On November 3, 2022 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, 2022 (Press release, Intellia, NOV 3, 2022, View Source [SID1234623002]).

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"During the most recent quarter, Intellia achieved significant clinical milestones across two landmark first-in-human studies," said Intellia President and Chief Executive Officer John Leonard, M.D. "We believe the latest data from our lead in vivo program, NTLA-2001, indicate it has the potential to set a new standard for how people living with ATTR amyloidosis are treated for this life-threatening disease. We are rapidly completing the dose-expansion portion of the study and are engaging with regulatory agencies, including in the U.S., as we move closer to a global, pivotal trial. Interim data from our second in vivo program, NTLA-2002, demonstrated robust reductions in both plasma kallikrein levels and the rate of swelling attacks in patients with hereditary angioedema. These initial data support the potential for a single dose of NTLA-2002 to permanently prevent the debilitating and potentially fatal HAE attacks that characterize this lifelong genetic disease. We look forward to presenting additional data from both NTLA-2001 and NTLA-2002 later this month."

Dr. Leonard continued, "Together, these interim datasets demonstrate the modularity of our CRISPR-based platform, providing powerful evidence of our ability to apply this technology broadly to address a wide range of diseases. Beyond gene knockout programs, we are advancing our first in vivo insertion candidate, NTLA-3001 for the treatment of alpha-1 antitrypsin deficiency, with plans to submit a regulatory filing next year."

Third Quarter 2022 and Recent Operational Highlights

In Vivo Program Updates

Transthyretin (ATTR) Amyloidosis

NTLA-2001: NTLA-2001 is the first investigational CRISPR-based therapy to be systemically delivered to edit genes inside the human body and has the potential to be the first single-dose treatment for ATTR amyloidosis. Delivered with the Company’s in vivo lipid nanoparticle (LNP) technology, NTLA-2001 offers the possibility of halting and reversing the disease by driving a deep, potentially lifelong reduction in transthyretin (TTR) protein after a single dose. NTLA-2001 is being evaluated in a Phase 1, two-part, open-label study in adults with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) or transthyretin amyloidosis with cardiomyopathy (ATTR-CM). NTLA-2001 is subject to a co-development/co-promotion agreement between Intellia, the lead party for this program, and Regeneron Pharmaceuticals, Inc.
ATTR-CM arm: Intellia announced in September positive interim results from the cardiomyopathy arm of the ongoing Phase 1 clinical trial of NTLA-2001. The interim data were from 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 were administered via intravenous infusion, and the change from baseline in serum TTR protein concentration was measured for each patient. These data showed deep and sustained mean serum TTR reductions of 93% and 92% at the 0.7 mg/kg and 1.0 mg/kg doses, respectively, at day 28. At both dose levels, NTLA-2001 was generally well-tolerated. Two of 12 patients reported transient infusion reactions, which was the only observed treatment-related adverse event. One patient in the 0.7 mg/kg dose NYHA Class III cohort experienced a Grade 3 infusion-related reaction, which resolved without clinical consequence. No clinically significant laboratory abnormalities were observed at either dose level. These data support NTLA-2001’s potential as a one-time treatment to permanently inactivate the TTR gene and reduce the disease-causing protein in people with ATTR-CM.
Intellia initiated dosing at a 55 mg dose, the fixed dose corresponding to 0.7 mg/kg, in Part 2, the dose-expansion portion of the study. The Company remains on track to complete, by the end of this year, planned enrollment of both arms of the Phase 1 study that will inform the dose selection for subsequent pivotal studies.
Intellia will be presenting interim clinical data from the cardiomyopathy arm in a Late-Breaking Science session on November 5, 2022, at this year’s American Heart Association (AHA) Scientific Sessions, taking place in Chicago, Illinois.
Hereditary Angioedema (HAE)

NTLA-2002: NTLA-2002 leverages Intellia’s proprietary in vivo LNP delivery technology 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, and 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 September positive interim results from an ongoing Phase 1/2 clinical study of NTLA-2002, its second in vivo genome editing candidate, at the 2022 Bradykinin Symposium held in Berlin, Germany. Administration of single doses of NTLA-2002 led to dose-dependent reductions in plasma kallikrein, with mean reductions of 65% and 92% in the 25 mg (n=3) and 75 mg (n=3) dose cohorts, respectively, by week eight. In addition to plasma kallikrein levels, HAE attack rates are also being measured in the study, with the first analysis occurring at the end of the pre-specified 16-week primary observation period. A single dose of 25 mg of NTLA-2002 resulted in a 91% mean reduction in HAE attacks through the 16-week observation period. Additionally, two of the three patients have not had a single HAE attack since treatment, and all three patients have been attack-free since week 10 (based on follow-up through weeks 24 – 32). Patients in the 75 mg cohort had not completed the primary 16-week observation period. At both dose levels, NTLA-2002 was generally well-tolerated, and the majority of adverse events were mild in severity.
Intellia will be presenting additional data at the American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting, taking place November 10 – 14 in Louisville, Kentucky. The new presentation is expected to include interim safety and kallikrein reduction data from the 50 mg dose cohort, and additional safety, kallikrein reduction and attack rate data from the 25 mg and 75 mg dose cohorts from the dose-escalation portion of the study.
Intellia expects to select up to two doses to further evaluate in the Phase 2, placebo-controlled, dose-expansion portion of the study, slated to begin in the first half of 2023. Intellia anticipates expanding country and site participation, including U.S. clinical sites, as part of the Phase 2 study.
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 IV infusions of A1AT augmentation therapy or lung transplant in severe cases.
Intellia is conducting Investigational New Drug (IND)-enabling activities for NTLA-3001, with plans to file an IND or IND-equivalent in 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.
Ex Vivo Program Updates

