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Guadecitabine Granted Orphan Designation for AML

Published: Tuesday, Oct 06, 2015

Dr Mohammad Azab

Mohammad Azab, MD

The FDA has granted an orphan drug designation to the next-generation hypomethylating agent (HMA) guadecitabine (SGI-110) as a potential treatment for patients with acute myeloid leukemia (AML), according to a statement from the drug's developer, Astex Pharmaceuticals.

The new designation was based on data from a phase I study, which demonstrated that guadecitabine was safe and effect for patients with AML and myelodysplastic syndromes (MDS). In addition to these findings, phase II trials have explored the agent, with results still pending presentation. Based on these results, Astex has launched an 800-patient phase III study for guadecitabine in patients with AML.

“We are delighted that FDA has granted orphan drug status to guadecitabine for the treatment of AML," Mohammad Azab, MD, president and chief medical officer at Astex, said in a statement. "This designation supports our conviction that new therapies are desperately needed for patients who are diagnosed with AML, particularly those for whom standard intensive induction chemotherapy is unsuitable, and helps underpin the rationale for commencing the ASTRAL-1 trial, the largest clinical study ever conducted in this group of patients.”

In the phase I study, 93 patients with AML or MDS received guadecitabine across various dose-escalation cohorts. Patients in the study were relapsed or refractory to standard treatments, including HMAs. The primary endpoint of the study was focused on safety, tolerability, and the determination of a maximum tolerated or biologically effective dose.

According to data published in Lancet Oncology, clinical response was observed in 8.1% of patients treated with guadecitabine in the AML cohort (n = 74). For those with MDS (n = 19), 31.5% experienced a clinical response. 

The maximum tolerated dose for those with MDS was identified as 90 mg/m2 for 5 consecutive days. In the AML arm, a maximum tolerated dose was not found. Based on a plateau in dose-related DNA demethylation in pharmacokinetic (PK) and pharmacodynamic (PD) analyses, guadecitabine at 60 mg/m2 for 5 consecutive days was identified as the biologically effective dose.

“This study demonstrates that guadecitabine is safe, and showed that the drug resulted in improved PK exposure and PD demethylation over what has been reported for the first-generation HMAs. It also confirmed the importance of DNA demethylation as a PD marker for clinical response," lead author Jean-Pierre Issa, MD, from Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, said in a statement in August when the results were published.

The most common grade ≥3 AEs were febrile neutropenia (41%), pneumonia (29%), thrombocytopenia (25%), anemia (25%), and sepsis (17%). The most common serious AEs were febrile neutropenia (31%), pneumonia (28%), and sepsis (17%).

"In this study we observed induced clinical responses in heavily pretreated patients including prior treatment with current HMAs," senior author Hagop Kantarjian, MD, from The University of Texas MD Anderson Cancer Center, said in a statement when the findings were published. "Together with the results of a large phase II study to be published later, these data support further investigation, including the recently commenced global phase III study in treatment-naïve AML patients.”

In the phase III study, known as ASTRAL-1, guadecitabine is being explored as a frontline treatment for patients with AML who are ineligible for intensive induction chemotherapy. This trial plans to enroll 800 patients and will compare guadecitabine with physician's choice of low-dose cytarabine, decitabine, or azacitidine. The dual primary endpoints are complete response rate and overall survival (NCT02348489).

The orphan drug designation is granted to treatments for rare diseases or conditions and provides tax credits for clinical trials and a waiver of the prescription drug user fee. Outside of these items, the designation does not change the standard regulatory requirements for marketing applications.


Issa J-PJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16(9):1099-1110.



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