REGV131-LNP1265 / Intellia Therap, Regeneron - LARVOL DELTA

BEYOND-9: A Trial to Learn if REGV131-LNP1265 is Safe and Works to Help the Body Make Clotting Factor in Pediatric, Adolescent and Adult Patients With Hemophilia B (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Disorders • Hemophilia • Hemophilia B • Pediatrics • Rare Diseases

Trial-in-progress: A two-part open-label study of an in vivo CRISPR/Cas9-based coagulation factor IX targeted gene insertion therapy (REGV131-LNP1265), in participants with hemophilia B (BEYOND-9) (ISTH 2024) - "Study endpoints are outlined in Table 1. Conclusion(s) : Enrollment will commence in July 2024 with consent obtained from all participants. Following adult data review, pediatric expansion cohorts may open."

Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Pediatrics • Rare Diseases

BEYOND-9: A Trial to Learn if REGV131-LNP1265 is Safe and Works to Help the Body Make Clotting Factor in Pediatric, Adolescent and Adult Patients With Hemophilia B (clinicaltrials.gov) - P1/2 | N=130 | Not yet recruiting | Sponsor: Regeneron Pharmaceuticals

New P1/2 trial • Hematological Disorders • Hemophilia • Pediatrics • Rare Diseases

Molecular Characterization of CRISPR-Based Targeted Gene Insertion of Factor 9 as a Potential Treatment for Hemophilia B (ASGCT 2023) - "This will aid us in using this model for dose selection and gain mechanistic understanding of our platform. Our targeted gene insertion approach has the potential to become a durable solution to several monogenic diseases."

Hematological Disorders • Hemophilia • Rare Diseases

Targeted Gene Insertion of Factor 9 as a Potential Durable Treatment for Hemophilia B (ASGCT 2023) - "We are developing a suite of molecular tools to further monitor and characterize insertion products at the level of DNA, RNA, and protein. Our Factor 9 gene insertion program may represent a novel treatment for patients with hemophilia B and highlights the potential of our liver gene insertion platform technology to address a variety of indications that would benefit from durable gene replacement therapy."

Hematological Disorders • Hemophilia • Rare Diseases

Intellia Therapeutics Announces Third Quarter 2021 Financial Results and Highlights Recent Company Progress (GlobeNewswire) - "Intellia Therapeutics, Inc...today reported financial results for the third quarter ended September 30, 2021, and recent operational highlights....In the third quarter, Intellia and Regeneron nominated a Factor 9 (F9) gene insertion development candidate for its Hemophilia B (Hem B) program, leveraging their jointly developed targeted transgene insertion capabilities to insert F9. This candidate is part of a co-development/co-funding agreement between Intellia and Regeneron, the lead party for this program. F9 is a gene that encodes for Factor IX (FIX), a blood-clotting protein that is missing or defective in Hem B patients. In preclinical studies, the companies demonstrated the first CRISPR/Cas9-mediated targeted transgene insertion in the liver of NHPs, which resulted in circulating FIX levels at or above those found in normal human plasma."

Licensing / partnership • Preclinical • Genetic Disorders • Hemophilia

[VIRTUAL] DEVELOPMENT OF NTLA-2001, A CRISPR/CAS9 GENOME EDITING THERAPEUTIC FOR THE TREATMENT OF ATTR (ISOA 2020) - "One-time gene disruption of the TTR gene by CRISPR/Cas9-LNP resulted in durable and robust decrease in serum TTR protein levels in vivo. Favorable tolerability of the delivery system was aided by transient exposure to the CRISPR/Cas9 and LNP components. These findings show pharmacologic activity of TTR LNP and support further development of NTLA-2001 for the treatment for patients with ATTR polyneuropathy and/or cardiomyopathy."

Amyloidosis • Cardiomyopathy • Cardiovascular • Gastrointestinal Disorder • Pain

[VIRTUAL] DEVELOPING A HUMANIZED TRANSTHYRETIN MOUSE MODEL FOR THERAPEUTIC VALIDATION (ISOA 2020) - "We describe a second generation of humanization which should improve human protein expression. Finally, we demonstrate the utility of rationally designed mouse models to validate transthyretin as a potential target for CRISPR/Cas9 therapeutics."

