Celltrion USA Announces U.S. FDA Approval of ZYMFENTRA ® (infliximab-dyyb), the First and Only Subcutaneous infliximab, for the Treatment of People With Inflammatory Bowel Disease

Today, Celltrion USA announced that the U.S. Food and Drug Administration (FDA) has approved ZYMFENTRA^® (infliximab-dyyb) for maintenance therapy in adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD) following treatment with an infliximab product administered intravenously.¹

Following the submission of a Biologics License Application (BLA) under the 351 (a) pathway of the Public Health Service Act (a “stand-alone” BLA) in December 2022, the FDA approved ZYMFENTRA based on phase III pivotal data that evaluated the efficacy and safety of ZYMFENTRA as maintenance therapy in patients with moderately to severely active UC (LIBERTY-UC) and CD (LIBERTY-CD). Based on the results of the LIBERTY UC and LIBERTY CD studies, ZYMFENTRA demonstrated superiority in the primary endpoints of clinical remission (UC and CD) and endoscopic response (CD) compared to placebo as maintenance therapy after induction therapy of intravenous formulation of infliximab in patients with UC and CD, over a 54-week study period. The overall safety profile of ZYMFENTRA was similar to that of placebo during maintenance period in both studies with no new safety signals seen.^2,3

“There remains an unmet need for patients who suffer from the day-to-day burden of living with moderately to severely active Crohn’s disease and ulcerative colitis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA. “The approval of ZYMFENTRA provides an innovative and effective treatment option that offers patients with IBD an alternative administration option providing control of how and where they receive their treatment, reinforcing our commitment to providing high-quality and affordable treatment options that deliver substantial value to patients and our healthcare system.”

“As a healthcare professional dedicated to improving the lives of patients with IBD, I am excited to see further data that validate a convenient treatment option that could allow more patients in the U.S. to have greater control of their disease management,” said Dr. Jean-Frederic Colombel of Icahn School of Medicine at Mount Sinai.

“As someone dedicated to improving the lives of patients with IBD, I am excited to see data supporting the efficacy and safety of a new formulation offering convenience and improved access to a well-known and proven drug,” said Dr. Andres Yarur of Cedars-Sinai Medical Center.

ZYMFENTRA will be under patent protection by 2037 for its dosage form and route of administration by 2040.

About the pivotal LIBERTY-UC study

The LIBERTY-UC is a randomized, placebo-controlled, double-blind, phase III study designed to evaluate the superiority of subcutaneous ZYMFENTRA relative to placebo treatment in efficacy and safety during maintenance therapy in patients with moderate to severe active UC after induction therapy of intravenous formulation of infliximab. A total of 438 patients with response after induction were randomized at Week 10. The rate of clinical remission at Week 54 was significantly greater in ZYMFENTRA (43.2%) compared to placebo (20.8%) (P<0.0001). The safety profile during maintenance phase was generally comparable between ZYMFENTRA and placebo arms. Most common adverse events are COVID-19, anemia, arthralgia, injection site reaction, increased alanine aminotransferase, and abdominal pain.

About the pivotal LIBERTY-CD study

The LIBERTY-CD is a randomized, placebo-controlled, double-blind, phase III study designed to evaluate the superiority of the subcutaneous ZYMFENTRA relative to placebo treatment in efficacy and safety during maintenance therapy in patients with moderate to severe active CD after induction therapy of intravenous formulation of infliximab. A total of 343 patients with response after induction were randomized at Week 10. At Week 54, the clinical remission rate was greater in ZYMFENTRA than placebo arm (62.3% and 32.1% respectively, with P <0.0001). In parallel, the endoscopic response rate at week 54 was also greater in ZYMFENTRA arm than placebo arm (51.1% and 17.9% respectively, with P <0.0001). The safety profile during maintenance phase was generally comparable between ZYMFENTRA and placebo arms. Most common adverse events are COVID-19, upper respiratory tract infection, headache, injection site reaction, diarrhea, increased alanine aminotransferase, and increased blood creatine phosphokinase, neutropenia, hypertension, urinary tract infection, dizziness, and leukopenia.

