On September 22, 2014 Amgen reported the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) seeking approval for its investigational bispecific T cell engager (BiTE) antibody construct, blinatumomab (Press release Amgen, SEP 22, 2014, View Source [SID:1234500759]). 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.

BiTE antibody constructs represent an innovative immunotherapy approach that helps the body’s immune system target cancer cells. 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 FDA states that breakthrough therapy designation, which is intended to expedite review of drugs for serious or life-threatening conditions, requires preliminary clinical evidence that demonstrates the drug may have substantial improvement over available therapies on at least one clinically significant endpoint.

“We look forward to working with regulatory authorities to make blinatumomab available for adult patients with acute lymphoblastic leukemia, who experience high relapse rates and have limited treatment options,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “The filing for blinatumomab brings us a step closer to first realizing the potential of BiTE technology and represents our commitment to evaluating this novel approach in a broad range of difficult-to-treat cancers.”

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.

“Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL,” said Anthony S. Stein, M.D., clinical professor, Hematology/Oncology at City of Hope. “Blinatumomab has the potential to significantly advance treatment options for patients living with this difficult-to-treat disease, and the BLA submission marks an important step toward achieving this goal.”

In the U.S., it is estimated that more than 6,000 cases of ALL will be diagnosed in 2014, and in the European Union, more than 7,000 cases of ALL are diagnosed each year. In adult patients with relapsed or refractory ALL, median overall survival is just three to five months.

On September 19, 2014 Children’s Cancer Institute and Abcam reported that they have entered into an exclusive licence, supply and distribution agreement for multidrug resistance protein 4 (MRP4/ABCC4) inhibitors, Ceefourin 1 and Ceefourin 2, for research purposes (Press release Children’s Cancer Institute, SEP 19, 2014, View Source [SID:1234500760]).

The first known selective inhibitors of MRP4, Ceefourin 1 and Ceefourin 2 are potent, chemically distinct compounds and are the first known selective inhibitors of MRP4, and represent important tools for investigating essential cellular processes such as multidrug resistance. The agreement was facilitated by Bio-Link Australia, a life sciences commercialisation company.

MRP4 is a protein that belongs to the ATP-Binding Cassette (ABC) transporter superfamily of membrane pumps that export molecules from the cell. MRP4 effectively effluxes elements that are potentially toxic to the cell, protecting it from deleterious chemical build ups and from xenobiotics, such as environmental toxins.

Previous research on MRP4 and other ABC transporter family members has shown that these proteins are often ‘hijacked’ by cancer cells, which produce them at high levels to pump out chemotherapy drugs, effectively protecting the cancer cells from treatment.

The novel MRP4 inhibitors, Ceefourin 1 and Ceefourin 2, discovered and characterised by Children’s Cancer Institute, are exciting new tools for researchers, allowing the further exploration of MRP4 function and potentially the basis for developing therapeutic drugs to treat cancer.

Lead researcher and Children’s Cancer Institute Deputy Director, Professor Murray Norris, said “High-throughput screening has identified Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of MRP4. Up to this point, researchers have not had access to effective MRP4 inhibitors without substantial confounding off-target effects – so this is quite an advancement for the field. Highly specific research reagents are of course crucial to accurately defining how these proteins work.

“We are delighted to now be able to make these research reagents available to the scientific community worldwide through our partnership with Abcam. These compounds should enable researchers to obtain new insights into MRP4 function and to modulate extracellular drug transport.”

Matthew Roe, Head of Reagents, Abcam said: “We are very pleased to partner with Children’s Cancer Institute, and to manage distribution of these reagents to the research community, helping to increase the impact of their findings and help scientists discover more.”

The Ceefourin MRP4 inhibitors now available from Abcam include:

Ceefourin 1 (ab145144)

Selective MRP4 inhibitor. Benzothiazol compound which potently and selectively inhibits MRP4-mediated substrate efflux. For example, Ceefourin 1 inhibits MRP4-mediated D-luciferin transport (IC50 = 1.5µM) as measured indirectly using a bioluminescence assay in HEK293-MRP4 cells with stable luciferase expression. Ceefourin 1 exhibits no detectable inhibition of other ABC transporters such as Pgp, ABCG2 and MRP1, MRP2, MRP3 and MRP5, and is non-toxic in normal fibroblast and cancer cell lines tested up to 50µM. Ceefourin 1 displays metabolic (>30 min) and acid stability (>24hrs at 37oC, pH 2) in a mouse liver microsomal assay and acid-stability assay, respectively.

