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bluebird bio Presents Oncology and Gene Therapy Data at the ASGCT 19th Annual Meeting

On May 9, 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 the presentation of pre-clinical data from its immuno-oncology and hematopoietic stem cell (HSC) gene therapy programs 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, MAY 9, 2016, View Source;p=RssLanding&cat=news&id=2166363 [SID:1234512103]).

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Additionally, two oral presentations given by bluebird’s academic collaborators highlighted previously presented data from bluebird bio’s ongoing gene therapy clinical trials. David Williams, M.D., president of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center presented 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, presented interim data from the HGB-205 study of LentiGlobin in severe sickle cell disease and transfusion-dependent β-thalassemia.

"The preclinical data presented at ASGCT (Free ASGCT Whitepaper) are testament to bluebird’s commitment to developing next-generation immuno-oncology and gene therapies. We are particularly excited about our oncology presentations, which highlighted our progress toward the generation of T cells with sustained anti-tumor activity as well as research on small-molecule regulated multi-chain chimeric antigen receptors known as Darics," said Philip Gregory, D.Phil., chief scientific officer, bluebird bio. "For our hematopoietic stem cell programs, scalable manufacturing and transduction efficiency remain areas of focus and importance for bluebird. Multiple presentations at ASGCT (Free ASGCT Whitepaper) discussed encouraging examples of our efforts on these fronts – with more to come as we continue to innovate in this critical direction."

Oncology Presentations:

Oral Abstract #277: Small Molecule-regulated Antigen Recognition System for Inducible T Cell Targeting of Cancer Cells

Overview and results presented by Wai-Hang Leung, Ph.D., bluebird bio.

bluebird bio scientists presented data on a small-molecule regulated CAR (Daric) for applications where it may be useful to turn antigen-driven T cell activity on or off, such as minimizing off-tumor activity. In addition to potentially providing an enhanced safety profile for CAR T cells, this technology could be applied in other indications such as autoimmune disease.
Daric engineered CAR T cells possess minimal activity in the absence of dimerizing agents (rapamycin / AP21967), and antigen-specific cytotoxicity and cytokine production are significantly upregulated with the addition of rapamycin / AP21967.
Oral Abstract #747: Towards the Clinical Application of BCMA CAR T cells: The Importance of Reduced Tonic Signaling and Methods to Enhance Memory T Cells

Results presented by Kevin Friedman, Ph.D., bluebird bio.

bluebird bio has developed a potent CAR targeting BCMA (bb2121) to treat multiple myeloma and some lymphomas. The initial clinical application of this technology to treat patients with multiple myeloma began in February.
bluebird bio scientists demonstrated that a property called tonic signaling can reduce CAR T cell durability and tumor control, but careful CAR engineering can avoid this problem. Furthermore, simple manufacturing changes involving inhibition of the PI3K pathway can significantly increase the potency and fitness of CAR T cells.
Abstract #323: Efficient Generation of CART Cells by Homology Directed Transgene Integration into the TCR-Alpha Locus

Results presented by Baeckseung Lee, Ph.D., bluebird bio.

Homology directed transgene integration combines nuclease-mediated gene disruption with site-specific integration of novel genetic material. Using bluebird bio’s proprietary gene editing technology, megaTALs, bluebird scientists demonstrated that this can be efficiently accomplished in primary human T cells by introducing a CD19 CAR into the TCR alpha gene (TRAC).
Nuclease generated CAR T cells had similar cytotoxicity and cytokine production compared to those made by lentiviral vector transduction. These data demonstrate the potential for megaTAL-mediated targeted gene addition as a robust method for the genetic editing of CAR T cells.
HSC Gene Therapy Presentations

Abstract #221: Staurosporine Increases Lentiviral Transduction of Human CD34+ Cells

Results presented by Melissa Bonner, Ph.D., bluebird bio.

bluebird has been evaluating numerous compounds for the potential to increase vector copy number (VCN) and enhance cell transduction in lentiviral vector (LVV)-based gene therapy.
Limited staurosporine treatment prior to LVV transduction can increase the proportion of modified cells, including long-term repopulating cells, in a gene modified cell product.
This work received an "Outstanding Poster Award" from the ASGCT (Free ASGCT Whitepaper).
Abstract #229: PGE2 Increases Lentiviral Vector Transduction Efficiency of Human HSC

Results presented by Garrett C. Heffner, Ph.D., bluebird bio.

