Clinical Trials

Date: 2017-06-24

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the 22nd Congress of the European Hematology Association (EHA)

Company: Agios Pharmaceuticals (USA -MA)

Product: AG-348

Action mechanism: pyruvate kinase activator. AG-348 is a novel, first-in-class, oral activator of both wild-type (normal) and mutated pyruvate kinase-R (PKR) enzymes. Pyruvate kinase is  involved in the second to last reaction in glycolysis and has several tissue-specific isoforms (PKR, PKL, PKM1 and PKM2). The inherited mutations in PKR enzymes cause a deficit in cellular energy within the red blood cell, as evidenced by a decline in the energy metabolite ATP (adenosine triphosphate) and a build-up of the metabolite 2,3-DPG (2,3-diphosphoglycerate), and lead to a hematologic rare genetic disorder known as pyruvate kinase deficiency, or PK deficiency.  AG-348 is wholly owned by Agios.

Disease: pyruvate kinase deficiency

Therapeutic area: Rare diseases - Genetic diseases

Country: Canada, France, Italy, The Netherlands, UK, USA

Trial details:

• DRIVE-PK is a global Phase 2, open-label safety and efficacy trial evaluating AG-348 in adult, transfusion-independent patients with PK deficiency. The study includes two arms of up to 25 patients each, receiving a dose of 50 milligrams (mg) or 300 mg twice daily for at least six months. Hemoglobin levels are assessed in weekly intervals for the first 3 weeks of study and then at weeks 6, 9, 12, 16, 20 and 24. (NCT02476916 )

Latest news:  

