10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2025

Commission File Number 001-37923

CRISPR THERAPEUTICS AG

(Exact name of registrant as specified in its charter)

Switzerland Not Applicable

Baarerstrasse 146300 Zug, Switzerland Not Applicable

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: +41 (0)41561 32 77

Securities registered pursuant to Section 12(b) of the Act:

Title of each class TradingSymbol(s) Name of each exchange on which registered

Common Shares, nominal value CHF 0.03 CRSP The Nasdaq Global Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No ☐

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐ No ☒

Indicate by check mark whether the registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☒ Accelerated filer ☐

Non-accelerated filer ☐ Smaller reporting company ☐

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☒

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No☒

The aggregate market value of the common shares held by non-affiliates of the Registrant was approximately $4.1 billion, based on the closing price on the Nasdaq Global Market of the Registrant’s common shares on June 30, 2025 (the last trading day of the Registrant’s second fiscal quarter of 2025).

The number of the Registrant’s common shares outstanding as of February 10, 2026 was 95,985,312.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s Definitive Proxy Statement relating to the 2026 Annual General Meeting of Shareholders, which the Registrant intends to file with the Securities and Exchange Commission pursuant to Regulation 14A within 120 days after the end of the Registrant’s fiscal year ended December 31, 2025, are incorporated by reference into Part III of this Report.

Table of Contents

Page

PART I

Item 1. Business 1

Item 1A. Risk Factors 44

Item 1B. Unresolved Staff Comments 93

Item 1C. Cybersecurity 93

Item 2. Properties 94

Item 3. Legal Proceedings 94

Item 4. Mine Safety Disclosures 95

PART II

Item 6. Reserved 99

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 110

Item 8. Financial Statements and Supplementary Data 110

Item 9A. Controls and Procedures 110

Item 9B. Other Information 113

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 113

PART III

Item 10. Directors, Executive Officers and Corporate Governance 114

Item 11. Executive Compensation 114

Item 14. Principal Accountant Fees and Services 114

PART IV

Item 15. Exhibits and Financial Statement Schedules 115

Risk Factor Summary

Our business is subject to a number of risks and uncertainties of which you should be aware before making an investment decision in our business. These risks are discussed more fully in the “Risk Factors” section of this Annual Report on Form 10-K. These risks include, but are not limited to, the following:

•

We have incurred significant operating losses since our inception and anticipate that we will incur continued losses for the foreseeable future.

•

We will need to raise substantial additional funding, which will dilute our shareholders. If we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate some of our product development programs or commercialization efforts.

•

If we are unable to advance our product candidates to clinical development, obtain regulatory approval and ultimately commercialize our product candidates, or experience significant delays in doing so, our business will be materially harmed.

•

Our CRISPR/Cas9 gene editing product candidates are based on a relatively new gene editing technology, which makes it difficult to predict the time and cost of development and of subsequently obtaining regulatory approval, if at all. There have only been a limited number of clinical trials of product candidates based on gene editing technology.

•

The U.S. Food and Drug Administration, or FDA, the National Institutes of Health, the Medicines and Healthcare products Regulatory Agency, or MHRA and the European Medicines Agency, or EMA, have demonstrated caution in their regulation of gene therapy treatments, and ethical and legal concerns about gene therapy and genetic testing may result in additional regulations or restrictions on the development and commercialization of our product candidates, which may be difficult to predict.

•

If any of the product candidates we may develop or administration processes we rely on cause undesirable side effects, it could delay or prevent their regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval.

•

If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

•

Positive results from early preclinical studies or preliminary results from clinical trials of our product candidates are not necessarily predictive of the results of later preclinical studies and any future clinical trials of our product candidates. If we cannot replicate the positive results from our earlier preclinical studies of our product candidates in our later preclinical studies, clinical trials and future clinical trials, we may be unable to successfully develop, obtain regulatory approval for and commercialize our product candidates.

•

Adverse public perception of gene editing and cellular therapy products may negatively impact demand for, or regulatory approval of, our product candidates.

•

The commercial success of any of our products or product candidates will depend upon its degree of market acceptance by physicians, patients, third-party payors and others in the medical community.

•

We face significant competition in the biotechnology and pharmaceutical industries.

•

We have partnered with Vertex Pharmaceuticals Incorporated, or Vertex, on our lead program CASGEVY; Vertex has significant control over the CASGEVY program.

•

Gene editing and gene silencing products are novel and may be complex and difficult to manufacture. We could experience manufacturing problems or regulatory requirements that result in delays in the development, approval or commercialization of our product candidates or otherwise harm our business.

•

Our status as a Swiss corporation may limit our flexibility with respect to certain aspects of capital management and may cause us to be unable to make distributions without subjecting our shareholders to Swiss withholding tax.

•

If we are unable to obtain, maintain or protect intellectual property rights related to our proprietary gene editing technology and product candidates, we may not be able to compete effectively in our markets.

•

The intellectual property landscape around gene editing technology, including CRISPR/Cas9, is highly dynamic, and third parties may initiate and prevail in legal proceedings alleging that the patents that we in-license or own are invalid or that we are infringing, misappropriating, or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.

Throughout this Annual Report on Form 10-K, the “Company,” “CRISPR,” “CRISPR Therapeutics,” “we,” “us,” and “our,” except where the context requires otherwise, refer to CRISPR Therapeutics AG and its consolidated subsidiaries; “our board of directors” refers to the board of directors of CRISPR Therapeutics AG; and we generally refer to CASGEVY (exagamglogene autotemcel [exa-cel]), as “CASGEVY.”

“CRISPR Therapeutics®” standard character mark and design logo, “CRISPRXTM,” “CRISPR TXTM,” “CTX112TM,” “CTX211TM,” “CTX213TM,” “CTX310®,” “CTX321TM,” “CTX340TM,” “CTX460TM”, “CTX611TM and “SyNTaseTM” are trademarks and registered trademarks of CRISPR Therapeutics AG. CASGEVY® and the CASGEVY logo are registered trademarks of Vertex Pharmaceuticals Incorporated, and Vertex Pharmaceuticals Incorporated is the manufacturer and exclusive license holder of CASGEVY. All other trademarks and registered trademarks contained in this Annual Report on Form 10-K are the property of their respective owners.Solely for convenience, trademarks, service marks and trade names referred to in this Annual Report on Form 10-K may appear without the ® or TM symbols and any such omission is not intended to indicate waiver of any such rights.

Special Note Regarding Forward-Looking Statements and Industry Data

This Annual Report on Form 10-K contains “forward-looking statements” that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this Annual Report on Form 10-K are forward-looking statements. These statements are often identified by the use of words such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “potential,” “will,” “would” or the negative or plural of these words or similar expressions or variations, although not all forward-looking statements contain these identifying words. Forward-looking statements in this Annual Report on Form 10-K include, but are not limited to, statements about:

•

our strategic plans to develop and, if approved, subsequently commercialize any product candidates we may develop, including plans and expectations for the commercialization of, and anticipated benefits of, CASGEVY, including plans for patient access to CASGEVY;

•

the safety, efficacy and clinical progress of various clinical programs, including those for CASGEVY, zugocabtagene geleucel, CTX213, CTX310, CTX321 and CTX611;

•

the status of clinical trials, including development timelines and discussions with regulatory authorities related to product candidates under development by us and our collaborators;

•

the results of our preclinical studies and clinical trials, including our ongoing clinical trials and any planned clinical trials, and our research and development programs;

•

the actual or potential benefits of regulatory designations, such as orphan drug, fast track and regenerative medicine advanced therapy in the United States or such European equivalents, including the PRIority MEdicines designation;

•

our ability to advance product candidates into, and successfully complete, clinical trials;

•

the size and growth potential of the markets for our product candidates and our ability to serve those markets, including our estimates regarding the addressable patient population and potential market opportunity for our current and future product candidates;

•

the rate and degree of market acceptance of our product candidates and the success of competing therapies that are or become available;

•

our internal manufacturing capabilities and operation of our cell therapy manufacturing facility;

•

our intellectual property coverage and positions, including those of our licensors and third parties as well as the status and potential outcome of proceedings involving any such intellectual property;

•

the expected benefits of our collaborations;

•

our strategy, goals, and anticipated financial performance;

•

our anticipated expenses, ability to obtain funding for our operations and the sufficiency of our cash resources;

•

the therapeutic value, development, and commercial potential of gene editing technologies and therapies, including CRISPR/Cas9 and SyNTase, as well as other technologies we develop and use, including delivery and siRNA; and

•

the volatility of capital markets and unfavorable macroeconomic conditions resulting from factors including rising inflation, changes in or disruptions of U.S. governmental agencies, new or increased international tariffs and retaliatory tariffs, interest rate and currency rate fluctuations, new laws and regulations or amendments to existing laws and regulations in the U.S. and foreign countries, trade protection measures, economic sanctions and economic slowdowns or recessions, banking instability, monetary policy changes, geopolitical tensions or the outbreak of hostilities or war.

Any forward-looking statements in this Annual Report on Form 10-K reflect our current views with respect to future events or to our future financial performance and involve known and unknown risks, uncertainties and assumptions that could cause our actual results and the timing of certain events to differ materially from future results expressed or implied by the forward-looking statements.

iii

Factors that could cause or contribute to such differences include, but are not limited to, those identified herein, and those discussed in the section titled “Risk Factors,” set forth in Part I, Item 1A of this Annual Report on Form 10-K. You should not rely upon forward-looking statements as predictions of future events. Such forward-looking statements speak only as of the date of this report. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make or enter into.

You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to this Annual Report on Form 10-K completely and with the understanding that our actual future results, performance or achievements may be materially different from what we expect. Except as required by law, we undertake no obligation to update any forward-looking statements to reflect events or circumstances after the date of such statements.

This Annual Report on Form 10-K includes statistical and other industry and market data, which we obtained from our own internal estimates and research, as well as from industry and general publications and research, surveys, and studies conducted by third parties. Industry publications, studies, and surveys generally state that they have been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. While we believe that each of these studies and publications is reliable, we have not independently verified market and industry data from third‐party sources. While we believe our internal company research is reliable and the market definitions are appropriate, neither such research nor these definitions have been verified by any independent source.

PART I

Item 1. Business.

BUSINESS

Overview

Our mission is to create transformative gene-based medicines for serious human diseases. We are a leading biopharmaceutical company focused on the development of CRISPR-based therapeutics, including by using CRISPR/Cas9 technology. CRISPR/Cas9 is a revolutionary technology for gene editing, the process of precisely altering specific sequences of genomic DNA. We have advanced this technology from discovery to an approved medicine with unparalleled speed, culminating in the landmark first approval of a CRISPR-based therapy, CASGEVY (exagamglogene autotemcel [exa-cel]), in 2023 with our collaborators at Vertex Pharmaceuticals Incorporated, or Vertex.

We have established a portfolio of therapeutic programs spanning four core franchises: hemoglobinopathies, in vivo,CAR T approaches and regenerative medicine. Depending on the program, we take either an ex vivo approach, in which we edit cells outside of the human body before administering them to the patient, or an in vivo editing approach, where we deliver the CRISPR-based therapeutic directly to target cells within the human body.

•

Hemoglobinopathies: Our most advanced program, CASGEVY, has received approval in the United States and other countries for the treatment of eligible patients with severe sickle cell disease, or SCD, or transfusion-dependent beta thalassemia, or TDT, two genetic disorders of hemoglobin, or hemoglobinopathies, with high unmet medical need. In addition, we have further research efforts, also in collaboration with Vertex, on targeted conditioning and in vivo editing of hematopoietic stem cells that have the potential to expand the number of patients that could benefit significantly.

•

In vivo approaches: We are advancing a portfolio of programs leveraging in vivo editing for both common and rare diseases, as well as using siRNA approaches.

•

CAR T: We are progressing next-generation gene-edited cell therapy programs, including allogeneic chimeric antigen receptor T cell, or CAR T, candidates for autoimmune indications and oncology.

•

Regenerative medicine: We are advancing a deviceless beta cell replacement product candidate consisting of unencapsulated precursor islet cells derived from induced pluripotent stem cells for the treatment of Type 1 diabetes, or T1D.

We continue to innovate on our platform to develop next-generation technologies that can enable new therapies. We are developing other technologies, including delivery technologies and other gene editing technologies, like SyNTase. Through our efforts, we aim to unlock the full potential of gene-based therapeutics to create medicines that can transform people’s lives. We believe that our innovative research, translational expertise, and clinical development experience, position us as a leader in the development of CRISPR-based therapeutics and may enable us to create an entirely new class of highly effective and potentially curative therapies for patients with both common and rare diseases for whom current biopharmaceutical approaches have had limited success.

Hemoglobinopathies

CASGEVY is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy, in which a patient’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin in red blood cells, which can compensate for the defective adult hemoglobin in patients with SCD and TDT. CASGEVY is the first therapy to emerge from our strategic partnership with Vertex and is being advanced under a joint development and commercialization agreement between us and Vertex and certain of its affiliates.

In 2023, CASGEVY became the first-ever approved CRISPR-based gene-editing therapy in the world. To date, CASGEVY has been approved in the United States, European Union, Great Britain, Canada, Switzerland and certain countries in the Middle East for the treatment of eligible patients 12 years and older with SCD or TDT. Efficacy data presented to date support the profile of this therapy as a potential one-time functional cure for people with severe SCD and TDT.

We continue to advance our internally developed targeted conditioning program, as well as in vivo hematopoietic stem cell editing approaches utilizing lipid nanoparticle-mediated delivery through preclinical studies. Both initiatives could significantly expand the addressable patient populations for SCD and TDT.

In Vivo Liver Editing

We have established a leading platform for in vivo gene editing and are rapidly advancing a pipeline of in vivo gene editing

candidates that target the liver, taking advantage of validated lipid nanoparticle, or LNP, delivery technologies, and aim to treat diseases where we can produce a strong therapeutic effect by safely disrupting a gene with well-understood genetic association. We have established a proprietary LNP delivery platform to enable gene editing in the liver using both CRISPR/Cas9 and our novel, proprietary SyNTase editing technologies. Our in vivo portfolio includes cardiovascular investigational programs, such as CTX310, directed towards angiopoietin-related protein 3 or ANGPTL3, which is currently in an ongoing Phase 1b clinical trial. Additionally, we have a number of earlier stage investigational in vivo programs leveraging gene disruption in the liver for both common and rare diseases, including CTX340, directed towards angiotensinogen for the treatment of refractory hypertension, our next-generation LPA program, CTX321, and CTX460, directed towards SERPINA1 using our proprietary SyNTase editing platform, for the treatment of alpha-1 antitrypsin deficiency. We are also pursuing additional delivery technologies, including LNPs, for delivery to tissues beyond the liver, including hematopoietic stem cells and T cells.

siRNA-based Programs

Our siRNA-based portfolio includes clinical-stage programs in cardiovascular and thromboembolic diseases, developed in collaboration with Sirius Therapeutics and certain of its affiliates, or Sirius.

