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NICE recommends VARGATEF® (nintedanib*) in combination with docetaxel as an option for patients with non-small cell lung cancer of adenocarcinoma histology within its licensed indication

On June 3, 2015 Boehringer Ingelheim reported that following a review by the National Institute for Health and Care Excellence (NICE) in the UK, VARGATEF (nintedanib*) in combination with docetaxel has been recommended for use within the National Health Service (NHS) in England and Wales (Press release, Boehringer Ingelheim, JUN 3, 2015, View Source [SID:1234505215]).1 This is positive news for patients with locally advanced metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma histology who have had limited treatment options that have been shown to extend survival after first-line chemotherapy.

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Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "We are delighted with this announcement from NICE which represents an important milestone in the effort to extend survival for patients with adenocarcinoma of the lung following initial treatment with chemotherapy. The survival advantage demonstrated by VARGATEF, in combination with docetaxel, has been shown with a predictable and generally manageable safety profile."

NICE has issued a Final Appraisal Determination (FAD) for VARGATEF and, subject to any appeal by consultees, the FAD may be used as the basis for the institute’s guidance on the use of the appraised technology in the NHS in England and Wales.1 Nintedanib, in combination with docetaxel, is the first and only triple angiokinase inhibitor available for EU patients with advanced NSCLC of adenocarcinoma histology after first-line chemotherapy.

Since the launch of VARGATEF in January 2015 it has also been:

accepted for use without restriction within NHS Scotland, as per its licensed indication2

accepted by the Swedish Dental and Pharmaceutical Benefits Agency to be subsidised as a treatment of advanced lung cancer patients with adenocarcinoma in combination with docetaxel after first-line chemotherapy3

assessed by the German IQWiG who indicated an added benefit for the treatment of advanced lung cancer patients with adenocarcinoma in combination with docetaxel after first-line chemotherapy without brain metastases4

These announcements are based on the outcomes of the LUME-Lung 1 study which demonstrated:5

nintedanib, plus docetaxel, significantly prolonged progression-free survival compared to docetaxel alone for patients with
adenocarcinoma (PFS: primary endpoint; 4.0 vs 2.8 months)

nintedanib, plus docetaxel, significantly extended overall survival to beyond one year for patients with adenocarcinoma, compared to docetaxel alone (OS: key secondary endpoint; 12.6 vs 10.3 months)

nintedanib, plus docetaxel, enabled 1 in 4 patients with adenocarcinoma to live for at least two years after first-line chemotherapy

Nintedanib in combination with docetaxel demonstrated a generally manageable side-effect profile without further compromising patients’ overall, health-related, quality of life compared to chemotherapy alone. The most common adverse events for patients taking docetaxel vs nintedanib plus docetaxel included: nausea 18% vs 24%; vomiting 9% vs 17%; diarrhoea 22% vs 42% and elevated liver enzymes 8% vs 29%.5

Adenocarcinoma is the most common type of lung cancer and the majority of patients are diagnosed in an advanced stage.6 Most patients will experience disease progression during or after first-line chemotherapy and there is a significant need for new, effective second-line treatments.5

VARGATEF was granted EU marketing authorisation in November 2014 and in combination with docetaxel is indicated for use in adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology, after first-line chemotherapy.

Celgene and bluebird bio to Develop Anti-BCMA Product Candidates; bluebird bio Regains Rights to CAR T Programs Outside of BCMA

On June 3, 2015 bluebird bio reported that its existing global collaboration agreement with Celgene Corporation (Nasdaq: CELG) has been amended and restated to focus on developing product candidates targeting B-cell maturation antigen (BCMA) during a three-year collaboration term (Press release, bluebird bio, JUN 3, 2015, View Source [SID:1234505224]).

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The original collaboration, initiated in 2013, was focused on applying gene therapy technology to genetically modify a patient’s own T cells to target and destroy cancer cells. BCMA is the first target selected to advance to the clinic under this collaboration. BCMA is a cell surface protein that is expressed in normal plasma cells and in most multiple myeloma cells, but is absent from other normal tissues.

