CRISPR Therapeutics AG

CRISPR Therapeutics AG (CRISPR) is a biopharmaceutical company focused on developing gene-based medicines, primarily utilizing CRISPR/Cas9 technology for gene editing. The company's core business model revolves around advancing this technology from discovery to commercialization, generating revenue through product sales, collaboration agreements, and milestone payments. CRISPR has established a portfolio of therapeutic programs across four core franchises: hemoglobinopathies, in vivo approaches, CAR T, and regenerative medicine. The company employs both ex vivo and in vivo editing approaches, where cells are either edited outside the body and then administered, or the therapeutic is delivered directly to target cells within the body, respectively. Primary customer segments include patients with serious human diseases, and the company aims to provide potentially curative therapies for both common and rare conditions ¹.

CRISPR's most advanced program is CASGEVY (exagamglogene autotemcel [exa-cel]), developed in collaboration with Vertex Pharmaceuticals Incorporated (Vertex). CASGEVY is a non-viral, ex vivo CRISPR/Cas9 gene-edited cell therapy approved in the United States, European Union, Great Britain, Canada, Switzerland, and certain Middle Eastern countries for eligible patients aged 12 and older with severe sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT) ². This therapy works by editing hematopoietic stem and progenitor cells at the erythroid specific enhancer region of the BCL11A gene, leading to increased production of fetal hemoglobin, which compensates for defective adult hemoglobin ³. The company also has research efforts with Vertex on targeted conditioning and in vivo editing of hematopoietic stem cells to expand the addressable patient population for SCD and TDT ⁴.

In its in vivo approaches, CRISPR is advancing a portfolio of programs targeting the liver using lipid nanoparticle (LNP) delivery technologies, leveraging both CRISPR/Cas9 and its proprietary SyNTase editing technologies. This portfolio includes cardiovascular investigational programs such as CTX310, which targets angiopoietin-related protein 3 (ANGPTL3) and is in an ongoing Phase 1b clinical trial ⁵. Other early-stage in vivo programs include CTX340 for refractory hypertension, CTX321 for elevated lipoprotein (a) (Lp(a)), and CTX460 for alpha-1 antitrypsin deficiency, utilizing the SyNTase editing platform ⁶. Additionally, CRISPR has an siRNA-based portfolio, including CTX611 (formerly SRSD107), a novel double-stranded, long-acting siRNA targeting human coagulation factor XI (FXI) messenger RNA, developed in collaboration with Sirius Therapeutics. CTX611 is in an ongoing Phase 2 clinical trial for preventing venous thromboembolism (VTE) in patients undergoing total knee arthroplasty ⁷.

The CAR T franchise is progressing next-generation gene-edited cell therapy programs, including zugocabtagene geleucel (zugo-cel; formerly CTX112), an allogeneic chimeric antigen receptor T cell (CAR T) candidate targeting Cluster of Differentiation 19 (CD19). Zugo-cel incorporates edits designed to enhance CAR T potency, reduce exhaustion, and evade the immune system, leading to increased manufacturing robustness ⁸. Zugo-cel is being investigated in clinical trials for autoimmune diseases like systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis, immune thrombocytopenia purpura, and warm autoimmune hemolytic anemia, as well as in oncology for relapsed or refractory B-cell malignancies ⁹. The regenerative medicine franchise is advancing CTX213, a deviceless beta cell replacement product candidate for Type 1 diabetes (T1D), consisting of unencapsulated precursor islet cells derived from induced pluripotent stem cells ¹⁰.

For the fiscal year ended December 31, 2025, CRISPR reported total collaboration revenue of $205.0 million ¹¹. The company incurred significant operating losses since its inception and anticipates continued losses for the foreseeable future ¹². While profitable in 2021 due to an upfront payment from Vertex, CRISPR is not currently profitable and does not expect to be in future years ¹³. As of December 31, 2025, the company had cash, cash equivalents, and marketable securities of approximately $1,975.8 million ¹⁴. This compares to $1,903.8 million as of December 31, 2024 ¹⁵. The company's share of net profits and net losses for CASGEVY is allocated 40% to CRISPR and 60% to Vertex, effective July 1, 2021 ¹⁶. For the years ended December 31, 2022, 2023, and 2024, CRISPR had the option to defer costs on the CASGEVY program exceeding $110.3 million annually, but this deferral option is no longer available starting in 2025, leading to increased development and commercialization expenses for the program ¹⁷.

