publication date: Apr. 27, 2018

Drugs and Targets

Mylotarg approved in EU for previously untreated, de novo, CD33-positive AML in combination with Chemotherapy

The European Commission approved Mylotarg (gemtuzumab ozogamicin) in combination with daunorubicin and cytarabine for the treatment of patients age 15 years and above with previously untreated, de novo, CD33-positive acute myeloid leukemia, except acute promyelocytic leukemia.

The drug is sponsored by Pfizer Inc.

Mylotarg is the first and only AML therapy approved in the European Union that targets CD33, an antigen expressed on AML cells in up to 90% of patients.

The European Commission’s approval of Mylotarg was based on data from an investigator-led, phase III randomized, open-label study (ALFA-0701) in previously untreated, de novo patients. Mylotarg received approval by the FDA in September 2017 for adults with newly diagnosed CD33-positive acute myeloid leukemia, and adults and children 2 years and older with relapsed or refractory CD33-positive AML.

Hepatotoxicity, including life-threatening and sometimes fatal hepatic failure and VOD/SOS, have been reported in patients treated with MYLOTARG. Other special warnings and precautions include myelosuppression and infusion-related reactions.

In the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatotoxicity, including VOD/SOS (3.8%), hemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). In monotherapy studies, clinically relevant serious adverse reactions also included infusion related reactions (2.5%), thrombocytopenia (21.7%), and neutropenia (34.3%).

The most common adverse reactions (> 30%) in the combination therapy study were hemorrhage and infection. In monotherapy studies the most common adverse reactions (> 30%) included pyrexia, nausea, infection, chills, hemorrhage, vomiting, thrombocytopenia, fatigue, headache, stomatitis, diarrhea, abdominal pain, and neutropenia.

Mylotarg is an antibody-drug conjugate composed of the cytotoxic agent calicheamicin, attached to a monoclonal antibody targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90 percent of AML patients. When MYLOTARG binds to the CD33 antigen on the cell surface it is absorbed into the cell and calicheamicin is released causing cell death.

Mylotarg was approved by the FDA in September 2017 for adults with newly diagnosed CD33-positive acute myeloid leukemia, and adults and children 2 years and older with relapsed or refractory CD33-positive AML.

 

Nektar, Takeda to evaluate combining CD122-biased agonist and dual SYK and FLT-3 inhibitor

Nektar Therapeutics and Takeda Pharmaceutical Co. Ltd. join a clinical collaboration to evaluate Nektar’s investigational medicine, NKTR-214, with Takeda’s investigational medicine, TAK-659, as a potential combination treatment regimen in multiple cancer settings. 

NKTR-214 is an investigational immuno-stimulatory therapy designed to expand specific cancer-fighting T cells and natural killer cells directly in the tumor micro-environment and increase expression of PD-1 on these immune cells.  TAK-659 is a dual inhibitor of both spleen tyrosine kinase, a kinase involved in cell proliferation and FLT-3, a cytokine receptor in the receptor tyrosine kinase class III. 

Under the agreement, Nektar and Takeda will each maintain global commercial rights to their respective investigational medicines.  Nektar and Takeda will split the costs related to the clinical trial and each company will contribute their respective compounds to the clinical collaboration.

The first trial is expected to start in the second half of 2018 and will evaluate the combination of an every three-week schedule of NKTR-214 with oral daily doses of TAK-659 in patients with Non-Hodgkin Lymphoma.KTR-214 is an investigational immuno-stimulatory therapy designed to expand specific cancer-fighting CD8+ effector T cells and natural killer cells directly in the tumor micro-environment and increase expression of PD-1 on these immune cells.

NKTR-214 targets CD122 specific receptors found on the surface of these cancer-fighting immune cells in order to stimulate their proliferation.  NKTR-214 is being evaluated in multiple clinical trials in cancer patients.  It has an antibody-like dosing regimen similar to the existing checkpoint inhibitor class of approved medicines.

TAK-659 is an orally-available investigational reversible dual SYK/FLT-3 inhibitor. SYK is a non-receptor cytoplasmic kinase that binds to phosphorylated immuno-receptor tyrosine-based activating motifs and mediates cellular proliferation and survival.

Mutations in FLT-3 genes can result in the constitutive activation of the FLT-3 receptor and result in acute myeloid leukemia and acute lymphoblastic leukemia. TAK-659 demonstrates both direct- and immune-mediated tumor cell kill mechanisms. It is currently being explored in clinical studies as a single agent and in combination in solid and hematological malignancies.

 

Pfizer gets Complete Response Letter for trastuzumab biosimilar

Pfizer Inc. announced it has received a Complete Response Letter from FDA in response to the Biologics License Application for the company’s proposed trastuzumab biosimilar. In the CRL, FDA highlighted the need for additional technical information.

The additional requested information does not relate to safety or clinical data submitted in the application, the company said. Pfizer said it’s working closely with FDA to address the contents of the letter.

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