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Item 1. Business

2025-03-05 compared with 2024-02-28 · 356 added, 338 removed, 890 unchanged (44% of the section changed)

We are a clinical stage genome editing company dedicated to developing potentially transformative genomic medicines to treat a broad range of serious diseases.

We are a pioneering gene editing company dedicated to developing potentially transformative genomic medicines to treat a broad range of serious diseases.

The promise of genomic medicines is supported by the advancing knowledge of the human genome and by harnessing the progress in technologies for cell therapy, gene therapy, and, most recently, gene editing.

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We believe we are the only human genome editing company with a platform that includes CRISPR/Cas9, CRISPR/Cas12a, engineered forms of both of these CRISPR systems, and foundational intellectual property for both of these CRISPR systems.

Because of the broad nature of this platform, we believe we can create gene editing molecules for over 95% of the human genome.

To achieve this, we are focused on advancing gene editing medicines to treat hemoglobinopathies, beginning with the continued development of renizgamglogene autogedtemcel (“reni-cel”) (formerly known as EDIT-301) towards regulatory approval and commercialization, and leveraging the insights gained from this program to pursue next generation in vivo gene editing medicines targeting hematopoietic stem cells (“HSCs”).

We are also pursuing the development of in vivo gene editing medicines for other organs and tissues that we believe will significantly differentiate our genome editing approach from the current standards of care for serious diseases.

As part of these efforts, we are using strategic partnerships and collaborations and pursuing further opportunities to extend the reach of our intellectual property portfolio and access complementary technologies to expedite our drug discovery and clinical execution objectives.

Ex vivo Hemoglobinopathies

Using our proprietary AsCas12a enzyme, we can efficiently and specifically edit HSCs, which we believe can lead to best-in-class medicines for hemoglobinopathies.

Our lead program, reni-cel, is an experimental ex vivo gene-edited medicine to treat sickle cell disease (“SCD”), a severe inherited blood disease that causes premature death, and transfusion-dependent beta thalassemia (“TDT”), the most severe form of beta-thalassemia, an inherited blood disorder characterized by severe anemia.

We are investigating reni-cel in a single Phase 1/2/3 clinical trial, referred to as the RUBY trial, for the treatment of severe SCD.

In 2022, we dosed the first patient in the RUBY trial, and after completing sequential dosing of the first two patients, we commenced concurrent patient dosing in the first quarter of 2023.

Through February 28, 2024, we have enrolled 40 patients and dosed 18 patients in the RUBY trial .

We continue to enroll and dose patients in the adult cohort of the RUBY trial, with multiple patients scheduled for dosing in the second quarter of 2024.

We have also initiated enrollment in the adolescent cohort.

In December 2021, the U.S.

Food and Drug Administration (“FDA”) cleared our Investigational New Drug application (“IND”) for a Phase 1/2 clinical trial of reni-cel for the treatment of TDT, which we refer to as our EdiTHAL trial.

We dosed the first patient in this trial in the first quarter of 2023 and commenced concurrent patient dosing in the second quarter of 2023.

Through February 28, 2024, we have enrolled 9 patients and dosed 7 patients in the EdiTHAL trial, and we continue to enroll and dose patients.

In December 2023, we presented new safety and efficacy data in 17 patients treated with reni-cel in both the RUBY and EdiTHAL trials.

Eleven of these patients were treated in the RUBY trial and six were treated in the EdiTHAL trial.

This clinical data, which remained consistent with and further confirmed earlier clinical results shared in June 2023

and December 2022, supports our belief that reni-cel can be a clinically differentiated, one-time, durable medicine that can provide life-changing clinical benefits to patients with SCD and TDT, specifically driving early and robust correction of anemia and sustained increases in fetal hemoglobin.

For additional information regarding these clinical data, please see “Business—Our Gene Editing Medicine Programs—Hemoglobinopathies.” We expect to provide further clinical data updates for both the RUBY and EdiTHAL trials in mid-2024 and by year-end 2024.

We believe that our unique editing approach, and the data to date from the RUBY trial, support potential differentiation of our reni-cel experimental medicine.

The CRISPR nuclease used in the program is a proprietary high fidelity, highly specific, engineered AsCas12a enzyme for which we have exclusively licensed the foundational intellectual property to develop and commercialize human therapeutics.

This enzyme has demonstrated high efficiency editing of multipotent long-term HSCs for sustained efficacy and durability.

Its use to target the HBG1 and HBG2 promoters to mimic naturally occurring human mutations, analogous to patients with naturally occurring hereditary persistence of fetal hemoglobin, is potentially a more effective approach with better long-term safety than other editing targets and mechanisms.

In particular, based on the clinical data to date from our reni-cel trials, in which we have seen correction of anemia, we believe that sustained, normal levels of total hemoglobin could be an important point of differentiation.

Chronic anemia significantly reduces the quality of life in patients and is a risk factor for end organ damage.

In vivo Medicines

We are also pursuing the development of next generation in vivo administered gene editing medicines, in which the medicine is injected or infused into the patient to edit the cells inside their body.

Leveraging our differentiated approach from our reni-cel program, we are initially focused on editing HSCs through targeted delivery of our AsCas12a enzyme to our clinically validated HBG1 and HBG2 promotor site.

The myeloablative busulfan conditioning regimen for HSC transplantation that is necessary for current gene editing therapies for SCD and TDT requires that patients undergo immunosuppression at the time of transplant and carries with it the long-term burdens of infertility and oncogenesis.

Because of the broad nature of this platform, we believe we can create gene editing molecules for more than 95% of the human genome.

We seek to be a leader in in vivo programmable gene editing, leveraging cutting edge gene editing technology to deliver therapies that simplify the usability for patients, minimize the burdens to patients and healthcare systems, and are meaningfully differentiated from the current standards of care, while also allowing a simpler, more scalable manufacturing process that can reduce costs to manufacture and administer the therapies relative to ex vivo treatments.

Our approach is focused on the in vivo use of functional upregulation, which aims to increase the expression of a normal gene copy and thereby increases its normal protein function to treat diseases caused by genetic mutations that eliminate or disrupt normal function.

We are able to upregulate by editing regulatory sequences upstream and downstream of a gene, which allows us to address those diseases where the gene knockdown approach, which aims to reduce the expression of one or more targeted genes, will not be effective.

Further, upregulation enables us to create treatments designed for most or all patients with the same disease, regardless of the specific genetic mutation causing the disease.

We previously demonstrated proof of concept of our functional upregulation strategy in our clinical trials of renizgamglogene autogedtemcel (“reni-cel”), an experimental ex vivo gene-edited medicine to treat sickle cell disease (“SCD”), a severe inherited blood disease that causes premature death, and transfusion-dependent beta thalassemia (“TDT”), the most severe form of beta-thalassemia, an inherited blood disorder characterized by severe anemia.

In our former reni-cel program, we used our indel CRISPR technology to upregulate the expression of the gamma globin gene, a functional homolog of the beta globin gene, through direct editing of the HBG1/2 promotor site using our highly specific and efficient proprietary engineered AsCas12a enzyme.

While we are no longer developing reni-cel, clinical data from our reni-cel program demonstrated that we can efficiently and specifically edit hematopoietic stem cells (“HSCs”), resulting in robust and clinically meaningful improvements for treated patients and a safety profile consistent with myeloablative busulfan conditioning and autologous HSC transplant.

We believe the ability to provide in vivo gene editing, in which the medicine is injected or infused into the patient to edit the cells inside their body, and functionally upregulate normal gene expression and normal protein function in the target tissues holds the potential to significantly expand the addressable therapeutic possibilities of CRISPR-based gene editing.

To that end, our preclinical efforts are also focused on the creation of a “plug ‘n play” lipid nanoparticle (“LNP”) platform to enable delivery of the gene editing cargo to multiple cells and tissues, including HSCs, the liver and other cells and tissues.

In October 2024, we shared our achievement of in vivo preclinical proof of concept of hematopoietic stem and progenitor cell (“HSPC”) editing and fetal hemoglobin (“HbF”) induction in humanized mice engrafted with human HSCs and lacking their own hematopoietic cells using a novel and proprietary targeted LNP (“tLNP”) formulation for non-liver, referred to as extrahepatic, tissue delivery.

Building on this achievement, in January 2025, we announced in vivo preclinical proof of concept of editing HSCs in non-human primates, a key step in developing a treatment for SCD and TDT.

We further announced in vivo delivery to two additional extrahepatic cell types in humanized mice using our proprietary lipid nanoparticle (“LNP”) targeting platform and in vivo editing of liver cells in non-human primates.

We expect to share additional in vivo preclinical proof of concept data in both HSCs and liver cells in 2025.

Preclinical Development

Leveraging our differentiated approach from our former reni-cel program, we are focused on editing HSCs through targeted delivery of our AsCas12a enzyme to our clinically validated HBG1 and HBG2 promotor site.

The myeloablative busulfan conditioning regimen for ex vivo HSC transplantation that is necessary for current gene editing therapies for SCD and TDT requires that patients undergo immunosuppression at the time of transplant and carries with it the long-term burdens of infertility and oncogenesis.

By editing HSCs directly in patients without transplantation, no myeloablative conditioning is required, thereby avoiding the adverse effects associated with current HSC transplantation protocols.

We believe such a product could be used in multiple different healthcare settings with a much lower burden on patients and treatment sites.

Beyond hemoglobinopathies, our discovery and development efforts are focused on in vivo gene editing medicines in other organs and tissues, with the goal of selecting therapeutic targets we believe have a significant probability of technical, clinical, regulatory, and commercial success.

In 2023, we strengthened and focused our discovery organization to build an in vivo gene editing pipeline, and are on track to establish in vivo preclinical proof-of-concept for an undisclosed indication by year-end 2024.

Business Development

We are pursuing the right combination of gene editing and targeted delivery tools through internal development and the in-licensing of complementary technologies, while also leveraging our intellectual property portfolio to drive potential out-licensing and partnership discussions that can accelerate the achievement of our goal of delivering lifesaving medicines to patients with previously untreatable diseases.

In December 2023, we and Vertex Pharmaceuticals Incorporated (“Vertex”) entered into a license agreement, under which Vertex obtained a non-exclusive license for our Cas9 gene editing technology for ex vivo gene editing medicines targeting the BCL11A gene in the fields of sickle cell disease and transfusion-dependent beta thalassemia, including Vertex’s CASGEVY TM (exagamglogene autotemcel).

We received a $50.0 million upfront cash payment and are eligible to receive an additional $50.0 million contingent upfront payment.

We are also eligible to receive annual license fees, ranging from $10.0 million to $40.0 million annually, inclusive of certain sales-based annual license fee increases, through 2034.

We believe such a product could be used in multiple types of healthcare settings with a much lower burden on patients and treatment sites, potentially enabling the treatment of larger patient populations around the world.

We are on track to declare a development candidate in HSCs for the in vivo treatment of SCD and TDT in mid-2025.

Our discovery and development efforts are also focused on in vivo gene editing medicines in liver cells and other tissues, with the goal of selecting therapeutic targets we believe have a significant probability of technical, clinical, regulatory, and commercial success.

We are on track to declare a development candidate for an in vivo gene editing medicine in liver cells for an undisclosed indication in mid-2025 and to establish and disclose an extrahepatic, non-HSC target cell type or tissue by the end of 2025.

In January 2025, we announced our strategic priorities through 2027, aimed to deliver transformative in vivo gene editing medicines for people living with serious diseases around the world.

Specifically, we aim to:

Launch clinical trials for multiple in vivo programs , including submitting at least one investigational new drug application or clinical trial application by mid-2026, beginning human trials by the second half of 2026, and initiating at least one late-stage clinical trial in the second half of 2027;

Achieve human in vivo proof of concept in at least one indication by the end of 2026 , validating our in vivo upregulation strategy in humans;

Expand the range of diseases addressable by in vivo gene upregulation , including announcing in vivo proof of concept in at least one additional tissue beyond HSCs and the liver by 2027, demonstrating the “plug ‘n play” potential of our proprietary extrahepatic LNP platform.

Licensing and Business Development

We are pursuing the right combination of gene editing and targeted delivery tools through internal development and the in-licensing of complementary technologies to build our preclinical pipeline and accelerate the achievement of our goal of delivering lifesaving medicines to patients with previously untreatable diseases.

For example, in 2024 we secured a collaboration and license agreement accessing LNPs targeting the liver in support of our strategy to upregulate certain liver targets, including our first undisclosed liver upregulation target.

We are also evaluating technologies as part of a “plug ‘n play” in vivo gene editing LNP delivery platform designed to allow the rapid development of new medicines for extrahepatic tissues.

We are also leveraging our gene editing technology in areas outside of our core focus through partnerships and collaborations.

For example, in cellular therapy medicines, we are leveraging partnerships to progress engineered cell medicines to treat various cancers.

We are advancing alpha-beta T-cell experimental medicines for the treatment of solid and liquid tumors in collaboration with Bristol Myers Squibb Company (“BMS”) through its wholly owned subsidiary, Juno Therapeutics, Inc.

(“Juno Therapeutics”).

This collaboration, which leverages our Cas9 and AsCas12a platform technologies, has resulted in 14 total programs.

We are also party to a non-exclusive collaboration and licensing agreement with Immatics to combine gamma-delta T cell adoptive cell therapies and gene editing for the treatment of cancer.

In January 2023, we sold our preclinical multiplexed edited induced human pluripotent stem cell -derived natural killer (“iNK”) cell medicine for the treatment of solid tumors, as well as an additional iNK program under development and certain related manufacturing technologies, to Shoreline Biosciences, Inc., and granted Shoreline a non-exclusive license to our gene editing technology to develop allogeneic gene editing natural killer cell medicines.

