On June 1, 2018 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported the first data from the ongoing Phase 1 study evaluating single agent AG-881 in advanced glioma and other solid tumors (Press release, Agios Pharmaceuticals, JUN 1, 2018, View Source [SID1234527032]). The data were featured in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. AG-881 is an investigational, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-1 (IDH1) and IDH2 enzymes, which was designed for enhanced brain penetrance for development in IDH-mutant glioma.

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"IDH mutant glioma is a distinct disease where patients are typically diagnosed in their thirties and forties and endure a deteriorating quality of life from the side effects associated with multiple rounds of surgery, radiation and chemotherapy and ultimately die of their disease," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "The AG-881 Phase 1 dose-escalation data are encouraging, as they demonstrate a favorable safety profile at lower dose levels and show signals of clinical activity that support further evaluation of the role of inhibiting mutant IDH in low-grade glioma."

"With no curative or approved targeted therapies for low-grade glioma and a poor long-term prognosis, we are committed to exploring the novel mechanism of action of our IDH inhibitors in this indication," said Chris Bowden, M.D., chief medical officer at Agios. "Data from our ivosidenib and AG-881 Phase 1 trials and the ongoing perioperative study, combined with feedback from regulators and the neurology community, will inform our pivotal development plan."

The ongoing Phase 1 dose-escalation trial is assessing the safety and tolerability of AG-881 in IDH1/2 mutant advanced solid tumors, including glioma. As of the March 29, 2018 data cut-off, 93 patients (52 with glioma and 41 with other solid tumors) have been treated with single agent AG-881. Enrollment is complete and 17 glioma patients and 1 non-glioma solid tumor patient remain on treatment. Study design, status and baseline characteristics for the 52 glioma patients are reported below.

Forty-eight percent of patients (n=25) had World Health Organization (WHO) classified Grade 2 tumors, 42% (n=22) had Grade 3 tumors, 8% (n=4) had Grade 4 tumors and 2% (n=1) was unknown.
Ninety-two percent of patients (n=48) had an IDH1 mutation and 6% (n=3) had an IDH2 mutation. One patient did not have a biopsy but was confirmed as IDH mutant positive due to 2-HG elevation by magnetic resonance spectroscopy (MRS).
The median age of these patients is 42.5 years (ranging from 16-73 years).
Patients received a median of two prior systemic therapies (ranging from one to six).
— Seventy-three percent of patients (n=38) had previously received temozolomide and 58% percent (n=30) had previously received radiotherapy.
Patients received daily doses of AG-881 ranging from 10 mg to 300 mg.
The median treatment duration was seven months (ranging from 0-27 months) for all glioma patients, 12 months (ranging from 1-27 months) for non-enhancing glioma and 3 months (ranging from 0- 27 months) for patients with enhancing disease.
Safety Data

The safety analysis conducted for all 93 treated patients as of the data cut-off demonstrated that AG-881 has a favorable safety profile at dose levels below 100 mg.

The majority of adverse events (AEs) reported by investigators were mild to moderate, with the most common (>33%) being fatigue, nausea, increases in alanine aminotransferase (ALT) and increases in aspartate aminotransferase (AST).
Grade 3 or higher AEs were observed in 33% of all patients (n=31).
Dose limiting toxicities (DLTs) of Grade 2 or higher elevated transaminases occurred in five glioma patients at the higher dose levels (≥100 mg) and resolved to Grade ≤1 with dose modification or discontinuation. There were no treatment-related on-treatment deaths.
A maximum tolerated dose (MTD) was not reached by Bayesian model; the doses chosen for further clinical development were based on safety, pharmacokinetics and pharmacodynamics data.

Efficacy Data

Efficacy data from the 52 glioma patients (23 with non-enhancing and 29 with enhancing disease) as of the data cut-off showed:

One patient with non-enhancing disease and a 1p19q co-deletion had a sustained minor response according to the investigator by Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG) and remains on treatment.
Seventy-five percent of patients (n=39) had a best response of stable disease, including 20 patients with non-enhancing disease.
Thirty-five percent of patients (n=18, including 13 patients with non-enhancing disease) remained on treatment for ≥1 year.
Efficacy data from the 41 patients with non-glioma solid tumors as of the data cut-off showed:

One patient with cholangiocarcinoma had a partial response, 37% of patients (n=15) had stable disease and 44% (n=18) had progressive disease.
The median treatment duration was 2 months (ranging from 0-18 months).
Ongoing Perioperative Study in Glioma
A perioperative ‘window’ trial with ivosidenib and AG-881 (10 mg and 50 mg) in up to 45 IDH1m non-enhancing low-grade glioma patients is ongoing. The goal of the trial is to confirm CNS penetrance and tumor 2-HG suppression of ivosidenib and AG-881 as part of the strategy to finalize pivotal development plans by year-end 2018.

About Glioma
Glioma presents in varying degrees of tumor aggressiveness, ranging from slower growing (low grade glioma) to rapidly progressing (high grade glioma-Glioblastoma Multiforme). Common symptoms include seizures, memory disturbance, sensory impairment and neurologic deficits. The long-term prognosis is poor with a five-year survival rate of 33 percent. Approximately 11,000 low-grade glioma patients are diagnosed annually in the U.S. and EU and approximately 80 percent have an IDH1 mutation.