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Intellia Therapeutics Presents New Data in In Vivo and Ex Vivo Programs at the 26th Annual Congress of the European Society of Gene and Cell Therapy

On October 18, 2018 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported its new data from three of its programs, including the company’s first data on complex edits, at the 26th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT), in Lausanne, Switzerland (Press release, Intellia Therapeutics, OCT 18, 2018, View Source [SID1234530291]).

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"We are extremely pleased to present an outstanding compilation of data today reflecting progress in our preclinical genome editing programs," said Intellia President and Chief Executive Officer John Leonard, M.D. "We showed that we can efficiently introduce complex edits in mice by inserting genes to express proteins that are deficient in some genetic diseases. By using our LNP delivery system in combination with AAV to deliver template DNA, we are opening the door for the development of therapies for a wide range of genetic diseases that require stable gene insertion and expression. In parallel, we are driving forward our ex vivo programs and other in vivo programs. Our researchers are gaining further insights into our ATTR program through our ongoing NHP studies, as well as working with our collaborators at Ospedale San Raffaele (OSR) to make excellent progress in our quest to advance the next generation of engineered cell therapy."

CRISPR-mediated, Targeted Gene Insertion Data

In a collaboration between Intellia and Regeneron Pharmaceuticals, Inc., researchers combined Intellia’s modular lipid nanoparticle (LNP) delivery system of CRISPR/Cas9 with a modular adeno-associated viral (AAV) insertion template to achieve supratherapeutic levels (levels higher than those required in a clinical setting) of gene expression in mice. Using Factor 9 (F9) as a model gene, the team demonstrated the first robust, efficient CRISPR-mediated targeted insertion into the liver. F9 is a gene that encodes Factor IX (FIX), a blood-clotting protein that is often missing or defective in hemophilia B patients.

Using Intellia’s proprietary bi-directional template, researchers detected hybrid mAlb-hF9 transcripts in >50 percent of hepatocytes following a single dose. Circulating human FIX protein levels of >30,000 ng/mL were achieved, which are predicted to correspond to levels 40-300 times higher than those capable of preventing bleeding episodes in hemophilia B patients, when using a wildtype or hyperfunctional version of F9 (sources: George, et al, NEJM, 2017; Simioni et al, NEJM, 2009). Researchers were able to vary FIX levels by modulating either the LNP or the AAV dose, and expression levels remained stable and ongoing in all cases throughout 12 weeks of observation.

This approach was repeated with Intellia’s wholly owned preclinical in vivo program in alpha-1 antitrypsin deficiency (AATD), another genetic disease of the liver associated with a mutation in the SERPINA1 gene that causes liver and lung dysfunction. Researchers used the LNP-AAV delivery combination of CRISPR/Cas9 components to insert donor template DNA encoding the SERPINA1 gene for AATD. The insertion resulted in blood protein levels in mice that corresponded to a range of SERPINA1 systemic levels required for normal lung function in humans.

Today’s presentation, titled "Supra-therapeutic levels of transgene expression achieved in vivo by CRISPR/Cas9 mediated targeted gene insertion," was made by Jonathan Finn, Ph.D., executive director, platform biology, Intellia. This presentation will be accessible through the Events and Presentations page of the Investor Relations section of Intellia’s website at www.intelliatx.com.

New Non-Human Primate Data from Intellia’s ATTR Program

Intellia also presented new data from non-human primate (NHP) studies in its transthyretin amyloidosis (ATTR) program further demonstrating a high correlation between liver editing and reduction of the transthyretin (TTR) protein. ATTR is a systemic, debilitating and fatal disease caused by one of approximately 136 different inherited mutations in the TTR gene. The company found that a liver editing rate of only ~35-40 percent in NHPs is needed to achieve a therapeutically meaningful reduction of TTR, specifically a TTR protein reduction of >60 percent. The data also demonstrated the transient nature of Intellia’s proprietary modular LNP delivery system, which was rapidly cleared from circulation, with all CRISPR/Cas9 components undetectable within five days of administration. Furthermore, rates of editing were durable over a six-month period without re-dosing the animals.

These data included results from ongoing collaborations with researchers at Regeneron and the University of Porto in Portugal, where ATTR is endemic in certain populations. Today’s presentation, titled "Delivering on the therapeutic potential of CRISPR/Cas9: Development of an LNP-mediated genome editing therapeutic for the treatment of ATTR," was made by Yong Chang, Ph.D., vice president, safety pharmacology, Intellia. This presentation will be accessible through the Events and Presentations page of the Investor Relations section of Intellia’s website at www.intelliatx.com.

Data Update from Intellia’s Acute Myeloid Leukemia Program

In a presentation titled "Hunting novel WT1-specific T cell receptors for immune gene therapy of acute myeloid leukemia," Intellia and its research collaborator, OSR, led by Chiara Bonini, M.D., Ph.D., deputy director of the Division of Immunology, Transplantation and Infectious Diseases at San Raffaele Hospital and University, shared an update on the company’s lead ex vivo program in acute myeloid leukemia (AML). Researchers presented in vitro data showing that CRISPR/Cas9 editing resulted in over 90 percent knockout of endogenous T cell receptors (TCRs). Subsequent transduction of Wilms’ Tumor 1 (WT1)-specific transgenic TCRs led to high expression of the inserted TCR with over 95 percent purity in isolated cytotoxic T cells (CD8+ T cells). T cells were fully functional and specifically killed leukemic blast cells that expressed the WT1 antigen and HLA-A*02:01 allele. Several additional TCRs directed to multiple WT1 epitopes and human leukocyte antigen (HLA) alleles are under investigation, including undergoing in vitro and in vivo functional testing.

Intellia and OSR are collaborating to develop best-in-class CRISPR-edited T cells directed to a specific epitope of WT1, a tumor-associated antigen overexpressed across a wide range of different tumor types and a known driver of leukocyte blasts in hematological cancers. Intellia’s first cell therapy tumor target is WT1 for the treatment of AML and other potential hematological malignancies, as well as for solid tumors.

Agios to Webcast Conference Call of Third Quarter 2018 Financial Results on November 1, 2018

On October 18, 2018 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that the company will host a conference call and live webcast on Thursday, November 1, 2018 at 8:00 a.m. ET to report its third quarter financial results and other business highlights (Press release, Agios Pharmaceuticals, OCT 18, 2018, http://investor.agios.com/news-releases/news-release-details/agios-webcast-conference-call-third-quarter-2018-financial [SID1234530260]).

A live webcast can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The conference call can be accessed by dialing 1-877-377-7098 (domestic) or 1-631-291-4547 (international) and referring to conference ID 5285068. The webcast will be archived and made available for replay on the company’s website beginning approximately two hours after the event

Daiichi Sankyo Initiates Phase 1 Study of AXL Inhibitor DS-1205 in Patients with EGFR-Mutated Metastatic Non-Small Cell Lung Cancer

On October 18, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the first patient has been dosed in a first-in-human phase 1 study assessing the safety and tolerability of DS-1205, a highly selective investigational AXL inhibitor, in combination with gefitinib in patients with metastatic or unresectable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who have progressed on therapy with tyrosine kinase inhibitors (TKIs) (Press release, Daiichi Sankyo, OCT 18, 2018, View Source [SID1234530247]).

For patients with metastatic EGFR-mutated NSCLC, targeted EGFR TKI therapies such as gefitinib, erlotinib, afatinib or osimertinib represent the first-line treatment of choice.3,4,5,6 However, patients eventually develop resistance to these treatments, typically experiencing disease progression within a year.3,4,5,6 Once a patient is resistant to all possible EGFR TKIs, there are limited treatment options, including chemotherapy, immunotherapy or investigational agents.3,6 Research suggests that inhibition of AXL, a receptor tyrosine kinase, may help delay or overcome the onset of resistance to the TKIs.1,2

"This first-in-human trial will build upon preclinical research to evaluate the potential of our AXL inhibitor, DS-1205, in combination with gefitinib in EGFR-mutated NSCLC that has progressed on TKI therapy," said Eric Slosberg, PhD, Head, Oncology Translational Development, Oncology Research and Development, Daiichi Sankyo. "We are evaluating for the first time in a clinical setting whether inhibition of the AXL pathway with DS-1205 may help prevent, delay or overcome the onset of resistance to EGFR TKIs, as we continue to research and develop new targeted therapy approaches for patients with metastatic NSCLC."

About the DS-1205 and Gefitinib Combination Study

The multicenter phase 1, open-label, two-part study will enroll patients with metastatic or unresectable EGFR-mutated NSCLC who have T790M mutation-negative tumors and have experienced disease progression during treatment with erlotinib, gefitinib or afatinib, or developed disease progression while on osimertinib. The first part of the study (dose escalation) will assess the safety, tolerability, pharmacokinetics and efficacy of DS-1205 in combination with gefitinib to determine the recommended dose for expansion. The second part of the study (dose expansion) will evaluate the safety, tolerability, pharmacokinetics and efficacy of the combination therapy. Study endpoints include safety, pharmacokinetics, objective response rate, duration of response, disease control rate, time to response, progression-free survival, overall survival and exploratory biomarker analyses. The study is expected to enroll approximately 60 patients at approximately 20 sites in Japan and other countries. For more information on the clinical trial, visit ClinicalTrials.gov.

Unmet Need in EGFR-Mutated Metastatic NSCLC

Lung cancer is the most common cancer in the world and the leading cause of cancer deaths.7, 8 There were approximately 1.8 million new cases of lung cancer reported globally and 1.69 million deaths from lung cancer in 2012.8 NSCLC is the most common form of lung cancer, accounting for approximately 80 to 85 percent of all cases. It is difficult to treat, particularly in advanced disease, and the five-year survival rate for metastatic NSCLC is only one percent.9

In the past decade, significant improvements in treatment have occurred due to the development of targeted therapies, such as EGFR TKIs, for advanced NSCLC.3 EGFR mutations have been reported in a wide range of NSCLC patients (from 10 to 50 percent), and frequency may vary based on ethnicity and other factors.3,10

While the majority of patients with EGFR-mutated tumors respond to EGFR TKIs, resistance eventually develops in more than half of these patients, and they typically experience disease progression within a year.11 Resistance may be acquired or intrinsic.3 The most common mechanism for acquired resistance to gefitinib, erlotinib or afatinib involves a secondary EGFR mutation called T790M, which may be treated with the EGFR TKI osimertinib.3,4,5,6 However, patients who experience disease progression following treatment with gefitinib, erlotinib or afatinib and whose tumors lack the T790M mutation, and patients who experience disease progression following osimertinib treatment have limited options such as chemotherapy, immunotherapy or investigational treatments.5,6

Researchers are exploring specific therapeutic strategies to overcome acquired resistance to EGFR TKIs.3 Studies have demonstrated that up-regulation of AXL, a receptor tyrosine kinase, may develop in some patients with EGFR-mutated NSCLC who experience disease progression on TKI therapy, and this up-regulation might be a mechanism of resistance to EGFR TKI treatment.11,12,13 Accordingly, inhibition of AXL might restore sensitivity to EGFR TKI treatment.11 While preclinical research has demonstrated that inhibition of AXL by DS-1205 restored sensitivity to erlotinib and the addition of DS-1205 to TKI therapy at the beginning of treatment delayed the onset of resistance to gefitinib, erlotinib or osimertinib, it is as yet to be confirmed that DS-1205 will work similarly in humans.1,2

Abnormal expression and activation of AXL have been correlated with poor prognosis, increased growth and metastasis, and drug resistance in many cancers including NSCLC.12,13

About DS-1205

Part of the investigational Breakthrough Science pipeline of Daiichi Sankyo Cancer Enterprise, DS-1205 is an investigational highly selective AXL inhibitor currently being evaluated in a phase 1 clinical study in combination with gefitinib for metastatic or unresectable EGFR-mutated NSCLC. DS-1205 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

Verastem Oncology Announces Executive Leadership Appointments and Changes

On October 18, 2018 Verastem, Inc. (Nasdaq: VSTM) (Verastem Oncology or the Company), focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, reported the appointment of Ironwood Pharmaceuticals, Inc.’s Chief Financial Officer Gina Consylman to its Board of Directors (Press release, Verastem, OCT 18, 2018, View Source;p=RssLanding&cat=news&id=2372372 [SID1234530233]). Ms. Consylman, who will also serve as the Chair of the Board’s Audit Committee, replaces Louise Phanstiel who is leaving the Board to pursue other professional opportunities.

In addition, Hagop Youssoufian, MSc, MD is transitioning to serve as Verastem Oncology’s Head of Medical Strategy from his prior role as Head of Hematology and Oncology Development. Dr. Youssoufian will be taking over responsibilities from Diep Le, MD, PhD who is stepping down as Chief Medical Officer. Kirk Taylor, MD has also joined the Company as Senior Vice President, Medical Affairs Strategy and Operations.

"We are delighted to have Gina and Kirk join the Verastem Oncology team as we enter this new period of growth with our first commercial product launch," said Robert Forrester, President and Chief Executive Officer of Verastem Oncology. "Gina brings a unique financial acumen to the Board of Directors with more than 25 years of experience in the fields of corporate finance, accounting and tax management for commercial-stage pharmaceutical companies, including organizations navigating through first commercial product launches. Kirk is an accomplished medical affairs executive and prior practicing clinician with vast experience leading global cross-functional teams and successfully bringing drug candidates and products to market. On behalf of the entire Board and management team, we sincerely welcome Gina and Kirk and look forward to their insights and contributions."

Mr. Forrester added, "Over the past several years, Hagop has played a pivotal role in the growth and success of Verastem Oncology and I have no doubt he will continue delivering successful results with distinction. The Board and I wish to express our gratitude to Louise and Diep for their outstanding contributions and service. They have each played important roles in building the Company into what we believe will be a successful commercial organization. We wish both Louise and Diep all the very best in their future endeavors."

"Verastem Oncology is entering an exciting new chapter and I am honored to join the Board of Directors to help the Company execute on its strategic and commercial corporate goals," said Ms. Consylman. "I believe the Company is well-positioned for the next stage of evolution with a robust commercialization plan to help address the significant unmet need for the patients and families suffering from hematological malignancies."

Ms. Consylman currently serves as Senior Vice President and Chief Financial Officer of Ironwood Pharmaceuticals, Inc., a commercial biotech company, where she oversees the finance, planning, accounting, tax, treasury and insurance functions. Prior to joining Ironwood, Gina was Vice President, Corporate Controller and Principal Accounting Officer of Analogic Corporation, a healthcare and security technology solutions company, where she led the company’s global accounting and treasury teams. Prior to Analogic, Gina held senior level accounting and corporate controller positions at Biogen Inc. and Varian Semiconductor Equipment Associates, Inc. (acquired by Applied Materials, Inc.). She began her career in public accounting at Ernst & Young LLP. Ms. Consylman holds a Bachelor of Science degree in accounting from Johnson & Wales University, a Master of Science degree in taxation from Bentley University, and is a Certified Public Accountant.

Dr. Taylor brings more than 21 years of pharmaceutical industry experience and 12 years in clinical practice to Verastem Oncology. He has led cross-functional teams as Chief Medical Officer and Senior Vice President, covering many parts of the world including the United States, Europe, Latin America, North America and Asia. Dr. Taylor has held executive leadership positions at Pfizer, Actelion, Biogen, Alzheon, Sanofi Genzyme, Prescient Medicine and Finch Therapeutics. Dr. Taylor specializes in late phase development and medical affairs. Dr. Taylor received his B.A. from Harvard University and his M.D. from SUNY Downstate. He completed his internship at Roosevelt Hospital Columbia University, his residency at the Albert Einstein College of Medicine, and a Post Doctorate at The University of California San Francisco, where he also served as a faculty member.

Covance and Definiens Collaborate to Integrate Digital Pathology into Precision Medicine Design and Development

On October 18, 2018 LabCorp (NYSE: LH), a leading global life sciences company, and Definiens, a pioneer in artificial intelligence (AI) based image analysis reported a strategic collaboration to improve global development of precision medicine (Press release, LabCorp, OCT 18, 2018, View Source;p=RssLanding&cat=news&id=2372210 [SID1234530176]). The collaboration, between Definiens and LabCorp’s Covance drug development business, will enable seamless integration of digital pathology with clinical-trial design and tissue-based testing solutions, resulting in a faster and more rigorous approach to biomarker validation and companion diagnostic co-development.

Companion diagnostics are used in conjunction with targeted drugs and therapies to identify patients who are likely to benefit from a specific treatment regimen or who may have increased risk for certain side effects. The companies expect the first application of these processes will be in oncology, particularly immuno-oncology.

LabCorp and Covance have been involved in the development of drugs and their associated companion diagnostics for more than 20 years and have supported approximately two-thirds of all FDA-approved companion diagnostics. Definiens leverages machine learning and deep-learning to comprehensively profile the tumor microenvironment and create unique patient phenotypic profiles. Its digital pathology applications enable biopharma companies to make more informed decisions regarding their oncology and immuno-oncology pipelines.

The collaboration will initially focus on multiplex immunohistochemistry (IHC) and in situ hybridization (ISH) applications in early-stage clinical programs, which allow researchers to obtain significantly more information from a single sample than with other standard methods. This approach is designed to enable the therapy to advance more quickly to pivotal clinical trial scale studies. Terms of the agreement have not been disclosed.

"This collaboration unites Definiens’ ground-breaking technology and innovation with Covance’s extensive experience in biomarker identification and companion diagnostics development," said John Ratliff, CEO, Covance. "Together, we can accelerate the pace of drug development, delivering the transformative potential of oncology therapies – and immuno-oncology in particular – to patients around the globe faster and more efficiently than ever before."

"Based on years of AI development, Definiens Tissue Phenomics is recognized as the premier technology for characterizing the tumor microenvironment for immuno-oncology applications," said Thomas Heydler, CEO, Definiens. "We are very excited to partner with Covance, the world leader in companion diagnostics, to demonstrate the power of Tissue Phenomics as an integral part of CDx development for clinical trials worldwide."