Type of information: Granting of a Market Authorisation in the EU
Product name: Yescarta™ - axicabtagene ciloleucel - KTE-C19)
Compound: autologous T cells transduced with retroviral vector encoding an anti-CD19 CD28/CD3 zeta chimeric antigen receptor
Therapeutic area: Cancer - Oncology - Rare diseases
- cell therapy/immunotherapy product/CAR-T cell therapy. Axicabtagene ciloleucel (KTE-C19) is Kite Pharma's lead product candidate in which a patient's T cells are genetically modified using a gammaretroviral vector to express a chimeric antigen receptor (CAR) designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias. CAR T therapy is manufactured specifically for each individual patient.
- Axicabtagene ciloleucel (KTE-C19) received Breakthrough Therapy Designation (BTD) by the FDA in December 2015 .
Company: Kite Pharma, a Gilead company (USA - CA)
- relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT), diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL)
• On August 27, 2018, Kite, a Gilead Company, announced that the European Commission (EC) has granted Marketing Authorization for Yescarta® (axicabtagene ciloleucel) as a treatment for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL), after two or more lines of systemic therapy. The Marketing Authorization approves axicabtagene ciloleucel for use in the 28 countries of the European Union, Norway, Iceland and Liechtenstein.
- The Marketing Authorization Application (MAA) is supported by data from the ZUMA-1 trial of axicabtagene ciloleucel in adult patients with refractory aggressive NHL. In the single-arm trial, 72 percent of patients (n=73/101) who received a single infusion of axicabtagene ciloleucel responded to therapy, with 51 percent (n=52/101) achieving a complete response (as assessed by an independent review committee, median follow-up of 15.1 months). At one year following infusion, 60 percent of patients were alive (95% CI: 50.2, 69.2) and the median overall survival (OS) had not been reached (95% CI: not estimable [NE]).
- Axicabtagene ciloleucel may cause side effects that are severe or life threatening, such as cytokine release syndrome (CRS) or neurological toxicities. In ZUMA-1, 12 percent of patients experienced Grade 3 or higher CRS and 31 percent experienced Grade 3 or higher neurologic toxicities. Overall 98 percent of patients recovered from CRS and/or neurologic adverse reactions. Treatment algorithms have been developed to manage some of the symptoms associated with both CRS and neurologic adverse reactions experienced by patients on axicabtagene ciloleucel. The most common Grade 3 or higher adverse reactions include encephalopathy, unspecified pathogen infection, CRS, bacterial infection, aphasia, viral infection, delirium, hypotension and hypertension.
- • On June 28, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Yescarta®, intended for the treatment of diffuse large cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL). As Yescarta® is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies.
- Yescarta®, which was designated as an orphan medicinal product on 16 December 2014, was reviewed under EMA’s accelerated assessment programme. Yescarta® will be available as a dispersion for infusion.
- The benefits with Yescarta® are its ability to achieve an objective response with a significant duration in patients with DLBCL and patients with PMBCL. The most common side effects are cytokine release syndrome, infections, pyrexia, diarrhoea, nausea, hypotension and fatigue.
- It is proposed that Yescarta® be administered in a qualified treatment centre. Therapy should be started and supervised by a healthcare professional experienced in the treatment of haematological malignancies and trained for administration and management of patients treated with Yescarta®.
- • On October 18, 2017, Kite, a Gilead Company, announced that the FDA has granted regular approval to Yescarta™ (axicabtagene ciloleucel), the first chimeric antigen receptor T cell (CAR T) therapy for 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 (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma, or TFL). Yescarta™ is not indicated for the treatment of patients with primary central nervous system lymphoma.
- Yescarta™ will be manufactured in Kite's state-of-the-art commercial manufacturing facility in El Segundo, California. The list price of Yescarta™ in the United States is $373,000.In the ZUMA-1 pivotal trial, Kite demonstrated a 99 percent manufacturing success rate with a median manufacturing turnaround time of 17 days, which is important to patients given the potential for rapid disease progression in this population.
- Yescarta™ has a Boxed Warning in its product label regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities. A Risk Evaluation and Mitigation Strategy (REMS) has been approved by the FDA for Yescarta™. The REMS program will inform and educate healthcare professionals about the risks associated with Yescarta™ therapy. Training and certification on the REMS program will be an integral part of the final authorization for centers offering Yescarta™.
- In 2017, Kite established a multi-disciplinary field team focused on providing education and logistics training for centers. Upon Yescarta's approval™, this team will provide final site certification to 16 centers, enabling them to make Yescarta™ available to appropriate patients. This support is designed to assure the safe and effective use of Yescarta™ for patients and physicians. Kite is actively working to train more than 30 additional centers with an eventual target of 70 to 90 centers across the United States. In support of Yescarta™ therapy, Kite has developed Kite Konnect™, a program enabled by an integrated technology platform that focuses on providing information and assistance throughout the Yescarta™ therapy process, including courier tracking for shipments and manufacturing status updates.
- Yescarta has been granted Priority Medicines (PRIME) regulatory support for DLBCL in the European Union. A Marketing Authorization Application (MAA) for axicabtagene ciloleucel is currently under review with the European Medicines Agency (EMA) and potential approval is expected in the first half of 2018.
- The approval of Yescarta™ is supported by data from the ZUMA-1 pivotal trial. In this study, 72 percent of patients treated with a single infusion of Yescarta™ (n=101) responded to therapy (overall response rate) including 51 percent of patients who had no detectable cancer remaining (complete remission; 95% CI: 41, 62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI: 8.1 months, not estimable [NE]).
