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Item 1. Business

2025-02-27 compared with 2024-02-22 · 570 added, 721 removed, 1483 unchanged (47% of the section changed)

We are a leading clinical-stage gene editing company, focused on developing potentially curative therapeutics using CRISPR/Cas9-based technologies.

CRISPR/Cas9, an acronym for C lustered, R egularly I nterspaced S hort P alindromic R epeats (“CRISPR”)/ C RISPR a ssociated 9 (“Cas9”), is a technology for genome editing, the process of altering selected sequences of genomic deoxyribonucleic acid (“DNA”).

To fully realize the transformative potential of CRISPR/Cas9-based technologies, we are building a full-spectrum gene editing company, by leveraging our modular platform, to advance in vivo and ex vivo therapies for diseases with high unmet need by pursuing two primary approaches.

For in vivo applications to address genetic diseases, we deploy CRISPR/Cas9 as the therapy.

Our in vivo programs use CRISPR/Cas9 to enable precise editing of disease-causing genes directly inside the human body.

In addition, we are advancing ex vivo applications to address immuno-oncology and autoimmune diseases, where we use CRISPR/Cas9 as the tool to create the engineered cell therapy.

For our ex vivo programs, CRISPR/Cas9 is used to engineer human cells outside the body.

Our deep scientific, technical and clinical development experience, along with our robust intellectual property (“IP”) portfolio, have enabled us to unlock broad therapeutic applications of CRISPR/ Cas9 and related technologies to create new classes of genetic medicine.

Treating—and potentially curing—a broad range of severe diseases will require multiple gene editing approaches.

With proprietary CRISPR/Cas9-based technology at the core of our platform, we continue to add new capabilities to expand our current solutions for addressing a multitude of life-threatening diseases.

These additions include our proprietary base editor and DNA writing technology, as well as novel CRISPR enzymes, which provide us with the capabilities to achieve multiple editing strategies.

We continue to advance our platform’s modular solutions and research efforts on genome editing technologies as well as delivery and cell engineering capabilities to generate additional development candidates.

Intellia Therapeutics, Inc.

(“we,” “us,” “our,” “Intellia,” or the “Company”) is a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies.

CRISPR is a gene editing technology which is also sometimes referred to as CRISPR/Cas or CRISPR/Cas9 when referring to the use of CRISPR technology with the Cas9 enzyme.

Since its inception, Intellia has focused on leveraging gene editing technology to develop novel, first-in-class medicines that address important unmet medical needs and advance the treatment paradigm for patients.

Intellia’s deep scientific, technical and clinical development experience, along with its people, are helping set the standard for a new class of medicine.

To harness the full potential of gene editing, Intellia continues to expand the capabilities of its CRISPR-based platform with novel editing and delivery technologies.

Our mission is to transform the lives of people with severe diseases by developing potentially curative genome editing treatments.

We believe we can deliver on our mission and provide long-term benefits for all of our stakeholders by focusing on four key elements:

• Develop potentially curative CRISPR/Cas9-based medicines;

• Advance our science;

• Be the best place to make therapies;

• Focus on long-term sustainability.

Our lead in vivo candidates, NTLA-2001 for the treatment of transthyretin (“ATTR”) amyloidosis and NTLA-2002 for the treatment of hereditary angioedema (“HAE”), are the first CRISPR/Cas9-based therapy candidates to be administered systemically, via intravenous (“IV”) infusion, for precision editing of a gene in a target tissue in humans.

In addition, we are advancing multiple ex vivo programs, wholly owned and in collaboration with partners, for the treatment of immuno-oncology and autoimmune diseases.

CRISPR/Cas9 Technology

The Nobel Prize-winning CRISPR/Cas9 system developed by one of our scientific co-founders, Dr.

Jennifer Doudna, and her collaborators, offers a revolutionary approach for therapeutic development due to its broad ability to precisely edit the genome.

This system can be used to make three general types of edits:

knockouts, repairs and insertions.

Each of these editing strategies takes advantage of the Cas9 endonuclease, an enzyme which can be programmed to edit double-stranded DNA at specific locations using a ribonucleic acid (“RNA”) molecule, called a guide RNA (“gRNA”).

The desired edits result from naturally-occurring biological mechanisms that effect particular types of genetic alterations.

CRISPR/Cas9 genome editing has the potential to make permanent, precisely targeted changes in a patient’s chromosomes and repair the underlying genetic mutation, whereas more traditional gene therapy typically involves introducing a non-permanent copy of a gene into a patient’s cells.

Our strategy is to advance our full-spectrum gene editing company, focused on developing and commercializing curative CRISPR/Cas9-based therapeutics, by leveraging our modular platforms.

Our lead in vivo product candidates, nexiguran ziclumeran (“nex-z”, also referred to as NTLA-2001) for the treatment of transthyretin (“ATTR”) amyloidosis and NTLA-2002 for the treatment of hereditary angioedema (“HAE”), are the first CRISPR-based therapy candidates to be administered systemically, via intravenous (“IV”) infusion, for precision editing of a gene in a target tissue in humans.

In addition, we are advancing ex vivo programs, wholly owned and in collaboration with partners, to develop product candidates for the treatment of immuno-oncology and autoimmune diseases, and multiple in vivo programs, also wholly owned and in collaboration with partners, to address diseases with significant unmet medical need by delivering gene editing therapeutics to organs outside the liver.

For over a decade, we have been applying novel technologies, such as CRISPR-based gene editing technologies and lipid nanoparticle (“LNP”) delivery technologies, to develop in vivo and ex vivo product candidates.

Our in vivo product candidates address genetic diseases by deploying our technologies, including CRISPR/Cas9 delivered by LNPs, as the therapy for diseases with high unmet need.

For our ex vivo product candidates, we apply our technologies to create engineered cell therapies to address immuno-oncology and autoimmune diseases.

Our deep scientific, technical and clinical development experience have enabled us to develop first-in-class therapeutic applications of CRISPR/Cas9 and our other technologies, opening a new frontier in genetic medicine.

Treating—and potentially curing—a broad range of severe diseases requires the application of multiple technologies.

With our proprietary technologies at the core of our platform, we continue to research and develop new gene editing and delivery technologies to expand our therapeutic opportunities, furthering progress on the frontier of genetic medicine and generating additional development candidates.

Our strategy is to develop and commercialize our product candidates and further our gene editing technology to develop new product candidates, expanding the application of gene editing medicine.

Our approach to realizing the broad potential of genome editing includes:

Focusing on Indications that Enable Us to Fully Develop the Potential of the CRISPR/Cas9 System.

To maximize our opportunity to rapidly develop clinically successful products, we have applied a risk-mitigated approach to selecting indications with significant unmet medical needs based on four primary criteria:

Focusing on Developing and Commercializing Our Lead In Vivo Product Candidates, Enabling the Potential of the CRISPR/Cas9 System.

We are focused on successfully completing late-stage clinical development of our lead product candidates, nex-z for the treatment of ATTR amyloidosis and NTLA-2002 for the treatment of HAE.

As the only in vivo genome editing product candidates in Phase 3 clinical trials, our lead product candidates are positioned at the forefront of genomic medicine.

Our strategy involves building a foundation designed to position us for the successful commercial launch of our product candidates.

Progressing Ex Vivo Therapeutic Programs.

We are researching proprietary engineered cell therapies to treat various cancers and autoimmune diseases.

We are deploying our LNP-based cell engineering platform and a proprietary allogeneic technology, a first-of-its-kind solution designed to avoid immune rejection by both T cells and natural killer (“NK”) cells, to advance a pipeline of wholly owned and partnered ex vivo programs.

We are pursuing targeting modalities, such as T cell receptors (“TCRs”) and chimeric antigen receptors (“CARs”), with broad potential in multiple immuno-oncology and autoimmune indications.

Advancing the Science of Genome Editing.

Since our founding, we have been at the scientific forefront of genome editing.

Our scientific co-founder, Dr.

Jennifer Doudna, and her collaborators developed the Nobel Prize-winning CRISPR/Cas9 system.

The versatility of this groundbreaking genome editing system opened the door to numerous scientific breakthroughs and provided the foundation of our genome editing therapeutics, including those that led to our first-in-class clinical product candidates.

The versatility of the CRISPR/Cas9 system is exemplified by the diverse types of edits it can facilitate, including knockouts, repairs and insertions, which can be accomplished solely by the endonuclease activity of the Cas9 enzyme or by fusing variants of the Cas9 enzyme to other proteins that can edit double-stranded deoxyribonucleic acid (“DNA”) at specific locations in various ways.

CRISPR/Cas9 systems comprise a Cas9 enzyme, or a variant thereof, and a ribonucleic acid (“RNA”) molecule, called a guide RNA (“gRNA”).

The complex formed by the Cas9 enzyme and the gRNA enable CRISPR/Cas9 systems’ features by precisely targeting and binding a specific sequence in double-stranded DNA.

We continue to advance the science of genome editing, and therapeutic applications of CRISPR/Cas9 systems, in order to maximize our opportunity to develop clinically successful products.

In executing this research strategy, we have applied a risk-mitigated approach to selecting indications with significant unmet medical needs based on four primary criteria:

• the type of edit:

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Specifically, we believe we can apply the learnings from our current programs to inform our selection of additional indications and targets of interest.

Aggressively Pursuing In Vivo Liver Indications to Develop Therapeutics with Our Proprietary Delivery System.

For our in vivo indications, we select well-validated targets in diseases with significant unmet medical needs where there are predictive biomarkers, or measurable indicators of a biological condition or state, with strong disease correlation and where the CRISPR/Cas9 technology and our proprietary delivery tools can be applied towards developing novel therapeutics.

Our current in vivo pipeline targets diseases of the liver.

Our two lead clinical programs in development aim to treat ATTR amyloidosis and HAE.

Both programs utilize our proprietary lipid nanoparticle (“LNP”) delivery system to knockout a target gene to halt production of an unwanted protein.

In addition, we are developing therapeutic candidates that leverage our modular gene insertion platform to restore native protein for the treatment of the lung manifestation of alpha-1 antitrypsin deficiency (“AATD”), hemophilia A, hemophilia B, and additional disease indications.

Progressing Ex Vivo Therapeutic Programs.

We are independently researching proprietary engineered cell therapies to treat various cancers and autoimmune diseases.

We are deploying our LNP-based cell engineering platform and allogeneic technology, a first-of-its-kind engineering solution designed to avoid both T cell and natural killer (“NK”) cell-mediated rejection, to advance a pipeline of wholly owned and partnered ex vivo programs.

We are pursuing targeting modalities, such as T cell receptors (“TCRs”) and chimeric antigen receptors (“CARs”), with broad potential in multiple immuno-oncology and autoimmune indications.

Continuing to Leverage Strategic Partnerships to Accelerate Clinical Development.

We view strategic partnerships as important drivers for accelerating the achievement of our goal of rapidly developing potentially curative therapies.

The potential application of the CRISPR/Cas9 system and derivative technologies is extremely broad, and we plan to continue to identify partners who can contribute meaningful resources and technical expertise to our programs and allow us to more rapidly bring scientific innovation to a broader patient population.

For example, we continue to collaborate on in vivo programs with Regeneron Pharmaceuticals, Inc.

(“Regeneron”), a leader in genetics-driven drug discovery and development, and to advance our collaborations with AvenCell Therapeutics, Inc.

(“AvenCell”), a company with a world-leading clinical-stage universal chimeric antigen receptor T (“CAR-T”) cell platform;

SparingVision SAS (“SparingVision”), a genomic medicine company developing vision saving treatments for ocular diseases;

Kyverna Therapeutics, Inc.

(“Kyverna”), a cell therapy company engineering a new class of therapies for autoimmune and inflammatory diseases;

and ONK Therapeutics, Ltd.

(“ONK”), a cell therapy company engineering a new class of NK cell therapies to treat cancer.

Growing Our Leadership Position in the Field of Genome Editing.

We believe we have built the broadest and deepest gene editing toolbox, which enables us to select the best tools for each therapeutic application.

We continue to invest internally in developing and deploying our platform capabilities, including innovative genome editing, delivery and cell engineering technologies to advance new therapeutic programs.

We have built a broad genome editing toolbox, which enables us to select the best tools to develop novel product candidates for each therapeutic application.

We continue to invest selectively in developing and deploying our platform capabilities, including innovative genome editing, delivery and cell engineering technologies to advance new therapeutic programs.

We will also continue to explore accessing external technologies or opportunities to enhance our leadership position in developing innovative therapeutics.

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In Vivo Programs

Our selection criteria include identifying diseases that originate in the liver;

have well-defined mutations that can be addressed by a knockout or insertion approach;

have readily measurable therapeutic endpoints with observable clinical responses;

and for which effective treatments are absent, limited or unduly burdensome.

Our initial in vivo indications target genetic liver diseases, including our ATTR amyloidosis, HAE and AATD development programs.

Our current efforts on in vivo delivery focus on the use of LNPs for delivery of the CRISPR/Cas9 complex to the liver.

Our lead in vivo programs are the only Phase 3 genome editing product candidates designed to address unmet need in patients with ATTR amyloidosis and HAE.

Our in vivo research efforts focus on pursuing additional targets within the liver and expanding delivery technology to enable product candidates for diseases outside the liver.

Hereditary Angioedema (“HAE”) Program

HAE is a rare, genetic disease characterized by severe, recurring and unpredictable inflammatory attacks in various organs and tissues of the body, which can be painful, debilitating and life-threatening.

The most common areas of the body to develop swelling are the limbs, face, intestinal tract and airway.

Minor trauma or stress may trigger an attack but swelling often occurs without a known trigger.

Episodes involving the intestinal tract cause severe abdominal pain, nausea and vomiting.

Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway.

The disease is caused by increased levels of bradykinin, a protein which leads to swelling.

Most patients with HAE have a deficiency of C1 esterase inhibitor (“C1-INH”) protein, which normally prevents the overproduction of bradykinin that causes the recurring, debilitating and potentially fatal swelling attacks in people living with HAE.

It is estimated that approximately one in 50,000 people are affected by HAE.

Limitations of Current Treatment Options

Current treatment options often include life-long therapies, which may require chronic IV or subcutaneous (“SC”) administration as often as twice per week, or daily oral administration to ensure constant pathway suppression for disease control.

Despite chronic administration, breakthrough attacks still occur.

Kallikrein inhibition is a clinically validated strategy for the preventive treatment of HAE attacks.

NTLA-2002 is a wholly owned, investigational in vivo CRISPR-based therapy designed to knock out the kallikrein B1 (“KLKB1”) gene in the liver, with the goal of achieving lifelong control of HAE attacks after a single dose.

It also aims to eliminate the significant treatment burden associated with currently available HAE therapies.

About the NTLA-2002 Clinical Program

In October 2024, we announced the initiation of the Phase 3 HAELO study of NTLA-2002.

HAELO is a global, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of NTLA-2002 in 60 adults with Type I or Type II HAE.

Patients will be randomized 2:1 to receive a single 50 mg infusion of NTLA-2002 or placebo.

Patients randomized to the placebo arm will be eligible for optional crossover to NTLA-2002 at week 28.

The primary endpoint is the number of HAE attacks from week 5 through week 28.

In January 2025, we announced that the first patient had been dosed in the global Phase 3 study.

We expect to complete enrollment in the second half of 2025 and submit a biologics license application (“BLA”) in the second half of 2026 to support plans for a potential United States (“U.S.”) launch in 2027.

Also in October 2024, we presented positive Phase 2 data from the ongoing Phase 1/2 study of NTLA-2002, with results continuing to support the potential of NTLA-2002 to be a functional cure for HAE in most patients.

Eight of 11 patients in the 50 mg arm ceased having any attacks during the 16-week primary observation period after a single dose of NTLA-2002.

These eight patients continued to be attack-free as of the cutoff date.

NTLA-2002 was well tolerated.

The most frequent adverse events (“AEs”) were headache, fatigue and nasopharyngitis.

There have been no serious AEs, and all AEs were either Grade 1 or 2.

These interim data were published in The New England Journal of Medicine and presented at the 2024 American College of Allergy, Asthma & Immunology (“ACAAI”) Scientific Meeting in Boston, Massachusetts.

We expect to present longer-term data from the ongoing Phase 1/2 study in 2025, which will include patients in the Phase 2 portion who initially received a 25 mg dose or placebo and were subsequently given the 50 mg dose of NTLA-2002 selected for the Phase 3 study.

We have received five regulatory designations for NTLA-2002, including orphan designation in the European Union (“EU”) granted by the European Commission (“EC”) in November 2023.

NTLA-2002 was also granted orphan designation and Regenerative Medicine Advanced Therapy (“RMAT”) designation by the U.S.

Food and Drug Administration (“FDA”), the Innovation Passport by the United Kingdom (“U.K.”) Medicines and Healthcare products Regulatory Agency (“MHRA”), as well as access to the Priority Medicine (“PRIME”) program by the European Medicines Agency (“EMA”).

Access to the PRIME program 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.

Transthyretin (“ATTR”) Amyloidosis Program

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Over 120 different genetic mutations are currently known to cause ATTRv.

Deposits of TTR amyloid in the heart, nerves and/or other tissues can lead to diverse disease manifestations, including two main hereditary forms – ATTRv with polyneuropathy (“ATTRv-PN”), and ATTRv with cardiomyopathy

(“ATTRv-CM”).

Typical onset of disease symptoms is during adulthood and can be fatal within two to 15 years.

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Limitations of Current Treatment Options

Currently, there are four therapies for the treatment of ATTRv-PN approved in the United States (“U.S.”), and five approved in most major markets outside of the U.S.

Currently, there are three marketed therapies for the treatment of ATTRv-PN approved in the U.S., and five approved in most major markets outside of the U.S.

While these therapies have shown the potential to slow or halt the progression of neuropathic symptoms, and in some patients lead to an improvement in symptoms, their approved prescribing instructions require them to be administered chronically for the life of the patient in order to sustain benefit.

Additionally, patient response to these therapies varies.

While some patients may experience symptomatic improvement after being treated with these therapies, the disease continues to progress in many of the treated patients, which highlights the continued need for efficacious and potentially curative therapies.

At present, there is only one therapy approved for transthyretin amyloidosis with cardiomyopathy (“ATTR-CM”) (including both ATTRv-CM and ATTRwt-CM) which has shown the ability to improve patient outcomes, though most patients still appear to have the progressive disease.

At present, there are two therapies approved for ATTR amyloidosis with cardiomyopathy (“ATTR-CM”) (including both ATTRv-CM and ATTRwt-CM) which have shown the ability to improve patient outcomes, though most patients still appear to have the progressive disease.

As with the treatments for ATTRv-PN, chronic, lifetime dosing is required to sustain the therapeutic effects.

NTLA-2001 is the first investigational CRISPR-based therapy to be systemically delivered to edit a target gene inside the human body.

NTLA-2001 has the potential to become the first single-dose treatment for ATTR amyloidosis.

It is designed to inactivate the TTR gene that encodes for the TTR protein.

Delivered with our in vivo LNP technology, 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.

Nex-z is an investigational CRISPR-based therapy designed to inactivate the TTR gene in liver cells, thereby preventing the production of TTR protein for the treatment of ATTR amyloidosis.

Delivered with our in vivo LNP technology, nex-z 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.

Using this approach, we aim to address ATTR amyloidosis regardless of the disease manifestation.

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We believe our approach may improve patient outcomes by significantly and consistently reducing TTR protein after a single dose, as opposed to life-long, chronic therapy.

About the NTLA-2001 Clinical Program

The global, pivotal Phase 3 MAGNITUDE trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of NTLA-2001 in adults with ATTR-CM.

We are actively enrolling patients, including in the U.S., and are on track to dose a first patient in the first quarter of 2024.

About the Nex-z Clinical Program

ATTR Amyloidosis with Cardiomyopathy (“ATTR-CM”):

In 2024, we initiated the pivotal Phase 3 MAGNITUDE trial.

The MAGNITUDE trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of nex-z in adults with ATTR-CM.

The primary endpoint of the study is a composite of cardiovascular (“CV”)-related mortality and events.

Patients will be randomized 2:1 NTLA-2001:placebo, with a single 55 mg infusion of NTLA-2001 administered.

MAGNITUDE trial enrollment is ongoing and we are also actively preparing for a global pivotal Phase 3 study of NTLA-2001 for the treatment of ATTRv-PN in 2024.

Advancing to a Phase 3 study was supported by a Phase 1 study of NTLA-2001, which was a two-part, open-label study in adults with ATTR amyloidosis, either ATTR-CM or ATTRv-PN.

For both the ATTR-CM and ATTRv-PN arms of the Phase 1 study, the primary objectives were to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of NTLA-2001.

Patients received a single dose of NTLA-2001 via IV administration.

In November 2023, we announced new positive interim data from the Phase 1 study of NTLA-2001.

Updated data from over 60 patients showed consistent, deep, and durable serum TTR reduction was achieved with a single dose of NTLA-2001, including in 29 patients who reached 12 months or more of follow-up as of the data cutoff 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 ug/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

These interim data were presented at the 4th International ATTR Amyloidosis Meeting, held in Madrid, Spain.

We plan to present updated data from the ongoing Phase 1 study in 2024.

NTLA-2001 has received orphan drug designation for the treatment of ATTR amyloidosis by both the European Commission (“EC”) and the U.S.

Food and Drug Administration (“FDA”).

NTLA-2001 is the subject of a co-development and co-promotion (“Co/Co”) arrangement directed to our first collaboration target with Regeneron, ATTR (the “ATTR Co/Co”), for which we are the clinical and commercial lead party and Regeneron is the participating party.

Regeneron shares in approximately 25% of worldwide development costs and commercial profits for the ATTR program.

Patients will be randomized 2:1 nex-z:placebo, with a single 55 mg infusion of nex-z administered.

In March 2024, the first patients in the U.S.

and globally were dosed.

The MAGNITUDE trial is currently enrolling and we anticipate enrollment to exceed 550 total patients by the end of 2025.

In November 2024, we presented new data from the ATTR-CM arm of the ongoing Phase 1 study.

Across all patients (n=36), a single dose of nex-z led to consistently rapid, deep and sustained serum TTR reduction, regardless of baseline levels, through the latest follow-up.

At month 12, the mean serum TTR reduction was 90%, and the mean absolute residual serum TTR concentration was 17 µg/mL.

With 11 patients who had reached 24 months of follow-up as of November 2024, all patients continued to show a sustained response with no evidence of a waning effect over time.

The consistently low levels of serum TTR are anticipated to reduce the rate of ongoing amyloid formation and potentially allow for amyloid clearance and improvement in cardiac function.

Nex-z was generally well tolerated across all patients.

Hereditary ATTR Amyloidosis with Polyneuropathy (“ATTRv-PN”):

In November 2024, we announced that the FDA has cleared our nex-z Investigational New Drug (“IND”) application to initiate the MAGNITUDE-2 pivotal Phase 3 trial for ATTRv-PN.

MAGNITUDE-2 is an international, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of nex-z in 50 adults with ATTRv-PN.

Patients will be randomized 1:1 to receive a single 55 mg infusion of nex-z or placebo.

Patients randomized to the placebo arm will be eligible for optional crossover to receive nex-z following month 18.

The primary endpoints are the change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at month 18 and serum TTR at day 29.

The mNIS+7 scale is a validated measure specifically designed to assess and quantify polyneuropathy impairment, including muscle weakness, muscle stretch reflexes, sensory loss and autonomic impairment.

We are actively screening patients for the Phase 3 MAGNITUDE-2 study and are on track to dose the first patient in the first quarter of 2025.

In November 2024, we presented new data from the ATTRv-PN arm of the ongoing Phase 1 study.

Across patients who received a dose of 0.3 mg/kg or higher (n=33), the mean serum TTR reduction was 91% and the mean absolute residual serum TTR concentration was 20 µg/mL at month 12.

With 16 patients who had reached 24 months of follow-up as of November 2024, all patients continued to show a sustained response with no evidence of a waning effect over time.

It is anticipated that greater TTR reduction may lead to a greater clinical benefit in patients with ATTRv-PN.

Nex-z was generally well tolerated across all patients and at all dose levels tested.

Nex-z has received orphan drug designation for the treatment of ATTR amyloidosis by both the FDA and the EC and has received RMAT designation from the FDA for the treatment of ATTRv-PN.

We expect to present longer-term data from both ATTR-CM and ATTRv-PN patients in the Phase 1 study in 2025, which will include updated measures of clinical efficacy and safety.

Nex-z is the subject of a co-development and co-promotion (“Co/Co”) agreement (the “ATTR Co/Co”) with Regeneron Pharmaceuticals, Inc.

(“Regeneron”), for which we are the clinical and commercial lead party and Regeneron is the participating party.

Regeneron shares in approximately 25% of worldwide development costs and commercial profits for the ATTR program and has an option to enter into a co-promotion agreement for the U.S.

commercialization.

For more information regarding our collaboration with Regeneron, see the section below entitled “ Collaborations - Regeneron Pharmaceuticals, Inc.

Hereditary Angioedema (“HAE”) Program

The most common areas of the body to develop swelling are the limbs, face, intestinal tract and airway.

Minor trauma or stress may trigger an attack but swelling often occurs without a known trigger.

Episodes involving the intestinal tract cause severe abdominal pain, nausea and vomiting.

Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway.

The disease is caused by increased levels of bradykinin, a protein which leads to swelling.

It is estimated that approximately one in 50,000 people are affected by HAE.

Limitations of Current Treatment Options

Despite chronic administration, breakthrough attacks still occur.

Kallikrein inhibition is a clinically validated strategy for the preventive treatment of HAE attacks.

NTLA-2002 is our wholly owned candidate for the treatment of HAE.

NTLA-2002 is designed to knock out the kallikrein B1 (“ 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.

About the NTLA-2002 Clinical Program

Our multi-national Phase 1/2 study is evaluating the safety, tolerability, activity, pharmacokinetics and pharmacodynamics of NTLA-2002 in adults with Type I or Type II HAE.

This includes the measurement of kallikrein protein levels and activity, as well as HAE attack rate.

The Phase 1 portion of the study was an open-label, single-ascending dose design.

Two dose levels of NTLA-2002 were identified from Phase 1 for further evaluation in the Phase 2, randomized, placebo-controlled portion of the study.

In January 2024, we announced that enrollment and dosing was completed in the Phase 2 portion of the study.

