CRISPR Therapeutics AG is a gene editing 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. The company intends to apply this technology to disrupt, delete, correct and insert genes to treat genetic diseases and to engineer advanced cellular therapies. The company has advanced this technology from discovery to a...
CRISPR Therapeutics AG is a gene editing 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. The company intends to apply this technology to disrupt, delete, correct and insert genes to treat genetic diseases and to engineer advanced cellular therapies. The company has 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 the company’s collaborators at Vertex Pharmaceuticals Incorporated, or Vertex.
The company has established a portfolio of therapeutic programs spanning four core franchises: hemoglobinopathies, CAR T, in vivo approaches and type 1 diabetes. Depending on the program, the company takes either an ex vivo approach, in which the company edits cells outside of the human body before administering them to the patient, or an in vivo editing approach, where the company delivers the CRISPR-based therapeutic directly to target cells within the human body.
Hemoglobinopathies: The company’s 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, the company has further research efforts 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.
CAR T: The company is progressing multiple next-generation gene-edited cell therapy programs, including allogeneic chimeric antigen receptor T cell, or CAR T, candidates for the treatment of hematological and solid tumor cancers and autoimmune diseases.
In vivo approaches: The company is advancing a portfolio of programs leveraging in vivo editing for both common and rare diseases, including the treatment and prevention of cardiovascular disease.
Type 1 diabetes: The company has multiple parallel efforts using allogeneic, gene-edited, hypoimmune, stem cell-derived beta islet cell precursors to address type 1 diabetes, or T1D, without the need for chronic immunosuppression, including both encapsulated and unencapsulated approaches.
The company continues to innovate on its platform to develop next-generation technologies that can enable new therapies. Through these efforts, the company intends to unlock the full potential of CRISPR-based therapeutics to create medicines that can transform people's lives. The company’s research, translational expertise, and clinical development experience, position the company as a leader in the development of CRISPR-based therapeutics and may enable the company to create an entirely new class of highly effective and potentially curative therapies for patients with both rare and common 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 the company’s strategic partnership with Vertex and is being advanced under a joint development and commercialization agreement between the company 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, Kingdom of Saudi Arabia, Kingdom of Bahrain and the United Arab Emirates 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.
The company continues to advance its 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.
CAR T
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. The company is advancing several cell therapy programs for oncology and/or autoimmune indications, including two next-generation allogeneic CAR T programs, CTX112 targeting Cluster of Differentiation 19, or CD19, and CTX131 targeting Cluster of Differentiation 70, or CD70. These product candidates incorporate edits designed to enhance CAR T potency, reduce CAR T exhaustion and evade the immune system. An additional edit in CTX131 is designed to prevent the CAR T cells from killing other CAR T cells. In addition, these next-generation candidates exhibit increased manufacturing robustness, with a higher and more consistent number of CAR T cells produced per batch.
CTX112 is being developed for both hematologic malignancies and autoimmune indications. It is being investigated in an ongoing clinical trial designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory B-cell malignancies who have received at least two prior lines of therapy, as well as an ongoing clinical trial in adult patients with systemic lupus erythematosus, systemic sclerosis, and inflammatory myositis.
CTX131 is being developed for both solid tumors and hematologic malignancies. It is being investigated in ongoing clinical trials designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors and hematologic malignancies, including T cell lymphomas, or TCL.
The company is producing CTX112 and CTX131 for clinical trials at the company’s internal GMP manufacturing facility in Framingham, Massachusetts.
The company’s CRISPR/Cas9 platform enables the company to innovate continuously by incorporating incremental edits into next-generation products. The company is advancing several additional investigational CAR T programs, including an autologous, gene-edited CAR T program targeting glypican-3, or GPC3, for the potential treatment of solid tumors.