About ZYMFENTRA^® (infliximab-dyyb)

ZYMFENTRA is a subcutaneous version of Celltrion’s infliximab biosimilar. ZYMFENTRA blocks the action of tumor necrosis factor-alpha (TNF-alpha), a protein that can be overproduced in response to certain diseases and cause the immune system to attack normal, healthy parts of the body.

The infliximab biosimilar developed and manufactured by Celltrion was the world's first monoclonal antibody biosimilar. It is indicated for the treatment of eight autoimmune diseases including Crohn’s disease (CD) and ulcerative colitis (UC). It was approved by the European Commission under the trade name REMSIMA^® in September 2013 and launched in major EU countries in early 2015. The U.S. Food and Drug Administration approved the biosimilar in April 2016 under the trade name INFLECTRA^®.

Subcutaneous infliximab (trademarked as REMSIMA^® SC in the EU) has received EU marketing authorization for the treatment of people with CD, UC, rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis in adult patients. In the U.S., ZYMFENTRA has received FDA approval for the maintenance treatment of adult patients with moderately to severely active UC and CD.

About Celltrion USA

Celltrion USA is Celltrion Healthcare’s U.S. subsidiary established in 2018. Headquartered in New Jersey, Celltrion USA is committed to expanding access to innovative biologics to improve care for U.S. patients. Celltrion currently has five biosimilars approved by the U.S. FDA: INFLECTRA^® (infliximab-dyyb), TRUXIMA^® (rituximab-abbs), HERZUMA^® (trastuzumab-pkrb), VEGZELMA^®(bevacizumab-adcd), and YUFLYMA^®(adalimumab-aaty). Celltrion USA will continue to leverage Celltrion Healthcare’s unique heritage in biotechnology, supply chain excellence, and best-in-class sales capabilities to improve access to high-quality biopharmaceuticals for U.S. patients.

ZYMFENTRA (infliximab-dyyb) U.S. Use and Important Safety Information

ZYMFENTRA is a prescription medicine indicated in adults for maintenance treatment of:

• moderately to severely active Crohn’s disease following treatment with an infliximab product administered intravenously.
• moderately to severely active ulcerative colitis following treatment with an infliximab product administered intravenously.

It is not known if ZYMFENTRA is safe and effective in children under 18 years of age.

What is the most important information I should know about ZYMFENTRA?

SERIOUS INFECTIONS

Patients treated with ZYMFENTRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Discontinue ZYMFENTRA if a patient develops a serious infection or sepsis.

Reported infections include:

• Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with ZYMFENTRA. Treatment for latent infection should be initiated prior to treatment with ZYMFENTRA.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with ZYMFENTRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with ZYMFENTRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Risk of infection may be higher in patients greater than 65 years of age, patients with comorbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with infliximab included arthritis bacterial, pneumonia, and urinary tract infection.

MALIGNANCIES

Malignancies, some fatal, have been reported in children, adolescents, and young adults treated with TNF blockers, including infliximab products.

Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. Carefully assess the risks and benefits of treatment with ZYMFENTRA, especially in these patient types.

In clinical trials of all TNF blockers, more cases of malignancies were observed compared with controls and the expected rate in the general population. In clinical trials of some TNF blockers, including infliximab products, more cases of other malignancies were observed compared with controls. As the potential role of TNF blocker therapy in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy.

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

CONTRAINDICATIONS

ZYMFENTRA is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab-dyyb, other infliximab products, any of the inactive ingredients of ZYMFENTRA or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness).

HEPATITIS B VIRUS REACTIVATION

TNF blockers, including infliximab products, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating ZYMFENTRA. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing ZYMFENTRA for patients identified as carriers of HBV, and monitor closely for active HBV infection during and following termination of therapy with ZYMFENTRA. Discontinue ZYMFENTRA in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of ZYMFENTRA, and monitor patients closely.