Data from the Phase 2 study will inform the dose of NTLA-2002 selected for the pivotal Phase 3 study.

We expect to initiate the global pivotal Phase 3 study, including U.S.

patients, in the second half of 2024, subject to regulatory feedback.

In January 2024, we also announced that positive interim results from the Phase 1 portion of the Phase 1/2 study were published in the New England Journal of Medicine .

These results were first reported in June 2023 at the European Academy of Allergy and Clinical Immunology Hybrid Congress.

Across all ten patients, a 95% mean reduction in monthly attack rate was observed after a single dose of NTLA-2002 through the latest follow-up.

The median duration of follow-up was 9.0 months (range of 5.6 - 14.1 months).

At all three dose levels evaluated in the Phase 1 portion of

the study, NTLA-2002 was well tolerated, and the most frequent adverse events reported were mild, transient infusion-related reactions and fatigue.

We plan to present updated data from the Phase 1 and new data from the Phase 2 portion of the study in 2024.

We have received five regulatory designations for NTLA-2002, including orphan designation in the European Union (“EU”) granted by the EC in November 2023.

NTLA-2002 was also granted orphan designation and Regenerative Medicine Advanced Therapy (“RMAT”) designation by the FDA, the Innovation Passport by the United Kingdom (“U.K.”) Medicines and Healthcare products Regulatory Agency (“MHRA”) as well as access to the Priority Medicine (“PRIME”) program by the European Medicines Agency (“EMA”).

Access to the PRIME program 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.

Alpha-1 Antitrypsin Deficiency (“AATD”) Program

AATD is a genetic disorder that results in increased risk for lung and/or liver disease.

Alpha-1 antitrypsin (“A1AT”), which is encoded by the SERPINA1 gene, is a serine protease inhibitor that is primarily produced in the liver and has a wide range of biological functions, one of which is to inhibit neutrophil elastase.

Patients with AATD have genetic variants of A1AT which cause the enzyme to accumulate in the liver, reducing the amount of functioning A1AT in the bloodstream.

This has two prominent potential downstream clinical manifestations.

The first is an increased risk for progressive liver disease, resulting from an accumulation of mutant A1AT enzyme in the liver.

The second, and more common, effect is enhanced risk for emphysema resulting from reduced inhibition of neutrophil elastase in the lungs.

Both clinical manifestations are progressive and potentially fatal.

It is estimated that there are approximately 250,000 individuals globally and greater than 60,000 individuals in the U.S.

with the ZZ genotype, the genotype most associated with AATD and the downstream clinical manifestations.

There are another 1.25 million individuals globally estimated to have the SZ genotype, who are also at enhanced risk of developing AATD.

While augmentation therapy is available for the treatment of AATD, the effect on pulmonary exacerbations and on the progression of emphysema in AATD has not been conclusively demonstrated in randomized, controlled clinical trials.

Limitations of Current Treatment Options

There are multiple therapies approved by the FDA to treat patients with emphysema caused by hereditary AATD.

All marketed therapies are plasma-derived alpha-1 proteinase inhibitors (alpha-1 antitrypsin) given through IV infusion, with the goal of augmenting naturally-occurring low levels of A1AT.

To maintain benefit, current therapies are usually given weekly for the duration of a patient’s lifetime.

Currently marketed therapies may slow the progression of disease and lung dysfunction, but there remains high unmet need for more effective, and less burdensome, therapies that can further slow, halt, or even reverse disease progression.

NTLA-3001 is our 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 A1AT protein, with the potential to restore permanent expression of functional A1AT protein to therapeutic levels after a single dose.

Our approach seeks to improve patient outcomes, including eliminating the need for weekly IV infusions of A1AT augmentation therapy or lung transplant in severe cases.

In December 2023, we submitted a clinical trial application (“CTA”) to initiate a first-in-human, Phase 1 study of NTLA-3001 and plan to dose the first patient in 2024.

In Vivo Research Programs

We continue to work on various liver-focused programs, such as hemophilia A and hemophilia B, which we are co-developing with Regeneron, as well as other liver targets, which we are working on both independently and in partnership with Regeneron, that would leverage our wide-ranging gene editing capabilities to knockout, insert and make consecutive edits to the genome.

We are further advancing editing and delivery strategies to expand the reach of CRISPR-based gene editing to tissues outside of the liver.

For example, we have presented preclinical data establishing proof-of-concept for non-viral genome editing of bone marrow and hematopoietic stem cells (“HSCs”) in mice.

This represented our first demonstration of systemic in vivo genome editing in bone marrow using our proprietary non-viral delivery platform.

We believe these results extend our modular in vivo capabilities to treat inherited blood disorders such as sickle cell disease.

In September 2023, we entered into an expanded research collaboration with Regeneron to develop additional in vivo CRISPR-based gene editing therapies focused on neurological and muscular diseases.

In addition, we are collaborating with SparingVision to develop novel genomic medicines utilizing CRISPR/Cas9 technology for the treatment of ocular diseases.

Ex Vivo Programs

We are advancing multiple preclinical programs, wholly owned and in collaboration with partners, utilizing our allogeneic platform for the treatment of immuno-oncology and autoimmune diseases.

Our 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.

• We are developing allogeneic cellular therapies, which are cells derived from unrelated donors and modified outside of the human body to allow them to be administered to an unrelated patient.

These allogeneic cellular therapies could be used to treat both oncological and immunological diseases.

Our proprietary technologies, including our LNP-based cell engineering platform and novel allogeneic solution, are designed to offer significant advantages over both autologous cell therapies and allogeneic approaches being investigated by others.

Preclinical data presented on our differentiated allogeneic engineering platform showed allogeneic T cells were shielded from immune rejection, both host T and NK cell attack.

• We are advancing engineered CAR and TCR cells as immuno-oncological therapies.

This includes collaborations with AvenCell and Kyverna, who are leveraging our ex vivo allogeneic cell engineering platform to develop novel CAR-T cell therapy candidates for a variety of therapeutic indications, as well as ONK to advance CRISPR-edited NK cell therapy candidates.

Ex Vivo Research Programs

We are researching engineered cell therapies to treat a range of hematological and solid tumors.

We are pursuing modalities, such as TCRs and CARs, with broad potential in multiple indications.

We are advancing efforts for allogeneic therapies to move from liquid to solid tumors.

Our researchers are developing and improving cell-engineering manufacturing and delivery processes that, we believe, may allow us to deliver T cell therapies with high levels of editing, robust levels of cell expansion, desirable memory phenotypes, improved function and no translocations above background levels.

Our proprietary T cell engineering process using LNPs to engineer cell therapies enables multiple, sequential gene edits.

We and our collaboration partners are advancing preclinical programs utilizing our allogeneic platform for the treatment of immuno-oncology and autoimmune diseases.

Our proprietary allogeneic cell engineering platform avoids both T cell- and NK cell-mediated rejection in preclinical models, an unsolved challenge with other investigational allogeneic approaches.

Cell therapies engineered with our allogeneic platform, combined with edits to enhance cell function, could offer a new approach to target both hematological and solid tumors.

Our proprietary cell engineering technologies, including our LNP-based cell engineering platform and novel allogeneic solution, are designed to offer significant advantages over both autologous cell therapies and allogeneic approaches being investigated by others, and could be used to treat patients with cancer.

• We are developing an allogeneic CAR T cell therapy, which uses cells derived from unrelated donors and modified outside of the human body to allow them to be administered to and persist in an unrelated patient.

Preclinical data based on our differentiated allogeneic engineering platform applied a novel combination of gene edits, including knockout of specific human leukocyte antigen (“HLA”) Class I and II proteins to avoid rejection by T cells while retaining and matching one select HLA protein that is important for blocking NK cells.

This strategy led to persistent allogeneic T cells, comparable to autologous T cells, in preclinical models.

With our approach, we may be able to pursue a simplified HLA matching strategy between healthy donor T cells and recipient patients, allowing for the development of an “off-the-shelf” therapy that could address the majority of the patient population with only a small set of donors.

• In addition, we strategically partner with others who possess complementary capabilities or technologies to bring forth innovative engineered cell therapy candidates outside of our core areas of focus, such as our collaborations with AvenCell Therapeutics, Inc., Kyverna Therapeutics, Inc., and ONK Therapeutics, Ltd.

We have shared preclinical data demonstrating that our LNP-based engineering technology is a significant improvement over electroporation, the standard engineering process used to introduce proteins and nucleic acids into cells.

The resulting T cells engineered with LNPs had improved cell properties and performance both in vitro and in vivo as compared to electroporation.

The data support the ability of our platform to be used for a variety of targeting modalities, including CARs and TCRs, and to support both autologous and allogeneic T cell candidates.

The LNP-based approach has been used in multiple ex vivo candidates in development by us and our collaborators.

Our proprietary allogeneic solution to create engineered T cells with high anti-tumor activity may be uniquely capable of persisting in the patient to maintain durable responses.

Notably, a novel combination of gene edits, including knockout of specific human leukocyte antigen (“HLA”) Class II and some HLA proteins while retaining other HLA proteins, yielded T cells capable of avoiding rejection by host T and NK cells in preclinical models.

With our approach, we are able to pursue a simplified HLA matching strategy between healthy donor T cells and recipient patients, allowing for the development of an “off-the-shelf” therapy that addresses the majority of the patient population with

only a small set of donors.

Our allogeneic platform is being deployed for investigational TCR-T and CAR-T cell therapies.

Our genome editing capabilities include a novel, proprietary cytosine deaminase base editor technology.

We have demonstrated the technology’s potential for enhanced cell engineering, with multiple simultaneous gene knockouts achieving >90% T cell editing efficiency and no detectable increase in translocation above background levels.

Our Genome-Editing Platform

Our robust genome-editing platform forms the foundation of our full-spectrum therapeutic product pipeline based on CRISPR/Cas9 and derivative technologies.

Our modular platform is based on our proprietary components that can serve both in vivo and ex vivo programs, as well as our delivery technologies that can be used in either program type.

In addition to the components described below, we believe we have developed robust, high volume (high throughput) capabilities centering around enabling strategic target identification and validation that we believe will provide us with a competitive advantage in creating successful therapeutic products.

Our Research Programs

We are expanding the range of diseases that can be targeted with our CRISPR-based technologies by expanding our genome editing and delivery technologies to develop new product candidates.

This includes advancing gene editing programs in tissues outside the liver, either independently or in collaboration with partners, and using new gene editing technologies, including DNA writing.

We are committed to staying at the forefront of the genome editing revolution and will continue to advance our technology platform through a mix of both internal research and development and external opportunities in order to potentially serve more patients across a broad set of diseases.

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These additions include our proprietary base editor, as well as novel CRISPR-derivative enzymes, which provide us with the capabilities to achieve multiple editing strategies.

We have built a high throughput, scalable data processing and analysis, or informatics, infrastructure to support various aspects of our platform, including gRNA selection and evaluation of on- and off-target editing in cells.

Depending on the desired editing strategy, we use proprietary bioinformatics methods to design candidate guides and select those that we believe are both highly specific and have high cutting efficiency.

As we grow our experimental data set, we continue to incorporate gRNA performance into our algorithms to improve their predictive power.

Guide RNA Qualification

As part of the process to identify gRNAs for potential development candidates, we screen numerous gRNAs for their ability to generate the required edit at the genomic site of interest, called on-target activity, as well as any potential propensity to generate unwanted events at other sites in the genome, also known as off-target activity.

To evaluate on-target activity, we use high throughput sequencing methods to analyze the genomes of edited cells, allowing us to assess overall editing efficiency and to examine the nature of the editing events, such as specific insertions or deletions.

For gRNAs selected through our primary on-target screens, we perform a variety of analyses to look for possible off-target editing events, including bioinformatic evaluations and experimental methods.

Part of our approach involves identifying candidates with no or few off-target sites based on experimental measurements of genome-wide DNA breaks, as well as targeted sequencing of such candidate sites to evaluate actual off-target editing events in relevant cell types.

We continue to optimize our gRNA qualification capability over time by increasing our throughput, improving our off-target activity detection accuracy and increasing our bioinformatics predictive accuracy.

Guide RNA Format

CRISPR/Cas9 systems can function with gRNAs having a variety of modifications, such as changes to the gRNA sequence or chemical modifications of nucleotides.

As part of our development of CRISPR/Cas9 therapeutics, we have engineered modified gRNAs to, for example, improve editing efficiency, specificity and stability inside cells, as well as to reduce the likelihood of an immune response.

We believe our work in this area will allow us to develop the most appropriate gRNAs for therapeutic applications.

Our current preferred Cas9 protein is derived from a species of bacteria called S.

pyogenes (“ Spy” ), which is the Cas9 used in the vast majority of published CRISPR/Cas9 literature to date.

We are exploring other naturally occurring

Cas9 proteins and nucleases from other bacteria, which may differ from Spy Cas9 in aspects such as specificity, size or mechanism of DNA recognition, binding and cutting.

We are pursuing these alternative Cas9 forms and other nucleases through ongoing internal work, collaborations with our existing partners and scientific founders, and in-licensing opportunities.

We also are investigating targeted modifications of Cas9 that can modulate DNA activity by mechanisms other than cleavage.

We believe that different therapeutic applications may be best addressed using different forms of Cas9 or other nucleases, depending on the target cell or tissue of interest, the delivery method and the desired type of edit.

Types of Edits

The CRISPR/Cas9 system, by itself, primarily functions to cut DNA, while the resulting desired therapeutic editing events are performed by the cell, subsequent to the cut, as the cell seeks to rejoin the cut ends.

One type of edit is caused by a DNA repair mechanism that is prone to losing or adding short lengths of DNA around the cut site.

The resulting changes in the DNA impair the function of any encoded protein, causing a knockout edit.

Using a combination of our informatics, gRNA qualification and format, and nuclease platform capabilities, we have developed an efficient process to identify gRNAs that create this kind of edit at high frequency while possessing high specificity for the on-target site and no substantial off-target effects.

Based on both NHP and rodent disease models, we have demonstrated the ability to knockout multiple targets in the liver, including TTR , KLKB1 , SERPINA1 , hydroxyacid oxidase 1 (“ HAO1”) and lactate dehydrogenase A (“ LDHA”) .

We believe these data demonstrate the modular nature of our proprietary LNP delivery system.

Gene Insertion

While knockout edits can be made using solely a Cas9 protein and gRNA, other kinds of editing, involving repair and insertion, additionally require a template DNA that contains a desired genomic sequence that may be inserted or used to correct a patient’s original sequence.

For ex vivo applications, in addition to delivering a Cas9-gRNA complex to cleave the cellular DNA sequence at the desired location, the desired DNA template may be delivered by physical means such as LNP in combination with a Cas9-gRNA complex, or by other means such as viral vectors or chemical means.

For in vivo applications, we have developed combination approaches for delivering the editing machinery by LNP, and the repair and insertion templates by adeno-associated virus ( “ AAV”) vectors.

We are independently advancing our in vivo gene insertion platform for multiple genes of interest to treat a variety of diseases, such as AATD, and working closely with Regeneron to advance programs for the treatment of hemophilia A and hemophilia B.

We have demonstrated in NHP and rodent preclinical models the ability to precisely insert a gene, including SERPINA1 and Factor 9 (“F9” ) , to produce normal human levels of the missing protein.

In February 2024, Regeneron and Intellia announced the clearance by the FDA of an investigational new drug (“IND”) application to initiate a clinical trial for our investigational in vivo CRISPR-based F9 gene insertion program for people living with hemophilia B.

A Phase 1, first-in-human study is expected to begin in mid-2024.

Regeneron leads development and commercialization of hemophilia A and B programs in collaboration with us.

DNA Writing Technology

Our DNA writing technology may enable a range of precise editing strategies.

These strategies include targeted corrections, insertions, deletions, and the full range of single-nucleotide changes, which could provide new ways to edit disease-causing genes and broaden the therapeutic potential for genomic medicines.

In Vivo Delivery

We are focusing our initial in vivo applications in the liver, where we deliver the CRISPR/Cas9 therapy intravenously to patients using our proprietary LNP platform.

Our proprietary LNPs encapsulate the therapeutic cargo, providing it with stability, selective delivery, improved pharmacologic properties and controlled circulation time.

Our therapeutic cargo is designed to degrade relatively quickly, resulting in transient expression of Cas9.

We see multiple advantages of using LNPs as an in vivo delivery vehicle, particularly as optimized by us for delivery of the CRISPR/Cas9 system or its components.

First, LNPs have

been clinically validated as an effective delivery vehicle of therapeutic nucleic acids to the liver after IV administration.

LNPs have shown to have favorable tolerability in humans, with toxicities being dose-dependent, monitorable and reversible.

Additionally, LNPs are chemically well-defined and have a completely synthetic route of manufacture, which permits greater scalability, product quality and controls.

We have applied our comprehensive genome editing platform to discover and develop multiple product candidates with complex compositions, including LNPs comprising messenger RNA and gRNA as well as adeno-associated virus (“AAV”) vectors when required for insertion.

The product candidates we discovered and developed, both wholly owned and together with our collaborators, apply a broad spectrum of genome editing approaches, including the knockout, insertion, and/or modification of genes.

Based on both non-human primate (“NHP”) and rodent disease models, we have demonstrated the ability to knockout multiple targets in the liver, including TTR , KLKB1 , SERPINA1 , hydroxyacid oxidase 1 (“ HAO1”) and lactate dehydrogenase A (“ LDHA”) .

We have also demonstrated in NHP and rodent preclinical models the ability to precisely insert a gene, including SERPINA1 and Factor 9 (“F9” ), to produce normal human levels of the missing protein.

In addition, we have developed a leading LNP platform that has proven to be critical to the initial success of our, and our collaborators’, liver-focused product candidates, where we deliver the CRISPR/Cas9 therapy intravenously to patients using our

proprietary LNP platform.

In our research programs, we are focusing on applying those learnings from our initial in vivo applications in the liver, to expand our delivery technology to develop product candidates that require delivery to tissues other than the liver.

We believe that our proprietary LNP platform provides distinct advantages over other delivery technologies because, inter alia , our LNPs provide our product candidates with stability, selective delivery, improved pharmacologic properties and controlled circulation time.

LNPs are chemically well-defined and have a completely synthetic route of manufacture, which permits greater scalability, product quality and controls.

LNPs are tunable, do not exhibit cargo size limitations and can co-formulate different nucleic acid components, such as messenger RNA and gRNAs.

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(“Novartis”) and in-licensed by us for use with all genome editing technologies, including CRISPR/Cas9 products.

To date, we have successfully demonstrated well-tolerated in vivo editing in various animal models, including in mouse, rat and NHP livers, with a single dose of systemically delivered LNPs.

In addition, we have moved into late-stage human clinical trials using LNPs as the delivery mechanism.

Based on interim data reported from the first-in-human study of NTLA-2001, we have also successfully demonstrated that LNP delivery of CRISPR/Cas9 is well-tolerated in humans.

We plan to continue to further improve on our LNP system to optimize delivery of a variety of CRISPR/Cas9 therapeutic components, including templates for repair and insertion edits.

In parallel, we are exploring additional delivery vehicles, including synthetic particles and viral vectors.

We also are developing delivery strategies that we believe will allow us to target other tissues.

Ex Vivo Delivery

Cellular therapies are based on the administration of engineered human cells that are modified to provide or restore necessary functions in the cells of patients, or to target and eliminate cells with harmful attributes, such as cancer cells.

The cells to be modified ex vivo can come from the individual patient (autologous source) or from another individual (allogeneic source).

The CRISPR/Cas9 system can be used to modify cells outside the body using clinically proven delivery methods, such as electroporation.

We are exploring these standard methods in parallel with our own newly-developed proprietary LNP-based delivery methods, which may provide advantages such as increased delivery efficiency and cell viability.

Ex Vivo Allogeneic Platform

We have developed a proprietary allogeneic cell engineering platform to overcome one of the key challenges to current allogeneic approaches employed by others, which is host rejection of the adoptive cell therapy.

In preclinical studies, our allogeneic technology demonstrated the ability to create T cells with high anti-tumor activity capable of avoiding host T and NK cells, and thereby persisting to maintain durable responses.

Our proprietary approach leverages a novel combination of sequential edits, including knockout of HLA Class II and HLA-A while retaining HLA-B and HLA-C proteins.

With our approach, we can pursue a simplified HLA matching strategy between healthy donor T cells and recipient patients, allowing for the development of an “off-the-shelf” therapy that addresses the majority of the patient population with only a small set of donors.

Our allogeneic platform is being deployed for investigational TCR-T and CAR-T cell therapies.

Collaborations and Other Arrangements

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Under this agreement, we also may access the Regeneron Genetics Center and proprietary mouse models to be provided by Regeneron for a limited number of our liver programs.

We amended the 2016 Regeneron Agreement in May 2020 to, among other things, (a) extend the technology collaboration, and related target selection rights, until April 2024, which Regeneron has since further extended to April 2026;

(b) increase the number of exclusive in vivo targets to which Regeneron may develop CRISPR/Cas-based therapeutic products to fifteen;

and (c) grant Regeneron a non-exclusive license under certain of our IP to independently develop and commercialize up to 10 CRISPR/Cas-based ex vivo gene edited products made using certain defined cell types.

As currently amended, the technology collaboration, and related target selection rights, under the 2016 Regeneron Agreement extends until April 2026.

In addition, the 2016 Regeneron Agreement has been amended to (a) increase the number of exclusive in vivo targets to which Regeneron may develop CRISPR/Cas-based therapeutic products to fifteen and (b) grant Regeneron a non-exclusive license under certain of our intellectual property (“IP”) to independently develop and commercialize up to 10 CRISPR/Cas-based ex vivo gene edited products made using certain defined cell types.

In September 2023, we further amended the 2016 Regeneron Agreement (the “2023 Regeneron Amendment”) to expand the research and development collaboration to develop additional in vivo CRISPR-based gene editing therapies focused on neurological and muscular diseases.

The expanded research and development collaboration will leverage our proprietary Nme2 CRISPR/Cas9 genome editing systems adapted for viral vector delivery and designed to precisely modify a target gene and Regeneron’s proprietary antibody-targeted AAV vectors and delivery systems.

Under the 2023 Regeneron Amendment, the companies will collaborate to research and develop products directed to two in vivo non-liver targets initially;

The expanded research and development collaboration leverages our proprietary Nme2 CRISPR/Cas9 genome editing systems adapted for viral vector delivery and designed to precisely modify a target gene and Regeneron’s proprietary antibody-targeted AAV vectors and delivery systems;

each party will have the opportunity to lead potential development and commercialization for one product candidate, and the party that is not leading development and commercialization will have the option to enter into a co-development and co-commercialization agreement for the target.

We also have entered into three co-development and co-funding agreements with Regeneron, specifically the ATTR Co/Co and co-development and co-funding agreements for the treatment of hemophilia A and hemophilia B (the “Hemophilia Co/Co”) agreements.

Our collaboration with Regeneron under the ATTR Co/Co and Hemophilia Co/Co agreements is described above in the section entitled “ Our Pipeline – In Vivo Research Programs ”.

In October 2023, Regeneron notified us that it was exercising its one-time option to extend the technology collaboration term for an additional two years (the “2024 Technology Collaboration Extension”), until April 2026, in exchange for a nonrefundable payment of $30.0 million due in April 2024.

Refer to Note 9 to our consolidated financial statements of this Annual Report on Form 10-K for a detailed description of the terms related to the 2016 Regeneron Agreement and the 2020 Regeneron Amendment.

Under the 2016 Regeneron Agreement, we will be eligible to receive up to $320.0 million per in vivo target in development and commercial milestone payments, as well as up to mid-single-digit royalties on potential future sales.

In 2018, we entered into the ATTR Co/Co agreement with Regeneron.

In May 2020, we entered into co-development and co-funding agreements for the treatment of hemophilia A and hemophilia B (the “Hemophilia Co/Co”) agreements.

We terminated the hemophilia B Co/Co agreement in September 2024.

We will continue to support Regeneron with the development of gene editing products directed to hemophilia B, as applicable, under the 2016 Regeneron Agreement.

AvenCell Therapeutics, Inc.

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In exchange for the license, we received a 33.33% equity interest in AvenCell at the time of the initial closing.

In July 2021, we also entered into a co-development and co-funding agreement to co-develop and co-commercialize allogeneic universal CAR-T cell products for an immuno-oncology indication (the “AvenCell Co/Co”), which we terminated in November 2022 as a result of re-prioritizing our ex vivo programs.

Our obligations under the terminated agreement were completed in the second quarter of 2023.

In the fourth quarter of 2024, AvenCell completed a Series B financing which resulted in our equity interest being reduced to below 10%.

We have one option to enter into an additional co-development and co-funding agreement for a payment of $30.0 million to AvenCell.

Refer to Notes 9 and 10 to our consolidated financial statements of this Annual Report on Form 10-K for additional information related to the terms of the agreements between us and AvenCell.

SparingVision SAS (“SparingVision”)

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SparingVision will lead and fund the preclinical and clinical development for the genome editing product candidates pursued under the collaboration.

We will also be eligible to receive certain research, development and commercial milestone cash payments (up to approximately $200.0 million per product) as well as royalties on

potential future sales of products arising from the collaboration.

We will also be eligible to receive certain research, development and commercial milestone cash payments (up to approximately $200.0 million per product) as well as royalties on potential future sales of products arising from the collaboration.

We will have an option to obtain exclusive U.S.

commercialization rights for product candidates arising from two of three collaboration targets.

Refer to Notes 9 and 10 to our consolidated financial statements of this Annual Report on Form 10-K for additional information related to the terms of the agreement between us and SparingVision.

In December 2024 SparingVision provided notice to us to terminate one of their three ocular targets due to a reprioritization strategy, effective in November 2024.

Kyverna Therapeutics, Inc.

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Kyverna would retain all rights outside of the U.S., and we would receive low-to-mid-single-digit royalties on net sales generated outside of the U.S.

Refer to Notes 9 and 10 to our consolidated financial statements of this Annual Report on Form 10-K for additional information related to the terms of the agreement between us and Kyverna.

ONK Therapeutics, Ltd (“ONK”)

ONK Therapeutics, Ltd.

In February 2022, we announced a license, collaboration and option agreement with ONK for the development of engineered NK cell therapies to cure patients with cancer.

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In addition, the agreement grants us options to co-develop and co-commercialize up to two products worldwide with rights to lead commercialization in the U.S.