As part of its work to evaluate small molecules that may increase VCN and enhance cell transduction, bluebird identified PGE2 as a VCN enhancer in CD34+ cells.
PGE2 improves VCN approximately 2-fold from multiple healthy normal CD34+ cell donors as well as donors with primary hemoglobinopathies. These increases in VCN also result in an increased percentage of cells with integrated lentiviral vector leading to improved globin expression in in vitro preclinical models.
Abstract #458: Development of a stable producer cell line for scalable lentiviral vector production for gene therapy of hemoglobinopathies

Results presented by Sarah Slauson, bluebird bio

Current manufacturing of clinical grade lentiviral vectors commonly relies on transient infection of adherent 293T cells. An inducible producer cell line grown in suspension culture represents a potentially more scalable manufacturing process for vector production, eliminating the need for costly plasmid and transfection reagents.
bluebird bio scientists have developed 293F-based stable packaging and producer cell lines for inducible production of LentiGlobin BB305, and reported the successful production of LentiGlobin BB305 at research scale in suspension culture.
Abstract #473: Qualification of a p24 ELISA Assay for Quantitation of Total Lentiviral Vector Concentration

Results presented by Elisabeth Boucher, bluebird bio.

The availability of reliable analytical tools to characterize purified LVV product and in-process samples is critical to successful LVV process development. In support of late-stage process characterization, it is essential to qualify the assay and demonstrate its suitability to test in-process samples in different matrices.
Scientists at bluebird bio reported on the qualification of a p24 ELISA assay for LVV quantitation, showing precision, repeatability, specificity and accuracy within an established range, adequate to support late-stage process characterization activities.
Abstract #709: Characterization of Nanoparticles in Lentiviral Vector Preparations

Results presented by Erik Hansen, bluebird bio.

Progress to late-stage clinical development of lentivirus based gene therapies and CAR T therapies will require enhanced characterization of the purified lentivirus product. LVV preparations are complex and utilize host cells that produce not only the viral particles of interest, but also a variety of closely related impurities that can include microvesicles. These cell-derived impurities can overlap key biophysical and biochemical attributes of the LVV, making them challenging to analyze.
bluebird bio scientists reported on the use of various analytical tools to further characterize LVV preparations in terms of particle size distribution and counts, as well as methods for determining the total particle to infectious particle ratio.

A synthetic glycopeptide for anti-tumor immunotherapy: from design to first use in human

Within the framework of developing a carbohydrate-based vaccine against cancer, we designed and prepared the MAG-Tn3, a fully synthetic immunogen based on the tumor-associated Tn antigen (Company Pipeline, Institut Pasteur, MAY 9, 2016, View Source [SID:1234512094]). The MAG-Tn3 is a glycopeptide associating Tn clusters with a pan-DR CD4+ T cell epitope, on a tetravalent backbone. It is a promising therapeutic vaccine against adenocarcinomas (breast, lung, and prostate cancer, among others). Our study demonstrates the feasibility of the synthesis of this complex glycopeptide as a drug-grade compound. Based on these results, and on successful in vivo experiments in mice and non-human primates, a phase I clinical trial for this vaccine candidate is scheduled to start in 2015 in patients with cancer.

