AbbVie Announces European Commission Approval of TEPKINLY® (epcoritamab) for Adults with Relapsed or Refractory Diffuse Large B-cell Lymphoma

• TEPKINLY^® (epcoritamab) is the first and only subcutaneous bispecific antibody approved as a monotherapy for adult patients with relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy
• Conditional marketing authorization approval from the European Commission is supported by data from the pivotal Phase 1/2 EPCORE™ NHL-1 clinical trial
• TEPKINLY represents AbbVie's second approved hematological cancer treatment in the European Union

NORTH CHICAGO, Ill., Sept. 25, 2023 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that the European Commission (EC) has granted conditional marketing authorization for TEPKINLY^® (epcoritamab) as a monotherapy for the treatment of adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. TEPKINLY is the first and only subcutaneous T-cell engaging bispecific antibody approved for the treatment of this patient population in the European Union (EU), as well as Liechtenstein, Norway and Iceland.

DLBCL is the most common type of B-cell non-Hodgkin's lymphoma worldwide.¹ While patients may have access to chemoimmunotherapy regimens to treat their disease, they face limited treatment options, with few readily available, off-the-shelf medicines, especially for those whose disease has relapsed or become refractory to prior treatments.¹

"The European Commission approval of epcoritamab represents a significant milestone in our aspiration with Genmab to develop a potential core therapy for patients with B-cell malignancies, like DLBCL," said Roopal Thakkar, senior vice president, development and regulatory affairs, chief medical officer, AbbVie. "With this milestone achievement, TEPKINLY is now the second approved cancer treatment in the EU from our oncology portfolio, and AbbVie's third blood cancer medicine across the world. We remain committed to developing new innovative medicines that help improve the lives of people with hematological cancers."

This conditional approval is supported by data from the pivotal EPCORE™ NHL-1 Phase 1/2 open-label, multi-cohort, multi-center, single-arm trial evaluating the preliminary efficacy and safety of TEPKINLY in patients with R/R large B-cell lymphoma (LBCL), including its subtype DLBCL. In this study, DLBCL patients treated with TEPKINLY (N=139) achieved an overall response rate of 62 percent and a complete response rate of 39 percent. The median duration of response was 15.5 months (range: 9.7, not reached).

Results from the trial showed that TEPKINLY demonstrated a manageable safety profile across the LBCL patient cohort (N=167), which included the DLBCL patient population. The most common adverse reactions (≥ 20 percent) were cytokine release syndrome, fatigue, neutropenia, injection site reaction, musculoskeletal pain, abdominal pain, pyrexia, nausea and diarrhea.

"Relapsed or refractory DLBCL is an aggressive cancer and patients can face a difficult and emotional treatment journey. At this point in the journey, a patient may have had multiple lines of therapy and will already have experienced relapse," said Anna Sureda, M.D., Ph.D., head of clinical hematology department, Institut Català d'Oncologia – L'Hospitalet, Barcelona, Spain. "This European Commission approval represents an important moment for the DLBCL patient community and brings with it a potential opportunity for effective disease management for a condition with limited available treatment options."

Conditional marketing authorization is granted to medicines that address an unmet medical need, where the benefit of its immediate availability to patients outweighs the risk of limited data availability, and where comprehensive data will be provided.²

TEPKINLY is being co-developed by AbbVie and Genmab as part of the companies' oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. AbbVie will continue to pursue regulatory submissions for epcoritamab across international markets throughout the year.

About the EPCORE™ NHL-1 Trial
EPCORE™ NHL-1 evaluated epcoritamab as a monotherapy in patients with CD20+ relapsed or refractory (R/R) large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy.³ The study included a dose escalation part and an expansion part.³ The primary efficacy endpoint was overall response rate determined by Lugano criteria (2014) as assessed by an independent review committee.³ More information can be found on www.clinicaltrials.gov.