In addition, we are leveraging our intellectual property portfolio to drive potential out-licensing opportunities that can provide non-dilutive capital or more broadly enable programs to more rapidly move towards commercialization and benefit patients.

editing medicines targeting the BCL11A gene in the fields of SCD and TDT, including Vertex’s CASGEVY TM (exagamglogene autotemcel).

We received a $50.0 million upfront cash payment in the fourth quarter of 2023 and the 2024 annual license fee of $10.0 million in the first quarter of 2024.

The license agreement further provides for the payment by Vertex of a potential additional $50.0 million contingent upfront payment and further future fixed and sales-based annual license fees, ranging from $10.0 million to $40.0 million annually, inclusive of certain sales-based annual license fee increases, through 2034.

We are required to pay The Broad Institute, Inc.

(“Broad”) and the President and Fellows of Harvard College (“Harvard”) a mid-double-digit percentage of amounts received from Vertex under the license agreement as it relates to Cas9 technology licensed by us from Broad and Harvard.

(“Broad”) and the President and Fellows of Harvard College (“Harvard”) a mid-double-digit percentage of amounts payable to us from Vertex under the license agreement as it relates to Cas9 technology licensed by us from Broad and Harvard.

In October 2024, we entered into an agreement (the “DRI Agreement”) with a wholly owned subsidiary of DRI Healthcare Trust (“DRI”) providing for an upfront cash payment by DRI to us of $57.0 million in exchange for the acquisition by DRI of up to 100% of certain of the annual license fees owed to us under the Vertex license agreement, which fees range from $5.0 million to $40.0 million per year (inclusive of certain sales-based annual license fees that may become due), and a mid-double-digit percentage of the $50.0 million contingent upfront payment, in each case after subtracting amounts owed by us to Broad and Harvard.

We have retained rights to our portions of certain other sales-based annual license fees and the contingent upfront payment that may become due under the license agreement with Vertex, and the amounts that correspond to our licensor obligations.

In August 2023, we entered into a license agreement with Vor Biopharma Inc.

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Under this agreement, we received an upfront payment and are eligible for future development, regulatory and commercial milestone payments, as well as royalties on medicines utilizing the related intellectual property.

In cellular therapy medicines, we are leveraging partnerships to progress engineered cell medicines to treat various cancers.

(“Juno Therapeutics”).

This collaboration, which leverages our Cas9 and AsCas12a platform technologies, has resulted in 13 total programs.

We have also entered into a non-exclusive collaboration and licensing agreement with Immatics N.V.

to combine gamma-delta T cell adoptive cell therapies and gene editing to develop medicines for the treatment of cancer.

Our Core Capability — Gene Editing

Gene editing is the process of revising, removing, or repairing defective DNA in situ .

In general, gene editing corrects the defective DNA in its native genomic location, and consequently the repaired genetic region retains the cell’s normal control and feedback mechanisms.

In general, gene editing repairs the defective DNA in its native genomic location, and consequently the repaired genetic region retains the cell’s normal control and feedback mechanisms.

Gene editing typically takes advantage of naturally occurring DNA repair mechanisms, including non-homologous end joining (“NHEJ”) and homology directed repair (“HDR”), to achieve its desired therapeutic outcome.

Edits that are repaired by NHEJ typically disrupt a gene or eliminate a disease-causing mutation.

Edits that are repaired by NHEJ typically result in an insertion or deletion (indel) that can disrupt a regulatory sequence to functionally upregulate normal gene expression and normal protein function.

Edits that are repaired by HDR, including targeted insertion, aim to correct or replace aberrant DNA sequences.

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This ability to target multiple DNA sequences expands the applicability of CRISPR technology and also creates the potential for self-regulating systems that control exposure to the editing machinery.

To address more than one target, other gene editing technologies require the engineering, characterization, manufacture, and delivery of distinct nuclease proteins for each target.

To address more than one

target, other gene editing technologies require the engineering, characterization, manufacture, and delivery of distinct nuclease proteins for each target.

• Ability to achieve a range of different types of edits.

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Firstly, a lower molecular weight enzyme will have advantages for delivering the endonuclease using a viral vector due to the inherent size limitations of most such delivery systems.

For example, the Cas9 enzyme from SaCas9 is significantly smaller than that from Streptococcus pyogenes (“ S.

For example, the Cas9 enzyme from Staphylococcus aureus Cas9 is significantly smaller than that from Streptococcus pyogenes (“ S.

pyogenes ” or “SpCas9”) (3,159 vs.

4,104 base pairs), and this decreased size is

important when working with adeno-associated viral vectors (“AAV”) as a delivery vector, which has an effective packaging limit of approximately 4,700 base pairs.

4,104 base pairs), and this decreased size is important when working with adeno-associated viral vectors (“AAV”) as a delivery vector, which has an effective packaging limit of approximately 4,700 base pairs.

Secondly, we have gained access to modified versions of Cas12a and Cas12a guide RNAs that increase Cas12a activity.

This increased activity may allow us to use Cas12a editing in more indications where editing at a Cas12a susceptible site is desirable from a biological perspective but technically difficult with the wild-type Cas12a editing system.

Reni-cel for SCD and TDT is one such example.

Thirdly, identifying Cas9 and Cas12a enzymes with different editing properties will expand the number of potential editing sites in the human genome.

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The guide RNA molecule is another component of our gene editing platform.

We seek to use reprogrammable guide RNA in which changing the targeting region of the guide RNA can create a new product for a new disease target, thus enabling the rapid development of new medicines.

We have made substantial advances in the design, synthesis, modification, analysis, and characterization of guide RNAs.

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Our strategy is to leverage existing delivery technologies to target cell types of interest while developing next generation capabilities as warranted.

We have developed a variety of delivery approaches, including electroporation for efficient delivery to blood cells ex vivo , lipid nanoparticles for non-viral in vivo delivery, and AAVs for in vivo viral delivery.

We have made substantial advances in the ex vivo delivery of CRISPR systems to a number of cell types.

We have been able to demonstrate greater than 90% ex vivo editing in HSCs using ribonucleoprotein complexes, which consist of the Cas9 or Cas12a endonuclease complexed with its guide RNA.

These results are consistent across multiple cell donors and multiple target genes.

In addition, we have taken advantage of the smaller S.

aureus Cas9 and existing AAV technology to construct an “all-in-one” viral vector that is able to deliver the DNA coding for the nuclease protein and one or two guide RNAs directly to cells, which we believe has substantial advantages for manufacturing and delivery compared to approaches that rely on multiple vectors.

To optimize the specificity of our product candidates, there are a number of different aspects of the product configuration that we customize in addition to the sequence and quality of the guide RNA, including the length of the guide RNA, the type of Cas9 or Cas12a enzyme, including engineered forms, the delivery vector, the use of tissue-selective promoters, and the duration of exposure, all of which contribute to overall specificity.

We have developed a variety of delivery approaches, including lipid nanoparticles for non-viral in vivo delivery, AAVs for in vivo viral delivery, and electroporation for efficient delivery to blood cells ex vivo for our former reni-cel program.

We have made substantial advances in the in vivo delivery of CRISPR systems to a number of cell types.

Using a novel tLNP platform and HSC targeting strategy, we have achieved in vivo HSPC editing at a level of 29% and HSC editing of approximately 40% after a single dose in a humanized mouse model.

Subsequently, our initial non-human primate study, which used one of our optimized tLNPs, resulted in delivery of the GFP reporter to to 75% of HSCs and achieved on average 17% HBG1/2 allelic editing after a single dose.

By substituting different targeting ligands conjugated to the tLNP, we expect our proprietary tLNP platform to enable specific targeting of different cell types.

In addition, using a separate LNP platform for liver delivery, in a non-human primate study, we achieved editing of approximately 65%, near the theoretical maximum liver editing of 70%, reflecting efficient editing of hepatocytes, with negligible editing in non-target tissues using our AsCas12a enzyme and a liver LNP.

To date, we have achieved in vivo delivery to two extra-hepatic, non-HSC cells in humanized mice.

To optimize the specificity of our product candidates, there are a number of different aspects of the product configuration that we customize in addition to the sequence and quality of the guide RNA, including the length of the guide RNA, the type of Cas9 or Cas12a enzyme, including engineered forms, the delivery vector, including targeting moiety, and the duration of exposure, all of which contribute to overall specificity.

Our Gene Editing Medicine Programs

Our research and development efforts are focused on hemoglobinopathies and developing next generation in vivo medicines, including in vivo editing of HSCs and other organs and tissues.

Our research and development efforts are focused on next generation in vivo medicines, including in vivo editing of HSCs, liver cells and other tissues.

Our product development strategy is to target diseases where gene editing can be used to enable or enhance therapeutic outcomes for patients, while maximizing probability of technical, clinical, regulatory and commercial success.

We believe the therapeutic programs and delivery technologies we have chosen to pursue to date and those that are currently under development will demonstrate the depth

and breadth of our ability to deploy our genome editing platform to develop differentiated, transformational medicines for previously untreatable diseases.

The following summarizes our product candidates, research programs and disease areas:

Ex vivo Hemoglobinopathies

We are developing an approach for gene editing in HSCs to support the advancement of research programs to treat non-malignant hematological diseases.

Our most advanced program, reni-cel, is an ex vivo gene editing medicine designed to treat SCD and TDT.

We believe the therapeutic programs and delivery technologies we have chosen to pursue to date and those that are currently under development will demonstrate the depth and breadth of our ability to deploy our genome editing platform to develop differentiated, transformational medicines for previously untreatable diseases.

The following summarizes our research programs and disease areas:

Hemoglobinopathies

We are developing an approach for in vivo gene editing in HSCs to support the advancement of research programs to treat non-malignant hematological diseases.

Our initial focus is on the development of therapies to treat SCD and TDT.

Sickle cell disease is an inherited life-threatening hematological disorder, which starts to cause serious complications in early childhood.

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We are actively pursuing a distinct gene editing approach to treating these hemoglobinopathies.

Our desired attributes in reni-cel include rapid correction of anemia to normal physiological hemoglobin levels, fetal hemoglobin (“HbF”) levels in excess of 40%, a safety profile consistent with myeloablative busulfan conditioning and autologous hemopoietic or CD34+ stem cell transplant, and all treated SCD patients free of vaso-occlusive events (“VOEs”) and all treated TDT patients achieving transfusion independence.

To this end, we have developed reni-cel, an experimental, autologous gene editing medicine that uses our novel AsCas12a gene editing nuclease to target the HBG1/2 promoter in human CD34+ cells and disrupt the binding site of the BCL11A, consistent with observed naturally occurring human mutations.

We aim to use our AsCas12a gene editing nuclease to target the HBG1/2 promoter of the gamma-globin gene in human CD34+ cells and disrupt the binding site of the BCL11A, consistent with observed naturally occurring human mutations.

These mutations mimic the asymptomatic condition of hereditary persistence of fetal hemoglobin (“HPFH”) with high levels of HbF in red blood cells.

HbF levels greater than 30% are associated with a significant reduction in, or the absence of, SCD symptoms, particularly VOEs.

By editing the HBG1/2 promoter in the beta-globin gene, we seek to generate protective changes that increase HbF production in a manner that is independent of erythropoietic stress, resulting in reduced sickling and VOEs in SCD patients, and resolving anemia and transfusion dependence in TDT patients.

Reni-cel is the first experimental medicine in development generated using CRISPR/Cas12a (also known as Cpf1) gene editing.

We have focused our efforts on editing a site within the beta-globin locus that we believe has the potential to create superior expression of HbF since patients with elevated HbF levels have better clinical outcomes.

We believe that

reni-cel has the potential to impact beta-globin expression by increasing HbF and decreasing sickle globin.

In particular, our preclinical data shows that editing the HBG1/2 promotor in human CD34+ cells results in greater red blood cell production, normal proliferative capacity, and improved red blood cell health when compared to editing the BCL11A erythroid enhancer (“BC11Ae”).

Likewise, we believe our approach will reduce the sickle globin and, therefore, not have to compete for alpha globin in the same cell unlike lentiviral gene therapy approaches.

Our preclinical studies identified the potential that BC11Ae might result in deleterious lineage skewing when editing the BCL11Ae locus.

Finally, gene editing is more specific than lentiviral expression.

HbF levels greater than 30% are associated with a significant reduction in, or the absence of, SCD symptoms, particularly vaso-occlusive events (“VOEs”).

By editing the HBG1/2 promoter in the gamma-globin gene, we seek to

generate protective changes that increase HbF production in a manner that is independent of erythropoietic stress, resulting in reduced sickling and VOEs in SCD patients, and resolving anemia and transfusion dependence in TDT patients.

We have focused our efforts on editing a site within the beta-globin locus, which includes the gamma-globin gene, that we believe has the potential to create superior expression of HbF since patients with elevated HbF levels have better clinical outcomes.

We believe that beta-globin expression can be impacted by increasing HbF and decreasing sickle globin.

In particular, our preclinical data shows that editing the HBG1/2 promotor of the gamma-globin gene in human CD34+ cells results in greater red blood cell production when compared to editing the BCL11A erythroid enhancer (“BC11Ae”) in the BCL11a gene.

Our preclinical studies thereby identified the potential that editing the BC11Ae locus might result in deleterious lineage skewing.

Our preclinical studies also demonstrated that editing the HBG1/2 promotor in human CD34+ cells results in greater HbF expression in erythroid lineage progeny when compared to editing the BCL11Ae.

