Item 1. Business
Item 1. Business.
Overview
We are a clinical-stage C lustered R egularly I nterspaced S hort P alindromic R epeats (“CRISPR”) genome-editing biopharmaceutical company dedicated to developing transformative therapies for patients with devastating diseases. Our genome-editing platform is based on our novel chRDNA ( C RISPR h ybrid R NA- DNA , or “chRDNA,” pronounced “chardonnay”) genome-editing technology, which enables more precise genome editing of allogeneic cell therapies.
Our allogeneic, or off-the-shelf, chimeric antigen receptor (“CAR”) -T (“CAR-T”) cell therapy product candidates are manufactured in advance with cells from healthy donors, with the goal of enabling broad patient access, rapid patient treatment, and increased manufacturing scale. Our allogeneic CAR-T cell therapy product candidates in clinical development are directed at CD19 and B cell maturation antigen (“BCMA”), established cell surface targets against which autologous CAR-T cell therapeutics have already demonstrated clinical proof of concept. We use our chRDNA technology to armor our cell therapy product candidates through genome-editing strategies, such as checkpoint disruption and immune cloaking, to enhance activity against hematologic malignancies.
We are advancing two clinical-stage allogeneic CAR-T cell therapy product candidates for the treatment of patients with hematologic malignancies:
• Vispacabtagene regedleucel (“vispa-cel,” formerly CB-010): an allogeneic anti-CD19 CAR-T cell therapy that has been evaluated in patients with relapsed or refractory B cell non-Hodgkin lymphoma (“r/r B-NHL”) in our ANTLER phase 1 clinical trial.
• CB-011: an allogeneic anti-BCMA CAR-T cell therapy that is being evaluated in patients with relapsed or refractory multiple myeloma (“r/r MM”) in our CaMMouflage phase 1 clinical trial.
We believe vispa-cel, if approved, will have several advantages over commercially available autologous CAR-T cell therapies, including broad patient access, shorter time to treatment with an off-the-shelf product, significantly lower manufacturing costs, and a substantially smaller footprint for manufacturing. Vispa-cel has received regenerative medicine advanced therapy (“RMAT”) designation for relapsed or refractory large B cell lymphoma (“r/r LBCL”), fast track designation for r/r B-NHL, and orphan drug designation for follicular lymphoma (“FL”) from the U.S. Food and Drug Administration (“FDA”).
We believe CB-011, if approved, will have several advantages over both commercially available bispecific antibody therapies and commercially available autologous CAR-T cell therapies, including a single-dose treatment regimen, potentially low rates of grade 3 or greater infections, and rapid immune recovery compared to bispecific antibody therapies, as well as broader patient access, shorter time to treatment with an off-the-shelf product, significantly lower manufacturing costs, and a substantially smaller footprint for manufacturing compared to autologous CAR-T cell therapies. CB-011 has received fast track and orphan drug designations for r/r MM from the FDA.
On April 24, 2025, we announced a strategic pipeline prioritization with workforce and cost reduction initiatives to focus resources on our vispa-cel and CB-011 product candidates. At that time, we disclosed that we had discontinued our GALLOP phase 1 trial of vispa-cel for the treatment of lupus prior to dosing the first patient; our AMpLify phase 1 clinical trial of CB-012, an allogeneic anti-C-type lectin-like molecule-1 (“CLL-1”) CAR-T cell therapy for the treatment of relapsed or refractory acute myeloid leukemia (“r/r AML”), as additional data would be needed to advance this program; and our preclinical research. Patients treated in the AMpLify phase 1 clinical trial continue to be followed as part of our long-term follow-up study. Additionally, we announced that our workforce was reduced by 47 employees, or approximately 32% of our workforce. In connection with the discontinuation of the AMpLify phase 1 clinical trial for our CB-012 product candidate, we terminated our Exclusive License Agreement, dated November 13, 2020, with Memorial Sloan Kettering Cancer Center (“MSKCC”) (as amended, “MSKCC Agreement”), effective August 11, 2025.
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Allogeneic CAR-T Cell Therapies
Allogeneic, or off-the-shelf, CAR-T cell therapies offer several advantages over commercially available autologous CAR-T cell therapies, including broad patient access, shorter time to treatment and increased manufacturing scale with a substantially smaller footprint:
• Broad patient access: Only 25% of second-line (“2L”) relapsed or refractory large B cell lymphoma (“LBCL”) patients currently receive commercially available autologous CAR-T cell therapies. Many patients cannot wait weeks to months for autologous CAR-T cell therapy or their T cells are too dysfunctional to manufacture their individual therapy. With allogeneic CAR-T cell therapy, many more patients could be served as these cell therapies are manufactured in advance from healthy donor T cells, making them readily available off-the-shelf for rapid patient treatment. Additionally, commercially available autologous CAR-T cell therapies are primarily available at academic centers of excellence in metropolitan areas, whereas most patients are cared for in the community hospital setting and not at academic centers. Allogeneic CAR-T cell therapies can be administered in academic centers of excellence and in appropriate community hospital settings, suggesting broader patient access to treatment.
• Rapid patient treatment: Commercially available autologous CAR-T cell therapies are manufactured from the patient’s own T cells and require weeks to months for apheresis, manufacturing, product release, and delivery back to the patient for treatment. Given the long wait time, more than 50% of patients who receive autologous CAR-T cells require bridging therapy, adding additional therapies to their treatment. With allogeneic CAR-T cell therapy, patients can begin the treatment regimen the same day they become eligible.
• Increased manufacturing scale with smaller footprint: For autologous CAR-T cell therapy, manufacturing requires multiple large plants to meet the needs of the patient population, and one manufacturing batch yields one treatment for one patient, which cannot be further scaled. In addition, manufacturing failures can prevent a patient from receiving their treatment. In contrast, our allogeneic CAR-T cell therapy product candidates are manufactured from cells from healthy donors, prepared in advance of treatment in a single suite at a contract manufacturing organization (“CMO”) at significantly lower cost of manufacturing than autologous CAR-T cell therapies. These manufacturing attributes allow the number of doses per manufacturing batch to be scaled for broad patient access.
Our CRISPR chRDNA Genome-Editing Technology
Genome-editing technologies used to date have limited efficiency, specificity, and versatility for performing the multiple, precise genomic edits necessary for allogeneic CAR-T cell therapy manufacturing. Our CRISPR chRDNA genome-editing technology is designed to address these limitations and enables us to apply armoring strategies to enhance allogeneic CAR-T cell therapy activity against diseases.
Using our chRDNA genome-editing technology, we have successfully demonstrated multiplex genome editing while maintaining genomic integrity. Our allogeneic CAR-T cell therapy product candidates incorporate increasing numbers of genome edits, as shown in the figure below. We believe this level of editing sophistication and editing fidelity can unlock the broad potential of allogeneic cell therapies by:
• Mitigating the risk of graft-versus-host disease (“GvHD”) : Development of an allogeneic CAR-T cell therapy requires genome editing to remove proteins from donor T cells that may recognize and attack a patient’s tissue, which, without removal, would pose a risk of GvHD. To mitigate the risk of GvHD, we engineer our allogeneic CAR-T cell therapies with a knockout of the T cell receptor alpha constant (“ TRAC ”) gene in order to eliminate expression of the T cell receptor (“TCR”) from the surface of the CAR-T cells.
• Enhancing the activity of allogeneic cell therapies for potentially durable activity : Our chRDNA technology enables us to apply tailored armoring strategies to our allogeneic CAR-T cells, including (i) checkpoint disruption, through the knockout of programmed cell death protein 1 (“PD-1”) to enhance the activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion; and (ii) immune cloaking, through removal of the endogenous beta-2 microglobulin (“B2M”) protein and insertion of a beta-2-microglobulin–human-leukocyte-antigen-E–(“B2M–HLA-E”) peptide fusion, to reduce rejection by the patient’s immune system.
• Improving the genomic integrity of our products: We have observed that our cell therapy product candidates have significantly lower levels of off-target edits compared to those made using first-generation CRISPR-Cas9 genome editing, and we believe we maintain genomic integrity, including during multiplex editing.
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1 To Caribou’s knowledge
We believe that our chRDNA genome-editing technology has broad potential to generate ex vivo and in vivo cell and gene therapies. We own a robust worldwide patent portfolio protecting our Cas9 chRDNA and our Cas12a chRDNA compositions and genome-editing methods.
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Our Pipeline
We are focused on the development of our pipeline of allogeneic CAR-T cell therapies. We are advancing two clinical-stage allogeneic CAR-T cell therapies for the treatment of patients with hematologic malignancies. Our pipeline is shown below:
Our Strategy
Our mission is to develop innovative, transformative therapies for patients with devastating diseases through the use of our novel chRDNA genome-editing technology. Our overarching goal is to build an integrated company that develops, manufactures, and commercializes genome-edited cell therapies that have the potential to treat patients with significant unmet needs. Our current focus is on two clinical-stage allogeneic CAR-T cell therapies for treating patients with hematologic malignancies; our chRDNA technology also has the potential for additional applications. Key components of our strategy include:
• Applying our chRDNA genome-editing technology to engineer allogeneic CAR-T cell therapies that have the potential for durable activity against multiple diseases. Our chRDNA technology enables us to develop allogeneic cell therapies with the potential to achieve enhanced activity against diseased cells through the use of armoring strategies, including (i) mitigation of the risk of GvHD through prevention of TCR expression; (ii) checkpoint disruption through a knockout of PD-1 to enhance the activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion; and (iii) immune cloaking through removal of the B2M protein and insertion of a B2M–HLA-E-peptide fusion to reduce rejection by the lymphoid compartment of a patient’s immune system.
• Developing allogeneic CAR-T cell therapies against clinically validated targets to derisk our clinical programs. Vispa-cel, directed to the CD19 antigen, has been evaluated in our ANTLER phase 1 clinical trial in patients with r/r B-NHL. CB-011, directed to the BCMA antigen, is being evaluated in our CaMMouflage phase 1 clinical trial in patients with r/r MM. CD19 and BCMA antigens are the targets of several commercially available autologous CAR-T cell therapies, which reduces target risk as we evaluate the safety and efficacy of our allogeneic CAR-T cell therapies in clinical trials.
• Pursuing select applications of our technology and indications on our own and through new strategic collaborations. We believe that our technology has broad potential to generate cell and gene therapies in oncology, autoimmune diseases, and additional therapeutic areas. Potential applications include in vivo and ex vivo therapies. We may selectively pursue these indications and applications through new strategic collaborations.
Our Team
Our team and our culture are critical to our mission to develop innovative, transformative therapies for patients with devastating diseases through the use of our novel CRISPR chRDNA genome-editing technology. Our mission-driven team includes leaders who have significant experience in the development of cell and gene therapies, including driving global clinical and regulatory strategies for commercially available autologous CAR-T cell therapies through all phases of development.
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We were founded in 2011 by globally-recognized pioneers in CRISPR genome editing and nucleic acid biology: Jennifer A. Doudna, Ph.D., who was a co-recipient of the 2020 Nobel Prize in Chemistry for the development of CRISPR-Cas9 as a method for genome editing; Martin Jinek, Ph.D., Associate Professor at the University of Zurich in the Department of Biochemistry; James Berger, Ph.D., Professor in the Department of Biophysics and Biophysical Chemistry at the Johns Hopkins University School of Medicine; and Rachel E. Haurwitz, Ph.D., who has served as our president and chief executive officer since our formation. Drs. Doudna and Jinek serve on our scientific advisory board (“SAB”), which also includes world experts in CAR-T cell development, immunotherapies, oncology, patient care, and clinical trial development to support commercialization.
Genome-Editing Background
Genome editing is a class of technologies that facilitate engineering specific changes to deoxyribonucleic acid (“DNA”) sequences inside living cells. Genome editing can occur in two steps, as shown in the figure below. In the first step, a double-stranded break (“DSB”) is made at the location of the genome where the edit is desired. A cell typically has two ways to repair the DSB, which results in the knockout of a gene or the insertion of new genetic material: non-homologous end joining (“NHEJ”) and homology-directed repair (“HDR”), respectively. NHEJ is an error-prone process in which the broken DNA ends are reattached. During NHEJ, the cell typically inserts or deletes nucleotides at the DSB. These insertions and deletions (“indels”) generally disrupt the coding sequence for the targeted gene, resulting in the knockout of the targeted sequence. HDR, by contrast, is a more controlled repair system where the cell incorporates donor DNA delivered during the editing process into the DSB, resulting in the site-specific insertion of the provided DNA sequence.
The canonical CRISPR system utilizes a CRISPR-associated (“Cas”) protein Cas9, which can cut genomic DNA. Cas9 is targeted to a specific site in a genome by a guide ribonucleic acid (“RNA”). One of the disadvantages of CRISPR-Cas9 genome editing is the occurrence of off-target editing, edits that occur at sites in the genome other than at the intended target site due to the ability of RNA guides to bind to DNA sequences similar to the target DNA sequence. Off-target edits throughout the genome can alter an oncogene or tumor suppressor gene, impact the biology of the target cell, or have other negative consequences on therapeutic development. Additionally, the simultaneous occurrence of both on-target and off-target edits may lead to genomic rearrangements, including chromosomal translocations, that may be problematic for immune cell therapeutics, especially for ones requiring multiple edits.