Preclinical • Amyloidosis • Cardiovascular • Congestive Heart Failure • Heart Failure • Rare Diseases

[VIRTUAL] CRISPR-BASED REPLACEMENT OF THE ENDOGENOUS T-CELL REPERTOIRE WITH NOVEL, HIGH-AVIDITY, NATURAL T CELL RECEPTORS TO WT1 FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (EBMT 2021) - "With tailored, high precision CRISPR/Cas9 genome editing tools, we combined TCR targeted integration into the TRAC locus with TRBC knock-out, thus avoiding the risk of TCR mispairing and maximizing TCR expression and function... T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and potentially other WT1-expressing tumors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD4 • CD8 • IFNG • WT1

[VIRTUAL] CRISPR-BASED REPLACEMENT OF THE ENDOGENOUS T-CELL REPERTOIRE WITH NOVEL, HIGH-AVIDITY, NATURAL T CELL RECEPTORS TO WT1 FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (EBMT 2021) - "With tailored, high precision CRISPR/Cas9 genome editing tools, we combined TCR targeted integration into the TRAC locus with TRBC knock-out, thus avoiding the risk of TCR mispairing and maximizing TCR expression and function... T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and potentially other WT1-expressing tumors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD4 • CD8 • IFNG • WT1

[VIRTUAL] CRISPR-BASED REPLACEMENT OF THE ENDOGENOUS T-CELL REPERTOIRE WITH NOVEL, HIGH-AVIDITY, NATURAL T CELL RECEPTORS TO WT1 FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (EBMT 2021) - "With tailored, high precision CRISPR/Cas9 genome editing tools, we combined TCR targeted integration into the TRAC locus with TRBC knock-out, thus avoiding the risk of TCR mispairing and maximizing TCR expression and function... T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and potentially other WT1-expressing tumors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD4 • CD8 • IFNG • WT1

[VIRTUAL] CRISPR-BASED REPLACEMENT OF THE ENDOGENOUS T-CELL REPERTOIRE WITH NOVEL, HIGH-AVIDITY, NATURAL T CELL RECEPTORS TO WT1 FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA (EBMT 2021) - "With tailored, high precision CRISPR/Cas9 genome editing tools, we combined TCR targeted integration into the TRAC locus with TRBC knock-out, thus avoiding the risk of TCR mispairing and maximizing TCR expression and function... T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and potentially other WT1-expressing tumors."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD4 • CD8 • IFNG • WT1

[VIRTUAL] NTLA-2002: CRISPR/Cas9-mediated gene knockout of KLKB1 to treat hereditary angioedema (AAAAI 2021) - "KLKB1 gene editing, plasma kallikrein concentration and activity, and vascular leakage were evaluated.  Results In the huKLKB1 mouse, a single administration of NTLA-2002 resulted in robust KLKB1 gene editing (∼70%), subsequent reductions in total plasma kallikrein (>90%) and abrogation of captopril-induced vascular leakage . In the monkey, a single administration of cyno-specific LNP formulation resulted in robust gene editing (∼70%) and reductions in both total kallikrein protein and activity (>95%) . Further, these reductions have been maintained for at least 15 months in an ongoing monkey study.  Conclusions A single administration of NTLA-2002 resulted in robust, durable reduction of kallikrein protein and activity, supporting further development as a potential one-time treatment option for patients with HAE."

Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Intellia Therapeutics Achieves Normal Human Alpha-1 Antitrypsin Protein Levels in Non-Human Primates Through Targeted Gene Insertion for the Treatment of AAT Deficiency (GlobeNewswire) - "Single-course administration of genome editing system provides potentially curative approach to AAT deficiency; Intellia Therapeutics, Inc....is presenting the first demonstration of physiological protein levels of human alpha-1 antitrypsin...The company is presenting these data today at the Alpha-1 Foundation’s 20th Gordon L. Snider Critical Issues Workshop...The normal human AAT protein levels Intellia achieved following targeted insertion of the human SERPINA1 gene remained stable through 11 weeks in an ongoing NHP study. The observed levels of human AAT protein produced from the liver may be therapeutically sufficient to restore protease inhibition..."

Preclinical • Alpha-1 Antitrypsin Deficiency

[VIRTUAL] NTLA5001, a T Cell Product Candidate with CRISPR-Based Targeted Insertion of a High-Avidity, Natural, WT1-Specific TCR, Shows Efficacy in In Vivo Models of AML and ALL (ASH 2020) - "This can be achieved with CRISPR/Cas9-mediated replacement of the endogenous TCR α and β chains, by knocking out the TRAC and TRBC genes and inserting the tgTCR into the TRAC locus. NTLA-5001 is being advanced into clinical development for AML immunotherapy. Given the expression of WT1 in many solid tumors, engineered WT1 TCR-T cells are being further explored in those indications."

IO Biomarker • Preclinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Oncology • Solid Tumor • Wilms Tumor • CD8 • IL15 • WT1

Intellia Therapeutics Receives Grant to Develop Curative CRISPR/Cas9 In Vivo Sickle Cell Disease Treatments (GlobeNewswire) - "Intellia Therapeutics...announced that it has received a grant from the Bill & Melinda Gates Foundation to research in vivo sickle cell disease (SCD) treatments using its CRISPR/Cas9 genome editing technology. This pilot development program is part of the Gates Foundation’s broader initiative to accelerate the advancement of safe, effective and durable gene-based cures in developing countries within the next seven to 10 years."