Likewise, we believe our approach will reduce the sickle globin and, thereby not worsen alpha/beta globin chain imbalance as has been reported with lentiviral gene therapy in patients with SCD and alpha-thalassemia trait.

To get the high levels of beta-globin required for an efficacious therapy, there will be cells in the CD34+ population, which are cells that contain the long-term stem cells that repopulate the hematopoietic lineages, that carry more than twenty copies of the viral genome.

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As such, we believe our approach to editing the beta-globin locus provides the highest likelihood of providing clinical benefit in patients while minimizing potential safety risks.

In addition to our selection of the HBG1/2 promoter as our target, we believe that our use of AsCas12a, our proprietary, high-fidelity, high-specificity CRISPR nuclease, in reni-cel potentially provides patients with better clinical outcomes than those gene editing medicines using a Cas9 enzyme.

In addition to our selection of the HBG1/2 promoter as our target, we believe that our use of AsCas12a, our highly specific and efficient proprietary engineered CRISPR nuclease, potentially provides patients with better clinical outcomes than those gene editing medicines using a Cas9 enzyme.

AsCas12a has demonstrated superior characteristics that increase the efficiency of editing and significantly reduce off-target editing when compared to other CRISPR nucleases, including Cas9.

When combined with our comprehensive off-target assessment, which uses multiple statistically independent methods, including in silico, biochemical, and cellular, followed by a verification of candidate sites, our use of the high-specificity AsCas12a enzyme should provide high editing efficiency and low off-target editing, thereby delivering on our desired attributes for reni-cel.

Reni-cel has been granted a number of regulatory designations from the FDA, specifically Orphan Drug and Rare Pediatric Disease designations for the treatment of both SCD and TDT, and regenerative medicine advanced therapy (“RMAT”) designation for severe SCD.

For additional information regarding these and certain other drug designations in the United States, see the section entitled, “Business — Government Regulation and Licensure of Products.”

Preclinical studies

Using our approach in preclinical studies, we tested the ability of CD34+ cells obtained from healthy donors and edited at the beta-globin locus to induce fetal hemoglobin.

As predicted from our preclinical in vitro studies, editing at the beta-globin site with Cas12a caused a robust, pancellular induction of HbF of approximately 45% above the background levels.

We also tested CD34+ cells obtained from sickle cell patients, which we edited at the beta-globin locus.

These studies showed that editing was highly efficient and reproducible, with approximately 90% editing in multiple sickle patient donors.

We found that reni-cel derived red blood cells had more than 50% HbF expression.

Further, reni-cel derived red blood cells had a significant improvement in deformability, which could aid red blood cell transit without sickling, and a four-fold decrease in sickling, when subjected to reduced oxygen levels compared to unedited control cells.

These data suggest reni-cel can provide potential clinical benefit for sickle patients.

In vivo studies revealed editing was highly efficient with greater than 90% editing in bone marrow cells from mice infused with edited CD34+ cells 16 weeks post-infusion.

In these mice, HbF expression was increased by approximately 50% in the red blood cells derived from these edited cells.

We also observed that approximately 90% of these cells were HbF positive, demonstrating that HbF expression was pan-cellular, which we believe is likely a critical property for potential clinical benefit.

For these reasons, we believe our approach of editing the hemoglobin locus to increase HbF has the potential to generate differentiated medicines to benefit patients with sickle cell disease and TDT.

Clinical trials

We are investigating reni-cel in two ongoing single-arm, open-label, multi-center clinical trials that are designed to assess the safety and efficacy of a single dose of reni-cel in patients with severe SCD, the Phase 1/2/3 RUBY trial, and TDT, the Phase 1/2 EdiTHAL trial.

Through February 28, 2024, we have enrolled 40 patients and dosed 18 patients in the RUBY trial .

We continue to enroll and dose patients in the adult cohort of the RUBY trial, with multiple patients scheduled for dosing.

We hav e also initiated enrollment in the adolescent cohort.

Through February 28, 2024, we have enrolled 9 patients and dosed 7 patients in the EdiTHAL trial, and continue to enroll and dose patients.

RUBY Trial in Severe SCD

In December 2023, we presented new safety and efficacy data in 11 patients treated with reni-cel in the RUBY trial as of the November 2023 cutoff.

All 11 patients are homozygous severe SCD, and during the two years prior to enrolling in the RUBY trial patients had a mean annual rate of severe VOEs of 4.0.

The mean follow-up period for the RUBY patients following reni-cel treatment was 6.5 months, with the first two patients having had 17- and 14- months of follow-up, respectively.

All 10 patients with greater than one month of follow-up had successful neutrophil and platelet engraftment after reni-cel dosing, with neutrophil engraftment within a month and platelet engraftment within 1.5 months.

None of the treated RUBY patients experienced any VOEs after reni-cel infusion and all remained VOE-free as of their last visit.

The six patients with five or more months follow-up maintained a normal hemoglobin level and a fetal hemoglobin level of greater than 40%, above the 30% threshold considered clinically meaningful for the reduction or elimination of SCD symptoms, particularly VOEs.

All 10 patients treated in the RUBY trial with more than one month of follow-up followed a similar trajectory of total hemoglobin and fetal hemoglobin increases.

Reni-cel was well-tolerated by all 11 patients and demonstrated a safety profile consistent with myeloablative conditioning with busulfan and autologous HSC transplant.

No serious adverse events related to reni-cel treatment were reported after reni-cel infusion.

We expect to provide clinical data updates for the RUBY trial in mid-2024 and by year-end 2024.

EdiTHAL Trial in TDT

In December 2023, we presented new safety and efficacy data in six patients treated with reni-cel in the EdiTHAL trial as of the November 2023 cutoff.

The mean follow-up period for the EdiTHAL patients following reni-cel treatment was 4.1 months, with follow-up periods ranging from one to eight months, and four patients with at least three months of follow-up.

All six patients had successful neutrophil and platelet engraftment after reni-cel dosing.

The five patients with more than one month follow-up demonstrated early and robust total hemoglobin and fetal hemoglobin increases, with total hemoglobin rising above the transfusion independence threshold of 9 g/dL.

The increased total hemoglobin level was driven by the rapid and robust increase of HbF expression.

After reni-cel infusion, the mean HbF levels increased to 9.4 g/dL at month four and remained high over the follow-up period.

These data show that hemoglobin and HbF fractions increase at a trajectory similar to RUBY patients at the same time points.

Reni-cel was well-tolerated by all six patients and demonstrated a safety profile consistent with myeloablative conditioning with busulfan and autologous HSC transplant.

No serious adverse events related to reni-cel treatment were reported after reni-cel infusion.

We expect to provide clinical data updates for the EdiTHAL trial in mid-2024 and by year-end 2024.

In Vivo Gene Editing Medicines

We seek to additionally develop targeted in vivo gene editing medicines, initially focused on HSCs but expanding to other organs and tissues in the future.

The clinical data from our ex vivo reni-cel program demonstrated successful hemoglobin induction, creating a foundation for development of in vivo HSC gene editing medicines.

We believe that the ability to edit HSCs directly in patients without transplantation will allow the treatment of larger patient populations due to the elimination of the current myeloablative conditioning requirement, enabling access to such a product across health systems with a lower burden on patients and treatment centers.

Business Development

We are focused on driving solutions for people living with serious, previously untreatable diseases by leveraging our gene editing platform – in the form of developing our own clinically differentiated medicines and in the form of licenses and sublicenses to other pharmaceutical and biotechnology companies developing medicines.

Strategic partnerships are a key component of our strategy, allowing us to access capabilities and resources in support of our therapeutic programs.

Further, as the exclusive licensee of Broad’s Cas12a patent estate and Broad and Harvard’s Cas9 patent estates for human medicines, we actively seek opportunities to out-license and partner our robust intellectual property portfolio to accelerate the development and commercialization of CRISPR/Cas9- and Cas12a-based products in multiple therapeutic areas.

We have, and continue to seek, parties for exclusive and non-exclusive licenses to expand the reach of our foundational intellectual property and enable the development of transformative medicines for a broader patient population.

Prior to the discontinuation of the clinical development of reni-cel, our experimental ex vivo gene editing medicine previously under investigation for the treatment of SCD and TDT, we investigated reni-cel in a single Phase 1/2/3 clinical trial, referred to as the RUBY trial, for the treatment of severe SCD and in a Phase 1/2 clinical trial for the treatment of TDT, referred to as the EdiTHAL trial.

We believe the RUBY and EdiTHAL clinical trials of reni-cel validated our distinct gene editing approach to treating hemoglobinopathies.

Reni-cel consists of patient-derived CD34+ HSPCs edited at the gamma globin gene ( HBG1 and HBG2 ) promoters by AsCas12a.

Despite the robust and clinically meaningful improvements observed in these trials, we determined in December 2024 not to pursue commercialization for reni-cel in order to optimize our cost structure and accelerate our intent to achieve in vivo human proof of concept in approximately two years.

Building on our experience with reni-cel, in October 2024, we announced that we achieved in vivo preclinical proof of concept of HBG1/2 editing in HSPC and HbF induction in humanized mice engrafted with human HSPCs and lacking their own hematopoietic cells.

Utilizing an HSC targeting strategy and a novel, Editas-proprietary tLNP for extrahepatic tissue delivery, we achieved an editing level of 29% in HSPCs and 40% in HSCs after a single dose.

Editing with our proprietary tLNP formulation resulted in the functional outcome of HbF induction, indicated by the presence of HbF expressing human red blood cells (on average 20%) that populate in the host by one month.

More recently, in January 2025, we announced new in vivo preclinical proof of concept data in non-human primates editing HSCs.

In this initial non-human primate study , we achieved delivery of the GFP reporter to 75% of HSCs and achieved on average 17% HBG1/2 allelic editing after a single dose, resulting in a mean editing of 17%, near the 20% predicted therapeutically relevant editing threshold based on allogeneic HSC transplant data.

We are currently evaluating further optimized tLNP formulations we expect to enable us to achieve therapeutic editing levels.

Liver and Other Cells/Tissues

We seek to additionally develop in vivo gene editing medicines targeted to liver cells and other cells/tissues.

In preclinical studies for an undisclosed liver target, we have achieved an editing level of approximately 65% in non-human primates, near the theoretical maximum liver editing level of 70%, with minimal non-target tissue editing using AsCas12a and a liver targeted LNP.

This editing resulted in robust serum biomarker reduction from the baseline of approximately 80%.

We believe our proprietary targeting LNP platform will enable specific targeting of different extrahepatic cell types by substitution of different targeting ligands conjugated to the LNP.

In preclinical studies, we have demonstrated in vivo proof of concept for this “plug n’ play” LNP delivery platform to two additional cell types beyond HSCs in humanized mice.

Licensing and Business Development

We are focused on driving solutions for people living with serious, previously untreatable diseases by leveraging our gene editing platform.

Through in-licensing of complementary technologies, we can expand our existing gene editing platform and further drive the development of our in vivo pipeline.

This was recently demonstrated with our entry into a collaboration and license agreement to access LNPs targeting the liver.

Using this in-licensed LNP, we achieved in vivo editing of hepatocytes in non-human primates, furthering our strategy to upregulate certain liver targets, including our first undisclosed liver upregulation target.

Further, as the exclusive licensee of Broad and Harvard’s Cas9 patent estates and Broad’s Cas12a patent estate for human medicines, we actively seek opportunities to out-license and partner our robust intellectual property portfolio to drive the development of CRISPR-based medicines in therapeutic areas outside of our core focus and to provide non-dilutive capital.

Examples of these licensing efforts include our non-exclusive license to Vor for the development of ex vivo Cas9 gene-edited HSC therapies for the treatment and/or prevention of hematological malignancies;

our non-exclusive license to Vertex for our Cas9 gene editing technology for ex vivo gene editing medicines targeting the BCL11A gene in the fields of SCD and TDT, including Vertex’s CASGEVY TM (exagamglogene autotemcel);

and our non-exclusive license to Immatics N.V.

of our AsCas12a technology to advance gamma-delta T cell therapies for the treatment of cancer.

and our non-exclusive license to Immatics of our AsCas12a technology to advance gamma-delta T cell therapies for the treatment of cancer.

In our collaboration with BMS, we are researching and developing engineered alpha-beta T cell therapies to treat solid and liquid tumors leveraging our platform technologies, including Cas9 and AsCas12a.

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In May 2015, we entered into a collaboration and license agreement with Juno Therapeutics, a subsidiary of BMS, for the research and development of engineered T cells with CARs and eTCRs that have been genetically modified to recognize and kill other cells.

We and BMS amended and restated this agreement in May 2018 and November 2019 (the “BMS Collaboration Agreement”) and, in connection with the amendment and restatement in November 2019, we entered into a license agreement with BMS (such agreement, the “BMS License Agreement,” and together with the BMS Collaboration Agreement, the “BMS Agreements”).

We and BMS amended and restated this agreement in November 2019 and further amended it in March 2024 (such agreement, as amended and restated to date, the “BMS Collaboration Agreement”).

In connection with the amendment and restatement in November 2019, we entered into a license agreement with BMS (such agreement, the “BMS License Agreement,” and together with the BMS Collaboration Agreement, the “BMS Agreements”).

Under the terms of the BMS Collaboration Agreement, we received an upfront payment of $25.0 million, amendment fees totaling $75.0 million and have received milestone payments totaling $30.0 million, in addition to certain opt-in fees.