CD30+ Lymphomas

NTLA-6001: NTLA-6001 is an allogeneic CAR-T development candidate targeting CD30 for the treatment of CD30-expressing hematologic cancers, including relapsed or refractory classical Hodgkin lymphoma (cHL). NTLA-6001 is the first wholly owned candidate developed using Intellia’s proprietary allogeneic cell engineering platform.
Intellia is conducting IND-enabling activities for NTLA-6001.
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.
Intellia plans to advance at least one additional new in vivo development candidate by the end of 2022.
Allogeneic Platform: In October, at the European Society of Gene & Cell Therapy 29th Congress, Intellia highlighted its proprietary allogeneic solution to create engineered T cells with high anti-tumor activity, which have the potential to be uniquely capable of persisting in the patient to maintain durable responses. Notably, a novel combination of gene edits, including knockout of HLA Class II and HLA-A while retaining HLA-B and HLA-C proteins, yielded T cells capable of avoiding rejection by host T and natural killer (NK) cells in preclinical models. By only matching for HLA-B and HLA-C with homozygous donors for a 2/2 match, Intellia’s approach allows for a simplified HLA matching strategy between healthy donor T cells and recipient patients. Development of such an "off-the-shelf" therapy aims to address the majority of the patient population with only a small set of donors. Intellia’s allogeneic platform is being deployed for investigational TCR-T and CAR-T cell therapies.
Upcoming Events

The Company will participate in the following events during the fourth quarter of 2022:

American Heart Association Scientific Sessions 2022, November 5, Chicago
American College of Allergy, Asthma & Immunology 2022 Annual Scientific Meeting, November 12, Louisville
Piper Sandler 34th Annual Healthcare Conference, November 29, New York
Upcoming Milestones

The Company has set forth the following for pipeline progression:

In Vivo

NTLA-2001 for ATTR amyloidosis:
Present additional interim data from ATTR-CM arm of Phase 1 study at AHA
Complete planned enrollment of Phase 1 study for both ATTRv-PN and ATTR-CM subjects by the end of this year
NTLA-2002 for HAE:
Present additional interim data from Phase 1/2 study at ACAAI
Initiate Phase 2 portion of the study in 1H 2023
NTLA-3001 for AATD: File an IND or IND-equivalent in 2023
Advance at least one additional new in vivo development candidate by the end of 2022
Third Quarter 2022 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $848.7 million as of September 30, 2022, compared to $1.1 billion as of December 31, 2021. The decrease was driven by cash used to fund operations of approximately $276.2 million as well as the acquisition of Rewrite for $45.0 million. The decrease was offset in part by $62.1 million in net equity proceeds raised from the Company’s "At the Market" (ATM) agreement and $15.1 million in proceeds from employee-based stock plans. Subsequent to the end of the third quarter, through October 27, 2022, the Company increased its cash position by approximately $115 million. This included an additional $107.2 million in net equity proceeds raised from its ATM agreement and an additional $8.3 million received for ATM transactions with trade dates in September that were settled in October.
Collaboration Revenue: Collaboration revenue increased by approximately $6.1 million to $13.3 million during the third quarter of 2022, compared to $7.2 million during the third quarter of 2021. The increase was primarily driven by our collaborations with AvenCell and Kyverna.
R&D Expenses: Research and development expenses increased by $36.2 million to $96.7 million during the third quarter of 2022, compared to $60.5 million during the third 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 $3.4 million to $22.1 million during the third quarter of 2022, compared to $18.7 million during the third quarter of 2021. This increase was primarily related to employee-related expenses, including stock-based compensation of $2.4 million.
Net Loss: The Company’s net loss was $113.2 million for the third quarter of 2022, compared to $71.6 million during the third quarter of 2021.
Conference Call to Discuss Third Quarter 2022 Results

The Company will discuss these results on a conference call today, Thursday, November 3, 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 3, at 12 p.m. ET.