On April 18, 2016 bluebird bio, Inc. (Nasdaq: BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic and rare diseases and T cell-based immunotherapies for cancer, reported that data from clinical, preclinical, and research and manufacturing programs will be highlighted in ten presentations at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 19th Annual Meeting, taking place May 4-7, 2016 in Washington, D.C (Press release, bluebird bio, APR 18, 2016, View Source;p=RssLanding&cat=news&id=2158031 [SID:1234510988]).

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Two oral presentations given by bluebird’s academic collaborators will highlight previously presented data from bluebird bio’s ongoing gene therapy clinical trials. David Williams, M.D., chief of hematology/oncology at Boston Children’s Hospital will present interim data from the Starbeam Study of Lenti-D in cerebral adrenoleukodystrophy, and Marina Cavazzana, M.D., Ph.D., of Hospital Necker, University Paris Descartes, will present interim data from the HGB-205 study of LentiGlobin in severe sickle cell disease and transfusion-dependent β-thalassemia.

Eight additional presentations will be featured at the meeting, highlighting progress across the company’s preclinical, research and process development activities.

"As bluebird continues to build a differentiated T cell oncology franchise, we are excited to present three oncology abstracts that highlight our work on the next generation of technology for T cell-based immunotherapy – including methods of generating T cells with sustained anti-tumor activity, small-molecule regulated chimeric antigen receptors (CARs) and genome editing to generate improved CAR T cells," said Philip Gregory, D.Phil., chief scientific officer, bluebird bio. "From our hematopoietic stem cell programs, we will also share updates in five presentations covering improvements in scalable manufacturing, transduction efficiency and assay development – critical areas for making gene therapy available to more patients."

The abstracts are now available online on the ASGCT (Free ASGCT Whitepaper) Annual Meeting website.

Details of bluebird bio’s oral presentations are as follows:

Title: A Phase 2/3 Study of the Efficacy and Safety of Ex Vivo Gene Therapy With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy
Abstract Number: 250
Session: Clinical Trials Spotlight Symposium
Date: Thursday, May 5, 2016
Time: 9:00 – 9:20 a.m.
Location: Thurgood Marshall North/East
Note: Data previously presented at the 2016 American Academy of Neurology Annual Meeting

Title: Small Molecule-regulated Antigen Recognition System for Inducible T Cell Targeting of Cancer Cells
Abstract Number: 277
Session: Cancer-Immunotherapy, Cancer Vaccines I
Date: Thursday, May 5, 2016
Time: 5:15 – 5:30 p.m.
Location: Washington 4

Title: Clinical Outcomes of Gene Therapy with BB305 Lentiviral Vector for Sickle Cell Disease and β-Thalassemia
Abstract Number: 279
Session: Hematologic & Immunologic Diseases I
Date: Thursday, May 5, 2016
Time: 4:00 – 4:15 p.m.
Location: Washington 5-6
Note: Data previously presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting

Title: Towards the Clinical Application of BCMA CAR T cells: The Importance of Reduced Tonic Signaling and Methods to Enhance Memory T Cells
Abstract Number: 747
Session: Cancer-Immunotherapy, Cancer Vaccines III
Date: Saturday, May 7, 2016
Time: 10:45 – 11:00 a.m.
Location: Thurgood Marshall North

Details of bluebird bio’s poster presentations are as follows:

Title: PGE2 Increases Lentiviral Vector Transduction Efficiency of Human HSC
Abstract Number: 229
Session: Hematologic & Immunologic Diseases I
Date: Wednesday, May 4, 2016
Time: 5:30 p.m. – 7:30 p.m.
Location: Exhibit Hall C & B South

Title: Staurosporine Increases Lentiviral Transduction of Human CD34+ Cells
Abstract Number: 221
Session: Hematologic & Immunologic Diseases I
Date: Wednesday, May 4, 2016
Time: 5:30 p.m. – 7:30 p.m.
Location: Exhibit Hall C & B South

Title: Qualification of a p24 ELISA Assay for Quantitation of Total Lentiviral Vector Concentration
Abstract Number: 473
Session: Pharmacology/Toxicology Studies or Assay Development
Date: Thursday, May 5, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

Title: Efficient Generation of CART Cells by Homology Directed Transgene Integration into the TCR-Alpha Locus
Abstract Number: 323
Session: Targeted Genome Editing II
Date: Thursday, May 5, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

Title: Development of a Stable Producer Cell Line for Scalable Lentiviral Vector Production for Gene Therapy of Hemoglobinopathies
Abstract Number: 458
Session: Vector and Cell Engineering/Manufacturing I
Date: Thursday, May 5, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

Title: Characterization of Nanoparticles in Lentiviral Vector Preparations
Abstract Number: 709
Session: Vector and Cell Engineering/Manufacturing II
Date: Friday, May 6, 2016
Time: 6:00 p.m. – 8:00 p.m.
Location: Exhibit Hall C & B South