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The exploitation of Alpha-beta T Cells and Other Derived T Cells specifically excludes the exploitation of T Cells that express a T cell receptor dimer consisting of a gamma (γ) chain and a delta (δ) chain, which we refer to as gamma-delta T Cells.

During the research term under the BMS Collaboration Agreement, we may research ribonucleoprotein complexes comprising an RNA-guided engineered nuclease paired with an oligonucleotide (“RNP Complexes”) that recognize or modulate the expression of up to twenty gene targets selected by BMS (each, a “Research Program”) for the purpose of

identifying the RNP Complexes that may be used in the creation of potential drug development candidates.

The initial research term is five years from the November 2019 effective date of the BMS Collaboration Agreement.

BMS may extend the research term for up to two one-year periods upon written notice to us and payment to us of a mid to high single digit million-dollar payment upon each extension.

BMS ’ right to extend the research term for the second one-year period is subject to our consent.

Pursuant to the March 2024 amendment, we provided BMS the ability to select up to three additional gene targets for research subject to the payment of a low single digit million-dollar payment for each new target selected.

The research term, as amended, extends to November 2026, with options to extend the collaboration for up to an additional two years under certain circumstances, including the payment of a high single digit million-dollar payment.

Under the BMS Collaboration Agreement, if BMS elects to opt-in with respect to a Research Program, it shall make a mid-six digit dollar payment to us and we shall amend the BMS License Agreement to include such Research Program by executing a licensed program addendum for such Research Program.

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Also, we are required to achieve certain development milestones within specified time periods for products incorporating the technologies covered by the Harvard/Broad Cas9-I Patent Rights.

Harvard and Broad have the right to terminate our license with respect to the Harvard/Broad

Cas9-I Patent Rights covering the technology or technologies with respect to which we fail to achieve these development milestones.

Harvard and Broad have the right to terminate our license with respect to the Harvard/Broad Cas9-I Patent Rights covering the technology or technologies with respect to which we fail to achieve these development milestones.

The licenses granted by Broad and Harvard to us under the Cas9-I License Agreement are subject to retained rights of the U.S.

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This annual license maintenance fee is creditable against royalties owed on licensed products and services in the same year as the maintenance fee is paid.

We are obligated to reimburse Broad and Harvard for expenses associated with the prosecution and maintenance of the Harvard/Broad Cas9-I Patent Rights, including expenses associated with any interference proceedings in the USPTO, any opposition proceedings in the EPO, or any other inter partes or other post grant proceedings in these or other jurisdictions where we are seeking patent protection.

Therefore, we are obligated to reimburse Broad and/or Harvard for expenses associated with the interference and opposition proceedings involving patents licensed to us under this agreement (described in more detail under “Risk Factors—Risks Related to Our Intellectual Property—Some of Our In-Licensed Patents are Subject to Priority and Validity Disputes” in Part I, Item 1A of this Annual Report on Form 10-K).

Broad and Harvard are collectively entitled to receive clinical and regulatory milestone payments totaling up to $14.8 million in the aggregate per licensed product approved in the United States, the European Union and Japan for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

Patent and Trademark Office (“USPTO”), any opposition proceedings in the European Patent Organization, or any other inter partes or other post grant proceedings in these or other jurisdictions where we are seeking patent protection.

Therefore, we are obligated to reimburse Broad and/or Harvard for expenses associated with the interference and

opposition proceedings involving patents licensed to us under this agreement (described in more detail under Part I, Item 1A “Risk Factors—Risks Related to Our Intellectual Property—Some of Our In-Licensed Patents are Subject to Priority and Validity Disputes” of this Annual Report on Form 10-K).

Broad and Harvard are collectively entitled to receive clinical and regulatory milestone payments totaling up to $14.8 million in the aggregate per licensed product approved in the United States, the European Union (the “EU”) and Japan for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

If we undergo a change of control during the term of the Cas9-I License Agreement, these clinical and regulatory milestone payments will be increased by a certain percentage in the mid double-digits.

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We are responsible for the cost of the interference proceeding and appeal with respect to these patents and this patent application.

Broad and Harvard are required to maintain any application or patent within the Harvard/Broad Patents Rights so long as we meet our obligation to reimburse Broad and Harvard for expenses related to prosecution and there is a good faith basis for doing so.

If we cease payment for the prosecution of any Harvard/Broad Patent Right, then any license granted to us with respect to such Harvard/Broad Patent Right will terminate.

Broad and Harvard are required to maintain any application or patent within the Harvard/Broad Cas9-I Patent Rights so long as we meet our obligation to reimburse Broad and Harvard for expenses related to prosecution and there is a good faith basis for doing so.

If we cease payment for the prosecution of any Harvard/Broad Cas9-I Patent Right, then any license granted to us with respect to such Harvard/Broad Cas9-I Patent Right will terminate.

We have the first right, but not the obligation, to enforce the Harvard/Broad Cas9-I Patent Rights with respect to our licensed products so long as certain conditions are met, such as providing Broad and Harvard with evidence demonstrating a good faith basis for bringing suit against a third party.

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Broad and Harvard may terminate the agreement upon a specified period of notice in the event of our uncured material breach, such notice period varying depending on the nature of the breach.

Both Broad and Harvard may terminate the Cas9-I License Agreement immediately if we challenge the enforceability, validity, or scope of any Harvard/Broad Patent Right or assist a third party to do so, or in the event of our bankruptcy or insolvency.

Both Broad and Harvard may terminate the Cas9-I License Agreement immediately if we challenge

the enforceability, validity, or scope of any Harvard/Broad Cas9-I Patent Right or assist a third party to do so, or in the event of our bankruptcy or insolvency.

Neither Broad nor Harvard acting alone has the right to terminate the Cas9-I License Agreement.

However, Broad and Harvard may separately terminate the licenses granted to us with respect to their

respective patent rights upon the occurrence of the same events that would give rise to the right of both institutions acting collectively to terminate the Cas9-I License Agreement.

However, Broad and Harvard may separately terminate the licenses granted to us with respect to their respective patent rights upon the occurrence of the same events that would give rise to the right of both institutions acting collectively to terminate the Cas9-I License Agreement.

The Broad Institute—Cpf1 License Agreement

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and the modification of the tobacco plant with specified exceptions.

Tokyo and the National Institute of Health (“NIH”) are joint owners on certain Cpf1 Patent Rights.

Tokyo and the U.S.

National Institutes of Health (“NIH”) are joint owners on certain Cpf1 Patent Rights.

Broad has only granted a license to us with respect to its interests and to Tokyo’s interests in these U.S.

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Pursuant to the Cpf1 License Agreement, and as of December 31, 2024, we have certain rights under 13 U.S.

patents, 10 pending U.S.

patent applications, five European patents and related validations, six pending European patent applications, and other related patent applications in jurisdictions outside of the United States and Europe.

patents, nine pending U.S.

patent applications, six European patents and related validations, six pending European patent applications, and other related patent applications in jurisdictions outside of the United States and Europe.

We are obligated to use commercially reasonable efforts to research, develop, and commercialize licensed products in the Exclusive Cpf1 Field.

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If a third party requests a license under the Cpf1 Patent Rights for the development and commercialization of a product that would be subject to our exclusive license grant from Broad (a “Cpf1 Third Party Proposed Product Request”), Broad may notify us of such request.

A Cpf1 Third Party Proposed Product Request must be accompanied by a research, development and commercialization plan reasonably satisfactory to Broad, including evidence that the third party has, or reasonably expects to have, access to any necessary intellectual property and funding.

Product”) and we can demonstrate such ongoing efforts to Broad’s reasonable satisfaction, or (ii) if we, directly or through any of our affiliates or sublicensees, wish to do so either alone or with a collaboration partner, and we can demonstrate to Broad’s reasonable satisfaction that we are interested in researching, developing, and commercializing a Cpf1 Licensee Product, that we have a commercially reasonable research, development, and commercialization plan to do so, and we commence and continue reasonable commercial efforts under such plan.

intellectual property and funding.

Broad may not grant a Cpf1 Third Party Proposed Product Request (i) if we, directly or through any of our affiliates, sublicensees, or collaborators are researching, developing, or commercializing a product directed to the same gene target that is the subject of the Cpf1Third Party Proposed Product Request (“Cpf1 Licensee Product”) and we can demonstrate such ongoing efforts to Broad’s reasonable satisfaction, or (ii) if we, directly or through any of our affiliates or sublicensees, wish to do so either alone or with a collaboration partner, and we can demonstrate to Broad’s reasonable satisfaction that we are interested in researching, developing, and commercializing a Cpf1 Licensee Product, that we have a commercially reasonable research, development, and commercialization plan to do so, and we commence and continue reasonable commercial efforts under such plan.

If we, directly or through any of our affiliates, sublicensees, or collaborators, are not researching, developing, or commercializing a Cpf1 Licensee Product nor able to develop and implement a plan reasonably satisfactory to Broad, Broad may grant an exclusive or non-exclusive license to the third party on a gene target-by-gene target basis.

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If we, directly or through any of our affiliates, sublicensees, or collaborators, are not researching, developing, or commercializing a product directed toward the gene target designated by Broad and are not able to develop and implement a plan reasonably satisfactory to Broad, Broad is entitled to reserve all rights under the Cpf1 License Agreement, including the right to grant exclusive or non-exclusive licenses to third parties, to develop and commercialize products directed to such gene target, our license with respect to such gene target will terminate, and we will not be entitled under the Cpf1 License Agreement to develop and commercialize products directed to such gene target.

Under the Cpf1 License Agreement, we paid Broad and Wageningen an aggregate upfront license fee in the mid seven digits and issued to Broad and Wageningen promissory notes (the “Initial Promissory Notes”) in an aggregate principal amount of $10.0 million, which we settled in full in 2017.

Broad and Wageningen are collectively entitled to receive clinical and regulatory milestone payments totaling up to $20.0 million in the aggregate per licensed product approved in the United States, the European Union and Japan for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

Under the Cpf1 License Agreement, Broad and Wageningen are collectively entitled to receive clinical and regulatory milestone payments totaling up to $20.0 million in the aggregate per licensed product approved in the United States, the EU and Japan for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

If we undergo a change of control during the term of the Cpf1 License Agreement, certain of these clinical and regulatory milestone payments will be increased by a certain percentage in the mid double-digits.

We are also obligated to make additional payments to Broad and Wageningen, collectively, of up to an aggregate of $54.0 million upon the occurrence of certain sales milestones per licensed product for the prevention or treatment of a human disease that afflicts at least a specified number of patients in the aggregate in the United States.

Broad and Wageningen are collectively entitled to receive clinical and regulatory milestone payments totaling up to $6.0 million in the aggregate per licensed product approved in the United States, the European Union and Japan for the prevention or treatment of an ultra-orphan disease.

Broad and Wageningen are collectively entitled to receive clinical and regulatory milestone payments totaling up to $6.0 million in the aggregate per licensed product approved in the United States, the EU and Japan for the prevention or treatment of an ultra-orphan disease.

We are also obligated to make additional payments to Broad and Wageningen, collectively, of up to an aggregate of $36.0 million upon the occurrence of certain sales milestones per licensed product for the prevention or treatment of an ultra-orphan disease.

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If we sublicense any of the Cpf1 Patent Rights to a third party, Broad and Wageningen, collectively, had the right to receive high single-digit to low double-digit percentages of the sublicense income, which percentage decreased to a high single-digit percentage in 2022 for sublicenses executed thereafter.

Under the Cpf1 License Agreement, Broad and Wageningen are also entitled, collectively, to receive success payments in the event our market capitalization reaches specified thresholds ascending from a high nine digit dollar amount to $10.0 billion (“Market Cap Success Payments”) or sale of our company for consideration in excess of those thresholds, (“Company Sale Success Payments,” which with the Market Cap Success Payments, the “Success Payments”).

Success Payments are payable by us in cash, in shares of our common stock, with such shares being valued for such purpose at the closing price of our common stock as reported the Nasdaq Stock Market for the trading day immediately preceding the date of such payment if our common stock was then listed on the Nasdaq Stock Market, or in the form of promissory notes (the “Promissory Notes”).

(“Company Sale Success Payments,” which with the Market Cap Success Payments, the “Success Payments”).

Market Cap Success Payments are payable by us in cash, in shares of our common stock, with such shares being valued for such purpose at the closing price of our common stock as reported the Nasdaq Stock Market for the trading day immediately preceding the date of such payment if our common stock was then listed on the Nasdaq Stock Market, or in the form of promissory notes (the “Promissory Notes”).

The Promissory Notes bear interest at 4.8% per annum.

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Other Broad Agreements

In addition to the Cas9-I License Agreement and the Cpf1 License Agreement, in December 2016, we entered into a license agreement with Broad for certain Cas9 compositions of matter and their use for gene editing, which was amended in January 2021 and February 2024 (as amended, the “Cas9-II Agreement”), and, in June 2018, we entered into a

Sponsored Research Agreement with Broad providing for Broad to conduct research useful or relevant to genome editing in the field of genomic medicines for the prevention of treatment of human diseases with funding from us, which was amended in January 2021 (as amended, the “Sponsored Research Agreement”).

Under the Cas9-II Agreement and the Sponsored Research Agreement, we have potential obligations with respect to success payments, which are described in Note 8 to the Notes to Consolidated Financial Statements included in Item 8 of this Annual Report on Form 10-K.

in January 2021 and February 2024 (as amended, the “Cas9-II Agreement”), and, in June 2018, we entered into a Sponsored Research Agreement with Broad providing for Broad to conduct research useful or relevant to genome editing in the field of genomic medicines for the prevention of treatment of human diseases with funding from us, which was amended in January 2021 (as amended, the “Sponsored Research Agreement”).