About TEPKINLY^® (epcoritamab)
TEPKINLY is an investigational IgG1-bispecific antibody created using Genmab's proprietary DuoBody^® technology. Genmab's DuoBody^®-CD3 technology is designed to direct cytotoxic T-cells selectively to elicit an immune response toward target cell types. TEPKINLY is designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells and induces T-cell mediated killing of CD20+ cells.⁴ CD20 is expressed on B-cells and is a clinically validated therapeutic target in many B-cell malignancies, including DLBCL, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.^5,6

The U.S. Food and Drug Administration (FDA) approved epcoritamab under the brand name EPKINLY™ (epcoritamab-bysp) in May 2023 for the treatment of adult patients with R/R DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma, after two or more lines of systemic therapy. EPKINLY is approved under the FDA's Accelerated Approval program based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

EU Indications and Important Safety Information about Tepkinly^® ▼ (epcoritamab) 

Indications
Tepkinly (epcoritamab) as monotherapy is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Important Safety Information

Contraindications
Hypersensitivity to the active substance or to any of the excipients.

Special warnings and precautions for use
Cytokine release syndrome (CRS)
CRS, which may be life-threatening or fatal, occurred in patients receiving Tepkinly. The most common signs and symptoms of CRS include pyrexia, hypotension and hypoxia. Other signs and symptoms of CRS in more than two patients include chills, tachycardia, headache and dyspnoea.

Most CRS events occurred in Cycle 1 and were associated with the first full dose of Tepkinly. Administer prophylactic corticosteroids to mitigate the risk of CRS. Patients should be monitored for signs and symptoms of CRS following Tepkinly administration. Patients should be hospitalised for 24 hours after administration of the Cycle 1 Day 15 dose of 48 mg to monitor for signs and symptoms of CRS. At the first signs or symptoms of CRS, institute treatment of supportive care with tocilizumab and/or corticosteroids as appropriate. Patients should be counselled on the signs and symptoms associated with CRS and patients should be instructed to contact their healthcare professional and seek immediate medical attention should signs or symptoms occur at any time. Management of CRS may require either temporary delay or discontinuation of Tepkinly based on the severity of CRS.

Immune effector cell-associated neurotoxicity syndrome (ICANS)
ICANS, including a fatal event, have occurred in patients receiving Tepkinly. ICANS may manifest as aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral oedema. The majority of cases of ICANS occurred within Cycle 1 of Tepkinly treatment, however some occurred with delayed onset. Patients should be monitored for signs and symptoms of ICANS following Tepkinly administration. Patients should be hospitalised for 24 hours after administration of the Cycle 1 Day 15 dose of 48 mg to monitor for signs and symptoms of ICANS. At the first signs or symptoms of ICANS treatment with corticosteroids and non-sedating-anti-seizure medicinal products should be instituted as appropriate. Patients should be counselled on the signs and symptoms of ICANS and that the onset of events may be delayed. Patients should be instructed to contact their healthcare professional and seek immediate medical attention should signs or symptoms occur at any time. Tepkinly should be delayed or discontinued as recommended.

Serious infections
Treatment with Tepkinly may lead to an increased risk of infections. Serious or fatal infections were observed in patients treated with Tepkinly in clinical studies. Administration of Tepkinly should be avoided in patients with clinically significant active systemic infections. As appropriate, prophylactic antimicrobials should be administered prior to and during treatment with Tepkinly. Patients should be monitored for signs and symptoms of infection, before and after Tepkinly administration, and treated appropriately. In the event of febrile neutropenia, patients should be evaluated for infection and managed with antibiotics, fluids and other supportive care, according to local guidelines.

Tumour Lysis Syndrome (TLS)
TLS has been reported in patients receiving Tepkinly. Patients at an increased risk for TLS are recommended to receive hydration and prophylactic treatment with a uric acid lowering agent. Patients should be monitored for signs or symptoms of TLS, especially patients with high tumour burden or rapidly proliferative tumours, and patients with reduced renal function. Patients should be monitored for blood chemistries and abnormalities should be managed promptly.

Tumour flare
Tumour flare has been reported in patients treated with Tepkinly. Manifestations could include localized pain and swelling. Consistent with the mechanism of action of Tepkinly, tumour flare is likely due to the influx of T-cells into tumour sites following Tepkinly administration. There are no specific risk factors for tumour flare that have been identified; however, there is a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with Tepkinly should be monitored and evaluated for tumour flare at critical anatomical sites.

