On February 23, 2023 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage genome editing company focused on developing potentially curative therapies leveraging CRISPR-based technologies, reported operational highlights and financial results for the fourth quarter and year ended December 31, 2022 (Press release, Intellia, FEB 23, 2023, View Source [SID1234627616]).

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"Intellia has hit the ground running with multiple milestones already achieved in early 2023. In addition to recently initiating the global Phase 2 study of NTLA-2002 outside of the U.S., we have also submitted an IND application to enable inclusion of patients in the U.S.," said Intellia President and Chief Executive Officer John Leonard, M.D. "As we look ahead, we are poised to submit an IND application for NTLA-2001 and initiate a global pivotal trial for the cardiomyopathy manifestation of ATTR amyloidosis. Additionally, we look forward to presenting new and important clinical data from the ongoing Phase 1 study, which builds on the growing body of data that support NTLA-2001’s potential to transform the ATTR amyloidosis treatment landscape for patients with cardiomyopathy or polyneuropathy. In parallel, we are advancing NTLA-3001, our first wholly owned in vivo gene insertion candidate, which may normalize levels of the missing protein in patients with alpha-1 antitrypsin deficiency. Together, we believe these efforts move us closer to setting a new standard of care for people living with serious diseases and expanding Intellia’s impact as the leading genome editing company."

Fourth Quarter 2022 and Recent Operational Highlights

In Vivo Program Updates

Transthyretin (ATTR) Amyloidosis

NTLA-2001: NTLA-2001 is an in vivo, systemically delivered investigational CRISPR-based therapy designed to inactivate the TTR gene in liver cells and thereby prevent the production of transthyretin (TTR) protein for the treatment of ATTR amyloidosis. NTLA-2001 offers the possibility of halting and reversing the disease by driving a deep, consistent and potentially lifelong reduction in TTR protein after a single dose. NTLA-2001 is subject to a co-development/co-promotion agreement between Intellia, the lead party for this program, and Regeneron Pharmaceuticals, Inc.
ATTR Amyloidosis with Cardiomyopathy (ATTR-CM):
Intellia announced in November 2022 positive interim results from the cardiomyopathy arm of the ongoing Phase 1 clinical trial of NTLA-2001 at the American Heart Association (AHA) Scientific Sessions 2022 held in Chicago, Illinois. The interim data from the dose-escalation portion of the study included 12 adult patients with ATTR-CM with New York Heart Association (NYHA) Class I – III heart failure. Single doses of 0.7 mg/kg and 1.0 mg/kg of NTLA-2001 led to greater than 90% mean serum TTR reductions. These deep reductions in serum TTR were sustained through the observation period, with patient follow-up ranging from four to six months. At both dose levels, NTLA-2001 was generally well-tolerated. One patient in the 0.7 mg/kg dose NYHA Class III cohort experienced a Grade 3 infusion-related reaction, which resolved without clinical sequalae. No clinically significant laboratory abnormalities were observed at either dose level.
In December 2022, the planned enrollment of the dose-expansion portion of the ATTR-CM arm was completed to support a U.S. Investigational New Drug (IND) application submission for the pivotal study. The Company anticipates submitting an IND application in mid-2023 and initiating a global pivotal trial for ATTR-CM by year-end 2023, subject to regulatory feedback.
The Company plans to present additional data from the ATTR-CM arm of the Phase 1 study in 2023, including longer-term safety and durability data, as well as emerging clinical endpoints.
Hereditary ATTR Amyloidosis with Polyneuropathy (ATTRv-PN):
During the first quarter of 2023, the planned enrollment of the dose-expansion portion of the ATTRv-PN arm in the Phase 1 study was completed to inform a pivotal study. The Company is preparing for a global pivotal study, which will include discussions with regulatory authorities.
The Company plans to present additional clinical data from the ATTRv-PN arm of the Phase 1 study in 2023.
Hereditary Angioedema (HAE)