• • On June 24, 2017, Agios Pharmaceuticals presented updated data from its wholly owned pyruvate kinase-R (PKR) activator AG-348 demonstrating the potential for the first disease-modifying treatment for patients with pyruvate kinase (PK) deficiency at the 22nd Congress of the European Hematology Association (EHA). The company now looks forward to advancing AG-348 into a global pivotal program in the first half of 2018.
• DRIVE PK is an ongoing global open-label, Phase 2, safety and efficacy trial evaluating AG-348 in adult, transfusion-independent patients with PK deficiency. As of the March 27, 2017 data cut-off, 48% of all 52 treated patients (n=25/52) and 57% of patients with at least 1 missense mutation (n=24/42) treated with AG-348 experienced a maximum Hb increase from baseline of >1.0 g/dL. Hb increases were rapid with a median time to a Hb increase of >1.0 g/dL of 10 days.
• Enrollment in DRIVE PK was completed in November 2016 with 52 patients. Patients were randomized to a starting dose of 50 mg or 300 mg twice daily, treated for six months in a core treatment period and then offered up to two years of treatment in an extension period. As of the data cut-off, 15 patients remain in the core period, 29 patients completed the core treatment period and 21 remain in the extension period. The median baseline hemoglobin (Hb) for all patients was 8.9 gram per deciliter (g/dL) (ranging from 6.5 to 12.3 g/dL). Forty-three of the 52 patients (83%) had been splenectomized prior to study entry and 25 (48%) have received prior iron chelation therapy.
• Safety Data: A safety analysis conducted for all 52 treated patients as of the data cut-off shows that AG-348 continues to be well tolerated.
• The majority of treatment-related adverse events were Grade 1-2; the most frequent were headache, insomnia and nausea. Three patients experienced treatment related AEs leading to discontinuation: chest discomfort/pleural effusion (n=1), pharyngitis/nausea (n=1) and anemia (n=1). Five patients experienced drug-related serious adverse events: withdrawal hemolysis followed by anemia (n=1), anemia (n=1), osteoporosis (n=1), hypertriglyceridemia (n=1) and pharyngitis (n=1). ° Grade 4 hypertriglyceridemia at week 24 resolved upon AG-348 discontinuation (patient had Grade 1 hypertriglyceridemia at baseline). Preliminary measurements of testosterone in men suggest aromatase inhibition by AG-348 with the majority of testosterone changes remaining within the normal range. Longer follow-up is required to assess clinical significance. Efficacy Data:
• In the efficacy analysis of all 52 treated patients, 25 patients overall and 24 of 42 patients with at least one missense mutation achieved rapid, robust and sustained Hb increases from baseline of >1.0 g/dL as of the data cut-off.
• In patients who had Hb increases of >1.0 g/dL, the mean maximum Hb increase was 3.5 g/dL (range 1.1-5.8 g/dL). The median time to a Hb increase of >1.0 g/dL was 10 days (range 7–141 days). Median baseline Hb in patients who experienced a maximum Hb increase of >1.0 g/dL was 9.7 g/dL (range 7.5–12.3 g/dL) vs. 8.0 g/dL (range 6.5–10.1 g/dL) in patients who did not experience the increase. In patients with a Hb increase of >1.0 g/dL improvements in hemolysis associated parameters were observed: ° An increase in haptoglobin and decrease in lactate dehydrogenase (LDH) were observed in the first weeks of dosing. ° Rapid decreases in reticulocytes were observed.
• • On December 4, 2016, Agios Pharmaceuticals presented new data on AG-348 at the 2016 American Society of Hematology Annual Meeting and Exposition (ASH). AG-348, is being evaluated in the Phase 2 DRIVE PK study in patients with pyruvate kinase (PK) deficiency. Updated data from DRIVE PK with additional patients and longer follow-up demonstrate that 47% of all efficacy evaluable patients (n=15/32) and 58% of evaluable patients with at least 1 missense mutation (n=15/26) treated with AG-348 experienced a maximum hemoglobin (Hb) increase from baseline of >1.0 gram per deciliter (g/dL). Efficacy evaluable patients were required to have received AG-348 for at least three weeks. Hb increases >1.0 g/dL were observed in patients randomized to two doses and the maximum increase ranged from 1.2-5.2 g/dL with a mean maximum increase of 3.6 g/dL. Hb increases were also rapid and sustained, with a median time to a hemoglobin increase of >1.0 g/dL of 1.4 weeks. Agios also presented the first data demonstrating a direct link between increases in hemoglobin levels and activation of the PKR pathway (rate of metabolism) in patients treated with AG-348. The target enrollment has been reached with a total of 52 patients enrolled. As of the September 23, 2016 data cut-off: Thirty-four patients had been treated in the study and are included in the safety analysis and 32 patients with at least 3 weeks of data are included in the efficacy analysis. Seventeen patients completed the initial 24 week treatment period. In the 32 patients for whom efficacy could be evaluated, the mean baseline Hb was 9.2 g/dL. Twenty-eight of the 34 patients (82%) had been splenectomized prior to study entry. A safety analysis was conducted based on all 34 treated patients as of the data cut-off. AG-348 was well-tolerated, and the majority of treatment-related adverse events (AEs) were Grade 1-2; the most frequent being headache, nausea and insomnia. Two patients experienced serious adverse events (SAEs). One Grade 2 AE of osteoporosis was previously reported in a patient with osteopenia at baseline assessment. One patient experienced withdrawal hemolysis and anemia after AG-348 was temporarily discontinued due to a rapid treatment-related Hb increase, but stayed in the study and is continuing to receive treatment with AG-348 at a lower dose. Sex steroids were assessed at baseline, week 12 and week 24 for male and female patients. Increases in free testosterone and decreases in estradiol indicate aromatase inhibition by AG-348. Bone density scan data (n = 17) show high variability and are inconclusive. Clinical significance of the aromatase inhibition remains unclear. In the efficacy analysis (n=32), 15 of 32 total evaluable patients and 15 of 26 evaluable patients with at least one missense mutation achieved rapid, robust and sustained hemoglobin increases from baseline of >1.0 g/dL as of the data cut-off. In patients who had hemoglobin increases of >1.0 g/dL, the mean maximum hemoglobin increase was 3.6 g/dL (range 1.2-5.2 g/dL). The median time to a hemoglobin increase of >1.0 g/dL was 1.4 weeks (range 1.1-21.0 weeks). Further data are needed to obtain a greater understanding of the relationship between genotype and response. Preliminary observations show: Of the 26 evaluable patients with at least one missense mutation, 15 have shown an increase in hemoglobin of >1.0 g/dL. None of the six patients with two non-missense mutations showed increases in hemoglobin of >1.0 g/dL. Five patients homozygous for R479H (missense-missense) were also non-responders. Additional studies were conducted on the red blood cells of eight DRIVE PK patients. In this subset, four patients who had hemoglobin level increases >1.0 g/dL on AG-348 experienced a greater than 50% average increase in the rate of metabolism of the PKR pathway. None of the four patients with <1.0 g/dL increase experienced significant metabolic changes.
• • On June 11, 2016, Agios Pharmaceuticals announced initial data demonstrating that AG-348 achieved proof-of-concept in an ongoing Phase 2 study (DRIVE-PK) of patients with pyruvate kinase (PK) deficiency, Data have been presented  at the 21st Congress of the European Hematology Association (EHA) taking place June 9-12, 2016 in Copenhagen . DRIVE-PK is the first study to evaluate the safety and efficacy of AG-348 in patients with PK deficiency. As of the March 27, 2016 data cut-off, 18 transfusion-independent patients (13 with at least one missense mutation and five with two non-missense mutations) were treated with twice-daily dosing of AG-348 for up to six months. Treatment resulted in rapid and sustained hemoglobin increases of >1.0 g/dL in nine out of 18 patients (nine of 13 patients with at least one missense mutation), ranging from 2.3-4.9 g/dL with a mean maximum hemoglobin increase of 3.4 g/dL. It is estimated that approximately 80 percent of all PK deficiency patients carry at least one missense mutation.

Is general: Yes