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Our CRISPR chRDNA Technology
Overview
We deploy a new, next-generation CRISPR genome-editing platform, our novel chRDNA technology, which uses hybrid guides containing both RNA and DNA for editing genomic DNA to engineer our allogeneic CAR-T cell therapies. The presence of DNA in a chRDNA guide significantly improves editing specificity relative to an all-RNA guide. The addition of DNA into the guide increases the fidelity by reducing the binding of the guide to the target sequence, thereby resulting in even less binding of the chRDNA guide to non-target sequences that may be similar to, but different from, the intended target sequence. Our chRDNA technology uses the canonical Streptococcus pyogenes Cas9 protein or the Acidaminococcus sp . Cas12a protein and a guide that is composed of a mixture of RNA and DNA nucleotides in both the region that interacts with the chromosomal target DNA and in the region that does not interact with the target DNA. Like Cas9, Cas12a is a Cas protein used to edit genomic DNA site-specifically. The advantages of our chRDNA technology include:
• Specificity: Our chRDNA guides mediate higher genome-editing specificity as compared to all-RNA guides. Significantly fewer off-target events are observed using our chRDNA guides versus first-generation CRISPR-Cas9 or CRISPR-Cas12a systems using all-RNA guides. The improved genome-editing specificity from the use of our chRDNA guides leads to a high degree of editing specificity with lower levels of off-target events.
Our chRDNA guides retain high affinity to edit a genome at the intended location; however, these guides have lower affinity for potential off-target sites to reduce the likelihood of a genome edit at an unintended location. We evaluated the integrity and performance of chRDNA guides by employing two unique assays, the SITE-Seq® assay and the VINE assay, on two genes known from the scientific literature to exhibit high rates of off-target editing with either the Cas9 or Cas12a protein and all-RNA guides. All-RNA guides generated both robust on-target and off-target editing. In contrast to the all-RNA guides, the chRDNA guides maintained robust on-target editing but induced minor to no detectable off-target editing. We developed chRDNA guides that target the exact same genomic locations that achieve equivalent on-target editing compared to the all-RNA guides.
• High efficiency: We achieve a high degree of on-target gene knockout and site-specific gene insertion efficiency, facilitating robust multiplex editing, including multiple gene insertions. For example, Cas12a chRDNA genome editing used in generating CB-011 leads to approximately 76-80% gene insertion rates for two separate site-specific gene insertions, which represent both high and reproducible gene insertion rates, and greater than 60% of manufacturing-scale CAR-T cells have all four intended edits (two knockouts and two site-specific knock-ins).
Achieving high efficiency gene insertion is more challenging than achieving high efficiency gene knockout. To insert genes into T cells with our chRDNA technology, we transduce the cells with adeno-associated virus serotype 6 (“AAV6”), which contains the DNA template of interest to facilitate the integration of the DNA into the double-stranded break generated by the Cas9 chRDNA complex or the Cas12a chRDNA complex via the HDR pathway. Our chRDNA genome-editing technology does not rely on lentiviral or retroviral genome-editing methods, which are used in commercially available autologous CAR-T cell therapies to insert the CAR gene randomly into the genome and which may increase the risk of genomic mutagenesis.
• Versatility : Our chRDNA guides are compatible with, and offer utility across, multiple cell types, including T cells.
• Simplicity : Our chRDNA guides are manufactured using standard, scalable solid-phase phosphoramidite chemistry.
Genome-Editing Strategies for Allogeneic CAR-T Cell Therapies
CAR-T cells will generally proliferate in response to antigen engagement via the specificity of their respective CAR. However, allogeneic CAR-T cells are rapidly rejected by a patient’s immune system due to their divergent donor-derived genetic profile and cell surface human leukocyte antigen (“HLA”) presentation. We believe engineering CAR-T cells to achieve enhanced target cell killing activity is necessary for the realization of the full potential of allogeneic cell therapies. Furthermore, development of an allogeneic CAR-T cell therapy requires genome editing to prevent TCR expression on donor T cells that would otherwise pose a risk of GvHD.
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Checkpoint Disruption Strategy
One of the approaches we deploy to increase the activity of CAR-T cells is to remove PD-1 from the CAR-T cell surface. Engagement of the PD-1/PD-L1 axis leads to rapid exhaustion of T cells. This occurs when a T cell expressing PD-1 interacts with another cell expressing the ligand PD-L1. Diseased cells and the patient’s own cells can express PD-L1, leading to interaction with PD-1 and subsequent exhaustion of the CAR-T cells. We use our chRDNA technology to knock out the programmed cell death protein 1 (“ PDCD1”) gene to prevent PD-1 expression on the CAR-T cell surface, thereby disrupting PD-1/PD-L1-mediated exhaustion. We believe that knocking out PD-1 results in greater activity against disease in the patient, thereby enabling a potentially better therapeutic index relative to PD-1-expressing CAR-T cells.
Immune-Cloaking Strategy
Another approach we deploy to increase the persistence of our CAR-T cells is to immune cloak them to reduce their rapid immune-mediated rejection. The goal of immune cloaking is to maintain the allogeneic CAR-T cells in circulation for an extended period of time. Allogeneic CAR-T cells are foreign to the patient’s immune system and, unless modified, will be rapidly rejected. We use our Cas12a chRDNA technology to make multiple edits to T cells to immune cloak them and limit the rapid rejection by both the patient’s cytotoxic T cells and natural killer (“NK”) cells. Our edits remove all endogenous HLA class I antigens from the CAR-T cell surface and lead to the overexpression of HLA-E, a minor HLA antigen, on the CAR-T cell surface. The lack of endogenous HLA class I antigens and the presence of only HLA-E are designed to prevent the patient’s T cells and NK cells from rapidly rejecting the allogeneic therapy. These cells are unlikely to persist indefinitely, and ultimately other types of immune cells in the patient will eliminate the allogeneic CAR-T cells. Our edits are designed to maintain the CAR-T cells in circulation longer to enhance the activity of the CAR-T cell therapy to destroy a larger proportion of the targeted cells.
Our Clinical Programs
Our current focus is on advancing two clinical-stage allogeneic CAR-T cell therapies for treating patients with hematologic malignancies.
Vispa-cel
Overview: Strategy and Rationale
Our vispa-cel CAR-T cell therapy product candidate is an allogeneic CAR-T cell therapy targeting CD19-positive hematologic malignancies. Vispa-cel has been evaluated in our first-in-human, open-label, multicenter ANTLER phase 1 clinical trial (NCT04637763) in the United States, Australia, and Israel in adults with r/r B-NHL.
To our knowledge, our vispa-cel product candidate is the first allogeneic CAR-T cell therapy in a clinical trial with a PD-1 knockout, and we believe the PD-1 knockout enhances the potential for durable activity of an allogeneic CAR-T cell therapy. Other CAR-T cell therapies that express endogenous PD-1 could become rapidly exhausted and lose activity due to the interaction between PD-1 and its ligand PD-L1. PD-1/PD-L1 engagement leads to rapid exhaustion in T cells. This occurs when a T cell expressing PD-1 interacts with another cell expressing PD-L1. B cell tumors and the patient’s own cells express PD-L1, leading to interaction with PD-1 and subsequent exhaustion of the CAR-T cells. We prevent PD-1 expression on the vispa-cel CAR-T cells, thereby disrupting PD-1/PD-L1-mediated exhaustion. More than half of B-NHL tumors express PD-L1, correlating with poorer outcomes. We believe that knocking out PD-1 results in greater activity against disease in the patient, thereby enabling a potentially better therapeutic index relative to PD-1-expressing CAR-T cells.
Vispa-cel has received RMAT designation for r/r large B cell lymphoma (“LBCL”), fast track designation for r/r B-NHL, and orphan drug designation for FL from the FDA.
Target Indication
We are developing vispa-cel for the treatment of r/r B-NHL, with a focus on 2L LBCL patients who are primary refractory patients or who have relapsed after receiving one prior line of therapy.
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NHL is the most common hematologic malignancy with an estimated 80,350 individuals, or approximately 4% of all cancers, diagnosed in the United States in 2025 according to the National Cancer Institute SEER database. LBCL is a subtype of B-NHL and typically presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extranodal site. LBCL subtypes include diffuse large B cell lymphoma not otherwise specified (“DLBCL NOS”), high-grade B cell lymphoma (“HGBL”), primary mediastinal large B cell lymphoma (“PMBCL”), transformed follicular lymphoma (“tFL”), and transformed marginal zone lymphoma (“tMZL”). In the United States in 2025, approximately 34,000 people with LBCL were treated with first-line therapies and approximately 12,000 patients received second-line treatments.
Overall, for aggressive r/r B-NHL, newer immunologically-mediated therapies under investigation include checkpoint inhibitors, bispecific antibodies, and CAR-T cells. Commercially available autologous anti-CD19 CAR-T cell therapies have shown encouraging complete response (“CR”) rates, progression-free survival (“PFS”), and overall survival; however, there are many barriers preventing most 2L LBCL patients from receiving autologous CAR-T cell therapy, including limited patient access, length of time to treatment, and manufacturing capacity and scale limitations. Thus, there remains a significant unmet medical need for patients with r/r B-NHL.
ANTLER Phase 1 Clinical Trial for vispa-cel in r/r B-NHL
We evaluated vispa-cel in our ANTLER phase 1 clinical trial for the treatment of adult patients with aggressive forms of r/r B-NHL. Our ANTLER phase 1 clinical trial consisted of two parts: Part A was the dose escalation portion that followed a standard 3 + 3 design, with sequential, increasing single doses of vispa-cel, and was completed with 16 patients dosed at dose level 1 (40x10 6 viable CAR-T cells), dose level 2 (80x10 6 viable CAR-T cells), or dose level 3 (120x10 6 viable CAR-T cells). Part B was the dose expansion portion where vispa-cel was evaluated in additional patients to determine the recommended phase 2 dose (“RP2D”) in 2L LBCL patients. Dose level 2 (80x10 6 viable CAR-T cells) was selected as the RP2D. The ANTLER phase 1 clinical trial study design was as follows:
1 B-NHL subtypes include: DLBCL, HGBL, tFL, PMBCL, FL (follicular lymphoma, with POD24 (high risk)), MCL, MZL
2 LBCL subtypes include: DLBCL NOS (not otherwise specified), HGBL, transformed DLBCL from FL or MZL, and PMBC
Definitions: “DLBCL”: diffuse large B cell lymphoma; “FL”: follicular lymphoma; “POD24”: progression of disease within 24 months; “MCL”: mantle cell lymphoma; “MZL”: marginal zone lymphoma
On November 3, 2025, we announced results from our ANTLER phase 1 clinical trial evaluating vispa-cel in 2L LBCL patients, including the first data disclosure on 22 patients enrolled in the phase 1 confirmatory cohort to prospectively evaluate patients who received a dose of vispa-cel manufactured from a donor with at least four matching HLA alleles (of 12 total alleles) with the patient (“partial HLA matching”) as well as on additional LBCL patients from dose escalation and dose expansion.
As of September 2, 2025, the safety data cutoff date, our ANTLER clinical trial had enrolled 84 patients, including the confirmatory cohort of 22 2L LBCL patients designed to prospectively confirm the positive outcomes of partial HLA matching observed in earlier retrospective analyses. Following a lymphodepletion (“LD”) regimen of 60 mg/kg/day of cyclophosphamide for two days and 25 mg/m 2 /day of fludarabine for five days, each patient in the confirmatory cohort received a dose of vispa-cel at the RP2D (80x10 6 viable CAR-T cells) such that the patient and the T cell donor shared at least four of 12 HLA alleles. As of September 29, 2025, the efficacy data cutoff date, the results for the 22-patient confirmatory cohort were as follows:
• 82% (18/22) overall response rate (“ORR”)
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• 64% (14/22) CR rate
• 51% 12-month PFS
Median follow-up time for the confirmatory cohort was 6.0 months.
The announced results included an analysis of the 35 CD19-naïve, LBCL patients enrolled our ANTLER phase 1 clinical trial who received a dose of vispa-cel that met the criteria for our optimized product profile, which criteria are a young T cell donor under the age of 30 and a minimum of two of 12 HLA alleles matched between the patient and the T cell donor. Twenty of these 35 patients were enrolled in the confirmatory cohort, and the remaining 15 patients were enrolled in dose escalation or dose expansion. Thirty-two of the 35 patients were 2L patients and three of the 35 patients were third-line or later (“3L+”) patients. As of September 29, 2025, the efficacy data cutoff date, the results for the 35-patient optimized product cohort were as follows:
• 86% (30/35) ORR
• 63% (22/35) CR rate
• 53% 12-month PFS
Median follow-up time for the optimized cohort was 11.8 months.
The following is a summary of results for the confirmatory cohort and the optimized profile cohort for vispa-cel as of the September 29, 2025, efficacy data cutoff date:
1 2L LBCL 4+ HLA matched, dosed with 80x10 6 viable CAR-T cells
2 2L (N=32) and 3L+ (N=3) LBCL patients treated 40x10 6 viable CAR-T cells, 80x10 6 viable CAR-T cells, or 120x10 6 viable CAR-T cells, optimized for multiple factors, including 2+ HLA matched and young donor
3 Median follow up 6.0 months for confirmatory; 11.8 months for optimized
4 Median follow up 5.1 months for confirmatory; 7.9 months for optimized
Definitions: “DoR”: duration of response; “NE”: not evaluable; ”NR”: not reached; “mo”: month; “CI”: confidence interval
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The results are further summarized in the following swimmer plot for the optimized profile cohort 1 :
1 2L (N=32) and 3L+ (N=3) LBCL patients treated with 40x10 6 viable CAR-T cells, 80x10 6 viable CAR-T cells, or 120x10 6 viable CAR-T cells, optimized for multiple factors, including 2+ HLA matching and young donor-derived
* Patient diagnosed with lung adenocarcinoma after day 28 scan revealed a non-responsive lung nodule and was enrolled in our long-term follow-up study. As of the data cutoff date, patient was in continued response without additional anti-lymphoma therapy at one year post-vispa-cel treatment
Additional information:
• Long-term follow-up data reflect the last known response; marked time points indicate confirmation of no disease progression
• One vispa-cel-related grade 5 IEC-HS occurred on day 25 post-infusion
• Median duration of complete response (“DoCR”) was not reached in this cohort
• Certain patients converted from CR or partial response (“PR”) to progressive disease (“PD”) at various assessment time points as indicated in the chart above
• Efficacy data cutoff date: September 29, 2025
Definition: “IEC-HS”: immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome
Vispa-cel was generally well tolerated. As of September 2, 2025, the safety data cutoff date, treatment emergent adverse events (“TEAEs”) at any grade in 25% or greater of all 84 patients who received vispa-cel were thrombocytopenia (62%), cytokine release syndrome (“CRS”) (55%), anemia (52%), neutropenia (39%), hypokalemia (26%), and leukopenia (26%). In the confirmatory and optimized profile cohorts, there were no cases of GvHD or grade 3 or greater immune effector cell-associated neurotoxicity syndrome (“ICANS”), 1% of patients experienced grade 3 or greater CRS, and 28% (out of 80 patients) experienced prolonged cytopenias.