Financing • Sickle Cell Disease

Intellia Therapeutics, Inc. (NTLA) Q3 2020 Earnings Call Transcript (The Motley Fool) - "We've presented some data with respect to Alpha-1 in Murine models. And it's an area of active investigation for us thinking about how well we can express human proteins of interest in other targets, including Alpha-1 antitrypsin. So, this is an area that I would encourage you to stay tuned with."

Preclinical • Alpha-1 Antitrypsin Deficiency

Intellia Therapeutics (NTLA) Presents New Preclinical Data Showing Persistent In Vivo Editing and Durability of Effect Following CRISPR/Cas9-Based Treatment (Streetinsider.com) - "These data will be included in the company’s invited talk at this year’s 16th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), taking place virtually from September 27-30, 2020....Intellia will present additional data highlighting the potential of its liver insertion platform, as exemplified by the company’s hemophilia B program....Data shows the company achieved circulating activity levels for Factor IX (FIX), a blood-clotting protein that is missing or defective in hemophilia B patients, ranging from normal levels (50-150%...) to supratherapeutic levels in a six-week non-human primate study."

Preclinical • Hemophilia

Exploiting CRISPR-Genome Editing and WT1-Specific T Cell Receptors to Redirect T Lymphocytes Against Acute Myeloid Leukemia (ASGCT 2020) - "Upon simultaneous disruption of the endogenous TCR α and β chains using CRISPR/Cas9 technology (knock-out efficiency >98%), we efficiently introduced WT1-specific TCR into T cells either by random integration into the genome using lentiviral vector (LV) transduction or by exploiting targeted integration into the TCR α-chain locus using an adeno-associated vector (AAV)...Throughout the study, mice showed no signs of GvHD. In conclusion, we demonstrated that TCR-edited T cells can be effectively used to target WT1-expressing tumor cells in AML."

IO Biomarker • CASP3

"#IntelliaTherapeutics Reports Progress on #CRISPR/#Cas9 #AML #CancerTherapy Using Proprietary #CellEngineering Process at #ASGCT20 $NTLA https://t.co/8YPw22zZP1" (@1stOncology)

Oncology

FDA Accepts Investigational New Drug Application for CRISPR/Cas9-Based Sickle Cell Disease Therapeutic Candidate Developed Under Collaboration with Intellia Therapeutics (GlobeNewswire, Intellia Therapeutics, Inc.) - "Intellia Therapeutics...announced that the U.S. Food and Drug Administration (FDA) has accepted the Investigational New Drug (IND) application submitted by its collaborator, Novartis, for a CRISPR/Cas9-based engineered cell therapy for the treatment of sickle cell disease (SCD). This Phase 1/2 clinical trial will begin investigating OTQ923 in adult patients with severe complications of SCD. OTQ923 is a SCD treatment based on genome editing of hematopoietic stem cells (HSCs), using CRISPR/Cas9 RNA guides identified through Intellia’s cell therapy research collaboration with Novartis."

IND • New P1/2 trial

Intellia Therapeutics Announces Fourth Quarter and Full-Year 2019 Financial Results (GlobeNewswire, Intellia Therapeutics, Inc.) - "Additionally, Intellia presented the first demonstration of a consecutive in vivo gene knockout followed by a targeted insertion in an alpha-1 antitrypsin deficiency (AATD) mouse model....The Company continues to advance these platform capabilities and leverage them to develop the next wave of in vivo and ex vivo clinical candidates."

Pipeline update • Preclinical

GENERATION OF A LIBRARY OF WT1-SPECIFIC T-CELL RECEPTORS (TCR) FOR CRISPR-EDITED TRANSGENIC TCR T-CELL THERAPY WITH ACTIVITY AGAINST ACUTE MYELOID LEUKEMIA (EBMT 2020) - "Simultaneous editing of the endogenous TCR α and β chains using CRISPR/Cas9 technology (knock-out efficiency >90%), followed by transduction of T-cells with a lentiviral vector encoding the WT1-specific TCR (initially focusing on the most common HLA class I alleles), led to the expression of the inserted TCR in >95% of CD8+T-lymphocytes. In summary, we established a protocol enabling consistent and efficient tumor-specific TCR hunting, identification and characterization. TCR genes can be easily and rapidly used to redirect T-cell specificity against cancer cells by TCR gene editing."

IO Biomarker • CASP3 • CD8 • IFNG

Intellia Therapeutics presents in vivo and ex vivo data at the 2019 Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) (GlobeNewswire) - "Intellia Therapeutics...is presenting one oral presentation and four poster presentations at the 27th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) meeting taking place October 22-25, 2019, in Barcelona, Spain....Intellia Demonstrates Consecutive In Vivo Genome Editing in Alpha-1 Antitrypsin Deficiency Mouse Model..."

Preclinical

Intellia Therapeutics announces presentations at the 2019 Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) (BioSpace) - "Intellia Therapeutics...announced one oral presentation and four poster presentations were accepted for the 27th Annual Congress of the European Society of Gene and Cell Therapy (ESGCT) taking place October 22-25, 2019, in Barcelona, Spain."

Preclinical