CD20-negative disease 
There are limited data available on patients with CD20-negative DLBCL treated with Tepkinly, and it is possible that patients with CD20-negative DLBCL may have less benefit compared to patients with CD20-positive DLBCL. The potential risks and benefits associated with treatment of patients with CD20-negative DLBCL with Tepkinly should be considered.

Immunisation
Live and/or live-attenuated vaccines should not be given during Tepkinly therapy. Studies have not been conducted in patients who received live vaccines.

Fertility, pregnancy and lactation
Tepkinly is not recommended during pregnancy and in women of childbearing potential not using contraception. 

Effects on ability to drive and use machines
Tepkinly has minor influence on the ability to drive and use machines. Due to the potential for ICANS, patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines.

Undesirable effects
Summary of the safety profile
The most common adverse reactions (≥ 20%) were CRS, fatigue, neutropenia, injection site reactions, musculoskeletal pain, abdominal pain, pyrexia, nausea, and diarrhoea. Serious adverse reactions occurred in 52% of patients. The most frequent serious adverse reaction (≥ 10%) was cytokine release syndrome (31%). Seven patients (4.2%) experienced a fatal adverse reaction (pneumonia in 3 (1.8%) patients, viral infection in 3 (1.8%) patients and ICANS in 1 (0.6%) patient). Adverse reactions that led to discontinuation occurred in 6.6% of patients. Discontinuation of Tepkinly due to pneumonia occurred in 6 (3.6%) patients, viral infection in 3 (1.8%) patients, and CRS, ICANS, or fatigue in 1 (0.6%) patient each. Dose delays due to adverse reactions occurred in 32% of patients. Adverse reactions leading to dose delays (≥ 3%) were viral infections (9.6%), CRS (7.2%), neutropenia (4.8%), pyrexia (3.0%), and thrombocytopenia (3.0%).

This is not a complete summary of all safety information. 
See Tepkinly^® full Summary of Product Characteristics (SmPC) at www.ema.europa.eu
Globally, prescribing information varies; refer to the individual country product label for complete information.

EPKINLY™ (epcoritamab-bysp) U.S. IMPORTANT SAFETY INFORMATION

Important Warnings—EPKINLY can cause serious side effects, including:

• Cytokine Release Syndrome (CRS). CRS is common during treatment with EPKINLY and can be serious or life-threatening. Tell your healthcare provider or get medical help right away if you develop symptoms of CRS, including fever of 100.4°F (38°C) or higher, dizziness or lightheadedness, trouble breathing, chills, fast heartbeat, feeling anxious, headache, confusion, shaking (tremors), or problems with balance and movement, such as trouble walking.
  
  Due to the risk of CRS, you will receive EPKINLY on a "step-up" dosing schedule. The step-up dosing schedule is when you receive smaller "step-up" doses of EPKINLY on day 1 and day 8 of your first cycle of treatment (cycle 1). You will receive your first full dose of EPKINLY on day 15 of cycle 1. If your dose of EPKINLY is delayed for any reason, you may need to repeat the step-up dosing schedule. Before each dose in cycle 1, you will receive medicines to help reduce your risk of CRS. Your healthcare provider will decide if you need to receive medicine to help reduce your risk of CRS with future cycles.
   
• Neurologic problems. EPKINLY can cause serious neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive EPKINLY. Your healthcare provider may refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any symptoms of neurologic problems, including trouble speaking or writing, confusion and disorientation, drowsiness, tiredness or lack of energy, muscle weakness, shaking (tremors), seizures, or memory loss.

Due to the risk of CRS and neurologic problems, you should be hospitalized for 24 hours after receiving your first full dose of EPKINLY on day 15 of cycle 1. Your healthcare provider will monitor you for symptoms of CRS and neurologic problems during treatment with EPKINLY, as well as other side effects, and treat you if needed. Your healthcare provider may temporarily stop or completely stop your treatment with EPKINLY if you develop CRS, neurologic problems, or any other side effects that are severe.