Refer to Notes 9 and 10 to our consolidated financial statements of this Annual Report on Form 10-K for additional information related to the terms of the agreement between us and ONK.

Rewrite Therapeutics Inc.

On February 2, 2022, we entered into an Agreement and Plan of Merger with, inter alia , Rewrite Therapeutics, Inc.

(the “Rewrite Merger Agreement”).

On February 2, 2022, we entered into an Agreement and Plan of Merger with, inter alia , Rewrite (the “Rewrite Merger Agreement”).

Under the Rewrite Merger Agreement, we agreed to pay Rewrite’s former stockholders and option holders (the “Rewrite Holders”) (a) upfront consideration in an aggregate amount of approximately $45.0 million payable in cash, excluding customary purchase price adjustments, and (b) up to an additional $155.0 million in milestone payments, including $55.0 million upon the achievement of certain pre-specified research milestones and $100.0 million upon achievement of a certain regulatory approval milestone, payable through a mixture of $130.0 million in cash and $25.0 million in shares of common stock.

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ReCode Therapeutics, Inc.

On February 15, 2024, we announced a strategic collaboration with ReCode Therapeutics, Inc.

(“ReCode”), a clinical-stage genetic medicines company, to develop novel genomic medicines for the treatment of cystic fibrosis (“CF”).

CF is a genetic disease caused by mutations in the CFTR gene, leading to the accumulation of thick mucus in the lungs,

digestive systems and other organs.

CF can result in life-threatening infections, respiratory failure and other serious complications.

On February 14, 2024, we entered into a license, collaboration and option agreement with ReCode (the “ReCode LCA”), a clinical-stage genetic medicines company, to develop novel genomic medicines for the treatment of cystic fibrosis (“CF”).

The ReCode LCA leverages our proprietary CRISPR-based gene editing platform, including our DNA writing technology, and ReCode’s proprietary Selective Organ Targeting (“SORT”) LNP delivery platform to precisely correct one or more CF disease-causing gene mutations.

As part of the agreement, ReCode and Intellia will focus initial research efforts on therapeutic approaches that address CF for patients who have limited or no treatment options available, with the opportunity to expand the scope of the collaboration in later phases.

We will be responsible for the design of the editing strategy and research-grade components for the

investigational therapies.

ReCode will lead the subsequent preclinical and clinical development and worldwide commercialization for certain programs arising from the collaboration and we will be eligible to receive certain development and commercial milestone payments, as well as low-to-mid-single-digit royalties on potential future sales.

We also have an option to lead commercialization in the U.S.

for certain programs (the “Co/Co option”).

Potential Future Collaborations

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• intend to take additional steps, where appropriate, to further protect our IP rights, including, for example, through the use of copyright protection, trademark and regulatory protections available via orphan drug designations, data exclusivity, market exclusivity and patent term extensions.

Our licensed patent portfolio encompasses foundational filings on the use of CRISPR/Cas9 systems for genome editing, improvement modifications of these CRISPR systems, including base editor and DNA writing technologies, LNP technologies, TCRs for specific targets, and cell expansion technology relevant to stem cell-based therapies.

We access these patent estates from licensors, including Caribou Biosciences, Inc.

We have a broad portfolio of wholly owned and in-licensed patents and patent applications, including foundational filings on the use of CRISPR/Cas9 systems for genome editing, as well as improvement to CRISPR/Cas9 systems, such as base editor and DNA writing technologies, and delivery technologies, including LNP technologies.

We co-own some of these patent portfolios with our collaboration partners, such as Regeneron, and we have licensed some of these patent portfolios from licensors, including Caribou Biosciences, Inc.

(“Caribou”) and others.

In addition to our in-licensed IP, our IP portfolio includes over 70 patent families filed since 2015 covering solely or jointly owned technologies that we have developed independently or through our collaboration with Regeneron.

The patent families claim inventions relating to CRISPR/Cas9 improvements, methods for delivering CRISPR/Cas9 complexes, methods of treating diseases using CRISPR/Cas9 genome editing, and methods for analyzing editing events, among others.

Patents resulting from our internal portfolio, if issued, would expire no earlier than 2036.

If issued, patents resulting from our wholly owned patent portfolio, which may claim our product candidates, would expire no earlier than 2036.

We actively apply for, maintain, and plan to defend and enforce, as needed, our internally developed and externally licensed patent rights.

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In July 2014, we entered into a license agreement with Caribou (the “Caribou License”), as subsequently amended and supplemented, for an exclusive, worldwide license for human therapeutic, prophylactic, and palliative uses, except for anti-fungal and anti-microbial uses, defined in the license agreement as our field of use, of any CRISPR/Cas9-related patents and applications owned, controlled or licensed by Caribou as well as companion diagnostics to our product or product candidates.

The licensed Caribou patent portfolio includes several U.S.

and foreign patents and patent applications owned or licensed by Caribou, including over 50 patent applications in the U.S.

and internationally, related to the CRISPR/Cas platform and an exclusive sublicense in our field of use to the Regents of the University of California (“UC”) and University of Vienna’s (“Vienna”) rights in U.S.

The Caribou License includes an exclusive sublicense in our field of use to the Regents of the University of California (“UC”) and University of Vienna’s (“Vienna”) rights in U.S.

and foreign patents and patent applications covering the CRISPR/Cas9 technology, which they co-own with Dr.

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The UC/Vienna/Charpentier IP and Pioneer IP, and our rights to the same, are further described below.

We have agreed to pay 30.0% of Caribou’s patent prosecution, filing and maintenance costs for the IP included in the license agreement, which has amounted to a total of $9.1 million incurred through December 31, 2023.

We have agreed to pay 30.0% of Caribou’s patent prosecution, filing and maintenance costs for the IP included in the license agreement.

Any patents that grant or have granted from these applications will expire in or after 2034, assuming payment of necessary maintenance fees.

We also granted Caribou an exclusive, royalty-free, worldwide license, with the right to sublicense, to any CRISPR/Cas9 patents, patent applications and know-how in Caribou’s retained fields of use owned or developed by us between July 16, 2014 and January 30, 2018.

Caribou, which is obligated to pay a portion of our patent filing, prosecution and maintenance costs for any such licensed IP, also has an option to sublicense any CRISPR/Cas9 IP in-licensed by us for uses and activities in its retained field of use.

The Caribou License terminates on the expiration of the last-to-expire patent right that is licensed to either party.

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The earliest claimed priority date for the patents in the UC/Vienna/Charpentier IP is May 25, 2012.

As of December 31, 2023, this family includes over 50 issued patents in the U.S.

and over 30 granted patents outside the U.S., including for example the U.K., Australia, China, Japan, Israel, Mexico and the approximately 40 countries that are members of the European Patent Convention.

Applications continue to be prosecuted in the United States Patent and Trademark Office (“USPTO”) and other patent agencies across the world.

Patents issued from this family will expire in or after 2033, if successfully maintained.

In April 2013, Caribou entered into an exclusive, worldwide license in all fields, with the right to sublicense, for this patent family with UC/Vienna solely under UC/Vienna ownership rights.

Caribou’s license remains in effect for the life of the last-to-expire patent or last-to-be-abandoned patent application licensed, whichever is later.

Through our license agreement with Caribou, we have an exclusive sublicense to UC/Vienna’s interest in this foundational CRISPR/Cas9 patent family for use in human therapeutics, except for anti-fungal and anti-microbial uses as defined in the license agreement as our field of use.

As noted above, under the Caribou License, we have an exclusive, worldwide sublicense to UC/Vienna’s interest in this foundational CRISPR/Cas9 patent family in our field of use.

For therapeutic products covered by this license and their companion diagnostics, we will owe mid-single-digit royalties on net sales.

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Specifically, if we are in compliance with our obligations under our sublicense and Caribou and UC/Vienna terminate their agreement, UC/Vienna would replace Caribou as our licensor.

On June 25, 2019, the USPTO’s Patent Trial and Appeal Board (the “PTAB”) declared another interference between the UC/Vienna/Charpentier and certain patents issued to the Broad Institute, Massachusetts Institute of Technology, and the President and Fellows of Harvard College (collectively, the “Broad Institute patent family” or the “Broad”), which claim aspects of CRISPR/Cas9 systems and methods to edit genes in eukaryotic cells, including human cells.

Since 2015, certain U.S.

patents and patent applications within the UC/Vienna/Charpentier IP and a patent portfolio owned by the Broad Institute, Massachusetts Institute of Technology, and the President and Fellows of Harvard College (collectively, the “Broad Institute patent family” or the “Broad”) have been involved in interferences at the United States Patent and Trademark Office (“USPTO”)’s Patent Trial and Appeal Board (the “PTAB”).

The most recent interference began in 2019 (the “Broad Interference”) and its subject matter pertain to aspects of CRISPR/Cas9 systems and methods to edit genes in eukaryotic cells, including human cells.

An interference is an adversarial proceeding conducted by the PTAB to determine who was the first to invent a particular invention claimed in U.S.

patents and patent applications owned by different parties and in this situation, to determine which research group first invented the use of the CRISPR/Cas9 technology in eukaryotic cells and, therefore, is entitled to the patents covering the invention.

On August 26, 2019, the PTAB redeclared the interference to include additional UC/Vienna/Charpentier patent applications covering the invention that had also been found allowable by the USPTO.

As of December 31, 2023, the interference involved 14 allowable patent applications from the UC/Vienna/Charpentier eukaryotic patent family and 13 patents and one patent application from the Broad Institute

patent family.

The PTAB held a hearing in this interference on February 4, 2022.

On February 28, 2022, the PTAB issued a Decision of Priority and Judgment in the patent interference finding that the Broad patents and application have priority over the UC/Vienna/Charpentier involved applications with respect to the subject matter of the interference.

On March 30, 2022, UC/Vienna/Charpentier filed a notice of appeal in the Broad Interference, and the Broad Institute has cross-appealed.

In addition, the PTAB has instituted and completed the motions phase in interferences between the same 14 allowable patent applications in the UC/Vienna/Charpentier portfolio, and certain patent rights owned by ToolGen, Inc.

(“ToolGen”), and certain patent rights owned by Sigma-Aldrich Co.

As of December 31, 2024, the interference involved 14 allowable patent applications from the UC/Vienna/Charpentier eukaryotic patent family and 13 patents and one patent application from the Broad Institute patent family.

On February 28, 2022, the PTAB issued a Decision of Priority and Judgment in the patent interference, finding that the involved patents and application in the Broad Institute patent family have priority over the patent applications in the UC/Vienna/Charpentier IP with respect to the subject matter of the interference.

Both parties appealed to the U.S.

Court of Appeals for the Federal Circuit, which held a hearing in May 2024.

In addition, the PTAB has instituted and completed the motions phase in two interferences involving the same UC/Vienna/Charpentier patent applications involved in the Broad Interference—one interference involving certain patent rights owned by ToolGen, Inc.

(“ToolGen”) and another involving certain patent rights owned by Sigma-Aldrich Co.

LLC, a Merck KGaA subsidiary (“Sigma-Aldrich”).

In both interferences, ToolGen and Sigma-Aldrich, respectively, purport that their patent rights cover the use of CRISPR/Cas9 for gene editing in eukaryotic cells.

Both interferences are stayed pending a decision from the Court of Appeals for the Federal Circuit in the Broad Interference.

Both interferences are stayed pending a decision from the U.S.

Court of Appeals for the Federal Circuit in the Broad Interference.

If either the Broad, ToolGen or Sigma-Aldrich were to succeed in their respective interference, the prevailing party or parties could seek to assert its issued patents against us based on our CRISPR/Cas9-based activities, including product commercialization.

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In that event, we may be unable to further develop and commercialize one or more of our product candidates, which could harm our business significantly.

Pioneer Hi-Bred International (DuPont Company) Intellectual Property

Pioneer, including the DuPont Company, have licensed to Caribou on a worldwide basis, various patent families relating to CRISPR/Cas systems, components and methods of use generally and CRISPR/Cas9 specifically in certain fields, which include Intellia’s field of use under our license agreement with Caribou.

In July 2015, we exercised our option under the license agreement with Caribou to sublicense these Pioneer patent families in our field of use.

The license from Pioneer to Caribou will expire upon the expiration, abandonment or invalidation of the last patent or patent application licensed from Pioneer to Caribou.

The licensed Pioneer portfolio includes a family of applications filed by Vilnius University that discloses the components of a CRISPR/Cas9 system required for gene editing in non-bacterial organisms.

The USPTO has issued patents to Vilnius University with claims covering the in vitro assembly and use of a recombinant CRISPR/Cas9 complex to modify DNA.

Patents obtained from this patent family will expire in or after 2033, assuming payment of necessary maintenance fees.

We cannot ensure that these additional applications in this family will lead to issued claims that cover our products or activities.

Invention Management Agreement

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Under the Invention Management Agreement, Dr.

Charpentier retroactively consented to UC/Vienna’s CRISPR/Cas9 license to Caribou as well as Caribou’s sublicensing to Intellia certain of its rights to the UC/Vienna/Charpentier CRISPR/Cas9 IP, subject to the restrictions of our license from Caribou.

Charpentier retroactively consented to UC/Vienna’s CRISPR/Cas9 license to Caribou as well as Caribou’s sublicensing to Intellia

certain of its rights to the UC/Vienna/Charpentier CRISPR/Cas9 IP, subject to the restrictions of our license from Caribou.

Under the agreement, the parties commit to maintain and coordinate the prosecution, defense and enforcement of the CRISPR/Cas9 foundational patent portfolio worldwide, and each of the co-owners of the IP grants cross-consents to all existing and future licenses and sublicenses based on the rights of another co-owner.

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We have entered into certain manufacturing and supply arrangements with third party suppliers to support production of our product candidates and their components.

In addition, we have entered into a lease to build out a new manufacturing facility in Waltham, Massachusetts, which would support good manufacturing practice (“GMP”) manufacturing for preclinical through commercial supply.

We plan to continue to rely on qualified third party organizations and our own capabilities to produce or process bulk compounds, formulated compounds, viral vectors or engineered cells for IND-supporting activities and to supply materials for clinical trials.

We expect that clinical and commercial quantities of any in vivo product or engineered cells that we may seek to develop will be manufactured in GMP compliant facilities and by processes that comply with FDA and other regulatory agency requirements.

At the appropriate time in the product development process of each product candidate, we will determine whether to use our internal manufacturing capabilities and facilities or continue to rely on third parties to manufacture commercial quantities of such products that we may successfully develop.

We expect that clinical and commercial quantities of any in vivo product or engineered cells that we may seek to develop will be manufactured in good manufacturing practice (“GMP”) compliant facilities and by processes that comply with FDA and other regulatory agency requirements.

The biotechnology and pharmaceutical industries are extremely competitive in the race to develop new products.

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For any products that we may ultimately commercialize, not only will we compete with any existing therapies and those therapies currently in development, but we will also have to compete with new therapies that may become available in the future.

Specific to our NTLA-2001 program, we are aware of other companies that are currently commercializing or developing products and therapies used to treat ATTR amyloidosis, including Alnylam Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, BridgeBio Pharma Inc., Ionis Pharmaceuticals, Inc., Metagenomi Technologies, LLC, Novo Nordisk A/S and Pfizer, Inc.

Specific to our NTLA-2002 program, we are aware of other companies that are currently commercializing or developing products used to treat HAE including ADARx Therapeutics, Inc., Astria Therapeutics Inc., BioCryst Pharmaceuticals Inc., BioMarin Pharmaceutical Inc., CSL Limited, Ionis Pharmaceuticals, Inc., KalVista Pharmaceuticals, Inc., Pharming Group N.V., Pharvaris N.V.

Specific to our nex-z program, we are aware of other companies that are currently commercializing or developing products and therapies used to treat ATTR amyloidosis, including Alnylam Pharmaceuticals, Inc., AstraZeneca Pharmaceuticals LP, BridgeBio Pharma Inc., Bayer AG, Ionis Pharmaceuticals, Inc., Metagenomi Technologies, LLC, Novo Nordisk A/S, Pfizer, Inc.

and YolTech Therapeutics.

Specific to our NTLA-2002 program, we are aware of other companies that are currently commercializing or developing products used to treat HAE, including ADARx Therapeutics, Inc., Astria Therapeutics Inc., BioCryst Pharmaceuticals Inc., CSL Limited, Ionis Pharmaceuticals, Inc., KalVista Pharmaceuticals, Inc., Pharming Group N.V., Pharvaris N.V.

and Takeda Pharmaceutical Company Limited.

Competitors in our efforts to provide other genetic therapies to patients can be grouped into at least three sets based on their product discovery platforms:

Our platform and product foci are on the development of therapies using CRISPR-based technologies.

Genome editing companies focused on CRISPR-based technologies include:

Beam Therapeutics Inc., Caribou Biosciences, Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Metagenomi Technologies, LLC, Prime Medicine, Inc., ToolGen, Inc.

and Verve Therapeutics Inc.

There are also companies developing therapies using additional gene-editing technologies, which include Allogene Therapeutics, Inc., bluebird bio, Inc., Cellectis S.A., Homology Medicines, Inc., Poseida Therapeutics, Inc., Precision Biosciences, Inc., Prime Medicine, Inc.

and Sangamo Therapeutics, Inc.

Arbor Biotechnologies, Inc., Beam Therapeutics Inc., Caribou Biosciences, Inc., CRISPR Therapeutics AG, EdiGene, Inc., Editas Medicine, Inc., Emendo Biotherapeutics, Inc., Ensoma, Inc., Excision Biotherapeutics, Inc., Integra Therapeutics, S.L., Mammoth Biosciences, Inc., Metagenomi Technologies, LLC, Modalis Therapeutics Inc., nChroma Bio (formerly Chroma Medicine, Inc.), Prime Medicine, Inc., Scribe Therapeutics, Inc., Tessera Therapeutics, Inc., ToolGen, Inc., Tune Therapeutics, Inc., Verve Therapeutics, Inc.

and YolTech Therapeutics.

There are also companies developing therapies using additional genome editing technologies, which include Allogene Therapeutics, Inc., bluebird bio, Inc., Cellectis S.A., Editas Medicine, Inc., Life Edit Therapeutics (an ElevateBio Company), Myeloid Therapeutics, Inc., Poseida Therapeutics, Inc.

(acquired by Roche Holdings, Inc.), Precision Biosciences, Inc., Prime Medicine, Inc., Sangamo Therapeutics, Inc., Seamless Therapeutics, Inc., Stylus Medicine, Inc.

and Tessera Therapeutics, Inc.

We are also aware of companies developing therapies in various areas related to our specific research and development programs.

For ex vivo , these companies include Allogene Therapeutics, Inc., Cellectis S.A., CRISPR Therapeutics AG and Precision BioSciences, Inc.

For in vivo , these companies include CRISPR Therapeutics AG, Editas Medicine, Inc., Excision Biotherapeutics, Inc., Locus Biosciences, Inc., Metagenomi Technologies, LLC, Precision Biosciences, Inc.

For ex vivo , these companies include Atara Biotherapeutics, Inc., Allogene Therapeutics, Inc., BRL Medicine, Inc., Caribou Biosciences, Inc., CARSgen Therapeutics Corporation, Cellectis S.A., CRISPR Therapeutics AG, Legend Biotech USA, Inc., Poseida Therapeutics, Inc.

(acquired by Roche Holdings, Inc.), Precision BioSciences, Inc., and Sana Biotechnology, Inc.

For in vivo , these companies include Beam Therapeutics Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Ensoma, Inc.,

Metagenomi Technologies, LLC, Orna Therapeutics, Inc., Precision Biosciences, Inc., Prime Medicine, Inc., Tessera Therapeutics, Inc., Vertex Pharmaceuticals, Inc.

and Verve Therapeutics, Inc.

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may begin, we must submit an IND application to the FDA, which reviews the clinical protocol and other information, and the IND application must become effective before clinical trials may begin.

Prior to initiating clinical trials in foreign countries, CTAs or other equivalent applications, similar to IND applications, must be approved.

Prior to initiating clinical trials in foreign countries, clinical trial applications (“CTAs”) or other equivalent applications, similar to IND applications, must be approved.

Biologic products must be approved by the FDA before they may be legally marketed in the U.S.

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Gene and Cell Therapy Products Development Process

The FDA approves biologics, including gene and cellular therapy products, through the Biologics License Application (“BLA”) process before they may be legally marketed in the U.S.

The FDA approves biologics, including gene and cellular therapy products, through the BLA process before they may be legally marketed in the U.S.

This process generally involves the following:

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or (iii) molecules that result from the replication of those described in (i) or (ii).

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

Specifically, under the NIH Guidelines,

supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.

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Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA.

The FDA reviews the application to determine, among other things, whether the proposed product is safe and effective (or, in the case of biologics, to ensure safety, purity

and potency), and whether the product is being manufactured in accordance with cGMP, and in certain cases, cGTP, requirements to ensure and preserve the product’s identity, safety, strength, quality, potency and purity.

The FDA reviews the application to determine, among other things, whether the proposed product is safe and effective (or, in the case of biologics, to ensure safety, purity and potency), and whether the product is being manufactured in accordance with cGMP, and in certain cases, cGTP, requirements to ensure and preserve the product’s identity, safety, strength, quality, potency and purity.

The FDA may refer applications for novel products or products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

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The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP and, if applicable, cGTP requirements are adequate to assure consistent production of the product within required specifications.

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements.

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted

in compliance with IND study requirements and GCP requirements.

To assure cGMP, cGTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production, and quality control.

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and the EU, as well as in other countries, there are a number of programs to expedite development, review and approval of products for serious or life-threatening disease or condition that address an unmet medical need in the relevant regulatory jurisdiction.

In the U.S., these FDA programs include Fast Track Designation, priority review, accelerated approval, Breakthrough Therapy designation and Regenerative Medicine Advanced Therapies.

In the U.S., these FDA programs include Fast Track Designation, priority review, accelerated approval, Breakthrough Therapy designation and RMAT.

Similar programs in the EU include accelerated assessment, conditional approval and the PRIME program.

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As part of the 21 st Century Cures Act, the FD&C Act was amended to facilitate an efficient development program for, and expedite review of regenerative advanced therapies, which include cell and gene therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products.

Gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues may meet the definition of a regenerative medicine therapy.

Gene therapies,

including genetically modified cells, that lead to a durable modification of cells or tissues may meet the definition of a regenerative medicine therapy.

This program is intended to facilitate efficient development and expedite review of regenerative medicine therapies, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify for RMAT designation.

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This exclusivity period, which may be shared amongst multiple first interchangeable products, lasts for the lesser of (i) one year after the first commercial marketing, (ii) 18 months after approval if there is no legal challenge, (iii) 18 months after the resolution in the applicant’s favor of a lawsuit challenging the biologic’s patents if an application has been submitted, or (iv) 42 months after the application has been approved if a lawsuit is ongoing within the 42-month period.

The BPCIA, however, is complex and only beginning to be interpreted and implemented

The BPCIA, however, is complex and only beginning to be interpreted and implemented by the FDA.

In addition, proposed legislation has sought to reduce the 12-year reference product exclusivity period.

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• the federal Anti-Kickback Statute, which prohibits, among other things, individuals or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe, or certain rebates), directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, either the referral of an individual, or the purchase, lease, order, arrangement for or recommendation of the purchase, lease, order, arrangement for any good, facility, item or service, for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs.

A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

A person or entity does not need to have

actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, the ACA provides that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act (“FCA”).

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laws govern the privacy and security of health and other personal information in certain circumstances, many of which differ from each other in significant ways and may not have the same requirements, thus complicating efforts to comply with their respective provisions;

federal physician payment transparency requirements, sometimes referred to as the “Physician Payments Sunshine Act,” created under the ACA, and their implementing regulations, which require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually, to the Centers for Medicare and Medicaid Services (“CMS”), information related to payments or other “transfers of value” made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other licensed healthcare practitioners, and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers, and their immediate family members.

federal physician payment transparency requirements, sometimes referred to as the “Physician Payments Sunshine Act,” created under the ACA, and their implementing regulations, which require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually, to Centers for Medicare & Medicaid Services (“CMS”), information related to payments or other “transfers of value” made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other licensed healthcare practitioners, and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers, and their immediate family members.

Failure to submit required information may result in civil monetary penalties for all payments, transfers of value or ownership or investment interests that are not timely, accurately, and completely reported in an annual submission;

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state and foreign laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures;

and state and foreign laws governing the privacy and security of health information in

certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Because of the breadth of these laws and the limited statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws.

In the event we decide to conduct clinical trials or enroll subjects in our future clinical trials, we may be subject to additional privacy restrictions.

In the EU, the General Data Protection Regulation (“GDPR”) regulates the collection, use, storage, disclosure, transfer or other processing of personal data, including personal health data.

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In California, the California Consumer Privacy Act (“CCPA”) requires covered businesses to comply with specific privacy and security obligations, such as providing disclosures to consumers in California about such companies’ data collection, use and sharing practices, and providing consumers the ability to opt-out of certain sales or transfers of personal information, and providing consumers with a private right of action for certain data breaches.

Further, the California Privacy Rights Act (“CPRA”) substantially modifies the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information and by establishing a state agency vested with the authority to enforce the CCPA.

The CPRA also creates additional obligations with respect to the processing of personal information, including regulating personal information collected about employees, applicants and retirees as well as that which is collected in a business-to-business capacity.

The law also created a new state regulatory agency that is vested with the authority to implement and enforce the CCPA.

Several other U.S.

states have either passed or enacted privacy legislation similar to the CCPA, which incorporate similar concepts of the CCPA, but contain key differences in the scope, application, and enforcement which may complicate compliance efforts.

If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to us, we may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and future earnings, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs, individual imprisonment, and additional reporting obligations and oversight if we become subject to a corporate integrity

agreement or other agreement to resolve allegations of non-compliance with this law, any of which could adversely affect our ability to operate our business and our financial results.

Further, in addition to comprehensive laws at the state level, some states have been proposing or passing laws that target particular aspects of privacy.

For example, the state of Washington has enacted a wide-ranging law that protects the privacy of medical and health-related information that is not covered by HIPAA and a small number of states have passed laws specifically focused on biometric information.

At the federal level, regulators and legislators in the U.S.

are increasingly scrutinizing and restricting certain personal data transfers and transactions involving foreign countries.