- In the study, 13 percent of patients experienced grade 3 or higher cytokine release syndrome (CRS) and 31 percent experienced neurologic toxicities. The most common (= 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections. Serious adverse reactions occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (including neutropenia, thrombocytopenia and anemia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred. FDA approved Yescarta™ with a Risk Evaluation and Mitigation Strategy (REMS). The required components of the Yescarta REMS are:
- Healthcare facilities that dispense and administer Yescarta™ must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta™ infusion, if needed for treatment of CRS.
- Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities.
- • On July 31, 2017, Kite Pharma announced that it has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for axicabtagene ciloleucel as a treatment for patients with relapsed/refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who are ineligible for autologous stem cell transplant. This application represents the first chimeric antigen receptor (CAR) T-cell therapy submitted to the EMA. The MAA for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial. In May 2016, the CHMP and CAT granted access to its newly established Priority Medicines (PRIME) regulatory initiative for axicabtagene ciloleucel in the treatment of patients with refractory DLBCL
- • On May 26, 2017, Kite Pharma announced that the FDA has accepted for priority review the Biologics License Application (BLA) for axicabtagene ciloleucel. The submission follows positive data demonstrated with a single infusion of axicabtagene ciloleucel in the ZUMA-1 Phase 2 trial in patients with refractory aggressive non-Hodgkin lymphoma (NHL). The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of November 29, 2017. The filing acceptance is supported by data from the ZUMA-1 Phase 2 trial which met the primary endpoint of objective response rate recorded after a single infusion of axicabtagene ciloleucel with 82 percent (p < 0.0001). At a median follow-up of 8.7 months, 44 percent of patients were in ongoing response, which included 39 percent of patients in complete response.
- The most common grade 3 or higher adverse events included anemia (43 percent), neutropenia (39 percent), decreased neutrophil count (32 percent), febrile neutropenia (31 percent), decreased white blood cell count (29 percent), thrombocytopenia (24 percent), encephalopathy (21 percent) and decreased lymphocyte count (20 percent). There were three deaths throughout the course of the registrational trial not due to disease progression, of which two events, were deemed related to axicabtagene ciloleucel.
- • On March 31, 2017, Kite Pharma announced that it has completed the rolling submission with the FDA of the Biologics License Application (BLA) for axicabtagene ciloleucel as a treatment for patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT). If approved, Kite plans to commercially launch axicabtagene ciloleucel in 2017. Kite is also planning a regulatory submission to the European Medicines Agency (EMA) for axicabtagene ciloleucel in 2017.
- • On December 5, 2016, Kite Pharma announced that it has initiated the rolling submission with the FDA of the Biologics License Application (BLA) for KTE-C19 as a treatment for patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT). The pivotal ZUMA-1 study supporting this submission enrolled patients with chemorefractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL), three subtypes of aggressive NHL . The company expects to complete its BLA submission by the end of the first quarter of 2017. Kite also announced that the United States Adopted Name, or USAN, for KTE-C19 will be axicabtagene ciloleucel. If approved, Kite plans to commercially launch KTE-C19 in 2017. Kite is also planning a regulatory submission to the European Medicines Agency (EMA) for axicabtagene ciloleucel in 2017. Kite was granted access to Priority Medicines (PRIME) regulatory support in 2016 by the EMA for axicabtagene ciloleucel (KTE-C19) for the treatment of refractory DLBCL.
- • On April 25, 2016, the FDA has granted orphan drug designation for autologous T-cells transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor (KTE-C19) for treatment of follicular lymphoma.
- • On December 7, 2015, Kite Pharma announced that the FDA has granted Breakthrough Therapy Designation status to KTE-C19, for the treatment of patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL). Four clinical trials are currently ongoing: ZUMA-1, ZUMA-2, ZUMA-3 and ZUMA-4.
- • On October 6-8, 2015, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for autologous T cells transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor for treatment of follicular lymphoma.
- • On November 11-13, 2014, the Committee for Orphan Medicinal Products (COMP) has recommended the granting of an orphan designation for autologous T cells transduced with retroviral vector encoding an anti-CD19 CD28/CD3 zeta chimeric antigen receptor for treatment of diffuse large B cell lymphoma.
Submission of marketing authorization application USA : 2017-03-31
Submission of marketing authorization application UE: 2017-07-31
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-10-18
UE authorization: 2018-08-27
Favourable opinion UE: 2018-06-28
Favourable opinion USA:
Orphan status USA: 2016-04-25
Orphan status UE: 2015-11-11/2014-12-16
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
- • On October 5, 2018, NHS England announced that adult cancer patients in England will receive a new game-changing therapy treatment under the first negotiated deal of its kind struck in Europe. This is the first time adult NHS patients will have access to CAR-T, and follows a deal NHS England reached last month to make CAR-T available for children and young people with a rare form of leukaemia.
- Axicabtagene ciloleucel is licenced to treat adult patients with diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma after two or more previous therapies have failed. Trials indicate that the therapy could potentially cure 40% of patients.
- Up to 200 patients a year will receive the treatment after NHS England negotiated a confidential deal with the manufacturer Gilead Sciences. The treatment would have cost nearly £300,000 per patient at its full list price, but the company’s commercial agreement with NHS England has enabled NICE to approve its entry into NHS England’s Cancer Drugs Fund.