Servier Announces FDA Approval of TIBSOVO® (ivosidenib tablets) in IDH1-Mutated Cholangiocarcinoma

BOSTON, Aug. 25, 2021 /PRNewswire/ -- Servier Pharmaceuticals, a growing leader in oncology committed to bringing the promise of tomorrow to the patients we serve, announced today that the U.S. Food and Drug Administration (FDA) approved TIBSOVO^® (ivosidenib tablets) for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. TIBSOVO is the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma.

The supplemental New Drug Application (sNDA) for TIBSOVO received Priority Review, which accelerated the review timeline and is typically given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists.

"Servier has been focused on exploring the significant potential of inhibiting mutant IDH enzymes as a novel approach to treating cancers with high unmet needs, including cholangiocarcinoma," said David K. Lee, CEO, Servier Pharmaceuticals. "We are proud to bring to patients the first and only targeted therapy for previously treated IDH1-mutated cholangiocarcinoma. We are grateful to the patients, caregivers, investigators and study teams who made this achievement possible through their participation in the ClarIDHy clinical trial."

The FDA approval of this indication is supported by data from the ClarIDHy study, the first and only randomized Phase 3 trial for previously treated IDH1-mutated cholangiocarcinoma. Results from the ClarIDHy study demonstrated a statistically significant improvement in the primary endpoint of progression-free survival (PFS) by an independent review committee (hazard ratio [HR] 0.37; 95% CI [0.25, 0.54], p<0.001).¹ The median PFS (95% CI) for TIBSOVO and placebo was 2.7 (1.6, 4.2) and 1.4 (1.4, 1.6) months, respectively. Thirty-two percent and 22% of patients randomized to TIBSOVO remained free of progression or death at 6 and 12 months, respectively, versus none on the placebo arm.  

The study protocol specified that patients randomized to placebo could cross over to TIBSOVO at the time of disease progression, and a high proportion of patients in the placebo arm (70.5%) crossed over to TIBSOVO. The study also showed the key secondary endpoint of overall survival (OS) favoring patients randomized to TIBSOVO compared to those randomized to placebo; however, statistical significance was not reached.¹ OS results are based on the final analysis of OS (based on 150 events which occurred 16 months after the final analysis of PFS. The median OS (95% CI) for TIBSOVO was 10.3 (7.8, 12.4) months; and placebo was 7.5 (4.8, 11.1) months without adjusting for crossover.

The safety profile observed in the study was consistent with previously published data.¹ The most common adverse reactions (≥15%) in patients with cholangiocarcinoma were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. 

The recommended TIBSOVO dosage for previously treated IDH1-mutated cholangiocarcinoma is 500 mg orally once daily with or without food until disease progression or unacceptable toxicity.

"Patients living with IDH1-mutated cholangiocarcinoma, especially those whose disease progresses following chemotherapy, are in urgent need of new treatment options," said Rachna T. Shroff, MD, Associate Professor of Medicine, University of Arizona, and Chief of GI Medical Oncology at the University of Arizona Cancer Center. "In addition to an acceptable safety profile, TIBSOVO demonstrated an impressive, significant benefit in progression-free survival, underscoring its importance as a new option for patients battling this aggressive cancer." 

Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts within and outside of the liver. An estimated 8,000 people in the United States are diagnosed with cholangiocarcinoma each year. However, the actual number of these cases is likely to be higher, as cholangiocarcinoma can be hard to diagnose, and may be misclassified as other types of cancer.² 

"Before today's approval of TIBSOVO, there were no approved targeted therapies available to cholangiocarcinoma patients harboring the IDH1 mutation, and limited chemotherapy options available to patients with advanced disease," said Stacie Lindsey, Founder and CEO, Cholangiocarcinoma Foundation. "This approval brings new hope to the cholangiocarcinoma community and we are excited that this much-needed new therapeutic option is being made available to patients."

Servier Pharmaceuticals is introducing ServierONE Patient Support Services, a program that offers one-on-one support to help patients who are prescribed TIBSOVO or other Servier products navigate their cancer journey. Eligible patients will have access to financial assistance, emotional support and other resources. More information can be found at www.servierone.com. 

