Agios Announces Withdrawal of European Marketing Authorization Application for TIBSOVO® as a Treatment for Relapsed or Refractory IDH1-mutant Acute Myeloid Leukemia

Rhea-AI Summary

Agios Pharmaceuticals has withdrawn its European Marketing Authorization Application for TIBSOVO® (ivosidenib) in treating adult patients with relapsed or refractory acute myeloid leukemia (AML) due to insufficient clinical data supporting its benefit-risk balance. The company is advancing two Phase 3 trials of TIBSOVO® in newly diagnosed AML, which could lead to future approvals in the U.S. and EU. The company emphasizes their commitment to developing targeted treatment options for AML patients.

Positive

• Advancing two Phase 3 trials for TIBSOVO® in newly diagnosed AML.
• Potential for future regulatory approvals based on trial outcomes.

Negative

• Withdrawal of European Marketing Authorization Application for TIBSOVO®.
• EMA feedback indicating insufficient data for a positive benefit-risk balance.

– Agios Continues to Advance Two Phase 3 Combination Trials of TIBSOVO^® in Newly Diagnosed AML Patients –

CAMBRIDGE, Mass., Oct. 16, 2020 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, today announced the withdrawal of its European Marketing Authorization Application (MAA) for TIBSOVO^® (ivosidenib tablets) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation. The decision is based on feedback from the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) that the available clinical data from the company’s
single arm, uncontrolled Phase 1 study do not sufficiently support a positive benefit-risk balance for the proposed indication.

“We are disappointed not to be able to bring TIBSOVO^® to AML patients in the EU based on our current data in the relapsed/refractory setting, given the tremendous need for new targeted treatment options for this devastating disease,” said Chris Bowden, M.D., chief medical officer at Agios. “We continue to believe in the benefit of TIBSOVO^® for patients with AML and are advancing our two ongoing Phase 3 randomized controlled trials evaluating TIBSOVO^® combinations in newly diagnosed AML. If these trials are positive, we anticipate pursuing approvals in these indications in both the U.S. and EU.”

About TIBSOVO^® Clinical Development in AML
Agios is currently enrolling two Phase 3 combination trials in newly diagnosed AML:

• AGILE, a Phase 3 trial of TIBSOVO^® in combination with azacitidine in newly diagnosed AML patients who are not eligible for intensive chemotherapy
• HOVON150/AMLSG29, an intergroup-sponsored Phase 3 trial evaluating TIBSOVO^® or IDHIFA^® (enasidenib) in combination with standard induction and consolidation chemotherapy in newly diagnosed AML patients who are eligible for intensive chemotherapy

The majority of AML patients with an IDH1 mutation are eligible for intensive therapy or non-intensive therapy.

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.

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 rare genetic 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: the potential benefits of TIBSOVO® (ivosidenib tablets); and Agios’ strategic plans and prospects. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “would,” “could,” “potential,” “possible,” “hope” 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, there can be no guarantee that any product candidate Agios or its collaborators is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. 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, without limitation: risks and uncertainties related to the impact of the COVID-19 pandemic to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to maintain key collaborations; and general economic and market conditions. 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.###

Contacts

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

Media:
Jessica Rennekamp, 857-209-3286
Associate Director, Corporate Communications
Jessica.Rennekamp@agios.com 

FAQ

What is the recent news regarding Agios Pharmaceuticals and TIBSOVO®?

Agios Pharmaceuticals has withdrawn its European Marketing Authorization Application for TIBSOVO® due to insufficient clinical data.

What trials is Agios conducting for TIBSOVO®?

Agios is advancing two Phase 3 trials for TIBSOVO® in newly diagnosed AML patients.

What was the reason for the withdrawal of TIBSOVO®'s application in Europe?

The withdrawal was based on feedback from the EMA indicating that available data did not support a positive benefit-risk balance.

What are the implications of the Phase 3 trials for TIBSOVO®?

If successful, the trials could lead to approvals for TIBSOVO® in both the U.S. and EU.

How might the withdrawal of the application affect Agios's stock?

The withdrawal may create short-term pressure on Agios's stock due to regulatory setbacks, but positive trial outcomes could lead to recovery.