Novartis’ Kymriah gets second FDA approval—for large B-cell lymphoma

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FDA approved Kymriah (tisagenlecleucel) suspension for intravenous infusion for its second indication – the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

The drug is sponsored by Novartis Pharmaceuticals Corp.

Kymriah is not indicated for patients with primary central nervous system lymphoma. Developed in collaboration with the University of Pennsylvania, Kymriah became the first chimeric antigen receptor T cell therapy to receive regulatory approval in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

The FDA approval is based on the pivotal phase II JULIET clinical trial, the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL.

JULIET was conducted in collaboration with Penn, and is the largest study examining a CAR-T therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the U.S., Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands. In the JULIET trial, patients were infused in the inpatient and outpatient setting.

In this Novartis-sponsored study, Kymriah showed an overall response rate of 50% (95% confidence interval, 38% – 62%), with 32% of patients achieving a complete response and 18% achieving a partial response in 68 patients evaluated for efficacy. The median duration of response was not reached among these patients, indicating sustainability of response.

In all patients infused with Kymriah (n=106), severe or life-threatening (grade III/IV) CRS, defined by the Penn Grading Scale, occurred in 23% of patients. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm.

Eighteen percent of all infused patients experienced grade III/IV neurologic events, which were managed with supportive care. Encephalopathy, a distinctive neurotoxicity associated with CAR-T therapies, was seen as severe or life-threatening in 11% of patients. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema have occurred.

Grade III/IV cytopenias lasting more than 28 days included thrombocytopenia (40%) and neutropenia (25%), and grade 3/4 infections occurred in 25%. The most common (>20%) adverse events in the JULIET study are CRS, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema and headache.

Kymriah is now the only CAR-T cell therapy to receive FDA approval for two distinct indications in non-Hodgkin lymphoma and B-cell ALL.

Kymriah is an immunocellular therapy that is a one-time treatment manufactured individually for each patient using the patient’s own T cells. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

To ensure all hospitals and their associated clinics are aware of how to manage the risks of cytokine release syndrome and neurological toxicities, Kymriah is available through a Risk Evaluation and Mitigation Strategy program. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Kymriah treatment.

To support safe patient access, Novartis has established a network of certified treatment centers throughout the country, which are fully trained on the use of Kymriah and appropriate patient care, and there are currently treatment centers which are certified and fully operational to begin treatment of eligible patients with DLBCL.

In January 2018, the European Medicines Agency granted accelerated assessment to the Marketing Authorization Application for Kymriah for the treatment of children and young adults with r/r B-cell ALL and for adult patients with r/r DLBCL who are ineligible for ASCT.

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