Type of information: Granting of a Market Authorisation in the US
Product name: Kymriah® - CTL019 (tisagenlecleucel-T)
Therapeutic area: Cancer - Oncology
- cell therapy/gene therapy/CAR-T cell therapy. CTL019 is a 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. CTL019 uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular responses as well as persistence of CTL019 after it is infused into the patient, which may be associated with long-lasting remissions in patients.
- 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)
- patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse
- • On August 30, 2017, the FDA announced that it has
issued a "historic action" making the first gene therapy available in the United States, ushering in a new approach to the treatment of cancer and other serious and life-threatening diseases. The FDA approved Kymriah® (tisagenlecleucel) 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. This autologous T-cell immunotherapy is a customized treatment created using an individual patient’s own T-cells. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.
- The safety and efficacy of Kymriah® were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. The overall remission rate within three months of treatment was 83 percent.Treatment with Kymriah® has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome, which is a systemic response to the activation and proliferation of CAR T-cells causing high fever and flu-like symptoms, and for neurological events. Both cytokine release syndrome and neurological events can be life-threatening. Other severe side effects of Kymriah® include serious infections, low blood pressure (hypotension), acute kidney injury, fever, and decreased oxygen (hypoxia). Most symptoms appear within one to 22 days following infusion of Kymriah®. Since the CD19 antigen is also present on normal B-cells, and Kymriah® will also destroy those normal B cells that produce antibodies, there may be an increased risk of infections for a prolonged period of time. Novartis has set a price at $475,000 per one-time treatment.
- The FDA also expanded the approval of Actemra® (tocilizumab) to treat CAR T-cell-induced severe or life-threatening cytokine release syndrome in patients 2 years of age or older. In clinical trials in patients treated with CAR-T cells, 69 percent of patients had complete resolution of cytokine release syndrome within two weeks following one or two doses of Actemra®.
Because of the risk of cytokine release syndrome and neurological events, Kymriah® is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use. The FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of Kymriah® are required to be trained to recognize and manage cytokine release syndrome and neurological events. Additionally, the certified health care settings are required to have protocols in place to ensure that Kymriah® is only given to patients after verifying that tocilizumab is available for immediate administration. The REMS program specifies that patients be informed of the signs and symptoms of cytokine release syndrome and neurological toxicities following infusion – and of the importance of promptly returning to the treatment site if they develop fever or other adverse reactions after receiving treatment with Kymriah®. To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah®
- .• On July 12, 2017, Novartis announced that the FDA Oncologic Drugs Advisory Committee (ODAC) unanimously (10-0) recommended approval of CTL019 (tisagenlecleucel), an investigational chimeric antigen receptor T cell (CAR-T) therapy, for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia.
- The ODAC recommendation is based on review of the CTL019 r/r B-cell ALL development program, which includes the Novartis-led ELIANA study, the first pediatric global CAR-T cell therapy registration trial. Findings from a US multicenter trial and a single site trial examining the safety and efficacy of CTL019 among pediatric and young adult patients with r/r B-cell ALL also supported the recommendation and the Biologics License Application.
- Earlier this year, Novartis submitted a BLA for CTL019 to the FDA, marking the first submission by Novartis for a CAR-T cell therapy. CTL019 previously received FDA Breakthrough Therapy designation and is under Priority Review by the FDA. The FDA will consider the vote as it reviews the BLA, although it is not obligated to follow the recommendation. Novartis continues to invest in the necessary infrastructure for the potential commercialization of CTL019, including manufacturing and the establishment of a network of certified treatment centers.
- Novartis plans additional filings for CTL019 in the US and EU later this year, including applications with the FDA and European Medicines Agency (EMA) for the treatment of adults with r/r diffuse large B-cell lymphoma.
• 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), in relapsed and refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia. This is the first BLA submission s for a CAR-T.
- The priority review designation and BLA submission for CTL019 is based on the results from the ELIANA study, 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. Ccytokine release syndrome was managed per protocol on a global scale using prior site education with implementation of the cytokine release syndrome treatment algorithm. There were no deaths due to cytokine release syndrome. 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.
- 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.
- 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.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-08-30
Favourable opinion UE:
Favourable opinion USA: 2017-07-12
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: