Date: 2015-12-06
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 2015 American Society of Hematology Annual Meeting and Exposition (ASH) taking place December 5-8, 2015 in Orlando
Company: Agios Pharmaceuticals (USA -MA)
Product: AG-221
Action
mechanism: enzyme inhibitor/isocitrate dehydrogenase inhibitor. AG-221 is an orally available, selective, potent inhibitor of the mutated isocitrate dehydrogenase (IDH) 2 protein, making it a highly targeted investigational medicine for the potential treatment of patients with cancers that harbor an IDH2 mutation. AG-221 has received orphan drug and fast track designations from the FDA. In September 2013, Agios initiated a Phase 1 multicenter, open-label, dose escalation clinical trial of AG-221 designed to assess the safety and tolerability of AG-221 in advanced hematologic malignancies. In October 2014, Agios initiated four expansion cohorts as part of the ongoing Phase 1 study and expanded its development program with the initiation of a Phase 1/2 study of AG-221 in advanced solid tumors. AG-221 is part of Agios' global strategic collaboration with Celgene Corporation . Under the terms of the collaboration, Celgene has worldwide development and commercialization rights for AG-221. Agios continues to conduct clinical development activities within the AG-221 development program and is eligible to receive up to $120 million in payments on achievement of certain milestones and royalties on net sales. For AG-120, Agios retains U.S. development and commercialization rights. Celgene has an exclusive license outside the United States . Celgene is eligible to receive royalties on net sales in the U.S. Agios is eligible to receive royalties on net sales outside the U.S. and up to $120 million in payments on achievement of certain milestones.
Disease: advanced hematologic malignancies
Therapeutic area: Cancer - Oncology
Country:
Trial
details: AG-221 is currently being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion cohorts of 25 patients each, evaluating patients with relapsed or refractory AML who are 60 years of age and older and transplant ineligible; relapsed or refractory AML patients under age 60; untreated AML patients who decline standard of care chemotherapy; and patients with other IDH2-mutant positive hematologic malignancies.
Latest
news: * On December 6, 2015, Agios Pharmaceuticals announced new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1/2 study evaluating single agent AG-221, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), in advanced hematologic malignancies. The data are being presented at the 2015 American Society of Hematology Annual Meeting and Exposition (ASH) taking place December 5-8, 2015 in Orlando . Data as of September 1, 2015 from 209 patients with IDH2 mutant positive advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than 50 patients were added as of the last analysis, and 66 patients remain on treatment. In patients with relapsed or refractory AML, the study had an overall response rate of 37 percent (59 of 159 response-evaluable patients) and a complete remission rate of 18 percent (29 of 159 response-evaluable patients). Responding relapsed or refractory AML patients were on study treatment for up to 18 months with a 6.9-month median response duration (not reported at previous data presentations). The overall safety profile observed was consistent with previously reported data. * On June 12, 2015, Agios Pharmaceuticals announced new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1 study evaluating single agent AG-221 in advanced hematologic malignancies. The data will be presented at the 20th Congress of the European Hematology Association (EHA) taking place June 11-14, 2015 in Vienna . AG-221 is currently being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion cohorts of 25 patients each, evaluating patients with relapsed or refractory AML who are 60 years of age and older and transplant ineligible; relapsed or refractory AML patients under age 60; untreated AML patients who decline standard of care chemotherapy; and patients with other IDH2-mutant positive hematologic malignancies. Data reported here are from patients receiving AG-221 administered from 60 mg to 450 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of May 1, 2015 . The median age of these patients is 69 (ranging from 22-90). Treatment with AG-221 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers. Data as of May 1, 2015 from 177 patients (104 in dose escalation and 73 from the first four expansion cohorts) with advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than half of the 177 patients remain on treatment. The study had an overall response rate of 40 percent (63 of 158 response-evaluable patients, using the criteria below) and a complete remission rate of 16 percent (26 of 158 response-evaluable patients). Patients responding to AG-221 continue to show durable clinical activity on treatment for more than 15 months, with an estimated 76 percent of responders staying on treatment for six months or longer. The overall safety profile observed was consistent with previously reported data with more than 100 additional patients treated as of the last analysis. This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-221 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded.
The ongoing Phase 1/2 trial includes a dose-escalation phase and five expansion cohorts. The first four expansion cohorts have completed enrollment. Data reported here are from patients receiving AG-221 administered from 50 mg to 650 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of September 1, 2015 . The median age of these patients is 69 (ranging from 19-100). Patients with relapsed or refractory AML received a median of two prior lines of therapy (ranging from one to six). These new data reflect responses in the evaluable population, which include all patients with a day 28 or later response assessment or discontinued before assessment.
Safety Data: A safety analysis was conducted for all 231 treated patients.
The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, diarrhea, fatigue and febrile neutropenia.
The serious adverse events (SAE) were mainly disease related. Twenty-three percent of patients had treatment-related SAEs, notably differentiation syndrome (4 percent), leukocytosis (4 percent) and nausea (2 percent). Drug-related Grade 5 SAEs include atrial flutter (one patient), cardiac tamponade (one patient), pericardial effusion (one patient) and respiratory failure (one patient).
A maximum tolerated dose (MTD) has not been reached.
Efficacy Data: Seventy-nine out of 209 total response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 38 percent.
Of the 79 patients who achieved an objective response, there were 37 (18 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), three CRs with incomplete hematologic recovery (CRi) and 22 partial remissions (PR).
Of the 159 patients with relapsed or refractory AML, 59 (37 percent) achieved an objective response, including 29 (18 percent) CRs, one CRp, nine mCRs, three CRis and 17 PRs.
Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including four CRs, one CRp, one mCR and four PRs.
Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including three CRs, one CRp and three mCRs.
Responding relapsed or refractory AML patients were on study treatment for up to 18 months with a median duration of treatment of 6.8 months (ranging from 1.8 to 18 months).
Responses were durable, with a median response duration of 6.9 months in patients with relapsed or refractory AML. Neutrophil and platelet improvements were observed in some patients with stable disease.
A safety analysis was conducted for all 177 treated patients as of May 1, 2015 . The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, fatigue, increased blood bilirubin and diarrhea.
The majority of serious adverse events (SAE) were disease related; SAEs possibly related to study drug were reported in 27 patients. A maximum tolerated dose (MTD) has not been reached. The all-cause 30-day mortality rate was 4.5 percent.
Efficacy Data: Sixty-three out of 158 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 40 percent as of May 1, 2015 .
Of the 63 patients who achieved an objective response, there were 26 (16 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), two CRs with incomplete hematologic recovery (CRi) and 18 partial remissions (PR).
Of the 111 patients with relapsed or refractory AML, 46 (41 percent) achieved an objective response, including 20 (18 percent) CRs, one CRp, 16 PRs, eight mCRs and one CRi.
Of the 22 patients with AML that had not been treated, seven achieved an objective response, including three CRs, two PRs, one mCR and one CRi.
Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including two CRs, one CRp and four mCRs.
Responses were durable, with duration on study drug more than 15 months and ongoing. As of the analysis date, an estimated 88 percent of responses lasted three months or longer, and 76 percent of responses lasted six months or longer.
