Agios Submits Supplemental New Drug Application to FDA for TIBSOVO® (ivosidenib tablets) for Patients with Previously Treated IDH1-Mutant Cholangiocarcinoma

Rhea-AI Summary

Agios Pharmaceuticals has submitted a Supplemental New Drug Application (sNDA) to the FDA for TIBSOVO® (ivosidenib tablets) to treat previously treated patients with IDH1 mutated cholangiocarcinoma. The company has requested priority review, which could shorten the review process to six months. Cholangiocarcinoma is a rare and aggressive cancer with limited effective therapies, particularly for patients whose disease has progressed after chemotherapy. The sNDA is backed by data from the ClarIDHy study, the only randomized Phase 3 trial for this condition.

Positive

• Submitted sNDA for TIBSOVO® targeting IDH1 mutated cholangiocarcinoma.
• Requested priority review from the FDA, potentially reducing review time to six months.
• Supported by data from the ClarIDHy study, the first Phase 3 trial for this indication.

Negative

• No approved systemic therapies currently exist for IDH1-mutated cholangiocarcinoma.
• Dependence on FDA's approval process adds uncertainty to future revenue from TIBSOVO®.

CAMBRIDGE, Mass., March 01, 2021 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and genetically defined diseases, today announced that it has submitted a Supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for TIBSOVO^® (ivosidenib tablets) as a potential treatment for patients with previously treated isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma. Agios has requested priority review for the application, which, if granted, could result in a six-month review process.

“Cholangiocarcinoma is a rare, aggressive cancer with limited effective therapies, and patients are in desperate need of new treatment options – particularly those who experience disease progression after chemotherapy,” said Chris Bowden, M.D., chief medical officer at Agios. “We are proud of the work we have done on behalf of these patients and look forward to working closely with the FDA during the review of the first oral therapy targeting an IDH1 mutation for patients with previously treated IDH1-mutated cholangiocarcinoma.”

The sNDA submission is supported by data from the ClarIDHy study, the first and only randomized Phase 3 trial for previously treated IDH1-mutated cholangiocarcinoma. Data from the study were previously presented at the European Society for Medical Oncology Congress (ESMO), held in September 2019 in Barcelona, Spain, and published in The Lancet Oncology on May 13, 2020. A final analysis of the data was featured in an oral presentation at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI) on January 17, 2021.

About Cholangiocarcinoma
Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts within and outside of the liver. IDH1 mutations occur in approximately 13% of cholangiocarcinoma cases and are not associated with prognosis. There are no approved systemic therapies for IDH1-mutated cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed advanced or metastatic disease.

About TIBSOVO^® (ivosidenib tablets)
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 AML 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.

Please see full Prescribing Information, including Boxed WARNING.

About Agios
Agios is focused on discovering and developing novel investigational medicines to treat malignant hematology, solid tumors and genetically defined diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across these three therapeutic areas, Agios has two approved oncology precision medicines and multiple first-in-class investigational therapies in clinical and/or preclinical development. For more information, please visit the company's website at www.agios.com.

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 for the FDA’s review of its sNDA for TIBSOVO® (ivosidenib tablets). The words "expects," "anticipates," "believes," "intends," "estimates," "plans," "will," "outlook" 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, an acceptance by the FDA of Agios’s sNDA for TIBSOVO® is not a guarantee of approval. 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: risks associated with the regulatory review process generally; the risk that the FDA may determine that the data included in the sNDA are insufficient for approval and that the Company must conduct additional clinical trials, or nonclinical or other studies, before the sNDA can be approved; the risk that the results of previously conducted studies involving TIBSOVO® will not be repeated or observed in ongoing or future studies or following commercial launch, if the sNDA is approved; and risks associated with the Company’s dependence on third parties with respect to regulatory matters for TIBSOVO®. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

Contact
Holly Manning, 617-844-6630
Director, Investor Relations
Holly.Manning@agios.com

FAQ

What does Agios Pharmaceuticals' recent PR about TIBSOVO® entail?

Agios submitted an sNDA to the FDA for TIBSOVO® to treat IDH1 mutated cholangiocarcinoma and requested a priority review.

What is cholangiocarcinoma and how does it relate to TIBSOVO®?

Cholangiocarcinoma is a rare bile duct cancer; TIBSOVO® aims to provide a treatment option for patients with the IDH1 mutation.

When did Agios submit the sNDA for TIBSOVO®?

Agios submitted the sNDA on March 1, 2021.

What is the significance of the ClarIDHy study for TIBSOVO®?

The ClarIDHy study is the first randomized Phase 3 trial for previously treated IDH1-mutated cholangiocarcinoma, supporting the sNDA submission.

What are the potential implications of FDA's priority review for TIBSOVO®?

If granted, priority review could shorten the FDA's review process for TIBSOVO® to six months.