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Date: 2017-03-29

Type of information: Acceptation for review of a NDA

Product name: CTL019 (tisagenlecleucel-T)

Compound: tisagenlecleucel-T

Therapeutic area: Cancer - Oncology

Action mechanism: cell therapy/gene therapy/CAR-T cell therapy. CTL019 is an investigational, personalized T cell therapy, which was pioneered by Carl June and his team at Penn. In a CTL019 treatment cycle, immune cells (T cells) are drawn from a patient's blood. Then, using CAR technology, the T cells are reprogrammed to "hunt" cancer cells that express specific proteins, called CD19. CD19 is associated with a number of B-cell malignancies including ALL, CLL, diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. When the T cells are re-introduced into the patient's blood, the cells proliferate and bind to the targeted cancer cells and destroy them. These autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD19 were previously known as CART19. Novartis and Penn have an exclusive global agreement to research, develop and commercialize personalized CAR T cell therapies for the treatment of cancers. Novartis holds the worldwide rights to CARs developed through the collaboration for all cancer indications, including the lead program CTL019.

Company: Novartis (Switzerland)

Disease: B-cell acute lymphoblastic leukemia (ALL)

Latest news: • On March 29, 2017, Novartis announced that the FDA has accepted the company's Biologics License Application (BLA) filing and granted priority review for CTL019 (tisagenlecleucel-T), an investigational chimeric antigen receptor T cell (CAR-T) therapy, in relapsed and refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). This is the first BLA submission by Novartis for a CAR-T. The priority review designation and BLA submission for CTL019 is based on the results from the Novartis-sponsored ELIANA study (NCT02435849), the first global CAR-T cell trial with study enrollment having occurred across 25 centers in the US, EU, Canada, Australia and Japan. In the Phase II study, 82% (41 of 50) of patients infused with CAR-T cells achieved complete remission or complete remission with incomplete blood count recovery at three months post CTL019 infusion. The data were presented at the American Society of Hematology meeting in December 2016 (Abstract #221). Forty-eight percent of patients in the ELIANA trial experienced grade 3 or 4 cytokine release syndrome (CRS), a known complication of an investigational therapy that may occur when the engineered cells become activated in the patient's body. CRS was managed per protocol on a global scale using prior site education with implementation of the CRS treatment algorithm. There were no deaths due to CRS. Fifteen percent of patients experienced grade 3 neurological and psychiatric events including confusion, delirium, encephalopathy, agitation and seizure. No cerebral edema was reported and no grade 4 neurological and psychiatric events were observed[1]. The submission is also supported by findings from a US multicenter trial and an earlier single site trial led by the Children's Hospital of Philadelphia (CHOP) examining the safety and efficacy of CTL019 among pediatric and young adult patients with r/r B-cell ALL. Stephan Grupp, MD, PhD, from CHOP was the lead investigator of the trials. "Even if a patient has difficult-to-treat relapsed/refractory leukemia, we have seen treatment with CTL019 in clinical trials put cancer into remission," said Grupp, Director of the Cancer Immunotherapy Frontier Program and Director of Translational Research for the Center for Childhood Cancer Research at CHOP. "This could be a first-of-its-kind treatment with exciting potential to help pediatric and young adult r/r B-cell ALL patients." Acute lymphoblastic leukemia makes up approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US. Patients with r/r ALL have limited treatment options, and the chance of survival for children with the disease who relapse or fail to attain remission is between 16% to 30 %. According to the FDA guidelines, Priority Review status may potentially shorten the window for the agency to take action on an application to within six months of the filing acceptance compared to a standard review. The designation aims to prioritize the evaluation of products that have the potential to provide significant improvements in the treatment, diagnosis or prevention of serious conditions when compared to standard applications. CTL019 previously received Breakthrough Therapy designation from the FDA for the treatment of patients with r/r ALL. Novartis plans additional filings for CTL019 in the US and EU markets later this year, including a BLA with the FDA for treatment of adults with r/r diffuse large B-cell lymphoma (DLBCL) and applications for marketing authorization with the European Medicines Agency in r/r B-cell ALL and r/r DLBCL. Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established. Access to investigational therapies is available only through carefully controlled and monitored clinical trials. These trials are designed to better understand the potential benefits and risks of the therapy. Because of the uncertainty of clinical trials, there is no guarantee that CTL019 will ever be commercially available anywhere in the world.

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Is general: Yes