Intellectual Property

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In addition, our trade secrets may otherwise become known or be independently discovered by competitors.

For more information regarding the risks related to our intellectual property, please see “Risk Factors—Risks Related to Our Intellectual Property.”

For more information regarding the risks related to our intellectual property, please see Part I, Item 1A “Risk Factors—Risks Related to Our Intellectual Property” of this Annual Report on Form 10-K

The term of individual patents depends upon the legal term for patents in the countries in which they are granted.

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patents, 74 pending U.S.

non-provisional patent applications, 16 European patents and related validations, 62 pending European patent applications, four pending U.S.

provisional patent applications, nine pending PCT patent applications, and other related patent applications in jurisdictions outside the United States and Europe that are related to our CRISPR technology and which include claims directed to our genome editing platform, including our directed editing component, as well as composition of matter and method of use claims for our

therapeutic programs.

non-provisional patent applications, 21 European patents and related validations, 67 pending European patent applications, 12 pending U.S.

provisional patent

applications, eight pending Patent Cooperation Treaty (“PCT”) patent applications, and other related patent applications in jurisdictions outside the United States and Europe that are related to our CRISPR technology and which include claims directed to our genome editing platform, including our directed editing component, as well as composition of matter and method of use claims for our therapeutic programs.

Four of these U.S.

patents, one of these European patents and their U.S., European and foreign counterpart applications are co-owned with Broad and Iowa and we have obtained an exclusive license to such co-ownership rights from these third parties in the field of prevention or treatment of human disease using gene therapy or genome editing.

In addition, five of these issued U.S.

In addition, six of these issued U.S.

patents and 11 of these pending U.S.

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As of December 31, 2024, we in-licensed 136 U.S.

patents, 59 European patents and related validations, and approximately 420 pending patent applications, including 87 pending U.S.

patents, 65 European patents and related validations, and 403 pending patent applications, including 84 pending U.S.

non-provisional patent applications, 55 pending European patent applications, and other related patents and patent applications in jurisdictions outside the United States and Europe that are related to our CRISPR technology collectively from various universities and institutions.

The patents and patent applications outside of the United States and Europe are held primarily in Canada, Japan, and Australia, although some of our in-licensed patent families were filed in a larger number of countries.

The patents and patent applications outside of the United States and Europe are held primarily in Canada, China, Japan, and Australia, although some of our in-licensed patent families were filed in a larger number of countries.

The claims from our in-licensed portfolio include claims to compositions of matter, methods of use, and certain processes.

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patent applications and we may not have any rights under any foreign patents that issue from any foreign equivalents thereof.

For more information regarding these license agreements, please see the section of this Annual Report on Form 10-K titled “Business —Intellectual Property Licenses.”

As of December 31, 2023, our registered trademark portfolio consisted of registrations in the United States for EDITAS, EDITAS in Stylized Letters and the Infinity Logo, registrations in Australia, China, the European Union, Japan, Switzerland and the United Kingdom for EDITAS, registrations in Australia, China, the European Union, Japan, Switzerland and the United Kingdom for the Infinity Logo, registrations in the European Union and United Kingdom for UDITAS, registrations in Australia, China, the European Union, Japan, Switzerland and the United Kingdom for SLEEK, and registrations in Australia, China, the European Union and United Kingdom for the Double Helix Design.

For more information regarding these license agreements, please see the section titled “Business —Intellectual Property Licenses” of Part I, Item 1 of this Annual Report on Form 10-K.

As of December 31, 2024, our registered trademark portfolio consisted of registrations in the United States for EDITAS, EDITAS in Stylized Letters and the Infinity Logo, registrations in Australia, China, the EU, Japan, Switzerland and the United Kingdom (the “UK”) for EDITAS, registrations in Australia, China, the EU, Japan, Switzerland and the UK for the Infinity Logo, registrations in the EU and the UK for UDITAS, registrations in Australia, China, the EU, Japan, Switzerland and the UK for SLEEK, and registrations in Australia, China, the EU and the UK for the Double Helix Design.

The biotechnology and pharmaceutical industries, including in the gene therapy, genome editing and cell therapy fields, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property and proprietary products.

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We compete in the segments of the pharmaceutical, biotechnology, and other related markets that utilize technologies encompassing genomic medicines to create therapies, including genome editing and gene therapy.

additional companies that are working to develop therapies in areas related to our research programs.

For example, in late 2023 and early 2024, the FDA approved Vertex’s CASGEVY TM (exagamglogene autotemcel), a Cas9 genome-edited cell medicine, for the treatment of SCD and TDT.

There are additional companies that are working to develop therapies in areas related to our research programs.

For hemoglobinopathies, these companies include Beam Therapeutics, bluebird bio, CRISPR Therapeutics, Ensoma, Kamau Therapeutics, Orna Therapeutics, Sanofi, Scribe Therapeutics, Tessera Therapeutics, Vertex, and Yoltech Therapeutics.

For example, in late 2023 and early 2024, the U.S.

Food and Drug Administration (“FDA”) approved Vertex’s CASGEVY TM (exagamglogene autotemcel), a Cas9 genome-edited cell medicine, for the treatment of SCD and TDT.

The FDA also approved in late 2023 bluebird bio’s LYFGENIA TM (lovotibeglogene autotemcel), a cell-based gene therapy, for the treatment of SCD.

If reni-cel is approved for marketing, these therapies will be directly competitive with reni-cel.

Our platform and product focus is the development of therapies using CRISPR technology specifically for genome editing.

Other companies developing CRISPR Cas9 or Cas12a technology or therapies using CRISPR Cas9 or Cas12a technology include Artisan Bio, AvenCell Therapeutics, Caribou Biosciences, CRISPR Therapeutics, EdiGene, ERS Genomics, Excision Biotherapeutics, Inscripta, Intellia Therapeutics, Kamau Therapeutics, Sigma-Aldrich, and ToolGen.

Other companies developing CRISPR Cas9 or Cas12a technology or therapies using CRISPR Cas9 or Cas12a technology include AvenCell Therapeutics, Caribou Biosciences, Cellistic, CRISPR Therapeutics, EdiGene, eGenesis, ERS Genomics, Excision Biotherapeutics, Inscripta, Intellia Therapeutics, Kamau Therapeutics, Sigma-Aldrich, ToolGen, and Yoltech Therapeutics.

In addition, there have been and may continue to be discoveries of new CRISPR-based gene editing technologies.

There are additional companies developing therapies using related CRISPR genome editing technologies, including other CRISPR nucleases, base editing, prime editing and gene writing.

These companies include Amber Bio, Arbor Biotechnologies, Beam Therapeutics, Chroma Medicine, Emendo Biotherapeutics, Epic Bio, Integra Therapeutics, KSQ Therapeutics, Locus Biosciences, Mammoth Biosciences, Metagenomi, Poseida Therapeutics, Prime Medicine, Scribe Therapeutics, Tessera Therapeutics, Tome Biosciences, Tune Therapeutics, and Verve Therapeutics.

These companies include Amber Bio, Arbor Biotechnologies, Beam Therapeutics, Eligo Biosciences, Emendo Biotherapeutics, Ensoma, Epic Bio, Integra Therapeutics, KSQ Therapeutics, Locus Biosciences, Mammoth Biosciences, Metagenomi, nChroma Bio, Poseida Therapeutics, Prime Medicine, Profluent Bio, Scribe Therapeutics, Tessera Therapeutics, Tune Therapeutics, and Verve Therapeutics.

There are also companies developing therapies using transcription activator-like effector nucleases, meganucleases, Mega-TALs and zinc finger nucleases.

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In addition to competition from other genome editing therapies, gene therapies or cell medicine therapies, any products that we may develop may also face competition from other types of therapies, such as small molecule, antibody, protein, oligonucleotide, or ribonucleic acid therapies.

For hemoglobinopathies, these companies include Acceleron Pharma, Agios Pharmaceuticals, Global Blood Therapeutics, Novartis Pharmaceuticals, and Vertex.

For hemoglobinopathies, these companies include Acceleron Pharma, Agios Pharmaceuticals, Novartis Pharmaceuticals, Pfizer, and Vertex.

In addition, many of our current or potential competitors, either alone or with their collaboration partners, may have greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, and marketing approved products than we do.

Mergers and acquisitions in the pharmaceutical, biotechnology, and gene therapy industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Smaller or other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

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Manufacturing

We currently perform some manufacturing activities such as the production of RNP Complexes for our various internal programs, as well as cell processing for reni-cel, and may also agree to produce RNP Complexes for our partners.

We currently perform some manufacturing activities such as the production of RNP Complexes for our various internal programs and may also agree to produce RNP Complexes for our partners.

These activities are performed on site at our existing facilities or at current good manufacturing practice-compliant space leased by us.

In June 2023, we entered into a multi-year agreement to increase our clean room capacity and move our current cell processing activities for reni-cel to a new third-party facility.

We expect to occupy this facility in the first half of 2024.

This new facility and increased capacity will support the scaling of our reni-cel program, including manufacturing clinical supply for the RUBY and EdiTHAL trials and preparing us for commercial readiness.

We contract with third parties for the manufacturing of our other materials for preclinical studies and our clinical trials, including gene editing materials for IND-supporting activities and early-stage clinical trials.

We have limited manufacturing operations and do not own or operate any substantial manufacturing facilities for large-scale production of our program materials.

While we have limited clinical manufacturing capabilities, at the appropriate time in the product development process of each product candidate, we will determine whether to expand our internal manufacturing capabilities or rely on third parties to manufacture commercial quantities of any products that we may successfully develop and have approved.

contracted manufacturing and reliance on collaboration partners is relatively cost-efficient and has eliminated the need for substantial direct investment in manufacturing facilities and additional staff.

We have limited manufacturing operations and do not own or operate any substantial manufacturing facilities for large-scale production of

our program materials.

At the appropriate time in the product development of each product candidate, we will determine whether to expand our internal manufacturing capabilities or rely on third parties to manufacture commercial quantities of any products that we may successfully develop and have approved.

The use of contracted manufacturing and reliance on collaboration partners is relatively cost-efficient and has eliminated the need for substantial direct investment in manufacturing facilities and additional staff.

Although we rely on contract manufacturers for certain materials, we have personnel with manufacturing experience to oversee our contract manufacturers.

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In certain instances, we may consider building our own commercial infrastructure.

In September 2023, we announced the strengthening of our executive team with the appointment of Caren Deardorf as our first Chief Commercial and Strategy Officer.

Deardorf will build and lead our commercial organization, strategy, and execution to support all launch, commercialization, and lifecycle management activities of our current product candidates and our future pipeline of product candidates.

As product candidates advance through our pipeline, our commercial plans may change.

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Government Regulation and Licensure of Products

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, pricing, reimbursement, sales, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products, including biological products.

Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, pricing, reimbursement, sales, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products, including biological products.

The processes for obtaining marketing approvals in the United States and in foreign 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.

The regulatory requirements applicable to product development, approval and marketing are subject to change, and regulations and administrative guidance often are revised or reinterpreted by government agencies in ways that may have a significant impact on our business.

Licensure and Regulation of Biologics in the United States

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• completion of the manufacture, under current Good Manufacturing Practices (“cGMP”) conditions, of the drug substance and drug product that the sponsor intends to use in human clinical trials along with required analytical and stability testing;

• design of a clinical protocol and submission to the FDA of an IND application for human clinical testing, which must become effective before human clinical trials may begin;

• design of a clinical protocol and submission to the FDA of an Investigational New Drug application (“IND”) 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 site before each clinical trial may be initiated;

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• satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCPs and the integrity of clinical data in support of the BLA;

• payment of user Prescription Drug User Free Act (“PDUFA”) securing FDA approval of the BLA and licensure of the new biologic product;

• payment of application and program fees pursuant to the Prescription Drug User Free Act (“PDUFA”) securing FDA approval of the BLA and licensure of the new biologic product;

• compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy (“REMS”) and any post-approval studies required by the FDA.

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These studies are generally referred to as IND-enabling studies.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards and the U.S.

Department of Agriculture’s Animal Welfare Act, if applicable.

The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND application.

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As a result, submission of the IND may result in the FDA not allowing the trials to commence or allowing the trial to commence on the terms originally specified by the sponsor in the IND.

If the FDA raises concerns or questions either during this initial 30-day period, or at any time during the IND process, it may choose to impose a partial or complete clinical hold.

Clinical holds are imposed by the FDA whenever there is concern for patient safety and may be a result of new data, findings, or developments in clinical, nonclinical, and/or chemistry, manufacturing, and controls.

If the FDA raises concerns or questions either during this initial 30-day period, or at any time following the allowance of the IND, it may choose to impose a partial or complete clinical hold.

This order issued by the FDA would delay either a proposed clinical study or cause suspension of an ongoing study, until all outstanding concerns have been adequately addressed and the FDA has notified the company that investigations may proceed.

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When a foreign clinical trial is not conducted under an IND, the sponsor must ensure that the trial complies with certain regulatory requirements of the FDA in order to use the trial as support for an IND or application for marketing approval.

Specifically, the FDA requires that such trials be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects.

GCP requirements encompass both ethical and data integrity standards for clinical trials.

Specifically, the FDA requires that such trials be conducted in accordance

with GCP, including review and approval by an independent ethics committee and informed consent from subjects.

The GCP requirements encompass both ethical and data integrity standards for clinical trials.

The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical trials, as well as the quality and integrity of the resulting data.

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The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board (“DSMB”).

