Otsuka’s guadecitabine fails phase 3 AML trial

Myeloblasts with Auer rods seen in acute myeloid leukemia
Myeloblasts with Auer rods seen in AML. (Paulo Henrique Orlandi Mourao/CC BY-SA 3.0)

Otsuka’s guadecitabine has missed its coprimary endpoints in a phase 3 acute myeloid leukemia (AML) trial. The DNA hypomethylating agent failed to beat the complete response or overall survival rates achieved in the control arm, leaving Otsuka looking to ongoing trials in other indications to save the drug.

Guadecitabine, which Otsuka acquired in its $886 million takeover of Astex, is designed to reverse aberrant DNA methylation, thereby restoring the expression of tumor suppressor genes. Otsuka’s own Dacogen has a similar mechanism of action but its short half-life diminishes its efficacy in forms of leukemia, resulting in sub-20% complete response rates. Guadecitabine is resistant to the enzyme that degrades Dacogen, potentially prolonging its half-life and increasing its efficacy.

The phase 3 trial in 815 AML treatment-naïve patients ineligible for intense induction chemotherapy dents that theory. Guadecitabine failed to achieve statistically-significant improvements in complete response or overall survival over a control arm made up of patients who received Dacogen, Celgene’s Vidaza or low-dose cytarabine. Otsuka is still assessing the secondary endpoint and safety data.


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Astex and Otsuka attributed the failure to the inclusion/exclusion criteria.

“The study used very strict criteria of ineligibility to receive intensive chemotherapy based on age or poor performance status or comorbidities, which made it a difficult population to show superior benefit of guadecitabine,” Astex president Mohammad Azab, M.D. said in a statement.

Guadecitabine’s failure against the coprimary endpoints eliminates the near-term prospect of the DNA hypomethylating agent coming to market as a treatment for elderly AML patients. However, the setback leaves scope for guadecitabine to advance in other patient populations, either as a single agent or in combination with chemotherapy or immunotherapy.

Otsuka is currently enrolling patients with previously-treated AML in one phase 3 clinical trial, and people with previously-treated myelodysplastic syndromes or chronic myelomonocytic leukemia in another. Further back, Otsuka and independent investigators are assessing guadecitabine as a single agent and as part of combination therapies in range of hematological cancers and solid tumors.

The mechanism of guadecitabine means there is reason to think it may prosper in combinations even if it struggles as a monotherapy. By restoring the expression of tumor suppressor genes, Otsuka’s drug could sensitive cancer cells to the effects of other drugs, including checkpoint inhibitors.

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