Phase 3 AGILE Data of TIBSOVO® (ivosidenib tablets) in Combination with Azacitidine for Patients with Previously Untreated IDH1-mutated Acute Myeloid Leukemia Published in the New England Journal of Medicine

Results from the trial present a significant advancement for patients living with previously untreated IDH1-mutated AML

Global Phase 3 trial of TIBSOVO (ivosidenib tablets) met its primary endpoint of event-free survival and all key secondary endpoints, complete remission rate, overall survival, complete remission and complete remission with partial hematologic recovery rate and objective response rate

PARIS and BOSTON, April 21, 2022 /PRNewswire/ -- Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, today announced the publication of results from the Phase 3 trial of TIBSOVO^® (ivosidenib tablets) in the New England Journal of Medicine (NEJM). The AGILE trial is a global Phase 3 double blinded placebo-controlled study of TIBSOVO in combination with the chemotherapy azacitidine in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) compared to azacitidine in combination with placebo. The study met the primary and all key secondary endpoints including overall survival. Servier is actively working with the FDA and health authorities across the globe to potentially bring this new indication to market.

"Patients with IDH1-mutated AML have a poor prognosis and have few, if any, treatment options, especially for newly diagnosed patients who are not eligible for intensive chemotherapy," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier Pharmaceuticals. "The publication of the compelling Phase 3 AGILE study data in NEJM, reinforces the clinical importance of these results and supports Servier's ongoing pursuit to serve patients with IDH1-mutated malignancies."

AML is a cancer of the blood and bone marrow marked by rapid disease progression and is the most common acute leukemia affecting adults with approximately 20,000 new cases estimated in the U.S. each year.^1,2 The majority of patients with AML eventually relapse. Relapsed or refractory AML has a poor prognosis.³ The five-year survival rate is approximately 29.5%.¹ IDH mutations are present in about 6 to 10 percent of AML cases.⁴

"We have significantly strengthened our position in oncology following the successful acquisition of the Agios Pharmaceuticals' oncology business in 2021," said Claude Bertrand, Executive Vice President, Research and Development, Servier. "Servier has placed oncology among its priorities and allocates more than 50% of its R&D budget to fighting cancer. This strategy initiated by the Group is now bringing results with new treatments and future indications for patients with hard-to-treat cancers."

The data from the global Phase 3 AGILE study show that TIBSOVO is the first IDH1 mutation specific targeted therapy to demonstrate improved event-free survival (EFS) and overall survival (OS) in combination with azacitidine compared to azacitidine plus placebo. Treatment with TIBSOVO in combination with azacitidine demonstrated a statistically significant improvement in EFS (hazard ratio [HR] = 0.33, 95% confidence interval [CI] 0.16, 0.69, 1-sided P = 0.0011).^5,6 The combination of TIBSOVO with azacitidine showed a statistically significant improvement in OS (HR = 0.44 [95% CI 0.27, 0.73; 1-sided P = 0.0005), with a median OS of 24.0 months vs. 7.9 months in the placebo + azacitidine arm.

In addition, the complete remission (CR) rate was 47.2% (n = 34/72) for TIBSOVO in combination with azacitidine vs. 14.9% (n = 11/74) for placebo plus azacitidine (P < 0.0001). CR + complete remission with partial hematologic recovery rate (CR + CRh rate) was 52.8% (n = 38/72) for TIBSOVO in combination with azacitidine vs. 17.6% (n = 13/74) for placebo plus azacitidine (P < 0.0001).The objective response rate (ORR) was 62.5% (n = 45/72) for TIBSOVO in combination with azacitidine vs. 18.9% (n = 14/74) for placebo plus azacitidine (P < 0.0001).

TIBSOVO[*] is currently approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Recently, TIBSOVO was approved as a first and only targeted therapy for patients with previously treated IDH1-mutated cholangiocarcinoma.

About the NCT03173248 AGILE Phase 3 AML Trial
The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of TIBSOVO in combination with azacitidine compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study's primary endpoint is EFS, defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.

Key secondary endpoints included CR rate, defined as the proportion of participants who achieve a CR; overall survival (OS), defined as the time from date of randomization to the date of death due to any cause; CR and complete remission with partial hematologic recovery (CRh) rate, defined as the proportion of participants who achieve a CR or CRh; and objective response rate (ORR), defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).

About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults, with approximately 20,000 new cases in the U.S., and 43,000 cases in Europe each year.^1,2,7 AML incidence significantly increases with age, and the median age of diagnosis is 68.¹ The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML.³ The five-year survival rate is approximately 29.5%.¹ For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia.⁴

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. As a privately held company, Servier has the unique freedom to devote all of its time and energy towards patients who require our treatments, care and innovation in areas of unmet medical need.

As a leader in oncology, Servier is committed to finding solutions that will address today's challenges. The company's oncology portfolio includes innovative medicines 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 has significantly accelerated its investment in hard-to-treat cancers with more than 50% of research and development dedicated to delivering significant advances in areas of high unmet need that may truly move the needle for our patients.

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 the company's 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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About Servier Group
Servier is a global pharmaceutical group governed by a Foundation. With a strong international presence in 150 countries and a total revenue of 4.7 billion euros in 2021, Servier employs 21,800 people worldwide. Servier is an independent group that invests over 20% of its brand-name revenue in Research and Development every year. To accelerate therapeutic innovation for the benefit of patients, the Group is committed to open and collaborative innovation with academic partners, pharmaceutical groups, and biotech companies. It also integrates the patient's voice at the heart of its activities.

A leader in cardiology, the ambition of the Servier Group is to become a renowned and innovative player in oncology. Its growth is based on a sustained commitment to cardiovascular and metabolic diseases, oncology, neuroscience and immuno-inflammatory diseases. To promote access to healthcare for all, the Servier Group also offers a range of quality generic drugs covering most pathologies.

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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 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.

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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.

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About TIBSOVO^® (ivosidenib tablets)

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.

References

1. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Acute Myeloid Leukemia (AML). https://seer.cancer.gov/statfacts/html/amyl.html. Accessed January 2022.
2. American Cancer Society. Acute Myeloid Leukemia (AML). https://www.cancer.org/content/dam/CRC/PDF/Public/8674.00.pdf. Accessed January 2022.
3. Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes Cancer. 2011; 2:95-107.
4. DiNardo C. Durable Remissions from Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. New England Journal of Medicine. 2018; 378:2386-98. Accessed January 2022.
5. Data on file. Servier. January 26, 2022.
6. ClinicalTrials.gov. Study of AG-120 (Ivosidenib) vs. Placebo in Combination with Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE). Available at: https://clinicaltrials.gov/ct2/show/NCT03173248. Accessed January 2022.
7. Visser O. Incidence, survival and prevalence of myeloid malignancies in Europe. European Journal of Cancer. 2012; 3257-3266.

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

SOURCE Servier Pharmaceuticals