On November 9, 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 third quarter ended September 30, 2023 (Press release, Intellia, NOV 9, 2023, View Source [SID1234637375]).

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"2023 has been a year of remarkable progress in which Intellia received two IND clearances for investigational in vivo CRISPR therapies. With the imminent start of the NTLA-2001 MAGNITUDE Phase 3 trial, Intellia has now become a late-stage drug development company," said Intellia President and Chief Executive Officer John Leonard, M.D. "Looking ahead, we expect to achieve several notable milestones in the coming weeks and months, including completing enrollment of the NTLA-2002 Phase 2 study in people with hereditary angioedema and submitting a regulatory filing to begin clinical development for NTLA-3001, our in vivo gene insertion program for people living with alpha-1 antitrypsin deficiency. We look forward to advancing our pipeline and platform as we move closer to realizing the potential of CRISPR-based medicines."

Third Quarter 2023 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.
ATTR Amyloidosis with Cardiomyopathy (ATTR-CM):
The Company announced in October that the U.S. Food and Drug Administration (FDA) cleared the NTLA-2001 Phase 3 Investigational New Drug (IND) application for the treatment of ATTR-CM. The MAGNITUDE pivotal Phase 3 trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of NTLA-2001 in approximately 765 patients with ATTR-CM. The primary endpoint of the study is a composite endpoint of cardiovascular (CV)-related mortality and CV-related events. Patients will be randomized 2:1 NTLA-2001:placebo, with a single 55 mg infusion of NTLA-2001 administered. The Company expects to initiate the study by year-end with patient dosing to commence early 2024.
Hereditary ATTR Amyloidosis with Polyneuropathy (ATTRv-PN):
The Company is actively preparing for a global pivotal Phase 3 study of NTLA-2001 for the treatment of ATTRv-PN, including discussions with regulatory authorities.
Updated Data from NTLA-2001 Phase 1 Study
In November, Intellia announced new positive interim results from the Phase 1 study of NTLA-2001. Updated data from over 60 patients showed consistent, deep and durable serum TTR reduction achieved with a single dose of NTLA-2001, including 29 patients who reached 12 months or more of follow-up as of the data cut-off date of May 11, 2023. Across all patients who received a dose of 0.3 mg/kg or higher (n=62), the median serum TTR reduction was 91% and the median absolute residual serum TTR concentration was 17 µg/mL at day 28. Across all patients and at all dose levels tested, NTLA-2001 was generally well tolerated, and the majority of adverse events were mild in severity. These interim data were presented at the 4th International ATTR Amyloidosis Meeting, held in Madrid, Spain.
Hereditary Angioedema (HAE)

NTLA-2002: NTLA-2002 is a wholly owned, in vivo, systemically delivered investigational CRISPR-based therapy. 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.
In October, Intellia announced that the European Medicines Agency (EMA) granted Priority Medicine (PRIME) designation to NTLA-2002 for the treatment of HAE. PRIME designation is granted by the EMA to drug candidates that may offer a major therapeutic advantage over existing treatments or that benefit patients without treatment options.
Following the identification of all patients, Intellia is on track to complete enrollment in the Phase 2 portion of the Phase 1/2 study in Q4 2023.
Intellia plans to initiate the global pivotal Phase 3 study, including U.S. patients, as early as the third quarter of 2024, subject to regulatory feedback.
Alpha-1 Antitrypsin Deficiency (AATD)

NTLA-3001 for AATD-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 plans to submit a Clinical Trial Application (CTA) in Q1 2024 to initiate a first-in-human, Phase 1 study of NTLA-3001.
NTLA-2003 for AATD-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.
Based on a prioritization of resources, the Company is making a strategic shift to halt further IND-enabling activities for NTLA-2003 to advance an AATD research-stage program leveraging the Company’s DNA writing technology.
Ex Vivo Program Updates

Intellia is advancing multiple preclinical 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.
Platform and Pipeline Expansion

As Intellia’s DNA writing technology has met key internal research milestones, the Company will now prioritize the advancement of a research-stage program for the treatment of AATD.
In October, Intellia and Regeneron announced an expanded research collaboration to develop additional in vivo CRISPR-based gene editing therapies focused on neurological and muscular diseases. The collaboration will leverage Regeneron’s proprietary antibody-targeted adeno-associated virus (AAV) vectors and delivery systems and Intellia’s proprietary Nme2 CRISPR/Cas9 (Nme2Cas9) systems adapted for viral vector delivery and designed to precisely modify a target gene.
Additionally, Regeneron has exercised its option to extend the existing technology collaboration term with Intellia for two years. The technology collaboration term now extends to April 2026, and Intellia will receive a $30 million payment in the first half of 2024.
In September, SparingVision announced that it had selected a second target as part of its strategic collaboration with Intellia to develop novel genomic medicines, utilizing CRISPR-based gene editing technologies for the treatment of ocular diseases.
Upcoming Event

The Company will participate in the Jefferies London Healthcare Conference, taking place November 14-16 in London.

Upcoming Milestones

The Company has set forth the following expected milestones for pipeline progression:

NTLA-2001 for ATTR amyloidosis:
Initiate a global pivotal study for NTLA-2001 for ATTR-CM by year-end 2023.
Prepare for a Phase 3 study of NTLA-2001 for the treatment of ATTRv-PN, including discussions with regulatory authorities.
NTLA-2002 for HAE:
Complete enrollment in the Phase 2 portion of the Phase 1/2 study in Q4 2023.
NTLA-3001 for AATD:
Submit a CTA application for NTLA-3001 for AATD-associated lung disease in Q1 2024.
Platform Innovation:
Advance novel gene editing technologies, including DNA writing and delivery to other tissues outside of the liver.
Third Quarter 2023 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $992.5 million as of September 30, 2023, compared to $1.3 billion as of December 31, 2022. The decrease was driven by cash used to fund operations of $343.2 million. The decrease was offset in part by $37.4 million of interest income, $12.6 million of reimbursement from its collaborators, $16.2 million of net equity proceeds from the Company’s "At the Market" (ATM) program and $7.7 million in proceeds from employee-based stock plans.
Collaboration Revenue: Collaboration revenue decreased by $1.3 million to $12.0 million during the third quarter of 2023, compared to $13.3 million during the third quarter of 2022.
R&D Expenses: Research and development expenses increased by $17.0 million to $113.7 million during the third quarter of 2023, compared to $96.7 million during the third quarter of 2022. This increase was primarily driven by the advancement of our lead programs and personnel growth to support these programs. Stock-based compensation expense included in research and development expenses was $21.2 million for the third quarter of 2023.
G&A Expenses: General and administrative expenses increased by $7.3 million to $29.4 million during the third quarter of 2023, compared to $22.1 million during the third quarter of 2022. This increase was primarily related to an increase in stock-based compensation of $5.3 million. Stock-based compensation expense included in general and administrative expenses was $14.1 million for the third quarter of 2023.
Net Loss: The Company’s net loss was $122.2 million for the third quarter of 2023, compared to $113.2 million during the third quarter of 2022.
Conference Call to Discuss Third Quarter 2023 Results

The Company will discuss these results on a conference call today, Thursday, November 9 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 November 9 at 12 p.m. ET.