On April 18, 2016 AstraZeneca reported new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, AstraZeneca, APR 18, 2016, View Source [SID:1234511011]). These agents use a variety of different pathways to disrupt tumour cells’ natural ability to repair themselves as they replicate, eventually causing the tumour cells to die.7,8 Illustrating the unique breadth of AstraZeneca’s approaches to DDR, presentations at AACR (Free AACR Whitepaper) featured molecules that disrupt multiple tumour cell repair processes, including single-strand break repair, double-strand break repair, and cell cycle regulation.1-6

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Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit said, "Taken together with the positive Phase II results of olaparib in patients with metastatic, castration-resistant prostate cancer published early this year,9 we are encouraged by the potential of PARP inhibition in multiple tumour types beyond ovarian cancer. The breadth of our pipeline showcases DDR monotherapies and combinations that could attack cancer in a multitude of novel ways – our first priority, as demonstrated here at AACR (Free AACR Whitepaper), is to follow the science to identify and quickly advance those molecules that have the potential to address the greatest unmet medical needs."

PARP Inhibition and Lynparza (olaparib): Beyond Ovarian Cancer

The PARP inhibitor olaparib is the cornerstone of AstraZeneca’s pipeline of personalised treatments targeting DDR mechanisms in cancer cells. Olaparib was combined with the investigational AKT inhibitor AZD5363 in a new Phase I trial of germline (g) BRCA and non-BRCA mutant (m) advanced cancer patients with ovarian, breast, prostate and bile duct cancers.1 Results showed that the olaparib-AZD5363 combination was well-tolerated with multiple responses, including 10 RECIST complete or partial responses (out of 37 evaluable patients) in both gBRCA and non-BRCAm tumours, as well as prior PARP inhibitor-treated cancers.1

Olaparib disrupts the repair of single-strand DNA breaks, a mode of action that has potential to work in a range of tumour types beyond ovarian cancer.10 AstraZeneca is researching how several different compounds can be combined with DDR molecules to provide a dual threat to tumour cells. For example, treatments such as AZD5363 that selectively inhibit the PI3K / AKT signalling pathway may complement olaparib’s interference with tumour DNA repair.1

Additional Mechanisms of DDR: Cell Cycle Disruption & Double-Strand Break Repair

AstraZeneca presented data on a variety of investigational compounds acting on different aspects of the DDR pathway, both in monotherapy and in combination. Most significant were early results from a Phase Ib open-label study of AZD1775, a novel small molecule designed to inhibit the Wee1 kinase.2 Wee1 is a protein kinase that helps regulate the cell cycle.5 In many tumours, Wee1 overexpression stops the cell cycle after DNA damage occurs, allowing tumour cells time to repair any damage.5,11 By inhibiting Wee1, the cell cycle continues despite damage, which can lead to tumour cell death.5 Assessing the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD1775, the Phase Ib safety run-in included patients with small-cell lung, non-small cell lung, head and neck, ovarian, breast, pancreas and unknown primary tumours.2 Early results demonstrated a partial or stable response in a third of patients (4/12), and AstraZeneca has initiated expansion cohorts in ovarian, breast and small-cell lung cancer.2 Other studies currently recruiting include a Phase I multi-centre, dose escalation study of AZD1775 combined with olaparib in refractory solid tumours.12

Several other new molecules in the clinical pipeline are entering Phase I development, including the first-in-class Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156.3 Pre-clinical in vivo activity of AZD0156 presented at AACR (Free AACR Whitepaper) demonstrated that inhibition of ATM during the DNA damage response enhanced the efficacy of a range of DNA-damaging agents, including olaparib, and support its further study in the clinical setting.3 AstraZeneca is now recruiting for a Phase I trial of AZD0156 as monotherapy or in combination with olaparib in patients with advanced solid tumours.13

Other ongoing DDR-focused studies include additional Phase I trials of the Aurora B kinase inhibitor AZD281114 and ATR inhibitor AZD6738 in solid tumours.15

On April 18, 2016 Heptares Therapeutics ("Heptares"), the wholly-owned subsidiary of Sosei Group Corporation (TSE Mothers Index: 4565), and Kymab Limited, a leading human monoclonal antibody biopharmaceutical company, reported that they have entered into a strategic collaboration to discover, develop and commercialise novel antibody therapeutics targeting a number of G protein-coupled receptors (GPCR) with an initial focus on immuno-oncology (Press release, Heptares, APR 18, 2016, View Source [SID:1234514761]).

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Immuno-oncology is an exciting new area in the treatment of cancer where the body’s immune system is activated to produce an immune response targeted at tumour cells. Immunotherapy drugs are poised to revolutionise the way cancer is treated and a number of immunotherapy antibody treatments have recently been approved. GPCRs are widely expressed on cells of the innate and adaptive immune system and play key roles in modulating cell migration and recruitment to the tumour environment, activation, survival, proliferation and differentiation. GPCRs act at critical checkpoints that can be targeted by novel immunotherapy antibodies.