NTLA-2002: NTLA-2002 is designed to knock out the KLKB1 gene in the liver, with the potential to permanently reduce total plasma kallikrein protein and activity, a key mediator of HAE. This investigational approach aims to prevent attacks for people living with HAE by providing continuous reduction of plasma kallikrein activity, following a single dose. It also aims to eliminate the significant treatment burden associated with currently available HAE therapies. NTLA-2002 is being evaluated in a Phase 1/2 study in adults with Type I or Type II HAE.
Intellia announced in November 2022 positive interim results from an ongoing Phase 1/2 clinical study of NTLA-2002 at the American College of Allergy, Asthma & Immunology (ACAAI) 2022 Annual Scientific Meeting held in Louisville, Kentucky. The data presented were from 10 adult patients with HAE in the Phase 1, dose-escalation portion of the study. Single doses of 25 mg (n=3), 50 mg (n=4) and 75 mg (n=3) of NTLA-2002 were administered via intravenous infusion, which led to deep, dose-dependent reductions in plasma kallikrein. All patients treated in the 25 mg and 75 mg cohorts, who completed the pre-specified 16-week observation period, maintained an attack-free status through the data cut-off date (patient follow-up ranged from 2.3 to 10.6 months). Patients in the 50 mg cohort had not completed the primary 16-week observation period. At all three dose levels, NTLA-2002 was generally well-tolerated, and the majority of adverse events were mild in severity. No clinically significant laboratory abnormalities were observed.
In January 2023, Intellia was awarded the Innovation Passport for NTLA-2002 by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA). The Innovation Passport is the point of entry into the U.K.’s Innovative Licensing and Access Pathway (ILAP), which is designed to accelerate time to market and facilitate patient access to innovative medicines.
Intellia announced today the initiation of patient screening in the Phase 2 portion of the Phase 1/2 of NTLA-2002 in New Zealand. The Company has selected 25 mg and 50 mg as the two, single dose levels for further evaluation in the randomized, placebo-controlled study.
Intellia announced today the Company recently submitted an IND application for NTLA-2002 to the U.S. Food and Drug Administration (FDA) to support the inclusion of U.S. sites in the Phase 2 portion of the study.
The Company plans to present additional clinical data from the Phase 1 portion of the first-in-human study in 2023, including safety, durability and attack-rate data across all three cohorts.
Alpha-1 Antitrypsin Deficiency (AATD)

NTLA-3001 for Associated Lung Disease: NTLA-3001 is a wholly owned, first-in-class CRISPR-mediated in vivo targeted gene insertion development candidate for the treatment of AATD-associated lung disease. It is designed to precisely insert a healthy copy of the SERPINA1 gene, which encodes the alpha-1 antitrypsin (A1AT) protein, with the potential to restore permanent expression of functional A1AT protein to therapeutic levels after a single dose. This approach seeks to improve patient outcomes, including eliminating the need for weekly intravenous infusions of A1AT augmentation therapy or lung transplant in severe cases.
Intellia is conducting IND-enabling activities for NTLA-3001 and plans to submit an IND or IND-equivalent filing in 2H 2023.
NTLA-2003 for Associated Liver Disease: NTLA-2003 is a wholly owned, in vivo knockout development candidate for the treatment of AATD-associated liver disease. It is designed to inactivate the SERPINA1 gene responsible for the production of abnormal A1AT protein in the liver. This approach aims to halt the progression of liver disease and eliminate the need for liver transplant in severe cases.
Intellia is conducting IND-enabling activities for NTLA-2003, with the expectation of completing these activities by year-end 2023.
Ex Vivo Program Updates

Immuno-oncology and Autoimmune Diseases

Intellia is advancing multiple programs, wholly owned and in collaboration with partners, utilizing its allogeneic platform for the treatment of immuno-oncology and autoimmune diseases. The Company’s proprietary allogeneic cell engineering platform is designed to avoid both T cell- and NK cell-mediated rejection, a key unsolved challenge with other investigational allogeneic approaches.
NTLA-6001 for CD30+ Lymphomas: Intellia is identifying collaboration opportunities to advance the development of a wholly owned, allogeneic CAR-T development candidate targeting CD30.
Research and Corporate Updates

Modular Platform and Pipeline Expansion: Intellia is expanding its industry-leading genome editing platform and scientific leadership through editing, delivery and cell engineering innovations that may enable broader in vivo and ex vivo applications.
In January 2023, Intellia achieved a research milestone with its DNA writing technology. A $25.0 million milestone payment was made to shareholders of Rewrite Therapeutics in February 2023.
Sickle Cell Disease (SCD) Program Updates:
Intellia’s SCD Research Efforts: Intellia is focused on developing an in vivo editing approach for the treatment of SCD to avoid the need for bone marrow transplantation. This is a wholly owned program currently in preclinical development.
Novartis’ SCD Program: In February 2023, Novartis opted to discontinue the development of its autologous, ex vivo, CRISPR-edited hematopoietic stem cell (HSC) program targeting fetal hemoglobin (HbF) for the treatment of SCD.
Upcoming Events

The Company will participate in the following events during the first quarter of 2023:

Cowen 43rd Annual Health Care Conference, March 6, Boston
Barclays Global Healthcare Conference, March 14, Miami
Upcoming Milestones

The Company has set forth the following for pipeline progression:

NTLA-2001 for ATTR amyloidosis:
Submit an IND application in mid-2023 to enable inclusion of U.S. sites in a pivotal study of NTLA-2001 for patients with ATTR-CM.
Present additional clinical data from the ongoing Phase 1 study of NTLA-2001 in 2023.
Initiate a global pivotal NTLA-2001 trial for ATTR-CM by year-end 2023, subject to regulatory feedback.
Prepare for a Phase 3 study of NTLA-2001 for the treatment of ATTRv-PN, including discussions with regulatory authorities.
NTLA-2002 for HAE:
Present additional clinical data from the ongoing first-in-human study of NTLA-2002 in 2023.
AATD Franchise:
Submit an IND or IND-equivalent application for NTLA-3001 for AATD-associated lung disease in 2H 2023.
Complete IND-enabling activities for NTLA-2003 for AATD-associated liver disease by year-end 2023.
Platform Innovation

Advance novel gene editing technologies, including DNA writing, and delivery to other tissues outside of the liver.
Fourth Quarter and Full-Year 2022 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $1.3 billion as of December 31, 2022, compared to $1.1 billion as of December 31, 2021. The increase was driven by $337.9 million from a follow-on offering in the fourth quarter of 2022, $227.9 million of net proceeds from the Company’s "At the Market" (ATM) program and $17.2 million in proceeds from employee-based stock plans. The increase was offset in part by cash used to fund operations of approximately $372.8 million and the acquisition of Rewrite for $45.0 million.
Collaboration Revenue: Collaboration revenue increased by $0.7 million to $13.6 million during the fourth quarter of 2022, compared to $12.9 million during the fourth quarter of 2021.
R&D Expenses: Research and development expenses increased by approximately $28.9 million to $100.0 million during the fourth quarter of 2022, compared to $71.2 million during the fourth quarter of 2021. This increase was primarily driven by the advancement of our lead programs and personnel growth to support these programs.
G&A Expenses: General and administrative expenses increased by $1.5 million to $23.6 million during the fourth quarter of 2022, compared to $22.1 million during the fourth quarter of 2021. This increase was primarily related to an increase in stock-based compensation of $2.6 million, offset in part by a decrease in legal expenses of $0.9 million.
Net Loss: The Company’s net loss was $113.4 million for the fourth quarter of 2022, compared to $81.2 million during the fourth quarter of 2021.
Conference Call to Discuss Fourth Quarter and Full-Year 2022 Results

The Company will discuss these results on a conference call today, Thursday, February 23, at 8 a.m. ET.

To join the call:

U.S. callers should dial 1-833-316-0545 and international callers should dial 1-412-317-5726, approximately five minutes before the call. All participants should ask to be connected to the Intellia Therapeutics conference call.
Please visit this link for a simultaneous live webcast of the call.
A replay of the call will be available through the Events and Presentations page of the Investors & Media section on Intellia’s website at intelliatx.com, beginning on February 23, at 12 p.m. ET.