Celgene and bluebird bio will work collaboratively on the initial, lead anti-BCMA product candidate (bb2121), with a Phase 1 clinical trial expected to begin enrollment in early 2016, and develop next-generation anti-BCMA product candidates. bluebird bio retains sole rights to develop all other chimeric antigen receptor (CAR) T cell programs developed by bluebird bio under the collaboration, including ongoing undisclosed preclinical programs with opportunities in both solid tumors and hematologic malignancies.

Under the terms of the amended and restated collaboration agreement:

bluebird bio will receive a $25 million payment to develop the lead anti-BCMA product candidate through a Phase 1 clinical trial and develop next-generation anti-BCMA product candidates.

bluebird bio will be responsible for the development of all anti-BCMA product candidates through the completion of Phase 1 studies.

Additionally, on a product-by-product basis within the anti-BCMA product program, Celgene has an option to develop and commercialize each product candidate worldwide, and bluebird bio has the option to share equally in the development, promotion and profits of each product candidate in the United States. In addition to the payments described above and consistent with the prior agreement, Celgene would also pay bluebird bio specified development and regulatory milestone payments as well as royalty payments on net sales.

"We have successfully achieved the initial goal of our collaboration with Celgene —identifying a promising lead development candidate in the CAR T cell field — and we are excited to focus our Celgene collaboration on the development of anti-BCMA products," said Nick Leschly, chief bluebird. "Celgene is a leader in developing and commercializing therapies for multiple myeloma, and we believe they are the best global partner for our first CAR T program. Together we look forward to entering the clinic early next year with bb2121 and continuing our collaboration around next-generation BCMA products."
"Our collaboration with bluebird bio has collectively made strong progress advancing a lead product candidate, targeting BCMA, toward the clinic in hematologic malignancies. We look forward to continuing to work with bluebird and build on the recent success to advance the anti-BCMA program and ultimately, to succeed on the goal of delivering a high-impact therapeutic in the CAR T arena," said Tom Daniel, M.D., President of Research and Early Development at Celgene.

A Unique Position in Immuno-oncology
Outside of BCMA, bluebird bio is independently pursuing the development of a broad portfolio of novel immuno-oncology therapeutics. This portfolio will leverage bluebird bio technology, including its lentiviral vector platform, gene editing capabilities and internal gene therapy and immuno-oncology expertise.

"Consistent with the long-term vision for bluebird bio, we are expanding our immuno-oncology T cell-based efforts in parallel with our late-stage hematopoietic stem cell-based programs," said Rob Ross, M.D., senior vice president, clinical development, bluebird bio. "Our goal is to initiate multiple clinical trials over the next several years against novel targets in both solid and hematologic malignancies by integrating our proprietary lentiviral and gene editing platforms with our immuno-oncology expertise and experience in implementing multi-center, industry-sponsored gene therapy studies. This is an exciting step in bluebird bio’s evolution and an opportunity for us to further realize the value that gene therapy can bring to patients and families in need."

Currently, bluebird bio has active pre-clinical research programs targeting multiple different, novel oncology antigens, including BCMA. These programs include various T cell therapies with significant academic and industry collaborations. bluebird bio recently announced a strategic collaboration with Five Prime Therapeutics, which marries Five Prime’s antigen discovery platform and certain human antibodies with bluebird bio’s immuno-oncology and gene therapy capabilities, with the potential for development candidates in both hematologic malignancies and solid tumors.

Merck Extends Immuno-Oncology Collaboration with Agenus

On June 3, 2015 Agenus reported that Merck, known as MSD outside the United States and Canada, through a subsidiary, has extended its collaborative research term under its existing collaboration and license agreement with Agenus, for the discovery and development of therapeutic antibodies to Merck proprietary immune checkpoints for the treatment of cancer (Press release, Agenus, JUN 3, 2015, View Source [SID:1234505219]).

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Under the terms of the original agreement, Agenus will discover and optimize fully human antibodies against two undisclosed Merck checkpoint targets using the Retrocyte Display platform. Merck will be responsible for the further development and commercialization of candidates generated under the collaboration. The discovery phase has been extended to April 2016. As previously disclosed, under the terms of the agreement, Agenus is eligible to receive approximately $100 million in milestone payments as well as royalties on worldwide product sales.

