Not waving but drowning: Takeda's blood cancer drug flunks phase 3, dealing further blow to hopes of approval flurry

Takeda HQ
Takeda targeted peaks sales of up to $800 million before the phase 3 failure of its blood cancer prospect.

Takeda’s Wave 1 pipeline is threatening to peter out into a ripple. The latest setback comes from a phase 3 blood cancer clinical trial, which found adding pevonedistat to chemotherapy did nothing to improve event-free survival.

Japan’s Takeda identified NEDD8-activating enzyme inhibitor pevonedistat as a way to disrupt protein homeostasis and thereby drive cancer cell death, leading it to advance the prospect into phase 3 and forecast peak sales of up to $800 million in myelodysplastic syndromes and acute myeloid leukemia (AML). The phase 3 study represented a big test of the hypothesis. Pevonedistat flunked the test.

Investigators randomized people with higher-risk myelodysplastic syndromes and low-blast AML to take either pevonedistat and azacitidine, sold by Bristol Myers Squibb as Vidaza, or the off-patent chemotherapy drug as a monotherapy. 

Takeda aimed to show that pevonedistat improves event-free survival. Events were recorded when a myelodysplastic patient died or developed AML, and when AML patients died. Adding pevonedistat to azacitidine delivered no benefits by that yardstick, causing the study to miss its primary endpoint. 

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The failure dents, but doesn’t destroy, the prospects of a drug that analysts at Jefferies expected to generate sales of around $670 million by 2030. Takeda is still studying pevonedistat in other clinical trials, including a phase 2 study in AML patients who are unfit for intensive chemotherapy that it has penciled in as supporting regulatory approvals in its fiscal 2024. 

Takeda was planning to win approval in higher-risk myelodysplastic syndromes next year, but that is now seemingly a non-starter given the failed phase 3 trial. The failure is the latest in the series of setbacks for the Wave 1 programs Takeda identified as prospects that could win approval from 2020 to 2024. 

In July, Takeda revealed the FDA had missed the PDUFA date for its Eohilia treatment of esophageal inflammatory disease eosinophilic esophagitis. The same month, European authorities converted Takeda’s dengue fever vaccine TAK-003 from accelerated to standard assessment. 

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Eohilia and TAK-003 are two of five non-COVID approvals targeted by Takeda in 2021. Pevonedistat was one of two approvals lined up for fiscal 2022. Question marks now hang over a significant slice of the drugs that were supposed to support a sharp upturn in Takeda’s prospects.

The exact strength of Takeda’s hand will become clearer next month when the FDA holds an advisory committee on cytomegalovirus prospect maribavir and makes a decision on whether to approve mobocertinib in non-small cell lung cancer. Takeda is targeting collective peak sales of up to $1.4 billion from the two drugs.