TIBSOVO* is also approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutated relapsed or refractory acute myeloid leukemia (AML) and for adults with newly diagnosed IDH1-mutated AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.

About Cholangiocarcinoma

Cholangiocarcinoma is a rare, aggressive cancer of the bile ducts within and outside of the liver. IDH1 mutations occur in up to 20% of cholangiocarcinoma cases in the U.S. and are not associated with prognosis.³ Prior to the approval of TIBSOVO, there were no approved targeted 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 Servier Pharmaceuticals

Servier Pharmaceuticals LLC is a commercial-stage company with a passion for innovation and improving the lives of patients, their families and caregivers. A privately held company, Servier has the unique freedom to devote its time and energy toward putting those who require our treatment and care first, with future growth driven by innovation in areas of unmet medical need.

As a growing leader in oncology, Servier is committed to finding solutions that will address today's challenges. The company's oncology portfolio of innovative medicines is designed to bring more life-saving treatments to a greater number of patients, across the entire spectrum of disease and in a variety of tumor types. 

Servier believes co-creation is fundamental to driving innovation and is actively building alliances, acquisitions, licensing deals and partnerships that bring solutions and accelerate access to therapies. With our commercial expertise, global reach, scientific expertise and commitment to clinical excellence, Servier Pharmaceuticals is dedicated to bringing the promise of tomorrow to the patients that we serve. More information: www.servier.us

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Press contact

Megan Talon
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INDICATIONS
TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with a susceptible IDH1 mutation as detected by an FDA-approved test with:

Acute Myeloid Leukemia (AML)

• Newly-diagnosed AML who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
• Relapsed or refractory AML.

Locally Advanced or Metastatic Cholangiocarcinoma

• Locally advanced or metastatic cholangiocarcinoma who have been previously treated.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS
Differentiation Syndrome in AML: 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. 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 can develop in patients treated with TIBSOVO. 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

• In patients with AML, 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).
• In patients with cholangiocarcinoma, the most common adverse reactions (≥15%) were fatigue (43%), nausea (41%), abdominal pain (35%), diarrhea (35%), cough (27%), decreased appetite (24%), ascites (23%), vomiting (23%), anemia (18%), and rash (15%). The most common laboratory abnormalities (≥10%) were hemoglobin decreased (40%), aspartate aminotransferase increased (34%), and bilirubin increased (30%).

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 for AML patients.

Disclosures
This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect.

Servier and its Affiliates are not acting as an advisor to the recipient of this information, and the ultimate decision to proceed with any transaction rests solely with the recipient of this information. Therefore, prior to entering into any proposed transaction, the recipient of this information should determine, without reliance upon Servier or its Affiliates, the economic risks and merits, as well as the legal, tax, and accounting characterizations and consequences, of the transaction and that it is able to assume these risks.

This statement also contains forward-looking statements that are subject to varying levels of uncertainty and risk. Investigational new drugs and indications are subject to further scientific and medical review and regulatory approval. They are not approved for use by the FDA.

Any reliance placed on this document is done entirely at the risk of the person placing such reliance. The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction.

The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest.

To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete.

To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same.

The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice.

¹ Zhu A, et al. Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib vs placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. Presented at Gastrointenstinal Cancer Symposium 2021. Available at: https://www.servier.us/sites/default/files/2021-04/ASCO-GI21 ClarIDHy.pdf.
² American Cancer Society. Key Statistics for Bile Duct Cancer. Available at: https://www.cancer.org/cancer/bile-duct-cancer/about/key-statistics.html. 
³ Boscoe, A., Rolland, C., & Kelley, R. (2019). Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. Journal Of Gastrointestinal Oncology, 10(4), 751-765. Available at:  https://jgo.amegroups.com/article/view/28868

*Servier has an exclusive collaboration and license agreement with CStone for the development and commercialization of TIBSOVO (ivosidenib tablets) in Mainland China, Taiwan, Hong Kong, Macau and Singapore.

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