HEPATOTOXICITY

Hepatobiliary disorders, including acute liver failure, jaundice abnormal hepatic function, hepatic steatosis, hepatitis, hepatotoxicity, hyperbilirubinemia, and non-alcoholic fatty liver, have been reported in patients receiving infliximab products postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, ZYMFENTRA should be discontinued, and a thorough investigation of the abnormality should be undertaken.

CONGESTIVE HEART FAILURE

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Some cases had a fatal outcome. In several exploratory trials of other TNF blockers in the treatment of CHF, there were greater proportions of TNF-blocker-treated patients who had CHF exacerbations requiring hospitalization or increased mortality. ZYMFENTRA has not been studied in patients with a history of CHF and ZYMFENTRA should be used with caution in patients with CHF.

HEMATOLOGIC REACTION

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to infliximab-product therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of ZYMFENTRA in patients who develop significant hematologic abnormalities.

HYPERSENSITIVITY AND OTHER ADMINISTRATION REACTIONS

In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylaxis, hypotension, and serum sickness) have been reported following administration of infliximab products. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA.

INJECTION SITE REACTIONS

In clinical studies, localized injection-site reactions were reported following administration of ZYMFENTRA. If a clinically significant injection-site reaction occurs, institute appropriate therapy and discontinue ZYMFENTRA.

NEUROLOGIC REACTIONS

Agents that inhibit TNF have been associated with central nervous system (CNS) manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering ZYMFENTRA in patients with these disorders and consider discontinuation if these disorders develop.

RISK OF INFECTION WITH CONCURRENT ADMINISTRATION OF OTHER BIOLOGICS PRODUCTS

Serious infections and neutropenia have been reported with concurrent use of ZYMFENTRA with other immunosuppressive biological products. The concurrent use of ZYMFENTRA with other immunosuppressive biological products used to treat UC and CD may increase the risk of infection and is not recommended.

RISK OF ADDITIVE IMMUNOSUPPRESSIVE EFFECTS FROM PRIOR BIOLOGICAL PRODUCTS

Consider the half-life and mode of action of prior biological products to avoid unintended additive immunosuppressive effects when initiating ZYMFENTRA.

AUTOIMMUNITY

Treatment with TNF blockers may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue ZYMFENTRA treatment if symptoms of a lupus-like syndrome develop.

VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

Prior to initiating ZYMFENTRA, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with ZYMFENTRA due to the possibility of clinical infections, including disseminated infections. At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to ZYMFENTRA.

ADVERSE REACTIONS

In clinical trials with ZYMFENTRA, the most common adverse reactions occurring in ≥3% of ZYMFENTRA-treated patients included site reactions, COVID-19, anemia, arthralgia, infection site reaction, increased alanine aminotransferase and abdominal pain for UC, and COVID-19, headache, upper respiratory tract infection, injection site reaction, diarrhea, increased blood creatine phosphokinase, arthralgia, increased alanine aminotransferase, hypertension, urinary tract infection, neutropenia, dizziness and leukopenia for CD.

This is the most important information to know about ZYMFENTRA. For more information, talk to your HCP.

Please click for Full U.S. Prescribing Information.

Globally, prescribing information varies; refer to the individual country product label for complete information.

References

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¹ Zymfentra Prescribing Information
² Hanauer SB et al., Subcutaneous infliximab (CT-P13) as maintenance therapy for Crohn’s disease: A phase 3, randomized, placebo-controlled study (LIBERTY-CD). Gastroenterology. 2023;164(Supplement_6):S220-S221; [Digestive Disease Week 2023, Presentation number 1028].
³ Sands BE et al., Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for ulcerative colitis: A phase 3, randomized, placebo-controlled study: Results of the LIBERTY-UC study. Gastroenterology. 2023;164(Supplement_6):S1083-S1084; [Digestive Disease Week 2023, Presentation number Tu1701].

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