Otsuka/Astex AML Candidate Guadecitabine Fails Phase III Trial

Mohammad Azab, M.D., Astex Pharmaceuticals president and CMO

Otsuka Pharmaceutical and its Astex Pharmaceuticals subsidiary acknowledged that their cancer candidate guadecitabine (SGI-110) has failed a Phase III trial assessing the DNA methyltransferase inhibitor in a subgroup of patients with acute myeloid leukemia (AML).

Guadecitabine missed the co-primary endpoints of the ASTRAL-1 trial (NCT02348489) of superior benefit in complete response and overall survival compared with the control arm of physician’s choice of azacitidine, decitabine, or low dose cytarabine, the companies said.

ASTRAL-1 was designed to assess guadecitabine in previously untreated adults with AML who were ineligible to receive intense induction chemotherapy. The companies said ASTRAL-1 was the largest global prospective study ever conducted in that specific patient population, with 815 patients randomized from 163 investigator sites in 24 countries worldwide.

Full data from ASTRAL-1 will be presented at an upcoming scientific meeting, Otsuka and Astex added.

The companies continue to evaluate the study’s secondary endpoints and safety data—which include including progression-free survival; composite CR (CR+ CR with incomplete hematologic recovery + CR with incomplete platelet recovery); overnight stays in hospital; red cell/platelet transfusions; quality of life (EQ-5D-5L); duration of response and safety.

“The study used very strict criteria of ineligibility to receive intensive chemotherapy based on age (over 75 years) or poor performance status (Eastern Cooperative Oncology Group performance status of 2 or 3) or comorbidities, which made it a difficult population to show superior benefit of guadecitabine,” Mohammad Azab, M.D., Astex’ president and CMO, said in a statement. “We are disappointed in the outcome of the ASTRAL-1 study.”

Guadecitabine joined Otsuka’s pipeline when the company acquired Astex for $866 million in 2013, in a deal intended to strengthen the buyer’s R&D efforts for central nervous system diseases and other disorders as well as speed up its drug development by applying Astex’ fragment-based Pyramid™ drug discovery technology.

A month before the acquisition was announced, Astex reported promising results for a Phase II trial of guadecitabine in acute myeloid leukemia and myelodysplastic syndrome.

Now, Otsuka and Astex said, they are focusing on completing two other Phase III studies for guadecitabine:

• ASTRAL-2 (NCT02920008), a randomized, open-label study in leukemia patients with relapsed or refractory AML following intensive chemotherapy; and
• ASTRAL-3 (NCT02907359), a randomized, open-label study in patients with relapsed and refractory myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) after failure of treatment with azacitidine, decitabine, or both.

Guadecitabine is also under study in more than 20 investigator and company-sponsored trials in other blood cancers and solid tumors, both alone and in combination with chemotherapy or immunotherapy.

Guadecitabine is a next-generation DNA hypomethylating agent designed to resist degradation by cytidine deaminase, and thus prolong the exposure of tumor cells to the active metabolite decitabine, thus ensuring greater uptake into the DNA of rapidly dividing cancer cells.

Through the action of decitabine, guadecitabine is intended to inhibit DNA methyl transferase with the potential to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells—which the companies reason may restore the expression of silenced tumor suppressor genes and tumor-associated antigens, and thus may have the potential to sensitize tumor cells to other anticancer agents, including immunotherapies, as well as to re-sensitize cancer cells previously resistant to chemotherapy.

Earlier this month, Otsuka signaled its intent to expand its pipeline in cancer—as well as infectious diseases, kidney diseases, and chronic pain—by agreeing to acquire Visterra for approximately $430 million. The deal is expected to close in the third quarter subject to customary closing conditions.