For example, the Biden Administration’s executive order Preventing Access to Americans’ Bulk Sensitive Personal Data and United States Government-Related Data by Countries of Concern, as implemented by Department of Justice regulations issued in December 2024, prohibits data brokerage transactions involving certain sensitive personal data categories, including health data, genetic data, and biospecimens, to countries of concern, including China.

The regulations also restrict certain investment agreements, employment agreements and vendor agreements involving such data and countries of concern, absent specified cybersecurity controls.

Actual or alleged violations of these regulations may be punishable by criminal and/or civil sanctions and may result in exclusion from participation in federal and state programs.

To the extent that any of our product candidates, once approved, are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or other transfers of value to healthcare professionals.

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Clinical Trial Approval

In April 2014, the EU adopted the new Clinical Trials Regulation, (EU) No 536/2014, which replaced the previous Clinical Trials Directive 2001/20/EC on 31 January 2022.

In April 2014, the EU adopted the Clinical Trials Regulation, (EU) No 536/2014, which replaced the previous Clinical Trials Directive 2001/20/EC on 31 January 2022.

The Clinical Trials Regulation is directly applicable in all EU Member States meaning no national implementing legislation in each EU Member State is required.

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726/2004, the centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal products, ATMPs, and products with a new active substance indicated for the treatment of certain diseases, including products for the treatment of cancer, HIV or AIDS, diabetes, neurodegenerative disorders, autoimmune and other immune dysfunctions and viral diseases.

For those products for which the use of the centralized procedure is not mandatory, applicants may elect to use the centralized procedure where either the product contains a new active substance indicated for the treatment of diseases other than those listed above, or where the applicant can show that the product constitutes a significant therapeutic, scientific or technical innovation or for which the centralized procedure is in the interest of patients at an EU level.

constitutes a significant therapeutic, scientific or technical innovation or for which the centralized procedure is in the interest of patients at an EU level.

Specifically, the grant of marketing authorization in the EU for ATMPs is governed by Regulation (EC) No.

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An orphan product can also obtain an additional two years of market exclusivity in the EU where an agreed Pediatric Investigation Plan (“PIP”) for pediatric studies has been complied with.

No extension to any supplementary protection certificate (“SPC”) can be granted on the basis of pediatric studies for orphan indications.

No extension to any supplementary protection certificate (“SPC”) can be granted on the basis of pediatric studies for a product with an orphan designation.

The criteria for designating an orphan medicinal product in the EU are similar in principle to those in the U.S.

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or (b) it is unlikely that the product, without the benefits derived from orphan status, would generate sufficient return in the EU to justify the necessary investment in its development;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation (EC) 847/2000.

defined in Regulation (EC) 847/2000.

Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.

The application for orphan designation must be submitted before the application for marketing authorization.

The applicant

will receive a fee reduction for the MAA if the orphan drug designation has been granted, but not if the designation is still pending at the time the MAA is submitted.

The applicant will receive a fee reduction for the MAA if the orphan drug designation has been granted, but not if the designation is still pending at the time the MAA is submitted.

Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

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Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each EU Member State and can differ from one country to another.

The aforementioned EU rules are generally applicable in the EEA, which consists of the EU Member States, plus Norway, Liechtenstein and Iceland.

All of the aforementioned EU rules are generally applicable in the EEA, which consists of the EU Member States, plus Norway, Liechtenstein and Iceland.

The EC introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).

The EC has provided the legislative proposals to the European Parliament and the European Council for their review and approval.

In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.

The EC has provided the legislative proposals to the European Parliament and the European Council for their review and approval, and, in April 2024, the European Parliament proposed amendments to the legislative proposals.

Once the EC’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.

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If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Brexit and the Regulatory Framework in the United Kingdom

formally left the EU on January 31, 2020.

The EU and the U.K.

have concluded a trade and cooperation agreement (“TCA”), which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not provide for wholesale mutual recognition of U.K.

and EU pharmaceutical regulations.

At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework currently continues to apply in Northern Ireland).

The regulatory regime in Great Britain therefore currently aligns with EU regulations in many ways, however it is possible that these regimes will diverge more significantly in the future now that Great Britain’s regulatory system is independent from the EU.

The MHRA in the U.K.

established a new medicines approval pathway following Brexit, known as the Innovative Licensing and Access Pathway (“ILAP”), which aims to accelerate the time to market and facilitate patient access to certain types of medicinal products in development which target a life-threatening or seriously debilitating condition, or where there is a significant patient or public health need.

The first step in the ILAP is receipt of an Innovation Passport, which allows for enhanced engagement with the MHRA and its partner agencies.

Once an Innovation Passport has been granted, the next step in the pathway is the preparation of a target development profile (“TDP”) document by the MHRA and the U.K.’s health technology assessment agencies.

The TDP sets out the regulatory and development milestones, identifies potential issues and creates a roadmap to achieving early patient access in the U.K.

The TDP also gives access to a toolkit where a number of tools can be selected as needed for a particular medicine or stage of development.

These tools include rolling review of an MAA, whereby data can be submitted for review on a rolling basis as it becomes available.

On January 1, 2024, a new international recognition framework was put in place by the MHRA, under which the MHRA may have regard to decisions on the approval of marketing authorizations made by the EMA and certain other regulators.

On February 27, 2023, the U.K.

government and the EC announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the U.K.

In particular, the MHRA will be responsible for approving all medicinal products destined for the U.K.

market (Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

A single U.K.-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the U.K., enabling products to be sold in a single pack and under a single authorization throughout the U.K.

The Windsor Framework was approved by the EU-U.K.

Committee on March 24, 2023, so the U.K.

Government and the EU will enact legislative measures to enact it into law.

On June 9, 2023, the MHRA announced that the medicines aspects of the Windsor Framework will apply from January 1, 2025.

Other Government Regulation

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Even if we obtain coverage for a given product, the resulting reimbursement payment rates might not be adequate for us to achieve or sustain profitability or may require co-payments that patients find unacceptably high.

Additionally, third party payors may not cover, or provide adequate reimbursement for, long-term follow-up evaluations required following the use of our gene-modifying products.

Additionally, third party payors may not cover, or provide adequate reimbursement for, long-term follow-up evaluations required following the use of our gene editing products.

Patients are unlikely to use, and health care providers may not prescribe, our product candidates unless coverage is provided, and reimbursement is adequate to cover a significant portion of the product’s cost to the patient.

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Moreover, increasing efforts by governmental and third party payors in the U.S.

and abroad to cap or reduce healthcare costs may cause such organizations to limit both coverage and the level of reimbursement for biological products and, as a result, they may not cover or provide adequate payment for our product candidates.

and abroad to cap or reduce healthcare costs may cause such organizations to

limit both coverage and the level of reimbursement for biological products and, as a result, they may not cover or provide adequate payment for our product candidates.

In addition, we expect to experience pricing pressures in connection with the sale of any of our product candidates upon their approval due to the trend toward managed healthcare, the increasing influence of health maintenance organizations, cost containment initiatives and additional legislative changes.

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For example, the EU provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

A Member State may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

An EU Member State may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

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• increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

during their coverage gap period, as a condition for a manufacturer’s outpatient drugs being covered under Medicare Part D;

• created a Medicare Part D coverage gap discount program, in which manufacturers must agree to provide a 70% point‑of‑sale discount off the negotiated price of applicable branded drugs to eligible beneficiaries during their coverage gap period, as a condition for a manufacturer’s outpatient drugs being covered under Medicare Part D;

• extended a manufacturer’s Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;

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• On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

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The IRA includes several provisions that will impact our business to varying degrees, including provisions that create a $2,000 out-of-pocket cap for Medicare Part D beneficiaries, impose new manufacturer financial liability on all drugs in Medicare Part D, allow the U.S.

government to negotiate Medicare Part B and Part D

pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation, and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

government to negotiate Medicare Part B and Part D pricing for certain high-cost drugs and biologics without generic or biosimilar competition, require companies to pay rebates to Medicare for drug prices that increase faster than inflation, and delay the rebate rule that would require pass through of pharmacy benefit manager rebates to beneficiaries.

Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.

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The effect of the IRA on our business and the healthcare industry in general is not yet known.

• In addition, President Biden has issued multiple executive orders that have sought to reduce prescription drug costs.

In February 2023, the Department of Health and Human Services also issued a proposal in response to an October 2022 executive order from President Biden that includes a proposed prescription drug pricing model that will test whether targeted Medicare payment adjustments will sufficiently incentivize manufacturers to complete confirmatory trials for drugs approved through FDA’s accelerated approval pathway.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

• At a federal level, President Trump reversed some of President Biden’s executive orders including rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans.” President Trump may issue new

executive orders designed to impact drug pricing, and/or rescind or modify the previous administration’s efforts to address drug costs.

A number of these and other proposed measures may require authorization through additional legislation to become effective.

Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.

We cannot predict what healthcare reform initiatives may be adopted in the future.

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Human Capital

We believe the success of Intellia’s mission largely depends on our ability to attract and retain highly skilled employees.

We believe programs that foster company engagement, diversity, equity and inclusion, growth and development while providing competitive compensation and benefits will attract a diverse population of employees who will bring innovative ideas and creative solutions that will enable the achievement of our goals.

Company Communications and Engagement .

Many of our employees actively participate in our Cultural Ambassador program, fostering a grassroots approach to engagement with support and guidance from our executive leadership team.

Our Cultural Ambassador programs focus on the following:

diversity, equity and inclusion, continuous learning, wellness and sustainability, social events, community outreach, and Intellia values and engagement.

Diversity, Equity and Inclusion.

As we continue to grow as an organization, we remain dedicated to championing a culture that celebrates diversity and fosters collaboration inside the organization and in our community.

Through our partnerships, we can build key relationships in our community and help pave the way for those wanting to pursue a career in the biotechnology industry.

We are committed to increasing representation of underrepresented minorities at Intellia, particularly in leadership roles.

Our recruiting team underwent bias awareness training, and we have sponsored career fairs and conferences at organizations focused on underrepresented communities to ensure we continue to attract the best talent and increase representation.

In addition, current employees are participating in unconscious bias training throughout the year.

We continue to expand our DEI efforts with the launch of Employee Resource Groups (“ERGs”) which are voluntary, employee-led groups focused on fostering a diverse, inclusive workplace aligned with ONE Intellia.

They are led and participated in by employees who share a characteristic, whether by identity or interest.

The groups exist to provide support and help in personal or career development and to create a safe space where employees can bring their whole selves to the table.

Coworkers are also invited to join the ERG to support their colleagues.

Our team of Senior and Executive Vice Presidents is 54% female and 31% are ethnically diverse.

Overall, as of February 16, 2024, our employee population consists of 54% women and 46% men.

Compensation and Benefits, Health and Wellness.

We are committed to equitable pay, irrespective of gender, race, ethnicity, or sexual orientation, and conduct comprehensive pay-equity analyses on a semi-annual basis.

We believe the success of Intellia’s mission largely depends on our ability to attract and retain highly skilled employees who bring high integrity, innovative ideas, and creative solutions to Intellia.

In order to attract and retain such highly skilled employees with desired expertise and experience, we support programs that foster our company values, as well as employee engagement, growth and development, while providing competitive compensation and benefits.

We believe it is imperative that the board of directors and senior management strongly support a no-tolerance stance for workplace harassment, biases and unethical behavior.

All employees, including senior management and directors, are required to abide by, review and confirm compliance to our Code of Business Conduct and Ethics and other internal policies that outline our high expectations.

Many of our employees actively participate in our employee engagement programs, which are designed as a grassroots approach to employee engagement with support and guidance from our executive leadership team.

Our engagement programs are an expression of our company values—ONE, EXPLORE, DISRUPT, and DELIVER.

Our employee resource groups, including groups focused on mentorship, career development, social activities, and affinity groups, exist to provide support and help in personal or career development and to create a safe space where employees can bring their whole selves to our collaborative workplace.

Our employee engagement groups are led by employee volunteers, supported by executive sponsors, and all of our employees are invited to participate to support their colleagues.

As we build our company and execute our strategy, we continue to support a culture that celebrates diverse expertise and experiences and fosters collaboration inside the organization and in our community.

We believe in enabling and supporting a collaborative environment that allows our employees’ varying voices to be heard and reinforces our company values.

As part of our efforts to foster a collaborative environment, support employee engagement, and attract top talent, we provide several types of development trainings for our management teams, including our human resources recruiting team, such as bias awareness training.

In addition, we have sponsored career fairs and conferences at organizations focused on scientists and other highly skilled biotechnology professionals with diverse experiences and backgrounds.

We are committed to equitable pay, irrespective of gender, race, ethnicity, sexual orientation, marital status, veteran status, disability or any other legally protected status and conduct comprehensive pay-equity analyses on a semi-annual basis.

We offer competitive benefits, including competitive salaries, excellent health insurance, and a 401(k) match.

We are committed to pay equity, regardless of race, color, religion, gender, national origin, age, sexual orientation, marital or veteran status, disability, or any other legally protected status.

Growth and Development .

Investing in our employees’ personal and career growth is an important priority at Intellia.

We aim to provide a wide range of on-the-job development opportunities, as well as in-person, virtual and off-site training seminars, and tools.

Our goal is to ensure our employees have the skills they may need in the future.

Of particular importance is fostering leadership with our quarterly “Development Day” series, which serves as a reminder for employees to check-in with themselves and their manager on their development goals.

Additionally, we offer seminars and tools to our employees focused on career development within the organization.

As part of these initiatives, we conduct an annual development program for our employees to work with their managers to set professional development goals and an action plan.

Our goal is to ensure our employees have the skills they need to find success now and in the future.

Of particular importance is fostering leadership with a wide variety of development programming for our employees, including seminars and tools focused on career development within the organization.

We also have an internal mentorship program for our research and development employees, who can work with more senior employees to learn new skills.

Conduct and Ethics.

We believe it is imperative that the board of directors and senior management strongly support a no-tolerance stance for workplace harassment, biases and unethical behavior.

All employees, including senior management, are required to abide by, review and confirm compliance to the company’s Code of Business Conduct and Ethics Policy and other internal policies that outline our high expectations.

As of February 14, 2025, we had 403 full-time employees, 303 of whom were primarily engaged in research and development activities and 109 of whom have an M.D.

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Our principal executive offices are located at 40 Erie Street, Suite 130, Cambridge, Massachusetts 02139.

Our telephone number is (857) 285-6200, and our website is located at www.intelliatx.com.

Our telephone number is (857)

285-6200, and our website is located at www.intelliatx.com.

References to our website are inactive textual references only and the content of our website should not be deemed incorporated by reference into this Annual Report on Form 10-K.

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The SEC’s Internet website address is http://www.sec.gov.

A copy of our Corporate Governance Guidelines, Code of Conduct and Business Ethics and the charters of the Audit Committee, Compensation and Talent Development Committee and Nominating and Corporate Governance Committee are posted on our website, www.intelliatx.com, under “Investors & Media”.

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A copy of our Corporate Governance Guidelines, Code of Conduct and Business Ethics and the charters of the Audit Committee, Compensation and Talent Development Committee, Nominating and Corporate Governance Committee, and Science and Technology Committee are posted on our website, www.intelliatx.com, under “Investors & Media.”

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Investing in our common stock involves a high degree of risk.

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CRISPR/Cas9 genome editing technology has only recently been clinically validated for human therapeutic use.

The approaches we are taking to discover and develop novel therapeutics using CRISPR/Cas9 systems are unproven and may never lead to marketable products.

If we are unable to develop viable product candidates, achieve regulatory approval for any such product candidate or market and sell any product candidates, we may never achieve profitability.

We are focused on developing curative medicines utilizing CRISPR/Cas9 genome editing technology, including in vivo therapies and ex vivo engineered cell therapies.

We are focused on developing novel therapeutics utilizing CRISPR/Cas9 genome editing technology, including in vivo therapies and ex vivo engineered cell therapies.

Although there have been significant advances in recent years in the fields of gene therapy and genome editing, in vivo CRISPR-based genome editing technologies are relatively new and their therapeutic utility is largely unproven.

Our approach to developing therapies centers on using CRISPR/Cas9 technology to alter, introduce or remove genetic information in vivo to treat various disorders, or to engineer human cells ex vivo to create therapeutic cells that can be introduced into the human body to address the underlying disease.

Successful development of products by us will require solving a number of issues, including developing or obtaining technologies to safely deliver a therapeutic agent into target cells within the human body or engineer human cells while outside of the body such that the modified cells can have a therapeutic effect when delivered to the patient, optimizing the efficacy and specificity of such products, and ensuring and demonstrating the therapeutic selectivity, efficacy, potency, purity and safety of such products.

The approaches we are taking to discover and develop novel therapeutics using CRISPR/Cas9 systems are unproven and may never lead to marketable products.

Successful development of products by us will require solving a number of issues, including developing or obtaining technologies to safely deliver a therapeutic agent into target cells within the human body or engineer human cells while outside of the body such that the modified cells can have a therapeutic effect when delivered to the patient, optimizing the efficacy and specificity of such products, and demonstrating the therapeutic selectivity, efficacy, potency, purity and safety of such products.

There can be no assurance we will be successful in solving any or all of these issues.

With regards to CRISPR/Cas9-based therapies specifically, we are in clinical-stage development for NTLA-2001 and NTLA-2002 and advancing towards clinical testing for our other in vivo and ex vivo product candidates.

Although one CRISPR/Cas9-edited ex vivo therapy has been recently approved in the United States (“U.S.”) and European Union (“EU”), no genome editing in vivo therapy has been approved in the U.S., EU countries or other key jurisdictions, and the potential to successfully obtain approval for any of our CRISPR/Cas9 product candidates remains unproven.

With regards to CRISPR/Cas9-based therapies specifically, we are in clinical-stage development for nex-z and NTLA-2002 and advancing towards clinical testing for our other in vivo and ex vivo product candidates.

Although one CRISPR/Cas9-edited ex vivo therapy has been approved in the United States (“U.S.”) and European Union (“EU”), no genome editing in vivo therapy has been approved in the U.S., EU countries or other key jurisdictions, and the potential to successfully obtain approval for any of our CRISPR/Cas9 product candidates remains uncertain.

If we are unable to develop viable product candidates, achieve regulatory approval for any such product candidate or market and sell any resulting product, we may never achieve profitability.

Our future success also is highly dependent on the successful development of CRISPR-based genome editing technologies, cellular delivery methods and therapeutic applications for the indications on which we have focused our ongoing research and development efforts.

We may decide to alter or abandon these programs as new data become available and we gain experience in developing CRISPR/Cas9-based therapeutics.

We cannot be sure that our CRISPR/Cas9 efforts and technologies will yield satisfactory products that are safe and effective, sufficiently pure or potent, manufacturable, scalable or profitable in our selected indications or any other indication we pursue.

indications or any other indication we pursue.

We cannot guarantee that progress or success in developing any particular CRISPR/Cas9-based therapeutic product will translate to other CRISPR/Cas9-based products.

Public perception and related media coverage of potential therapy-related efficacy or safety issues, including adoption of new therapeutics or novel approaches to treatment, as well as ethical concerns related specifically to genome editing and CRISPR/Cas9, may adversely influence the willingness of subjects to participate in clinical trials, or if any therapeutic is approved, of physicians and patients to accept these novel and personalized treatments.

Public perception and related media coverage of potential therapy-related efficacy or safety issues, including adoption of new therapeutics or novel approaches to treatment, as well as ethical concerns related specifically to genome editing and CRISPR-based therapies, may adversely influence the willingness of subjects to participate in clinical trials, or if any therapeutic is approved, of physicians and patients to accept these novel and personalized treatments.

Physicians, healthcare providers and third party payors often are slow to adopt new products, technologies and treatment practices, particularly those that may also require additional upfront costs and training.

Physicians may not be willing to undergo training to adopt these novel and potentially personalized therapies, may decide the particular therapy is too complex or potentially risky to adopt without appropriate training, and may choose not to administer the therapy.

Physicians may not be willing to undergo training to adopt these novel therapies, may decide the particular therapy is too complex or potentially risky to adopt without appropriate training, and may choose not to administer the therapy.

Further, due to health conditions, genetic profile or other reasons, certain patients may not be candidates for the therapies.

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It is impossible to predict whether legislative changes will be enacted, regulations, policies or guidance changed, or interpretations by agencies or courts changed, or what the impact of such changes, if any, may be.

Based on these and other factors, healthcare providers and payors may decide that the benefits of these new therapies do not or will not outweigh their costs.

Based on these and other factors, healthcare providers and payors may decide that the benefits of these new therapies do not or will not outweigh their costs, which would affect our ability to market and sell our product candidates and achieve profitability.

Clinical development involves a lengthy and expensive process, with an uncertain outcome.

We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of any product candidates.

All of our programs are still in the discovery, preclinical or clinical stage.

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Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain approval of their products.

We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of any product candidates.

Successful completion of clinical trials is a prerequisite to submitting a Biologics License Application (“BLA”) to the U.S.

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• clinical trials of any product candidates may fail to show safety or efficacy, or could produce negative or inconclusive results, which could result in having to conduct additional preclinical studies or clinical trials or terminating the product development programs;

pace of enrollment is slower than anticipated, or subjects drop out or fail to return for post-treatment follow-up at a higher rate than we anticipated;

• we may not be able to initiate or complete clinical trials of a product candidate if the required number of subjects is larger than we anticipated, the number of subjects willing to enroll is smaller than required, the pace of enrollment is slower than anticipated, or subjects drop out or fail to return for post-treatment follow-up at a higher rate than we anticipated;

• we may need to educate medical personnel, including clinical investigators, and patients regarding the potential benefits and side effect profile of each of our product candidates;

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• animal models may not exist, or available animal models may be inadequate, for some of the human diseases we choose to pursue in our programs, or the preclinical studies we perform as part of our programs;

• our third party contractors may fail to comply with regulatory requirements or meet their performance obligations to us in a timely manner, or at all, or may deviate from the clinical trial protocol or drop out of the trial, which may require that we add new clinical trial sites or investigators;

• our third party contractors, clinical trial sites or investigators may fail to comply with regulatory requirements or meet their performance obligations to us in a timely manner, or at all, or may deviate from the clinical trial protocol or drop out of the trial, which may require that we add new clinical trial sites or investigators;

• we may elect to, or regulators, IRBs or ethics committees may require that we or our investigators, suspend or terminate clinical research or trials for various reasons, including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks;

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• we may face challenges in establishing sales and marketing capabilities in anticipation of, and after obtaining, any regulatory approval to gain market authorization;

• the FDA or other regulatory authorities may revise the requirements for authorizing our clinical trials or approving our product candidates, or their interpretation of the authorization or approval requirements may not be what we anticipate or require us to adopt a Risk Evaluation and Mitigation Strategy (“REMS”) or similar requirements as a condition of approval;

• the FDA or other regulatory authorities may revise the requirements for authorizing our clinical trials or approving our product candidates, or their interpretation of the authorization or approval requirements may not be what we anticipate or require us to adopt Risk Evaluation and Mitigation Strategy (“REMS”) as a condition of approval;

• we may not ultimately obtain regulatory approval for a BLA, or corresponding applications outside the U.S., such as a marketing authorization application in the U.K.

and other similar regulatory authorities, such as the EMA, which may have very limited or no experience with the clinical development of CRISPR/Cas9-based therapeutics, particularly in vivo therapeutics.

We could also encounter delays if a clinical trial is suspended or terminated by us, the IRBs of the institutions in which such trials are being conducted, the relevant ethics committee or the FDA or other relevant regulatory authorities, or

if the Data Monitoring Committee (“DMC”) for such trial recommends such suspension or termination.

Such authorities may impose or recommend such a suspension or termination due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities, resulting in the imposition of a clinical hold, manufacturing or quality control issues, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product or treatment, failure to establish or achieve clinically meaningful trial endpoints, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.

and other similar regulatory authorities, which may have very limited or no experience with the clinical development of CRISPR/Cas9-based therapeutics, particularly in vivo therapeutics.

Such authorities may impose or recommend such a suspension or termination due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our study protocols, inspection of the clinical trial operations or trial site by the FDA or other regulatory authorities, resulting in the imposition of a clinical hold, manufacturing or quality control issues, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product or treatment, failure to establish or achieve clinically meaningful trial endpoints, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.

Many of the factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also lead to a delay in submitting a BLA or comparable marketing application or ultimately lead to the denial of regulatory approval of our product candidates.

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Additionally, because our in vivo technology potentially involves genome editing across multiple cell and tissue types, we are subject to many of the challenges and risks that other genome editing therapeutics and gene therapies face, including:

• regulatory guidance regarding the requirements governing gene and genome editing therapy products have changed and may continue to change in the future, including, e.g., the finalized guidance document titled “Human Gene Therapy Products Incorporating Human Genome Editing” that the FDA issued in January 2024;

• regulatory guidance for gene and genome editing therapy products has changed and may continue to change in the future, including, e.g., the finalized guidance document titled “Human Gene Therapy Products Incorporating Human Genome Editing” that the FDA issued in January 2024 and the draft guidance document titled “Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products” published in November 2024;

• to date, only a limited number of products that involve in vivo gene transfer have been approved globally;

• improper modulation of a gene sequence, including unintended editing events, insertion of a sequence into certain locations in a patient’s chromosome or other effects related to the biodistribution of our product candidates, could lead to cancer, other aberrantly functioning cells or other diseases, including death;

• transient expression of the Cas9 protein or other genome editing components of our product candidates could lead to patients having an immunological reaction towards those cells, which could be severe or life-threatening;

• transient expression of the Cas9 protein or other genome editing components of our product candidates could lead to patients having an immunological reaction towards those modified cells, which could be severe or life-threatening;

• corrective expression of a missing protein in patients’ cells could result in the protein being recognized as foreign, and lead to a sustained immunological reaction against the expressed protein or expressing cells, which could be severe or life-threatening;

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For example, patients treated with engineered cell-based gene therapies may experience an allogeneic response leading to allograft rejection and potential local and systemic toxicities, which could be severe or life-threatening.

To date, most human clinical trials utilizing either in vivo or ex vivo CRISPR-based therapeutics, including our clinical trials for NTLA-2001 for transthyretin (“ATTR”) amyloidosis and NTLA-2002 for hereditary angioedema (“HAE”), are still at a clinical stage, with only one ex vivo CRISPR-based therapeutic product approved in December 2023 in the U.S.