Ceefourin 2 (ab145145)

Selective MRP4 inhibitor. Pyrazolopyrimidine compound which potently inhibits MRP4-mediated substrate efflux. For example, Ceefourin 2 inhibits MRP4-mediated D-luciferin transport (IC50 = 7.0µM) as measured indirectly using a bioluminescence assay in HEK293-MRP4 cells with stable luciferase expression. Ceefourin 2 exhibits no detectable inhibition of other ABC transporters, such as Pgp, ABCG2 and MRP1, MRP2, MRP3 and MRP5. Ceefourin 2 displayed limited toxicity in two of eleven cancer cell lines tested up to 50µM, and exhibited no toxicity in two normal fibroblast lines tested to the same concentration. Ceefourin 2 shows metabolic stability (>30 min) in a mouse liver microsomal assay and limited acid-stability (half life < 2 hr at 37oC, pH 2). Ceefourin is a trademark of Children’s Cancer Institute. Ceefourin 1 and Ceefourin 2 are claimed under Australian provisional patent application 2014902472. Reference: High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Published in Biochemical Pharmacology.

On September 19, 2014 Gilead Sciences reported that the European Commission has granted marketing authorization for Zydelig (idelalisib), 150 mg tablets, a first-in-class oral treatment for two incurable blood cancers – chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL) (Press release Gilead Sciences, SEP 19, 2014, View Source [SID:1234500758]). For the treatment of CLL, Zydelig has been approved for use in combination with rituximab for patients who have received at least one prior therapy; or as first-line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. For the treatment of FL, Zydelig has been approved as a monotherapy in patients who are refractory to two prior lines of treatment. Zydelig inhibits PI3K delta, a protein that is overexpressed in many B-cell malignancies and plays a role in the viability, proliferation and migration of these cancer cells.

CLL and FL are slow-growing incurable blood cancers that can lead to life-threatening complications such as anemia, serious infection and bone marrow failure requiring treatment. The goal of therapy for patients with these cancers is to improve overall survival and quality of life.

“Although chemo-immunotherapy is initially used to treat both CLL and FL, relapse is common and many patients run out of treatment options to treat the disease as it progresses,” said Peter Hillmen, PhD, Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust. “Further, CLL patients with the 17p deletion or TP53 mutation are not suitable for chemo-immunotherapy, requiring alternative first-line treatment options. Thus, Zydelig is a welcomed treatment option that offers a new approach in the management of these cancers.”

A chromosome 17 deletion – del (17p) or a mutation in the TP53 gene in CLL cells have been linked to poor prognosis and a more rapid disease progression. For these patients most conventional chemotherapy treatments are not effective and deliver poor responses of relatively short duration. Treatment options are limited for these patients.

“Zydelig represents an important therapeutic advance for patients living with CLL and FL,” said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. “Gilead is pleased to be making a difference in the lives of people living with these blood cancers and we are committed to helping ensure timely access to the treatment for patients who may benefit from therapy.”

The approval of Zydelig in CLL is supported primarily by data from a randomized, placebo-controlled Phase 3 trial (Study 116) of Zydelig plus rituximab in 220 patients with relapsed CLL who were not able to tolerate standard chemotherapy. Study 116 was stopped early in October 2013 by an independent Data Monitoring Committee due to a highly statistically significant benefit in progression-free survival (PFS) in the Zydelig plus rituximab arm compared with the rituximab only treatment arm (hazard ratio = 0.18 (95 percent CI: 0.10, 0.32), p<0.0001). Median PFS was not reached in the Zydelig plus rituximab arm (95 percent CI: 10.7 months, NR) and was 5.5 months in the placebo plus rituximab arm (95 percent CI: 3.8, 7.1). The approval in FL, the most common type of indolent non-Hodgkin lymphoma (iNHL), is supported by data from a single-arm Phase 2 study (Study 101-09) of Zydelig monotherapy in 125 iNHL patients refractory to rituximab and alkylating-agent-containing chemotherapy. In the 72 patients with FL in this study, Zydelig achieved an overall response rate of 54 percent and the median duration of response was not reached (range: 0.0, 14.8+ months). Results of Study 116 and Study 101-09 were published in The New England Journal of Medicine in March 2014. Adverse drug reactions (including Grade ≥3) reported in clinical studies in patients with hematological malignancies receiving Zydelig included infections, neutropenia, pneumonitis, diarrhea/colitis, increased transaminase (indicator of liver function), rash and pyrexia. For additional safety information, see the Summary of Product Characteristics at www.ema.europa.eu.