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The following is a summary of notable adverse events for all three cohorts in the ANTLER phase 1 clinical trial as of the September 2, 2025, safety data cutoff date:
1 2L LBCL 4+ HLA matched, dosed with 80x10 6 viable CAR-T cells
2 2L (N=32) and 3L+ (N=3) LBCL patients treated with 40x10 6 viable CAR-T cells, 80x10 6 viable CAR-T cells, or 120x10 6 viable CAR-T cells, optimized for multiple factors, including 2+ HLA matching and young donor-derived
3 Prolonged cytopenias are defined as grade 3 or grade 4 neutropenia, thrombocytopenia, or anemia ongoing at day 28 (+/- 5 days) post-CAR-T cell infusion, based on laboratory data, distinct from investigator-reported clinical adverse events
4 Includes one vispa-cel-related grade 5 IEC-HS that occurred day 25 post-infusion
A cohort of 3L+ LBCL patients with prior exposure to CD19-targeted therapy enrolled five patients as of the September 2, 2025, safety data cutoff date. Enrollment in this cohort has been paused to focus on CD19-naïve patients.
Planned Pivotal Phase 3 Clinical Trial in 2L r/r LBCL
Based on these data, we are planning to conduct a randomized, controlled pivotal phase 3 clinical trial of vispa-cel in approximately 250 2L LBCL CD19-naïve patients who are ineligible for autologous stem cell transplant and autologous CAR-T cell therapy. We believe there is a meaningful commercial opportunity within this population, as approximately 60% of the 12,000 2L LBCL patients treated annually in the United States are considered ineligible for autologous stem cell transplant and autologous CAR-T cell therapy. Patients randomized to the study arm would receive a single dose of vispa-cel at the RP2D of 80x10 6 viable CAR-T cells following lymphodepletion with 60 mg/kg/day of cyclophosphamide for two days and 25 mg/m 2 /day of fludarabine for five days. Patients randomized to the comparator arm would be treated with the investigator’s choice of standard of care immunochemotherapy agents. The primary endpoint would be PFS, and an interim analysis is planned. Secondary endpoints would include ORR, CR rate, DoR, DoCR, overall survival, quality of life, and safety. We are in ongoing engagement with the FDA regarding the design of our pivotal trial for vispa-cel; however, we cannot provide any assurance that our proposed pivotal trial design will ultimately meet FDA requirements and/or recommendations or lead to regulatory approval.
CB-011
Overview: Strategy and Rationale
CB-011 is an allogeneic CAR-T cell therapy targeting BCMA-positive malignancies that is being evaluated in our ongoing open-label, multicenter CaMMouflage phase 1 clinical trial (NCT05722418) in the United States in adults with r/r MM. We acquired a novel humanized single-chain variable fragment (“scFv”) directed to BCMA that we use for the generation of the BCMA-specific CAR in CB-011.
To our knowledge, CB-011 is the first anti-BCMA CAR-T cell therapy incorporating an immune cloaking approach that includes both the removal of the B2M protein and insertion of a B2M–HLA-E-peptide fusion. This immune cloaking armoring strategy results in no endogenous class I HLA alleles expressed on the CAR-T cell surface. This reduces the number of potential mismatched HLA alleles to six from 12, resulting in a reduced risk of rapid immunologic clearing of the CAR-T cells by the patient.
CB-011 has received fast track and orphan drug designations for r/r MM from the FDA.
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Target Indication
We are developing CB-011 for the treatment of r/r MM. In 2025, 1.8% of all cancers in the United States were MM according to the National Cancer Institute SEER database. The median age of diagnosis is 69 years, and there were an estimated 36,110 new cases in 2025 in the United States with an estimated 12,030 deaths in 2025. Five-year survival in these patients is approximately 62%.
There has been significant interest in and activity against BCMA as a target, and autologous CAR-T cell therapy products and bispecific antibodies targeting BCMA are commercially available. Commercially available anti-BCMA autologous CAR-T cell therapies have shown encouraging CR rates, PFS, and overall survival; however, there are many barriers limiting the number of patients who receive autologous CAR-T cell therapy, including restricted patient access, length of time to treatment, and manufacturing capacity and scale limitations. Approximately 10% of patients with r/r MM receive an autologous CAR-T cell therapy. Commercially available bispecific antibodies require patients to receive frequent treatments and are associated with high infection rates. Additionally, many treatments for r/r MM are multi-drug regimens comprising varying routes of administration and/or complicated dosing schedules; these regimens can be complex and burdensome for both patients and physicians. Due to limited patient access and treatment burden, there is a need for an off-the-shelf, readily available, single-dose treatment for patients with r/r MM.
CaMMouflage Phase 1 Clinical Trial for CB-011 in r/r MM
We are evaluating CB-011 in our CaMMouflage phase 1 clinical trial in adult patients with r/r MM. Our CaMMouflage phase 1 clinical trial is being conducted in two parts: Part A was the dose escalation part following a standard 3 + 3 design, with sequential, increasing single doses of CB-011 with the ability to add additional patients at safe dose levels to further evaluate activity and safety. Part B is the dose expansion portion where anti-BCMA treatment-naïve and anti-BCMA treatment-exposed r/r MM patients receive CB-011 at the recommended dose for expansion (“RDE”) determined in Part A. The CaMMouflage phase 1 clinical trial study design is as follows:
1 300 mg/m 2 cyclophosphamide and 30 mg/m 2 fludarabine daily for three days
2 500 mg/m 2 cyclophosphamide and 30 mg/m 2 fludarabine daily for three days
Definition: “IMiD”: immunomodulatory drug; “MTD”: maximum tolerated dose; “PI”: proteasome inhibitor
On November 3, 2025, we announced results from the dose escalation portion of our ongoing CaMMouflage phase 1 trial evaluating CB-011 in r/r MM patients. As of the data cutoff date of September 24, 2025, 48 patients were enrolled in the dose escalation portion of the trial, which is now completed. The dose escalation portion enrolled patients who were fourth- or later-line (“4L+”) and all patients had received prior treatment with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. In dose escalation, prior treatment with an autologous CAR-T cell therapy was not permitted and no BCMA-targeted therapy was permitted within the prior three months.
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We evaluated two different LD regimens and multiple CAR-T cell dose levels. Thirty-five patients were treated with an LD regimen of 500 mg/m 2 cyclophosphamide and 30 mg/m 2 fludarabine daily for three days (the “selected LD regimen”). A single dose of CB-011 preceded by the selected LD regimen resulted in responses at all dose levels evaluated (150x10 6 viable CAR-T cells, N=6; 300x10 6 viable CAR-T cells, N=13; 450x10 6 viable CAR-T cells, N=13; and 800x10 6 viable CAR-T cells, N=3). Also on November 3, 2025, we announced that the 450x10 6 viable CAR-T cell dose with the selected LD regimen is our RDE.
1 150x10 6 , 300x10 6 , 450x10 6 , or 800x10 6 viable CAR-T cells
2 MRD negative at ≤10 -5
3 MRD not evaluable in one patient
4 MRD available for three patients
Definitions: “MRD”: minimal residual disease; ”sCR”: stringent complete response; “VGPR”: very good partial response
The results for the 12-patient, BCMA-naïve cohort treated with the selected LD regimen and the 450x10 6 viable CAR-T cell dose were as follows:
• 92% (11/12) ORR
• 75% (9/12) CR/sCR rate
• 91% (10/11) evaluable patients achieved MRD negativity (≤10 -5 )
• Seven of the 12 patients remain on study as of the data cutoff date in VGPR or better six months or longer following receipt of a single dose of CB-011
The median follow-up for patients dosed with the RDE was 8.3 months, and the longest responding patient in this cohort was, as of the data cut off date, in an sCR at 15 months post-infusion.
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The results are further summarized in the following swimmer plot for the 12-patient, BCMA-naïve cohort treated with the selected LD regimen and the 450x10 6 viable CAR-T cell dose:
1 MRD negative at ≤10 -5
Additional information:
• One patient who had previously withdrawn from the trial died on day 90 of treatment-related ICAHT; one patient died of pneumonia on day 50 (not treatment-related)
• Data shown are from BCMA-naïve patients dosed at the 450x10 6 viable CAR-T cell dose with the selected LD regimen
Definitions: “EMD”: extramedullary disease; “ICAHT”: immune effector cell-associated hematotoxicity; “mo”: months
CB-011 had a manageable safety profile across all dose levels and lymphodepletion regimens (N=48), with no cases of GvHD, immune effector cell-associated enterocolitis (“IEC-EC”), parkinsonism, or cranial nerve palsies. TEAEs in 25% or greater of all patients treated with CB-011 following the selected LD regimen (N=35) were as follows: neutropenia (80%), anemia (60%), thrombocytopenia (49%), infections (49%), dizziness (31%), cytokine release syndrome (31%), fatigue (31%), leukopenia (29%), decreased appetite (29%), constipation (26%), and pyrexia (26%). Notable adverse events in the RDE cohort included one CB-011-related grade 5 ICAHT on day 90, one grade 5 pneumonia not related to CB-011 on day 50, and one grade 4 CB-011-related Guillain-Barré Syndrome on day 129, which is resolving. In the cohort evaluating the 300x10 6 viable CAR-T cell dose level following the selected LD regimen, there was one grade 5 respiratory syncytial virus not related to CB-011 on day 73. Prophylactic measures for cytopenias and infections and early intervention for IEC-HS have been successfully implemented in our clinical protocol.
The following is a summary of notable adverse events in the CaMMouflage phase 1 clinical trial as of the September 24, 2025 data cutoff date:
1 LD regimen of 500 mg/m 2 cyclophosphamide and 30 mg/m 2 fludarabine daily for three days
2 Any continued ≥ grade 3 cytopenia based on laboratory data at ≥ day 35; denominator is those evaluable at day 35 (+/-5 days)
We initiated the dose expansion portion of the CaMMouflage phase 1 clinical trial in late 2025.
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Strategic Agreements
We recognize the broad opportunity presented by our genome-editing technologies to benefit patients, and we appreciate that we do not have sufficient resources to fully exploit this potential across multiple indications and applications. As part of our strategy to maximize the value and benefit of our technologies, we are exploring mutually beneficial strategic collaborations with other biotechnology or pharmaceutical companies. Additionally, we have in-licensed or taken assignment of key technologies important for the development of our product candidates.
Pfizer Investment
On June 29, 2023, we entered into a Securities Purchase Agreement (“Securities Purchase Agreement”) with Pfizer Inc. (“Pfizer”), pursuant to which we, in a private placement transaction, sold to Pfizer 4,690,431 shares of our common stock, par value $0.0001 per share, at a purchase price of $5.33 per share, for aggregate gross proceeds of approximately $25.0 million (“Pfizer Investment”). The issuance and sale of the shares to Pfizer closed on June 30, 2023. We granted certain registration rights to Pfizer under the Securities Purchase Agreement covering the resale of the shares. Unless otherwise agreed by Pfizer, we have agreed to use the proceeds from the Pfizer Investment solely in connection with (i) the development program for our allogeneic anti-BCMA CAR-T cell therapy known as CB-011 that is being evaluated in our CaMMouflage clinical trial and/or (ii) any other single-targeted anti-BCMA CAR-T cell therapy using an anti-BCMA scFv owned or controlled by us (collectively, cell therapies described in clauses (i) and (ii) are referred to as a “BCMA Product Candidate”), for 36 months expiring on June 29, 2026.
On June 29, 2023, in connection with the Pfizer Investment, we and Pfizer also entered into an Information Rights Agreement, having a 36-month term and expiring on June 29, 2026. Under the Information Rights Agreement, we granted Pfizer a 30-calendar day right of first negotiation (“ROFN”) if we commence or engage with any third party with respect to a potential grant of rights to develop and/or commercialize a BCMA Product Candidate, including, without limitation, a license agreement, a co-promotion/co-commercialization agreement, a profit share agreement, a joint venture agreement, or an asset sale agreement (a “Grant of Program Rights”). If we and Pfizer do not reach an agreement with respect to a Grant of Program Rights within the 30-day period, then we may pursue negotiations and enter into an agreement with any third party. If we and such third party do not reach agreement on the Grant of Program Rights within a specified time period, Pfizer’s right of first negotiation will be reinstated. Under the Information Rights Agreement, we also agreed to grant Pfizer the right to designate one representative to serve on our SAB. Through an information sharing committee, we provide calendar quarter updates to Pfizer regarding the development program for a BCMA Product Candidate. Additionally, we agreed to provide Pfizer access to any preclinical or interim or final clinical data (including raw data) and results generated as part of the development program for a BCMA Product Candidate at the same time that we provide such data to a third party (other than to our service providers or the FDA or other regulatory authorities), subject to certain confidentiality exceptions.
