Treatment Option for HR-MDS in more than 10 years after getting breakthrough designation

On 30th July Takeda’s Pevonedistat received a breakthrough designation as a Novel Treatment Option for Higher-Risk Myelodysplastic Syndromes (HR-MDS). The designation was granted on the basis of the Pevonedistat-2001 Phase 2 study, which evaluated pevonedistat plus azacitidine versus azacitidine alone in patients with rare leukemias, including HR-MDS.

Pevonedistat  NCT02610777  •	Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Takeda’s Pevonedistat-2001 Phase 2 study analyses

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.

Why does this breakthrough designation actually a big deal?

Pevonedistat is the first inhibitor of the NEDD8 activating enzyme (NAE). Pevonedistat has already showed great efficacy in pre-clinical trials and has received FDA’s breakthrough designation considering a number of endpoints, including overall survival (OS), event-free survival (EFS), complete remission (CR) and transfusion independence, as well as the adverse event profile. The drug is a potential advancement in addressing the needs of people living with HR-MDS, for whom few therapies exist but the benefits are limited.

Some ongoing combination with Pevonedistat

Pevonedistat is a first in class NEDD8-activating enzyme (NAE) inhibitor. Pevonedistat in combination with azacitidine demonstrated promising clinical activity in a Phase 2 study of patients with higher-risk myelodysplastic syndromes (HR-MDS), higher-risk chronic myelomonocytic leukemia (HR-CMML) and acute myeloid leukemia (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 in a Phase 2 study in unfit AML in a triple combination with azacitidine and venetoclax.

Ongoing Trials Pevonedistat

NCT Number






Myelodysplastic Syndrome|Leukemia, Myelomonocytic, Chronic|Leukemia, Myeloid, Acute


Phase 3



Myelodysplastic Syndromes|Leukemia, Myelomonocytic, Chronic|Leukemia, Myeloid, Acute


Phase 2


Leukemia, Myeloid, Acute|Myelodysplastic Syndromes

Pevonedistat |Azacitidine

Phase 1


Myelodysplastic Syndromes|Leukemia, Myelomonocytic, Chronic|Leukemia, Myeloid, Acute|Renal Insufficiency|Hepatic Impairment


Phase 1


Acute Myelogenous Leukemia|AML|Advanced Myelodysplastic Syndromes|MDS


Phase 1


(Triple Combination)

Acute Myeloid Leukemia (AML)

Pevonedistat|Venetoclax |Azacitidine

Phase 2


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