We have ongoing clinical trials in various countries for NTLA-2001 and NTLA-2002 for patients with ATTR amyloidosis and HAE, respectively.

To date, most human clinical trials utilizing either in vivo or ex vivo CRISPR-based therapeutics are still at a clinical stage, with only one ex vivo CRISPR-based therapeutic product approved in the U.S.

We have ongoing clinical trials in various countries for nex-z for transthyretin (“ATTR”) amyloidosis and NTLA-2002 for hereditary angioedema (“HAE”).

There is no certainty that the FDA or other similar agencies will continue to apply to all our CRISPR/Cas9 product candidates the same regulatory pathway and requirements it is applying to other in vivo therapies or ex vivo engineered therapeutics.

In addition, if any product candidates encounter safety or efficacy problems, development delays, regulatory issues or other problems, our development plans and business could be significantly harmed.

For the reasons described above, among others, regulatory bodies, particularly the FDA, have requested, and may request in the future, additional

preclinical studies for genome editing products, such as additional studies related to toxicology, biodistribution or reproductive health, and/or preclinical studies earlier in clinical development compared to other therapeutic modalities.

For the reasons described above, among others, regulatory bodies, particularly the FDA, have requested, and may request in the future, additional preclinical studies for genome editing products, such as additional studies related to toxicology, biodistribution or reproductive health, and/or preclinical studies earlier in clinical development compared to other therapeutic modalities.

Although the FDA cleared the INDs that we have submitted, it is possible that the FDA may impose requirements that result in a delay of any of our programs, including our submission of a BLA or comparable marketing application, or their regulatory approval.

For example, following the March 2023 IND clearance for NTLA-2002, the FDA requested supplemental preclinical data related to the inclusion of female patients of child-bearing potential.

We expect to submit these data in advance of the planned Phase 3 trial, which will complement the clinical data collected from female patients of child-bearing potential dosed in the ongoing Phase 1/2 study.

We cannot guarantee the timing or outcome of these preclinical studies or whether the FDA may require that additional preclinical studies be conducted before commencement of our Phase 3 trial for NTLA-2002.

If we are unable to complete the required studies satisfactorily, the FDA or other regulatory bodies could require that we exclude certain patient populations from clinical studies, place our clinical studies on hold, or require us to cease further clinical studies or deny approval of such product candidates.

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Any of these occurrences may harm our ability to identify and develop product candidates, and may harm our business, financial condition, results of operations and prospects significantly.

We may experience manufacturing delays or other issues that prevent us from executing the clinical trials for NTLA-2001, NTLA-2002, NTLA-3001 or our other product candidates on the timeline we expect.

Moreover, we cannot guarantee that the FDA, MHRA, the New Zealand Medicines and Medical Devices Safety Authority, or other regulatory authorities will not change their requirements in the future or approve amendments to our INDs or equivalent regulatory filings, including for NTLA-2001, NTLA-2002, NTLA-3001 or our other product candidates on the timeline we expect.

We may experience manufacturing delays or other issues that prevent us from executing the clinical trials for nex-z and NTLA-2002 or our other product candidates on the timeline we expect.

Moreover, we cannot guarantee that the FDA, MHRA, the New Zealand Medicines and Medical Devices Safety Authority, or other regulatory authorities will not change their requirements in the future or that they will approve amendments to our INDs or equivalent regulatory filings, including for nex-z and NTLA-2002, or our other product candidates, on the timeline we expect.

Results, including data from our preclinical and clinical studies, are not necessarily predictive of our other ongoing and future preclinical and clinical studies, and they do not guarantee or indicate the likelihood of approval of any potential product candidate by the FDA or any other regulatory agency.

If we cannot replicate positive results from any of our preclinical or clinical activities and studies, we may be unable to successfully develop, obtain regulatory approval for and commercialize any potential product candidate.

From time to time, we may disclose interim data from our clinical trials, such as the interim results of our ongoing Phase 1 study of NTLA-2001 or Phase 1/2 study of NTLA-2002 or planned Phase 1 study of NTLA-3001.

Interim data from clinical trials that have not been completed are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available or as patients from our clinical trials continue other treatments for their disease.

From time to time, we may disclose interim data from our clinical trials, such as the interim results of our ongoing Phase 1 study of nex-z or Phase 1/2 study of NTLA-2002.

Interim data from clinical trials that have not been completed are subject to the risk that the later results may be materially different as patient enrollment continues.

We also make assumptions, estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data.

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For more information regarding these risks, see also the remainder of this risk factor section.

Negative public opinion and increased regulatory scrutiny of CRISPR/Cas9 use, genome editing or gene therapy generally may damage public perception of the safety of any product candidates that we develop and adversely affect our ability to conduct our business or obtain regulatory approvals for such product candidates.

Gene therapy in general, and genome editing in particular, remain novel technologies, with only a limited number of gene therapy products approved to date in the U.S.

Public perception may be influenced by claims that gene therapy or genome editing, including the use of CRISPR/Cas9, is unsafe or unethical, or carries an undue risk of side

effects, such as improper modification of a gene sequence in a patient’s chromosome that could lead to cancer, and gene therapy or genome editing may not gain the acceptance of the public or the medical community.

In particular, our success will depend upon physicians who specialize in the treatment of diseases targeted by our product candidates prescribing treatments that involve the use of our product candidates in lieu of, or in addition to, existing treatments with which they are more familiar and for which greater clinical data may be available.

Negative public opinion and increased regulatory scrutiny of CRISPR/Cas9 use, genome editing or gene therapy may damage public perception of the safety of our product candidates and adversely affect our ability to conduct our business or obtain regulatory approvals for such product candidates.

Gene therapy in general, and genome editing in particular, remain novel technologies, with only a limited number of gene therapy products, and only one ex vivo genome editing product, approved to date in the U.S.

Public perception may be influenced by claims that gene therapy or genome editing, including the use of CRISPR/Cas9, is unsafe or unethical, or carries an undue risk of side effects, such as improper modification of a gene sequence in a patient’s chromosome that could lead to disease such as cancer, and gene therapy or genome editing may not gain the acceptance of the public or the medical community.

In particular, our success will depend upon physicians who specialize in the treatment of diseases targeted by our product candidates prescribing our product candidates in lieu of, or in addition to, existing treatments with which they are more familiar and for which greater clinical data may be available.

In addition, responses by the U.S., state or foreign governments to negative public perception or ethical concerns may result in new legislation or regulations that could limit our ability to develop or commercialize any product candidates, obtain or maintain regulatory approval or otherwise achieve profitability.

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Serious adverse events, such as these, in our clinical trials, or other clinical trials involving gene therapy or genome editing products or our competitors’ products, even if not ultimately attributable to the relevant product candidates, and the resulting publicity could result in increased government regulation, unfavorable public perception, potential regulatory delays in the testing or approval of our product candidates, stricter labeling requirements for those product candidates that are approved and a decrease in demand for any such product candidate.

In addition, the use of the technology by third parties in areas that are not being pursued by us, such as for targeting and editing of embryonic cells, could adversely impact public and governmental perceptions regarding the ethics and risks of the CRISPR/Cas9 technology and lead to social or legal changes that could limit our ability to apply the technology to develop human therapies addressing disease.

In addition, the use of genome editing technology by third parties in areas that are not being pursued by us, such as for targeting and editing of embryonic cells, could adversely impact public and governmental perceptions regarding the ethics and risks of CRISPR/Cas9 technology and lead to social or legal changes that could limit our ability to apply the technology to develop human therapies addressing disease.

For example, reports of the use of CRISPR/Cas9 in China and Russia to edit embryos in utero have generated, and may continue to generate, negative public perception about the use of the technology in humans.

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Inconclusive results, lack of efficacy, adverse events or additional safety concerns in clinical trials that we or others conduct may impede the regulatory approval process or overall market acceptance of our product candidates.

Therapeutic applications of genome editing technologies, and CRISPR/Cas9 in particular, for both in vivo products and ex vivo products, are unproven and must undergo rigorous clinical trials and regulatory review before receiving marketing authorization.

Therapeutic applications of genome editing technologies, and CRISPR/Cas9 in particular, for both in vivo products and ex vivo products, are uncertain and must undergo rigorous clinical trials and regulatory review before receiving marketing authorization.

If the results of our clinical studies or those of any other third parties, including with respect to genome editing technology or engineered cell therapies, are inconclusive or fail to show efficacy or if such clinical trials give rise to safety concerns or adverse events, we may:

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If we fail to develop product candidates, our commercial opportunity, if any, will be limited.

We are at a clinical stage of development and our technology and approach has not yet led, and may never lead, to the approval or commercialization of any of our product candidates, including NTLA-2001 for ATTR amyloidosis or NTLA-2002 for HAE, or for other product candidates, including NTLA-3001 for alpha-1 antitrypsin deficiency, being deemed appropriate for clinical development and ultimately approval by a regulatory agency.

We are at a clinical stage of development and our technology and approach has not yet led, and may never lead, to the approval or commercialization of any of our product candidates, including nex-z for ATTR amyloidosis, NTLA-2002 for HAE, or to our other preclinical stage product candidates being deemed appropriate for clinical development and ultimately approval by a regulatory agency.

Even if we are successful in building our pipeline of product candidates, completing clinical development, establishing the necessary manufacturing processes and capabilities, obtaining regulatory approvals and commercializing product candidates will require substantial additional funding and are subject to the risks of failure inherent in therapeutic product development.

Investment in biopharmaceutical product development involves significant risk that any potential product candidate will fail to demonstrate acceptable safety and efficacy profiles, gain regulatory approval, or become commercially viable.

We cannot provide any assurance that we will be able to successfully advance any of our product candidates, including NTLA-2001, NTLA-2002, NTLA-3001 or product candidates developed through our collaborations, through the entire research and development process.

We cannot provide any assurance that we will be able to successfully advance any of our product candidates, including nex-z, NTLA-2002 or product candidates developed through our collaborations, through the entire research and development process.

Any of our other programs may show promise yet fail to yield product candidates for clinical development or commercialization for many reasons.

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• product labeling or product insert requirements of the FDA or other regulatory authorities;

• limitations or warnings contained in the labeling approved by the FDA or other regulatory authorities;

• limitations or warnings contained in the labeling approved by the FDA or other regulatory authorities, which may include warnings or other information about possible unintended DNA changes;

• the timing of market introduction of our product candidates;

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• the cost of treatment in relation to alternative treatments;

• the amount of upfront costs or training required for healthcare providers to administer our product candidates;

• the amount of upfront costs or training required for healthcare providers to administer our product candidates, which may include availability of adequate facilities and equipment;

• the availability of adequate coverage, reimbursement and pricing by government authorities and other third party payors;

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Risks Related to Third Party and Licensed Intellectual Property

Third party claims of intellectual property infringement against us, our licensors or our collaborators may prevent or delay our product discovery and development efforts.

Third party claims of intellectual property infringement against us, our licensors or our collaborators may prevent or delay our product discovery, research, development, and/or commercialization efforts.

Our commercial success depends in part on our avoiding infringement of the valid patents and proprietary rights of third parties.

Numerous U.S.

and foreign issued patents and pending patent applications owned by third parties exist in the fields in which we are developing our product candidates and in areas potentially related to components and methods we use or may use in our research and development efforts.

As industry, government, academia and other biotechnology and pharmaceutical research expands and more patents are issued, the risk increases that our product candidates may give rise to claims of infringement of the patent rights of others.

Our development candidates are complex and may include multiple components such as Cas9 protein or messenger ribonucleic acid encoding Cas9 protein, guide ribonucleic acids (“gRNAs”), targeting molecules, or formulation components such as lipids.

We cannot guarantee that any of these components of our technology, processes, future product candidates or the use of such product candidates do not infringe third party patents.

As our product candidates advance through development, as research in the fields in which we work expands, and as more patents are issued, the risk increases that our product candidates, or the resulting products, may give rise to claims of infringement of patent rights owned or controlled by third parties.

Our product candidates are complex and may include multiple components, such as Cas9 protein or messenger ribonucleic acid encoding Cas9 protein, guide ribonucleic acids (“gRNAs”), targeting molecules, virus or virus-like particles, or formulation components, such as lipids and lipid nanoparticles.

We cannot guarantee that any of these components of our technology, processes, or future product candidates, or the commercialization or use of such product candidates, do not infringe third party patents.

It is also possible that we have failed to identify relevant third party patents or applications.

Because patent rights are granted jurisdiction-by-jurisdiction, our freedom to practice certain technologies, including our ability to research, develop and commercialize our product candidates, may differ by country.

Because patent rights are granted jurisdiction-by-jurisdiction, our freedom to practice certain technologies, including our ability to research, develop and/or commercialize our product candidates, or the resulting products, may differ by country.

Third parties may assert that we infringe their patents or that we are otherwise employing their proprietary technology without authorization and may sue us.

There may be third party patents with claims to compositions, formulations, methods of manufacture or methods of use or treatment that cover product candidates we discover and develop.

There may be third party patents with claims to compositions, formulations, methods of manufacture or methods of use or treatment that cover product candidates we discover, research, develop, and/or commercialize.

For example, on July 8, 2024, BlueAllele Corp.

(“BlueAllele”) filed a complaint alleging infringement by Intellia of various patents in the U.S.

District Court for the District of Delaware, as more fully discussed in the Legal Proceedings section below.

Because patent applications can take many years to issue, there may be currently pending patent applications that may later result in issued patents that our product candidates may infringe.

In addition, third parties may obtain patents in the future and claim that use of our technologies or the manufacture, use or sale of our product candidates or products that we develop infringes these patents.

If a court of competent jurisdiction were to hold that we infringed such patents,

the holders of any such patents may be able to block our ability to commercialize the applicable product candidate or products unless we obtain a license under the applicable patents, or until such patents expire or are finally determined to be held invalid or unenforceable.

Such a license may not be available on commercially reasonable terms or at all.

Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us.

We could be forced, including by court order, to cease commercializing, manufacturing or importing the infringing technology or product.

In addition, we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent.

A finding of infringement could prevent us from commercializing one or more of our product candidates or products that we develop, force us to redesign our infringing products or force us to cease some or all of our business operations, any of which could materially harm our business and could prevent us from further developing and commercializing such products or future product candidates, thereby causing us significant harm.

If we are unable to obtain a necessary license to a third party patent on commercially reasonable terms, our ability to commercialize our product candidates or products that we develop may be impaired or delayed, which could in turn significantly harm our business.

If a court of competent jurisdiction were to hold that we infringed such patents, the holders of any such patents may be able to obtain a court order, or other form of relief, blocking our ability to commercialize, manufacture, import, and/or use the applicable product candidate, or resulting products, in the applicable jurisdiction(s) unless we obtain a license under the applicable patents, or until such patents expire or are finally determined to be held invalid or unenforceable.

Such a license may not be available on commercially reasonable terms or at all, or obtaining such a license may result in significant costs or delays.

Even if we were able to obtain a license, it could be limited in scope or geography or it could be non-exclusive, i.e., our competitors may be able to obtain a similar license on substantially the same or better terms.

If we are unable to obtain a license on reasonable terms, we could be forced, including by court order, to cease commercializing, manufacturing, importing, and/or using the infringing technology or product, or to redesign our infringing products, which could result in significant costs or delays.

In addition, we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found

to have willfully infringed a patent.

Any of the foregoing assertions or results could materially harm our business, cause significant costs or delays to our plans, and/or prevent us from further developing and commercializing the affected product candidates or products, thereby causing us significant harm.

In addition, we may be obligated to defend and/or indemnify our existing or potential collaborators, clinical investigators, contract manufacturing organizations (“CMOs”), CROs, consultants or vendors if a third party asserts similar infringement claims against them based on use of our technologies or the manufacture, use or sale of our product candidates or products that we develop, including product candidates or products developed with our collaborators.

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Even if we are not found liable for infringing or misappropriating the intellectual property of a third party, such claims could be expensive and time-consuming to defend and could result in adverse publicity that could harm our business.

Third parties may seek to claim intellectual property rights that encompass or overlap with intellectual property that we own or license from them or others.

Legal proceedings may be initiated to determine the scope and ownership of these rights, and could result in our loss of rights, including injunctions or other equitable relief that could effectively block our ability to further develop and commercialize our product candidates or products that we develop, including product candidates or products developed with our collaborators.

Third parties may seek to obtain intellectual property rights that encompass or overlap with intellectual property that we own or license from them or others.

Legal proceedings may be initiated to determine the scope and ownership of these rights, and could result in our loss of intellectual property rights.

As discussed above, legal proceedings asserting that we infringe, do not own, or do not have the right to exploit intellectual property rights of a third party could result in legal orders, such as injunctions or other equitable relief, that could effectively block our ability to further develop and commercialize our product candidates or products that we develop, or require us to obtain a license to such third party’s intellectual property rights, resulting in significant costs or delays.

In addition, as discussed above, such legal proceedings could affect product candidates or products developed with our collaborators, which may also require us to defend and/or indemnify our collaborators.

For example, through a license agreement between Caribou Biosciences, Inc.

and us (the “Caribou License”), we sublicense the rights of the Regents of the University of California and the University of Vienna (collectively, “UC/Vienna”) to a worldwide patent portfolio that covers methods of use and compositions relating to engineered CRISPR/Cas9 systems for, among other things, cleaving or editing DNA and altering gene product expression in various organisms, including eukaryotic cells.

We sublicense the UC/Vienna rights to this portfolio for human therapeutic, prophylactic and palliative uses, including companion diagnostics, except for anti-fungal and anti-microbial uses.

This patent portfolio to-date includes, for example, multiple granted, allowed, and/or allowable patent applications in the U.S., as well as granted patents from the European Patent Office, the United Kingdom’s Intellectual Property Office, the German Patent and Trade Mark Office, Australia’s Intellectual Property agency and China’s Intellectual Property Office, among others.

We sublicense the UC/Vienna rights to this patent portfolio for human therapeutic, prophylactic and palliative uses, including companion diagnostics, except for anti-fungal and anti-microbial uses.

Because UC/Vienna co-own this portfolio with Dr.

Emmanuelle Charpentier (who has separately licensed her rights to other parties), we refer to this co-owned worldwide patent portfolio as the “UC/Vienna/Charpentier patent family.”

Third parties could assert that our licensors, such as UC/Vienna/Charpentier, do not have rights to the licensed technology (such as the CRISPR/Cas9 technology in the case of the Caribou License), including inventorship and ownership rights to currently issued or allowable patents, or that any rights owned by our licensors, such as UC/Vienna/Charpentier, are limited.

If such third parties were found to have rights to the licensed technology (such as CRISPR/Cas9 technology), we could be required to obtain rights from such parties or cease our development and commercialization efforts.

For example, under our Caribou License, we have rights to patent applications owned by UC/Vienna/Charpentier covering certain aspects of CRISPR/Cas9 systems to edit genes in eukaryotic cells, including human cells (collectively, the “UC/Vienna/Charpentier eukaryotic patent family”).

The Broad Institute, Massachusetts Institute of Technology, the President and Fellows of Harvard College and the Rockefeller University (collectively, the “Broad Institute”) co-own patents and patent applications that also claim CRISPR/Cas9 systems to edit genes in eukaryotic cells (collectively, the “Broad Institute patent family”).

Because the respective owners of various UC/Vienna/Charpentier patent applications and the Broad Institute patent family both allege owning intellectual property claiming overlapping aspects of CRISPR/Cas9 systems and methods to edit genes in eukaryotic cells, including human cells, our ability to market and sell CRISPR/Cas9-based human therapeutics may be adversely impacted depending on the scope and actual ownership over the inventions claimed in the competing patent portfolios.

On June 25, 2019, the Patent Trial and Appeal Board (“PTAB”) of the U.S.

Patent and Trademark Office (“USPTO”) declared an interference between the UC/Vienna/Charpentier eukaryotic patent family and the Broad Institute patent

family to determine which research group first invented the use of the CRISPR/Cas9 technology in eukaryotic cells and, therefore, is entitled to the U.S.

Emmanuelle Charpentier (who has separately licensed her rights to other parties), we refer to this co-owned worldwide patent portfolio as the “UC/Vienna/Charpentier patent family.” In addition, we have granted further sublicenses to this portfolio to our collaborators in certain fields of use.

The UC/Vienna/Charpentier patent portfolio to-date includes, for example, multiple granted, allowed, and/or allowable patent applications in the U.S., as well as granted patents from the European Patent Office, the United Kingdom’s Intellectual Property Office, the German Patent and Trade Mark Office, Australia’s Intellectual Property agency and China’s Intellectual Property Office, among others.

Third parties could assert, and have in the past asserted, that our licensors do not have rights to the licensed patents and/or patent applications (such as, in the case of the Caribou License, the UC/Vienna/Charpentier patent family), including inventorship and ownership rights to currently issued or allowable patents.

In addition, third parties could assert, and have asserted, that our licensors, or any rights owned by our licensors, such as UC/Vienna/Charpentier, are limited.

If such third parties were found to have rights to patents or patent applications covering our licensed technology (such as CRISPR/Cas9 technology), they could assert that we infringe such patents and, as discussed above, we may be required to obtain rights from such parties (e.g., by obtaining a license) or cease our development and commercialization efforts.

Even if such third parties are not ultimately successful in their claims, such assertions could result in significant costs or delays to our programs.

For example, various patent applications within the UC/Vienna/Charpentier patent family and the Broad Institute patent family have been involved in patent interferences and other patent challenges in the U.S.

and other jurisdictions, in which the respective owners have alleged, and are alleging, that they invented and/or own intellectual property claiming overlapping aspects of CRISPR/Cas9 systems.

Specifically, certain patent applications within the UC/Vienna/Charpentier patent family, licensed to us under the Caribou License, covering certain aspects of CRISPR/Cas9 systems to edit genes in eukaryotic cells, including human cells (collectively, the “UC/Vienna/Charpentier eukaryotic patent family”) have been the subject of patent interferences involving patents and patent application co-owned by the Broad Institute, Massachusetts Institute of Technology, the President and Fellows of Harvard College and the Rockefeller University (collectively, the “Broad Institute”) that also claim CRISPR/Cas9 systems to edit genes in eukaryotic cells (collectively, the “Broad Institute patent family”).

For example, on June 25, 2019, the Patent Trial and Appeal Board (“PTAB”) of the U.S.

Patent and Trademark Office (“USPTO”) declared an interference between the UC/Vienna/Charpentier eukaryotic patent family and the Broad Institute patent family to determine which research group first invented the use of the CRISPR/Cas9 technology in eukaryotic cells and, therefore, is entitled to the U.S.

patents covering that invention.

The interference involved 14 allowable patent applications from the UC/Vienna/Charpentier eukaryotic patent family and 13 patents and one patent application from the Broad Institute patent family.

The interference involved 14 allowable patent applications from the UC/Vienna/Charpentier eukaryotic patent family

and 13 patents and one patent application from the Broad Institute patent family.

On February 28, 2022, the PTAB issued a Decision of Priority and Judgment in the interference finding that the Broad Institute patent family has priority over the UC/Vienna/Charpentier patent family with respect to the subject matter of the interference.

An appeal and cross-appeal from the interference are pending at the United States Court of Appeals for the Federal Circuit as Case Nos.

22-1594 and 22-1653.

On December 14, 2020, the PTAB declared an additional interference between the same 14 allowable patent applications in the UC/Vienna/Charpentier patent family, and one patent application owned by ToolGen, Inc.

And, on June 21, 2021, the PTAB declared another interference between the same 14 allowable patent applications in the UC/Vienna/Charpentier patent family and one patent application owned by Sigma-Aldrich Co.

22-1594 and 22-1653 (the “Interference Appeal”), and the oral argument occurred on May 7, 2024.

In addition, on December 14, 2020, the PTAB declared an interference between the same 14 allowable patent applications in the UC/Vienna/Charpentier eukaryotic patent family, and one patent application owned by ToolGen, Inc.

And, on June 21, 2021, the PTAB declared another interference between the same 14 allowable patent applications in the UC/Vienna/Charpentier eukaryotic patent family and one patent application owned by Sigma-Aldrich Co.

LLC (a subsidiary of Merck KGaA).

Because the patent applications involved in these interferences also purport to cover the use of CRISPR/Cas9 for gene editing in eukaryotic cells, the PTAB seeks to determine between the various groups which one invented first and is entitled to the resulting U.S.

A decision on motions issued in the ToolGen interference on September 28, 2022, and the priority phase of that interference was suspended until a mandate concludes the Federal Circuit appeal and cross-appeal in the UC/Vienna/Charpentier interference with the Broad Institute.

A decision on motions issued in the ToolGen interference on September 28, 2022, and the priority phase of that interference was suspended until a mandate concludes the Interference Appeal.

The Sigma-Aldrich interference is in its motions phase, and an order scheduling oral argument issued on October 24, 2022.

If either the Broad Institute, ToolGen or Sigma-Aldrich were to succeed in any of their respective interferences, the prevailing party or parties could seek to assert its issued patents against us based on our CRISPR/Cas9-based activities, including commercialization.

In addition, the prevailing party may assert similar infringement claims against our existing or potential collaborators, clinical investigators, CMOs, CROs, consultants or vendors, and we may be obligated to defend and/or indemnify those parties against such infringement claims.

In addition, other third parties, such as Vilnius University and Harvard University, filed patent applications claiming CRISPR/Cas9-related inventions around or within a year after the first patent application filed in the UC/Vienna/Charpentier patent family and allege (or may allege) that they invented one or more of the inventions claimed by UC/Vienna/Charpentier before UC/Vienna/Charpentier.

In addition, other third parties, such as Vilnius University (whose patents we have sublicensed under our Caribou Agreement) and Harvard University, filed patent applications claiming CRISPR/Cas9-related inventions around or within a year after the first patent application filed in the UC/Vienna/Charpentier patent family and allege (or may allege) that they invented one or more of the inventions claimed by UC/Vienna/Charpentier before UC/Vienna/Charpentier.

If the USPTO deems the scope of any of such third party’s claims sufficiently overlap with the allowable claims from the applicable patent applications in the UC/Vienna/Charpentier patent family, the USPTO could declare other interference proceedings to determine the actual inventor of such claims.

If these third parties were to prevail in their inventorship claims or obtain patent claims that cover our product candidates or related activities through these various legal proceedings, then we could be prevented from utilizing the intellectual property we have licensed from Caribou, as well as from developing and commercializing all or some of our products candidates unless we can obtain rights to the third parties’ intellectual property or avoid or invalidate it.