ProMab Biotechnologies, Inc. (“ProMab”)
On January 31, 2020, we entered into a Sale and Assignment Agreement with ProMab (as amended, “ProMab Agreement”) under which we purchased a humanized scFv targeting BCMA and a patent family related thereto for an upfront cash payment of $0.4 million and the potential payments of future royalties to ProMab. To date, six U.S. patents have granted (U.S. Patent Nos. 10,927,182; 11,021,542; 11,142,583; 11, 299,549; 11,472,884; and 12,435,152) in this patent family. Our anti-BCMA CB-011 CAR-T cell therapy product candidate contains this BCMA scFv. Under the terms of the ProMab Agreement, in the event that CB-011 is approved by the FDA, we will owe ProMab low-single-digit percent royalties on net sales until the expiration, abandonment, or invalidation of the last patent within the assigned patent family (i.e., 2040, without patent term adjustment (“PTA”) or patent term extension (“PTE”)). Such royalties may be reduced by no more than 50% if we must pay royalties to a third party for other intellectual property covering our product. Either party may terminate the ProMab Agreement in the event of an uncured material breach or bankruptcy of the other party. If ProMab terminates the ProMab Agreement due to our uncured material breach or bankruptcy, we must cease the manufacture, use, and sale of any products or product candidates incorporating the purchased anti-BCMA scFv.
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Pioneer Hi-Bred International, Inc. (“Pioneer,” now Corteva Agriscience)
On July 13, 2015, we entered into an Amended and Restated Collaboration and License Agreement (as amended, “Pioneer Agreement”) with Pioneer (then a DuPont company) that superseded and replaced a prior Collaboration and License Agreement entered into on September 10, 2014. Under the terms of the Pioneer Agreement, we and Pioneer cross-licensed background CRISPR intellectual property portfolios. Pioneer granted us an exclusive worldwide license, with the right to sublicense, to its background CRISPR intellectual property in the field of research tools, and a non-exclusive license, with the right to sublicense, for CRISPR in therapeutics and all fields outside of the Pioneer field, including in the field of human and animal therapeutics. We granted Pioneer an exclusive license, with the right to sublicense, to our background CRISPR intellectual property, including the CVC IP discussed below, in certain agricultural crops, specified microorganisms, a defined industrial bio field, and certain nutrition and health applications (“Pioneer Exclusive Field”), and a non-exclusive license, with the right to sublicense, to Pioneer for CRISPR in certain defined fields outside of research reagents. The Pioneer Agreement continues until the expiration, abandonment, or invalidation of the last patent or patent application within the licensed intellectual property; provided, however, that the parties may terminate the Pioneer Agreement by mutual consent or either party may unilaterally terminate the Pioneer Agreement if there is an uncured breach of a payment obligation, bankruptcy, or failure to maintain or own licensed intellectual property by the other party if the non-breaching party is materially adversely affected by such failure. Under the terms of the Pioneer Agreement, we are obligated to pay low-single-digit percent royalties to Pioneer for our research tool products as well as certain sublicensing revenue in that field. We are eligible to receive milestone payments from Pioneer in the event certain regulatory and commercial milestones are met, for a total of up to $22.4 million, related to specified row crops and we are also eligible to receive low-single-digit percent royalties for defined agricultural products and certain sublicensing revenue in that field.
The chRDNA patent family was developed under a three-year research collaboration between us and Pioneer, which ended December 31, 2016. Initially, this patent family was owned by Pioneer under the terms of the Pioneer Agreement, and we and Pioneer split the costs of patent prosecution and maintenance equally. Pioneer granted us an exclusive license to the chRDNA patent family in the fields of human and animal therapeutics and research tools as well as a non-exclusive license in certain other fields outside of the Pioneer Exclusive Field. Through an amendment to the Pioneer Agreement, dated December 18, 2020, Pioneer assigned the chRDNA patent family to us. Pioneer retained all of its existing rights (including its sublicensing rights) to the chRDNA patent family despite the change in ownership. As consideration for the assignment, we made an upfront payment of $0.5 million and are obligated to pay all patent prosecution and maintenance costs going forward; up to $2.8 million in regulatory milestone payments and up to $20.0 million in sales milestones for any therapeutic products that are covered by the chRDNA patent family; and a low-single-digit percentage of licensing revenue we receive for licensing the chRDNA patent family in the therapeutic field after December 2020. The sublicensing agreements that we entered into prior to December 18, 2020 (for example, the Intellia Agreement discussed below) are not subject to these economics.
Intellia Therapeutics, Inc. (“Intellia”)
On July 16, 2014, we entered into a License Agreement (as amended, “Intellia Agreement”) with Intellia, LLC (now Intellia Therapeutics, Inc.), under which we granted Intellia an exclusive worldwide license, with the right to sublicense, to certain CRISPR-Cas9 technology for a defined field of human therapeutics in exchange for Intellia stock. The Intellia Agreement included a license to certain of our future CRISPR-Cas9 intellectual property until such time as our direct or indirect ownership percentage in Intellia dropped below 10%, called the IP cut-off date, which occurred on January 30, 2018. Intellia granted us an exclusive worldwide license, with the right to sublicense, to its CRISPR-Cas9 technology for all fields outside of the defined field of human therapeutics, including a license to certain of Intellia’s future CRISPR-Cas9 intellectual property until the IP cut-off date. Each party had the right to opt in to any licenses in its field of use entered into by the other party prior to the IP cut-off date, subject to the terms and conditions of such license, and Intellia opted into our Pioneer Agreement and thus has a license to the Pioneer background CRISPR-Cas9 intellectual property. Under the Intellia Agreement, each party is responsible for 30% of the other party’s expenses for prosecution and maintenance of the licensed intellectual property, including 30% reimbursement of the patent prosecution and maintenance costs that we pay to UC/Vienna as described below. The milestones and royalties set forth in the Intellia Agreement are those in the UC/Vienna Agreement and so we pass through any payments received from Intellia to UC/Vienna. The Intellia Agreement continues for the life of the licensed patents and patent applications; provided, however that either party may terminate upon the occurrence of certain events.
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In 2018, Intellia initiated an arbitration proceeding over whether two patent families relating, respectively, to CRISPR-Cas9 chRDNA guides and Cas9 scaffolds, were included in the Intellia Agreement. An interim award from the arbitration panel in 2019 determined that both patent families are included in the Intellia Agreement, but the panel granted us an exclusive leaseback to Cas9 chRDNA guides under economic terms to be negotiated by the parties. On June 16, 2021, we entered into a leaseback agreement with Intellia (“Leaseback Agreement”), which resolved the arbitration proceeding. Pursuant to the Leaseback Agreement, in exchange for Intellia’s grant to us of an exclusive license to certain intellectual property relating to CRISPR-Cas9, including Cas9 chRDNAs, for use solely in the manufacture of our vispa-cel product candidate, we paid Intellia an upfront cash payment of $1.0 million and we will owe up to $23.0 million in potential future regulatory and sales milestones. Additionally, we will owe Intellia low- to mid- single-digit percent royalties on net sales of our vispa-cel product candidate until the expiration, abandonment, or invalidation of the last patent within the intellectual property relating to CRISPR-Cas9, including that relating to Cas9 chRDNAs (i.e., 2036, without PTA or PTE).
The Regents of the University of California (“UC”) and the University of Vienna (“Vienna”)
On April 16, 2013, we entered into an Exclusive License for Methods and Compositions for RNA-Directed Target DNA Modification and for RNA-Directed Modulation of Transcription with UC and Vienna (as amended, “UC/Vienna Agreement”), under which we received an exclusive worldwide license, with the right to sublicense, in all fields to the foundational CRISPR-Cas9 patent family co-owned by UC, Vienna, and Dr. Emmanuelle Charpentier (“CVC IP”). Dr. Charpentier has not granted us any rights to the CVC IP, either directly or indirectly. The UC/Vienna Agreement continues until the last-to-expire patent or last-to-be-abandoned patent application of the CVC IP; provided, however, that UC/Vienna may terminate the UC/Vienna Agreement upon the occurrence of certain events, including our uncured material breach of a material term of the UC/Vienna Agreement, and we may terminate the UC/Vienna Agreement at our sole discretion upon written notice. Without PTA or PTE, the CVC IP will expire in 2033. For products and services sold by us that are covered by the CVC IP, we will owe low- to mid-single-digit percent royalties on net sales, subject to a minimum annual royalty. Prior to such time that we are selling products, we owe UC/Vienna an annual license maintenance fee. We will owe UC/Vienna up to $3.1 million in potential regulatory and clinical milestone payments in the field of human therapeutics and diagnostics. Additionally, we pay UC/Vienna a specified percentage of sublicensing revenue we receive including cash and equity under our sublicensing agreements, subject to certain exceptions. If we include intellectual property owned or controlled by us in such sublicense, we pay UC/Vienna a low-double-digit percentage of sublicensing revenues received under the sublicense. If we do not include intellectual property owned or controlled by us in such sublicense, we pay UC/Vienna 50% of sublicensing revenues received under the sublicense. To date, we have entered into over 30 sublicensing agreements in a variety of fields such as human therapeutics, animal therapeutics, agriculture, forestry, research reagents, transgenic animals, certain livestock targets, internal research, bioproduction, cell lines, and microbial applications that include the CVC IP as well as other Cas9 intellectual property owned or controlled by us. We are obligated to reimburse UC for its prosecution and maintenance costs of the CVC IP. The CVC IP is currently involved in administrative proceedings at the U.S. Patent and Trademark Office (“USPTO”) and at the European Patent Office (“EPO”). See Risk Factors - “Our ability to continue to receive licensing revenue and to enter into new licensing arrangements related to the foundational CRISPR-Cas9 intellectual property will be substantially impaired if such intellectual property is limited by administrative patent proceedings or other patent challenges, ” in Item 1A of this Annual Report on Form 10-K.
On December 15, 2016, we entered into a Consent to Assignments, Licensing and Common Ownership and Invention Management Agreement (“IMA”) with UC, Vienna, Dr. Emmanuelle Charpentier, Intellia Therapeutics, CRISPR Therapeutics AG, ERS Genomics Ltd., and TRACR Hematology Ltd. relating to the CVC IP. Under the IMA, each of the owners of the CVC IP (i.e., UC, Vienna, and Dr. Charpentier) retroactively consented to all licenses and sublicenses granted by the other owners and their licensees and also gave prospective consent to any licenses and sublicenses that may be granted in the future. Additionally, the IMA provides for, among other things, (i) good faith cooperation among the parties regarding patent maintenance, defense, and prosecution of the CVC IP; (ii) cost-sharing under which CRISPR Therapeutics AG reimburses us for 50% of what we reimburse UC for patent prosecution and maintenance costs; 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 or abandonment date of the CVC IP.
On March 14, 2019, we entered into a Memorandum of Understanding with UC/Vienna, wherein we agreed that, for sublicensees in the fields of human therapeutics and companion diagnostics, we would pay UC/Vienna the royalties and milestones set forth in the UC/Vienna Agreement for products sold by our sublicensees, not the specified percentage of such sublicensing income received by us. We also agreed to various provisions that must be included in all future sublicensing agreements, including specific provisions for exclusive sublicenses.
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Intellectual Property
We seek and obtain patent protection for our chRDNA genome-editing technology and product candidates. We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection. Our success will depend significantly on our ability to obtain and maintain patent and trade secret protection for our chRDNA genome-editing technology and product candidates, our ability to defend and enforce our intellectual property rights, and our ability to operate without infringing any valid and enforceable intellectual property rights of third parties.
As of February 27, 2026, we owned 66 granted U.S. patents, 254 granted foreign patents, and 147 pending patent applications throughout the world. The patent portfolio owned by us includes U.S. and foreign patents and patent applications covering methods and compositions relating generally to our Cas9 chRDNA and Cas12a chRDNA technology (which, for granted U.S. patents, without PTA or PTE, will expire in 2036). Additionally, our portfolio includes U.S. and foreign patents and patent applications covering methods and compositions relating to the anti-BCMA binding domain of our CB-011 product candidate (which, for granted U.S. patents, without PTA or PTE, will expire in 2040). In general, we file our patent applications in the United States and Europe as well as in numerous other foreign patent jurisdictions.
Additionally, we have substantial patent protection on CRISPR-Cas9 methods and compositions, CRISPR Type I systems, and other genome-editing technologies. The patent term in the United States and other countries is 20 years from the date of filing of the first non-provisional application to which priority is claimed. In the United States, patent term may be lengthened by a PTA, which compensates a patentee for administrative delays by the USPTO in granting a patent or may be shortened if a patent is terminally disclaimed over an earlier-filed patent. Additionally, under the Drug Price Competition and Patent Term Restoration Act of 1984 (“Hatch-Waxman Amendments”), the term of a patent that covers an FDA-approved biologic may also be eligible for a PTE of up to five years, which is designed to compensate for the patent term lost during clinical trials and the FDA regulatory review process. A PTE cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent claiming a drug or biologic, methods of use, or methods of manufacturing may be restored. Moreover, a patent can only be restored once and, if a single patent is applicable to multiple products, it can only be extended based on one product. Similar provisions to extend the term of a patent that covers an approved product are available in Europe and certain other foreign jurisdictions. Without any PTE, the earliest expiration date of our granted U.S. patents is in 2032 and the latest expiration date of our granted U.S. patents is in 2043.
As of February 27, 2026, we owned 27 trademark registrations worldwide, including 7 U.S. trademark registrations. We have registered “CARIBOU,” “CARIBOU BIOSCIENCES,” “SITE-SEQ,” and the Caribou logo as trademarks in relevant classes in the United States, European Union (“EU”), and certain other jurisdictions.
We also rely upon trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain our competitive position. We seek to protect these trade secrets and other confidential information, in part, by entering into confidentiality agreements with parties who have access to them. We also enter into confidentiality and invention assignment agreements with our employees and our agreements with consultants include invention assignment obligations.
Competition
We currently compete across the fields of cell therapy and genome editing. We believe that our novel CRISPR-Cas12a chRDNA genome-editing technology has broad potential applicability across human therapeutic indications, including in vivo and ex vivo applications.