This group may recommend continuation of the study as planned, changes in study conduct, or cessation of the study at designated check points based on certain available data from the study to which only the DSMB has access.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data monitoring committee (“DMC”).

Finally, research activities involving infectious agents, hazardous chemicals, recombinant DNA, and genetically altered organisms and agents may be subject to review and approval of an Institutional Biosafety Committee in accordance with NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.

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Failure to exhibit due diligence with regard to conducting Phase 4 clinical trials could result in withdrawal of approval for products.

In December 2022, with the passage of Food and Drug Omnibus Reform Act (“FDORA”), Congress required sponsors to develop and submit a diversity action plan for each phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.

In December 2022, with the passage of Food and Drug Omnibus Reform Act (“FDORA”), Congress required sponsors to develop and submit a diversity action plan (“DAP”) for each phase 3 clinical trial or any other “pivotal study” of a new drug or biological product.

These plans are meant to encourage the enrollment of more diverse patient populations in late-stage clinical trials of FDA-regulated products.

Specifically, actions plans must include the sponsor’s goals for enrollment, the underlying rationale for those goals, and an explanation of how the sponsor intends to meet them.

In addition to these requirements, the legislation directs the FDA to issue new guidance on diversity action plans.

In addition to these requirements, the legislation directs the FDA to issue new guidance on DAPs.

In June 2024, as mandated by FDORA, the FDA issued draft guidance outlining the general requirements for DAPs.

Unlike most guidance documents issued by the FDA, the DAP guidance when finalized will have the force of law because FDORA specifically dictates that the form and manner for submission of DAPs are specified in FDA guidance.

On January 27, 2025, in response to an Executive Order issued by President Trump on January 21, 2025, on Diversity, Equity and Inclusion programs, the FDA removed this draft guidance from its website.

This action raises questions about the applicability of statutory obligations to submit DAPs and the agency’s current thinking on best practices for clinical development.

In June 2023, the FDA issued draft guidance with updated recommendations for GCPs aimed at modernizing the design and conduct of clinical trials.

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In addition, the FDA issued draft guidance outlining recommendations for the implementation of decentralized clinical trials.

Sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S.

National Institutes of Health (“NIH”).

Sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the NIH.

The NIH’s Final Rule on registration and reporting requirements for clinical trials became effective in 2017, and both NIH and the FDA have signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.

Although the FDA has historically not enforced these reporting requirements due to Department of Health and Human Services’ (“HHS”) long delay in issuing final implementing regulations, FDA has issued pre-notices for voluntary corrective action and several notices of non-compliance during the past two years.

While these notices of non-compliance did not result in civil monetary penalties, the failure to submit clinical trial information to clinicaltrials.gov, as required, is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.

Although the FDA has historically not enforced these reporting requirements due to Department of Health and Human Services’ (“HHS”) long delay in issuing final implementing regulations, FDA has as of December 2024 issued six notices of non-compliance, thereby signaling the government’s willingness to begin enforcing these requirements against non-compliant clinical trial sponsors.

While these notices of non-compliance did not result in civil monetary penalties, the failure to submit clinical trial information to clinicaltrials.gov is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.

Violations may also result in injunctions and/or criminal prosecution or disqualification from federal grants.

Interactions with the FDA During the Clinical Development Program

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Type A meetings are those that are necessary for an otherwise stalled product development program to proceed or to address an important safety issue.

Type B meetings include pre-IND and pre-NDA meetings as well as end of phase meetings such as EOP2 meetings.

Type B meetings include pre-IND and pre-new drug application (“NDA”) meetings as well as end of phase meetings such as EOP2 meetings.

A Type C meeting is any meeting other than a Type A or Type B meeting regarding the development and review of a product.

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Those plans must contain an outline of the proposed pediatric study or studies the sponsor plans to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation.

The sponsor, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other, and agree upon a final plan.

The sponsor, the FDA, and the FDA’s internal review

committee must then review the information submitted, consult with each other, 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, FDA will meet early in the development process to discuss pediatric study plans with sponsors and FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than 90 days after FDA’s receipt of the study plan.

In addition, the FDA will meet early in the development process to discuss pediatric study plans with sponsors and the FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than 90 days after the 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.

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The FDA is required to send a PREA Non-Compliance letter to sponsors who have failed to submit their pediatric assessments required under PREA, have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although FDA has taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although the FDA has taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric subpopulations of what is otherwise a common disease.

In May 2023, the FDA issued new draft guidance that further describes the pediatric study requirements under PREA.

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The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.

The FDA has issued numerous guidance documents regarding gene therapies.

The FDA has issued numerous guidance documents regarding gene therapies, including a draft guidance issued in November 2024 to address frequently asked questions surrounding the development of cellular and gene therapy products.

Although the FDA has indicated that these and other guidance documents it previously issued are not legally binding, compliance with them is likely necessary to gain approval for any gene therapy product candidate.

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Manufacturers and others involved in the manufacture and distribution of products must also register their establishments with the FDA and certain state agencies.

Both domestic and foreign manufacturing establishments must

Both domestic and foreign manufacturing establishments must register and provide additional information to the FDA upon their initial participation in the manufacturing process.

Any product manufactured by or imported from a facility that has not registered, whether foreign or domestic, is deemed misbranded under the FDCA.

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The FDA conducts a preliminary review of all applications within 60 days of receipt and must inform the sponsor at that time or before whether an application is sufficiently complete to permit substantive review.

In pertinent part, FDA’s regulations state that an application “shall not be considered as filed until all pertinent information and data have been received” by the FDA.

In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File (“RTF”) determination to the sponsor.

In pertinent part, the FDA’s regulations state that an application “shall not be considered as filed until all pertinent information and data have been received” by the FDA.

In the event that the FDA determines that an application does not satisfy this standard, it will issue a Refuse to File (“RTF”) determination to the sponsor.

On the other hand, once the submission has been accepted for filing, the FDA begins an in-depth review of the application.

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Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

With passage of FDORA, Congress clarified FDA’s authority to conduct inspections by expressly permitting inspection of facilities involved in the preparation, conduct, or analysis of clinical and non-clinical studies submitted to FDA as well as other persons holding study records or involved in the study process.

With passage of FDORA, Congress clarified the FDA’s authority to conduct inspections by

expressly permitting inspection of facilities involved in the preparation, conduct, or analysis of clinical and non-clinical studies submitted to the FDA as well as other persons holding study records or involved in the study process.

Moreover, the FDA will review a sponsor’s financial relationship with the principal investigators who conducted the clinical trials in support of the NDA.

That is because, under certain circumstances, principal investigators at a clinical trial site may also serve as scientific advisors or consultants to a sponsor and receive compensation in connection with such services.

Depending on the level of that compensation and any other financial interest a principal investigator may have in a sponsor, the sponsor may be required to report these relationships to the FDA.

The FDA will then evaluate that financial relationship and determine whether it creates a conflict of interest or otherwise affects the interpretation of the trial or the integrity of the data generated at the principal investigator’s clinical trial site.

If so, the FDA may exclude data from the clinical trial site in connection with its determination of safety and efficacy of the investigational product.

In connection with its review of a BLA, the FDA may refer the application to an advisory committee for review, evaluation, and recommendation as to whether the application should be approved.

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To qualify for the Breakthrough Therapy program, product candidates must be intended to treat a serious or life-threatening condition and preliminary clinical evidence must indicate that such product candidates may demonstrate substantial improvement on one or more clinically significant endpoints over existing therapies.

The FDA will seek to ensure the sponsor of a Breakthrough Therapy product candidate receives intensive guidance on an efficient development program, intensive

involvement of senior managers and experienced staff on a proactive, collaborative and cross-disciplinary review and rolling review.

The FDA will seek to ensure the sponsor of a Breakthrough Therapy product candidate receives intensive guidance on an efficient development program, intensive involvement of senior managers and experienced staff on a proactive, collaborative and cross-disciplinary review and rolling review.

• Priority review.

A product candidate is eligible for priority review if it treats a serious condition and, if approved, it would be a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention compared to marketed products.

FDA aims to complete its review of priority review applications within six months as opposed to 10 months for standard review.

The FDA aims to complete its review of priority review applications within six months as opposed to 10 months for standard review.

• Regenerative advanced therapy.

With passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies.

A product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product candidate has the potential to address unmet medical needs for such disease or condition.

The benefits of a regenerative advanced therapy designation include early interactions with the FDA to expedite development and review, benefits available to Breakthrough Therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.

Accelerated Approval

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With passage of FDORA in December 2022, Congress modified certain provisions governing accelerated approval of drug and biologic products.

Specifically, the new legislation authorized FDA to:

require a sponsor to have its confirmatory clinical trial underway before accelerated approval is awarded, require a sponsor of a product granted accelerated approval to submit progress reports on its post-approval studies to FDA every six months (until the study is completed;

Specifically, the new legislation authorized the FDA to:

require a sponsor to have its confirmatory clinical trial underway before accelerated approval is awarded, require a sponsor of a product granted accelerated approval to submit progress reports on its post-approval studies to the FDA every six months (until the study is completed);

and use expedited procedures to withdraw accelerated approval of an NDA or BLA after the confirmatory trial fails to verify the product’s clinical benefit.

Further, FDORA requires the agency to publish on its website “the rationale for why a post-approval study is not appropriate or necessary” whenever it decides not to require such a study upon granting accelerated approval.

• Regenerative advanced therapy.

With passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies.

In March 2023, the FDA issued draft guidance that outlines its current thinking and approach to accelerated approval.

The agency indicated that the accelerated approval pathway is commonly used for approval of oncology drugs due to the serious and life-threatening nature of cancer.

Although single-arm trials have been commonly used to support

accelerated approval, a randomized controlled trial is the preferred approach as it provides a more robust efficacy and safety assessment and allows for direct comparisons to an available therapy.

Subsequently, in December 2024 and January 2025, the FDA issued additional draft guidances relating to accelerated approval.

These guidances describe the FDA’s latest thinking on what it means to conduct a confirmatory trial with due diligence and how the agency plans to interpret whether such a study needs to be underway at the time of approval.

While these guidances are currently only in draft form and will ultimately not be legally binding even when finalized, sponsors typically observe the FDA’s guidance closely to ensure that their investigational products qualify for accelerated approval.

Post-Approval Regulation

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Moreover, with passage of the Pre-Approval Information Exchange Act (the “PIE Act”) in December 2022, sponsors of products that have not been approved may proactively communicate to payors certain information about products in development to help expedite patient access upon product approval.

In addition, in October 2023, the FDA published draft guidance outlining the agency’s non-binding policies governing the distribution of scientific information on unapproved uses to healthcare providers.

This draft guidance calls for such communications to be truthful, non-misleading, factual, and unbiased and include all information necessary for healthcare providers to interpret the strengths and weaknesses and validity and utility of the information about the unapproved use

If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

In addition, in January 2025, the FDA published final guidance outlining the agency’s non-binding policies governing the distribution of scientific information on unapproved uses to healthcare providers.

This final guidance calls for such communications to be truthful, non-misleading, factual, and unbiased and include all information necessary for healthcare providers to interpret the strengths and weaknesses and validity and utility of the information about the unapproved use

This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products.

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An application for designation as an orphan product can be made any time prior to the filing of an application for approval to market the product.

A product becomes an orphan when it receives orphan drug designation from the Office of Orphan Products Development at the FDA based on acceptable

confidential requests made under the regulatory provisions.

A product becomes an orphan when it receives orphan drug designation from the Office of Orphan Products Development at the FDA based on acceptable confidential requests made under the regulatory provisions.

The product must then go through the review and approval process like any other product.

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In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” Although there have been legislative proposals to overrule this decision, they have not been enacted into law.

On January 23, 2023, FDA announced that, in matters beyond the scope of that court order, FDA will continue to apply its existing regulations tying orphan-drug exclusivity to the uses or indications for which the orphan drug was approved.

On January 23, 2023, the FDA announced that, in matters beyond the scope of that court order, the FDA will continue to apply its existing regulations tying orphan-drug exclusivity to the uses or indications for which the orphan drug was approved.

Pediatric Exclusivity

Pediatric exclusivity is another type of non-patent marketing exclusivity 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 regulatory exclusivity, including the non-patent and orphan exclusivity.

This six-month exclusivity may be granted if a BLA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.

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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.

In December 2022, Congress clarified through FDORA that FDA may approve multiple first interchangeable biosimilar biological products so long as the products are all approved on the first day on which such a product is approved as interchangeable with the reference product.

In December 2022, Congress clarified through FDORA that the FDA may approve multiple first interchangeable biosimilar biological products so long as the products are all approved on the first day on which such a product is approved as interchangeable with the reference product.

An application for a biosimilar product may not be submitted to the FDA until four years following the date of approval of the reference product.

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A patent claiming a new biologic product, its method of use or its method of manufacture may be eligible for a limited patent term extension under the Hatch-Waxman Act, 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 the IND and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date.

Only one patent applicable to an approved product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question.

Only one patent applicable to an approved product is eligible for

the extension, and the application for the extension must be submitted prior to the expiration of the patent in question.

A patent that covers multiple products for which approval is sought can only be extended in connection with one of the approvals.

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This guidance builds upon existing policy regarding the labeling of companion diagnostics.

In its 2014 guidance, the FDA stated that if evidence is sufficient to conclude that the companion diagnostic is appropriate for use with

a specific group of therapeutic products, the companion diagnostic’s intended use/indications for use should name the specific group of therapeutic products, rather than specific products.