If either the Broad Institute, ToolGen or Sigma-Aldrich were to succeed in any of their respective interferences, or if other third parties, such as Vilnius University or Harvard University, pursue claims and succeed in such claims, the prevailing party or parties could assert its issued patents against us based on our CRISPR/Cas9-based activities, including research, development, and commercialization of our product candidates or resulting products.

In addition, such claims could result in the loss of rights to certain patents and patent applications in the UC/Vienna/Charpentier patent family and, thus, we (and our sublicensees) could lose the benefits that we obtained under our Caribou License to the UC/Vienna/Charpentier patent family.

The prevailing party may also assert similar infringement claims against our existing or potential collaborators, clinical investigators, CMOs, CROs, consultants or vendors, and we may be obligated to defend and/or indemnify those parties against such infringement claims.

As discussed above, such allegations or litigation may affect our ability to market and sell CRISPR/Cas9-based human therapeutics and may result in significant costs or delays to our programs.

Further, many third parties, including the third parties described above, have also filed patent applications and obtained patents covering aspects of the CRISPR/Cas9 technology in other key jurisdictions, including the EU members, the U.K., China and Japan.

If these patents are deemed valid and cover our product candidates or related activities, we could be prevented from developing and commercializing all or some of our product candidates unless we license the relevant intellectual property or avoid it.

If these patents are deemed valid and cover our product candidates or related activities, we could be prevented from developing and/or commercializing all or some of our product candidates, or the resulting products, unless we license the relevant intellectual property or avoid it.

Defense of any potential infringement claims, regardless of their merit, would involve substantial litigation expense, would be a substantial diversion of management and other employee resources from our business and may impact our reputation.

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In that event, we could be unable to further develop and commercialize our product candidates, which could harm our business significantly.

We depend on intellectual property licensed from third parties and termination or modification of any of these licenses could result in the loss of significant rights, which would harm our business.

For example, the BlueAllele litigation described above has required us to divert resources to the defense of BlueAllele’s allegations.

We have licensed intellectual property from third parties for use in our programs, and termination or modification of any of these licenses could result in the loss of those intellectual property rights, which could harm our business.

We are dependent on patents, know-how and proprietary technology, both our own and licensed from others, including Caribou.

Any termination of these licenses, loss by our licensors of the rights they receive from others, diminution of our rights or those of our licensors, or a finding that such intellectual property lacks legal effect, could result in the

loss of significant rights and could harm our ability to commercialize any product candidates.

For example, UC/Vienna could challenge Caribou’s rights under their agreement, including Caribou’s right to sublicense its rights to others, such as Intellia, and on what terms such a sublicense would be granted, each of which could adversely impact our rights under our agreement with Caribou.

Similarly, Caribou or other licensors, or other third parties from which we derive rights, could challenge the scope of our licensed rights or fields under our license agreement, which could adversely impact our exclusive rights to use CRISPR/Cas9 technology in our human therapeutics field.

For example, in connection with the arbitration regarding the scope of the Caribou License, we executed a leaseback agreement with Caribou granting it a sublicense to develop and commercialize CB-010, which is a chimeric antigen receptor T (“CAR-T”) cell therapy directed at CD19.

The leaseback agreement could adversely affect our business or that of our collaborators developing similar human therapeutics.

Disputes have and may arise between us and our licensors, our licensors and their licensors, or us and third parties that co-own intellectual property with our licensors or their licensors, regarding intellectual property subject to a license agreement, including those relating to:

• the scope of rights, if any, granted under the license agreement and other interpretation-related issues;

• whether and the extent to which our technology, products and processes infringe on, or derive from, intellectual property of the licensor that is not subject to the license agreement;

• whether our licensor or its licensor had the right to grant the license agreement, or whether they are compliant with their contractual obligations to their respective licensor(s);

Disputes have and may arise between us and our licensors (e.g., Caribou), our licensors (e.g., Caribou) and their licensors (e.g., UC/Vienna), or us and third parties that co-own intellectual property with our licensors or their licensors, regarding the scope of our rights to intellectual property that is subject to a license agreement, including those relating to:

• the scope of rights, if any, granted under the license agreement (e.g, the Caribou License) and other issues related to the terms of the license agreement;

• whether and the extent to which our technology, products and processes infringe, or derive from, intellectual property of the licensor that is not subject to the license agreement;

• whether our licensor or its licensor in the case of a sublicense (e.g., UC/Vienna as Caribou’s licensor in the case of our Caribou License) had the right to grant the license agreement, or whether they are compliant with their contractual obligations to their respective licensor(s);

• whether third parties are entitled to compensation or equitable relief, such as an injunction, for our use of the intellectual property without their authorization;

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We cannot be certain that such activities by our licensors or their respective licensors have been or will be conducted in compliance with applicable laws and regulations or in our best interests or will result in valid and enforceable patents or other intellectual property rights.

enforcement or defense, we cannot ensure the cooperation of our licensors or, in some cases, other necessary parties, such as the co-owners of the intellectual property from which we have not yet obtained a license.

Pursuant to the terms of the license agreements with our licensors, the licensors may have the right to control enforcement of our licensed patents or defense of any claims asserting the invalidity of these patents and, even if we are permitted to pursue such enforcement or defense, we cannot ensure the cooperation of our licensors or, in some cases, other necessary parties, such as the co-owners of the intellectual property from which we have not yet obtained a license.

We cannot be certain that our licensors or their licensors, and in some cases, their respective co-owners, will allocate sufficient resources or prioritize their or our enforcement of such patents or defense of such claims to protect our interests in the licensed patents.

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In addition, even when we have the right to control patent prosecution of licensed patents and patent applications, enforcement of licensed patents, or defense of claims asserting the invalidity of those patents, we may still be adversely affected or prejudiced by actions or inactions of our licensors and their counsel that took place prior to or after our assuming control.

We may not be successful in obtaining or maintaining necessary rights to product components and processes or other technology for our product development pipeline.

We may not be successful in obtaining or maintaining in-licensed rights to product components and processes or other technology for our product development pipeline.

The growth of our business will likely depend in part on our ability to acquire or in-license additional proprietary rights.

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(“Rewrite”), and these milestones and royalty payments could adversely affect our ability to research, develop and obtain approval of product candidates, as well as the overall profitability for us of any products that we may seek to commercialize.

In order to maintain our intellectual property rights under these agreements, we will need to meet certain specified

milestones, subject to certain cure provisions, in the development of our product candidates.

In order to maintain our intellectual property rights under these agreements, we will need to meet certain specified milestones, subject to certain cure provisions, in the development of our product candidates.

Further, our counterparties, including our licensors (or their licensors) or licensees, may dispute the terms, including amounts, that we are required to pay under the respective agreements.

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It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.

Moreover, in some circumstances, we do not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology that we license from third

We may also require the cooperation of our licensors or other necessary parties, such as the co-owners of the intellectual property from which we have not yet obtained a license, in order to enforce the licensed patent rights, and such cooperation may not be provided.

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There is a substantial amount of litigation as well as administrative proceedings for challenging patents, including interference, derivation, reexamination, and other post-grant proceedings before the USPTO and oppositions and other comparable proceedings in foreign jurisdictions, involving patents and other intellectual property rights in the biotechnology and pharmaceutical industries, and we expect this to be true for the CRISPR/Cas9 space as well.

Indeed, a number of third parties have filed oppositions challenging the validity, and seeking the revocation, of several CRISPR/Cas9 genome editing patents granted to UC/Vienna/Charpentier by the European Patent Office (“EPO”).

To date, UC/Vienna/Charpentier have successfully defended before the EPO’s opposition division the validity of their first European patent, which covers compositions comprising Cas9 and single gRNA molecules, as well as methods of editing DNA in vitro or ex vivo using Cas9 and single gRNAs.

The opponents to this patent have appealed the decision of the EPO’s opposition division.

If UC/Vienna/Charpentier fail in defending the validity of its first European patent, we may lose valuable intellectual property rights, such as the right to exclude others from using such intellectual property.

Such an outcome could have a material adverse effect on our business in Europe.

Similarly, third parties are opposing the other patents issued by the EPO to UC/Vienna/Charpentier, including their second European patent that was recently revoked by the EPO’s opposition division, a decision that UC/Vienna/Charpentier have appealed.

Although the claims of these other patents are more limited in scope compared to the first European patent, the inability to defend their respective validity could result in loss of valuable rights.

In addition, since the passage of the America Invents Act in 2013, U.S.

law also provides for other procedures to challenge patents, including inter partes reviews and post-grant reviews, that add uncertainty to the possibility of challenge to our developed or licensed patents and patent applications in the future.

Furthermore, for U.S.

applications in which all claims are entitled to a priority date before March 16, 2013, an interference proceeding can be provoked by a third party or instituted by the USPTO to determine who was the first to invent any of the subject matter covered by the patent claims of our applications.

See the above risk factor titled “ Third party claims of intellectual property infringement against us, our licensors or our collaborators may prevent or delay our product discovery and development efforts .”

As discussed above, a number of third parties have filed oppositions challenging the validity, and seeking the revocation, of several CRISPR/Cas9 genome editing patents granted to UC/Vienna/Charpentier by the European Patent Office (“EPO”).

law also provides for other procedures to challenge patents, including inter partes reviews, post-grant reviews and, in certain circumstances, interference or derivation proceedings, that add uncertainty to the possibility of challenge to our developed or licensed patents and patent applications in the future.

See the above risk factor entitled “ Third party claims of intellectual property infringement against us, our licensors or our collaborators may prevent or delay our product discovery, research, development and/or commercialization efforts .”

Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to practice the invention or stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products.

Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized.

As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

As a result, our

owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

Furthermore, even if they are unchallenged, our patents and patent applications may not adequately protect our intellectual property or prevent others from designing their products to avoid being covered by our claims.

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Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions.

misappropriation of our patents or other intellectual property rights, or the marketing of competing products in violation of our proprietary rights.

The legal systems of certain countries, such as China, Brazil, Russia, India and South Africa, do not favor the enforcement of patents, trade secrets and other intellectual property, particularly those relating to biopharmaceutical products, which could make it difficult in those jurisdictions for us to stop the infringement or misappropriation of our patents or other intellectual property rights, or the marketing of competing products in violation of our proprietary rights.

Proceedings to enforce our patent and other intellectual property rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business.

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With respect to the validity of our patents, for example, we cannot be certain that there is no invalidating prior art of which we, our patent counsel, and the patent examiner were unaware during prosecution.

If a defendant were to prevail on a legal assertion of invalidity, unpatentability and/or unenforceability, we would lose at least part, and perhaps all, of the

patent protection on our product candidates.

For example, as highlighted in the above risk factor entitled “ We could be unsuccessful in obtaining or maintaining adequate patent protection for one or more of our products or product candidates, or asserting and defending our intellectual property rights that protect our products and technologies” , various third parties have filed challenges to the validity of UC/Vienna/Charpentier’s European patents, which cover compositions comprising Cas9 and gRNA molecules, as well as methods of editing DNA in vitro or ex vivo using Cas9 and gRNAs.

If UC/Vienna/Charpentier fail in defending the validity of these patents, we may lose valuable intellectual property rights, such as the exclusive right to use such intellectual property.

If a defendant were to prevail on a legal assertion of invalidity, unpatentability and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates.

For example, as highlighted in the above risk factor entitled “ We could

be unsuccessful in obtaining or maintaining adequate patent protection for one or more of our products or product candidates, or asserting and defending our intellectual property rights that protect our products and technologies ,” various third parties have filed, and may file in the future, challenges to the validity of patents we own or license (e.g., patents or patent applications in the UC/Vienna/Charpentier patent family).

If we or the owners of patents we license (e.g., UC/Vienna/Charpentier) fail in defending the validity of these patents, we (and our sublicensees) may lose the benefit of patents and patent applications we own or license (e.g., patents and patent applications licensed under the Caribou License), as discussed above.

Such an outcome could have a material adverse effect on our business in Europe.

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Trade secrets, however, may be difficult to protect.

We seek to protect our proprietary processes, in part, by entering into confidentiality agreements with our employees, consultants, outside scientific advisors, contractors, and collaborators, and we also rely on federal and state laws requiring our directors, employees, contractors and collaborators to protect our proprietary information.

We seek to protect our proprietary processes, in part, by entering into confidentiality agreements with our employees, consultants, outside scientific advisors, contractors (including CMOs and CROs), and collaborators, and we also rely on federal and state laws requiring our directors, employees, consultants, contractors (including CMOs and CROs), and collaborators to protect our proprietary information.

Although we use reasonable efforts to protect our trade secrets, our employees, consultants, outside scientific advisors, contractors, and collaborators might intentionally or inadvertently disclose our trade secret information to competitors.

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Furthermore, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the U.S.

As a result, we may encounter significant

problems in protecting and defending our intellectual property both in the U.S.

As a result, we may encounter significant problems in protecting and defending our intellectual property both in the U.S.

If we are unable to prevent unauthorized material disclosure of our intellectual property to third parties, or misappropriation of our intellectual property by third parties, we may not be able to establish or maintain a competitive advantage in our market, which could materially adversely affect our business, operating results, and financial condition.

Our trade secrets and other confidential information of ours may also be exposed through cybersecurity attacks, ransomware attacks, and other hacking attempts directed at our information technology systems and those of our employees, consultants, outside scientific advisors, contractors, vendors and collaborators.

of our employees, consultants, outside scientific advisors, contractors, vendors and collaborators.

For more information, see the risk factor section entitled “ Risks Related to Data and Privacy.

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We were founded and commenced operations in mid-2014.

All of our product candidates are still in the preclinical development or clinical stage.

All of our product candidates are still in preclinical development or clinical trials.

We have not yet demonstrated our ability to successfully complete any clinical trials, including large-scale, pivotal clinical trials, obtain marketing approvals, manufacture clinical and commercial scale therapeutics, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful commercialization.

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For the foreseeable future, we expect to continue to rely on additional financing to achieve our business objectives.

Our future capital requirements will depend on and could increase significantly as a result of many factors, including the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our current or future product candidates, including additional expenses attributable to adjusting our development plans (including any supply related matters).

testing and clinical trials for our current or future product candidates, including additional expenses attributable to adjusting our development plans (including any supply related matters).

We will require additional capital for the further development and commercialization of any product candidates and may need to raise additional funds sooner if we choose to expand more rapidly than we presently anticipate or due to other unanticipated factors.

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Any of the foregoing could harm our business and we cannot anticipate all of the ways in which the current economic climate, further political developments and financial market conditions could adversely impact our business.

Inadequate funding for, or change of priorities or disruptions at, the FDA and other government agencies in or outside the U.S.

could hinder their ability to hire, retain, or deploy key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from performing normal business functions on which the operation of our business may rely, which could negatively impact our business.

The ability of the FDA and other similar regulatory agencies to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel and authorization to accept the payment of user fees, reallocation of resources to address unique or new healthcare issues (or other future public health concerns), and statutory, regulatory, and policy changes.

In addition, government funding of other government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.

For example, over the last several years, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA and the Securities and Exchange Commission (the “SEC”), have had to furlough critical FDA, SEC and other government employees and stop critical activities.

If a prolonged government shutdown occurs in the U.S.

or other jurisdictions where we plan to conduct our clinical trials, manufacturing, or other operations, it could significantly impact the ability of the relevant agency, such as the FDA, to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

Risks Related to Manufacturing and Supply

In vivo genome editing products and ex vivo engineered cell therapies based on CRISPR/Cas9 genome editing technology are novel and may be complex and difficult to manufacture.

We could experience manufacturing problems that result in delays in the development, approval or commercialization of our product candidates or otherwise harm our business.

The manufacturing process used to produce CRISPR/Cas9-based in vivo and engineered cell therapy product candidates may be complex, as they are novel and have not been validated for late phase clinical and commercial production and may require components that are difficult to obtain or manufacture at the necessary quantities and in accordance with regulatory requirements.

In vivo genome editing products and ex vivo engineered cell therapies based on CRISPR/Cas9 genome editing technology are novel, complex and difficult to manufacture.

The manufacturing processes used to produce CRISPR/Cas9-based in vivo genome editing product candidates and ex vivo engineered cell therapy product candidates are novel and complex.

In addition, our manufacturing processes may require components that are difficult to obtain or manufacture at the necessary quantities and in accordance with regulatory requirements.

Several factors could cause production interruptions, including equipment malfunctions;

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As a result, assays of the finished product or relevant components may not be sufficient to ensure that the product will perform in the intended manner.

For this reason, we will employ multiple steps to control the manufacturing process to ensure that the process results in product candidates that meet their specifications, but complications at any one step could adversely impact our manufacturing of products.

Further, we may encounter problems achieving adequate quantities and quality of clinical grade materials that meet the FDA or other relevant regulatory agency’s applicable standards or our specifications with consistent and acceptable production yields and costs.

For this reason, we will employ multiple steps to control the manufacturing process to ensure that the process results in product candidates that meet their specifications, but complications

at any one step could adversely impact our manufacturing of products.

Further, we may encounter problems achieving adequate quantities and quality of clinical (or, if approved commercial) grade materials that meet the FDA or other relevant regulatory agency’s applicable standards or our specifications with consistent and acceptable production yields and costs.

Manufacturing process irregularities, even minor deviations from the normal process, could result in product defects or manufacturing issues that cause lot failures, product recalls, product liability claims and litigation, insufficient inventory or production interruption.

In addition, product manufacturing and supply could be delayed if the FDA and other regulatory authorities require us to submit lot samples, testing results and protocols, or if they require that we not distribute a lot until they authorize the product’s release.

Further, certain of our product candidates may require components that are unavailable or difficult to acquire or manufacture at the necessary scale and in compliance with regulatory requirements to support our clinical trials or, if approved, commercial efforts.

We could experience manufacturing problems that result in delays in the development, approval or commercialization of our product candidates or otherwise harm our business.

Certain of our product candidates may require components that are unavailable or difficult to acquire or manufacture at the necessary scale and in compliance with regulatory requirements to support our clinical trials or, if approved, commercial efforts.

We expect to continue to rely on third party CMOs to manufacture these components and the final product candidates for the foreseeable future.

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These issues could result in delays in production or difficulties in maintaining compliance with applicable regulatory requirements.

Any of these manufacturing and supply issues or delays could restrict our ability to meet clinical or market demand for our products, and be costly to us and otherwise harm our business, financial condition, results of operations and prospects.

Any of these manufacturing and supply issues or delays could restrict our ability to meet clinical or market demand for our product candidates or products and be costly to us and otherwise harm our business, financial condition, results of operations and prospects.

Further, any problems in manufacturing processes or facilities could make us a less attractive collaborator for potential partners, including larger pharmaceutical companies and academic research institutions, which could limit our access to additional attractive development programs.

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Risks Related to Obtaining Regulatory Approval

While the regulatory framework for approval of gene therapy including genome editing products exists, the limited precedent for genome-edited products makes the regulatory approval process potentially more unpredictable and we may experience significant delays in the clinical development and regulatory approval, if any, of our product candidates.

While the regulatory framework exists for approval of gene therapy products, including genome editing products, the limited precedent for genome editing products make the regulatory approval process potentially more unpredictable and we may experience significant delays in the clinical development and regulatory approval, if any, of our product candidates.

The research, testing, manufacturing, labeling, approval, selling, import, export, marketing and distribution of drug products, including genome editing therapeutics and engineered cell therapies, are subject to extensive regulation by the FDA in the U.S.

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For example, we are not permitted to market any drug or biological product, including in vivo products or engineered cell therapies, until we receive regulatory approval from the relevant regulatory agency, such as the FDA in the U.S.

or EMA in the EU.

or European Commission in the EU.

We expect the novel nature of our product candidates to create challenges or raise questions from regulatory agencies in obtaining regulatory approval.

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Other non-regulatory entities may impact the regulatory agencies’ and ethics committees’ evaluation and approval decision regarding our product candidates.

For example, in December 2018, the World Health Organization (“WHO”) established the Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing.

While the standards are expected to focus primarily on germline modifications, the guidelines could impact somatic cell editing research programs, such as ours.

In March 2019, the WHO Expert Advisory Committee recommended initiating the first phase of a new global registry (the “Registry”) to track research on human genome editing.

Accepting this recommendation, the WHO announced plans in August 2019 for an initial phase of the registry using the International Clinical Trials Registry Platform.

This phase will include worldwide registries for both somatic cell editing and germline editing clinical trials.

Although registration of these clinical trials in the WHO’s Registry currently is voluntary, failure to register could impact the evaluation by the regulators and ethics committees.

In July 2021, the WHO Expert Advisory Committee issued recommendations and a governance framework for human genome editing research intended for the international, regional, national and institutional level.

For example, the WHO recommended that:

clinical trials using somatic human genome editing technologies be reviewed and approved by the appropriate research ethics committee before inclusion in its Registry;

basic and preclinical gene editing research also be included in a registry;

somatic or germline human genome editing research should only take place in jurisdictions with domestic policy and oversight mechanisms;

and relevant patent holders help ensure equitable access to human genome editing interventions.

We cannot predict the impact of the WHO’s current and future

recommendations, or any policies or actions that ethics committees or regulatory agencies may take in response to such recommendations, on our research, clinical and business plans and results.

For example, the World Health Organization (“WHO”) has established or recommended standards and registries for research using genome editing technologies.

We cannot predict the impact of the WHO’s current and future recommendations, or any policies or actions that ethics committees or regulatory agencies may take in response to such recommendations, on our research, clinical and business plans and results.

Patient enrollment is a significant factor in the timing of clinical trials and is affected by many factors, including willingness of physicians to use an experimental therapy, the availability of existing treatments, the trial’s geographic locations and the number of patients in each geographic location.

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We are currently conducting and may in the future conduct other clinical trials for our product candidates outside the U.S., and the FDA and comparable foreign regulatory authorities may not accept data from such trials.

We are currently conducting our Phase 3 clinical trial of NTLA-2001, and may in the future conduct clinical trials for our other product candidates, some of which are outside the U.S.

We are currently conducting our Phase 3 clinical trials of nex-z and NTLA-2002, and may in the future conduct clinical trials for our other product candidates outside the U.S.

The acceptance of data from clinical trials conducted outside the U.S.

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If the FDA or any comparable foreign regulatory authority does not accept such data, it would result in the need for additional trials, which could be costly and time-consuming, and which may result in product candidates that we may develop not receiving approval for commercialization in the applicable jurisdiction.

We have received orphan drug designation for NTLA-2001 and NTLA-2002 and may in the future seek orphan drug designation for some of our other product candidates, but we may be unable to obtain such designations or to maintain the benefits associated with orphan drug status, including market exclusivity, which may cause our revenue, if any, to be reduced.

We have received orphan drug designation for nex-z and NTLA-2002 and may in the future seek orphan drug designation for some of our other product candidates, but we may be unable to obtain such designations or to maintain the benefits associated with orphan drug status, including market exclusivity, which may cause our revenue, if any, to be reduced.

Regulatory authorities in some jurisdictions, including the U.S.

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Orphan drug designation must be requested before submitting a BLA.

In the U.S., orphan drug designation entitles a party to financial incentives such as opportunities

for grant funding towards clinical trial costs, tax advantages and user-fee waivers.

In the U.S., orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.

After the FDA grants orphan drug designation, the generic identity of the product and its potential orphan use are disclosed publicly by the FDA.

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Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the approval of another marketing application for the same drug for the same indication for that time period.

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In addition, the FDA can subsequently approve a marketing application for the same drug, or a product with the same active moiety, for treatment of the same disease or condition if it concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

Similarly, the EMA may grant a marketing authorization to a similar medicinal product for the same indication as an authorized orphan product at any time if it is established that the second product, although similar, is safer, more effective or otherwise clinically superior to the authorized product.

The FDA and EMA also can approve a different drug for the same orphan indication, or the same drug for a different indication, during the orphan exclusivity period.

We have received orphan drug designation from the FDA for NTLA-2001 for the treatment of ATTR amyloidosis and from the FDA and European Commission (“EC”) for NTLA-2002 for the treatment of HAE.

Similarly, the European Commission (“EC”) may grant a marketing authorization to a similar medicinal product for the same indication as an authorized orphan product at any time if it is established that the second product, although similar, is safer, more effective or otherwise clinically superior to the authorized product.

The FDA and EC also can approve a different drug for the same orphan indication, or the same drug for a different indication, during the orphan exclusivity period.

We have received orphan drug designation from the FDA for nex-z for the treatment of ATTR amyloidosis and from the FDA and EC for NTLA-2002 for the treatment of HAE.

We may seek orphan drug designation for some of our other product candidates in orphan indications in which there is a medically plausible basis for the use of these product candidates.

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We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business.

In addition, the EC introduced a legislative proposal in April 2023 that, if implemented, could reduce the current 10-year marketing exclusivity period in the EU for certain orphan medicines.

In addition, proposed amendments to EU regulations regarding orphan medicines are under consideration that, if implemented, could reduce the current 10-year marketing exclusivity period in the EU for certain orphan medicines.

Depending on what changes the FDA and the EC may make to their orphan drug regulations and policies, our business could be adversely impacted.

We have received regenerative medicine advanced therapy (“RMAT”) designation by the FDA for NTLA-2002 for the treatment of HAE, and may in the future seek such designation for some of our product candidates, but such designation may not actually lead to a faster development or regulatory review or approval process and we may be unable to obtain or maintain the benefits associated with such designation.

We have received the RMAT designation from the FDA for NTLA-2002 for the treatment of HAE.

We have received regenerative medicine advanced therapy (“RMAT”) designation by the FDA for nex-z for the treatment of ATTRv-PN and for NTLA-2002 for the treatment of HAE, and may in the future seek such designation for some of our other product candidates, but such designation may not actually lead to a faster development or regulatory review or approval process and we may be unable to obtain or maintain the benefits associated with such designation.

We have received the RMAT designation from the FDA for nex-z for the treatment of ATTRv-PN and NTLA-2002 for the treatment of HAE.

A product candidate is eligible for RMAT designation if:

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This program is intended to facilitate efficient development and expedite review of RMATs.

A BLA for a product candidate with RMAT designation may be eligible for priority review or accelerated approval through (1) surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit or (2) reliance upon data obtained

from a meaningful number of sites.

Benefits of such designation also include early interactions with the FDA to discuss any potential surrogate or intermediate endpoint to be used to support accelerated approval.