Do not drive or use heavy or potentially dangerous machinery if you develop dizziness, confusion, tremors, drowsiness, or any other symptoms that impair consciousness until your symptoms go away. These may be symptoms of CRS or neurologic problems.

EPKINLY can also cause other serious side effects, including:

• Infections. EPKINLY can cause serious infections that may lead to death. Your healthcare provider will check you for symptoms of infection before and during treatment. Tell your healthcare provider right away if you develop any symptoms of infection during treatment, including fever of 100.4°F (38°C) or higher, cough, chest pain, tiredness, shortness of breath, painful rash, sore throat, pain during urination, or feeling weak or generally unwell.
• Low blood cell counts. Low blood cell counts are common during treatment with EPKINLY and can be serious or severe. Your healthcare provider will check your blood cell counts during treatment. EPKINLY may cause low blood cell counts, including low white blood cell counts (neutropenia), which can increase your risk for infection; low red blood cell counts (anemia), which can cause tiredness and shortness of breath; and low platelet counts (thrombocytopenia), which can cause bruising or bleeding problems.

Your healthcare provider may temporarily stop or completely stop treatment with EPKINLY if you develop certain side effects.

Before you receive EPKINLY, tell your healthcare provider about all of your medical conditions, including if you:

• have an infection.
• are pregnant or plan to become pregnant. EPKINLY may harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do a pregnancy test before you start treatment with EPKINLY. You should use effective birth control (contraception) during treatment and for 4 months after your last dose of EPKINLY. Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment with EPKINLY.
• are breastfeeding or plan to breastfeed. It is not known if EPKINLY passes into your breast milk. Do not breastfeed during treatment with EPKINLY and for 4 months after your last dose of EPKINLY.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of EPKINLY include CRS, tiredness, muscle and bone pain, injection site reactions, fever, stomach-area (abdominal) pain, nausea, and diarrhea.

These are not all the possible side effects of EPKINLY. Call your doctor for medical advice about side effects.

You are encouraged to report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch or to Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622).

Please see the Full Prescribing Information and Medication Guide, including Important Warnings.

About AbbVie in Oncology

At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potential breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit http://www.abbvie.com/oncology.

About AbbVie 

AbbVie's mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on LinkedIn, Facebook, Instagram, X (formerly Twitter), and YouTube.

AbbVie Forward-Looking Statements 

Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions and uses of future or conditional verbs, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2022 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law. 

¹ Sehn, Salles. "Diffuse Large B-Cell Lymphoma." N Engl J Med. 2021;384:842-858. DOI: 10.1056/NEJMra2027612.
² European Medicines Agency. Conditional Marketing Authorisation. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000925.jsp. Accessed August 2023.
³ First-in-human (FIH) trial in patients with relapsed, progressive or refractory B-cell lymphoma - clinicaltrials.gov. in. (n.d.). https://classic.clinicaltrials.gov/ct2/show/NCT03625037. Accessed August 2023.
⁴ Engelberts et al. "DuoBody-CD3xCD20 induces potent T-cell-mediated killing of malignant B cells in preclinical models and provides opportunities for subcutaneous dosing." EBioMedicine. 2020;52:102625. DOI: 10.1016/j.ebiom.2019.102625.
⁵ Rafiq, Butchar, Cheney, et al. "Comparative Assessment of Clinically Utilized CD20-Directed Antibodies in Chronic Lymphocytic Leukemia Cells Reveals Divergent NK Cell, Monocyte, and Macrophage Properties." J. Immunol. 2013;190(6):2702-2711. DOI: 10.4049/jimmunol.1202588.
⁶ Singh, Gupta, Almasan. "Development of Novel Anti-Cd20 Monoclonal Antibodies and Modulation in Cd20 Levels on Cell Surface: Looking to Improve Immunotherapy Response." J Cancer Sci Ther. 2015;7(11):347-358. DOI: 10.4172/1948-5956.1000373.

SOURCE AbbVie