In its 2014 guidance, the FDA stated that if evidence is sufficient to conclude that the companion diagnostic is appropriate for use with a specific group of therapeutic products, the companion diagnostic’s intended use/indications for use should name the specific group of therapeutic products, rather than specific products.

The 2020 guidance expands on the policy statement in the 2014 guidance by recommending that companion diagnostic developers consider a number of factors when determining whether their test could be developed, or the labeling for approved companion diagnostics could be revised through a supplement, to support a broader labeling claim such as use with a specific group of oncology therapeutic products (rather than listing an individual therapeutic product(s)).

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Device manufacturers must also establish registration and device listings with the FDA.

A medical device manufacturer’s manufacturing processes and those of its suppliers are required to comply with the applicable portions of the Quality System Regulation, which covers the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging and shipping of medical devices.

packaging and shipping of medical devices.

Domestic facility records and manufacturing processes are subject to periodic unscheduled inspections by the FDA.

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Whether or not it obtains FDA approval for a product, a sponsor will need to obtain the necessary approvals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions.

The process governing approval of medicinal products in the European Union generally follows the same lines as in the United States.

The process governing approval of medicinal products in the EU generally follows the same lines as in the United States.

It entails satisfactory completion of preclinical studies and adequate and well-controlled clinical trials to establish the safety and efficacy of the product for each proposed indication.

It also requires the submission to the relevant competent authorities of a marketing authorization application (“MAA”) and granting of a marketing authorization by these authorities before the product can be marketed and sold in the European Union.

Non-clinical Studies

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Clinical Trial Approval

On January 31, 2022, the new Clinical Trials Regulation (EU) No 536/2014 became effective in the European Union and replaced the prior Clinical Trials Directive 2001/20/EC.

The new regulation aims at simplifying and streamlining the authorization, conduct and transparency of clinical trials in the European Union.

On January 31, 2022, the new Clinical Trials Regulation (EU) No 536/2014 became effective in the EU and replaced the prior Clinical Trials Directive 2001/20/EC.

The new regulation aims at simplifying and streamlining the authorization, conduct and transparency of clinical trials in the EU.

Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical trial to be conducted in more than one Member State of the European Union (“EU Member State”) will only be required to submit a single application for approval.

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Furthermore, the sponsor may only start a clinical trial at a specific study site after the applicable ethics committee has issued a favorable opinion.

Parties conducting certain clinical studies must, as in the U.S., post clinical trial information in the European Union at the EudraCT website:

The CTR foresees a three-year transition period.

The extent to which ongoing and new clinical trials will be governed by the CTR varies.

Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the Clinical Trials Directive, remain governed by said Directive until January 31, 2025.

After this date, all clinical trials (including those which are ongoing) will become subject to the provisions of the CTR.

Parties conducting certain clinical studies must, as in the U.S., post clinical trial information in the EU at the EudraCT website:

https://eudract.ema.europa.eu.

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Marketing Authorization

To obtain a marketing authorization for a product under the European Union regulatory system, a sponsor must submit an MAA, either under a centralized procedure administered by the EMA or one of the procedures administered by competent authorities in European Union Member States (decentralized procedure, national procedure, or mutual recognition procedure).

A marketing authorization may be granted only to a sponsor established in the European Union.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the European Union, a sponsor must demonstrate compliance with all measures included in an EMA-approved PIP, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, class waiver, or a deferral for one or more of the measures included in the PIP.

To obtain a marketing authorization for a product under the EU regulatory system, a sponsor must submit an MAA, either under a centralized procedure administered by the EMA or one of the procedures administered by competent authorities in EU Member States (decentralized procedure, national procedure, or mutual recognition procedure).

A marketing authorization may be granted only to a sponsor established in the EU.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the EU, a sponsor must demonstrate compliance with all measures included in an EMA-approved PIP, covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, class waiver, or a deferral for one or more of the measures included in the PIP.

The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid for all EU Member States.

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The European Commission grants or refuses marketing authorization in light of the opinion delivered by the EMA.

Specifically, the grant of marketing authorization in the European Union for products containing viable human tissues or cells such as gene therapy medicinal products is governed by Regulation 1394/2007/EC on advanced therapy medicinal products, read in combination with Directive 2001/83/EC of the European Parliament and of the Council, commonly known as the Community code on medicinal products.

Specifically, the grant of marketing authorization in the EU for products containing viable human tissues or cells such as gene therapy medicinal products is governed by Regulation 1394/2007/EC on advanced therapy medicinal products, read in combination with Directive 2001/83/EC of the European Parliament and of the Council, commonly known as the Community code on medicinal products.

Regulation 1394/2007/EC lays down specific rules concerning the authorization, supervision, and pharmacovigilance of gene therapy medicinal products, somatic cell therapy medicinal products, and tissue engineered products.

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Under the centralized procedure, the CHMP established at the EMA is responsible for conducting an initial assessment of a product.

Under the centralized procedure in the European Union, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops when additional information or written or oral explanation is to be provided by the sponsor in response to questions of the CHMP.

Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops when additional information or written or oral explanation is to be provided by the sponsor in response to questions of the CHMP.

Accelerated evaluation may be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health and, in particular, from the viewpoint of therapeutic innovation.

If the CHMP accepts such a request, the time limit of 210 days will be reduced to 150 days, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that it is no longer appropriate to conduct an accelerated assessment.

Conditional Marketing Authorization

In specific circumstances, EU legislation (Article 14–a Regulation (EC) No 726/2004 (as amended by Regulation (EU) 2019/5 and Regulation (EC) No 507/2006 on Conditional MA for Medicinal Products for Human Use) enables sponsors to obtain a conditional marketing authorization prior to obtaining the comprehensive clinical data required for an application for a full marketing authorization.

Such conditional approvals may be granted for product candidates (including medicines designated as orphan medicinal products) if (1) the product candidate is intended for the treatment, prevention or medical diagnosis of seriously debilitating or life-threatening diseases;

(2) the product candidate is intended to meet unmet medical needs of patients;

(3) the benefit of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required;

(4) the risk-benefit balance of the product candidate is positive;

and (5) it is likely that the sponsor will be in a position to provide the required comprehensive clinical trial data.

A conditional marketing authorization may contain specific obligations to be fulfilled by the marketing authorization holder, including obligations with respect to the completion of ongoing or new studies and with respect to the collection of pharmacovigilance data.

Conditional marketing authorizations are valid for one year, and may be renewed annually, if the risk-benefit balance remains positive, and after an assessment of the need for additional or modified conditions or specific obligations.

The timelines for the centralized procedure described above also apply with respect to the review by the CHMP of applications for a conditional marketing authorization.

Exceptional Circumstances

A marketing authorization may also be granted “under exceptional circumstances” when the applicant can show that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced.

This may arise in particular when the intended indications are very rare and, in the present state of scientific knowledge, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles.

This marketing authorization is close to the conditional marketing authorization as it is reserved to medicinal products to be approved for severe diseases or unmet medical needs and the applicant does not hold the complete data set legally required for the grant of a marketing authorization.

However, unlike the conditional marketing authorization, the applicant does not, and will not in the future, have to provide the missing data.

Although the marketing authorization “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually and the marketing authorization is withdrawn in case the risk-benefit ratio is no longer favorable.

Under these procedures, before granting the marketing authorization, the EMA or the competent authorities of the member states make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety, and efficacy.

Except conditional marketing authorizations, marketing authorizations have an initial duration of five years.

After these five years, the authorization may be renewed on the basis of a reevaluation of the risk-benefit balance.

Specialized Procedures for Gene Therapies

The grant of marketing authorization in the European Union for gene therapy products is governed by Regulation 1394/2007/EC on advanced therapy medicinal products, read in combination with Directive 2001/83/EC of the European Parliament and of the Council, commonly known as the Community code on medicinal products.

The grant of marketing authorization in the EU for gene therapy products is governed by Regulation 1394/2007/EC on advanced therapy medicinal products, read in combination with Directive 2001/83/EC of the European Parliament and of the Council, commonly known as the Community code on medicinal products.

Regulation 1394/2007/EC includes specific rules concerning the authorization, supervision, and pharmacovigilance of gene therapy medicinal products.

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Regulatory Data Protection in the European Union

In the European Union, new chemical entities approved on the basis of a complete independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity pursuant to Regulation (EC) No 726/2004, as amended, and Directive 2001/83/EC, as amended.

Data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic (abbreviated) application for a period of eight years.

During the additional two-year period of market exclusivity, a generic marketing authorization application can be submitted, and the innovator’s data may be referenced, but no generic medicinal product

can be marketed until the expiration of the market exclusivity.

In the EU, new chemical entities approved on the basis of a complete independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity pursuant to Regulation (EC) No 726/2004, as amended, and Directive 2001/83/EC, as amended.

Data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application for a period of eight years.

The overall ten-year period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in comparison with existing therapies.

Even if a compound is considered to be a new chemical entity so that the innovator gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.

In this context, it should be noted that the EU pharmaceutical legislation is currently undergoing a complete review process, in the context of the Pharmaceutical Strategy for Europe initiative, launched by the European Commission in November 2020.

The European Commission’s proposal for revision of several legislative instruments related to medicinal products was published in April 2023 and includes, among other things, provisions that would potentially reduce the duration of regulatory data protection.

The European Parliament requested several amendments in April 2024.

At this time, the proposed revisions remain to be agreed and adopted by the European Parliament and European Council and the proposals may therefore be substantially revised before adoption, which is not anticipated before early 2026.

The revisions may, however, have a significant impact on the pharmaceutical industry in the long term, if and when adopted.

Periods of Authorization and Renewals

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Once renewed, the marketing authorization is valid for an unlimited period, unless the European Commission or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal period.

Any authorization that is not followed by the placement of the drug on the European Union (“EU”) market (in the case of the centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid.

Any authorization that is not followed by the placement of the drug on the EU market (in the case of the centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid.

Regulatory Requirements after Marketing Authorization

Following approval, the holder of the marketing authorization is required to comply with a range of requirements applicable to the manufacturing, marketing, promotion and sale of the medicinal product.

These include compliance with the European Union’s stringent pharmacovigilance or safety reporting rules, pursuant to which post-authorization studies and additional monitoring obligations can be imposed.

In addition, the manufacturing of authorized products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the EMA’s GMP requirements and comparable requirements of other regulatory bodies in the European Union, which mandate the methods, facilities, and controls used in manufacturing, processing and packing of drugs to assure their safety and identity.

Finally, the marketing and promotion of authorized products, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the European Union under Directive 2001/83EC, as amended.

These include compliance with the EU’s stringent pharmacovigilance or safety reporting rules, pursuant to which post-authorization studies and additional monitoring obligations can be imposed.

In addition, the manufacturing of authorized products, for which a separate manufacturer’s license is mandatory, must also be conducted in strict compliance with the EMA’s GMP requirements and comparable requirements of other regulatory bodies in the EU, which mandate the methods, facilities, and controls used in manufacturing, processing and packing of drugs to assure their safety and identity.

Reimbursement and Pricing of Prescription Pharmaceuticals

In the E.U., similar political, economic and regulatory developments to those in the United States may affect our ability to profitably commercialize our product candidates, if approved.

In the EU, similar political, economic and regulatory developments to those in the United States may affect our ability to profitably commercialize our product candidates, if approved.

In markets outside of the U.S.

and the E.U., reimbursement and healthcare payment systems vary significantly by country and many countries have instituted price ceilings on specific products and therapies.

In many countries, including those of the E.U., the pricing of prescription pharmaceuticals is subject to governmental control and access.

and the EU, reimbursement and healthcare payment systems vary significantly by country and many countries have instituted price ceilings on specific products and therapies.

In many countries, including those of the EU, the pricing of prescription pharmaceuticals is subject to governmental control and access.

In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.

To obtain reimbursement or pricing approval in some countries, pharmaceutical firms may be required to conduct a clinical trial that compares the cost-effectiveness of the product to other available therapies.

To obtain reimbursement or

pricing approval in some countries, pharmaceutical firms may be required to conduct a clinical trial that compares the cost-effectiveness of the product to other available therapies.

Orphan Drug Designation and Exclusivity

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847/2000 provide that a product can be designated as an orphan drug by the European Commission if its sponsor can establish:

that the product is intended for the diagnosis, prevention or treatment of (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the European Union when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the European Union and that without incentives it is unlikely that the marketing of the drug in the European Union would generate sufficient return to justify the necessary investment.

For either of these conditions, the sponsor must demonstrate that there exists no satisfactory method of diagnosis, prevention, or treatment of the condition in question that has been authorized in the European Union or, if such method exists, the drug will be of significant benefit to those affected by that condition.

that the product is intended for the diagnosis, prevention or treatment of (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the EU when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the necessary investment.

For either of these conditions, the sponsor must demonstrate that there exists no satisfactory method of diagnosis, prevention, or treatment of the condition in question that has been authorized in the EU or, if such method exists, the drug will be of significant benefit to those affected by that condition.

An orphan drug designation provides a number of benefits, including fee reductions, regulatory assistance, and the possibility to apply for a centralized European Union marketing authorization.

Marketing authorization for an orphan drug

leads to a ten-year period of market exclusivity.

Marketing authorization for an orphan drug leads to a ten-year period of market exclusivity.

During this market exclusivity period, neither the EMA nor the European Commission or the member states can accept an application or grant a marketing authorization for a “similar medicinal product.” A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

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Patent Term Extensions in the European Union and Other Jurisdictions

The European Union also provides for patent term extension through Supplementary Protection Certificates, or SPCs.