In terms of year-over-year comparisons, collaboration revenue increased from $105.0 million in 2024 to $205.0 million in 2025 ¹⁸, primarily due to research and development milestones achieved by Vertex under the Non-Ex License Agreement ¹⁹. The company's cash, cash equivalents, and marketable securities increased from $1,903.8 million in 2024 to $1,975.8 million in 2025 ²⁰. The shift in cost deferral for the CASGEVY program from 2024 to 2025 indicates a notable change in business mix, with CRISPR now incurring a larger direct share of development and commercialization expenses for CASGEVY ²¹.

Significant operational developments during the period include the continued advancement of CASGEVY, which received approvals in multiple countries for SCD and TDT, and positive data from pivotal studies in children aged 5 to 11 years old with SCD or TDT were presented at ASH in December 2025 ²². In children with SCD, all 4 patients with sufficient follow-up achieved the primary endpoint of being free from vaso-occlusive crises for at least 12 consecutive months ²³. In children with TDT, all 6 patients with sufficient follow-up achieved transfusion independence for at least 12 consecutive months ²⁴. Longer-term data for patients aged 12 and older also demonstrated durable clinical benefits, with 100% of SCD patients (45/45) achieving VF12 and 98.2% of TDT patients (55/56) achieving TI12 ²⁵. The company also presented positive Phase 1 data for CTX310 in November 2025, showing dose-dependent, durable reductions in circulating ANGPTL3, triglycerides, and LDL ²⁶, leading to its advancement into Phase 1b clinical trials ²⁷. In May 2025, CRISPR partnered with Sirius Therapeutics for siRNA-based programs, including co-development and co-commercialization of CTX611, and received approximately $70.0 million in common shares and a $25.0 million cash payment ²⁸. Additionally, zugo-cel demonstrated encouraging preliminary clinical data in autoimmune rheumatologic diseases, with all 4 treated patients showing significant clinical improvement at Day 28 assessment ²⁹, and maintained drug-free DORIS clinical remission through Month 9 for the first SLE patient ³⁰. In immuno-oncology, zugo-cel showed an overall response rate of 90% (9/10) and a complete response rate of 70% (7/10) in relapsed or refractory LBCL patients at the recommended Phase 2 dose of 600 million cells ³¹.

CRISPR expects its cash, cash equivalents, and marketable securities of approximately $1,975.8 million as of December 31, 2025, to be sufficient to fund its current operating plan through at least the next 24 months ³². The company anticipates that its expenses will increase substantially as it continues clinical trials for its various wholly-owned and partnered programs, continues research and preclinical and clinical development of product candidates, seeks to identify additional research programs and product candidates, conducts preclinical studies to support IND applications and initiate clinical trials, expands and defends its intellectual property estate, seeks marketing approvals, further develops its gene editing and other proprietary technologies, hires additional personnel, establishes or expands manufacturing capabilities, acquires or in-licenses other technologies, and establishes sales, marketing, and distribution infrastructure ³³.

A major growth area for CRISPR is the expansion of its hemoglobinopathies franchise beyond CASGEVY. The company, in collaboration with Vertex, is pursuing next-generation efforts in targeted conditioning regimens, which could offer benefits over the myeloablative conditioning regimen currently used with CASGEVY ³⁴. Additionally, they are pursuing in vivo editing of hematopoietic stem cells in SCD and TDT, with both initiatives having the potential to significantly expand the addressable patient populations for these diseases ³⁵. The total addressable patient population with severe SCD or TDT in the United States, Canada, Europe, and parts of the Middle East is estimated to be approximately 60,000 individuals ³⁶.

Another significant growth vector is the in vivo liver editing platform. CRISPR is rapidly advancing a pipeline of in vivo gene editing candidates that target the liver, leveraging validated lipid nanoparticle (LNP) delivery technologies. The company aims to treat diseases where a strong therapeutic effect can be produced by safely disrupting a gene with a well-understood genetic association ³⁷. This includes cardiovascular investigational programs like CTX310, which targets ANGPTL3 and is in an ongoing Phase 1b clinical trial, and earlier-stage programs such as CTX340 for refractory hypertension, CTX321 for elevated Lp(a), and CTX460 for alpha-1 antitrypsin deficiency, utilizing the proprietary SyNTase editing platform ³⁸. CTX310 has demonstrated dose-dependent, durable reductions in circulating ANGPTL3, triglycerides, and LDL in Phase 1 data, supporting its advancement into Phase 1b clinical trials for severe hypertriglyceridemia and refractory hypercholesterolemia ³⁹.

Operationally, CRISPR expects to continue incurring significant and increasing operating losses for the foreseeable future ⁴⁰. Beginning in 2025, the company no longer has the option to defer certain costs on the CASGEVY program under the Amended A&R Vertex JDCA, which will result in increased development and commercialization expenses for the CASGEVY program ⁴¹. These expenses are expected to exceed CRISPR's share of revenue for the foreseeable future ⁴². The company continues to invest in its internal manufacturing capabilities, with an approximately 50,000 square foot cell therapy manufacturing facility in Framingham, Massachusetts, intended for clinical and commercial production of product candidates and components ⁴³. This facility is designed for flexibility and scalability to support current clinical programs and potential commercial supply, as well as future programs like in vivo and T1D ⁴⁴.

CRISPR plans to continue making significant investments in its manufacturing capabilities in Framingham, Massachusetts, and in partnerships with third-party organizations for its gene editing programs to advance and commercialize these programs ⁴⁵. The company's future capital requirements will depend on the scope, progress, results, and costs of clinical trials, drug discovery, preclinical development, and laboratory testing for its wholly-owned and partnered product candidates, as well as the costs, timing, and outcome of regulatory review ⁴⁶. The costs of establishing and maintaining a supply chain, the success of collaborations, the achievement of milestones, and the costs of intellectual property protection and enforcement will also influence capital needs ⁴⁷.

CRISPR's business is subject to several material risks. The company has incurred significant operating losses since its inception and anticipates continued losses, requiring substantial additional funding that could dilute shareholders if not raised on attractive terms ⁴⁸. The development of CRISPR/Cas9 gene editing product candidates is based on a relatively new technology, making the time and cost of development and regulatory approval difficult to predict, with limited clinical trial experience in this field ⁴⁹. Undesirable side effects from product candidates or administration processes, such as off-target DNA cuts or immunologic reactions, could delay or prevent regulatory approval, limit commercial potential, or result in negative consequences post-marketing ⁵⁰. Delays or difficulties in patient enrollment for clinical trials could also impede regulatory approvals ⁵¹. The company faces significant competition in the biotechnology and pharmaceutical industries from various sources, including large pharmaceutical companies, academic institutions, and other gene editing, gene therapy, nucleic acid therapy, and cell therapy companies, some of which may have greater resources ⁵². Adverse public perception of gene editing and cellular therapy products, influenced by safety, ethical, or moral concerns, may negatively impact demand or regulatory approval ⁵³. Furthermore, the intellectual property landscape around gene editing, including CRISPR/Cas9, is highly dynamic, and third parties may initiate legal proceedings alleging patent invalidity or infringement, the outcome of which is uncertain and could materially harm the business ⁵⁴. For example, ToolGen, Inc. initiated a lawsuit in the fourth quarter of 2025 alleging patent infringement by CASGEVY ⁵⁵.

Management's message to shareholders emphasizes the company's mission to create transformative gene-based medicines for serious human diseases, highlighting the rapid advancement of CRISPR/Cas9 technology from discovery to an approved medicine with CASGEVY. They underscore the importance of continuous innovation to unlock the full potential of gene editing, including next-generation editing modalities like SyNTase and advanced delivery technologies. The strategic priorities for the period ahead include continuing the clinical development and potential commercialization of CASGEVY, advancing the diverse portfolio of therapeutic programs across hemoglobinopathies, in vivo approaches, CAR T, and regenerative medicine, and expanding the intellectual property estate to protect proprietary technologies. Management explicitly states that with the cash, cash equivalents, and marketable securities on hand as of December 31, 2025, they expect to fund the current operating plan through at least the next 24 months ⁵⁶. They acknowledge the expectation of continued significant operating losses for the foreseeable future due to ongoing research, development, and commercialization efforts, particularly with the cessation of the CASGEVY cost deferral option in 2025, which will increase expenses related to the program ⁵⁷.