The biopharmaceutical industry, in particular the cell therapy and genome editing fields, is characterized by intense investment and competition aimed at rapidly advancing new technologies. Our vispa-cel and CB-011 product candidates will face substantial competition from multiple technologies, marketed products, and numerous other therapies being developed by other biopharmaceutical companies, larger and better funded pharmaceutical companies, academic research institutions, governmental agencies, and private research institutions. Many of our competitors, either alone or with their collaborators, have substantially greater financial, technical, and other resources, such as larger research and development staff, and/or greater expertise in research and development, nonclinical testing, conducting clinical trials, established manufacturing capabilities and facilities, and experienced marketing organizations with well-established sales forces. In addition, there is extensive patent infringement litigation in the biopharmaceutical industry and, in the future, we may bring or defend such litigation against our competitors.
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We believe that, if approved, our CAR-T cell therapy product candidates have the potential to offer beneficial products to patients due to genome edits we make with our chRDNA technology with the goal of extending robust CAR-T cell activity in patients. Because of the promising therapeutic effect of cell therapies, including the potential benefit of allogeneic treatment alternatives, we expect increasing competition from companies such as:
• Autologous T cell therapy : Autologous T cell therapies directed at CD19 have been commercialized by Novartis AG (Kymriah®), Kite Pharma, Inc., a Gilead Sciences, Inc. company (Yescarta®, Tecartus®), and Bristol-Myers Squibb Company (Breyanzi®). Autologous cell therapies directed at BCMA have been commercialized by Bristol-Myers Squibb Company (Abecma®) and Legend Biotech Corporation with their partner Johnson & Johnson (Carvykti®). Autologous T cell therapies are being developed by a number of additional companies, including but not limited to AbelZeta Pharma Inc., Arcellx, Inc., Arsenal Biosciences, Inc., Astellas Pharma Inc., Autolus Therapeutics plc, AvenCell Therapeutics, Inc., Bristol-Myers Squibb Company, Cabaletta Bio, Inc., Eureka Therapeutics, Inc., Gracell Biotechnologies Inc., an AstraZeneca PLC company, Iovance Biotherapeutics, Inc., Johnson & Johnson, Kite Pharma, Inc. (a Gilead Sciences Inc. company), Kyverna Therapeutics, Inc., Legend Biotech Corporation, Lyell Immunopharma, Inc., March Biosciences, Inc., Miltenyi Biotec, Mustang Bio, Inc., Novartis AG, Precigen, Inc., Regeneron Pharmaceuticals, Inc. (through its acquisition of the 2seventy bio, Inc. research pipeline), F. Hoffman-La Roche Ltd (through its acquisition of Poseida Therapeutics, Inc.), TCR² Therapeutics Inc., Triumvira Immunologics Inc., and TScan Therapeutics, Inc.;
• Allogeneic T cell therapy: Other companies are developing allogeneic T cell therapies, including Allogene Therapeutics, Inc., Atara Biotherapeutics, Inc., AvenCell Therapuetics, Inc., Cellectis S.A., CRISPR Therapeutics AG, Fate Therapeutics, Inc., Gracell Biotechnologies (an AstraZeneca PLC company), Imugene Limited, Kite Pharma, Inc. (a Gilead Sciences, Inc. company), Legend Biotech Corporation, March Biosciences, Inc., F. Hoffman La-Roche Ltd (through its acquisition of Poseida Therapeutics, Inc.), and Sana Biotechnology, Inc.;
• In vivo T cell therapy : Companies such as AbbVie Inc. (through its acquisition of Capstan Therapeutics, Inc.), Bristol-Myers Squibb Company (through its acquisition of Orbital Therapeutics), CREATE Medicines, Inc., GigaMune, Inc., Kite Pharma, Inc. (a Gilead Sciences Inc. company) (through its acquisition of Interius BioTherapeutics, Inc.), Kelonia Therapeutics, Inc., Legend Biotech Corporation, and Umoja Biopharma, Inc. are developing in vivo T cell therapies;
• Allogeneic NK cell therapy: Companies are developing allogeneic NK cell therapies, including Artiva Biotherapeutics, Inc., Celularity Inc., Century Therapeutics, Inc., Fate Therapeutics, Inc., ImmunityBio, Inc., Nkarta, Inc., NKGen Biotech, Inc., and Senti Biosciences, Inc.; and
• Other cell therapies: Other companies are developing CAR-expressing immune cell therapies derived from regulatory T cells, including Cabaletta Bio and Kyverna Therapeutics, Inc., and from gamma-delta T cells, including Adicet Bio, Inc., CytoMed Therapeutics Limited, and IN8bio, Inc.
Additionally, multiple biotechnology and pharmaceutical companies are developing other directly competitive technologies, such as small molecules, antibodies, bispecific antibodies, trispecific antibodies, and antibody-drug conjugates. Bispecific antibodies have received regulatory approval and are also in development for different lines of therapy for patients with relapsed or refractory DLBCL, including those from AbbVie Inc. (Epkinly®), F. Hoffman-La Roche Ltd (Columnvi® and Lunsumio®) and for different lines of therapy for patients with r/r MM, including those from Johnson & Johnson (Tecvayli® and Talvey®), Pfizer (Elrexfio®), and Regeneron Pharmaceuticals, Inc. (Lynozyfic®).
Compared to first-generation CRISPR genome-editing approaches, our chRDNA genome-editing technology has shown improved specificity, a reduction in off-target edits and translocations and, when paired with Cas12a, an advanced capability to perform multiplexed edits, in particular multiplexed insertions. Although we believe that our novel technologies and intellectual property position offer competitive advantages, we face competition from multiple other genome-editing technologies and companies. Other companies developing CRISPR-based technologies include, among others, Arbor Biotechnologies, Inc., Beam Therapeutics Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Intellia Therapeutics, Inc., Mammoth Biosciences, Inc., Metagenomi Therapeutics, Inc., and Scribe Therapeutics, Inc. Companies developing other genome-editing technologies include, among others, Allogene Therapeutics, Inc., Cellectis S.A., Precision BioSciences, Inc., Prime Medicine, Inc., Sangamo Therapeutics, Inc., and Wave Life Sciences Ltd.
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Manufacturing
Manufacturing CAR-T cell therapies requires multiple components. Our allogeneic CAR-T cell therapies are manufactured starting with cells from healthy donors, and clinical product candidates are prepared, qualified, released, and available on an off-the-shelf basis prior to patient dosing. Our allogeneic CAR-T therapies are cryogenically stored in freezers, making them readily available for patient treatment on demand. To date, we have successfully scaled our manufacturing processes so that one manufacturing run from a healthy donor can produce sufficient cell yield for approximately 200-300 doses of vispa-cel and 50-100 doses for CB-011.This is in contrast to commercially available autologous CAR-T cell therapy where one manufacturing run is required for each patient to be treated using the patient’s cells that may have already been depleted by prior treatments, a process that can take several weeks to months to deliver product for patient treatment.
For our CAR-T product candidates, we have optimized the manufacturing process that we developed in-house and have transferred these processes to CMOs that manufacture current good manufacturing practices (“cGMP”)-grade material for our clinical trials. Additionally, we have developed analytical methods to characterize and test the safety, purity, and potency of our cells based upon our manufacturing processes and regulatory requirements. We have made a significant investment in process development to optimize and control our product candidate characteristics and to also improve our supply capabilities.
For the manufacturing of our allogeneic CAR-T cell therapy product candidates, we have developed a platform process that is scaled to support commercial manufacturing. Our process development and manufacturing core competencies and advantages include:
• optimization and learnings across all of our product candidates, allowing for consistency and increased process robustness;
• internal process development to facilitate optimization of manufacturing processes and technical transfers to manufacturing sites;
• readily available and commercially-established equipment that further enables the transfer from our process development lab to cGMP operations;
• custom engineering and development to create the necessary specific requirements for our product candidates, while leveraging the broader platform to ensure robust processes;
• removal of residual TCR-positive T cells after genome editing to minimize the risk of GvHD in patients;
• process understanding and cell manufacturing control for continuous optimization of productivity and product candidate quality;
• product candidate optimization from translational learnings across one of the largest allogeneic clinical efficacy and safety data sets;
• closed manufacturing systems;
• highly specific development efforts focused on enhancing cell viability;
• extensive core process knowledge of gene knockout, CAR expression, and gene insertion;
• process control and optimization, allowing for increased retention of early memory T cell phenotypes; and
• platform scale and efficiency to accommodate commercial high yield per batch, with further yield optimization processes available.
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The CMOs that are currently manufacturing the clinical supplies of our product candidates are located in the United States and are subject to cGMP requirements. We have dedicated cGMP suites at our CMOs for the manufacture of our cell therapy product candidates. We use multiple CMOs to individually manufacture the critical and starting materials for our product candidates, including cGMP chRDNA guides, Cas9 and Cas12a proteins, and AAV6 vectors used in the manufacture of our CAR-T cells. Our chRDNA genome-editing is a next-generation CRISPR technology that does not rely on lentiviral or retroviral genome-editing methods, which are used in commercially available autologous CAR-T cell therapies to insert the CAR gene randomly into the genome, which may increase the risk of genomic mutagenesis. We expect to rely on CMOs for manufacturing our product candidates to expedite readiness for future clinical trials, and most of the CMOs we currently contract with have demonstrated capabilities for commercial manufacturing. Additionally, we may decide to build our own manufacturing facility in the future, or we may deploy a hybrid approach to manufacturing, to provide us with greater flexibility and control over our clinical or commercial manufacturing needs.
Government Regulation
As a biotechnology company, we are subject to extensive legal and regulatory requirements, including those related to research, development, testing, manufacture, product approval and licensure, quality control, packaging, storage, record keeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of our product candidates. Relevant regulatory authorities include, but are not limited to, the FDA; the European Medicines Agency (“EMA”), an agency of the EU in charge of the evaluation and supervision of medicinal products; the European Commission, which is the executive arm of the EU; and other national, state, local, and provincial regulatory authorities. The United States and certain jurisdictions outside the United States also regulate the pricing and reimbursement 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. In addition, the regulatory framework for the collection, use, safeguarding, sharing, transfer, and other processing of information worldwide is rapidly evolving and is likely to remain uncertain for the foreseeable future.
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 (“PHSA”), and the Federal Food, Drug, and Cosmetic Act (“FDCA”), and their implementing regulations promulgated by the FDA. Failure to comply with the applicable requirements at any time during the product development process, including nonclinical testing, clinical testing, the approval process, or post-approval process, may subject us to delays in the conduct of a clinical trial, delays in regulatory review and approval, and/or administrative or judicial sanctions. Such sanctions may include, but are not limited to, the FDA’s refusal to allow us to proceed with clinical testing of our product candidates, refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, receipt of 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, U.S. Department of Justice (“DOJ”), or other governmental entities.
As we seek approval to market and distribute a new biologic in the United States, we generally must satisfactorily complete each of the following steps:
• nonclinical studies performed in accordance with the FDA’s current Good Laboratory Practice (“cGLP”) regulations;
• manufacture and testing of clinical investigational product according to cGMPs;
• submission to the FDA of an investigational new drug (“IND”) application for human clinical testing, which must become effective before human clinical trials may begin;
• approval by an independent institutional review board (“IRB”), representing each clinical trial site before each clinical trial may be initiated, or by a central IRB if appropriate;
• performance of adequate and well-controlled human clinical trials required to establish the safety and efficacy of the product candidate for each proposed indication, in accordance with the FDA’s current Good Clinical Practice (“cGCP”) regulations including, but not limited to, informed consent and investigator financial disclosure requirements;
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• preparation and submission to the FDA of a biologics license application (“BLA”) seeking approval of our product candidates for one or more proposed indications, including submission of detailed information on the manufacture and composition of our product candidates and proposed labeling;
• review of the BLA by an FDA advisory committee, where applicable;
• satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities, including those of any third-party manufacturers, at which the product, or components thereof, are produced in order to assess compliance with cGMP requirements and to ensure that the facilities, methods, and controls are adequate to preserve and ensure the product’s safety, purity, and potency, and, if applicable, the FDA’s current Good Tissue Practice (“cGTP”), for the use of human cell and tissue products;
• satisfactory completion of any FDA audits of the nonclinical study and clinical trial sites to ensure compliance with cGLPs and cGCPs, respectively, and the integrity of nonclinical and clinical data in support of a BLA;
• payment of any user fees and securing FDA approval of a BLA; and
• compliance with any post-approval requirements, including the potential requirement to implement Risk Evaluation and Mitigation Strategy (“REMS”), adverse event reporting, and compliance with any post-approval studies required or requested by the FDA.
Nonclinical Studies and IND Applications
Before testing any investigational biologic candidate in humans, we must submit an IND application and receive clearance from the FDA to initiate a clinical trial. The results of our nonclinical testing, including laboratory evaluation of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy of the product, together with manufacturing information, are submitted to the FDA as part of the IND application. An IND is an exemption from the restrictions of the FDCA, which would otherwise preclude an unapproved biologic candidate from being shipped in interstate commerce. Under a cleared IND, the unapproved biologic candidate may be shipped in interstate commerce for use in an investigational clinical trial, provided that the product candidate meets certain quality and labeling requirements. An IND automatically becomes effective 30 calendar days after receipt by the FDA, unless before that time the FDA places the trial on clinical hold. In such a case, the IND sponsor must correct the deficiencies cited in the hold letter or otherwise satisfy the FDA that the investigation may proceed before the clinical trial can begin. When the sponsor submits a response to the issues identified in the hold letter, the FDA should respond in writing to the sponsor within 30 days of the complete response by either removing or maintaining the clinical hold. The FDA may impose a partial or full clinical hold with respect to our product candidate. A partial clinical hold is a delay or suspension of fewer than all of the investigational clinical trial, or certain parts of the investigational clinical trial, subject to the IND.
Human Clinical Trials in Support of a BLA
Our clinical trials involve the administration of our product candidate to patients with the disease to be treated and are conducted under the supervision of a qualified principal investigator in accordance with cGCP requirements. Clinical trials are conducted under study protocols detailing, among other things, the objectives of the clinical trial, 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.