CTX611 (formerly known as SRSD107) is a novel double-stranded, long-acting siRNA, designed to target the human coagulation factor XI, or FXI, messenger RNA and inhibit FXI protein expression. Through modulation of the intrinsic coagulation pathway, CTX611 is intended to provide anticoagulant and antithrombotic effects. Supported by clinical experience conducted by Sirius in two Phase 1 clinical trials, CTX611 is being developed as a long-acting FXI inhibitor with the potential to support infrequent, including semi-annual, subcutaneous administration. CTX611 is in an ongoing Phase 2 clinical trial in patients undergoing total knee arthroplasty.

CAR T

We believe CRISPR/Cas9 has the potential to create the next generation of CAR T cell therapies that may have a superior product profile and allow broader patient access compared to current autologous therapies. We are advancing cell therapy programs for autoimmune indications and oncology, including our lead next-generation product candidate zugocabtagene geleucel (zugo-cel; formerly CTX112), which targets Cluster of Differentiation 19, or CD19, and incorporate edits designed to enhance CAR T potency, reduce CAR T exhaustion and evade the immune system. As a result of the next-generation edits, zugo-cel exhibits increased manufacturing robustness, with a higher and more consistent number of CAR T cells produced per batch. We are producing zugo-cel for clinical trials at our internal GMP manufacturing facility in Framingham, Massachusetts.

Zugo-cel continues to advance in both autoimmune disease and hematologic malignancies. In autoimmune disease, it is being investigated in an ongoing clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with systemic lupus erythematosus, or SLE, systemic sclerosis, and inflammatory myositis, and a second clinical trial in immune thrombocytopenia purpura and warm autoimmune hemolytic anemia. In oncology, the Phase 1/2 clinical trial in adult patients with relapsed or refractory B-cell malignancies who have received at least two prior lines of therapy is ongoing. We have also established a collaboration and clinical supply agreement with Eli Lilly to evaluate zugo-cel together with pirtobrutinib in aggressive B-cell lymphomas, further expanding the program’s development in oncology. Zugo-cel has been granted RMAT designation by the U.S. Food and Drug Administration for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma.

Our CRISPR/Cas9 platform enables us to innovate continuously by incorporating incremental edits into next-generation products. We are advancing several additional investigational CAR T programs.

Regenerative Medicine

We continue to advance our regenerative medicine portfolio, including in diabetes. We are advancing CTX213, a deviceless beta cell replacement product candidate consisting of unencapsulated precursor islet cells derived from induced pluripotent stem cells for the treatment of T1D. To date, CTX213 has demonstrated preclinical efficacy data via direct administration. In addition, we have granted a non-exclusive license to certain of our CRISPR/Cas9 intellectual property to Vertex to accelerate Vertex’s development of hypoimmune cell therapies for T1D in exchange for certain milestones and royalties.

Partnerships

Given the numerous potential therapeutic applications for CRISPR/Cas9, we have partnered strategically to broaden the indications we can pursue and accelerate development of programs by accessing specific technologies and/or disease-area expertise. We maintain broad partnerships to develop gene-based therapeutics in specific disease areas. For additional information regarding certain of these partnerships, please see “Business—Strategic Partnerships and Collaborations.”

Hemoglobinopathies. In 2015, we partnered with Vertex and entered into a strategic collaboration, option and license agreement, which focused on the discovery and development of gene-based treatments for hemoglobinopathies and cystic fibrosis using CRISPR/Cas9 gene-editing technology. In 2017, Vertex exercised its option to co-develop and co-commercialize the

hemoglobinopathies program and we entered into a joint development and commercialization agreement with Vertex, which we amended and restated in 2021, pursuant to which, among other things, we are co-developing and co-commercializing CASGEVY for TDT and SCD.

siRNA. In May 2025, we partnered with Sirius and entered into the Sirius Agreement pursuant to which, among other things, we and Sirius will collaborate on the research, development, manufacture, commercialization and use of the Sirius Collaboration Products, including co-development and co-commercialization of CTX611; and (2) Sirius granted us options to exclusively license Sirius siRNA technology to target up to two licensed targets from a list of reserved targets for the research, develop, manufacture and commercialization of siRNA Licensed Products, For the first Sirius Collaboration Product successfully developed, we will be the lead party responsible for Phase 3 global development and commercialization efforts in the United States and Sirius will be the lead party responsible for Phase 3 development (subject to the global development plan) and commercialization efforts in Greater China.

Other Partnerships. We have entered into a number of additional collaborations, research and license agreements in other therapeutic areas, including an additional agreements with Vertex including for the treatment of Duchenne muscular dystrophy, or DMD, and myotonic dystrophy type 1, or DM1, as well as diabetes, and others, including to support and complement our hematopoietic stem cell, CAR T, in vivo and diabetes programs and platform.

Gene Editing Background

There are thousands of diseases caused by aberrant DNA sequences. Traditional small molecule and biologic therapies have had limited success in treating many of these diseases because they fail to address the underlying genetic causes. Newer approaches, such as RNA therapeutics and viral gene therapy, more directly target the genes related to disease, but each has clear limitations. RNA-based therapies, such as mRNA and siRNA may provide clinical benefit in certain diseases, however, these approaches face challenges with repeat dosing and related toxicities. Non-integrating viral gene therapy platforms, such as adenovirus-associated vectors, or AAV, may have limited durability because they do not permanently change the genome and have limited efficacy upon re-administration due to resulting immune responses. Integrating viral gene therapy platforms, such as lentivirus, permanently alter the genome but do so randomly, which leads to the potential for undesirable mutations. Additionally, cells may recognize the transduced genes as foreign and respond by reducing their expression, limiting their efficacy. Thus, while our understanding of genetic diseases has increased since the mapping of the human genome, our ability to treat them effectively has been limited.

We believe gene editing has the potential to enable a next generation of therapeutics and provide potentially curative therapies to many genetic diseases through precise gene modification. Furthermore, the ability to alter DNA sequences precisely has applications beyond the treatment of genetic diseases. CRISPR/Cas9 gene editing could also enable the engineering of cell-based therapies to make them more efficacious, safer and available to a broader group of patients. Cell therapies have already begun to make a meaningful impact in certain diseases and gene editing could help accelerate that progress across diverse disease areas, including oncology, autoimmune diseases and diabetes.

The process of gene editing involves precisely altering DNA sequences within the genomes of cells using enzymes to cut the DNA at specific locations. After a cut is made, natural cellular processes repair the DNA to either silence or correct undesirable sequences, potentially reversing their negative effects. Importantly, because the genome itself is modified in this process, the change is permanent in the patient. Earlier generations of gene editing technologies, such as zinc finger nucleases, or ZFNs, transcription-activator like effector nucleases, or TALENs, and meganucleases, rely on engineered protein-DNA interactions to govern the location of editing. While these systems were an important first step to demonstrate the potential of gene editing, their development has been challenging in practice due to the complexity of engineering protein-DNA interactions. In contrast, CRISPR/Cas nucleases are guided by RNA-DNA interactions, which are more predictable and straightforward to engineer and apply.

The CRISPR/Cas9 Technology

CRISPR/Cas9 stands for Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and evolved as a naturally occurring defense mechanism that protects bacteria against viral infections. Dr. Emmanuelle Charpentier and her collaborators elucidated this mechanism and developed ways to adapt and simplify it for use in gene editing. In recognition of this groundbreaking work, Dr. Charpentier was awarded the 2020 Nobel Prize in Chemistry along with her collaborator, Dr. Jennifer Doudna of the University of California, Berkeley. The CRISPR/Cas9 technology they described consists of three basic components: Cas9, CRISPR RNA, or crRNA, and trans-activating CRISPR RNA, or tracrRNA. Cas9, in combination with these two RNA molecules, is described as “molecular scissors” that can make specific cuts and edits in selected double-stranded DNA.

Dr. Charpentier and her collaborators further simplified the system for use in gene editing by combining the crRNA and tracrRNA into a single RNA molecule called a guide RNA, or gRNA. The gRNA binds to Cas9 and can be programmed to direct the Cas9 enzyme to a specific DNA sequence based on Watson-Crick base pairing rules. The CRISPR/Cas9 technology can be used to make cuts in DNA at specific sites of targeted genes, providing a powerful tool for developing gene editing-based therapeutics.

Once the DNA is cut, the cell uses naturally occurring DNA repair mechanisms to rejoin the cut ends. If a single cut is made, a

process called non-homologous end joining can result in the addition or deletion of base pairs, disrupting the original DNA sequence and causing gene inactivation. A larger fragment of DNA can also be deleted by using two gRNAs that target separate sites. After cleavage at each site, non-homologous end joining unites the separate ends, deleting the intervening sequence. Alternatively, if a DNA template is added alongside the CRISPR/Cas9 machinery, the cell can correct a gene or even insert a new gene through a process called homology-directed repair.

CRISPR/Cas9 gene editing

Given the versatility of CRISPR/Cas systems, multiple groups have developed new technologies based on CRISPR/Cas9, such as base editing and reverse transcriptase editing. While still nascent, such new CRISPR-based technologies could have advantages in select disease applications. As a result, we have continued to invest in broadening our CRISPR platform so we can employ a variety of technologies as appropriate.

Next-generation Editing Modalities

While we have made significant progress with our current portfolio of programs, we recognize that we may be able to bring transformative therapies to even more patients by continuing to innovate to unlock the full potential of gene editing. We are focused on innovating next-generation editing modalities. For example, we have developed a proprietary, next-generation, site-specific gene correction platform called SyNTase editing. SyNTase editors represent a significant advance over currently described prime editing systems by combining compact Cas9 proteins with a novel class of engineered polymerases. Together, these components enable gene correction with greater efficiency and precision, while also supporting scalable manufacturing. Using AI-guided structural modeling and large-scale screening, the polymerase was optimized to support gene correction activity based on synthetic nucleotide templates. When integrated with optimized Cas9, SyNTase editors can utilize engineered templates with improved serum stability, enabling higher target correction efficiency. In addition, we are also developing technologies to enable whole gene correction and insertion via non-viral DNA delivery and all-RNA systems.

We believe that gene-based medicines will form the basis of an entirely new class of therapeutics with the potential to treat both common and rare diseases. To turn this promise into reality, we have built a broad and diversified pipeline of product candidates leveraging gene-based technologies, including CRISPR/Cas9 gene editing technology.

Our Pipeline

The following table summarizes the status of our product development pipeline:

Hemoglobinopathies

Hemoglobinopathies are a diverse group of inherited blood disorders that result from variations in the synthesis or structure of hemoglobin. Our lead program in hemoglobinopathies, CASGEVY, is the first-ever approved CRISPR-based gene-editing therapy in the world. It is the first therapy to emerge from our strategic partnership with Vertex and is being advanced under a joint development and commercialization agreement, with Vertex leading commercialization. CASGEVY has received approvals in the United States and multiple other countries worldwide for the treatment of eligible patients with SCD or TDT. SCD and TDT are caused by mutations in the gene encoding the beta globin protein. Beta globin is an essential component of hemoglobin, a protein in red blood cells that delivers oxygen and removes carbon dioxide throughout the body.

CASGEVY (exagamglogene autotemcel [exa-cel])

CASGEVY is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy, in which a patient’s own hematopoietic stem and progenitor cells, or HSPCs, are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. This edit results in the production of high levels of fetal hemoglobin, or HbF; hemoglobin F, in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth.

This HbF upregulation approach mimics a phenomenon observed in natural human genetics. In most patients with SCD or TDT, HbF disappears in infancy, at which point the symptoms of the disease begin to manifest. However, some patients have elevated levels of HbF that persist into adulthood, a condition known as hereditary persistence of fetal hemoglobin, or HPFH. These patients are often asymptomatic or experience much milder forms of disease because elevated HbF compensates for the defective adult hemoglobin. This protective HPFH condition has been shown to result from specific changes to these individuals’ genomic DNA, including in regions associated with genetic regulatory elements that control the expression levels of the globin genes, such as BCL11A. We chose to pursue this HbF upregulation strategy—rather than directly correcting the mutated beta globin gene—given the efficiency and consistency of the editing approach involved, the ability of this approach to counteract a wide variety of different beta globin mutations, including patients with TDT, and the natural history data supporting absence of symptoms in patients with HPFH.

Patients treated with CASGEVY first undergo a treatment that mobilizes a population of HSPCs, from the bone marrow into the bloodstream. Blood cells are collected from the patient’s bloodstream and transferred to a manufacturing facility where the HSPCs are sorted and CRISPR/Cas9 gene-editing is performed. Following manufacturing, the edited cells, now called CASGEVY, are transferred back to the clinical site. Patients are preconditioned with a treatment that ablates their bone marrow prior to infusion of CASGEVY.

We and Vertex continue to investigate CASGEVY, including in clinical trials designed to assess the safety and efficacy of a

single dose of CASGEVY in patients ages 12 to 35 with severe SCD and TDT, respectively, two pivotal trials in patients 5 to 11 years of age, one in severe SCD and a second in TDT, and long-term follow-up clinical trials designed to follow participants for up to 15 years after CASGEVY infusion. Overall, CASGEVY safety data presented to date is generally consistent with an autologous stem cell transplant and myeloablative conditioning. Efficacy data presented to date support the profile of CASGEVY as a potential one-time functional cure for people with severe SCD and TDT.

At the American Society of Hematology annual meeting, or ASH, in December 2025, positive data from the pivotal studies of CASGEVY in children ages 5 to 11 years old with SCD or TDT were presented. In children with SCD, 11 patients have been dosed with CASGEVY in the Phase 3 CLIMB-151 clinical study, and all (4/4) patients with sufficient follow-up (4/4) achieved the primary endpoint of being free from vaso-occlusive crises, or VOCs, for at least 12 consecutive months, or VF12. In children with TDT, 13 patients have been dosed with CASGEVY in the Phase 3 CLIMB-141 clinical study, and all patients with sufficient follow-up (6/6) achieved the primary endpoint of transfusion independence for at least 12 consecutive months while maintaining a weighted average hemoglobin of at least 9 g/dL (TI12). The safety profile of CASGEVY in younger patients is consistent with myeloablative conditioning and autologous transplant in both SCD and TDT, as established in clinical studies in older patients. Consistent with studies in older patients, children treated with CASGEVY have durable increases in HbF and stable allelic editing.

