Legend Biotech Announces Acceptance of Its New Drug Application for Ciltacabtagene Autoleucel (Cilta-Cel) in China

Legend Biotech Corporation (NASDAQ: LEGN), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, announced today that China's National Medical Products Administration (NMPA) has formally accepted its New Drug Application (NDA) for ciltacabtagene autoleucel (cilta-cel). This submission is based on results from the confirmatory Phase 2 clinical study CARTIFAN-1 (NCT03758417), which was done in China and looked at how well and safely cilta-cel worked in adult patients with relapsed or refractory multiple myeloma who had already tried three or more types of treatment, such as a proteasome inhibitor and an immunomodulatory drug. Saijuan Chen, M.D., hematologist and molecular geneticist, Academician of the Chinese Academy of Engineering, and principal investigator of the CARTIFAN-1 clinical trial, said: "Incidence and mortality rates of multiple myeloma have recently increased in China, and the disease remains incurable. As a result, there is a huge unmet medical need for new treatment options. The CARTIFAN-1 study found that cilta-cel helped people with relapsed or refractory multiple myeloma in a deep and long-lasting way. We hope this drug becomes available to eligible patients as soon as possible." Ying Huang, Ph.D., Chief Executive Officer of Legend Biotech, said: "Meeting medical needs and serving patients around the world has always been the goal of Legend Biotech's innovative research and development. Cilta-cel has been approved for marketing in the United States and Japan and has received conditional marketing authorization in Europe. We look forward to the possibility of providing a new treatment option for appropriate patients with relapsed and refractory multiple myeloma in China.

Ciltacabtagene autoleucel is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient's own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The cilta-cel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells. In December 2017, Legend Biotech Corporation entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel. In February 2022, cilta-cel was approved by the U.S. Food and Drug Administration (FDA) under the brand name CARVYKTI® for the treatment of adults with relapsed or refractory multiple myeloma. In May 2022, the European Commission (EC) granted conditional marketing authorization of CARVYKTI® for the treatment of adults with relapsed and refractory multiple myeloma. In September 2022, Japan's Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI®. Cilta-cel was granted Breakthrough Therapy Designation in the U.S. in December 2019 and in China in August 2020. In addition, cilta-cel received a PRIority MEdicines (PRIME) designation from the European Commission in April 2019. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, from the European Commission in February 2020, and from the Pharmaceuticals and Medicinal Devices Agency (PMDA) in Japan in June 2020. In March 2022, the European Medicines Agency's Committee for Orphan Medicinal Products recommended by consensus that the orphan designation for cilta-cel be maintained on the basis of clinical data demonstrating improved and sustained complete response rates following treatment.

CARTIFAN-1 (NCT03758417) is a Phase 2 open-label, confirmatory trial evaluating the efficacy and safety of cilta-cel in Chinese patients with relapsed/refractory multiple myeloma who have received at least three prior lines of treatment, including a proteasome inhibitor and immunomodulatory drug. The primary endpoint is overall response rate. Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells. In 2022, it is estimated that more than 21,000 people will be diagnosed with multiple myeloma, and more than 16,000 people will die from the disease in China. While some patients with multiple myeloma have no symptoms at all, most are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems, or infections. Although treatment may result in remission, unfortunately, patients will most likely relapse. Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulatory agents, and an anti-CD38 monoclonal antibody, have poor prognoses and few treatment options available.

CARVYKTI® (ciltacabtagene autoleucel) is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. CYTOKINE RELEASE SYNDROME (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI® in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 1‑12 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Ensure that a minimum of two doses of tocilizumab are available prior to the infusion of CARVYKTI®. Monitor patients at least daily for 10 days following CARVYKTI® infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

NEUROLOGIC TOXICITIES, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI®. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, peripheral neuropathies, and cranial nerve palsies. Overall, one or more subtypes of neurologic toxicity occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). The most frequent manifestations of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%). Of the 25 patients experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion. A fatal outcome following Guillain-Barré Syndrome has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Six patients in CARTITUDE-1 developed peripheral neuropathy, with a median time of onset of 62 days (range 4-136 days). Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)/MACROPHAGE ACTIVATION SYNDROME (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction. Because of the risk of CRS and neurologic toxicities, CARVYKTI® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI® REMS.

PROLONGED AND RECURRENT CYTOPENIAS: In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia, and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion. Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were seen in 63%, 18%, 60%, and 37% of patients respectively after recovery from initial Grade 3 or 4 cytopenia following infusion.

INFECTIONS: Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1). Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients with hypogammaglobulinemia.

HYPOGAMMAGLOBULINEMIA was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI® and administer IVIG for IgG <400 mg/dL. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI® treatment, and until immune recovery following treatment. HYPERSENSITIVITY REACTIONS have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. SECONDARY MALIGNANCIES may develop and patients should be monitored life-long. Due to the potential for neurologic events, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI® infusion and should refrain from driving and engaging in hazardous activities during this initial period.

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia. Legend Biotech is a global biotechnology company dedicated to treating, and, one day, curing, life-threatening diseases. Headquartered in Somerset, New Jersey, Legend Biotech is developing advanced cell therapies across a diverse array of technology platforms, including autologous and allogeneic chimeric antigen receptor T-cell and natural killer (NK) cell-based immunotherapy. From their three R&D sites around the world, they apply these innovative technologies to pursue the discovery of cutting-edge therapeutics for patients worldwide.