Under the agreement, Heptares will apply its StaR platform to create stable antigens based on multiple GPCR targets chosen by the companies. Kymab will then use its Kymouse human antibody discovery platform to generate antibodies in response to immunisation with these antigens. The Kymouse platform will assure the highest probability of finding the best-in-class antibodies with highly attractive drug properties. Promising leads will be progressed using the partners’ complementary skills, resources and development capabilities in order to bring innovative products into the clinic. Under the agreement, the companies will jointly conduct and share the costs of each antibody discovery and development programme.

Malcolm Weir, Chairman and CEO of Heptares, said: "GPCRs have long been intractable targets for antibody discovery resulting in dearth of products. We believe that our proven StaR technology can unlock this substantial opportunity, not just in immuno-oncology but also across other therapeutic areas where GPCR-targeted biologics could have a significant impact. By entering into strategic collaborations with companies with world-leading antibody discovery technologies, such as Kymab, we have the potential to discover, develop and commercialise a highly valuable pipeline of new biologic products."

David Chiswell, CEO of Kymab, said: "Antibodies are important therapeutic agents for cancer and other indications. Our collaboration with Heptares will allow us to combine stable antigens based on multiple GPCR targets with our world-class Kymouse platform, which has unparalleled diversity and will therefore rapidly identify and yield highly selective potent human monoclonal antibodies for unmet medical needs."

In this analysis, we compared costs and explored the cost-effectiveness of subsequent-line treatment with cetuximab or panitumumab in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) after previous chemotherapy treatment failure. Data were used from ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in Patients With KRAS Wild-Type Metastatic Colorectal Cancer), a Phase III, head-to-head randomized noninferiority study comparing the efficacy and safety of panitumumab and cetuximab in this population.
A decision-analytic model was developed to perform a cost-minimization analysis and a semi-Markov model was created to evaluate the cost-effectiveness of panitumumab monotherapy versus cetuximab monotherapy in chemotherapy-resistant wild-type KRAS (exon 2) mCRC. The cost-minimization model assumed equivalent efficacy (progression-free survival) based on data from ASPECCT. The cost-effectiveness analysis was conducted with the full information (uncertainty) from ASPECCT. Both analyses were conducted from a US third-party payer perspective and calculated average anti-epidermal growth factor receptor doses from ASPECCT. Costs associated with drug acquisition, treatment administration (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions were estimated in both models. The cost-effectiveness model also included physician visits, disease progression monitoring, best supportive care, and end-of-life costs and utility weights estimated from EuroQol 5-Dimension questionnaire responses from ASPECCT.
The cost-minimization model results demonstrated lower projected costs for patients who received panitumumab versus cetuximab, with a projected cost savings of $9468 (16.5%) per panitumumab-treated patient. In the cost-effectiveness model, the incremental cost per quality-adjusted life-year gained revealed panitumumab to be less costly, with marginally better outcomes than cetuximab.
These economic analyses comparing panitumumab and cetuximab in chemorefractory wild-type KRAS (exon 2) mCRC suggest benefits in favor of panitumumab. ClinicalTrials.gov identifier: NCT01001377.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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On April 18, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that positive data for VYXEOS (cytarabine:daunorubicin) Liposome for Injection (also known as CPX-351), its lead product candidate, were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, April 16-20, 2016 (Press release, Celator Pharmaceuticals, APR 18, 2016, View Source [SID:1234510967]).

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The presentation, titled "CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes," was based on research conducted in the laboratory of Jeffrey Tyner, Ph.D. at Oregon Health & Science University and examined the ex vivo sensitivity of AML cells derived from newly diagnosed patients to VYXEOS.

The profile of ex vivo AML blast sensitivity to VYXEOS mirrors the efficacy profile observed clinically and may provide a means to identify specific AML patient genotypes/phenotypes that could benefit most from VYXEOS treatment. The increased sensitivity of FLT3-ITD+ (internal tandem duplication) blasts to VYXEOS is an example of how such analyses may identify additional AML patient populations warranting further clinical investigation.

FLT3-ITD mutant expression has historically been a predictor of poor patient outcomes to conventional treatment regimens. A notable result from this research was the observation that AML cells exhibiting the FLT3-ITD mutation were approximately five times more sensitive to VYXEOS than AML cells with normal FLT3. In addition, there was evidence that increased sensitivity to VYXEOS is associated with increased uptake of the drug-laden liposomes by leukemia cells.

"Testing cell killing activity against fresh AML cells outside the body allows us to identify specific AML cell-VYXEOS interactions that could be exploited clinically," said Dr. Tyner. "We are particularly excited about the marked increase in sensitivity of FLT3-ITD cells to VYXEOS and are working to better understand the mechanism underlying this phenomenon."

"VYXEOS continues to deliver positive efficacy read-outs," said Lawrence Mayer, Ph.D., President and Chief Scientific Officer at Celator. "The encouraging activity of VYXEOS against AML cells harboring the FLT3-ITD mutant phenotype opens exciting opportunities to test VYXEOS in this AML patient population. We will submit data from patients exhibiting this mutation, who were treated in the recently completed Phase 3 trial, to an upcoming medical conference."

The poster will be available on Celator’s website (www.celatorpharma.com) at the conclusion of the AACR (Free AACR Whitepaper) meeting.