Agios Announces Initial Phase 1 Data Demonstrating Clinical Activity of AG-221, First-in-Class Inhibitor of IDH2 Mutations, in Patients with Advanced Blood Cancers
- Significant Clinical Responses and Reduction of 2HG Biomarker in Early Cohorts -
- Data Presented at AACR Corroborate Company’s Precision Medicine
Approach in Targeting Cancer Metabolism; Company to Host Investor
“This is the first clinical trial of an inhibitor of mutant IDH, and
while the primary objectives of this study are to determine the safety
and tolerability of AG-221, we were also able to demonstrate promising
clinical activity, including multiple complete remissions, in patients
whose blood cancers carried an IDH2 mutation, even at the lowest tested
The preliminary data to be presented by Dr. Stein show that in the first two cohorts of the Phase 1 trial of AG-221, six of seven evaluable patients had objective responses, including three complete remissions (CR) and two complete remissions with incomplete platelet recovery (CRp). AG-221 also substantially lowered plasma levels of the oncometabolite 2-hydroxyglutarate (2HG) with a favorable exposure profile and good tolerability to date.
“We are very encouraged by these early data,” said
AG-221 is an orally available, selective, potent inhibitor of the
mutated IDH2 protein. As of
In today’s presentation, efficacy data will be presented for patients from the first two cohorts (30 mg and 50 mg twice a day). These cohorts enrolled 10 patients with relapsed or refractory AML whose disease had progressed after or was refractory to between one and four prior therapeutic regimens. Median age of these patients was 62.5 years, and all 10 patients had documented mutations in IDH2. Of these patients, seven were evaluable for efficacy (three patients did not complete a full 28-day cycle of therapy and died due to complications of disease-related infection, all in the first dose cohort).
Of the seven evaluable patients, six patients had investigator-assessed objective responses, including three patients who achieved complete remission (CR), two patients who achieved complete remission with incomplete platelet recovery (CRp) and one patient with a partial response (PR). One patient with a CR was removed from the study to undergo a bone marrow transplant; all other responses are ongoing with patients continuing to receive drug.
Treatment with AG-221 has been well tolerated to date, with no dose-limiting toxicities reported. Possible drug-related severe adverse events were reported in two patients, including one patient with an abnormally elevated white blood count and one patient with confusion and respiratory failure in the setting of disease-related infection.
The mechanism of response is consistent with preclinical studies, including substantial reduction of plasma 2HG levels, as well as evidence of cellular differentiation and normalization of cell counts in the bone marrow and blood. This differentiation effect is distinct from that seen with traditional chemotherapeutics used as standard of care for AML regimens.
Preliminary analysis of pharmacokinetics (PK) at the 30 mg and 50 mg dose levels demonstrated excellent oral AG-221 exposure and a mean plasma half-life of greater than 40 hours. Based on this PK profile, AG-221 is now being evaluated on a once-a-day and twice daily schedule in parallel. Dose escalation continues on both schedules, as the maximum tolerated dose has not been achieved.
AG-221 is a part of Agios’ global strategic collaboration with
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About the Study
The ongoing Phase 1 multicenter, open-label, dose-escalation clinical trial of AG-221 is designed to assess the safety and tolerability of AG-221 as a single agent administered orally once or twice daily in a 28-day cycle. The study is only enrolling subjects who have an IDH2-mutant hematologic malignancy, including AML and myelodysplastic syndrome. Key objectives in the study include determining maximum tolerated dose, PK, pharmacodynamics or PD (including inhibition of 2HG), and preliminary clinical activity of AG-221. Disease-specific expansion cohorts are being enrolled at the maximally tolerated or biologically relevant dose. Please refer to www.clinicaltrials.gov for additional clinical trial details.
About IDH Mutations and Cancer
The connection between cancer and metabolism has been the central focus for scientists at Agios, who were the first to identify the neo-morphic activity of isocitrate dehydrogenase (IDH) mutations to produce high levels of the oncometabolite 2-hydroxyglutarate (2HG) in research first published in Nature in 2009. IDH1 and IDH2 are metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies. Agios research revealed the potential of IDH1 and IDH2 mutations as novel therapeutic targets in cancer.
Agios and its collaborators recently demonstrated that IDH1 and IDH2 mutations initiate and drive cancer growth by blocking differentiation, or maturation, of primitive cells. Agios believes that inhibition of these mutated proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the
meaning of The Private Securities Litigation Reform Act of 1995. Such
forward-looking statements include those regarding Agios’ expectations
and beliefs about: the potential of IDH1/IDH2 as therapeutic targets;
the potential benefits of Agios’ product candidates AG-221 and AG-120;
its plans and timelines for the clinical development of AG-221 and
AG-120; and the benefit of its strategic plans and focus. The words
“anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,”
“predict,” “project,” “would” and similar expressions are intended to
identify forward-looking statements, although not all forward-looking
statements contain these identifying words. Such statements are subject
to numerous important factors, risks and uncertainties that may cause
actual events or results to differ materially from Agios’ current
expectations and beliefs. For example, there can be no guarantee that
any product candidate Agios is developing will successfully commence or
complete necessary preclinical and clinical development phases, or that
development of any of Agios’ product candidates will successfully
continue. There can be no guarantee that any positive developments in
Agios’ business will result in stock price appreciation. Management’s
expectations and, therefore, any forward-looking statements in this
press release could also be affected by risks and uncertainties relating
to a number of other important factors, including: Agios’ results of
clinical trials and preclinical studies, including subsequent analysis
of existing data and new data received from ongoing and future studies;
the content and timing of decisions made by the U.S.
Agios Pharmaceuticals, Inc.
Dan Budwick, 973-271-6085
Onsite Media Contact:
Sheryl Seapy, 949-903-4750