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Date: 2018-07-26

Type of information: Positive opinion for the granting of a Market Authorisation in the EU

Product name: Blincyto™

Compound: blinatumomab

Therapeutic area: Cancer - Oncology

Action mechanism:

  • monoclonal antibody/BiTE® antibody. Blinatumomab is a BiTE® antibody designed to direct the body's cell-destroying T cells against target cells expressing CD19, a protein found on the surface of B-cell derived leukemias and lymphomas. Bispecific T cell engager (BiTE®) antibodies are a type of immunotherapy being investigated for use in fighting cancer by helping to engage the body's immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibodies help place the T cells within reach of the targeted cell, with the intent of allowing it to inject toxins and trigger the cell to die (apoptosis).

Company: Amgen (USA - CA)

Disease:

  • Philadelphia -negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL)
  • adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD

Latest news:

  • On November 16, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion to expand the current indication for Blincyto® (blinatumomab) monotherapy to include adult patients with Philadelphia chromosome negative CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 percent. The application included data from the Phase 2 BLAST study in frontline and relapsed/refractory ALL, the largest prospective trial for MRD-positive ALL ever conducted.
  • The CHMP opinion is based on data from the Phase 2 BLAST study, which found that Blincyto® induced a complete MRD response, or no detectable MRD, in 78 percent of patients within one treatment cycle. Safety results among MRD-positive patients were consistent with the known safety profile of Blincyto® in relapsed or refractory B-cell precursor ALL.
  • • On September 24, 2018, Amgen announced that the Japanese Ministry of Health, Labour and Welfare has granted marketing approval for Blincyto® for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. Blincyto® was developed in Japan by Amgen Astellas BioPharma K.K. (AABP), a joint venture between Amgen and Astellas Pharma. The approval is based on data from multiple global studies, including the Phase 3 TOWER study and Japan Phase 1b/2 Horai study.
  • • On 26 July 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for Blincyto® (blinatomumab). The committee adopted an extension of indication as follows: Blincyto® is indicated as monotherapy for the treatment of paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
  • The full indications for Blincyto® will be as follows:
  • Blincyto® is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL).
  • Blincyto® is indicated as monotherapy for the treatment of paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-cell precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
  • • On June 19, 2018, Amgen announced that the European Commission (EC) has granted a full marketing authorization for Blincyto® based on the overall survival (OS) data from the Phase 3 TOWER study in adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). In the TOWER study, Blincyto® demonstrated a superior improvement in median OS over standard of care (SOC) chemotherapy. Median OS was 7.7 months (95 percent CI: 5.6, 9.6) for Blincyto® versus four months (95 percent CI: 2.9, 5.3) for SOC (HR for death=0.71; p=0.012). For patients treated in first salvage, the median OS was 11.1 months for Blincyto® versus 5.3 months for SOC (HR=0.6, 95 percent CI: 0.39, 0.91). Safety results among subjects who received Blincyto® were comparable to those seen in the previous Phase 2 studies of Blincyto® in adult patients with Ph- relapsed or refractory B-cell precursor ALL. These results were published in The New England Journal of Medicine
  • • On March 29, 2018, the FDA  granted accelerated approval to Blincyto® to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse.
  • The efficacy of Blincyto in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least 1 out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of Blincyto treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.
  • The side effects of Blincyto when used to treat MRD-positive B-cell precursor ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), fever (pyrexia), headache, infusion related reactions, low levels of certain blood cells (neutropenia, anemia), febrile neutropenia (neutropenia and fever) and low levels of platelets in the blood (thrombocytopenia).
  • This new indication for Blincyto was approved under the accelerated approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study in randomized controlled trials is required to verify that achieving undetectable MRD with Blincyto improves survival or disease-free survival in patients with ALL. The FDA granted this application Priority Review and it received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
  • • On November 24, 2015, Amgen announced that the European Commission (EC) has granted conditional marketing authorization for Blincyto® (blinatumomab) for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL). The conditional marketing authorization for Blincyto® is based on results of two Phase 2 studies, study '211 and '206. In the pivotal '211 trial, 42.9 percent of patients achieved complete remission (CR) or CR with partial hematological recovery (CRh*) with single-agent Blincyto®. The most serious adverse reactions that occurred during Blincyto® treatment in the pivotal '211 trial included infections, neurologic events, neutropenia/febrile neutropenia, cytokine release syndrome and tumor lysis syndrome. Study '211 evaluated Blincyto® in an open-label, multicenter, single-arm Phase 2 study. Eligible patients were at least 18 years of age with Ph- relapsed or refractory B-precursor ALL relapsed with first remission duration of less than or equal to 12 months in first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and had at least10 percent blasts in bone marrow. The primary endpoint was the CR/CRh* rate within two cycles of Blincyto®. Of the 189 patients evaluated in the trial, 42.9 percent (81/189; 95 percent CI, 35.7 - 50.2) achieved CR or CRh* within two cycles of treatment with Blincyto® with the majority of responses (79 percent [64/81]) occurring within the first cycle of treatment. In a prespecified exploratory analysis, 82.2 percent (60/73) of minimal residual disease (MRD) evaluable patients with CR/CRh* also had an MRD response. The most common adverse reactions (greater than 20 percent) were infusion-related reactions (67.2 percent), infections (63 percent), pyrexia (59.8 percent), headache (34.4 percent), febrile neutropenia (28 percent), peripheral edema (25.9 percent), nausea (24.3 percent), hypokalemia (23.8 percent), constipation (20.6 percent) and anemia (20.1 percent). The most serious adverse reactions that occurred during BLINCYTO treatment included: infections (31.7 percent), neurologic events (16.4 percent), neutropenia/febrile neutropenia (15.3 percent), cytokine release syndrome (0.5 percent) and tumor lysis syndrome (0.5 percent). Blincyto® was granted orphan drug designation by the European Medicines Agency in 2009 for the treatment of ALL.