In Vivo
The company’s in vivo gene editing strategy focuses on gene disruption and whole gene correction – the two technologies required to address the vast majority of the most prevalent severe monogenic diseases as well as many common diseases. The company has established a leading platform for in vivo gene editing and are rapidly advancing a broad portfolio of in vivo programs, supported by an internal lipid nanoparticle, or LNP, team to enable liver-directed and extrahepatic programs with novel lipids, formulations, and targeting moieties. The company’s first in vivo programs target the liver, taking advantage of validated LNP delivery technologies, and intends to treat diseases where the company can produce a strong therapeutic effect by safely disrupting a gene with well-understood genetic association. For example, the company’s first two in vivo programs utilizing the company’s proprietary LNP platform, CTX310 and CTX320, intends to address cardiovascular disease by disrupting the validated targets angiopoietin-like protein 3, or ANGPTL3, and lipoprotein (a), or Lp(a), respectively. Phase 1 clinical trials for both CTX310 and CTX320 are ongoing. The company has a number of earlier stage investigational in vivo programs leveraging gene disruption in the liver for both rare and common diseases. The company also has programs focused on gene correction in the liver, including programs leveraging technologies developed by the company’s CRISPR-X research team.
Type 1 Diabetes
The company is developing gene-edited stem cell-derived therapies for the treatment of T1D. The company’s 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. The company has three parallel efforts to achieve this goal: (1) CTX211, an allogeneic, gene-edited, hypoimmune, stem cell derived product candidate in a device that is implanted into patients and intended to produce insulin in a glucose-dependent manner, and which is in an ongoing clinical trial; (2) CTX213, a research stage deviceless beta cell replacement product candidate consisting of unencapsulated precursor islet cells derived from edited stem cells; and (3) the company has granted a non-exclusive license to certain of the company’s CRISPR/Cas9 intellectual property to Vertex to accelerate Vertex’s development of hypoimmune cell therapies for T1D in exchange for certain milestones and royalties.
CRISPR-X
While the company has made significant progress with its portfolio of programs, the company recognizes that the company needs to continue to innovate to unlock the full power of gene editing and bring potentially transformative therapies to even more patients. The company has a dedicated early-stage research team called CRISPR-X that focuses on innovating next-generation editing modalities. CRISPR-X is developing technologies to enable whole gene correction and insertion via non-viral DNA delivery and all-RNA systems, without requiring homology-directed repair or viral delivery of DNA.
Partnerships
Given the numerous potential therapeutic applications for CRISPR/Cas9, the company has partnered strategically to broaden the indications the company can pursue and accelerate development of programs by accessing specific technologies and/or disease-area expertise. The company maintains broad partnerships to develop gene editing-based therapeutics in specific disease areas.
Hemoglobinopathies
In 2015, the company 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 the company entered into a joint development and commercialization agreement with Vertex, which the company amended and restated in 2021, pursuant to which, among other things, the company is co-developing and co-commercializing CASGEVY for TDT and SCD.
Diabetes
Beginning in 2018, the company partnered with ViaCyte, Inc., or ViaCyte (now a wholly-owned subsidiary of Vertex), to pursue the discovery, development and commercialization of gene-edited allogeneic stem cell therapies for the treatment of diabetes. In 2023, ViaCyte elected to opt-out of the collaboration with the company for the co-development and co-commercialization of gene-edited stem cell therapies for the treatment of diabetes. Per the opt-out terms, the on-going collaboration assets will be wholly owned by the company, subject to a royalty on future sales owed to ViaCyte. The company’s product candidate, CTX211, being developed for the potential treatment of T1D, resulted from this collaboration, and which the company is continuing to advance in a Phase 1 clinical trial. Additionally, in 2023, the company entered into a non-exclusive license agreement with Vertex for Vertex to utilize certain of the company’s 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.
Other Partnerships
The company has entered into a number of additional collaborations and license agreements in other therapeutic areas, including an additional agreement with Vertex for the treatment of Duchenne muscular dystrophy, or DMD, and myotonic dystrophy type 1, or DM1, and others to support and complement the company’s hematopoietic stem cell, CAR T, in vivo and T1D programs and platform, including agreements with: Nkarta, Inc., or Nkarta, to develop and commercialize products leveraging donor-derived, gene-edited CAR-NK cells; Capsida Biotherapeutics, Inc. to develop in vivo gene editing therapies delivered with engineered adeno-associated virus, or AAV, vectors; Roswell Park Comprehensive Cancer Center to advance a gene-edited autologous CAR T program against a new target; MaxCyte, Inc. on ex vivo delivery for the company’s hemoglobinopathy and CAR T programs; CureVac AG on optimized mRNA constructs and manufacturing for certain in vivo programs; and KSQ Therapeutics, Inc. on intellectual property for the company’s allogeneic immuno-oncology programs.
Pipeline
Hemoglobinopathies
The company’s 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 the company’s 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. The company choses 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.
The company and Vertex continue to investigate CASGEVY, including (1) three 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; (2) two clinical trials in patients 5 to 11 years of age, one in severe SCD and a second in TDT; and (3) long-term follow-up clinical trials designed to follow participants for up to 15 years after CASGEVY infusion. 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.
As of December 31, 2024, CASGEVY had been approved by regulatory authorities in the United States, European Union, Great Britain, Canada, Switzerland, Kingdom of Saudi Arabia, Kingdom of Bahrain and the United Arab Emirates for the treatment of eligible patients 12 years and older with SCD or TDT. The company estimates 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.
Next-generation Efforts
Building upon CASGEVY, the company is pursuing next-generation efforts in targeted conditioning regimens with an anti-CD117 (cKit) antibody-drug conjugate, or ADC, for specific depletion of hematopoietic stem cells, which could offer benefits over the myeloablative conditioning regimen currently used with CASGEVY. In addition, the company is pursuing in vivo editing of hematopoietic stem cells. Either of these efforts could broaden the number of patients that can benefit from the company’s therapies.
CAR T
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. Development across all the company’s CAR T programs and product candidates is focused on immuno-oncology and autoimmune indications.
Immuno-oncology
The company expects that the cellular engineering strategies that are ultimately successful in immuno-oncology will involve multiple genetic modifications, an application for which 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.
In the company’s immuno-oncology cell therapies, the company is using the multiplexing ability of CRISPR/Cas9 both to enable allogeneic administration and to introduce additional genetic edits that intends to improve the efficacy profile of these product candidates. Furthermore, the company is leveraging its CRISPR platform to enable a process of continuous innovation in which the company incorporates incremental edits into next-generation products to try to increase treatment benefit further. The company continues to expand its multiplexing capabilities to help the company realizes the full potential of engineered cell therapy in immuno-oncology across all tumor types, including solid tumors.
Next-generation Allogeneic CAR T Candidates
The company is advancing several cell therapy programs, including two next-generation, investigational, gene-edited, healthy donor-derived allogeneic CAR T product candidates in clinical trials: CTX112 targeting CD19 and CTX131 targeting CD70. These next-generation candidates build upon the company’s 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. The company’s CRISPR/Cas9 platform has enabled the company to incorporate additional edits into the company’s next-generation product candidates, and reflect the company’s intention of continuously to bring potentially transformative medicines to patients as quickly as possible. Preliminary data from ongoing clinical trials of CTX112 and CTX131, suggest that these candidates may improve upon the clinical profile of the company’s first generation candidates.
CTX112 and CTX131 each incorporate 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. The company identified this combination of edits through systematic screening of dozens of new and previously described genes. CTX131 has an additional edit, a knock-out of CD70 to prevent CAR T cell fratricide and further increase potency.
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 CTX112 and CTX131 lead to significantly higher CAR T cell expansion and functional persistence in patients compared to the first-generation candidates. In addition, the next-generation candidates exhibit increased manufacturing robustness, with a higher and more consistent number of CAR T cells produced per batch. The company is producing CTX112 and CTX131 for clinical trials at the company’s internal GMP manufacturing facility.
CTX112
Immuno-oncology
The company is investigating CTX112 in an ongoing clinical trial designed to assess the safety and efficacy of CTX112 in adult patients with relapsed or refractory B-cell malignancies who have received at least two prior lines of therapy. In this trial, the company uses a standard lymphodepletion regimen consisting of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for three days.
The company presented initial data from its ongoing Phase 1/2 clinical trial of CTX112 in relapsed or refractory B-cell malignancies at the 2024 American Society of Hematology Annual meeting. This is an open-label, multicenter, study evaluating the safety and efficacy of CTX112 in a high-risk patient population (58% primary refractory disease; 67% >3 prior therapies; 50% with tumor sum of the products of diameters > 4000 mm2). CTX112 demonstrated tolerability with no Cytokine Release Syndrome, Immune Effector Cell-Associated Neurotoxicity Syndrome, or infections Grade greater than or equal to 3. In addition, overall response rate across all dose levels was 67%, while complete response rate was 50%, which is consistent with approved autologous CAR T products. Based on this preliminary data, CTX112 has been granted Regenerative Medicine Advanced Therapy, or RMAT, designation by the FDA for the treatment of relapsed or refractory follicular lymphoma and marginal zone lymphoma.
The most recent CTX112 data demonstrates responses in patients who have received prior T-cell engager-based therapies, or TCEs, with responses observed in all six patients, including three large B-cell lymphoma patients, who either relapsed post-TCE treatment or were refractory to TCEs. In addition, pharmacokinetic data highlights dose-dependent cell expansion with Cmax comparable to approved autologous CAR T products.
Autoimmune Disease
In addition, CTX112 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, systemic sclerosis, and inflammatory myositis. 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. CTX112 has the potential to produce a similar B cell ‘reset’.
CTX131
The company is advancing CTX131 for the potential treatment of both solid tumors and certain hematologic malignancies. Several cancers express CD70, including renal cell carcinoma, mesothelioma, glioblastoma, pancreatic, lung and ovarian cancers, non-Hodgkin’s lymphoma and certain TCL, while normal tissues do not express or show extremely limited expression of CD70. Allogeneic CAR T approaches for TCL may have greater potential to meet the unmet need in this patient population given the patients’ own T cells are not suitable for autologous manufacturing.
CTX131 is being investigated in ongoing clinical trials designed to assess the safety and efficacy of the product candidate in adult patients with relapsed or refractory solid tumors, as well as in hematologic malignancies, including TCLs. In this clinical trial, the company uses a standard lymphodepletion regimen consisting of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for three days.
Additional Candidates
The company is advancing several additional CAR T programs against new targets. For one such candidate, the company has developed an innovative partnership model with a leading cancer center, Roswell Park Comprehensive Cancer Center, or Roswell Park, to validate the novel target GPC3 in the clinic. With Roswell Park, the company is advancing a gene-edited, autologous CAR T candidate targeting GPC3, expressed in hepatocellular carcinoma. Roswell Park will conduct manufacturing and a first-in-human clinical trial, while the company retains commercial rights. This structure will enable the company to assess the safety and activity of this gene-edited product candidate rapidly. Based on the clinical results, the company can choose to continue advancing the autologous program internally or develop an allogeneic version to expand the opportunity further.
In Vivo Approaches
The company has 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 rare and common diseases, including those difficult to address with ex vivo approaches.
The company’s lead in vivo programs target the liver and take advantage of the clinically established and validated lipid nanoparticle, or LNP, delivery technologies now available. 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. The company’s first programs in the liver intends to treat diseases where the company can produce a strong therapeutic effect by safely disrupting a gene with well-understood genetic association. For example, the company’s two clinical programs, CTX310 and CTX320, intends to address cardiovascular disease by disrupting the validated targets ANGPTL3 and lipoprotein (a), or Lp(a), respectively.
Beyond the liver, for delivery to hematopoietic stem cells and other extrahepatic tissues, the company is pursuing multiple delivery technologies, including LNPs. Through internal efforts and external collaborations, the company is developing new delivery modalities to support future in vivo therapeutics.
Cardiovascular and Dyslipidemia Programs
The company intends 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, the company intends 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, the company’s 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
The company’s lead 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 in an ongoing Phase 1 clinical trial in patients with mixed dyslipidemia, homozygous familial hypercholesterolemia, or HoFH, heterozygous familial hypercholesterolemia, or HeFH, and severe hypertriglyceridemia, or sHTG.
CTX320
The company’s second in vivo product candidate, CTX320, targets another protein associated with CVD: 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. CTX320 consists of a gRNA targeting LPA, the gene encoding apo(a), and messenger RNA encoding Cas9 delivered via LNP. By reducing levels of apo(a), CTX320 should reduce plasma levels of Lp(a) substantially, as supported by preclinical data showing that treatment with CTX320 decreases Lp(a) levels by over 90% in NHPs. CTX320 is in an ongoing Phase 1 clinical trial in patients with elevated Lp(a).
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.
Additional In Vivo Programs
Building upon CTX310 and CTX320, the company has a number of earlier stage investigational in vivo programs leveraging gene disruption in the liver for both rare and common diseases. These include CTX340, targeting angiotensinogen for refractory hypertension, as well as CTX450, targeting 5’-aminolevulinate synthase 1 for acute hepatic porphyria, which the company is progressing through preclinical studies. In addition, the company has programs focused on gene correction in the liver, including the first programs leveraging technologies developed by the company’s CRISPR-X group.
Type 1 Diabetes
The company is advancing a series of programs focused on the development of gene-edited stem cell-derived therapies for the treatment of type 1 diabetes, or T1D. The company’s 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.
The company’s 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. The speed, specificity and multiplexing efficiency of CRISPR/Cas9 make the company’s technology well suited to this task. Furthermore, the company’s CRISPR platform enables a process of continuous innovation, with additional edits incorporated into next-generation product candidates with the intends of increasing treatment benefit further. This feature of the CRISPR/Cas9 platform has led the company to pursue a multi-pronged product strategy:
CTX211, is an allogeneic, gene-edited, hypoimmune, stem cell derived product candidate in a device that is implanted into patients and intended to produce insulin in a glucose-dependent manner.
The company has research efforts focused on a deviceless beta cell replacement approach, CTX213, which consists of unencapsulated precursor islet cells derived from edited stem cells.
The company granted a non-exclusive license to certain of the company’s CRISPR-Cas9 gene editing intellectual property to Vertex in March 2023 to accelerate Vertex’s development of hypoimmune cell therapies for T1D.
CTX211
CTX211 is an investigational, allogeneic, gene-edited, hypoimmune, stem cell-derived beta cell replacement therapy developed by applying the company’s gene editing technology to ViaCyte’s proprietary stem cell capabilities. CTX211 incorporates 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. CTX211 benefits from work on a precursor product candidate, which only had four of these edits. Collectively, the edits in CTX211 improve the ability of beta cells to evade the immune system in vitro and in vivo in preclinical models, as shown below. In addition, CTX211 has been shown to reverse hyperglycemia in a diabetic rat model. CTX211 is being investigated in an ongoing Phase 1/2 clinical trial designed to assess the safety, tolerability and efficacy of CTX211 in adult patients with T1D.
CRISPR-X: Further Unlocking the Potential of The company’s Gene Editing Platform
While the company has made significant progress with the company’s portfolio of programs, the company recognizes that it can bring transformative therapies to even more patients by continuing to innovate to unlock the full potential of gene editing. In late 2022, the company launched a new early-stage research team known as CRISPR-X that focuses on innovative research to develop next-generation gene editing modalities. CRISPR-X is developing technologies to enable whole gene correction and insertion without requiring: (1) homology-directed repair, which occurs at low efficiency in many cells, or (2) viral delivery of a DNA template, which creates toxicity risks and technical challenges. These technologies include all-RNA gene correction, non-viral delivery of DNA and novel editing and insertion techniques. These efforts complement other core platform capabilities, such as gRNA selection, on- and off-target assessment, multiplexing and lipid nanoparticle discovery.
Other Vertex Partnered Programs
The company has partnered with Vertex, a global leader in rare diseases, in several other disease areas beyond SCD and TDT. The company has entered into license agreements with Vertex with respect to cystic fibrosis, or CF, where Vertex has extensive expertise, and DMD. In addition, the company has entered into a collaboration agreement on DM1, in which the company retains the option to co-develop and co-commercialize products. The company’s 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.
Strategic Partnerships and Collaborations
Vertex
The company, and certain of its affiliates, has 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, the company has 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; and a Strategic Collaboration and License Agreement, as amended in April 2021, or the 2019 Collaboration Agreement. In addition, the company and Vertex entered into a non-exclusive license agreement in March 2023, or the Non-Ex License Agreement, pursuant to which the company agreed to license to Vertex, on a non-exclusive basis, certain of the company’s gene editing intellectual property.
2015 Collaboration Agreement
Pursuant to the 2015 Collaboration Agreement, the company agreed to provide technology and options to obtain licenses relating to the company’s CRISPR/Cas technology to Vertex.
Joint Development Agreement
In December 2017, the company 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, the company 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 the company’s 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. The company and Vertex amended the A&R Vertex JDCA in December 2023.
2019 Collaboration Agreement
In June 2019, the company and Vertex entered the 2019 Collaboration Agreement, pursuant to which the company and Vertex agreed to collaborate to develop and commercialize products for the treatment of DMD and DM1. The company and Vertex amended the 2019 Collaboration Agreement in April 2021.
The 2019 Collaboration Agreement includes, among other things, provisions relating to the following:
Governance. The company and Vertex will form a joint advisory committee to provide high-level oversight and coordination of the activities covered by the 2019 Collaboration Agreement.
Development and Commercialization. The 2019 Collaboration Agreement provides that Vertex will be responsible for development and commercialization activities, subject to the company’s option, exercisable during a specified exercise period, to co-develop and co-commercialize products for the treatment of DM1.
Non-Exclusive License Agreement
In March 2023, the company and Vertex entered the Non-Ex License Agreement, pursuant to which the company agreed to license to Vertex, on a non-exclusive basis, certain of the company’s 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.
Intellectual Property
‘CRISPR Therapeutics’ standard character mark and design logo, ‘CRISPRX,’ ‘CRISPR TX,’ ‘CTX112,’ ‘CTX131,’ ‘CTX211,’ ‘CTX213,’ ‘CTX310,’ ‘CTX320,’ ‘CTX330,’ ‘CTX340,’ and ‘CTX450,’ are trademarks and registered trademarks of the company.
The company’s wholly-owned intellectual property estate includes over one hundred (100) active patent families and over seventy (70) 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, the company has patent applications pending throughout the world, including in the United States, Europe, Australia, China, Canada and Japan. The granted patents and any other patents that may ultimately issue from these patent families are expected to expire starting in 2033, not including any applicable patent term extensions.
The company’s U.S. trademark estate consists of eighteen (18) pending applications, including, for example, for CRISPR-X, CRISPR THERAPEUTICS, CTX112, CTX131, CTX310 and CTX320, as well as seven U.S. registrations, including for CRISPR THERAPEUTICS and the CRISPR THERAPEUTICS logo. The company’s international trademark estate consists of multiple pending applications and registrations, including pending applications for CRISPR THERAPEUTICS standard character mark in Germany and Switzerland, and registrations in Benelux, Italy, Spain, and the U.K. For the CRISPR THERAPEUTICS logo, the company has pending applications in Germany, Korea and Switzerland; and registrations in Benelux, Brazil, Canada, EU, Hong Kong, Italy, Japan, Mexico, Singapore, South Africa, Spain, and the U.K. The company has registrations for CTX112 in the EU, Switzerland, and the U.K. The company has registrations for CTX131 in the EU, Switzerland, and the U.K. The company has a pending application for CTX213 in Canada. The company has registrations for CTX310 in Australia, New Zealand and Switzerland, and a pending application in Canada. The company has registrations for CTX320 in Australia, New Zealand and Switzerland. The company has a registration for CTX330 in Switzerland.
Enabling Technologies
The company has entered into a number of additional collaborations and license agreements to support and complement the company’s ex vivo and in vivo programs, including agreements related to: technologies to deliver CRISPR/Cas9 ex vivo and in vivo; additions to the company’s hematopoietic stem cell and in vivo programs, including two grants to advance gene editing therapies for HIV; and enhancements to the company’s CAR T and regenerative medicine cell therapy programs and platform. For example, the company has entered into agreements with Nkarta to develop and commercialize products leveraging donor-derived, gene-edited CAR-NK cells; Capsida Biotherapeutics, Inc. to develop in vivo gene editing therapies delivered with engineered AAV vectors; Roswell Park Comprehensive Cancer Center to advance a gene-edited autologous CAR T program against new targets; MaxCyte, Inc. on ex vivo delivery for the company’s hemoglobinopathy and CAR T programs; CureVac AG on optimized mRNA constructs and manufacturing for certain in vivo programs; and KSQ Therapeutics Incorporated on intellectual property for the company’s allogeneic immuno-oncology programs.
Government Regulation
In the United States, the company’s 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.
In addition to the foregoing, state, and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservation and Recovery Act, and the Toxic Substances Control Act, affect the company’s business. These and other laws govern the use, handling, and disposal of various biologic, chemical, and radioactive substances used in, and wastes generated by, operations.
Research and Development
The company’s research and development expenses were $320.7 million for the year ended December 31, 2024.
History
CRISPR Therapeutics AG was founded in 2013. The company was incorporated in 2013.
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