If we wish to conduct a clinical trial outside of the United States, we may, but need not, obtain FDA authorization to conduct the clinical trial under an IND. When a foreign clinical trial is conducted under an IND, FDA IND requirements must be met unless waived. If a non-U.S. clinical trial is not conducted under an FDA IND, we may submit data from a well-designed and well-conducted clinical trial to the FDA in support of our BLA as long as the clinical trial is conducted in compliance with cGCP and the FDA is able to validate the data from the clinical trial through an onsite inspection if the FDA deems it necessary.
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For clinical trials conducted in the United States, each clinical trial must be reviewed and approved by an IRB, either centrally or individually at each institution at which our clinical trials will be conducted. The IRB will consider, among other things, our clinical trial design, subject informed consent, ethical factors, and the safety of human subjects. The IRB must operate in compliance with FDA regulations governing IRBs. The FDA, the applicable IRB, or we may suspend or terminate a clinical trial, in whole or in part, at any time for various reasons, including a finding that the clinical trial is not being conducted in accordance with FDA requirements or that the subjects or patients are being exposed to an unacceptable health risk. Some clinical trials receive additional oversight by an independent group of qualified experts organized by us, known as a data safety monitoring board or committee. This group receives and reviews data from the clinical trial on an ongoing basis and may recommend continuation of the clinical trial as planned, changes in clinical trial conduct, or cessation of the clinical trial at designated check points based on such data.
In addition to the submission of an IND application to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules may be subject to oversight of institutional biosafety committees (“IBCs”), as set forth in the National Institutes of Health (“NIH”) Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (“NIH Guidelines”). Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as: (i) molecules that are constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant nucleic acids); (ii) nucleic acid molecules that are chemically or by other means synthesized or amplified, including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules (i.e., synthetic nucleic acids); or (iii) molecules that result from the replication of those described in (i) or (ii). Specifically, under the NIH Guidelines, supervision of qualifying trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution. The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial. Although the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.
Furthermore, the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) requires a clinical trial sponsor to submit a diversity action plan for pivotal clinical trials, unless a waiver is granted by the FDA. The action plan must include information such as the sponsor’s goal for enrollment (by sex, ethnic characteristics, age), the rationale behind the enrollment goals, the subject patient population, potential barriers for enrollment, among others. This requirement is not yet in effect as it will become applicable to all clinical trials that begin enrollment 180 days after FDA publishes its final guidance on this topic. The final guidance has not yet been published. In January 2025, the FDA removed its June 2024 draft guidance on clinical trial diversity action plans from its website, and it is not clear how the FDA will enforce the statutory requirement under FDORA.
Clinical trials typically are conducted in three sequential phases.
• Phase 1 clinical trials are initially conducted in a limited population of healthy humans or, for our product candidates, in patients, such as cancer patients, in order to test the product candidate for safety, including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion, and pharmacodynamics, and to identify a recommended phase 2 dose.
• Phase 2 clinical trials are generally conducted in a limited patient population to identify possible adverse effects and safety risks, evaluate the efficacy of the product candidate for specific targeted indications, and to determine dose tolerance and optimal dosage. We may conduct multiple phase 2 clinical trials to obtain information prior to beginning larger and costlier phase 3 clinical trials. In appropriate circumstances, a phase 2 clinical trial may serve as the basis for an application, in which case a separate phase 3 clinical trial may not be necessary.
• Phase 3 clinical trials are undertaken within an expanded patient population to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the product candidate and to provide an adequate basis for physician labeling.
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These phases may overlap or be combined. For example, a phase 1/2 clinical trial may contain both a dose-escalation stage and a dose-expansion stage, the latter of which may confirm tolerability at the recommended dose for expansion in future clinical trials (as in traditional phase 1 clinical trials) and provide insight into the anti-tumor effects of the investigational therapy in selected subpopulation(s). Typically, during the development of oncology therapies, all subjects enrolled in phase 1 clinical trials are disease-affected patients and, as a result, considerably more information on clinical activity may be collected during such trials than during Phase 1 clinical trials for non-oncology therapies. In most cases, the FDA requires two adequate and well-controlled phase 3 clinical trials to demonstrate the safety and efficacy of the biologic. In rare instances, a single phase 3 trial may be sufficient when either (i) the trial is a large, multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible, or (ii) the single trial is supported by confirmatory evidence. Approval on the basis of a single trial may be subject to a requirement for additional post-approval studies.
In addition, the manufacturer of an investigational biologic in a phase 2 or phase 3 clinical trial for a serious or life-threatening disease is required to make available, such as by posting on its website, its policy on evaluating and responding to requests for expanded access to such investigational biologic.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators. Annual progress reports detailing the status of clinical trials must be submitted to the FDA. Written IND safety reports must be submitted to the FDA and the investigators within 15 calendar days of receipt by us after determining that the information qualifies for such expedited reporting. IND safety reports are required for suspected unexpected serious adverse reactions (“SUSARs”), findings from other studies or animal or in vitro testing that suggest a significant risk to humans in our clinical trials, and any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. Additionally, we must notify FDA within seven calendar days after receiving information concerning any unexpected fatal or life-threatening suspected adverse reaction.
Guidance Governing Gene Therapy Products
The FDA has defined a gene therapy product as one that mediates its effects by transcription and/or translation of transferred genetic material or by specifically altering host (human) genetic sequences. Examples of gene therapy products include nucleic acids (e.g., plasmids, in vitro transcribed ribonucleic acid), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient. Within the FDA, the Center for Biologics Evaluation and Research (“CBER”) regulates gene therapy products. Within CBER, the review of gene therapy and related products is consolidated in the Office of Therapeutic Products, and the FDA has established the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its reviews. The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.
For example, in January 2024, the FDA issued a guidance document titled “Considerations for the Development of Chimeric Antigen Receptor T Cell Products; Guidance for Industry,” which provides recommendations regarding collection and handling of cellular starting materials, vector manufacturing and testing processes, CAR-T cell design and development considerations, pharmacology and toxicology, clinical trial considerations, manufacturing processes, analytical comparability, etc. In this guidance the FDA outlined factors that sponsors should consider in conducting clinical trials using CAR-Ts, including defining appropriate study populations based on potential toxicities of CAR-T cells, such as cytokine-release syndrome and neurological toxicities, diagnostic tests that can identify patients with tumors that have the target antigens, selection of appropriate dosage levels based on viable transduced CAR-T cells, etc. The FDA also issued a guidance document titled “Human Gene Therapy Products Incorporating Human Genome Editing” in January 2024, which provides recommendations for sponsors that are developing gene therapy products involving genetic editing of somatic cells, as well as information that sponsors should provide to the FDA prior to beginning a clinical trial, including information on the design of the gene editing component; delivery mechanisms for the gene editing components; information on chemistry, manufacturing, and controls (“CMC”); risk of unregulated proliferation; potential implications of off-site gene editing; etc. The FDA also has issued other guidance documents that relate to gene therapies, such as “Human Gene Therapy for Rare Diseases,” and it is likely that the FDA will continue to issue additional guidelines with respect to the development and regulatory submission of cell and gene therapy products in the future that may affect our product candidates.
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The guidance documents provide additional factors that the FDA will consider at each of the above stages of development and relate to, among other things, the proper nonclinical assessment of gene therapies; the CMC information that should be included in an IND; the proper design of tests to measure product potency in support of a BLA; and measures to observe delayed adverse effects in subjects who have been exposed to investigational gene therapies when the risk of such effects is elevated. The FDA usually recommends that sponsors observe subjects for potential gene therapy-related delayed adverse events. Depending on the product type, long term follow up can be up to 15 years or as short as five years.
Clinical Trial Registry
There also are requirements governing the reporting of ongoing clinical trials and completed clinical trial results to the U.S. government-sponsored database, www.ClinicalTrials.gov, within certain timeframes. We are required to register and disclose certain clinical trial information, including the product information, patient population, phase of investigation, clinical trial sites and investigators, and other aspects of the clinical trial on www.ClinicalTrials.gov. We are also obligated to disclose the results of our clinical trials after completion. Disclosure of the results of these clinical trials can be delayed until the new product candidate or new indication being studied has been approved, up to a maximum of two years.
Compliance with cGMP and cGTP Requirements
Before approving a BLA, the FDA typically will inspect the facility or facilities where our product candidates are manufactured. The FDA will not approve a BLA unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to ensure consistent production of the product within required specifications. The PHSA emphasizes the importance of manufacturing controls for products such as biologics whose attributes cannot be precisely defined. Material changes in manufacturing equipment, location, or process post-approval may result in additional regulatory review and require approval.
The FDA also will not approve a product if our manufacturing is not in compliance with cGTPs, which are requirements found in FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues, and cellular and tissue-based products (“HCT/Ps”), which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient. The primary intent of the cGTP requirements is to ensure that cell- and tissue-based products are manufactured in a manner designed to prevent the introduction, transmission, and spread of communicable disease. FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, when applicable, to evaluate donors through screening and testing.
Review and Approval of a BLA
The results of product candidate development, nonclinical testing, and clinical trials, including negative or ambiguous results as well as positive findings, are submitted to the FDA as part of a BLA requesting a license to market the product. A BLA must contain sufficient manufacturing information and detailed information on the composition of the product candidate and proposed labeling as well as payment of a user fee, unless the criteria for a fee waiver or exemption are met. Under the PHSA, the FDA will approve a BLA if it determines that our product candidate is safe, pure, and potent and the manufacturing facility meets standards designed to ensure that our product continues to be safe, pure, and potent.
The FDA has 60 calendar days after submission of a BLA to conduct an initial review to determine whether the BLA is acceptable for filing based on the agency’s threshold determination that the BLA is sufficiently complete to permit substantive review. Once the submission has been filed, the FDA begins an in-depth review of the application. Under the goals agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”), for a new molecular entity, the FDA has 10 months from the date that BLA is filed in which to complete its initial review of a standard application and respond to us, and six months from such filing date for a priority review of the application. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs. The review process and the PDUFA goal date may be extended by three months if the FDA determines that we have submitted a major amendment.
The FDA may refer our BLA to an advisory committee for review, evaluation, and recommendation as to whether our BLA should be approved. In particular, the FDA may refer to an advisory committee application for a biologic that present difficult questions of safety or efficacy. Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates, and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
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On the basis of the FDA’s evaluation of the application and accompanying information, including the results of the inspection of the manufacturing facilities and any FDA audits of nonclinical study and clinical trial sites to ensure compliance with cGMPs, cGLPs, and cGCPs, respectively, the FDA will issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of our product candidate with specific prescribing information for specific indications. If our BLA is not approved, the FDA will issue a complete response letter, which will contain the deficiencies that preclude approval of the application and outline recommended actions we might take to obtain approval of our BLA. If we receive a complete response letter, we may submit to the FDA information that represents a complete response to the issues identified by the FDA. Such resubmissions are classified under the PDUFA as either class 1 or class 2. The classification of a resubmission is based on the information submitted by us in response to the complete response letter. Under the goals and policies agreed to by the FDA under the PDUFA, the FDA has two months to review a class 1 resubmission and six months to review a class 2 resubmission. The FDA will not approve an application until deficiencies identified in the complete response letter have been addressed. Alternatively, if we receive a complete response letter, we may either withdraw our BLA or request a hearing.
As a condition of a BLA approval, the FDA may limit the approved indications for use of our products. The FDA may also require that contraindications, warnings, or precautions be included in the product labeling. In addition, the FDA may require or request post-approval studies, including phase 4 clinical trials. The FDA may also require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, to help ensure that the benefits of the product outweigh the potential risks. REMS can include medication guides, communication plans for healthcare professionals, and elements to ensure safe use (“ETASU”). ETASU can include, but are not limited to, specific or special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs. After approval, many types of changes to the approved product, such as adding new indications, certain manufacturing changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval.
Fast Track, Breakthrough Therapy, Priority Review, and RMAT Designations
The FDA is authorized to facilitate and expedite development and review of new biologics intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition. These programs include fast track designation, breakthrough therapy designation, priority review, and RMAT designation. These designations are not mutually exclusive, and our product candidates may qualify for one or more of these programs. Although these programs are intended to expedite product development and approval, they do not alter the standards for FDA approval.
The FDA may designate one or more of our product candidates as a fast track product if our product candidate is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life-threatening disease or condition, and it can be demonstrated that our product candidate has the potential to address an unmet medical need for such a disease or condition. Our current product candidates have been designated as fast track products, which means we may have greater interactions with the FDA, and the FDA may initiate review of sections of our fast track product candidate’s application before the application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by us, that a fast track product candidate may be effective. We must also provide, and the FDA must approve, a schedule for the submission of the remaining information, and we must pay applicable application user fees. However, the FDA’s goal timeline for reviewing a rolling submission does not begin until the last section of the application is submitted. In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process, or if our designated product candidate development program is no longer being pursued.
Our product candidates may obtain breakthrough therapy designations if they are intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that our product candidates may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints. The FDA may take certain actions with respect to product candidates with such designations, including holding meetings with us throughout the development process, providing timely advice to us regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team, and taking other steps to provide guidance on the design of the clinical trials in an efficient manner. Breakthrough therapy designation may be rescinded if our product candidate no longer meets the qualifying criteria.
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The FDA may determine that an application will receive priority review designation if the application is for a product candidate that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA makes such determination on a case-by-case basis, compared with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting adverse reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, or evidence of safety and effectiveness in a new subpopulation. A priority review designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for acting on a marketing application from 10 months to six months following filing of the application.