  • • On September 24, 2015, the Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorisation for Blincyto® (blinatumomab) for the treatment of Philadelphia chromosome-negative acute lymphoblastic leukaemia. Conditional marketing authorisations are one of the mechanisms put in place by the Agency to facilitate market access for medicines that fulfill unmet medical needs. Blincyto® has an orphan designation.
  • • On December 3, 2014, Amgen announced that the FDA has granted approval of Blincyto™ (blinatumomab) for the treatment of patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. With this approval, Blincyto™ becomes the first FDA -approved bispecific CD19-directed CD3 T-cell engager (BiTE®) antibody construct product, and the first single-agent immunotherapy to be approved for the treatment of patients with Ph- relapsed or refractory B-cell precursor ALL.
  • The approval was based on the achievement of durable complete remission (CR) and response with a reduction in minimal residual disease (MRD) to less than 10-4 in a multicenter single-arm trial (Protocol MT103-211) that enrolled 185 patients with R/R ALL. Blinatumomab was administered by continuous infusion for 4 weeks of a 6-week cycle. Up to two cycles were used for induction and three cycles for consolidation. In Protocol MT103-211, 32% (95% CI, 26% - 40%) of patients with R/R ALL attained CR with 2 cycles of treatment with single-agent blinatumomab, and the response was durable (median 6.7 months; range, 0.46 - 16.5 months). Furthermore, 31% (95% CI, 25%-39%) of the patients in the study had a CR with or without complete hematological recovery but with reduction in MRD to
  • Of the 185 patients evaluated in the trial, 41.6 percent (77/185; 95 percent CI: 34.4-49.1) achieved complete remission or complete remission with partial hematologic recovery (CR/CRh*) within two cycles of treatment with blinatumomab, which was the primary endpoint of the study. The majority of responses (81 percent [62/77]) occurred within the first cycle of treatment. Among patients who achieved CR/CRh*, 39 percent (30/77) went on to HSCT, and 75.3 percent (58/77 95 percent CI: 64.2-84.4) achieved minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level.
  • Safety was evaluated in 212 patients with R/R ALL treated with blinatumomab. The most common adverse reactions (greater than or equal to 20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). A neurological toxicity occurred in approximately 50% of patients and was a frequent reason for interruption of therapy.
  • For patients weighing at least 45 kg, the recommended dose and schedule for blinatumomab is 9 mcg/day on days 1-7 and at 28 mcg/day on days 8-28 of the first 42-day cycle, and 28 mcg/day on days 1-28 in later cycles.
  • Amgen and its subsidiary Onyx Pharmaceuticals, Inc. , which will commercialize Blincyto™ in the U.S., have announced the availability of Onyx Pharmaceuticals 360TM (Onyx 360), to patients receiving Blincyto™ in the U.S. Onyx 360 is a comprehensive patient and caregiver support and services program designed to help patients navigate the treatment journey, including reimbursement and payment support, treatment support and referrals to third-party organizations for day-to-day needs and emotional support.
  • • On October 9, 2014, Amgen announced that the FDA has accepted for review the Biologics License Application (BLA) for the investigational bispecific T cell engager (BiTE®) antibody construct, blinatumomab. The BLA is for the treatment of adults with Philadelphia-negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), a rapidly progressing cancer of the blood and bone marrow.1 As part of the acceptance, the FDA granted blinatumomab priority review with a Prescription Drug User Fee Act (PDUFA) action date of May 19, 2015. A Marketing Authorization Application (MAA) has also been submitted to the European Medicines Agency (EMA) via the centralized procedure for approval to market blinatumomab for the treatment of adults with Ph- relapsed/refractory B-precursor ALL.
  • • On September 22, 2014, Amgen announced submission of a Biologics License Application (BLA) to the FDA seeking approval for its investigational bispecific T cell engager (BiTE®) antibody construct, blinatumomab. The BLA is for the treatment of adults with Philadelphia -negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). Blinatumomab, the first of the BiTE® antibody constructs, has received both orphan drug designation and breakthrough therapy designation from the FDA for the treatment of ALL. The submission includes data from a Phase 2 trial of adult patients with Ph- relapsed/refractory B-precursor ALL treated with blinatumomab, which successfully met its primary endpoint.
  • • On July 1, 2014, Amgen announced that the FDA has granted Breakthrough Therapy Designation to investigational bispecific T cell engager (BiTE®) antibody blinatumomab, for adults with Philadelphia -negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), a rapidly progressing cancer of the blood and bone marrow1. The Breakthrough Therapy Designation was based on the results of a Phase 2 trial of 189 adult patients with Ph- relapsed/refractory B-precursor ALL treated with blinatumomab. Data from the Phase 2 trial were most recently presented at the 50th Annual Meeting of the American Society of Clinical Oncology ( ASCO ) and the 19th Congress of the European Hematology Association (EHA).

Patents:

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: 2014-12-03/2018-03-29

UE authorization: 2015-11-23

Favourable opinion UE: 2015-09-24/2018-07-26

Favourable opinion USA:

Orphan status USA: 2008-05-16

Orphan status UE: 2009-07-24

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes