On February 10, 2020 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 that it is presenting new data from two of its development programs at Keystone Symposia’s Engineering the Genome Conference, a joint meeting with the Emerging Cellular Therapies: Cancer and Beyond Conference, taking place Feb. 8-12, 2020, in Banff, Canada (Press release, Intellia Therapeutics, FEB 10, 2020, View Source [SID1234554087]). Intellia researchers are presenting data in support of the company’s lead engineered cell therapy development candidate, NTLA-5001 for the treatment of the hematological cancer, acute myeloid leukemia (AML). Intellia also is sharing preclinical results for its hereditary angioedema (HAE) program, which is Intellia’s third CRISPR/Cas9 development program, announced in January 2020.

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"Intellia continues to demonstrate strong progress across both our engineered cell therapy and in vivo pipelines," said Intellia President and Chief Executive Officer John Leonard, M.D. "We are observing very favorable preclinical data with our engineered T cells, and we are moving ahead with IND-enabling studies and manufacturing for NTLA-5001, to enable a regulatory submission in the first half of 2021.

"On the in vivo side, the data from our HAE development program reinforce the modularity of Intellia’s non-viral delivery genome editing platform and how it is enabling independent, single-dose therapies for multiple monogenic diseases. For HAE, we expect to nominate a development candidate in the first half of this year," continued Dr. Leonard.

New Data from Intellia’s Engineered Cell Therapy Development Program for AML

NTLA-5001, which is Intellia’s first engineered T cell therapy development candidate and is wholly owned, utilizes a T cell receptor (TCR)-directed approach to target the Wilms’ Tumor 1 (WT1) intracellular antigen for the treatment of AML. The company’s WT1-TCR T cell approach aims to develop a broadly applicable treatment for AML patients, regardless of mutational background of a patient’s leukemia.

The company is presenting data demonstrating that the selection of a natural, high-affinity TCR, in combination with CRISPR-enabled engineering and targeted insertion, results in an engineered T cell capable of specific and potent killing of primary AML blasts. Today’s presentation at Keystone builds on data previously presented last fall at the Annual Congress of the European Society of Gene and Cell Therapy (ESGCT).

The data being presented at the Keystone conference substantiate the advantages that a homogeneous T cell product developed through CRISPR engineering, like NTLA-5001, may have over traditional T cell engineering approaches. In particular, traditional T cell engineering methods typically result in a T cell product that carries two different TCRs, one endogenous and one transferred, which can pair in various combinations of alpha and beta chains and form mixed TCRs with unknown specificities. Intellia researchers are sharing today that the precise replacement of the endogenous TCR with the transgenic TCR (tgTCR) resulted in T cells with improved tgTCR expression levels and in 95% of edited T cells carrying exclusively the desired pairs of the tgTCR alpha and beta chains. This therapeutic TCR profile is expected to yield improved T cell product homogeneity, as researchers showed that Intellia’s T cell editing approach results in superior function of the engineered T cells toward WT1-positive targets in vitro. This therapeutic TCR profile is also expected to result in lower reactivity against unwanted targets on normal tissues that could lead to toxicities, including graft-versus-host disease (GvHD).

Researchers identified that the selected lead WT1 TCR exhibits high avidity (in the nM range) to its target epitope and shows tight epitope specificity. Being a natural TCR isolated from a healthy donor, it may have a lower cross-reactivity risk than many affinity-matured TCRs. Cells engineered with Intellia’s lead WT1 TCR also demonstrated no detectable cytotoxicity toward bone marrow CD34+ cells, which express WT1 at low levels. This is an advantage over current CAR-T cell approaches targeting CD33 or CD123 in AML, which have been shown to induce severe bone marrow toxicity.

Furthermore, the data demonstrate that specific and potent killing of WT1-positive primary AML blasts result from T cells expressing Intellia’s lead WT1 TCR when cocultured in vitro. This outcome was observed across multiple patient samples that harbor the frequent HLA-A*02:01 allele and that express different WT1 levels as well as AML characteristics. These data validate that the epitope targeted by the lead WT1 TCR, which is distinct from a previously evaluated RMF epitope, is presented efficiently and broadly by AML tumor cells that carry the correct human leukocyte antigen (HLA) restriction. Intellia’s lead WT1 TCR also has the potential to target WT1-positive solid tumors, such as ovarian cancer, glioblastoma, lung cancer and mesothelioma.

The company plans to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) in the first half of 2021 for NTLA-5001 for the treatment of AML. Details on today’s presentations on WT1 TCR T cells, including data from ongoing collaborations with researchers at IRCCS Ospedale San Raffaele, Milan, at Keystone are as follows:

"Developing Next-Generation Engineered TCR-T Cells with CRISPR"
Presenter: Birgit Schultes, Ph.D., vice president, cell therapy, Intellia
Session: "Genome Editing as a Biology Discovery Tool"
Presentation date/time: Mon., Feb. 10, 2020, 8-11:15 a.m. MT
Location: Van Horne C

"Multiple Genome Editing of Early Differentiated T Cells for Cancer Immunotherapy"
Presenter: Chiara Bonini, M.D., Ph.D., deputy director of the Division of Immunology, Transplantation and Infectious Diseases at IRCCS Ospedale San Raffaele
Session: "Next Generation Immune Cell Engineering"
Presentation date/time: Mon., Feb. 10, 2020, 8-11:15 a.m. MT
Location: Van Horne A/B
First Data Presented on Potential CRISPR/Cas9-Based Therapy for HAE, Intellia’s Third Development Program

Researchers presented yesterday at the Keystone conference the company’s first dataset in support of Intellia’s development program for HAE. HAE is a rare genetic disorder characterized by recurring and unpredictable severe swelling attacks in various parts of the body, and is significantly debilitating or even fatal in certain cases. The disease is caused by increased levels of the bradykinin protein. Most patients with HAE have a C1 esterase inhibitor (C1-INH) protein deficiency, which normally prevents the unregulated release and buildup of bradykinin.

Intellia’s HAE treatment hypothesis involves knocking out the kallikrein B1 (KLKB1) gene to reduce kallikrein activity, which is involved in the biological pathway for release of bradykinin. Intellia expects this reduction to correlate with a decrease in bradykinin activity, thus, preventing the activation of endothelial cells that causes vascular leakage and angioedema in HAE patients. The data presented at the Keystone conference showed that the knockout of KLKB1 produces in non-human primates (NHPs) a 90% reduction in kallikrein activity, a level that translates to a therapeutically meaningful impact on HAE attack rates (Source: Banerji et al., NEJM, 2017). This kallikrein activity reduction was sustained for at least five months in an ongoing NHP study, in a highly reproducible manner observed across both rodent and NHP studies.

Similar to its lead in vivo program, for the treatment of transthyretin amyloidosis (ATTR), Intellia’s potential HAE therapy utilizes the company’s modular non-viral lipid nanoparticle (LNP) system to deliver CRISPR/Cas9. Intellia’s proprietary LNP-based delivery system includes two basic components: Cas9 messenger RNA (mRNA) and a guide RNA (gRNA). The gRNA is the only variable portion of the LNP delivery system and is the sole component that needs to be changed from the LNP-based delivery system that forms the foundation of NTLA-2001, Intellia’s development candidate for the treatment of ATTR for which the company intends to submit an IND application in mid-2020.

Intellia continues to evaluate several potential guide RNAs and expects to nominate a development candidate for HAE in the first half of 2020. Intellia’s KLKB1 HAE program is subject to an option by Regeneron to enter into a Co/Co agreement, in which Intellia would remain the lead party.

Yesterday’s short talk, titled "In Vivo Delivery of CRISPR/Cas9 to the Liver Using Lipid Nanoparticles Enables Gene Knockout Across Multiple Targets in Rodent and Non-Human Primates," was made by Jessica Seitzer, director, genomics, Intellia. These data included results from ongoing collaborations with researchers at Regeneron.