The FDA may grant product candidates RMAT designations if such product candidates are regenerative medicine therapies intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that they have the potential to address unmet medical needs for such disease or condition. RMAT designation provides potential benefits that include early interactions and more frequent meetings with the FDA to discuss the development plan for the product candidate and eligibility for rolling review and priority review. Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of surrogate or intermediate clinical trial endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites. RMAT-designated products that receive accelerated approval may, as appropriate, fulfill their post-approval requirements through the submission of clinical evidence, clinical trials, patient registries, or other sources of real-world evidence such as electronic health records, through the collection of larger confirmatory data sets as agreed with the FDA, or via post-approval monitoring of all patients treated with such therapy prior to approval of the therapy. RMAT designation may be rescinded if our product candidate no longer meets the qualifying criteria.
Accelerated Approval Pathway
The FDA may grant accelerated approval to our product candidates for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that our product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval when our product candidate has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (“IMM”) and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition, and the availability or lack of alternative treatments. Product candidates granted accelerated approval must meet the same statutory standards for safety and efficacy as those granted traditional approval.
For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a product candidate, such as an effect on IMM. The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints but has indicated that such endpoints generally could support accelerated approval where a clinical trial demonstrates a relatively short-term clinical benefit in a chronic disease setting in which assessing long-term clinical benefit is essential for traditional approval, but the short-term benefit is considered reasonably likely to predict long-term benefit.
The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a product candidate, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.
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The accelerated approval pathway is usually contingent on our agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe our product candidate’s clinical benefit, and, in most cases, the FDA may require that the trial be designed, initiated, and/or fully enrolled prior to approval. As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the product from the market on an expedited basis. All promotional materials for product candidates approved under accelerated approval are subject to prior review by the FDA unless the FDA informs us otherwise.
The FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval and is required to specify conditions of any required post-approval study, which may include milestones such as a target date of study completion. Sponsors are required to submit progress reports for required post-approval studies and any conditions required by the FDA not later than 180 calendar days following approval and not less frequently than every 180 days thereafter until completion or termination of the study. The FDA may initiate enforcement action for the failure to conduct with due diligence a required post-approval study, including a failure to meet any required conditions specified by the FDA or to submit timely reports.
Post-Approval Regulation
If regulatory approval for marketing of any of our product candidates is obtained, we will be required to comply with all regular post-approval regulatory requirements as well as any post-approval requirements that the FDA has imposed as part of the approval process. We will be required to report certain adverse reactions and manufacturing problems to the FDA, provide updated safety and efficacy information, and comply with requirements concerning advertising and promotion. Manufacturers of our products are required to register their establishments with the FDA and certain state agencies and are subject to periodic announced or ad hoc inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP regulations, which impose certain procedural and documentation requirements upon these manufacturers.
Our products may also be subject to official lot release, meaning that the manufacturer of our products is required to perform certain tests on each lot of the product before the product is released for distribution. If the product is subject to official lot release, the manufacturer must submit to the FDA samples of each lot, together with a release protocol showing a summary of the history of manufacture of the lot and the results of the manufacturer’s tests performed on the lot. The FDA may in addition perform certain confirmatory tests on lots of some products before releasing the lots for distribution.
Once a marketing approval is granted for our product candidate, the FDA may withdraw the approval if compliance with regulatory requirements is not maintained or if problems occur after our product reaches the market. Later discovery of previously unknown problems with our product, including adverse events of unanticipated severity or frequency, issues with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, imposition of post-marketing studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS.
Other potential consequences of a failure to comply with regulatory requirements include:
• restrictions on the marketing or manufacturing of our product, complete withdrawal of our product from the market, or product recalls;
• fines, untitled or warning letters, or holds on post-approval clinical trials;
• refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of our product license approvals;
• product seizure or detention, or refusal to permit the import or export of products or the raw materials or ingredients that are needed for product manufacture; or
• injunctions or the imposition of civil or criminal penalties.
The FDA strictly regulates marketing, labeling, advertising, and promotion of licensed and approved products that are placed on the market. Pharmaceutical products may be promoted only for the approved indications and in accordance with the provisions of the approved labeling.
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Orphan Drug Designation and Exclusivity
Orphan drug designation is available for drugs and biologics that are intended for rare diseases or conditions, defined as (i) a disease or condition that affects fewer than 200,000 individuals in the United States or (ii) a disease or condition that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available a biologic for the disease or condition will be recovered from sales of the product in the United States. If a drug or biologic becomes the first product that is approved for the same disease or condition for which the FDA has granted the designation, that product will be entitled to orphan drug exclusivity, which means the FDA may not approve any other application to market the same drug or biologic for the same orphan disease or condition for a period of seven years following the date of marketing approval, except in certain circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care, or in instances of product supply issues. In the case of a biologic, sameness is based on the principal molecular features of the product. Orphan drug exclusivity does not prevent FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.
To obtain an orphan drug designation, we must make a request before submitting our BLA for a particular product candidate. After the FDA grants orphan drug designation, the generic or trade name, or the chemical name or a meaningful description of the biologic, its designated orphan use and date of designation, and our company name are disclosed publicly by the FDA. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. In addition, other financial incentives, such as tax credits or exemption from the BLA application fee, may be available.
Pediatric Studies and Exclusivity
Under the Pediatric Research Equity Act of 2003 (as amended, “PREA”), a BLA or supplement to a BLA for a product candidate with certain novel characteristics must contain data to assess the safety and effectiveness of the product candidate for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product candidate is safe and effective.
Sponsors must submit a pediatric study plan to FDA outlining the proposed pediatric study or studies they plan to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation. The FDA must then review the information submitted, consult with the sponsor, and agree upon a final plan. The FDA or the sponsor may request an amendment to the plan at any time.
For products intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of a sponsor, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments. In addition, the FDA will meet early in the development process to discuss pediatric study plans with the sponsor and the FDA must meet with the sponsor by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than 90 calendar days after FDA’s receipt of the study plan. The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements, under specified circumstances. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan drug designation except a product with a new active ingredient that is a molecularly targeted cancer product intended for the treatment of an adult cancer and directed at a molecular target determined by the FDA to be substantially relevant to the growth or progression of a pediatric cancer.
Pediatric exclusivity is another type of nonpatent regulatory exclusivity for drugs and biologics in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing nonpatent regulatory exclusivity, including orphan drug exclusivity. This six-month exclusivity may be granted if pediatric data is submitted that sufficiently responds to a written request from the FDA for such data. The data do not need to show a product to be effective in the pediatric population studied; rather, if the clinical trial is deemed to be responsive to the FDA’s request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory periods of exclusivity that cover the product are extended by six months.
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Biosimilars and Exclusivity
The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (“Affordable Care Act”) includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created an abbreviated approval pathway for biologics that are biosimilar to or interchangeable with an FDA-licensed reference biologic in the United States. Starting in 2015, the FDA commenced licensing biosimilars under the BPCIA, and there are currently numerous biosimilars approved in the United States as well as a number of interchangeable biosimilar products.
For the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and proposed biosimilar product in terms of safety, purity, and potency in at least one condition of use for which the reference product is approved. For the FDA to approve a biosimilar product as interchangeable with a reference product, the agency must find that the biosimilar product can be expected to produce the same clinical results as the reference product, and, for products administered multiple times, that the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic. Even after the FDA approves a biosimilar product, the product, its manufacturing processes, post-approval clinical data, labeling, advertising, and promotional activities for the product will be subject to continuous requirements of and review by the FDA or other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, including mandatory post-marketing safety reporting; registration and listing requirements; cGMP requirements relating to quality control, quality assurance, and corresponding maintenance of records and documents; and requirements regarding recordkeeping.
Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date of first licensure of the reference product. “First licensure” typically means the initial date the particular product at issue was licensed in the United States. The FDA may not approve a biosimilar product until 12 years from first licensure of the reference product. The FDA does not assign a date of first licensure or award a new period of exclusivity for a biologic if the licensure is for a supplement for the biologic or for a subsequent application by the same sponsor or manufacturer (or licensor, predecessor in interest, or other related entity) of the biologic for a change that results in a new indication, route of administration, dosing schedule, dosing form, delivery system, delivery device or strength, or for a modification to the structure of the biologic that does not result in a change in safety, purity, or potency. Even if a product is considered to be a reference product eligible for exclusivity, another company could market a competing version of that product if the FDA approves a full BLA for such product containing our own nonclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of the product.
Patent Term Extension
A patent claiming a new biologic may be eligible for a limited PTE under the Hatch-Waxman Amendments, which permits a patent restoration of up to five years for patent term lost during product development and FDA regulatory review. The restoration period granted on a patent covering a product is typically one-half the time between the effective date of an IND and the submission date of a BLA, plus the time between the submission date of a BLA and the ultimate approval date, less any time during which due diligence was not conducted. PTE cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s regulatory approval date. Pursuant to 35 U.S.C. § 156, only one patent covering an approved product, or the use or manufacture thereof, is eligible for PTE, and the application for the extension must be submitted prior to the expiration of the patent in question and within 60 calendar days after regulatory approval. The patent, even if it covers multiple products for which approval is sought, can be extended only once. The USPTO reviews and approves the application for any PTE in consultation with the FDA. Similar provisions are available in Europe and other jurisdictions to extend the term of a patent that covers an approved biologic although the eligibility requirements for these extensions vary.
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Regulation and Procedures Governing Approval of Medicinal Products in Other Countries
In order to market any product outside of the United States, we must also comply with numerous and comprehensive regulatory requirements of other countries and jurisdictions, regarding quality, safety, and efficacy, and governing, among other things, clinical trials, marketing authorization, post-authorization requirements, commercial sales, import and export, reimbursement, and distribution of products. Whether or not we obtain FDA approval for our product candidates, we will need to obtain the necessary approvals from health regulatory authorities in other countries or jurisdictions before we can initiate clinical trials or marketing of our products in those countries or jurisdictions. Specifically, the process governing approval of medicinal products in the EU generally follows the same lines as in the United States, although the approval of a medicinal product in the United States is no guarantee of approval of the same product in the EU, either at all or within the same timeframe as approval may be granted in the United States. The process entails satisfactory completion of nonclinical studies and adequate and well-controlled clinical trials to establish the safety and efficacy of a product candidate for each proposed indication. It also requires the submission to the EMA or the relevant member state competent authorities, of a marketing authorization application and granting of a marketing authorization by the EMA or these authorities before the product can be marketed and sold in the EU.
U.S. Export Control Licensing Requirements and Other U.S. and Foreign Trade Regulations, Sanctions Laws, Anti-Corruption, and Anti-Money Laundering Laws
We develop product candidates that may be subject to varying U.S. export control licensing requirements and foreign investment regulations. In addition, U.S. international trade laws, including the U.S. Foreign Corrupt Practices Act of 1977, as amended (“FCPA”), and similar anti-bribery or anti-corruption laws, regulations, and rules of other countries in which we may choose to operate, could apply to our international activities. Anti-corruption laws generally prohibit companies and their employees and certain other third parties from authorizing, promising, offering, or providing, directly or indirectly, improper payments or anything else of value to recipients in the public or private sector in order to influence action. The FCPA also requires public companies to make and keep books and records that accurately and fairly reflect the transactions of the company and to devise and maintain an adequate system of internal accounting controls.
In addition, U.S. import and export regulations, anti-money laundering laws, and various economic and trade sanctions regulations administered by the U.S. Treasury Department’s Office of Foreign Assets Controls could apply to any international activities we may undertake.
Coverage, Pricing, and Reimbursement
Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we may obtain regulatory approval by the FDA or other government authorities. In the United States and other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services often rely on third-party payors to reimburse all or part of the associated healthcare costs. Patients are unlikely to use any products we may develop unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of our products. In addition, direct or indirect governmental price regulation may affect the prices that we may charge for our products.
United States
Even if any product candidates we may develop obtain regulatory approval, sales of such products will depend, in part, on the extent to which third-party payors, including government healthcare programs in the United States, such as Medicare and Medicaid, commercial health insurers, and managed care organizations provide coverage and establish adequate reimbursement levels for such products.
In general, factors payors consider in determining coverage and reimbursement are based on whether the product is:
• a covered benefit under its health plan;
• safe, effective, and medically necessary, including its regulatory approval status;
• medically appropriate for the specific patient;
• cost-effective; and
• neither experimental nor investigational.
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In the United States, no uniform policy of coverage and reimbursement for biologics, including cell and gene therapy products, exists among third-party payors. As a result, obtaining coverage and reimbursement approval for such a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical, and cost-effectiveness data regarding the product’s clinical benefits, medical necessity, and risks on a payor-by-payor basis, and we cannot provide any assurance that coverage and adequate reimbursement will be obtained. A decision by a third-party payor not to cover any product candidates we may develop could reduce physician utilization of such product candidates once approved and have a material adverse effect on our sales, results of operations and financial condition. Additionally, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved, and inadequate reimbursement rates, including significant patient cost sharing obligations, may deter patients from selecting our products. One payor’s determination to provide coverage for a product does not ensure that other payors will also provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive marketing approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
European Union
In the EU, the approval process and requirements governing pricing and reimbursement for any product candidate vary greatly between countries and jurisdictions. Some countries allow biologics to be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional testing or studies that compare the cost effectiveness of a particular biologic to currently available treatments, or so-called health technology assessments, in order to obtain reimbursement or pricing approval. The EU HTA Regulation 2021/2282 became effective in January 2022, is applicable from January 2025 with a phased implementation until 2030, and aims to harmonize clinical and scientific aspects of HTA across the EU.
Some countries, including several EU member states, set prices and reimbursement for biologics, with limited participation from the marketing authorization holders. For example, the EU provides options for its member states to restrict the range of biologics for which their national health insurance systems provide reimbursement and to control the prices of biologics for human use. EU member states may approve a specific price for a biologic or may instead adopt a system of direct or indirect controls on the profitability of the company providing the biologic. Many European countries have increased the level of discounting required in relation to the pricing of biologics and these efforts could continue as countries attempt to manage healthcare expenditures.
Healthcare Law and Regulation
Healthcare providers and third-party payors play a primary role in the recommendation and prescription of pharmaceutical products that are granted marketing approval. Arrangements with providers, consultants, third-party payors, customers, and patients are subject to broadly applicable fraud and abuse laws including anti-kickback laws, false claims laws, and health care provider payment transparency laws, as well as data privacy and security laws and other healthcare laws that may constrain our business and/or financial arrangements. Violation of these laws may result in significant civil monetary penalties, possible exclusion from participation in U.S. federal health care programs, and/or criminal penalties. The current administration has signaled that in 2026 healthcare providers and suppliers can expect to see an increase in enforcement efforts based on these laws.
Restrictions under applicable U.S. federal and state healthcare laws and regulations, as well as equivalent international laws, include but are not limited to the following:
• the U.S. federal Anti-Kickback Statute (“AKS”), which prohibits, among other things, individuals or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce, or reward, either the referral of an individual, or the purchase, lease, order, arrangement for or recommendation of the purchase, lease, order, arrangement for any good, facility, item, or service, for which payment may be made, in whole or in part, under a federal healthcare program, such as Medicare and Medicaid;
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• the U.S. civil and criminal false claims laws, including the civil U.S. False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false, fictitious, or fraudulent or knowingly making, using, or causing to be made or used a false record or statement to avoid, decrease, or conceal an obligation to pay money to the federal government. In addition, the government may assert that a claim including items and services resulting from a violation of the AKS or FDA promotional standards constitutes a false or fraudulent claim for purposes of the U.S. False Claims Act;
• the U.S. Beneficiary Inducement Statute, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value, with limited exceptions, to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of items or services reimbursable by a federal or state health program;
• the U.S. Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), and their respective implementing regulations (collectively “HIPAA”), which imposes criminal and civil liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private payors, or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services;
• HIPAA also imposes obligations with respect to safeguarding the privacy, security, and transmission of individually identifiable information that constitutes protected health information, including mandatory contractual terms and restrictions on the use and/or disclosure of such information without proper authorization;
• the federal transparency requirements known as the U.S. Physician Payments Sunshine Act, or Open Payments program, created under the Affordable Care Act, which requires certain manufacturers of drugs, devices, biologics, and medical supplies to report annually to the Centers for Medicare & Medicaid Services (“CMS”) information related to payments, including certain product development activities such as clinical trials, and other transfers of value made by that entity to covered recipients, currently defined to include doctors, dentists, optometrists, podiatrists, chiropractors, teaching hospitals, physician assistants, nurse practitioners, and certain other healthcare providers and requires certain manufacturers and applicable group purchasing organizations to report ownership and investment interests held by physicians or their immediate family members;
• U.S. price reporting laws, which require companies to calculate and report complex pricing metrics in an accurate and timely manner to government programs. Such laws may not only affect coverage, reimbursement, and pricing for our products, but can also result in civil penalties for late or incorrect reports;
• U.S. consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;
• the FCPA, which prohibits companies and their intermediaries from making, or offering or promising to make, improper payments to non-U.S. officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment;
• certain state and other laws that require pharmaceutical companies to comply with the state standards or pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the U.S. government in addition to requiring pharmaceutical manufacturers to report information related to payments to physicians and other health care providers or marketing expenditures;
• certain state and other laws that govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts; and
• analogous state and foreign laws and regulations, which may be broader in scope than their federal equivalents.
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Numerous federal and state laws and regulations, including federal health information privacy laws, state data breach notification laws, state health information privacy laws and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our collaborators and third-party providers. In December 2023, the U.S. Department of Health and Human Services (“HHS”) finalized its Health Data, Technology and Interoperability rule, establishing new standards for transparency, information exchange, and interoperability for health information technology. On February 25, 2025, the current administration issued an executive order requiring HHS to issue guidance and otherwise enforce regulations requiring meaningful price transparency and standardized, required disclosures aimed to allow patients to make well-informed healthcare decisions. California has enacted the California Consumer Privacy Act (“CCPA”). The CCPA gives California residents expanded rights to access and delete their personal information, opt out of certain personal information sharing and receive detailed information about how their personal information is used. The CCPA provides for civil penalties for violations, as well as a private right of action for data breaches that is expected to increase data breach litigation. Additionally, the California Privacy Rights Act amended the CCPA to impose additional data protection obligations on companies doing business in California, including additional consumer rights processes, limitations on data uses, new audit requirements for higher risk data, opt outs for certain uses of sensitive data, and creation of a new California data protection agency authorized to issue substantive regulations. The majority of the provisions went into effect on January 1, 2023, and additional compliance investment and potential business process changes may be required. In the United States, states are constantly amending existing laws, requiring attention to frequently changing regulatory requirements.
Healthcare Reform
In the United States, there have been, and continue to be, proposals by the federal government, state governments, regulators and third-party payors to control or manage the increased costs of health care and, more generally, to reform the U.S. healthcare system. The pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. For example, in March 2010, the Affordable Care Act (“ACA”) was enacted, which intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for the healthcare and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms, substantially changed the way healthcare is financed by both governmental and private insurers, and significantly impacts the U.S. pharmaceutical industry. Healthcare reforms that have been adopted, and that may be adopted in the future, could result in further reductions in coverage and levels of reimbursement for pharmaceutical products, increases in rebates payable under U.S. government rebate programs and additional downward pressure on pharmaceutical product prices.
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There has been increasing legislative and enforcement interest in the United States with respect to drug and biologic pricing practices since the ACA was enacted. Several healthcare reform initiatives culminated in the enactment of the Inflation Reduction Act (the “IRA”) in 2022, which, among other things, eliminated, beginning in 2025, the coverage gap under Medicare Part D by significantly lowering the enrollee maximum out-of-pocket costs and requiring manufacturers to subsidize, through a newly established manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs and biologics below the out-of-pocket limit, and 20% once the out-of-pocket limit has been reached. The IRA also requires HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D. The negotiated price may not exceed a statutory ceiling price. Only high-expenditure single-source biologics that have been approved for at least 11 years (seven years for single-source drugs) are eligible to be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year. For 2026, the first year in which negotiated prices become effective, CMS selected 10 high-cost Medicare Part D products in 2023, negotiations began in 2024, and the negotiated maximum fair price for each product has been announced. These negotiations resulted in significant price reductions for the products from their 2023 list prices, ranging from 38% to 79%, with an average price reduction of 59.4%. In addition, CMS selected and announced the negotiated maximum fair price for 15 additional Medicare Part D drugs, which will become effective in 2027. For 2028, CMS has selected an additional 15 drugs, comprised of drugs covered under Medicare Part D and, for the first time, drugs payable under Medicare Part B. For 2029 and subsequent years, 20 Part B or D drugs will be selected. The negotiated prices have represented, and will continue to represent, a significant discount from average prices to wholesalers and direct purchasers. Currently, a drug or biologic that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation. However, as a result of a statutory amendment enacted in July 2025, beginning with the 2028 negotiated price applicability year, a drug or biologic may be designated for more than one rare disease or condition and still be excluded from price negotiation, as long as the only approved indications are for such rare diseases or conditions. The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation, and, in 2024, CMS finalized regulations for the Medicare Part B and Part D inflation rebates. The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years. Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties.
These provisions may be subject to legal challenges. For example, the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have been challenged in multiple lawsuits brought by pharmaceutical manufacturers. The outcome of these lawsuits is uncertain, and some IRA drug discount provisions have not been challenged in litigation. Thus, while it is unclear how the IRA will be implemented, it will likely have a significant impact on the pharmaceutical industry and the pricing of products. It is unclear what policies will be advanced with respect to IRA implementation and other drug pricing proposals.
In May 2025, the administration published an executive order regarding most favored nation (“MFN”) drug pricing, which is sometimes referred to as “international reference pricing.” This executive order directs the Secretary of HHS to communicate MFN price targets to pharmaceutical manufacturers and, if significant progress toward MFN pricing is not delivered, to propose a rulemaking plan to implement MFN pricing. Recently, on December 23, 2025, CMS issued proposed regulations to establish, under the Center for Medicare and Medicaid Innovation, two mandatory MFN pricing demonstration models under Medicare Part B and Part D. If these rules or other MFN pricing rules are finalized, they are likely to mandate reduced pricing of at least some of the drugs and biologics in the United States if they are also sold in comparator countries.
At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, and marketing cost disclosure and transparency measures, and in some cases, designed to encourage importation from other countries and bulk purchasing.
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Additional Regulations
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the U.S. Occupational Safety and Health Act, the U.S. Resource Conservancy and Recovery Act, and the U.S. Toxic Substances Control Act, all affect our business. These and other state and local laws govern our use, handling, and disposal of various biological, chemical, and radioactive substances used in, and wastes generated by, our operations. If our operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines.
Employee and Human Capital Resources
Workforce Demographics
As of February 27, 2026, we had 97 total employees, all of whom were full-time. The majority of our employees are located in Berkeley, California. Our employees are not represented by labor unions or covered by collective bargaining agreements. We believe that our employee morale is healthy and consider our relationship with our employees to be good; however, in July 2024 and in April 2025, we announced workforce reductions, which may have negatively impacted our relationship with employees.
Talent Acquisition, Development, and Total Rewards
We recognize that attracting, developing, and retaining talent at all levels is vital to our continued success. We have implemented a comprehensive talent strategy that motivates our employees to perform to the best of their abilities and to achieve our objectives. We are committed to providing a competitive and comprehensive total rewards program that includes market-aligned salaries, performance-based incentives, long-term equity grants, and comprehensive benefits, including health and wellness programs, retirement savings plan (401k), an employee stock purchase plan (ESPP), and paid time off. We invest in employee learning and development by identifying and providing training and development programs, tuition reimbursement, and cross-training in areas of interest beyond hired roles. Employees have access to ongoing learning opportunities to enhance their skills and advance their careers.
We understand the importance of goal setting and ongoing career development conversations. We require our managers and employees to play an active role in the performance management process. Our performance management process is designed to increase clarity and accountability for roles and responsibilities, strengthen communication, and build trust, all while championing personal and professional growth, learning, and success.
Great teamwork is a critical foundation for Caribou. Our peer-to-peer rewards and recognition program helps us maintain a culture of recognition and teamwork by offering various options for our employees and managers to recognize and reward colleagues across the organization. We plan to continue to refine our efforts related to optimizing our use of human capital, including improvements in the way we hire, develop, reward, and retain employees.
The Herd at Caribou
Our employees are our greatest asset, and we aim to create an inclusive and collaborative environment with the overall goal of engaging our workforce to support our current clinical product candidates and future business goals, while protecting the long-term interests of our stockholders. Our culture is built around our core values: we are driven by patient need, innovation is in our chRDNA, together we are stronger, and integrity and ethics guide our decision making. We have built a culture where employees are empowered, their ideas are taken seriously, and their contributions are recognized.
We at Caribou refer to ourselves as “the herd.” We encourage and value social interactions among the herd. We hold bi-monthly herd meetings in a hybrid on-site/videoconferencing format and periodically have all-employee on-site events to strengthen our culture, such as participating in San Francisco Bay clean-up events. We strive to build a culture that is driven by our mission to develop innovative, transformative therapies through novel genome editing for patients with devastating diseases.
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We regularly conduct engagement surveys and use the feedback to enhance our workplace culture. Our well-being initiatives include mental health resources and flexible work arrangements to support our employees’ overall health and productivity. We have established a culture advisory group comprised of cross-functional representatives from various geographic locations. Based on feedback from our culture advisory group, along with the results of employee surveys, we have focused on highlighting how our daily work connects to our corporate values, connecting teams to other functions, helping employees understand how decisions that impact them or their roles are made, ensuring leadership accessibility, and engaging our employees across multiple communication channels.
We expect all employees to observe the highest levels of business ethics while delivering the highest levels of performance. We encourage employees to speak up and raise questions and concerns promptly about any situation that may violate our Code of Business Conduct, Scientific and Data Integrity, and Ethics or any other corporate policy. We believe that it is beneficial for employees to raise concerns so that we may consider them carefully and address them appropriately. We seek to promote an environment that fosters honest communications about matters of conduct related to our business activities, whether that conduct occurs within our company or involves one of our third-party suppliers, service providers, or collaborators. We work diligently to make clear that management is prepared to address any reported violations and to ensure that it is known that any form of retaliation is prohibited. In addition, we have an easily accessible hotline available to employees wishing to report complaints anonymously.
Involvement in Our Community
Our headquarters are located in Berkeley, California, and many of our employees are alumni of local universities. Our employees are talented and passionate people who are committed to making a difference in our community and beyond. We provide each of our employees with eight hours of paid volunteer time each year, which can be used for participating in school activities, voter registrations, environmental activities, and the like. We strive to mitigate our impact on the environment where possible and pursue innovative ways to minimize our environmental footprint. The City of Berkeley requires companies with 10 or more employees to have a commuter benefits program in place, and we offer pre-tax commuter benefits to ride public transportation. Additionally, we provide bicycle vouchers to employees who bike to work and have bike repair tools on site as well as bike storage areas. Our employees have access to electric vehicle charging stations.
Workforce Health and Safety
Workplace safety is a priority for us. To maintain a safe and healthy workplace, we have implemented Environment, Health, and Safety (“EHS”) initiatives that focus on key risk mitigation programs to identify, assess, and correct hazards. We also have a safety training program that is designed for employees to be assigned the appropriate training to understand how to safely perform their duties.
Information Available on the Internet
Investors and others should note that we announce material information to our investors using our investor relations website (cariboubio.com), our filings with the U.S. Securities and Exchange Commission (“SEC”), press releases, public conference calls, and webcasts. We use these channels to communicate with the public about our company, our business, our product candidates and other matters. Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act, are available on our website free of charge as soon as reasonably practicable after we electronically file the material with, or furnish it to, the SEC. The materials we file with or furnish to the SEC are also available at www.sec.gov.
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