Pentraxin-2 Platform

Promedior’s drug candidates are based on Pentraxin-2, an endogenous human protein that is specifically active at the site of tissue damage and works as an agonist to initiate a resolution process for prevention and potential reversal of fibrosis (Company Pipeline, Promedior, MAY 9, 2016, View Source [SID:1234512083])). Promedior’s Pentraxin-2 therapeutics harness the innate healing power of the immune system, acting as a master regulator upstream in the fibrosis cascade.

Normal wound healing consists of 3 distinct pathways: (1) inflammation, (2) proliferation, and (3) resolution. Fibrosis occurs when the normal wound healing response gets locked in the proliferation pathway, resulting in a cascade of excessive scar tissue formation that leads to tissue damage and organ dysfunction.

Pentraxin-2 directs the immune system to turn on the resolution pathway and simultaneously turn off the proliferation pathway, and works specifically in areas of tissue injury.

Pentraxin-2-based therapeutics have several advantages over other experimental approaches to treating fibrotic diseases:
· Potent Upstream Agonist: Fibrosis, the formation of dysregulated scar tissue, is a highly conserved process with many downstream redundancies in the pathway. By turning on a resolution pathway and thereby turning off the proliferation pathway upstream of significant redundancies, Pentraxin-2-based therapeutics offer the potential for a more robust approach to efficacy. In contrast, most competitive approaches target single downstream enzymes or cytokine targets, making it difficult to achieve efficacy without combination therapy.
· Specificity: Pentraxin-2’s natural mechanism of action involves specificity that targets activity to the damaged tissue microenvironment, ensuring that the drug effect occurs in areas of disease. Less specific approaches could lead to unintended side-effects and toxicity.
· Potential to Reverse Fibrosis and Recover Function: By simultaneously promoting resolution and turning off the proliferation pathway, Pentraxin-2-based therapeutics offer the potential to break down scar tissue and promote recovery of organ function. Preclinical results have demonstrated the ability to reverse fibrosis. Such reversal of fibrosis is possible due to the promotion of factors in the resolution pathway such as enzymes that break down the extracellular matrix that comprise the scar tissue in fibrotic tissue.
Extensive studies conducted by Promedior and its collaborators have demonstrated the ability of Pentraxin-2 to act as an upstream agonist that is specific for the damaged tissue microenvironment across many major tissue types and in several models of fibrotic disease, strongly supporting its potential as a novel anti-fibrotic agent. Promedior and its collaborators have published many of their findings in peer-reviewed journals and presented them at medical and scientific meetings.

PRM-151

PRM-151: Lead Product Candidate

Promedior’s lead product, PRM-151, is a recombinant form of human pentraxin-2 protein (rhPTX-2) formulated for intravenous injection (Company Pipeline, Promedior, MAY 9, 2016, View Source [SID:1234512082]). Promedior is initially focusing the clinical development of PRM-151 on rare systemic fibrotic diseases, such as Idiopathic Pulmonary Fibrosis (IPF) and myelofibrosis. Highlights of PRM-151’s clinical development include:

· A Phase 1a clinical study in healthy subjects and IPF patients demonstrated that PRM-151 was safe and well-tolerated
· A Phase 1b randomized, double-blind, placebo-controlled, multiple ascending dose study in IPF patients demonstrated that PRM-151 was generally safe and well‐tolerated and resulted in a mean improvement in Forced Vital Capacity (FVC) at 8 weeks after dosing for only two weeks, whereas patients receiving placebo had a decline in FVC. These data were · presented at the American Thoracic Society Annual Meeting on May 22, 2013.