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Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of product candidates in other jurisdictions.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other jurisdiction, but a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory approval process in others.

one jurisdiction may have a negative effect on the regulatory approval process in others.

For example, even if the FDA approves a product candidate, comparable regulatory authorities in foreign jurisdictions must also authorize the marketing and sale of the product candidate in those countries.

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If we fail to comply with the relevant regulatory requirements or to receive applicable marketing approvals, our target markets will be reduced and our ability to realize the full market potential of our product candidates will be harmed.

Existing regulatory policies may change, and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our product candidates.

In June 2024, the U.S.

Supreme Court overruled the Chevron doctrine, which gave deference to regulatory agencies’ statutory interpretations in litigation against federal government agencies, such as the FDA and Centers for Medicare & Medicaid Services (“CMS”), agencies within the U.S.

Department of Health and Human Services, where the law is ambiguous.

This decision may result in more lawsuits against the FDA to challenge longstanding decisions and policies of the FDA, which could undermine the FDA’s authority, lead to uncertainties in the industry, and disrupt the FDA’s normal operations, any of which could delay the FDA’s review of our regulatory submissions.

We cannot predict the full impact of this decision, future judicial challenges brought against the FDA, or the nature or extent of government regulation that may arise from future legislation or administrative action.

In addition, the leadership, personnel, policies, and/or priorities of government departments and agencies responsible for establishing and operating programs and regulations related to pharmaceutical products, such as the U.S.

Department of Health and Human Services, FDA and CMS, may change.

New leadership, personnel, policies, priorities, and/or regulations may affect our industry and/or products.

For example, FDA or CMS policies and practices concerning gene and cell therapies may change in a way that disparately impacts our product candidates, such as reducing the staff of these agencies or not retaining experienced staff at these agencies who have expertise relevant to our industry and/or products.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained, and we may not achieve or sustain profitability.

Risks Related to Ongoing Regulatory Obligations

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For example, the FDA or other regulatory agencies may also require a REMS or similar program as a condition of approval of our product candidates, which could entail requirements for long-term patient follow-up, a medication guide, physician communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

In addition, if the FDA or a comparable foreign regulatory authority approves our product candidates, we will have to comply with their respective legal or regulatory requirements including submissions of safety and other post-marketing information and reports and registration.

In addition, if the FDA or a comparable foreign regulatory authority approves our product

candidates, we will have to comply with their respective legal or regulatory requirements including submissions of safety and other post-marketing information and reports and registration.

The FDA or other regulatory agencies may seek to impose consent decrees, withdraw approval or prohibit the export or import of a product if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

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The FDA’s policies may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our product candidates.

In addition, as discussed above, the U.S.

Supreme Court’s June 2024 decision to overturn established case law giving deference to regulatory agencies’ interpretations of ambiguous statutory language has introduced uncertainty regarding the extent to which the FDA’s regulations, policies and decisions may become subject to increasing legal challenges, delays, and/or changes.

If we or our collaborators are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we or our collaborators are not able to maintain regulatory compliance, we or our collaborators may lose any marketing approval that we or our collaborators may have obtained, which would adversely affect our business, prospects and ability to achieve or sustain profitability.

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or disclose unauthorized activities to us.

If we obtain FDA approval of any of our product candidates and begin commercializing those products in the U.S., our potential exposure under such laws will increase significantly, and our costs associated

with compliance with such laws are also likely to increase.

These laws may impact, among other things, our current activities with clinical investigators and research patients, as well as proposed and future sales, marketing and education programs.

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Activities subject to these laws also involve the improper use of information obtained in the course of clinical trials or creating fraudulent data in our preclinical studies or clinical trials, which could result in regulatory sanctions and cause serious harm to our reputation.

It is not always possible to identify and deter misconduct by employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.

It is not always possible to identify and deter misconduct by employees and other third parties, and the precautions we take to

detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations.

Additionally, we are subject to the risk that a person or government could allege such fraud or other misconduct, even if none occurred.

If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

The exit of the United Kingdom from the EU may result in an increased regulatory burden of conducting business in Europe.

The U.K.’s withdrawal from the EU, or Brexit, became effective on January 31, 2020.

On December 24, 2020, the U.K.

and EU signed an EU-U.K.

Trade and Cooperation Agreement (“TCA”), which became provisionally applicable on January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of cGMP, inspections of manufacturing facilities for medicinal products and cGMP documents issued, but does not provide for wholesale mutual recognition of U.K.

and EU pharmaceutical regulations.

The regulatory regime in Great Britain therefore currently aligns for the most part with EU regulations;

however, it is possible that these regimes will diverge more significantly in the future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of U.K.

and EU pharmaceutical legislation.

For instance, the new Clinical Trials Regulation which became effective in the EU on January 31, 2022 and provides for a streamlined clinical trial application and assessment procedure covering multiple EU Member States has not been implemented into U.K.

law, and a separate application must be submitted for clinical trial authorization in the U.K.

In addition, Great Britain is no longer covered by the centralized procedure for obtaining European Economic Area (“EEA”)-wide marketing authorizations from the EMA for medicinal products and a separate process for authorization of drug products is required in Great Britain.

On January 1, 2024, a new international recognition framework was put in place in the U.K.

(known as the International Recognition Procedure, or IRP), whereby the MHRA will have regard to decisions made by certain foreign regulators, including the EMA and the competent authorities of the EU Member States.

Under this procedure, the MHRA will take into account the decision-making of such foreign regulators and will conduct a targeted assessment of the applications submitted through the IRP, but will retain the authority to reject applications if the evidence provided is considered insufficiently robust.

Any delay in obtaining, or an inability to obtain, any regulatory approvals, as a result of Brexit or otherwise, would delay or prevent us from commercializing our current or future product candidates in the U.K.

and could restrict our ability to generate revenue from that market.

Failure to comply with health and data protection laws and regulations could lead to government enforcement actions (which could include civil or criminal penalties), private litigation, and/or adverse publicity and could negatively affect our operating results and business.

We and many of our existing or potential collaborators, clinical investigators, CMOs, CROs, consultants or vendors are subject to federal, state, and foreign data protection laws and regulations (i.e., laws and regulations that address privacy and data security).

state consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure and protection of health-related and other personal information could apply to our operations or the operations of our collaborators.

In the U.S., numerous federal and state laws and regulations, including federal health information privacy laws, state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure and protection of health-related and other personal information could apply to our operations or the operations of our collaborators.

In addition, we may obtain health information from third parties (including research institutions from which we obtain clinical trial data) that are subject to privacy and security requirements under the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), or by comparable laws in other jurisdictions.

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The Commonwealth of Massachusetts, where most of our employees are based, also has laws that expand on federal laws or create additional rights for employees or obligations for employers.

For example, on July 1, 2018, the Massachusetts Equal Pay Act went into effect, which added protections employers must comply with regarding pay equity for “comparable work”.

For example, on July 1, 2018, the Massachusetts Equal Pay Act went into effect, which added protections employers must comply with regarding pay equity for “comparable work.” In addition, on July 31, 2024, Massachusetts passed the Frances Perkins Workplace Equity Act, requiring disclosure of the pay range for a particular job under certain circumstances, including job postings, promotions, or when an employee requests.

There is currently uncertainty regarding the exact scope of these new legal limits and such uncertainty may remain for the foreseeable future.

We may face increased employment and legal costs to ensure we are complying with this law.

In addition, on October 1, 2018, a new Massachusetts non-compete law went into effect, placing additional restrictions on employers seeking to enter into non-competition agreements with employees.

We may face increased employment and legal costs to ensure we are complying with these laws.

For example, the Massachusetts non-compete law limits the terms under which employers can enter into non-competition agreements with employees.

Further, other jurisdictions in which our employees may work limit enforcement of non-competition agreements.

For example, in California non-competition agreements with employees are generally unenforceable after termination of employment and Illinois contains strict laws affecting the enforcement of non-competition agreements.

Additionally, in California non-competition agreements with employees are generally unenforceable after termination of employment and Illinois contains strict laws affecting the enforcement of non-competition agreements.

These non-compete laws may negatively impact our ability to prevent employees from working with direct or indirect competitors in the future and may affect our ability to retain key talent in a competitive market.

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Further, government or employee claims that we have violated any of these laws, even if ultimately disproven, could result in increased expense and management distraction, as well as have an adverse reputational impact on us.

Inadequate funding for, substantial changes in leadership, personnel, policies or priorities of, or other disruptions at the FDA and other government agencies in or outside the U.S.

For example, over the last several years, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA and the Securities and Exchange Commission (“SEC”), have had to furlough critical FDA, SEC and other government employees and stop critical activities.

A prolonged government shutdown in the U.S.

or other jurisdictions where we plan to conduct our clinical trials, manufacturing, or other operations, or substantial changes in leadership, personnel, policies or priorities could significantly impact the ability of the relevant agency, such as the FDA, to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

Risks Related to Our Reliance on Third Parties

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If our collaboration partner in a material collaboration fails to develop, obtain regulatory approval for or ultimately commercialize any product candidate from the development programs governed by the respective collaboration agreements, including, e.g., a co-development or co-commercialization agreement, or breaches or terminates our collaboration with it, our business, financial condition, results of operations and prospects could be harmed.

In addition, any material alteration, in an adverse manner, of any material collaboration agreement, or dispute or litigation proceedings we may have related to a material collaboration in the future could delay development programs, create uncertainty as to ownership of or access to intellectual property rights, distract management from other business activities and generate substantial expense.

In addition, any material alteration, in an adverse manner, of any

material collaboration agreement, or dispute or litigation proceedings we may have related to a material collaboration in the future could delay development programs, create uncertainty as to ownership of or access to intellectual property rights, distract management from other business activities and generate substantial expense.

As described within Note 9, “Collaborations and Other Arrangements” of this Annual Report on Form 10-K, we have entered into co-development and co-promotion arrangements with Regeneron.

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We also may pursue strategic alliances and joint ventures that leverage our core technology and industry experience.

If we decide to

collaborate with other companies to discover, develop and commercialize therapeutic products, we face significant competition in seeking appropriate collaborators because, for example, third parties have comparable rights to the CRISPR/Cas9 system or similar genome editing technologies.

If we decide to collaborate with other companies to discover, develop and commercialize therapeutic products, we face significant competition in seeking appropriate collaborators because, for example, third parties have comparable rights to the CRISPR/Cas9 system or similar genome editing technologies.

In addition, we have limited experience with acquiring, disposing of or licensing assets or forming strategic alliances and joint ventures.

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Furthermore, we may not identify or complete these transactions in a timely manner, on a cost-effective basis, or at all, and we may not realize the anticipated benefits of any acquisition, license, strategic alliance or joint venture.

Risks Related to AvenCell

We launched a new company, AvenCell, alongside Cellex Cell Professionals GmbH and Blackstone Life Sciences Advisors L.L.C.

We are exposed to risks associated with the launch of the new company and may not realize the advantages we expect from it.

In July 2021, we launched AvenCell Therapeutics, Inc.

(“AvenCell”) alongside Cellex Cell Professionals GmbH (“Cellex”) and Blackstone Life Sciences Advisors L.L.C.

AvenCell acquired GEMoaB GmbH (“GEMoaB”), a wholly owned subsidiary of Cellex.

AvenCell combines GEMoaB’s clinical-stage universal CAR-T program and platforms with our allogeneic universal cell engineering platform, which we licensed to AvenCell pursuant to a license and collaboration agreement with AvenCell (the “AvenCell License”).

Under the AvenCell License, we will collaborate with AvenCell to develop at least seven allogeneic universal CAR-T cell therapies.

AvenCell may not be successful in the timeframe we expect, or at all.

We, BXLS, and Cellex (together with certain related entities) each have equal ownership of AvenCell and, therefore, share control over portions of the operations of AvenCell.

Other than our ownership interest in AvenCell and the potential to co-develop with AvenCell an allogeneic universal CAR-T cell therapy, we do not receive any financial benefit from AvenCell.

Because of our minority ownership in AvenCell, we have a lesser degree of control over its business operations than our own, thereby potentially increasing the financial, legal, operational and compliance risks Intellia may face in the future.

In addition, we may be dependent on controlling shareholders or management of AvenCell who may have business interests, strategies or goals that are inconsistent with ours.

These risks include the possibility that AvenCell, BXLS or Cellex has economic or business interests or goals that are or become inconsistent with our economic or business interests or goals;

is in a position to take action contrary to our instructions, requests, policies or objectives;

subjects us to unexpected liabilities or risks;

takes actions that reduce our return on investment, including reducing or eliminating the value of our ownership in AvenCell and related financial benefits;

acts in a manner that compromises our key licensed rights, or important IP or other rights that we own or license;

or takes actions that harm our reputation or restrict our ability to run our business.

Furthermore, as a result of our ownership in AvenCell, we are required to include AvenCell’s financial information in our consolidated financial results.

This could subject us to increased risk in accurately representing and incorporating AvenCell’s financial statements into our own, which could result in delayed filings with the SEC and the finding of a material or significant weakness, among others.

This could result in harmful consequences to our business, including an adverse reaction in the financial markets due to a loss of confidence in the reliability of our consolidated financial statements.

Risks Related to Our Reliance on Other Third Parties

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We are in the early stages of establishing our own manufacturing facility to provide preclinical, clinical and commercial supply of our product candidates and must rely on outside vendors, such as CMOs, to manufacture supplies and process our product candidates.

We have only recently begun to manufacture and process product candidate components on a clinical scale and may not be able to successfully complete or continue to do so.

We will make changes to optimize the manufacturing process, and cannot be sure that even minor changes in the process will result in therapies that are safe, pure and potent.

We are manufacturing and processing product candidate components on a clinical scale and may not be able to successfully continue to do so.

We are optimizing and will continue to optimize the manufacturing process for late-stage clinical and commercial supply, and cannot be sure that even minor changes in the process will result in therapies that are safe, pure and potent.

We are also unable to predict how changing global economic conditions or ongoing geopolitical conflicts and related global economic sanctions, or potential global health concerns will affect our third party suppliers and manufacturers.

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We also will depend on these entities for compliance with relevant legal and regulatory requirements for manufacture of our product candidates, including cGMP, and in certain cases, cGTP requirements.

If we or our CMOs cannot successfully manufacture material that conforms to our specifications and the strict relevant regulatory requirements, we and our CMOs will not be able to secure or maintain regulatory approval for our respective manufacturing facilities.

If we or our CMOs cannot successfully manufacture material that conforms to

our specifications and the strict relevant regulatory requirements, we and our CMOs will not be able to secure or maintain regulatory approval for our respective manufacturing facilities.

In addition, we have no control over the ability of our CMOs to maintain adequate quality control, quality assurance and qualified personnel, particularly as we increase the scale of our manufactured material.

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We expect to have to negotiate budgets and contracts with CROs, trial sites and other service and goods providers, which may result in delays to our development timelines and increased costs.

For example, in February

2023, the U.S.

Department of Justice investigated the research practices of a significant CRO with respect to their non-human primate imports.

Issues of that nature may affect our ability to conduct preclinical studies that are required to advance our product candidates.

We currently rely, and expect to continue to rely heavily, on third parties over the course of our preclinical studies and clinical trials, and, as a result, will have limited control over the clinical investigators and other service providers, and limited visibility into their day-to-day activities, including with respect to their compliance with the approved clinical protocol and other legal, regulatory and scientific standards.

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Further, if any of our CROs, clinical investigators or others involved in our clinical trials fail to comply with such laws and regulations, we could be held responsible for its actions or omissions and be negatively impacted.

In the event of non-compliance with the U.K.’s Data Protection Act 2018 and the U.K.

General Data Protection Regulation (“U.K.

GDPR”) (such laws collectively being described as “European Data Protection Law”), we could be subject to substantial fines and other penalties, including fines of up to 10,000,000 Euros or up to 2% of our total worldwide annual turnover for certain comparatively minor offenses, or up to 20,000,000 Euros or up to 4% of our total worldwide annual turnover for more serious offenses.

In the event of non-compliance with the EU General Data Protection Regulation (“EU GDPR”) and the EU GDPR in such form as incorporated into the laws of the U.K.

GDPR,” collectively with EU GDPR referred to as “GDPR”), we could be subject to substantial fines and other penalties, including fines of up to 20.0 million Euros (17.5 million GBP for the U.K.

GDPR) or up to 4% of our total worldwide annual turnover for the preceding financial year, whichever is higher.

The GDPR also confers a private right of action on data subjects and consumer

associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations.

Any third parties conducting our current or future clinical trials will not be our employees and, except for remedies that may be available to us under our agreements with such third parties, we cannot control whether they devote sufficient time and resources to our ongoing preclinical, clinical, and nonclinical programs.

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As a result, our financial results and the commercial prospects for our product candidates would be harmed, our costs could increase and our ability to generate revenue could be delayed.

A resurgence of the COVID-19 pandemic (or other future public health concern) and measures taken in response by U.S.

or other governments may have a significant impact on our CROs, clinical sites and other service and goods providers, which may affect our ability to initiate and complete preclinical studies and clinical trials.

Public health concerns and measures taken in response by U.S.

or other governments may significantly impact our CROs, clinical sites and other service and goods providers, which may affect our ability to initiate and complete preclinical studies and clinical trials.

If any of our relationships with these third party CROs, clinical sites or other third parties terminate, we may not be able to enter into arrangements with alternative CROs, clinical sites or other third parties or to do so on commercially reasonable terms.

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In addition, the transition to a new CRO may result in delays, which can materially impact our ability to meet our desired clinical development timelines.

Though we carefully manage our relationships with these parties, there can be no assurance that we will not encounter similar challenges or delays in

the future or that these delays or challenges will not have a material adverse impact on our business, financial condition and prospects.

Though we carefully manage our relationships with these parties, there can be no assurance that we will not encounter similar challenges or delays in the future or that these delays or challenges will not have a material adverse impact on our business, financial condition and prospects.

Risks Related to Data and Privacy

Our internal computer systems, or those of our collaborators or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our operations and development efforts.

Our internal computer systems, or those of our collaborators or other contractors or consultants, may fail or suffer security breaches, incidents, or compromises, which could result in a disruption of our operations and development efforts.

We are increasingly dependent upon information technology systems, infrastructure, and data to operate our business.

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Our third party collaborators, vendors and service providers (including our CMOs and CROs) also have access to large amounts of confidential information relating to our operations, including our research and development efforts.

The size and complexity of our information technology systems, and those of third party vendors, service providers and collaborators, and the large amounts of confidential information stored on those systems, make such systems potentially vulnerable to service interruptions or systems failures, or to security breaches from inadvertent or intentional actions by our employees, third party vendors, service providers, collaborators, and/or business partners, or from cyber-attacks by malicious third parties.

In addition to such risks, the adoption of new technologies may also increase our exposure to cybersecurity breaches and failures.

The size and complexity of our information technology systems, and those of third party vendors, service providers and collaborators, and the large amounts of confidential information stored on those systems, make such systems potentially vulnerable to service interruptions or systems failures, or to cybersecurity incidents, breaches or compromises from inadvertent or intentional actions by our employees, third party vendors, service providers, collaborators, and/or business partners, or from cyber-attacks by malicious third parties.

In addition to such risks, the adoption of new technologies may also increase our exposure to cybersecurity incidents, breaches, compromises and failures.

Further, having a significant portion of our workforce working from home for extended periods of time puts us at greater risk of cybersecurity attacks.

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Cyber-attacks could include the deployment of harmful malware, denial-of-service attacks, attacks enhanced or facilitated by artificial intelligence (“AI”), social engineering, “phishing” scams, ransomware, network security breaches, and other means to affect service reliability and threaten the confidentiality, integrity, and availability of information.

Certain of our service providers have been subject to such attacks in the past, and while no such attacks have resulted in a material impact to our business, our company or our service providers may be materially impacted by such attacks in the future.

We and certain of our service providers have been subject to such attacks in the past, and while no such attacks have resulted in a material impact to our business, our company or our service providers may be materially impacted by such attacks in the future.

Significant disruptions to our information technology systems could adversely affect our business operations and/or result in the loss, misappropriation, and/or unauthorized access, use, or disclosure of, or the prevention of access to, confidential information (including but not limited to trade secrets or other intellectual property, proprietary business information, and personal information), and could result in financial, legal, business, and reputational harm to us and would adversely affect our operations, including our discovery and research and development programs.

Any security breaches that lead to unauthorized access, use, or disclosure of personal information, including personal information regarding our employees or current or future clinical trial participants, could harm our reputation, require us to comply with onerous legal requirements under laws and regulations that protect the privacy and security of personal information, and subject us to significant liability including fines, litigation, and loss of current and future business.

Any security incidents, compromises or breaches that lead to unauthorized access, use, or disclosure of personal information, including personal information regarding our employees or current or future clinical trial participants, could harm our reputation, require us to

comply with onerous legal requirements under laws and regulations that protect the privacy and security of personal information, and subject us to significant liability including fines, litigation, and loss of current and future business.

Also, the loss of preclinical or clinical trial data from completed or future preclinical or clinical trials, respectively, could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.

To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed, and the further development and commercialization of our product candidates could be delayed.

Security breaches, insider threats and other inappropriate access can be difficult to detect, and any delay in identifying them may lead to increased harm of the types summarized and described above.

While we have implemented security measures to protect our information technology systems and infrastructure, there is no assurance that such measures will prevent service interruptions or security breaches or incidents that could adversely affect our business.

Cybersecurity incidents, breaches, compromises, insider threats and other inappropriate access can be difficult to detect, and any delay in identifying them may lead to increased harm of the types summarized and described above.

While we have implemented security measures to protect our information technology systems and infrastructure, there is no assurance that such measures will prevent service interruptions or security breaches, incidents or compromises that could adversely affect our business.

Interruptions in the availability of server systems or communications with internet or cloud-based services, or failure to maintain the security, confidentiality, accessibility or integrity of data stored on such systems, could harm our business.

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While we have undertaken measures to restrict the use of public AI platforms, their use by people, including our vendors, suppliers and contractors, with access to our proprietary and confidential information, including trade secrets, may continue to increase and may lead to the release of such information, which may impact our ability to realize the benefit of our intellectual property.

We have a process that assesses risks and opportunities for AI deployed at Intellia.

A growing number of legislators and regulators are adopting laws and regulations and have focused enforcement efforts on the adoption of AI, and use of such technologies in compliance with ethical standards and societal expectations.

These developments may increase our compliance burden and costs in connection with use of AI and lead to legal liability if we fail to meet evolving legal standards or if use of such technologies results in harms or other causes of action we did not predict.

For example, the EU’s Artificial Intelligence Act (“AI Act”) entered into force on August 1, 2024, with most provisions becoming effective on August 2, 2026.

This legislation imposes significant obligations on providers and deployers of AI systems, and encourages providers and deployers of AI systems to account for EU ethical principles in their development and use of these systems.

requirements depends on legal and risk determinations that rely on novel legal provisions that have not yet been interpreted by courts or regulators, and non-compliance can lead to significant fines.

Likewise, in the U.S., several states, including Colorado and California, passed laws that will take effect in 2026, to regulate various uses of AI, including to make consequential decisions.

In addition, various federal regulators have issued guidance and focused enforcement efforts on the use of AI in regulated sectors.

The FDA, for example, issued guidance on the use of AI in medical devices, requiring detailed risk management and review processes to obtain approvals.

If we use AI systems governed by these laws or regulations, we will need to meet higher standards of data quality, transparency, monitoring and human oversight, and we would need to adhere to specific and potentially burdensome and costly ethical, accountability, and administrative requirements, with the potential for significant enforcement or litigation in the event of any perceived non-compliance.

The rapid evolution of AI will require the application of significant resources to design, develop, test and maintain such systems to help ensure that AI is implemented in accordance with applicable law and regulation and in a socially responsible manner and to minimize any real or perceived unintended harmful impacts.

The use of certain AI technologies can also give rise to IP risks, including by disclosing or otherwise compromising our confidential or proprietary IP, or by undermining our ability to assert or defend ownership rights in IP created with the assistance of AI tools.

Our vendors may in turn incorporate AI tools into their offerings, and the providers of these AI tools may not meet existing or rapidly evolving regulatory or industry standards, including with respect to privacy and data security.

Further, bad actors around the world use increasingly sophisticated methods, including the use of AI, to engage in illegal activities involving the theft and misuse of personal information, confidential information and IP.

Any of these effects could damage our reputation, result in the loss of valuable property and information, cause us to breach applicable laws and regulations, and adversely impact our business.

Risks Related to Competition

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Specific to our NTLA-2002 program, we are aware of other companies that are currently commercializing or developing products used to treat HAE, including ADARx Therapeutics, Inc., Astria Therapeutics Inc., BioCryst Pharmaceuticals Inc., BioMarin Pharmaceuticals Inc., CSL Limited, Ionis Pharmaceuticals, Inc., KalVista Pharmaceuticals, Inc., Pharming Group N.V., Pharvaris N.V.

and YolTech Therapeutics.

and Takeda Pharmaceutical Company Limited.

Competitors in our efforts to provide other genetic therapies to patients can be grouped into at least three sets based on their product discovery platforms:

Our platform and product foci are on the development of therapies using CRISPR-based technologies.

Genome editing companies focused on CRISPR-based technologies include:

Beam Therapeutics Inc., Caribou Biosciences, Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Metagenomi Technologies, LLC, Prime Medicine, Inc., ToolGen, Inc.

and Verve Therapeutics Inc.

There are also companies developing therapies using additional genome editing technologies, which include Allogene Therapeutics, Inc., bluebird bio, Inc., Cellectis S.A., Homology Medicines, Inc., Poseida Therapeutics, Inc., Precision Biosciences, Inc., Prime Medicine, Inc.

and Sangamo Therapeutics, Inc.

and YolTech Therapeutics.

Myeloid Therapeutics, Inc., Poseida Therapeutics, Inc.

(acquired by Roche Holdings, Inc.), Precision Biosciences, Inc., Prime Medicine, Inc., Sangamo Therapeutics, Inc., Seamless Therapeutics, Inc., Stylus Medicine, Inc.

and Tessera Therapeutics, Inc.

We are also aware of companies developing therapies in various areas related to our specific research and development programs.

For ex vivo , these companies include Allogene Therapeutics, Inc., Cellectis S.A., CRISPR Therapeutics AG and Precision BioSciences, Inc.