"This collaboration has resulted in encouraging outcomes, and we’re delighted that a leader in the rapidly developing immuno-oncology space has elected to extend this discovery phase of our collaboration," said Robert Stein, MD, PhD, Chief Scientific Officer of Agenus Inc. "We believe our antibody generating technology is now the most extensive in vitro platform in the industry with significant advantages for creation of high quality antibody candidates."

Aptose Biosciences Granted Orphan Drug Designation by the U.S. FDA for APTO-253 in Acute Myeloid Leukemia

On June 2, 2015 Aptose Biosciences reported that the U.S. Food and Drug Administration (FDA) has granted the company orphan drug designation for APTO-253 for the treatment of acute myeloid leukemia (AML) (Press release, Aptose Biosciences, JUN 2, 2015, View Source [SID:1234505214]). APTO-253, a first-in-class inducer of the KLF4 gene, is the company’s lead product candidate in a Phase Ib clinical trial in patients with AML, high-risk myelodysplastic syndrome (MDS) and other hematologic malignancies in which KLF4 silencing is reported as operative.

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"AML is a particularly challenging cancer of the blood and bone marrow for which there are currently few treatment options," said William G. Rice, Ph.D., Chairman, President and CEO. "APTO-253, with its unique mechanism of action, has the potential to emerge as an entirely new therapeutic approach for this patient population, and receiving orphan drug designation is a key regulatory milestone along the path."

Epigenetic suppression of the Krüppel-like factor 4 (KLF4) gene has been reported in the scientific literature as a key transforming event in AML. APTO-253 is a first-in-class, targeted inducer of the KLF4 tumor suppressor gene, and has demonstrated a favorable safety profile with no evidence of suppression of the normal bone marrow. Preclinical studies have shown potent single-agent activity to kill AML cells and strong synergy as part of a combination strategy with various marketed and investigational agents. APTO-253 is currently in a Phase 1b clinical study in patients with relapsed or refractory hematologic malignancies.

Orphan drug designation is granted by the FDA to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States. Orphan drug status provides research and development tax credits, an opportunity to obtain grant funding, exemption from FDA application fees and other benefits. If APTO-253 is approved to treat AML, the orphan drug designation provides Aptose with seven years of marketing exclusivity.

About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a cancer derived from myeloid progenitor or stem cells that typically mature into red blood cells, white blood cells or platelets. AML initiates in the bone marrow when stem or progenitor cells lose cell cycle control, anti-apoptotic factor or other means to limit rampant proliferations. Leukemic cells have the ability to rapidly spread from the marrow to the bloodstream. Further, these rapidly proliferating cells quickly crowd out normal cells as they infiltrate other organs and tissue systems.

AML is the most common type of acute leukemia among adults, with an annual incidence of more than 18,000 patients, and causing more than 10,000 deaths each year in the U.S. It is a particularly devastating blood cancer, with less than 25 percent of newly diagnosed patients surviving beyond five years.

Synta Announces Ganetespib Program Updates

On June 2, 2015 Synta Pharmaceuticals reported updates to its clinical program for Ganetespib, a next-generation inhibitor of the chaperone protein Hsp90 (Press release, Synta Pharmaceuticals, JUN 2, 2015, View Source;p=RssLanding&cat=news&id=2055568 [SID:1234505212]). Ganetespib is currently being studied in several large, randomized studies, including the Phase 3 GALAXY-2 trial in non-small cell lung cancer, as well as a number of other investigator-sponsored studies in various malignancies, including acute myeloid leukemia, breast cancer and ovarian cancer.

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The Company announced today that the first patient has been enrolled in the Phase 2 portion of the GANNET53 study, a randomized, pan-European study evaluating the combination of ganetespib and paclitaxel vs. paclitaxel alone in over 200 patients with metastatic, predominantly p53 mutant, platinum-resistant ovarian cancer. Enrollment in the Phase 2 portion follows the successful completion of Phase 1, the results of which were recently presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. The Phase 1 data demonstrated that the combination of ganetespib 150 mg/m² with paclitaxel 80 mg/m² once weekly for 3 out of 4 weeks was generally well tolerated, with no dose limiting toxicities, and was therefore chosen for the randomized phase 2 trial. GANNET53 is sponsored by Innsbruck Medical University in Austria and funded by the European Commission.