· A Phase 2 clinical trial to evaluate PRM-151 in patients with myelofibrosis is ongoing. This trial is a multi-center, two-stage, adaptive design study to determine the efficacy and safety of PRM-151 as a single agent or added to a stable dose of ruxolitinib in patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), or Post-Essential Thrombocythemia MF (post-ET MF). Data were presented at the 2014 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the 2014 European Hematology Association (EHA) (Free EHA Whitepaper) meetings in June. Positive preliminary data demonstrated biologic activity with improvements across clinically relevant measures, including bone marrow fibrosis, hemoglobin, platelets, spleen volume, and symptoms. Clinical data showed improvements in four independent treatment groups of myelofibrosis patients who received PRM-151 weekly or monthly, either as a single agent or in patients with no further improvements on a stable dose of ruxolitinib1. Importantly, PRM-151 demonstrated safety and tolerability both alone and in combination with ruxolitinib, with no evidence of the myelosuppression commonly observed with other treatments. This recent data in myelofibrosis demonstrates the potential of Promedior’s immuno-oncology approach in fibrotic cancers.

PRM-151 has demonstrated efficacy in multiple preclinical models of fibrotic disease, including the reduction of established pulmonary fibrosis.

PureTech Teams with Siddhartha Mukherjee to Launch Vor BioPharma to Advance Novel Targeting Platform to Expand Applicability of CAR T-Cell Immunotherapies in Immuno-Oncology

On May 9, 2016 PureTech Health plc ("PureTech," LSE: PRTC) reported the launch of Vor BioPharma, an immuno-oncology company dedicated to developing a new class of targeted cell therapies (Press release, Vor BioPharma, MAY 9, 2016, View Source [SID:1234512244]).

The company, which is advancing a novel approach to chimeric antigen receptor (CAR) T-cell therapy, has licensed its core technology from the lab of Vor scientific co-founder, Siddhartha Mukherjee, M.D., Ph.D., Assistant Professor of Medicine at Columbia University and Pulitzer Prize-winning author of The Emperor of All Maladies: A Biography of Cancer.

"CAR T-cell therapies have shown remarkable progress in the clinic, yet their applicability beyond a small subset of cancers is currently very limited," said Sanjiv Sam Gambhir, M.D., Ph.D., Vor Scientific Advisory Board Member, Professor of Radiology and Bioengineering, Chair of the Department of Radiology, Director of the Canary Center for Cancer Early Detection and Director of the Molecular Imaging Program at Stanford University. "This technology seeks to address bottlenecks that prevent CAR T-cell therapy from becoming more broadly useful in treating cancers outside of B-cell cancers."

Researchers continue to make big advances in using the immune system to fight cancer. CAR T-cell therapy, which modifies the body’s own immune cells (T-cells) to recognize and kill cancer cells, has emerged as a promising therapy for patients with advanced B-cell leukemias. These approaches have focused on targeting markers that are present on all B-cells, both healthy and cancerous. While the body can safely function without B-cells, using CAR T-cell therapy to treat other cancers—which would involve targeting cells necessary for survival—remains elusive. Furthermore, CAR T-cell therapy has shown more limited results in treating solid tumors. Vor is developing an entirely new approach to CAR T-cell therapy that seeks to broaden its applicability in other cancers, particularly those with limited therapeutic options, by removing key barriers generated by current modalities.

"We continue to make great strides in developing new ways to treat cancer using the body’s immune system," said Dr. Mukherjee. "The positive clinical response researchers have achieved with CAR T-cell therapies in B-cell leukemias has led to great interest within the oncology community and is something we hope to achieve in other cancers over time."

"PureTech is excited to be collaborating with Sid Mukherjee and to have the support of a world-class team of immunologists and oncologists," said David Steinberg, Executive Vice President of PureTech Health and Co-Founder of Vor BioPharma. "We look forward to advancing this technology that has the potential to expand immuno-oncology to currently untreatable, fatal malignancies."