For in vivo , these companies include CRISPR Therapeutics AG, Editas Medicine, Inc., Excision Biotherapeutics, Inc., Locus Biosciences, Inc.

Metagenomi Technologies, LLC, Precision Biosciences, Inc.

(acquired by Roche Holdings, Inc.), Precision BioSciences, Inc., and Sana Biotechnology, Inc.

For in vivo , these companies include Beam Therapeutics Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Ensoma, Inc., Metagenomi Technologies, LLC, Orna Therapeutics, Inc., Precision Biosciences, Inc., Prime Medicine, Inc., Tessera Therapeutics, Inc., Vertex Pharmaceuticals, Inc.

and Verve Therapeutics, Inc.

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We are highly dependent on the research and development, clinical, manufacturing, commercialization, legal, financial and business development expertise of John M.

Leonard, M.D., our President and Chief Executive Officer, James Basta, our Executive Vice President, General Counsel and Corporate Secretary, Eliana Clark, our Executive Vice President and Chief Technical Officer, Glenn Goddard, our Executive Vice President, Chief Financial Officer and Treasurer, Derek Hicks, our Executive Vice President and Chief Business Officer, David Lebwohl, our Executive Vice President and Chief Medical Officer, and Laura Sepp-Lorenzino, our Executive Vice President and Chief Scientific Officer, as well as the other principal members of our management, scientific and clinical teams.

Leonard, M.D., our President and Chief Executive Officer, Edward J.

Dulac III, our Executive Vice President, Chief Financial Officer and Treasurer, James Basta, our Executive Vice President, General Counsel and Corporate Secretary, Eliana Clark, our Executive Vice President and Chief Technical Officer, Michael P.

Dube, our Chief Accounting Officer, David Lebwohl, our Executive Vice President and Chief Medical Officer and Birgit Schultes, our Executive Vice President and Chief Scientific Officer, as well as the other principal members of our management, scientific and clinical teams.

Although we have entered into employment arrangements with our executive officers, each of them may terminate their employment with us at any time.

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If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.

To help attract, retain, and motivate qualified employees in senior roles, we use equity-based awards and performance-based cash incentive awards.

Sustained declines in our stock price, or lower stock price performance relative to competitors, can reduce the retention value of our equity-based awards, which can impact the competitiveness of our compensation.

There can be no assurance that we will be successful in retaining existing personnel or recruiting new personnel.

Risks Related to Healthcare

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and some other jurisdictions, patients generally rely on third party payors to reimburse all or part of the costs associated with their treatment.

Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid in the U.S., and commercial payors are critical to new product acceptance.

Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid in the U.S., and commercial payors are critical to new product uptake.

Government authorities and other third party payors, such as private health insurers and health maintenance organizations, decide which drugs and treatments they will cover and the amount of reimbursement.

In the U.S., the principal decisions about reimbursement for new medicines are typically made by the Centers for Medicare & Medicaid Services (“CMS”), an agency within the U.S.

In the U.S., the principal decisions about reimbursement for new medicines are typically made by the CMS, an agency within the U.S.

Department of Health and Human Services.

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As a result, obtaining coverage and reimbursement approval of a product from a third party payor is a time-consuming and costly process that could require us to provide supporting scientific, clinical and cost-effectiveness data for the use of our products to each potential payor, with no assurance that coverage and adequate reimbursement will be obtained from all or any of them.

Even if we obtain coverage for a given product, the resulting reimbursement payment rates might be insufficient or may require co-payments that patients find unacceptably high, which may prevent us from

achieving or sustaining profitability.

Even if we obtain coverage for a given product, the resulting reimbursement payment rates might be insufficient or may require co-insurance or co-payments that patients find unacceptably high, which may prevent us from achieving or sustaining profitability.

Additionally, third party payors may not cover, or provide adequate reimbursement for, long-term follow-up evaluations required following the use of our genome editing products.

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and most other jurisdictions in which we intend to seek approval for our product candidates.

In addition, the collection and use of personal information, including Protected Health Information (“PHI”), is regulated by federal, state and foreign privacy, data security and data protection laws.

In addition, the collection and use of personal information, including Protected Health Information, is regulated by federal, state and foreign privacy, data security and data protection laws.

Failure to comply with these laws could impair our ability to properly sell our product candidates in particular jurisdictions and subject us to liability from private and governmental entities.

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Any failure to comply with these requirements may leave us exposed to possible enforcement actions and potential liability.

For more information on these laws and regulations see the section titled “ Business – Government Regulation and Product Approval – Other Healthcare and Privacy Laws .”

For more information on these laws and regulations see the section entitled “ Business – Government Regulation and Product Approval – Other Healthcare and Privacy Laws.

The scope and enforcement of each of these laws is not always certain and is subject to legislative, judicial or prosecutorial changes.

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federal and state governments, as well as other jurisdictions, have myriad laws regulating the collection, storage, distribution, safeguarding and use of personal information of employees, patients, agents, and others.

These different laws governing the privacy and security of health and other personal information often differ from each other in significant ways and may not have the same effective requirements, thus complicating efforts to comply with their respective provisions.

• in the U.S., HIPAA, as amended by HITECH, imposes requirements relating to the privacy, security and transmission of PHI on certain covered healthcare providers, health plans, and healthcare clearinghouses, and their respective business associates that perform services for them that involve the use or disclosure of such information.

These laws impose civil and criminal monetary penalties, and give state attorneys general the authority to file civil actions for damages or injunctions, and attorney’s fees, in federal courts to enforce the laws;

request deletion of their information, receive the information on record for them, know what categories of information are being maintained about them, and opt-out of certain sales of their information.

These different laws

governing the privacy and security of health and other personal information often differ from each other in significant ways and may not have the same effective requirements, thus complicating efforts to comply with their respective provisions.

• the California Consumer Privacy Act (“CCPA”) requires covered companies to provide disclosures to California consumers and afford such consumers rights with respect to their personal information, including the rights to request deletion of their information, receive the information on record for them, know what categories of information are being maintained about them, and opt-out of certain sales of their information.

The CCPA provides for civil penalties for violations, as well as a private right of action for certain data breaches that result in the loss of personal information, which may increase the likelihood of, and risks associated with, data breach litigation.

The CCPA was amended by the California Privacy Rights Act (“CPRA”), which became effective on January 1, 2023.

The CPRA substantially modified the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information, by establishing a state agency vested with the authority to enforce the CCPA and by creating additional obligations with respect to the processing of personal information, including regulating personal information collected about employees, applicants and retirees as well as that which is collected in a business to business capacity.

The CCPA was amended by the California Privacy Rights Act (“CPRA”), which went into effect on January 1, 2023, and substantially modified the CCPA, including by expanding consumers’ rights with respect to certain sensitive personal information, establishing a state agency vested with the authority to enforce the CCPA and by creating additional obligations with respect to the processing of personal information, including regulating personal information collected about employees, applicants and retirees as well as that which is collected in a business to business capacity.

We anticipate additional costs associated with CCPA and other U.S.

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In addition, other states have passed laws regulating specific aspects of privacy.

For example, the State of Washington recently passed a law that regulates health and medical information that is not subject to HIPAA and a small number of states have enacted laws that specifically target the collection and use of biometric information.

For example, the State of Washington recently passed a law, effective as of March 31, 2024, that regulates health and medical information that is not subject to HIPAA.

Similar laws have been passed in Connecticut and Nevada.

Additionally, a small number of states have enacted laws that specifically target the collection and use of biometric information.

Furthermore, other U.S.

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• around the world, many countries have enacted laws that regulate data protection.

In the EU and EEA the collection and use of personal data is regulated by the General Data Protection Regulation and the member states’ related data protection and privacy laws, and in the U.K.

Because the European Data Protection Law applies not only to businesses that are established within the EEA or the U.K.

In the European Economic Area (“EEA”), the collection and use of personal data is regulated by the GDPR and the member states’ related data protection and privacy laws.

As the GDPR applies not only to businesses that are established within the EEA or the U.K.

but also to any business that offers goods or services to individuals in those territories, it could apply to us.

European Data Protection Law imposes strict requirements, including special protections for “sensitive” personal data which includes health and genetic information of individuals in the EEA or the U.K.;

expanded disclosures about the personal data use;

The GDPR imposes strict requirements, including requirements to ensure an appropriate legal basis or condition applies to the processing of personal data, special protections for “sensitive” personal data which includes health and genetic information of individuals in the EEA or the U.K.;

disclosures about the personal data use;

information retention limitations;

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and additional oversight obligations relating to third parties retained to process the personal data.

European Data Protection Law grants or enhances the rights of individuals with respect to their personal data, including the rights to object to the processing of the data and request deletion of the same.

In addition, European Data Protection Laws include strict requirements on, and prohibit, the transfer of personal data subject to European Data Protection Law to jurisdictions that have not been deemed by competent authorities to offer “adequate” privacy protections (“third countries”), unless a derogation exists or a valid European Data Protection Law transfer mechanism (for example, the EC approved Standard Contractual Clauses, certification to the EU-U.S.

The GDPR grants or enhances the rights of individuals with respect to their personal data, including the rights to object to the processing of the data and request deletion of the same.

In addition, the GDPR includes strict requirements on, and prohibits, the transfer of personal data subject to GDPR to jurisdictions that have not been deemed by competent authorities to offer “adequate” privacy protections (“third countries”), unless a derogation exists or a valid GDPR transfer mechanism (for example, the EC approved Standard Contractual Clauses, certification to the EU-U.S.

Data Privacy Framework (which allows for transfers for relevant U.S.-based organizations who self-certify compliance and participate in the framework) and the U.K.

International Data Transfer Agreement/Addendum) has been put in place and a transfer impact assessment has been carried out.

Our compliance with international data transfer obligations under European Data Protection Law, where applicable, may require significant effort and cost, and may limit our ability to transfer such personal data to other jurisdictions or to work with certain service providers that process personal data, and may require us to make strategic considerations around where such personal data is stored.

Our compliance with international data transfer obligations under the GDPR, where applicable, may require significant effort and cost, and may limit our ability to transfer such personal data to other jurisdictions or to work with certain service providers that process personal data, and may require us to make strategic considerations around where such personal data is stored.

Further, although the EC has acknowledged that the U.K.

currently has adequate protections for international data transfers, there may be post-Brexit developments in the future that result in additional costs and operational challenges in complying with the U.K.

currently has adequate protections for international data transfers, there may be developments related to the U.K.’s withdrawal from the EU (“Brexit”) in the future that result in additional costs and operational challenges in complying with the U.K.

GDPR and any other developments regulating the transfer of personal data between the U.K.

For example, the U.K.

government has now introduced a Data Protection and Digital Information Bill (the “U.K.

government has introduced a Data Use and Access Bill (the “U.K.

Bill”) into the U.K.

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adequacy decision from the EC.

Failure to comply with the requirements of the European Data Protection Law may result in warning letters, mandatory audits, orders to cease/change the use of data, and financial penalties, including fines of up to 4% of global revenues, or 20.0 million Euros (£17.5 million in the U.K.), whichever is

Failure to comply with the requirements of the GDPR may result in warning letters, mandatory audits, orders to cease/change the use of data, and financial penalties, including fines of up to 4% of global revenues, or 20.0 million Euros (17.5 million GBP in the U.K.), whichever is greater.

Moreover, data subjects can seek damages for violations, and non-profit organizations can bring claims on behalf of data subjects.

The costs associated with ensuring compliance with these laws, including in particular European Data Protection Law, may be onerous and may adversely affect our business, financial condition, results of operations and prospects.

We may also need to rely on multiple third parties, such as partners and service providers, to meet these legal requirements, which could result in additional liability for us if they do not comply.

The costs associated with ensuring compliance with these laws, including in particular GDPR, may be onerous and may adversely affect our business, financial condition, results of operations and prospects.

We may also need to rely on multiple third parties,

such as partners and service providers, to meet these legal requirements, which could result in additional liability for us if they do not comply.

Efforts to ensure that we comply with all applicable healthcare and data privacy laws and regulations, as well as other domestic and foreign legal requirements, will involve substantial costs.

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and certain other jurisdictions, there have been, and are expected to continue to be, a number of legislative and regulatory changes to the healthcare system that could impact our ability to sell our products profitably.

In the U.S., however, significant uncertainty exists regarding the provision and financing of healthcare because the newly elected administration and federal legislators have publicly declared their intention to review and potentially significantly modify the current legal and regulatory framework for the healthcare system.

In addition, significant uncertainty exists in the U.S.

and certain other jurisdictions regarding the provision and financing of healthcare because the elected administrations in such countries have publicly declared their intention to review and potentially significantly modify the current legal and regulatory framework for the healthcare system.

We cannot predict the initiatives that may be adopted in the future.

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• the availability of capital.

Current legislation at the U.S.

federal and state levels seeks to reduce healthcare costs and improve the quality of healthcare.

For example, the U.S.

Affordable Care Act (“ACA”), enacted in March 2010, subjected biologic products to potential competition by lower-cost biosimilars;

introduced a new methodology to calculate manufacturers’ rebates under the Medicaid Drug Rebate Program for certain drugs, including infused or injected drugs;

increased manufacturers’ minimum Medicaid rebates under the Medicaid Drug Rebate Program;

extended the Medicaid Drug Rebate Program to pharmaceutical prescriptions of individuals enrolled in Medicaid managed care organizations;

imposed new annual fees and taxes for certain branded prescription drugs and biologic agents;

created the Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 70% point-of-sale discounts as of January 1, 2019, off negotiated prices on certain brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;

and provided incentives to programs that increase the federal government’s comparative effectiveness research.

Congress also could consider additional legislation to repeal, replace, or further modify elements of the ACA.

Thus, the full impact of the ACA, or any law replacing elements of it, and the political uncertainty regarding any repeal and replacement on the ACA, on our business remains unclear.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors, which may adversely affect our future profitability.

Risks Related to Our Common Stock

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If an active market for our common stock does not continue, it may be difficult for our stockholders to sell their shares without depressing the market price for the shares or sell their shares at or above the prices at which they acquired their shares or sell their shares at the time they would like to sell.

Any inactive trading market for our common stock may also impair our ability to raise capital to continue to fund our operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration.

Any inactive trading market for our common stock may also impair our ability to

raise capital to continue to fund our operations by selling shares and may impair our ability to acquire other companies or technologies by using our shares as consideration.

The price of our common stock historically has been volatile, which may affect the price at which you could sell any shares of our common stock.

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In the past, following periods of volatility in the market, securities class-action litigation has often been instituted against companies.

Even if the allegations against us are unfounded or we ultimately are not held liable, we may experience related negative publicity resulting in damage to our reputation.

Such litigation, if instituted against us, could result in substantial costs and diversion of management’s attention and resources, which could materially and adversely affect our business, financial condition, results of operations and growth prospects.

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Our principal stockholders and management own a significant percentage of our stock and, if they choose to act together, will be able to control or exercise significant influence over matters subject to stockholder approval.

As of December 31, 2023, our executive officers, directors, 5% or greater stockholders and their affiliates beneficially owned approximately 38.4% of our outstanding voting stock.

Our executive officers, directors, 5% or greater stockholders and their affiliates beneficially own a significant percentage of our outstanding voting stock.

These stockholders may have the ability to influence us through their ownership positions.

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Our uninsured cash deposits with such financial institutions may be at risk in the event they experience liquidity problems or other financial losses.

For example, in May 2023, the Federal Deposit Insurance Corporation (“FDIC”) took control of First Republic Bank and JP Morgan Chase & Co.

has since acquired a substantial amount of assets and certain liabilities of First Republic.

Although the U.S.

Department of Treasury, FDIC and Federal Reserve Board have announced a program to provide up to $25.0 billion of loans to financial institutions secured by certain government securities held by financial institutions to mitigate the risk of potential losses on the sale of such instruments, there is no guarantee that such loans will fully mitigate the risk of potential losses or that the U.S.

Department of Treasury, FDIC and Federal Reserve Board will provide access to uninsured funds in the future in the event of the closure of other banks or financial institutions, or that they would do so in a timely fashion.

In addition, although the U.S.

Department of Treasury, the Federal Deposit Insurance Corporation (“FDIC”) and Federal Reserve Board previously provided loans and other programs to mitigate the risk of potential losses from uninsured deposits, there is no guarantee that the U.S.

Department of Treasury, FDIC and Federal Reserve Board will provide access to such programs in the future in the event of the closure of other banks or financial institutions, or that they would do so in a timely fashion.

We assess our banking relationships as we believe necessary or appropriate, but uncertainty remains over liquidity concerns in the broader financial services industry, and our business, our business partners, or industry as a whole may be adversely impacted in ways that we cannot predict at this time, including our ability to access cash in amounts adequate to finance or capitalize our current and/or projected business operations could be significantly impaired by factors that affect the financial institutions with which we have banking relationships, and in turn, us.

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Our management and other personnel devote a substantial amount of time to these compliance initiatives.

Pursuant to Section 404 of the Sarbanes-Oxley Act of 2002 (“Section 404”), we are required to furnish a report by our management on our internal control over financial reporting, including an attestation report on internal control over financial reporting issued by our independent registered public accounting firm.

reporting issued by our independent registered public accounting firm.

We conduct a process each year to document and evaluate our internal control over financial reporting, which is both costly and challenging.

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Risks Related to Future Financial Condition

Future sales and issuances of our common stock or rights to purchase common stock, including pursuant to our equity incentive plans, could result in additional dilution of the percentage ownership of stockholders and could cause our stock price to fall.

We will need additional capital in the future to continue our planned operations in addition to the proceeds we received from our initial public offering (“IPO”) in May 2016 and follow-on public offerings since then.

Future sales and issuances of our common stock or rights to purchase common stock, including pursuant to our equity incentive plans and “at-the-market” offerings, could result in additional dilution of the percentage ownership of stockholders and could cause our stock price to fall.

We will need additional capital in the future to continue our planned operations.

To the extent we raise additional capital by issuing equity securities, our stockholders may experience substantial dilution.

We may sell common stock, convertible securities or other equity securities in one or more transactions at prices and in a manner we determine from time to time.

If we sell common stock, convertible securities or other equity securities in more

than one transaction, investors may be materially diluted by subsequent sales.

If we sell common stock, convertible securities or other equity securities in more than one transaction, investors may be materially diluted by subsequent sales.

These sales may also result in material dilution to our existing stockholders, and new investors could gain rights superior to our existing stockholders.

In March 2022, we entered into an Open Market Sale Agreement (the “2022 Sale Agreement”) with Jefferies LLC (the “Sales Agent”), to provide for the offering, issuance and sale of up to an aggregate amount of $400.0 million of our common stock from time to time in “at-the-market” offerings.

We will pay to the Sales Agent cash commissions of 3.0% of the gross proceeds of sales of common stock under the 2022 Sale Agreement.

Through December 31, 2023, we issued 7,518,163 shares of our common stock at an average price of $42 .

70 per share in accordance with the 2022 Sale Agreement for aggregate net proceeds of $310.9 million, after payment of cash commissions to the Sales Agent and approximately $0.5 million related to legal, account

Given the volatility in the capital markets, we may not be willing or able to continue to raise equity capital.

We may, therefore, need to turn to other sources of funding that may have terms that are not favorable to us, or reduce our business operations given capital constraints.

In addition, sales of a substantial number of shares of our outstanding common stock in the public market could occur at any time.

These sales, or the perception in the market that the holders of a large number of shares of common stock intend to sell shares, could reduce the market price of our common stock.

We cannot predict the effect that future sales of common stock or other equity-related securities would have on the market price of our common stock.

Investors who purchase shares in this offering at different times will likely pay different prices, and so may experience different outcomes in their investment results.

We will have discretion, subject to market demand, to vary the timing, prices and numbers of shares sold, and there is no minimum or maximum sales price.

Investors may experience a decline in the value of their shares as a result of share sales made at prices lower than the prices they paid.

Risks Related to our Charter and Bylaws

Anti-takeover provisions in our charter documents and under Delaware law could make an acquisition of us difficult, limit attempts by our stockholders to replace or remove our current management and adversely affect our stock price.

Provisions of our certificate of incorporation and by-laws may delay or discourage transactions involving an actual or potential change in our control or change in our management, including transactions in which stockholders might otherwise receive a premium for their shares, or transactions that our stockholders might otherwise deem to be in their best interests.

Therefore, these provisions could adversely affect the price of our stock.

Among other things, the certificate of incorporation and by-laws:

• permit the board of directors to issue up to 5,000,000 shares of preferred stock, with any rights, preferences and privileges as they may designate;

• provide that the authorized number of directors may be changed only by resolution of the board of directors;

• provide that all vacancies, including newly created directorships, may, except as otherwise required by law, be filled by the affirmative vote of a majority of directors then in office, even if less than a quorum;

• divide the board of directors into three classes;

• provide that a director may only be removed from the board of directors by the stockholders for cause;

• require that any action to be taken by our stockholders must be effected at a duly called annual or special meeting of stockholders, and may not be taken by written consent;

• provide that stockholders seeking to present proposals before a meeting of stockholders or to nominate candidates for election as directors at a meeting of stockholders must provide notice in writing in a timely manner, and meet specific requirements as to the form and content of a stockholder’s notice;

• prevent cumulative voting rights (therefore allowing the holders of a plurality of the shares of common stock entitled to vote in any election of directors to elect all of the directors standing for election, if they should so choose);

• require that, to the fullest extent permitted by law, a stockholder reimburse us for all fees, costs and expenses incurred by us in connection with a proceeding initiated by such stockholder in which such stockholder does not obtain a judgment on the merits that substantially achieves the full remedy sought;

• provide that special meetings of our stockholders may be called only by the chairman of the board, our chief executive officer (or president, in the absence of a chief executive officer) or by the board of directors;

• provide that stockholders will be permitted to amend the bylaws only upon receiving at least two-thirds of the total votes entitled to be cast by holders of all outstanding shares then entitled to vote generally in the election of directors, voting together as a single class.

In addition, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which generally prohibits a Delaware corporation from engaging in any of a broad range of business combinations with any “interested” stockholder for a period of three years following the date on which the stockholder became an “interested” stockholder.

Our certificate of incorporation and by-laws designate certain courts as the sole and exclusive forums for certain disputes between us and our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.

Our certificate of incorporation and by-laws provide that, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the State of Delaware is the sole and exclusive forum for any state law claims for any derivative action or proceeding brought on our behalf alleging state law claims, any action asserting a breach of fiduciary duty, any action asserting a claim against us arising pursuant to the Delaware General Corporation Law, our certificate of incorporation or our by-laws, any action to interpret, apply, enforce, or determine the validity of our certificate of incorporation or bylaws, or any action asserting a claim against us that is governed by the internal affairs doctrine (the “Delaware Forum Provision”).

The Delaware Forum Provision does not apply to claims arising under the Exchange Act or the Securities Act.

Our by-laws further provide that the U.S.

District Court for the District of Massachusetts will be the sole and exclusive forum for resolving any complaint asserting a cause of action arising under the Securities Act (the “Federal Forum Provision”).

We have chosen the U.S.

District Court for the District of Massachusetts as the exclusive forum for such Securities Act causes of action because our principal executive offices are located in Cambridge, Massachusetts.

Our by-laws provide that any person or entity purchasing or otherwise acquiring any interest in any shares of our common stock is deemed to have notice of and consented to the foregoing Delaware Forum Provision and the Federal Forum Provision.

The Delaware Forum Provision and the Federal Forum Provision may impose additional litigation costs on stockholders in pursuing the claims identified above, particularly if the stockholders do not reside in or near the State of Delaware or the Commonwealth of Massachusetts.

Additionally, the Delaware Forum Provision and the Federal Forum Provision may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers or other employees, which may discourage such lawsuits against us and our directors, officers and other employees.

Alternatively, if a court were to find the Delaware Forum Provision and the Federal Forum Provision to be inapplicable or unenforceable in an action, we may incur additional costs associated with resolving such action in other jurisdictions, which could adversely affect our business and financial condition.

The Court of Chancery of the State of Delaware or the U.S.

District Court for the District of Massachusetts may also reach different judgments or results than would other courts, including courts where a stockholder considering an action may be located or would otherwise choose to bring the action, and such judgments may be more or less favorable to us than our stockholders.

Risks Related to Tax Matters

Changes in tax law may adversely affect our business and financial condition.

The laws and rules dealing with U.S.

federal, state and local income taxation are routinely being reviewed and modified by governmental bodies, officials and regulatory agencies, including the Internal Revenue Service and the U.S.

Treasury Department.

We cannot predict whether, when, in what form, or with what effective dates, tax laws, regulations and rulings may be enacted, promulgated or issued, that could result in an increase in our or our stockholders’ tax liability.

Our ability to use our net operating loss ( “ NOL ” ) carryforwards and certain other tax attributes may be limited.

We have incurred substantial losses during our history and do not expect to become profitable in the near future, and we may never achieve profitability.

To the extent that we continue to generate taxable losses, unused losses will carry forward to offset future taxable income, if any, until such unused losses expire.

As of December 31, 2024, we had federal and state NOLs of $1,088.4 million and $1,079.2 million, respectively, some of which begin to expire in 2034.

Federal and certain state NOLs

generated in taxable years ending after December 31, 2017 are not subject to expiration.

As of December 31, 2024, we had federal and state research and development and other credit carryforwards of approximately $139.3 million and $77.9 million, which begin to expire in 2034 and 2029, respectively.

Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended (the “Code”), if a corporation undergoes an “ownership change,” generally defined as a greater than 50 percentage point change (by value) in its equity ownership by certain stockholders over a three-year period, the corporation’s ability to use its pre-change NOLs, and other pre-change tax attributes (such as research and development tax credits) to offset its post-change income or taxes may be limited.

During 2022, we completed an assessment of the available net operating loss carryforwards and other tax attributes under Section 382.

The analysis did not result in a material limitation to our tax attributes and the results of this analysis are reflected herein.

We have not completed an analysis through December 31, 2024.

To the extent there was a change in control during 2023 and 2024, our tax attributes could be subject to limitation.

We may experience ownership changes in the future.

As a result, if we earn net taxable income, our ability to use our pre-change NOLs and research and development tax credits to offset such taxable income and income tax, respectively, could be subject to limitations.

Similar provisions of state tax law may also apply.

As a result, even if we attain profitability, we may be unable to use a material portion of our NOLs and other tax attributes.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business