"The Phase 1 portion of GANNET53 has established the feasibility and tolerability of combining ganetespib and paclitaxel, and we eagerly look forward to the enrollment of, and results from the randomized Phase 2 portion of this trial." said Professor Nicole Concin of the Innsbruck Medical University in Austria and the GANNET53 trial Principal Investigator. "We are very excited about a recent scientific insight into the relationship of p53 gain-of-function mutations which are the molecular hallmark of aggressive, high-grade serous ovarian carcinoma, and Hsp90 inhibition leading to tumor cell death in vitro and significant tumor control and prolonged survival in a novel p53 mutant mouse model. This unique mechanism of action and encouraging preclinical data support our choice of the ganetespib combination in an effort to optimize treatment for women with platinum-resistant ovarian cancer."

The Company also announced today that results from the Phase 2 GALAXY-1 trial, a global, randomized, multi-center study designed to identify the patients with advanced non-small cell lung cancer (NSCLC) most likely to benefit from second-line treatment with ganetespib in combination with docetaxel versus docetaxel alone, have been published in the journal Annals of Oncology. As previously announced, a pre-specified stratification factor analysis demonstrated that patients diagnosed with advanced non-small cell lung adenocarcinoma more than six months prior to study entry derived the most benefit from combination treatment, leading to the selection of this population for the ongoing Phase 3 GALAXY-2 trial. Based on current projections and statistical assumptions, the first interim overall survival (OS) analysis of GALAXY-2 is on track to occur in the second half of 2015, and the second interim and final OS analyses will be conducted in 2016. The GALAXY-1 publication is available online here.

"We are pleased to see the GALAXY-1 findings published in the Annals of Oncology and look forward to understanding how outcomes from this trial translate to the ongoing, pivotal Phase 3 GALAXY-2 trial," said Dr. Suresh Ramalingam, M.D., Professor, Hematology & Medical Oncology, and Director, Division of Medical Oncology, of the Winship Cancer Institute of Emory University, and a principal investigator of the GALAXY program. "Ganetespib’s unique mechanism of action has the potential to play an important role in the evolving treatment landscape in lung cancer. I look forward to the outcome of GALAXY-2."

"We remain highly encouraged by the progress of the ganetespib program across a broad spectrum of malignancies and grateful to our collaborating investigators for their strong, ongoing support for what is today the most advanced, next generation inhibitor of Hsp90," said Chen Schor, President and Chief Executive Officer of Synta. "We look forward to several transformative milestones on the horizon, both for ganetespib and our lead HDC candidate, STA-12-8666."

About Ganetespib

Ganetespib, an investigational drug candidate, is a selective inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone which controls the folding and activation of a number of client proteins that drive tumor development and progression. Many solid and hematologic tumors are dependent on Hsp90 client proteins including proteins involved in "oncogene addiction" (ALK, HER2, mutant BRAF and EGFR, androgen receptor, estrogen receptor, and JAK2); proteins involved in resistance to chemotherapy and radiation therapy (ATR, BCL2, BRCA1/2, CDK1/4, CHK1, survivin, and WEE1); proteins involved in angiogenesis (HIF-1alpha, VEGFR, PDGFR, and VEGF); and proteins involved in metastasis (MET, RAF, AKT, MMPs, HIF-1alpha, and IGF-1R). In preclinical models, inhibition of Hsp90 by ganetespib results in the inactivation, destabilization, and eventual degradation of these cancer-promoting proteins. Ganetespib is being evaluated in trials in lung cancer, breast cancer, and other tumor types. The most common adverse event seen to date has been transient, mild or moderate diarrhea, which has been manageable with standard supportive care. Information on these trials can be found at www.clinicaltrials.gov. Ganetespib has received Fast Track designation from FDA for second-line treatment of non-small cell lung adenocarcinoma in combination with docetaxel.