Leading oncologists and immunologists are supporting Vor in developing its pipeline of novel immunotherapies. The company’s team of scientific founders and Scientific Advisory Board (SAB) members includes:

Joseph Bolen, Ph.D. – Scientific Advisory Board member and acting Chief Scientific Officer of Vor BioPharma and former President and Chief Scientific Officer of Moderna Therapeutics. Dr. Bolen has more than 30 years of industry and research experience and has been at the forefront of cancer and immunology research. He began his career at the NIH, where he contributed to the immunotherapies pipeline discovery of a class of proteins known as tyrosine kinase oncogenes as key regulators of the immune system. Dr. Bolen most recently oversaw all aspects of research and development for Moderna. Previously, he was Chief Scientific Officer and Global Head of Oncology Research at Millennium: The Takeda Oncology Company. Prior to joining Millennium in 1999, Dr. Bolen held senior research and development positions at Hoechst Marion Roussel, Schering-Plough, and Bristol-Myers Squibb.

Sanjiv Sam Gambhir, M.D., Ph.D. – Professor of Radiology, Materials Science & Engineering, and Bioengineering at Stanford University, where he is also the Chair of the Department of Radiology, Director of the Canary Center for Cancer Early Detection and Director of the Molecular Imaging Program. His research focuses on interrogating cellular and molecular events in living subjects through imaging and on the early detection of cancer. He is the recipient of over $90M in NIH funding as the principal investigator and served on the NCI Board of Scientific advisors for eight years. Dr. Gambhir has received several awards including the Hounsfield Medal, Tesla Medal, Holst Medal, and is an elected fellow of the National Academy of Medicine, as well as the National Academy of Inventors. He has co-founded several startups and is an advisor to several large corporations and biotechnology startups.

Dan Littman, M.D., Ph.D. – Howard Hughes Medical Institute Investigator and the Helen L. and Martin S. Kimmel Professor of Molecular Immunology and Professor of Pathology and Microbiology at New York University (NYU) School of Medicine. Dr. Littman has made numerous groundbreaking discoveries in the field of virology and immunology, including identification and isolation of receptors required for human immunodeficiency virus (HIV) entry, molecular mechanisms of immune cells that mediate autoimmunity and the role of specific members of the gut microbiota in T-cell differentiation. Dr. Littman is a Fellow of the American Academy of Arts and Sciences and is a Member of the National Academy of Sciences. He was awarded the 2004 New York City Mayor's Award for Excellence in Science and Technology.

Siddhartha Mukherjee, M.D., Ph.D. – Assistant Professor of Medicine at Columbia University and oncologist. Dr. Mukherjee is the author of The Emperor of All Maladies: A Biography of Cancer, winner of the 2011 Pulitzer Prize in general nonfiction, and The Laws of Medicine. He has published distinguished articles in numerous publications, including Nature, The New England Journal of Medicine, Cell and The New York Times.

Derrick J. Rossi, Ph.D. – Associate Professor in the Stem Cell and Regenerative Biology Department at Harvard Medical School and Harvard University. Dr. Rossi is an investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, and is also a principal faculty member of the Harvard Stem Cell Institute. TIME Magazine cited Dr. Rossi’s discovery of modified-mRNA reprogramming as one of the top ten medical breakthroughs of 2010. TIME Magazine also named Dr. Rossi as one of "People Who Mattered" in 2010, and as one of the 100 Most Influential People (Time 100) in 2011. Dr. Rossi co-founded Moderna Therapeutics and Intellia Therapeutics.

About Vor BioPharma

Vor BioPharma is an immuno-oncology company dedicated to developing a new class of targeted cell therapies to treat highly fatal malignancies. The company is advancing a novel approach to chimeric antigen receptor (CAR) T-cell therapy that has the potential to broaden its applicability and success rate in other cancers. Co-founded by PureTech Health ("PureTech", LSE: PRTC), Vor is working with some of the world’s leading oncologists and immunologists to develop a pipeline of potentially life-altering immunotherapies that extend beyond what is possible with current treatments. PureTech Health plc (PRTC.L) owns approximately 91% of the company on a diluted basis as of December 31, 2015. This calculation includes issued and outstanding shares as well as options to purchase shares and written commitments to issue shares or options, but excludes unallocated shares authorized to be issued pursuant to equity incentive plans.