In addition, longer-term data for people with SCD and TDT ages 12 years and older treated with CASGEVY were also presented at ASH. These data, as of April 2025, continue to demonstrate the transformative, durable clinical benefits that CASGEVY provides to people living with SCD or TDT. In SCD, 100% of patients (45/45) achieved VF12 in either CLIMB-121 or the long-term follow-up study CLIMB-131, with a mean duration of VOC-free for 35.3 months (range 12.9–67.7 months). In TDT, 98.2% of patients (55/56) achieved TI12 in either CLIMB-111 or CLIMB-131 with a mean duration of transfusion independence of 41.4 months (range 13–72.3 months). The safety profile remained consistent with myeloablative conditioning and autologous transplant in both SCD and TDT.

To date, CASGEVY has been approved by regulatory authorities in the United States, European Union, Great Britain, Canada, Switzerland, Kingdom of Saudi Arabia, Kingdom of Bahrain, Qatar, the United Arab Emirates and Kuwait for the treatment of eligible patients 12 years and older with SCD or TDT. We estimate that in the United States, Canada, Europe and parts of the Middle East, the total addressable patient population with severe SCD or TDT is approximately 60,000 individuals.

Beta Thalassemia

Beta thalassemia is a blood disorder that is associated with a reduction in the production of hemoglobin. This disease is caused by mutations that give rise to the insufficient expression of the beta globin protein, which can lead to symptoms related not only to the lack of hemoglobin, but also to the buildup of unpaired alpha globin proteins in red blood cells. The severity of symptoms associated with beta thalassemia varies depending on the levels of functional beta globin present in the blood cells. The unpaired alpha globin chains are toxic to red blood cells and reduce red blood cell lifespan. In the most severe cases, described as beta thalassemia major, functional beta globin is either completely absent or reduced, resulting in severe anemia. In these patients, the bone marrow cannot keep pace with the destruction of red blood cells, and thus these patients require regular blood transfusions. While chronic blood transfusions can be effective at addressing symptoms, they often lead to iron overload, progressive heart and liver failure, and eventually early death. Patients with mild forms of beta thalassemia may experience some mild anemia or even be asymptomatic. The total worldwide incidence of beta thalassemia is estimated to be 60,000 births annually and there are over 200,000 people worldwide who are alive and registered as receiving treatment for the disease.

The most common treatment for beta thalassemia is chronic blood transfusions. Transfusion-dependent patients typically receive transfusions every two to four weeks and chronic administration of blood often leads to elevated levels of iron in the body, which can cause organ damage over a relatively short period of time. Patients often undergo phlebotomy or are given iron chelators, or medicines to reduce iron levels in the blood, which are associated with their own significant toxicities. In developing countries, where chronic transfusions are not available, most patients die in early childhood. Also, a disease-modifying therapy for beta thalassemia, Reblozyl (luspatercept-aamt), received FDA approval in 2019.

A potentially curative therapy for beta thalassemia is allogeneic hematopoietic stem cell transplant, or allo-HSCT, but few patients elect to have this procedure given its associated morbidity and mortality and the lack of matched and willing donors. Another option is Zynteglo (betibeglogene autotemcel), an ex vivo autologous lentiviral gene therapy developed by Genetix Biotherapeutics (formerly bluebird bio), which the FDA approved for the treatment of certain patients with TDT in August 2022.

Sickle Cell Disease

SCD is an inherited disorder of red blood cells resulting from a specific mutation in the beta globin gene that causes abnormal red blood cell function. Under conditions of low oxygen concentration, the abnormal hemoglobin proteins aggregate within the red blood cells causing them to become sickled in shape and inflexible. These sickled cells obstruct blood vessels, restricting blood flow to organs, ultimately resulting in severe pain, infections, stroke, overall poor quality of life and early death. Patients also experience increased hemolysis, leading to anemia. The worldwide incidence of SCD is estimated to be 300,000 births annually and there are 20-25 million people worldwide with the disease.

As with beta thalassemia, in regions where medical infrastructure can support it, standard treatment for patients with SCD who have high levels of hemolysis involves chronic blood transfusions, which has the same associated risks of iron overload and toxicities associated with chelation therapy. The FDA and/or EMA have approved several disease-modifying therapies for SCD as well, such as hydroxyurea. Prior to December 2023, the only curative option was Allo-HSCT which is often avoided given the significant risk of transplant-related morbidity and mortality in these patients and the lack of matched and willing donors. In December 2023, the FDA approved Lyfgenia (lovotibeglogene autotemcel), an ex vivo autologous lentiviral gene therapy developed by Genetix Biotherapeutics (formerly bluebird bio), which carries a boxed warning for hematologic malignancy.

Next-generation Efforts

Building upon CASGEVY, we and Vertex are pursuing next-generation efforts in targeted conditioning regimens, which could offer benefits over the myeloablative conditioning regimen currently used with CASGEVY. In addition, we and Vertex are pursuing in vivo editing of hematopoietic stem cells in SCD and TDT. Either of these efforts could broaden the number of patients that can benefit from our therapies.

In Vivo Approaches - Liver Editing

We have established a leading platform for in vivo gene editing and are rapidly advancing a broad portfolio of in vivo programs. In vivo gene editing, or delivery of a CRISPR/Cas9-based therapeutic directly to tissues within the human body, could enable the treatment of many common and rare diseases, including those difficult to address with ex vivo approaches.

Our lead in vivo programs target the liver and take advantage of clinically established and validated lipid nanoparticle, or LNP, delivery technologies. LNPs have several advantages that make them well-suited for delivering CRISPR/Cas9 in vivo, including efficient and safe delivery to the liver, large cargo size and transient cargo expression. Our first programs in the liver aim to treat diseases where we can produce a strong therapeutic effect by safely disrupting a gene with well-understood genetic association. For example, our most advanced clinical program, CTX310, aims to address cardiovascular disease by disrupting the validated target ANGPTL3.

Beyond the liver, for delivery to hematopoietic stem cells, T cells and other extrahepatic tissues, we are pursuing multiple delivery technologies, including LNPs. Through internal efforts and external collaborations, we are developing new delivery modalities to support future in vivo therapeutics.

Cardiovascular and Dyslipidemia Programs

Cardiovascular disease, or CVD, is the leading cause of death globally, accounting for close to one third of all deaths, or nearly 20.5 million people, in 2021. CVD includes heart failure, stroke, atherosclerotic cardiovascular disease, or ASCVD, aortic valve calcification and more. Dyslipidemias are a leading cause of CVD. Dyslipidemias are characterized by abnormally high levels of lipids, including cholesterol, lipoproteins and triglycerides, in the bloodstream. Three of the most common dyslipidemias are hypercholesterolemia, hypertriglyceridemia and elevated lipoprotein (a), or Lp(a). Today’s chronic care treatment model of CVD involves daily medication, weekly injection, multiple infusions annually and/or surgical interventions. This model places a heavy burden on patients and the healthcare system. Adherence to lipid-lowering therapy remains a major challenge, and over 80% of people with very high cardiovascular risk do not reach low density lipoprotein, cholesterol, or LDL-C target goal.

We aim to transform the treatment paradigm for CVD by developing one-time in vivo editing therapies that can durably lower levels of atherogenic lipoproteins for a patient’s lifetime. To do so, we aim to disrupt genes like ANGPTL3 that when dysfunctional or inhibited result in lower levels of key lipoproteins and improved cardiovascular outcomes based on studies of natural human genetics and other therapeutic modalities. By recapitulating this benefit, we believe that our therapies have the potential to minimize or eliminate the need for additional treatments and improve long-term cardiovascular outcomes for both patients with severe genetic dyslipidemias and much larger ASCVD patient populations.

CTX310

Our most advanced in vivo product candidate, CTX310, targets the gene encoding angiopoietin-related protein 3, or ANGPTL3, for the treatment and prevention of CVD. ANGPTL3 plays an important role in lipid metabolism by inhibiting an enzyme called lipoprotein lipase, or LPL. LPL is the main enzyme that breaks down triglyceride-enriched lipoproteins like chylomicrons, very low density lipoprotein, or VLDL, and LDL. By preventing LPL from hydrolyzing these lipoproteins, ANGPTL3 activity increases the level of circulating triglycerides. Reducing ANGPTL3 expression by disrupting the ANGPTL3 gene increases LPL expression and thereby reduces triglyceride-rich lipoproteins, as well as LDL-C. This mechanism has been validated through natural history studies, as individuals with natural loss-of-function variants of ANGPTL3 have lower triglyceride levels, lower LDL-C levels, and a lower risk of coronary artery disease. CTX310, which consists of messenger RNA encoding Cas9 and a gRNA targeting ANGPTL3 delivered via LNP, aims to recapitulate this effect by disrupting the ANGPTL3 gene. CTX310 has been shown to decrease ANGPTL3 protein levels by nearly 90% in non-human primates, or NHPs, leading to a greater than 50% reduction in serum triglycerides. CTX310 is currently

being investigated in an ongoing Phase 1b clinical trial in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, mixed dyslipidemias, or severe hypertriglyceridemia.

In November 2025, we presented positive Phase 1 data from our ongoing clinical trial evaluating CTX310 during a late-breaking session at the American Heart Association Scientific Sessions and published simultaneously in The New England Journal of Medicine in a peer-reviewed article entitled “Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3.” A single-course treatment with CTX310 produced dose-dependent, durable reductions in circulating ANGPTL3 with a mean reduction from baseline of -73% (maximum -89%), a mean reduction in triglycerides, or TG, of -55% (maximum -84%) and a mean reduction of low-density lipoprotein, or LDL, of -49% (maximum -87%) at the highest dose. The Phase 1, open label, dose-escalation trial evaluated single-course intravenous doses of CTX310 ranging from 0.1 to 0.8 mg/kg (lean body weight) targeting ANGPTL3 in four patient groups: homozygous familial hypercholesterolemia, severe hypertriglyceridemia, or sHTG, heterozygous familial hypercholesterolemia, or mixed dyslipidemias (elevated TG and LDL). Eligible participants had uncontrolled TG levels >150 mg/dL and/or LDL cholesterol >100 mg/dL (or >70 mg/dL for those with established atherosclerotic cardiovascular disease) despite background standard of care per local guidelines. The majority of participants were receiving statins and/or ezetimibe, while 40% were taking PCSK9 inhibitors. The trial was designed to evaluate safety and tolerability as primary endpoints, with changes in circulating ANGPTL3 protein, TG, and LDL as secondary endpoints. Single-course ascending doses of CTX310 were administered to 15 participants across sequential cohorts, and all participants completed at least 28 days of follow-up as of the data cutoff. CTX310 was generally well tolerated, and no dose-limiting toxicities or serious adverse events related to treatment. Adverse events were generally mild to moderate. One participant experienced an allergic reaction that resolved the following day with supportive care. Infusion-related reactions occurred in three participants (two at 0.6 mg/kg and one at 0.8 mg/kg dose), all Grade 2. All events resolved, and all participants completed their infusions. One participant with elevated transaminases level at baseline had a Grade 2 elevation of transaminases that peaked by Day 4 and resolved completely by Day 14 without any rise in bilirubin. Overall, CTX310 demonstrated a well-tolerated safety and tolerability profile that supports continued advancement of the program.

CTX310 Phase 1a Demonstrated Clinically Meaningful Reductions in LDL-C and Triglycerides

Based on the positive Phase 1 results we have advanced CTX310 into Phase 1b clinical trials, prioritizing development in severe hypertriglyceridemia and refractory hypercholesterolemia.

Severe Hypertriglyceridemia (sHTG)

Hypertriglyceridemia is clinically defined as having triglyceride levels above l50 mg/dL. The most severe patients can have levels exceeding 2000 mg/dl. Hypertriglyceridemia is associated with CVD and acute pancreatitis. Like LDL-C, triglyceride levels can be affected by diet and lifestyle choices and treated with common therapies. However, over three million adults in the United

States still have severe hypertriglyceridemia, or sHTG. Known genetic conditions can cause sHTG, including familial chylomicronemia syndrome, or FCS, and multifactorial chylomicronemia syndrome, or MCS. There are parallels between FCS/MCS and homozygous familial hypercholesterolemia / heterozygous familial hypercholesterolemia, or HoFH/HeFH. FCS is the only true monogenic form of hypertriglyceridemia and is associated with extreme levels of triglycerides exceeding 885 mg/dL. The prevalence of FCS is 1 in 200,000 to 300,000 individuals in the United States and EU. MCS is polygenic in nature, meaning that the genetic underpinnings causing the disease to vary among individuals, and is clinically defined as having triglyceride levels between 150 and 885 mg/dL. MCS has a prevalence of 1 in 250 to 600 individuals.

Refractory Hypercholesterolemia

Hypercholesterolemia is defined by levels of LDL-C above 130 mg/dL and is associated with increased risk of heart disease and stroke. In hypercholesterolemia, high levels of LDL-C accumulate in blood vessels, leading to atherosclerosis. Treatment aims to reduce LDL-C levels to below 100 mg/dL with 70 mg/dL as the ultimate goal, but some patients cannot achieve this level of reduction through existing means. Patients with LDL-C levels above 200 mg/dL are considered to have familial hypercholesterolemia, or FH. Patients with FH have one or more genetic mutations that contribute to the disease in addition to diet and lifestyle. Patients with FH cannot metabolize LDL-C effectively, leading to high levels of circulating LDL-C, in some cases exceeding 1000 mg/dL. FH can be subcategorized by mutation status into HeFH, and HoFH. HoFH patients have the most severe phenotype, with LDL-C levels usually exceeding 400 mg/dL. HoFH patients often suffer from CVD early in life and have an average life expectancy of 33 years if untreated. HoFH has a prevalence of 1 in 200,000 to 1,000,000 adults. Refractory hypercholesterolemia is a condition defined by persistently high LDL-C levels despite maximum tolerated lipid-lowering therapies, including patients with and without FH.

Additional In Vivo Programs

In addition to CTX310, we have a number of earlier stage investigational in vivo programs, including: CTX340, CTX460 and CTX321. CTX340 is currently in Investigational New Drug application enabling, or IND-enabling, studies and is directed towards angiotensinogen for the treatment of refractory hypertension. CTX460 is the first investigational candidate to emerge utilizing our SyNTase editing platform and is directed towards SERPINA1 for the treatment of alpha-1 antitrypsin deficiency. CTX460 is currently in preclinical studies. Building on insights from CTX320, our next-generation product candidate, CTX321, is directed towards LPA, the gene encoding apolipoprotein(a), a major component of Lp(a). Like CTX320, CTX321 consists of a gRNA targeting LPA and messenger RNA encoding Cas9 delivered via LNP. CTX321 incorporates an updated guide RNA that demonstrates approximately two-fold greater potency in preclinical testing while utilizing the same LNP delivery system. CTX321 is currently in IND-enabling studies in patients with elevated Lp(a), which has shown to have an independent association with major adverse cardiovascular events.

Elevated Lp(a)

Lp(a) is a lipoprotein consisting of an LDL-like particle covalently bound to a protein called apolipoprotein(a), or apo(a). Lp(a) transports cholesterol in the blood and is highly atherogenic. It can infiltrate and bind to components of the extracellular matrix in the inner layers of the aortic valve and other areas of the circulatory system, resulting in increases in inflammation and fatty deposits that over time lead to a weakened aortic valve and other serious symptoms contributing to CVD. Lp(a) is its own independent risk factor for CVD. High concentrations of Lp(a), as well as genetic variants associated with high Lp(a) concentrations, are both associated with CVD. Elevated levels of Lp(a) above 50 mg/dL are directly associated with aortic valve calcification disease, or AVCD. Up to 20% of adults in the United States have Lp(a) levels above 50 mg/dL and over 1 million adults in the United States have AVCD. Additionally, 30% of patients with familial hypercholesterolemia have elevated Lp(a) levels. To date, there are no Lp(a) lowering therapies approved by the FDA.

Refractory hypertension

Hypertension is the leading cause of cardiovascular morbidity and mortality worldwide and adherence is a major limitation. Refractory hypertension is a phenotype of antihypertensive treatment failure, distinct from resistant hypertension and clinically-defined as uncontrolled blood pressure, typically >140/90 mmHg, despite treatment with five or more antihypertensive agents of different classes. To date, there are no FDA approved therapies specifically for refractory hypertension, though several therapies are indicated for resistant hypertension.

Alpha-1 Antitrypsin Disorder

Alpha-1 antitrypsin deficiency, or AATD, is a hereditary genetic disorder caused by mutations in the SERPINA1 gene, which encodes the protein alpha-1 antitrypsin, or AAT. AAT is a protease inhibitor synthesized primarily in the liver that protects the lungs from proteolytic enzymes, specifically neutrophil elastase. AATD mechanism of disease is characterized by a loss-of-function in the lungs and a toxic gain-of-function in the liver. In the lungs, insufficient levels of functional AAT lead to unchecked neutrophil elastase activity, causing the destruction of alveolar tissue and resulting in early-onset emphysema and chronic obstructive pulmonary disease, or COPD. In the liver, the most common disease-causing variant, the Z allele, causes the misfolded AAT protein to polymerize and accumulate within hepatocytes. This intracellular accumulation triggers an inflammatory cascade and cell death, leading to fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma, or HCC. AATD is the most common genetic cause of liver disease in

children and a significant genetic risk factor for COPD in adults. It is estimated that approximately 100,000 individuals in the United States are living with AATD, yet fewer than 10% of these individuals have been clinically diagnosed. While intravenous augmentation therapies are FDA-approved to slow the progression of lung emphysema by restoring plasma AAT levels, there are currently no approved pharmacotherapies to treat AATD-associated liver disease.

In Vivo Approaches - siRNA-based Programs

Our siRNA-based portfolio includes clinical-stage programs in cardiovascular and thromboembolic diseases, developed in collaboration with Sirius. CTX611 is a novel double-stranded siRNA designed to target the human coagulation factor XI, or FXI, messenger RNA and inhibit FXI protein expression. Through modulation of the intrinsic coagulation pathway, CTX611 is intended to provide anticoagulant and antithrombotic effects. By targeting FXI, CTX611 aims to reduce thrombotic events while minimizing the risk of bleeding, representing a differentiated approach compared to Factor Xa inhibitors. In addition, CTX611 may offer the potential for reversibility not observed with other anti-Factor XI modalities. The addressable population for CTX611 is a range of thromboembolic and clotting-related indications, including atrial fibrillation (AF), venous thromboembolism, or VTE, ischemic stroke, cancer-associated thrombosis, chronic kidney disease, peripheral vascular disease, chronic coronary artery disease.

Two Phase 1 clinical trials of CTX611 have been completed by Sirius, and single doses of CTX611 have been well tolerated. CTX611 demonstrated robust pharmacodynamic effects, including reductions of over 93% in FXI levels and FXI activity, along with more than a twofold increase in activated partial thromboplastin time relative to baseline. These effects were sustained, with responses maintained for up to six months post-dosing.

Supported by clinical experience to date, CTX611 is being developed as a long-acting FXI inhibitor with the potential to support infrequent, including semi-annual, subcutaneous administration. CTX611 is being investigated in an ongoing Phase 2 clinical trial in evaluating the safety and efficacy of the candidate in preventing VTE in patients undergoing total knee arthroplasty.

Thromboembolic and clotting-related indications

Thromboembolic conditions arise from dysregulation of the coagulation cascade, a series of enzymatic reactions that give rise to a fibrin clot. Historic anticoagulation therapies target enzymes, such as Factor Xa and Thrombin, which are essential for hemostasis. While these therapies are effective at preventing clotting complications, they come with inherent bleeding risk. More recent therapeutic strategies aim to target enzymes, such as Factor XI, that are critical for thrombosis, but largely redundant for hemostasis. These approaches aim to decouple hemostasis from thrombosis and, consequently, widen the therapeutic window for silencing approaches toward thromboembolisms.

Venous Thromboembolism, or VTE, describes the formation of blood clots in venous circulation, giving rise to two disparate indications: deep vein thrombosis, or DVT, and pulmonary embolism, or PE. DVT occurs when a thrombus forms in the deep veins, typically of the legs, pelvis, or arms, obstructing venous return and causing local pain and swelling. PE occurs when a portion of this thrombus embolizes and travels to the lungs, blocking pulmonary arteries and impairing oxygenation. VTE represents a massive public health burden, as the Centers for Disease Control and Prevention, or CDC, estimates that up to 900,000 individuals are affected by VTE in the United States annually, resulting in 60,000 to 100,000 deaths. The current standard of care consists of anticoagulation with agents such as Low Molecular Weight Heparin, vitamin K antagonists (e.g., warfarin), or Direct Oral Anticoagulants. While effective, these therapies indiscriminately inhibit the coagulation cascade, creating a dose-limiting risk of major bleeding.

CAR T

We expect that the cellular engineering strategies that are ultimately successful will involve multiple genetic modifications, an application for which we believe CRISPR/Cas9 will play a central role. While other gene editing platforms could potentially be used for these purposes, CRISPR/Cas9 is particularly well-suited for multiplexed editing, which is the modification and/or insertion of multiple genes within a single cell. Gene editing techniques that require different protein enzymes for each genetic modification may be limited in the number of edits they can make concurrently due to efficiency, cytotoxicity and/or manufacturing challenges. In contrast, CRISPR/Cas9 has the potential to efficiently make multiple edits using a single Cas9 protein and multiple small gRNA molecules.

We are using the multiplexing ability of CRISPR/Cas9 both to enable allogeneic administration and to introduce additional genetic edits that aim to improve the efficacy profile of these product candidates. Furthermore, we are leveraging our CRISPR platform to enable a process of continuous innovation in which we incorporate incremental edits into next-generation products to try to increase treatment benefit further. We continue to expand our multiplexing capabilities to help us realize the full potential of engineered cell therapy in immuno-oncology across all tumor types, including solid tumors.

We are advancing cell therapy programs for autoimmune indications and oncology, including a next-generation, investigational, gene-edited, healthy donor-derived allogeneic CAR T product candidate, zugocabtagene geleucel (zugo-cel; formerly CTX112), in clinical trials. Zugo-cel targets CD19 and builds upon our first-generation programs, which provided important proof of concept that allogeneic CAR T cells can produce durable remissions following a standard lymphodepletion regimen and demonstrated a well-tolerated safety profile. Our CRISPR/Cas9 platform has enabled us to incorporate additional edits into our next-generation product candidates, and reflect our mission of innovating continuously to bring potentially transformative medicines to patients as quickly as possible.

Zugo-cel incorporates two novel gene edits. These edits—knock-out of Regnase-1 and knock-out of transforming growth factor-beta receptor type 2, or TGFBR2—are designed to enhance CAR T potency and reduce CAR T exhaustion. Editing Regnase-1 removes an intrinsic “brake” on T cell function while editing TGFBR2 removes a key extrinsic “brake” on T cell anti-tumor activity. We identified this combination of edits through systematic screening of dozens of new and previously described genes.

In total, to generate zugo-cel we make five modifications to T cells taken from healthy donors using our gene editing technology:

Elimination of the T-cell receptor, or TCR, to reduce the risk of Graft versus Host Disease, or GvHD.

Site-specific insertion of a CD19-directed CAR into the TRAC locus.

Removal of the class I major histocompatibility complex, MHC I, from the cell surface to improve the persistence of the CAR T cells in an “off-the-shelf” setting.

Disruption of Regnase-1 to increase functional persistence, cytokine secretion and sensitivity, and effector function.

Disruption of TGFBR2 to reduce tumor microenvironment inhibition of multiple CAR T cell functions.

Our Next-Generation CRISPR Gene-edited Allogeneic CAR T Chassis

We believe this approach will have advantages over other allogeneic CAR T products in development that semi-randomly insert the CAR using an integrating virus and do not include edits to increase potency. Emerging clinical data from the ongoing clinical trial and pharmacology data, including pharmacokinetics, indicate that the novel potency gene edits in zugo-cel lead to significantly higher CAR T cell expansion and functional persistence in patients compared to first-generation candidates. In addition, zugo-cel exhibits increased manufacturing robustness, with a higher and more consistent number of CAR T cells produced per batch. We are producing zugo-cel for clinical trials at our internal GMP manufacturing facility in Framingham, Massachusetts.

Autoimmune disease

Autoimmune diseases can result from an immune response against the body’s own cells, tissues, or organs, also known as autoreactivity. Within autoimmune disease, there is a spectrum of autoreactivity that can manifest in a diverse array of symptoms. One form of autoreactivity is the presence of autoantibodies, which are a product of autoreactive, pathogenic B cells. Targeting these pathogenic B cells has been shown to ameliorate the symptoms of B-cell mediated autoimmune diseases. Several therapies have been approved for B-cell mediated autoimmune diseases, such as rituximab in rheumatoid arthritis; however, such therapies require chronic administration and largely do not achieve complete remission of disease.

Multiple groups have begun to demonstrate the utility of CAR T therapy for the treatment of various B-cell mediated autoimmune diseases, including systemic lupus erythematosus, or SLE, progressive systemic sclerosis and idiopathic immune myositis. Specifically, treatment with CD19-directed autologous CAR T cells after lymphodepletion has produced durable remissions in early clinical studies. Subsequently, several cell therapy approaches are being developed to treat B-cell mediated diseases.

Allogeneic CAR T therapy has the potential to provide meaningful clinical benefit with several potential advantages, including increased scalability, dramatically decreased cost of goods, reduced risk of toxicities and an improved patient experience with no need for apheresis. Removing the requirement for apheresis allows patients to continue to use concurrent medications instead of withdrawing them during the autologous CAR T cell manufacturing process, reducing the risk of disease-related flares. Autoimmune disease could represent a large additional opportunity for our allogeneic CAR T cell therapy platform across multiple indications, including SLE, progressive systemic sclerosis, idiopathic immune myositis, immune thrombocytopenia purpura, and warm autoimmune hemolytic anemia.

Systemic lupus erythematosus

Systemic lupus erythematosus, or SLE, is a chronic autoimmune disease characterized by the production of autoantibodies, particularly against nuclear components, which causes widespread deposition of immune complexes and tissue damage across multiple organ systems. SLE clinical presentation is variable, but can range from mild mucocutaneous symptoms to life-threating organ involvement. According to the CDC, conservative estimates suggest SLE affects approximately 200,000 individuals in the United States. Treatment strategies are stratified by disease severity, with antimalarials serving as the cornerstone of therapy to prevent flares. During active disease, corticosteroids and broad immunosuppressants e.g., methotrexate, mycophenolate mofetil are used to induce remission. Recent years have seen the FDA approval of targeted biologics, including belimumab, and anifrolumab a type I interferon receptor antagonist, as well as voclosporin specifically for lupus nephritis. However, many patients remain refractory to current treatments or suffer from significant steroid-induced toxicity.

Systemic Sclerosis

Systemic sclerosis, or SSC, is a chronic, multi-system autoimmune disease characterized by autoimmunity, vasculopathy, and fibrosis. Initiating endothelial cell injury, production of autoantibodies and activation of fibroblasts leads to production of excessive collagen and extracellular matrix proteins that drive thickening and hardening of skin and connective tissue. Beyond the skin, SSc can affect the lungs, kidneys, heart, and gastrointestinal tract. The prevalence of SSc varies, but is estimated to be approximately 17 per 100,000 individuals. The treatment landscape has evolved to target specific organ manifestations. For SSc-associated interstitial lung disease, Sc-ILD, the FDA has approved nintedanib, a tyrosine kinase inhibitor with antifibrotic activity, and tocilizumab, an IL-6 receptor antagonist. Standard management also includes broad immunosuppression with agents such as mycophenolate mofetil or cyclophosphamide. Despite these advances, significant unmet need remains for therapies that can halt or reverse the underlying fibrotic and vascular progression of the disease.

Idiopathic Inflammatory Myopathies

Idiopathic Inflammatory Myopathies, or IIM, otherwise known as myositis, are a group of systemic autoimmune disorders characterized by chronic muscle inflammation, progressive muscle weakness, and complicating extra-muscle manifestations. The pathophysiology of IIMs is immunologically complex, but, in part, is driven by autoantibody production. The annual incidence of IIM is estimated at approximately 1 to 20 cases per 1,000,000 individuals, with a prevalence of roughly 2 to 34 per 100,000. Treatment strategies rely heavily on broad immunosuppression, including high-dose corticosteroids often combined with steroid-sparing agents such as methotrexate or azathioprine. IVIG is FDA-approved for the treatment of dermatomyositis. For refractory cases, B-cell depleting agents, rituximab, or Janus Kinase inhibitors are increasingly utilized. However, a significant proportion of patients experience chronic disability, interstitial lung disease, and treatment-related toxicity.

Immune thrombocytopenia purpura

Immune thrombocytopenia purpura, or ITP, is an acquired autoimmune disorder characterized by isolated low platelet count (<100,000/μL) in the absence of other causes. The primary mechanism of disease includes production of autoantibodies that target glycoproteins on the surface of platelets, resulting in destruction by the immune system. Concurrently, these autoantibodies impair the ability of de novo platelet generation in the bone marrow. ITP manifests clinically as increased risk for bleeding, which can be life-threatening in cases of events such as intracranial hemorrhage, and significant fatigue. ITP occurs in approximately 31,000 patients in the U.S; the current therapeutic landscape include corticosteroids, intravenous immunoglobulin, or IVIG, and therapies that aim to increase platelet production or address autoantibody production e.g., B-cell depletion; however, a subset of these patients remain refractory.

Autoimmune hemolytic anemia (wAIHA)

Warm autoimmune hemolytic anemia (wAIHA) is a rare, life-threatening autoimmune disorder characterized by the production of polyclonal IgG autoantibodies that bind to antigens on the surface of red blood cells at physiological body temperatures, leading to recognition by macrophages and premature destruction. This accelerated destruction outpaces the bone marrow's compensatory

production of new red blood cells, resulting in severe anemia. wAIHA presents with symptoms of profound fatigue, dyspnea, jaundice, and dark urine, and carries a substantial risk of life-threatening thrombotic events. The annual incidence of wAIHA in the United States is estimated at approximately 1 to 6 cases per 100,000 individuals, with a prevalence of approximately 1 in 8,000 to 12,000 individuals. Currently, there are no FDA-approved pharmacotherapies specifically indicated for the treatment of wAIHA, but standard of care relies on broad immunosuppression, beginning with stabilization using high-dose corticosteroids and progressing to off-label use of B-cell depleting therapies for patients aiming to taper or who are refractory to high-dose steroids.

Immuno-oncology

Interest in the oncology community has grown rapidly in the field of immuno-oncology, or treatments that harness the immune system to attack cancer cells. Engineered immune cell therapy is one such approach, in which immune system cells such as T cells are genetically modified to enable them to recognize and attack cancerous cells.

Engineered cell therapy has demonstrated encouraging results leading to multiple approvals for autologous, or patient-derived, CAR T products in indications such as diffuse large B-cell lymphoma, multiple myeloma, and follicular lymphoma. These cell therapies require unique products to be created for each patient treated, an approach that has in the past proven challenging and cost prohibitive in the field of oncology. This bespoke manufacturing process takes time during which a patient’s disease can progress and sometimes fails to produce a viable product at all. In contrast, allogeneic, or donor-derived, engineered T-cell therapies can be manufactured ahead of time and administered “off-the-shelf,” enabling immediate availability, improved access and efficiency, simpler logistics, greater consistency, and re-dosing.

Large B-cell Lymphoma

Large B-Cell Lymphoma, or LBCL, represents a heterogeneous group of aggressive non-Hodgkin lymphomas resulting from the malignant transformation and rapid clonal proliferation of mature B-lymphocytes. While LBCL encompasses several subtypes, Diffuse Large B-Cell Lymphoma, or DLBCL, is the dominant clinical entity, accounting for approximately 80% of LBCL cases and 30-40% of all non-Hodgkin lymphomas globally. Pathologically, LBCL is characterized by the disruption of normal B-cell differentiation within the germinal center of lymph nodes, leading to the accumulation of large, rapidly dividing cells that express B-cell surface antigens such as CD19 and CD20. DLBCL is the most common lymphoid malignancy in adults, with an estimated ~18,000 new cases diagnosed annually in the United States. The standard of care for frontline treatment is the chemoimmunotherapy regimen R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), with which approximately 60-70% of patients achieve CR. However, some patients will have disease that is refractory to initial therapy or relapses after remission, or R/R LBCL. For these patients, the prognosis has historically been poor. While the recent approval of CD19-directed CAR-T cell therapies (e.g., axicabtagene ciloleucel, lisocabtagene maraleucel) and bispecific antibodies (e.g., epcoritamab, glofitamab) has transformed the treatment landscape, these modalities are associated with significant toxicities, such as cytokine release syndrome, or CRS, and neurologic events, or ICANS, and complex manufacturing logistics.

Zugocabtagene geleucel

Autoimmune disease

The autologous CAR T cells used successfully in autoimmune diseases to date appear to cause a B cell “reset” following deep B cell depletion whereby reconstituted B cells do not express high levels of autoantibodies. We believe that zugo-cel has the potential to produce a similar B cell “reset”.

Zugo-cel is being investigated in two ongoing clinical trials: a Phase 1 basket trial in autoimmune rheumatologic diseases, including systemic lupus erythematosus, or SLE, systemic sclerosis, or SSc, and inflammatory myositis and a second clinical trial in immune thrombocytopenia purpura and warm autoimmune hemolytic anemia. Zugo-cel has been granted RMAT designation by the FDA for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma.

Preliminary clinical data from the Phase 1 study in autoimmune rheumatologic diseases released in December 2025 and updated in January 2026 has been encouraging, and zugo-cel has been well tolerated to date. As of the original data cut-off on December 17, 2025, four patients (2 SLE and 2 immune-mediated necrotizing myopathy with interstitial lung disease) have been treated at a dose of 100 million cells and followed for at least 28 days post-infusion:

•

Zugo-cel cell expansion is comparable to that observed at the same dose in patients in the ongoing B-cell lymphomas trial.

•

Rapid and deep B-cell depletion in the periphery was observed within the first 1-2 days and maintained over the first month of treatment, with repopulating B-cells demonstrating a shift toward an unswitched, naïve repertoire.

•

All patients demonstrated significant clinical improvement at the Day 28 assessment.

•

The first patient with SLE, refractory to 9 prior therapies with a baseline Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 8, has maintained drug-free DORIS clinical remission through Month 6 following CAR T therapy.

•

Treatment has been well-tolerated, with no high-grade CRS or ICANS observed.

Updated data released in January 2026 indicate the first patient with SLE, refractory to 9 prior therapies with a baseline Systemic Lupus Erythematosus Disease Activity Index 2000, or SLEDAI-2K, score of 8, has maintained drug-free DORIS clinical remission through month 9 following CAR T therapy. Additionally, the second SLE patient with a baseline SLEDAI-2K score of 8, has sustained B cell depletion with SLEDAI-2K score of 0 through month 2 following CAR T therapy.

Summary of Zugo-cel Clinical Efficacy in SLE (N=2)

Immuno-oncology

We are investigating zugo-cel in an ongoing clinical trial designed to assess the safety and efficacy of zugo-cel in adult patients with relapsed or refractory CD19-positive B-cell malignancies who have received at least two prior lines of therapy. In this trial, we use a standard lymphodepletion regimen consisting of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for three days.

As of December 2025, a total of 39 patients have been treated across all 4 dose levels. The recommended Phase 2 dose, or RP2D, was recently endorsed at the 600 million cell dose for the LBCL cohort. As of the data cut-off of November 20, 2025, 10 patients with R/R LBCL have been treated at the RP2D of 600 million cell dose and have had at least one month of follow-up, with the following observations:

•

An overall response rate of 90% (9/10) and a complete response rate of 70% (7/10) were observed, including a complete response, or CR, in a patient who relapsed following autologous CAR T cell therapy.

•

Among patients who have completed 12-months of follow-up, 67% (2/3) remained in CR at the 12-month evaluation.

•

Peak mean CAR T cell expansion of approximately 1,700 cells/μL was observed at the RP2D, representing approximately a four-fold higher expansion compared with patients receiving 300 million cells.

•

Rates of Grade 3 CRS, ICANS and serious infections were 17%, 17%, and 8%, respectively, among all LBCL patients treated at the RP2D (n=12).

•

No Grade 3 ICANS or CRS has been observed at the 100 million cell dose, which is the dose currently being studied in the autoimmune basket trials.

As described below, positive clinical data generated through December 2025 support the advancement of zugo-cel into the Phase 2 portion of the ongoing Phase 1/2 clinical trial. Eligible disease subtypes include large B-cell lymphoma, or LBCL, follicular lymphoma grade 1-3a, marginal zone lymphoma, and mantle cell lymphoma.

Interim Zugo-cel Phase 1 Data Suggests Durability in LBCL at RP2D

Additional candidates

Our CRISPR/Cas9 platform enables us to innovate continuously by incorporating incremental edits into next-generation products. We are advancing several additional investigational CAR T programs. In addition, we are developing both transient and integrated in vivo CAR T therapies by targeting T cells with LNPs and leveraging our delivery, mRNA, and gene editing expertise.

Regenerative Medicine

We continue to advance our regenerative medicine portfolio, including in diabetes. We believe our gene editing capabilities have the potential to enable a beta-cell replacement product candidate that may deliver durable benefit to patients without the need for long-term immunosuppression.

Clinical data with allogeneic islet transplants indicate that beta-cell replacement approaches may offer benefit to patients with insulin-requiring diabetes. However, this approach requires collecting islets from cadavers, which is not a scalable process. In addition, because a patient’s immune system will identify these cadaveric cells as foreign, patients require long-term immunosuppression to avoid rejection. The first challenge can be solved by using beta cells derived from stem cells. Multiple groups have advanced stem cell-derived beta-cell replacement product candidates into clinical studies, but these product candidates still require chronic immunosuppression.

Our gene editing technology offers the potential to protect the transplanted cells from the patient’s immune system by ex vivo editing of immuno-modulatory genes within the stem cell line used to produce the pancreatic-lineage cells. We believe that the speed, specificity and multiplexing efficiency of CRISPR/Cas9 make our technology well suited to this task. Furthermore, our CRISPR platform enables a process of continuous innovation, with additional edits incorporated into next-generation product candidates with the aim of increasing treatment benefit further.

We are advancing CTX213, a deviceless beta cell replacement product candidate consisting of unencapsulated precursor islet cells derived from induced pluripotent stem cells for the treatment of T1D. CTX213 utilizes six gene edits designed to promote immune evasion and cell fitness: knock-out of B2M and TXNIP and knock-in of PD-L1, HLA-E, MANF and A20. CTX213 benefits from work on a precursor product candidate, CTX211, where a Phase 1 trial observed sustained c-peptide production 12 months post implantation and histology-confirmed survival of transplanted insulin producing islet cells, despite the fibrosis of the encapsulation device and infiltration of immune cells. Preclinical studies have shown direct administration of CTX213 leads to improved glycemic control and C-peptide production in a diabetic rat model.

In addition, in March 2023, we entered into a non-exclusive license agreement with Vertex for Vertex to utilize certain of our gene-editing intellectual property to exploit certain products for the diagnosis, treatment or prevention of diabetes type 1, diabetes type 2 or insulin dependent/requiring diabetes throughout the world. To date, we have recognized revenue of $205.0 million in upfront and milestone payments and remain eligible to receive additional research and development milestones and royalties on future products under the license.

Enabling Technologies

We have entered into a number of additional collaborations and license agreements to support and complement our ex vivo and in vivo programs, including agreements related to: technologies to deliver CRISPR/Cas9 ex vivo and in vivo; additions to our hematopoietic stem cell and in vivo programs, including two grants to advance gene editing therapies for HIV; and enhancements to our CAR T and regenerative medicine cell therapy programs and platform.

Other Vertex Partnered Programs

We have partnered with Vertex, a global leader in rare diseases, in several other disease areas beyond SCD and TDT. We have entered into license agreements with Vertex with respect to cystic fibrosis, or CF, where Vertex has extensive expertise, and DMD. In addition, we have entered into a collaboration agreement on DM1, in which we retain the option to co-develop and co-commercialize products. We believe that our CRISPR/Cas9 gene editing technology is well suited to address CF, DMD and DM1, all of which have significant patient populations with high unmet medical need.

Duchenne Muscular Dystrophy

DMD is an X-linked recessive genetic disease caused by mutations in the dystrophin gene, which results in a lack of the dystrophin protein. Because dystrophin plays a key structural role in muscle fiber function, the absence of this protein in muscle cells leads to significant cell damage and ultimately causes muscle cell death and fibrosis. Patients with the disease experience muscle degeneration, loss of mobility and premature death. DMD is among the most prevalent severe genetic diseases, occurring in one in 3,300 male births worldwide. There are currently several approved disease-modifying therapies in the United States for the treatment of DMD, including one for patients who have confirmed mutations of the dystrophin gene amenable to exon 51 skipping, two for patients who have confirmed mutations of the dystrophin gene amenable to exon 53 skipping, and one for patients who have confirmed mutations of the dystrophin gene amenable to exon 45 skipping. These mutations affect about 13%, 8% and 8% of the DMD population, respectively. In addition, in June 2023, the FDA granted accelerated approval for Elevidys (delandistrogene moxeparvovec), an AAV gene therapy carrying a micro-dystrophin gene for the treatment of ambulatory pediatric patients aged 4 through 5 years with DMD with a confirmed mutation in the DMD gene.

Myotonic Dystrophy Type 1

DM1 is an autosomal genetic disease caused by the expansion of a CTG trinucleotide repeat in the noncoding region of the DMPK gene. The disease affects the skeletal and smooth muscle, as well as other organ systems, such as the eye, heart, endocrine system, and central nervous system. The clinical manifestations of DM1 span a continuum from mild to severe. Based on these phenotypes, DM1 is classified into three somewhat overlapping forms: mild, classic, and congenital. Patients with mild DM1 have normal lifespans and typically develop cataracts, and experience mild sustained muscle contractions, or myotonia. Those with classic DM1 tend to have muscle weakness and wasting, myotonia, cataracts and often abnormalities in cardiac conduction, and may become physically disabled and have shortened lifespans. Patients with congenital DM1 commonly have intellectual disability and typically have hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death. DM1 affects around 1 in 8,000 people worldwide. No approved therapies exist to treat the underlying disease; instead, most interventions to date aim to address specific symptoms of the disease.

Cystic Fibrosis

CF is a progressive disease caused by mutations in the cystic fibrosis transmembrane regulator, or CFTR, gene resulting in the loss or reduced function of the CFTR protein. Patients with CF develop thick mucus in vital organs, particularly in the lungs, pancreas and gastrointestinal tract. As a result, CF patients experience chronic severe respiratory infections, chronic lung inflammation, poor absorption of nutrients, progressive respiratory failure and early mortality. The median age of death from CF in the United States was 31 years in 2017, with most deaths resulting from respiratory failure.CF is an orphan disease that is estimated to affect more than 70,000 patients in the United States and Europe. CF patients require lifelong treatment with multiple daily medications and hours of self-care. They often require frequent hospitalizations and sometimes even lung transplantation, which can prolong survival but is not curative.

Strategic Partnerships and Collaborations

We view strategic partnerships as a core component of our strategy, allowing us to access capabilities and resources in support of our therapeutic programs. We maintain broad strategic partnerships to develop gene editing-based therapeutics in specific disease areas.

Vertex

We, and certain of our affiliates, have entered into a series of agreements with Vertex, and or affiliates of Vertex, that contemplate certain research, development, manufacturing and commercialization activities involving various targets. Since October

2015, we have entered into a Strategic Collaboration, Option and License Agreement, as amended in 2017 and 2019, or the 2015 Collaboration Agreement; a Joint Development and Commercialization Agreement, or the Vertex JDA, which was amended and restated in April 2021, or the A&R Vertex JDCA, as amended in December 2023, or the Amended A&R Vertex JDCA. In addition, we and Vertex entered into a non-exclusive license agreement in March 2023, or the Non-Ex License Agreement, pursuant to which we agreed to license to Vertex, on a non-exclusive basis, certain of our gene editing intellectual property.

2015 Collaboration Agreement

Pursuant to the 2015 Collaboration Agreement, we agreed to provide technology and options to obtain licenses relating to our CRISPR/Cas technology to Vertex in exchange for a $75.0 million upfront payment. In 2015, in connection with the initial entry into the 2015 Collaboration Agreement, Vertex also made a $30.0 million equity investment in us.

The initial focus of the 2015 Vertex collaboration was to use CRISPR/Cas9 technology to discover and develop gene-based treatments for hemoglobinopathies and cystic fibrosis. In 2017, Vertex exercised its option to co-develop and co-commercialize the hemoglobinopathies program. Matters relating to hemoglobinopathies targets are governed by the Amended A&R Vertex JDCA, as summarized below. Further discovery efforts focused on a specified number of other genetic targets. Under the 2015 Collaboration Agreement, Vertex had the option to exclusively license treatments for a specified number of collaboration targets that emerged from the four-year research collaboration under certain of our platform and background intellectual property to develop, manufacture, commercialize, sell and use therapeutics directed to each such collaboration target. We were responsible for discovery activities, and the related expenses were fully funded by Vertex.

In October 2019, Vertex exercised the remaining options granted to it under the 2015 Collaboration Agreement to exclusively in-license three additional targets for the development of gene-based treatments using CRISPR-based gene editing. The targets include the cystic fibrosis transmembrane conductance regulator gene and two undisclosed targets. Under the terms of the 2015 Collaboration Agreement, we received an upfront payment of $30.0 million in connection with the option exercise and have the potential to receive up to $410.0 million in development, regulatory and commercial milestones, as well as royalty payments in the single digits to low teens on net product sales for each of the three targets. The milestone and royalty payments are each subject to reduction under certain specified conditions set forth in the 2015 Collaboration Agreement. For these targets, Vertex is solely responsible for all research, development, manufacturing and global commercialization activities and Vertex received exclusive rights to develop and commercialize products related to these targets globally. The research term of the 2015 Collaboration Agreement has expired, and Vertex no longer holds rights to in-license additional targets under the 2015 Collaboration Agreement.

Either party can terminate the 2015 Collaboration Agreement upon the other party’s material breach, subject to specified notice and cure provisions. Vertex also has the right to terminate the 2015 Collaboration Agreement for convenience at any time upon 90 days’ written notice prior to any product receiving marketing approval and upon 270 days’ notice after a product has received marketing approval. We may also terminate the 2015 Collaboration Agreement in the event Vertex challenges any of our patent rights.

Absent early termination, the 2015 Collaboration Agreement will continue until the expiration of Vertex’s payment obligations under the 2015 Collaboration Agreement.

Joint Development Agreement

In December 2017, we entered into the Vertex JDA with Vertex pursuant to which the parties agreed to, among other things, co-develop and co-commercialize CASGEVY and other product candidates specified in the Vertex JDA. In April 2021, we and Vertex agreed to amend and restate the Vertex JDA and entered into the A&R Vertex JDCA, pursuant to which the parties agreed to, among other things, (a) adjust the governance structure for the collaboration and adjust the responsibilities of each party thereunder; (b) adjust the allocation of net profits and net losses between the parties with respect to CASGEVY only; and (c) exclusively license (subject to our reserved rights to conduct certain activities) certain intellectual property rights to Vertex relating to the specified product candidates and products (including CASGEVY) that may be researched, developed, manufactured and commercialized under such agreement. We and Vertex amended the A&R Vertex JDCA in December 2023.

The A&R Vertex JDCA, as amended, includes, among other things, provisions relating to the following:

Governance; Activities. We and Vertex disbanded the previously established collaboration strategy team and all working groups established by such team and established a joint oversight committee to provide high-level oversight of the ongoing collaboration comprised of an equal number of representatives from each of CRISPR and Vertex. We and Vertex also formed a transition committee to provide for forum planning, discussing and sharing information regarding certain transition activities, which was disbanded following completion of such activities. The agreement provides that, subject to the terms and conditions of such agreement, Vertex has the right to conduct all research, development, manufacturing and commercialization activities relating to the specified product candidates and products (including CASGEVY) throughout the world subject to our reserved right to conduct certain activities. We will continue to participate in certain aspects of such activities in an observer capacity unless and to the extent otherwise agreed to by the parties.

Financial Terms. In the second quarter of 2021, in connection with the closing of the transaction contemplated by the

amendment and restatement of the Vertex JDA, we received a $900 million up-front payment from Vertex. Additionally, in connection with the FDA’s approval of CASGEVY on December 8, 2023 for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises, we received a $200.0 million milestone payment from Vertex in the first quarter of 2024. The net profits and net losses, as applicable, incurred under the Amended A&R Vertex JDCA with respect to all product candidates and products specified in such agreement, other than CASGEVY, shall be shared equally between us and Vertex. With respect to CASGEVY only, the net profits and net losses, as applicable, incurred under the agreement through July 1, 2021 in connection with the initial shared product (i.e., CASGEVY) were shared equally between us and Vertex, and beginning July 1, 2021, the net profits and net losses, as applicable, incurred under the agreement are allocated 40% to CRISPR and 60% to Vertex. In addition, for the years ended December 31, 2022, 2023 and 2024, the agreement allowed us to defer a portion of our share of costs under the arrangement if spending on the CASGEVY program exceeds $110.3 million annually. In December 2023, pursuant to the amendment, the parties agreed to (a) allocate certain costs arising from a license agreement with a third party, resulting in a current payment due to Vertex by CRISPR of $20 million upon an event specified in such amendment; and (b) adjust, under certain specified circumstances, the timing of and portion of CRISPR’s share of costs it is permitted to defer under the agreement. Any deferred amounts under the Amended A&R Vertex JDCA are payable to Vertex only as an offset against future profitability of the CASGEVY program and the amounts payable are capped at a specified maximum amount per year.

Termination. Either party can terminate the agreement upon the other party’s material breach, subject to specified notice and cure provisions, or, in the case of Vertex, in the event that we become subject to specified bankruptcy, winding up or similar circumstances. Either party may terminate the agreement in the event the other party commences or participates in any action or proceeding challenging the validity or enforceability of any patent that is licensed to such challenging party pursuant to the agreement. Vertex also has the right to terminate the agreement for convenience at any time after giving prior written notice.

If circumstances arise pursuant to which a party would have the right to terminate the agreement on account of an uncured material breach, such party may elect to keep the agreement in effect and cause such breaching party to be treated as if it had exercised its opt-out rights with respect to the products associated with such uncured material breach (described below) and the royalties payable to the breaching party would be reduced by a specified percentage.

Opt-Out Rights. Either party may opt out of the development of a product candidate under the agreement after predetermined points in the development of the product candidate, on a candidate-by-candidate basis. In the event of such opt-out, the party opting out will no longer share in the net profits and net losses associated with such product candidate and, instead, the opting-out party will be entitled to high single to mid-teen percentage royalties on the net sales of such product, if commercialized.

Non-Exclusive License Agreement

In March 2023, we and Vertex entered the Non-Ex License Agreement, pursuant to which we agreed to license to Vertex, on a non-exclusive basis, certain of our gene editing intellectual property to exploit certain products for the diagnosis, treatment or prevention of diabetes type 1, diabetes type 2 or insulin dependent/requiring diabetes throughout the world.

The Non-Ex License Agreement includes, among other things, provisions relating to the following:

Financial Terms. In connection with entering into the Non-Ex License, we received a $100.0 million upfront payment from Vertex and have subsequently received $105.0 million in research and development milestones achieved by Vertex through December 31, 2025. We are eligible to receive additional milestone payments from Vertex of up to $125.0 million in the aggregate. The milestones are dependent on the achievement of pre-determined research, development and commercial milestones for certain products utilizing the licensed intellectual property. We are also eligible to receive tiered royalties on the sales of certain products in the low to mid-single digits. In the event of any termination or expiration of the Non-Ex License Agreement, tiered royalties on the sales of certain products will continue in the low to mid-single digits.

Termination. Either party may terminate the Non-Ex License Agreement upon the other party’s material breach, subject to specified notice and cure provisions. We may also terminate the Non-Ex License Agreement in the event Vertex commences or participates in any action or proceeding challenging the validity or enforceability of any patent that is licensed to Vertex pursuant to the Non-Ex License Agreement. Vertex may also terminate the Non-Ex License Agreement upon our bankruptcy or insolvency, or for convenience upon the earlier of the achievement of certain milestone events or a specified period of time, after giving written notice.

Sirius Therapeutics

In May 2025, we entered into a Collaboration, Option and License Agreement, or the Sirius Agreement, with Sirius Therapeutics, or Sirius-CY, and Sirius Therapeutics, Inc., or Sirius-US, and together with Sirius-CY, Sirius, pursuant to which, among other things, (1) we and Sirius-US will collaborate on the research, development, manufacture, commercialization and use of certain collaboration products utilizing Sirius’ siRNA technology for targeting Factor XI, including CTX611 (formerly known as SRSD107), collectively, the Sirius Collaboration Products; and (2) Sirius granted to us options to exclusively license Sirius siRNA technology to target up to two licensed targets for the research, develop, manufacture and commercialization of licensed products, collectively the siRNA Licensed Products, in exchange for the potential to receive certain option fees, milestone payments and royalties.

Upfront Consideration. In connection with entering into the Sirius Agreement, we agreed to issue to Sirius-CY an aggregate of (i) approximately $70.0 million of our common shares, and (ii) a cash payment of $25.0 million. In connection with the issuance of our common shares, we and Sirius-CY entered into a share issuance agreement relating to the issuance of 1,842,105 registered common shares at an issue price of $38.00 per common share and which were subject to a customary lock-up.

Governance. We and Sirius established a joint steering committee to provide high-level oversight, decision-making and periodic updates regarding activities under the Sirius Agreement, including formation of additional committees, as applicable. Such committee is comprised of an equal number of representatives from each party and meets at least quarterly to review the progress of collaboration program activities and oversee the research program for licensed products. The committee endeavors to make all decisions by consensus. In the event it is unable to reach consensus, we have final decision-making authority on certain matters, including all matters related to siRNA Licensed Products after option exercise.

Termination Generally. Either party can terminate the Sirius Agreement upon the other party’s material breach, subject to specified notice and cure provisions, or upon the insolvency of the other party. To the extent permissible by applicable law, Sirius may also terminate the Sirius Agreement in the event we commence or participate in any action or proceeding challenging the validity or enforceability of any patent that is licensed to us pursuant to the Sirius Agreement. We also have the right to terminate the Sirius Agreement with respect to a siRNA Licensed Product, on a product-by-product basis, for convenience at any time upon 90 days’ written notice prior to first commercial sale of any siRNA Licensed Product and upon 180 days’ notice after first commercial sales of an siRNA Licensed Product.

Absent early termination or opt-out (and subject to the additional rights in lieu of termination described below), the Sirius Agreement will continue, (a) with respect to Sirius Collaboration Products, until the date on which such product is no longer commercialized, on a country-by-country and product-by-product basis; (b) with respect to siRNA Licensed Products, until expiration of all payment obligations under the Sirius Agreement, on a country-by-country and product-by-product basis.

Sirius Collaboration Products

With respect to Sirius Collaboration Products, the Sirius Agreement includes, among other things, provisions relating to the following:

•

Financial Terms. With respect to Sirius Collaboration Products, we and Sirius will equally share all development and commercialization costs. For the first collaboration product candidate successfully developed, we will be the lead party responsible for commercialization efforts in the United States and Sirius-US will be the lead party responsible for commercialization efforts in Greater China. The parties will determine the lead party responsible for commercialization in the rest of the world at a future date. The net profits and net losses, as applicable, incurred under the Sirius Agreement with respect to all Sirius Collaboration Products shall be shared equally between us and Sirius.

In addition, we will pay Sirius future development and regulatory milestones of up to an aggregate of $87.5 million one time regardless of the number of Sirius Collaboration Products that achieve the milestones, and, at our sole election, can be paid in cash, our common shares or a combination thereof.

•

Exclusivity. Under the Sirius Agreement, from the effective date of the Sirius Agreement and for so long as Sirius Collaboration Products are commercialized, neither party nor any of its affiliates may, alone or in conjunction with a third party, engage in activities to advance any siRNA-based pharmaceutical product, medical therapy, treatment, preparation, substance or formulation targeting factor XI or activities in a specified field.

•

Termination. If circumstances arise pursuant to which a party would have the right to terminate the Sirius Agreement with respect to a Sirius Collaboration Product for any reason, such party may elect to keep the Sirius Agreement in effect and cause such other party to be treated as if it had exercised its opt-out rights with respect to the products associated with such uncured material breach or other action leading to the termination right and, if there was an uncured material breach, the milestones and royalties payable to the breaching party would be reduced by a specified percentage and the breaching party may no longer participate in any joint committee, subcommittee or working group with respect to the collaboration products program.

•

Opt-Out Rights. Either party may opt out of the development of a Sirius Collaboration Product under the Sirius Agreement after the later of a period of time or a predetermined point in the development of such Sirius Collaboration Product, on a product-by-product basis. In the event of such opt-out, the party opting-out will no longer share in the net profits and net losses associated with such Sirius Collaboration Product and, instead, the opting-out party will be entitled to mid-single to low-double digit percentage tiered royalties on the net sales of such product, if commercialized. In addition, if the opting-out party is Sirius, Sirius will be entitled to certain milestone payments up to an aggregate of $340.0 million. If we are the opting-out Party, depending on the timing of the opt-out, we will be entitled to certain milestone payments up to an aggregate of $340.0 million, and if the opt-out is prior to the first commercial sale of the opt-out product, the opt-out milestone payments will be capped at a certain percentage of our cumulative development costs for such opt-out product.

siRNA Licensed Products

Under the Sirius Agreement, we have options to exclusively license Sirius siRNA technology to target up to two licensed targets from a list of seven reserved targets for the research, development, manufacture and commercialization of siRNA Licensed Products. Each option is exercisable during a specified exercise period defined by future events for each such licensed target. If we elect to exercise our option to a licensed target to research, develop, manufacture and commercialize siRNA Licensed Products, we will make a one-time $10.0 million payment per option, each, an Option Payment, to Sirius, in cash, our common shares or a combination thereof. The Option Payment is payable up to two (2) times.

•

Financial Terms. We will pay Sirius certain specified future development, regulatory and sales milestones of up to an aggregate of $300.0 million for the first siRNA Licensed Product relating to each licensed target, as well as tiered royalty payments in the mid-single digits to low double digits range on future sales of a commercialized siRNA Licensed Product. The royalty payments are subject to reduction under certain specified conditions set forth in the Sirius Agreement. In addition, at our sole election, certain development and regulatory milestones may be paid in cash, our common shares or a combination thereof. We are solely responsible for all research, development, manufacturing and global commercialization activities and associated costs for siRNA Licensed Products, as well as all associated costs related to Sirius activities set forth in any applicable research plan relating thereto.

•

Exclusivity. Under the Sirius Agreement, Sirius has agreed to certain exclusivity obligations with respect to siRNA-based products targeting reserved targets or licensed targets. Upon expiration of the nomination period, the reserved targets that are not licensed targets by us will no longer be subject to the exclusivity obligations.

•

Rights In-lieu of Termination. If circumstances arise pursuant to which we would have the right to terminate the Sirius Agreement with respect to siRNA Licensed Products for any reason (except termination by us for convenience), we may elect to keep the Sirius Agreement in effect and all amounts due under the Sirius Agreement with respect to siRNA Licensed Products on or after the date of the applicable material breach would be reduced by a specified percentage.

The foregoing descriptions of our strategic agreements are qualified in their entirety by reference to the full text of such agreements, copies of which are filed as exhibits to this Annual Report on Form 10-K.

Intellectual Property

We strive to protect and enhance the proprietary technology, inventions, know-how and improvements that we believe are commercially important to our business by seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties, that cover our gene editing technology and existing and planned therapeutic programs. We also rely on trade secret protection and confidentiality agreements to protect our proprietary technologies and know-how to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection, as well as continuing technological innovation and seeking in-licensing opportunities to develop, strengthen and maintain our proprietary position in the field of gene editing. We additionally rely on trademark protection, copyright protection and regulatory protection available via orphan drug designations, data exclusivity, market exclusivity, and, if relevant, patent term extensions. Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for our technology, our ability to defend and enforce our intellectual property rights and our ability to operate without infringing any valid and enforceable patents and proprietary rights of third parties. We also protect the integrity and confidentiality of our data, know-how and trade secrets by maintaining physical security of our premises and physical and electronic security of our information systems. Our granted patents and any other patents that may ultimately issue from our wholly-owned and in-licensed patent families described below are expected to expire starting in 2033, not including any applicable patent term extensions.

CRISPR-Owned Intellectual Property

We have developed a broad intellectual property estate intended to provide multiple layers of protection around our proprietary gene editing technologies, including CRISPR/Cas9 platform and next-generation editing technologies, and our other technologies, including in vivo delivery, as well as our product candidates. These patent families encompass filings covering our development programs (such as composition of matter, method of use, manufacturing processes, dosing and formulations), the use and improvement modifications of CRISPR/Cas9 systems for gene editing and next generation editing systems (such as improvements to component systems including nucleases and single or modified gRNAs, as well as novel Cas9 and polymerase variants and codon-optimized novel constructs), in vivo targets, technologies for delivering protein/nucleic acid complexes and RNA into cells (such as improved viral vector or lipid nanoparticle systems), and technology relevant to stem cell-based therapies and cancer therapies.

Overall, our wholly-owned intellectual property estate includes approximately eighty (80) active patent families and over one hundred twenty (120) granted or allowed patents, including in the United States, China, Europe, South Africa, Australia, Canada, China, Japan, Mexico and other selected countries in South America, the Middle East and Asia. In addition, we have patent

applications pending throughout the world, including in the United States, Europe, Australia, China, Canada and Japan.

Our U.S. trademark estate consists of approximately thirteen (13) pending applications, including, for example, for CRISPR-X, SYNTASE, CTX112, CTX213, CTX321, CTX340, CTX460 and CTX611, as well as nine U.S. registrations, including for CRISPR THERAPEUTICS, the CRISPR THERAPEUTICS logo, and CTX310. Our international trademark estate consists of multiple pending applications and registrations in various jurisdictions covering similar subject matter.

In-Licensed Intellectual Property from Dr. Charpentier

In addition to our wholly-owned intellectual property estate, in April 2014, we in-licensed all of Dr. Charpentier’s worldwide rights under a patent application filed in March 2013 pursuant to exclusive license agreements with Dr. Charpentier, which we collectively refer to as the Charpentier License Agreement. The Charpentier License Agreement covers certain aspects of our CRISPR/Cas9 technology platform including, for example, compositions of matter (e.g., CRISPR/Cas9 systems) and methods of use, including the use of CRISPR/Cas9 systems for gene editing. The Charpentier License Agreement is limited to therapeutic products, such as pharmaceuticals and biologics and any associated companion diagnostics, for the treatment or prevention of human diseases, disorders, or conditions. For further information about this license, please see “Business— License Agreements— License Agreements with Dr. Charpentier.”

The intellectual property exclusively licensed to CRISPR under the Charpentier License Agreement has named inventors who assigned their rights either to the Regents of the University of California, or California, or the University of Vienna, or Vienna. California’s rights are subject to certain overriding obligations to the sponsors of its research, including the Howard Hughes Medical Institute and the U.S. Government. Caribou Biosciences, or Caribou, has reported that it had an exclusive license to patent rights from California and Vienna, subject to a retained right to allow non-profit entities to use the inventions for research and educational purposes. Intellia Therapeutics, Inc., or Intellia, has reported that it had an exclusive license to such rights from Caribou in certain fields. We refer collectively to Dr. Charpentier, California, and Vienna as the “CVC Group”. We are or have been and will likely be in the future subject to quasi-litigation, inter partes administrative proceedings in various jurisdictions around the world including the U.S. Patent and Trademark Office, or USPTO, the European Patent Office and patent offices in Australia, Japan, China and India involving the patent portfolio. For further information regarding risks regarding these proceedings, please see generally “Risk Factors—Risks Related to Intellectual Property.”

In December 2016, we entered into a Consent to Assignments, Licensing and Common Ownership and Invention Management Agreement, or the IMA, with California, Vienna, Dr. Charpentier, Intellia, Caribou, ERS Genomics Ltd., or ERS, and our wholly-owned subsidiary TRACR Hematology Ltd., or TRACR. Under the IMA, California and Vienna retroactively consent to Dr. Charpentier’s licensing of her rights to the CRISPR/Cas9 intellectual property to CRISPR and TRACR pursuant to the Charpentier License Agreement and to ERS, in the United States and globally. The IMA also provides retroactive consent of co-owners to sublicenses granted by us, TRACR and other licensees, prospective consent to sublicenses they may grant in future, retroactive approval of prior assignments by certain parties, and provides for, among other things, (i) good faith cooperation among the parties regarding patent maintenance, defense and prosecution, (ii) cost-sharing arrangements, and (iii) notice of and coordination in the event of third-party infringement of the subject patents and with respect to certain adverse claimants of the CRISPR/Cas9 intellectual property. Unless earlier terminated by the parties, the IMA will continue in effect until the later of the last expiration date of the patents underlying the gene editing technology, or the date on which the last underlying patent application is abandoned. For further information regarding the effects of joint ownership in the United States and in other jurisdictions worldwide, please see “Risk Factors—The Intellectual Property That Protects Our Core Gene Editing Technology Is Jointly Owned, And Our License Is From Only One Of The Joint Owners, Materially Limiting Our Rights In The United States And In Other Jurisdictions.”

License Agreements

License Agreements With Dr. Charpentier

In April 2014, Dr. Charpentier concurrently entered into the following exclusive license agreements:

CRISPR License Agreement: We entered into an exclusive license agreement with Dr. Charpentier pursuant to which we were granted an exclusive worldwide, royalty-bearing license, including the right to sublicense, under Dr. Charpentier’s joint ownership interest in the intellectual property subject to such license agreement, to research, develop and commercialize therapeutic products such as pharmaceuticals or biological preparations, and any associated companion diagnostics, for the treatment or prevention of human diseases, disorders, or conditions, other than hemoglobinopathies, which we refer to as the CRISPR Field. Additionally, we were granted an exclusive, worldwide, royalty-free sublicense, including the right to sublicense, to research, develop, produce, commercialize and sell therapeutic products relating to the CRISPR Field which incorporate any intellectual property that TRACR develops under its license with Dr. Charpentier. In turn, we granted to Dr. Charpentier an exclusive license with the obligation to sublicense to TRACR any intellectual property we develop under the license with Dr. Charpentier for treatment and prevention of hemoglobinopathies in humans, including, without limitation, sickle cell disease and thalassemia. CRISPR is solely responsible for all clinical, regulatory and development costs.

TRACR License Agreement: TRACR entered into an exclusive license agreement with Dr. Charpentier pursuant to which we were granted an exclusive, worldwide, royalty-bearing license, including the right to sublicense, under Dr. Charpentier’s joint ownership interest in the intellectual property subject to such license agreement to research, develop, produce, commercialize and sell therapeutic and diagnostic products for the treatment and prevention of hemoglobinopathies in humans, including sickle cell disease and thalassemia, which we refer to as the TRACR Field. Additionally, TRACR received a non-exclusive, worldwide, royalty-free license, including the right to sublicense, to carry out internal pharmaceutical research for therapeutic products outside of the TRACR Field and an exclusive, worldwide, royalty-free sublicense, including the right to sublicense, to research, develop, produce, commercialize and sell therapeutic products relating to the TRACR Field which incorporate any intellectual property that CRISPR develops under its license with Dr. Charpentier. In turn, TRACR granted to Dr. Charpentier an exclusive license to sublicense to CRISPR any intellectual property that TRACR develops under the license with Dr. Charpentier for use in the CRISPR Field. TRACR is solely responsible for all clinical, regulatory and development costs.

As a general matter, the material terms and conditions of the CRISPR License Agreement and TRACR License Agreement are substantially the same other than the permitted fields of use under each such agreement (as noted above). As such, for ease of reference, we refer to the CRISPR License Agreement and the TRACR License Agreement individually and collectively as the Charpentier License Agreement.

The licenses granted under the Charpentier License Agreement are exclusive, even as to Dr. Charpentier, except that she retains a non-transferable right to use the technology for her own research purposes and in research collaborations with academic and non-profit partners. The exclusive license granted under the Charpentier License Agreement is granted only under Dr. Charpentier’s interest in the patent applications and the exclusivity is not granted under any other joint owner’s interest.

Under the terms of the Charpentier License Agreement, as consideration for the license, Dr. Charpentier received a technology transfer fee, as well as the right to receive an immaterial annual maintenance fee, immaterial clinical and regulatory milestone payments that are due after the initiation of certain clinical trial and regulatory events a low single digit percentage royalty on net sales of licensed products, and a low single digit percentage royalty on sublicensing revenue. We are obligated to use commercially reasonable efforts to obtain regulatory approval to market of a licensed therapeutic product under each Charpentier License Agreement.

Unless terminated earlier, the term of each Charpentier License Agreement will expire on a country-by-country basis, upon the expiration of the last to expire valid claim of the patents in-licensed to us or TRACR under the applicable Charpentier License Agreement in such country. We and TRACR have the right to terminate the agreement at will upon 60 days’ written notice to Dr. Charpentier. Each Charpentier License Agreement may be terminated by either party thereto upon 90 days’ notice in the event of a material breach by the other party, which is not cured during the 90-day notice period. Dr. Charpentier may terminate the license agreement immediately if we challenge the enforceability, validity, or scope of any in-licensed patent right under the Charpentier License Agreement.

Manufacturing

The manufacturing processes for cell and genetic therapies are complex and require customized systems, equipment, facilities and expertise for each program and therapy. Due to the critical importance of high-quality manufacturing and control of production timing and know-how, we are establishing internal manufacturing capabilities and have established our own cell therapy manufacturing facility to support our multifaceted strategy to develop treatments and therapies for people suffering from serious diseases through transformative gene-based medicines.

We have an approximately 50,000 square foot manufacturing facility in Framingham, Massachusetts intended for clinical and commercial production of our product candidates and certain components thereof for certain of our programs. The facility was designed with flexibility and scalability in mind in order to accommodate manufacturing and supply for our product pipeline. We believe it has the capacity to support, in whole or in part, the manufacture and supply of product for certain of our current clinical programs with the capability to scale-up to support potential commercial supply. In addition, we believe our facility has the capacity and necessary technology to support additional programs we may advance in the future, including some of our in vivo programs and our T1D program, as well as the production of various critical components, such as mRNA, we may utilize in the future. Our operations at this facility are compliant with current Good Manufacturing Practice, or cGMP, and in 2023 we began manufacturing certain of our product candidates, including zugo-cel, at this facility for our clinical trials of such product candidates.

In addition to utilizing our internal manufacturing facility, we expect we will continue to rely on external manufacturing capabilities realized via contract manufacturing organization relationships in the United States and abroad. We have entered into certain manufacturing and supply arrangements with third-party suppliers to support production of our product candidates and their components. We plan to continue to rely on qualified third-party organizations to produce or process bulk compounds, formulated compounds, viral vectors or engineered cells for IND-supporting activities and early-stage clinical trials. We expect that commercial quantities of any compound, vector, or engineered cells that we may seek to develop will be manufactured in facilities and by processes that comply with FDA and other regulations. At the appropriate time in the product development process, we will determine

whether to utilize our own manufacturing facility or continue to rely on third parties to manufacture commercial quantities of any products that we may successfully develop.

We continue to expect to make significant investment in our manufacturing capabilities in Framingham, Massachusetts and in partnerships with third-party organizations for our gene editing programs in order to continue to advance and, in the future, commercialize these programs.

In addition, as product candidates advance through our pipeline, our commercial plans may change. In particular, some of our research programs target potentially larger indications. Data, the size of the development programs, the size of the target market, the size of a commercial infrastructure and manufacturing needs may all influence our strategies in the United States, Europe and the rest of the world. Outside of the United States and Europe, where appropriate, we may elect in the future to utilize strategic partners, distributors or contract sales forces to assist in the commercialization of our products. In certain instances, we may consider building our own commercial infrastructure.

Competition

The biotechnology and pharmaceutical industries, including in the gene editing, gene therapy, nucleic acids therapies, and cell therapy fields, are characterized by rapidly advancing technologies, intense competition and a strong emphasis on intellectual property and proprietary products. While we believe that our technology, development experience and scientific knowledge provide us with competitive advantages, we currently face, and will continue to face, substantial competition from many different sources, including large pharmaceutical, specialty pharmaceutical and biotechnology companies; academic institutions and governmental agencies; and public and private research institutions, some or all of which may have greater access to capital or resources than we do. 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.

We compete in the segments of the pharmaceutical, biotechnology and other related markets that utilize technologies encompassing genomic medicines to create therapies, including gene editing and gene therapy, nucleic acid therapy, and cell therapy. In addition, we compete with companies working to develop these therapies by utilizing advanced extrahepatic delivery vectors. Companies across each of these vectors serve as competitive threats for CRISPR Therapeutics AG.

Gene editing and gene therapy competition

Our platform and product focus is on the development of therapies using CRISPR/Cas gene editing technology. We are aware of several companies focused on developing therapies in various indications using CRISPR/Cas gene editing technology, including Editas Medicine, Intellia Therapeutics, Metagenomi, and Scribe Therapeutics. In addition, several academic groups have developed new gene editing technologies, such as base editing, reverse transcriptase editing, and gene insertion via recombinases that may have utility in therapeutic development. Companies seeking to develop therapies based on these technologies include Beam Therapeutics, Prime Medicine, Tessera Therapeutics, and Verve Therapeutics (recently acquired by Eli Lilly).

Several companies are also pursuing alternative gene editing approaches using epigenetic editing, TALENs, meganucleases, and RNA editing. These companies include Allogene Therapeutics, Cellectis, Iovance Biotherapeutics, Factor Bioscience, Korro Bio, nChroma Bio, Precision BioSciences, Sangamo Therapeutics, Scribe Therapeutics, Tune Therapeutics, and Wave Life Sciences.

Several companies are pursuing traditional approaches toward gene therapy, primarily utilizing gene supplementation via AAVs or lentiviral vectors. These companies may also serve as competitive threats and include 4D Molecular Therapeutics, AskBio, Passage Bio, Sarepta Therapeutics, UniQure, and Voyager Therapeutics.

Nucleic acid therapies competition

In addition to our gene editing platform, we are engaged in development activities related to transient transcript silencing via siRNA. Several companies are developing nucleic acid therapies related to our siRNA development pipeline, including Alnylam, Arrowhead Therapeutics, Avidity Biosciences, Bayer, Biogen, Dyne Therapeutics, Eli Lilly, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Sarepta Therapeutics, Stoke Therapeutics, and Wave Life Sciences.

Cell therapy competition

We are aware of several companies developing both autologous and allogeneic cell therapies, of which both serve as key competitors. These competitors are developing ex vivo CAR T therapies, in vivo CAR T therapies, and stem cell-derived cell therapies and include Allogene, Autolus, BlueRock Therapeutics (acquired by Bayer in 2019), Bristol Myers Squibb, Caribou Biosciences, Cellectis, Fate Therapeutics, Iovance Biotherapeutics, Johnson & Johnson, Kite Pharma (acquired by Gilead Sciences in 2017), and Novartis.

Extrahepatic delivery

We are also aware of companies developing targeted lipid nanoparticles, lentiviral vectors, and/or non-viral approaches for the delivery of genetic medicine payloads to extrahepatic tissues. Of these companies, those focused on transduction of hematopoietic stem progenitor cells or their progeny (e.g., T-cells, B-cells, NK cells, dendritic cells) pose the greatest competitive threat, including Azalea Therapeutics, Beam Therapeutics, Capstan (recently acquired by AbbVie), Editas Medicine, Ensoma, Interius Biotherapeutics (recently acquired by Kite Pharma / Gilead Sciences), Tessera Therapeutics, Kelonia, Orbital (recently acquired by Bristol Myers Squibb), Sana Biotechnology, Stylus Medicine, and Umoja Biopharma.

Therapeutic area competition

We are also aware of companies developing therapies in various areas related to our specific research and development programs and therapeutic areas. In hemoglobinopathies, these companies include Azalea Therapeutics, Beam Therapeutics, Capstan (recently acquired by AbbVie), Editas Medicine, Ensoma, Interius Biotherapeutics (recently acquired by Kite Pharma / Gilead Sciences), Kelonia, Merck, Novartis Pharmaceuticals, Orbital (recently acquired by Bristol Myers Squibb), Pfizer, Sana Biotechnology, Stylus Medicine, Tessera Therapeutics and Umoja Biopharma. In immuno-oncology, these companies include Adicet Bio, Allogene Therapeutics, Bristol Myers Squibb, Caribou Biosciences, Cellectis, Century Therapeutics, Fate Therapeutics, Gilead Sciences, Legend Biotech, Novartis Pharmaceuticals and Poseida Therapeutics. In autoimmune disease, these companies include Allogene Therapeutics, AstraZeneca, Bristol Myers Squibb, Cabaletta Bio, Capstan (recently acquired by AbbVie), Caribou Biosciences, Century Therapeutics, Fate Therapeutics, Interius Biotherapeutics (recently acquired by Kite Pharma / Gilead Sciences), Kelonia, Nkarta Inc., Novartis, Orbital (recently acquired by Bristol Myers Squibb), Stylus Medicine, Tessera Therapeutics and Umoja Bio. In regenerative medicine, these companies include BlueRock Therapeutics (acquired by Bayer in 2019), Century Therapeutics, Sana Biotechnology, and Semma Therapeutics (acquired by Vertex in 2019).

In in vivo gene editing, the companies include Beam Therapeutics, Capstan (recently acquired by AbbVie), Editas Medicine, Intellia Therapeutics, Interius Biotherapeutics (recently acquired by Kite Pharma / Gilead Sciences), Kelonia, Metagenomi, Orbital (recently acquired by Bristol Myers Squibb), Prime Medicine, Sana Biotechnology, Scribe Therapeutics, Tessera Therapeutics, Umoja Biopharma and Verve Therapeutics (recently acquired by Eli Lilly).

Development of genetic medicines has rapidly increased outside of the United States, with a particular emphasis in China. There are several genetic medicine companies advancing therapies in this region with planned clinical trials outside of China and pose a competitive threat to CRISPR Therapeutics AG, including AccurEdit, HudiaGene, and Yoltech Therapeutics.

Gene editing is a highly active field of research and new technologies, related or unrelated to CRISPR, may be discovered and create new competition. These new technologies could have advantages over CRISPR/Cas9 gene editing in some applications and there can be no certainty that other gene editing technologies will not be considered better or more attractive than our technology for the development of products. For example, Cas9 may be determined to be less attractive than other CRISPR proteins, such as Cas12a or novel Cas enzymes that have yet to be discovered, or other CRISPR-associated nuclease variants that can edit human DNA, such as base editors and reverse transcriptase editors.

In addition to competition from other gene editing therapies or gene or cell therapies, any product we may develop may also face competition from other types of therapies, such as small molecule, antibody or protein therapies. New scientific discoveries may also cause CRISPR/Cas9 technology, or gene editing as a whole, to be considered an inferior form of therapy.

Many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical, biotechnology, and gene and cell therapy industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient, have broader acceptance and higher rates of reimbursement by third-party payors or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. Additionally, technologies developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be successful in marketing any product candidates we may develop against competitors. The key competitive factors affecting the success of all of our programs are likely to be their efficacy, safety, convenience, and availability of reimbursement.

If our current programs are approved for the indications for which we are currently planning clinical trials, they may compete with other products currently under development, including gene editing, gene therapy, and cell therapy products. Competition with

other related products currently under development may include competition for clinical trial sites, patient recruitment, and product sales. In addition, due to the intense research and development taking place in the gene editing field, including by us and our competitors, the intellectual property landscape is in flux and highly competitive. There may be significant intellectual property related litigation and proceedings relating to our owned and in-licensed, and other third-party, intellectual property and proprietary rights in the future. For example, see our discussion of the ‘048 interference, the ‘115 interference and European opposition proceedings in “Risk Factors—Risks Related to 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.”

Moreover, as a result of the expiration or successful challenge of our patent rights, we could face more litigation with respect to the validity and/or scope of patents relating to our competitors’ products and our patents may not be sufficient to prevent our competitors from commercializing competing products. The availability of our competitors’ products could limit the demand, and the price we are able to charge, for any products that we may develop and commercialize.

Government Regulation

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products, including biological products. Some jurisdictions outside of the United States also regulate the pricing of such products. The processes for obtaining marketing approvals in the United States and in other countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

Licensure and Regulation of Biologics in the United States

In the United States, our product candidates are regulated as biological products, or biologics, under the Public Health Service Act, or PHSA, and the Federal Food, Drug, and Cosmetic Act, or FDCA, and their implementing regulations. The failure to comply with the applicable U.S. requirements at any time during the product development process, including nonclinical testing, clinical testing, the approval process or post-approval process, may subject an applicant to delays in the conduct of a study, regulatory review and approval, and/or administrative or judicial sanctions. These sanctions may include, but are not limited to, the FDA’s refusal to allow an applicant to proceed with clinical testing, refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, untitled or warning letters, adverse publicity, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, and civil or criminal investigations and penalties brought by the FDA or the Department of Justice or other governmental entities.

An applicant seeking approval to market and distribute a new biologic in the United States generally must satisfactorily complete each of the following steps:

•

preclinical laboratory tests, animal studies and formulation studies all performed in accordance with the FDA’s Good Laboratory Practice, or GLP, regulations;

•

submission to the FDA of an Investigational New Drug, or IND, application for human clinical testing, which must become effective before human clinical trials may begin;

•

approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated, or by a central IRB if appropriate;

•

performance of adequate and well-controlled human clinical trials to establish the safety, potency, and purity of the product candidate for each proposed indication, in accordance with the FDA’s Good Clinical Practice, or GCP, regulations;

•

preparation and submission to the FDA of a Biologics License Application, or BLA, for a biologic product requesting marketing for one or more proposed indications, including submission of detailed information on the manufacture and composition of the product and proposed labeling;

•

review of the product by an FDA advisory committee, where appropriate or if applicable;

•

satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities, including those of third parties, at which the product, or components thereof, are produced to assess compliance with cGMP requirements and to assure that the facilities, methods, and controls are adequate to preserve the product’s identity, strength, quality, and purity, and, if applicable, the FDA’s current good tissue practice, or CGTP, for the use of human cellular and tissue products;

•

satisfactory completion of any FDA audits of the nonclinical study and clinical trial sites to assure compliance with GLPs and GCPs, respectively, and the integrity of clinical data in support of the BLA;

•

payment of user fees and securing FDA approval of the BLA; and

•

compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and

Mitigation Strategy, or REMS, adverse event reporting, and compliance with any post-approval studies required by the FDA.

Preclinical Studies and Investigational New Drug Application

Before testing any biologic product candidate in humans, including a gene therapy product candidate, the product candidate must undergo preclinical testing. Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as studies to evaluate the potential for efficacy and toxicity in animals. The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements. The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND application. The IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA imposes a clinical hold based on concerns or questions about the product or conduct of the proposed clinical trial, including concerns that human research subjects would be exposed to unreasonable and significant health risks. In that case, the IND sponsor and the FDA must resolve any outstanding FDA concerns before the clinical trials can begin.

As a result, submission of the IND may result in the FDA not allowing the trials to commence or not allowing the trial to commence on the terms originally specified by the sponsor in the IND. If the FDA raises concerns or questions either during this initial 30-day period, or at any time during the conduct of the IND study, including safety concerns or concerns due to non-compliance, it may impose a partial or complete clinical hold. This order issued by the FDA would either delay a proposed clinical study or cause suspension of an ongoing study, or in the case of a partial clinical hold limit a study, until all outstanding concerns have been adequately addressed and the FDA has notified the company that investigations may proceed or recommence but only under terms authorized by the FDA. This could cause significant delays or difficulties in completing planned clinical studies in a timely manner.

Human Clinical Trials in Support of a BLA

Clinical trials involve the administration of the investigational product candidate to healthy volunteers or patients with the disease to be treated under the supervision of a qualified principal investigator in accordance with GCP requirements. Clinical trials are conducted under study protocols detailing, among other things, the objectives of the study, inclusion and exclusion criteria, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. A protocol for each clinical trial and subsequent protocol amendments must be submitted to the FDA as part of the IND.

A sponsor who wishes to conduct a clinical trial outside the United States may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. If a non-U.S. clinical trial is not conducted under an IND, the sponsor may submit data from a well-designed and well-conducted clinical trial to the FDA in support of the BLA so long as the clinical trial is conducted in compliance with GCP and the FDA is able to validate the data from the study through an onsite inspection if the FDA deems it necessary.

CRSP US Equity

CRSP · 10-K · period ended 2025-12-31

Item 1. Business.

CRSP US Equity☆

CRSP · 10-K · period ended 2025-12-31

Item 1. Business.

CRSP US Equity