On November 22, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported updated data from the ongoing perioperative study, confirming brain penetrance and robust biomarker suppression with treatment of single agent vorasidenib or TIBSOVO (ivosidenib) in low-grade glioma with an IDH1 mutation (Press release, Agios Pharmaceuticals, NOV 22, 2019, View Source [SID1234551609]). The data were featured in an oral presentation at the Society for Neuro-Oncology (SNO) Annual Meeting in Phoenix. Vorasidenib, an investigational, oral, selective, inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) and IDH2 enzymes, was designed for enhanced brain penetrance and selected for pivotal development in IDH mutant low-grade glioma.
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"Now with data from both cohorts of the perioperative study, we have further evidence demonstrating that vorasidenib has excellent brain penetrance and suppresses 2-HG in IDH1 mutant gliomas," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "In addition, it is encouraging that the safety profile continues to be consistent, and preliminary efficacy data show objective tumor responses and durable disease control with postoperative treatment. These data support the selection of vorasidenib for pivotal development and help establish the potential role for IDH inhibitors in the treatment of low-grade glioma."
"These data build on our initial findings that led us to the selection of vorasidenib for a pivotal study in low-grade glioma," said Chris Bowden, M.D., chief medical officer at Agios. "Having now demonstrated brain penetrance, robust 2-HG suppression and an encouraging disease-control rate with vorasidenib, we’re confident in our ability to make a difference for patients with IDH mutant low-grade glioma and are on track to initiate the Phase 3 INDIGO study next month."
Perioperative Study of Vorasidenib and TIBSOVO
Vorasidenib and TIBSOVO are being evaluated as a single agent in an ongoing perioperative study in IDH1 mutant Grade 2/3 glioma. The primary endpoint is 2-hydroxyglutarate (2-HG) concentration in tumors resected following presurgical treatment with vorasidenib and TIBSOVO compared with untreated control tumors. Patients were randomized to 500 mg TIBSOVO once daily, 50 mg vorasidenib once daily or the control arm in cohort 1; and 250 mg TIBSOVO twice daily or 10 mg vorasidenib once daily in cohort 2. Patients were treated for four weeks prior to surgery and had the option to continue postoperative treatment until disease progression.
As of the July 26, 2019 data cutoff, 49 patients were randomized before surgery, and 39 remain on treatment. The median (range) postoperative treatment duration for all doses was 5.42 (0.9–13.5) months for vorasidenib and 6.93 (1.0–13.2) months for TIBSOVO. Baseline characteristics were similar across the control and treated groups. Overall, 88% of patients had World Health Organization (WHO) classified Grade 2 tumors. Less than a third of patients had prior radiation therapy and approximately half had prior systemic therapy.
Safety Data
The safety analysis conducted for all 49 patients as of the data cut-off demonstrated that vorasidenib and TIBSOVO continue to have favorable safety profiles consistent with the Phase 1 data.
The most common adverse events (AE) occurring in >25% of patients in the vorasidenib arm were diarrhea (29.2%), fatigue (29.2%) and nausea (29.2%). In the TIBSOVO arm, the most common AEs were headache (32%), diarrhea (28%) and anemia (28%).
8.3% of patients in the vorasidenib group developed transaminase elevations, including one Grade 3 transaminase elevation at 50 mg daily which resolved with dose interruption.
Grade 3 or higher events occurred in six (25.0%) vorasidenib patients and four (16.0%) TIBSOVO patients, with the majority related to postoperative complications.
No patient discontinued treatment due to an AE.
Pharmacokinetics and Pharmacodynamics
Vorasidenib and TIBSOVO demonstrated brain penetrance, with mean brain:plasma ratios of 3.16 (vorasidenib 10 mg), 1.74 (vorasidenib 50 mg), 0.13 (TIBSOVO 250 mg) and 0.10 (TIBSOVO 500 mg).
Mean percent reduction in 2-HG (95% CI) were 92.6% (76.1, 97.6) and 91.1% (72.0, 97.0), for vorasidenib 50 mg and TIBSOVO 500 mg, respectively, relative to untreated samples.
Efficacy Data
Data from the 42 efficacy evaluable patients (21 in the vorasidenib arm; 21 in the TIBSOVO arm) as of the data cut-off showed:
Among patients treated post-operatively with 50 mg vorasidenib, four patients (31%) achieved objective tumor responses (two achieved a partial response, defined as tumor shrinkage based on T2/FLAIR signal of at least 50%, and two achieved a minor response, defined as tumor shrinkage based on T2/FLAIR signal of at least 25% but less than 50%) according to the investigator by Response Assessment in Neuro-Oncology for low-grade glioma (RANO-LGG).
Among patients treated post-operatively with 500 mg TIBSOVO, four patients (31%) achieved confirmed responses (two achieved a partial response and two achieved a minor response) according to the investigator by RANO-LGG.
15 patients treated with vorasidenib and 16 patients treated with TIBSOVO experienced stable disease, resulting in disease control rates of 90% and 95% respectively.
About the Phase 3 INDIGO Study
The Phase 3 INDIGO study will evaluate 366 patients with IDH mutant Grade 2 non-enhancing glioma in a 1:1 double-blind randomization to either 50 mg of vorasidenib once daily or placebo.
The primary endpoint is progression free survival, as assessed by a blinded independent review committee.
Secondary endpoints include safety and tolerability, tumor growth rate as assessed by volume, overall response rate, time to next intervention and quality of life.
Crossover from placebo to vorasidenib upon centrally confirmed radiographic progression will be permitted.
The study will initiate by the end of 2019.
TIBSOVO and vorasidenib are not approved in any country for the treatment of patients with low-grade glioma.
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, and regardless of treatment, the majority of patients with low-grade gliomas will have recurrent disease that will progress over time. Approximately 11,000 low-grade glioma patients are diagnosed annually in the U.S. and EU and approximately 80 percent have an IDH mutation.
About TIBSOVO (ivosidenib)
TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:
Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION
WARNING: DIFFERENTIATION SYNDROME
Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.
WARNINGS AND PRECAUTIONS
Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.
If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.
QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.
Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.
ADVERSE REACTIONS
The most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS
Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.
QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.
LACTATION
Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.