The EU also provides for patent term extension through Supplementary Protection Certificates (“SPCs”).

The rules and requirements for obtaining an SPC are similar to those in the United States.

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These periods can be extended for six additional months if pediatric exclusivity is obtained, which is described in detail below.

Although SPCs are available throughout the European Union, sponsors must apply on a country-by-country basis.

Similar patent term extension rights exist in certain other foreign jurisdictions outside the European Union.

Although SPCs are available throughout the EU, sponsors must apply on a country-by-country basis.

Similar patent term extension rights exist in certain other foreign jurisdictions outside the EU.

Brexit and the Regulatory Framework in the United Kingdom

The United Kingdom’s (“UK”) withdrawal from the EU took place on January 31, 2020.

The EU and the UK reached an agreement on their new partnership in the Trade and Cooperation Agreement (the “Agreement”), which entered into force on May 1, 2021.

The Agreement focuses primarily on free trade by ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products.

Thereafter, the EU and the UK will form two separate markets governed by two distinct regulatory and legal regimes, except that Northern Ireland will continue to broadly follow EU laws as further described below.

As such, the Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the UK is no longer part of the single market.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency (“MHRA”) became responsible for supervising medicines and medical devices in Great Britain (“GB”), comprising England, Scotland, and Wales under domestic law whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol.

On February 27, 2023, the UK government and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

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

In particular, the MHRA will be responsible for approving all medicinal products destined for the UK market (i.e., GB and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, so the UK government and the EU will enact legislative measures to bring it into law.

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

The Human Medicines Regulations 2012 (SI 2012/1916) (as amended) (“HMR”) is the primary legal instrument for the regulation of medicines in the UK The HMR has incorporated into the domestic law the body of EU law instruments governing medicinal products that pre-existed prior to the UK’s withdrawal from the EU.

EU laws which have been transposed into UK law through secondary legislation continue to be applicable as “retained EU law”.

However, new legislation such as the (EU) Clinical Trials Regulation will not be applicable in GB.

Since a significant proportion of the regulatory framework for pharmaceutical products in the UK covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, MAs, commercial sales, and distribution of pharmaceutical

products is derived from EU directives and regulations, Brexit may have a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval, and commercialization of our product candidates in the UK For example, the UK is no longer covered by the centralized procedures for obtaining EU-wide MAs from the EMA, and a separate MA will be required to market our product candidates in the UK A new international recognition framework has been in place since January 1, 2024, whereby the MHRA will have regard to decisions on the approval of MAs made by the EMA and certain other regulators when determining an application for a new GB MA.

The UK’s withdrawal from the EU, commonly referred to as Brexit, took place on January 31, 2020.

The EU and the UK reached an agreement on their new partnership in the Trade and Cooperation Agreement, which entered into force on May 1, 2021.

As of January 1, 2021, the Medicines and Healthcare Products Regulatory Agency (the “MHRA”) became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law, whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol, as amended by the so called Windsor Framework agreed in February 2023.

As of January 1, 2025, the changes introduced by the Windsor Framework resulted in the MHRA being responsible for approving all medicinal products destined for the UK market (Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.

The MHRA relies on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended) (the “HMR”) as the basis for regulating medicines.

The HMR has incorporated into the domestic law the body of EU law instruments governing medicinal products that pre-existed prior to the UK’s withdrawal from the EU.

As of January 1, 2024, a new international recognition procedure (“IRP”) applies which intends to facilitate approval of pharmaceutical products in the UK.

The IRP is open to applicants that have already received an authorization

for the same product from one of the MHRA’s specified Reference Regulators (“RRs”).

The RRs notably include EMA and regulators in the EEA member states for approvals in the EU centralized procedure and mutual recognition procedure as well as the FDA (for product approvals granted in the U.S.).The RR assessment must have undergone a full and standalone review.

RR assessments based on reliance or recognition cannot be used to support an IRP application.

A CHMP positive opinion or an MRDC positive end of procedure outcome is an RR authorisation for the purposes of IRP.

General Data Protection Regulation

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Privacy Shield.

The European Union initiated the process to adopt an adequacy decision for the EU-U.S.

The EU initiated the process to adopt an adequacy decision for the EU-U.S.

Data Privacy Framework in December 2022 and the European Commission adopted the adequacy decision on July 10, 2023.

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The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and

imposing controls to manage costs.

Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs.

Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a particular indication.

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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, and customers are subject to broadly applicable fraud and abuse, anti-kickback, false claims laws, reporting of payments to physicians and teaching physicians and patient privacy laws and regulations and other healthcare laws and regulations that

may constrain our business and/or financial arrangements.

Restrictions under applicable federal and state healthcare laws and regulations, include the following:

federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving, or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;

kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;

• the federal civil and criminal false claims laws, including the civil 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 made or used a false record or statement to avoid, decrease, or conceal an obligation to pay money to the federal government;

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officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment;

Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

• the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act (“ACA”), as amended by the Health Care Education Reconciliation Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services (“CMS”) within the HHS, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members;

• analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by non-governmental third-party payors, including private insurers.

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A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2031 pursuant to the Coronavirus Aid, Relief and Economic Security Act (the “CARES Act”).

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

The Trump Administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

On January 28, 2021, however, President Biden rescinded those orders and issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access.

Under this Order, federal agencies are directed to re-examine:

policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19;

demonstrations and waivers under Medicaid and the ACA that may reduce coverage or undermine the programs, including work requirements;

policies that undermine the Health Insurance Marketplace or other markets for health insurance;

policies that make it more difficult to enroll in Medicaid and the ACA;

and policies that reduce affordability of coverage or financial assistance, including for dependents.

Pharmaceutical Prices

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congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid.

In 2020, President Trump issued several executive orders intended to lower the costs of prescription products and certain provisions in these orders have been incorporated into regulations.

These regulations include an interim final rule implementing a most favored nation model for prices that would tie Medicare Part B payments for certain physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021.

That rule, however, has been subject to a nationwide preliminary injunction and, on December 29, 2021, CMS issued a final rule to rescind it.

With issuance of this rule, CMS stated that it will explore all options to incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries' access to evidence-based care.

In addition, the HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program (“SIP”) to import certain prescription drugs from Canada into the United States.

That regulation was challenged in a lawsuit by the Pharmaceutical Research and Manufacturers of America (“PhRMA”) but the case was dismissed by a federal district court in February 2023 after the court found that PhRMA did not have standing to sue HHS.

Nine states (Colorado, Florida, Maine, New Hampshire, New Mexico, North Dakota, Texas, Vermont and Wisconsin) have passed laws allowing for the importation of drugs from Canada.

Certain of these states have submitted Section 804 Importation Program proposals and are awaiting FDA approval.

On January 5, 2024, the FDA approved Florida’s plan for Canadian drug importation.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The final rule would also eliminate the current safe harbor for Medicare drug rebates and create new safe harbors for beneficiary point-of-sale discounts and pharmacy benefit manager service fees.

It originally was set to go into effect on January 1, 2022, but has been delayed by Congress to January 1, 2032.

In October 2020, the HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program (“SIP”) to import certain prescription drugs from Canada into the United States.

Seven states (Colorado, Florida, Maine, New Hampshire, New Mexico, Texas and Vermont) have passed laws allowing for the importation of products from Canada.

North Dakota and Virginia have passed legislation establishing workgroups to examine the impact of a state importation program.

As of May 2024, five states (Colorado, Florida, Maine, New Hampshire and New Mexico) had submitted Section 804 Importation Program proposals to the FDA.

On January 5, 2023, the FDA approved Florida’s plan for Canadian product importation.

That state now has authority to import certain products from Canada for a period of two years once certain conditions are met.

Florida will first need to submit a pre-import request for each product selected for importation, which must be approved by the FDA.

The state will also need to relabel the products and perform quality testing of the products to meet FDA standards.

On August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”) was signed into law by President Biden.

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and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).

The IRA permits the Secretary of the HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

The IRA permits the

Secretary of the HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

Specifically, with respect to price negotiations, Congress authorized Medicare to negotiate lower prices for certain costly single-source drug and biologic products that do not have competing generics or biosimilars and are reimbursed under Medicare Part B and Part D.

CMS may negotiate prices for ten high-cost drugs paid for by Medicare Part D starting in 2026, followed by 15 Part D drugs in 2027, 15 Part B or Part D drugs in 2028, and 20 Part B or Part D drugs in 2029 and beyond.

The CMS may negotiate prices for ten high-cost drugs paid for by Medicare Part D starting in 2026, followed by 15 Part D drugs in 2027, 15 Part B or Part D drugs in 2028, and 20 Part B or Part D drugs in 2029 and beyond.

This provision applies to drug products that have been approved for at least 9 years and biologics that have been licensed for 13 years, but it does not apply to drugs and biologics that have been approved for a single rare disease or condition.

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The new law also caps Medicare out-of-pocket drug costs at an estimated $4,000 a year in 2024 and, thereafter beginning in 2025, at 2,000 a year.

On June 6, 2023, Merck filed a lawsuit against HHS and CMS asserting that, among other things, the IRA’s Drug Price Negotiation Program for Medicare constitutes an uncompensated taking in violation of the Fifth Amendment of the Constitution.

The first cycle of negotiations for the Medicare Drug Price Negotiation Program commenced in the summer of 2023.

On August 15, 2024, the HHS published the results of the first Medicare drug price negotiations for ten selected drugs that treat a range of conditions, including diabetes, chronic kidney disease, and rheumatoid arthritis.

The prices of these ten drugs will become effective January 1, 2026.

On January 17, 2025, the CMS announced its selection of 15 additional drugs covered by Part D for the second cycle of negotiations by February 1, 2025.

While there had been some questions about the Trump Administration’s position on this program, the CMS issued a public statement on January 29, 2025, declaring that lowering the cost of prescription drugs is a top priority of the new administration and the CMS is committed to considering opportunities to bring greater transparency in the negotiation program.

The second cycle of negotiations with participating drug companies will occur during 2025, and any negotiated prices for this second set of drugs will be effective starting January 1, 2027.

On June 6, 2023, Merck filed a lawsuit against the HHS and the CMS asserting that, among other things, the IRA’s Drug Price Negotiation Program for Medicare constitutes an uncompensated taking in violation of the Fifth Amendment of the Constitution.

Subsequently, a number of other parties, including the U.S.

Chamber of Commerce (“Chamber”), Bristol Myers Squibb Company, the Pharmaceutical Research and Manufacturers of America, Astellas, Novo Nordisk, Janssen Pharmaceuticals, Novartis, AstraZeneca and Boehringer Ingelheim, also filed lawsuits in various courts with similar constitutional claims against HHS and CMS.

The HHS has generally won the substantive disputes in these cases, and various federal district court judges have expressed skepticism regarding the merits of the legal arguments being pursued by the pharmaceutical industry.

Certain of these cases are now on appeal and, on October 30, 2024, the Court of Appeals for the Third Circuit heard oral argument in three of these cases.

Litigation involving these and other provisions of the IRA will continue with unpredictable and uncertain results.

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A number of states, for example, require drug manufacturers and other entities in the drug supply chain, including health carriers, pharmacy benefit managers, wholesale distributors, to disclose information about pricing of pharmaceuticals.

This is increasingly true with respect to products approved pursuant to the accelerated approval pathway.

State Medicaid programs and other payers are developing strategies and implementing significant coverage barriers, or refusing to cover these products outright, arguing that accelerated approval drugs have insufficient or limited evidence despite meeting the FDA’s standards for accelerated approval.

In addition, regional healthcare organizations and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription pharmaceutical and other healthcare programs.

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These laws are evolving and may increase both our obligations and our regulatory risks in the future.

In the health care industry generally, under HIPAA, the HHS has issued regulations to protect the privacy and security of protected health information (“PHI”) used or disclosed by covered entities including certain healthcare providers, health plans and healthcare clearinghouses.

In the health care industry generally, under HIPAA, the

HHS has issued regulations to protect the privacy and security of protected health information (“PHI”) used or disclosed by covered entities including certain healthcare providers, health plans and healthcare clearinghouses.

HIPAA also regulates standardization of data content, codes and formats used in healthcare transactions and standardization of identifiers for health plans and providers.

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HIPAA may apply to us in certain circumstances and may also apply to our business partners in ways that may impact our relationships with them.

Our clinical trials are regulated by the Common Rule, which also includes specific privacy-related provisions.

Our clinical trials will be regulated by the Common Rule, which also includes specific privacy-related provisions.

In addition to federal privacy regulations, there are a number of state laws governing confidentiality and security of health information that may be applicable to our business.

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The provisions in the CPRA may apply to some of our business activities.

In addition to California, at least eleven other states have passed comprehensive privacy laws similar to the CCPA and CPRA.

In addition to California, at least eighteen other states have passed comprehensive privacy laws similar to the CCPA and CPRA.

These laws are either in effect or will go into effect sometime before the end of 2026.

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Some of the provisions of these laws may apply to our business activities.

There are also states that are strongly considering or have already passed comprehensive privacy laws during the 2023 legislative sessions that will go into effect in 2024 and beyond, including New Hampshire and New Jersey.

Other states will be considering these laws in the future, and Congress has also been debating passing a federal privacy law.

There are also states that are strongly considering or have already passed comprehensive privacy laws during the 2024 legislative sessions that will go into effect in 2025 and beyond.

Other states will be considering similar laws in the future, and Congress has also been debating passing a federal privacy law.

There are also states that are specifically regulating health information that may affect our business.

For example, Washington state passed a health privacy law in 2023 that will regulate the collection and sharing of health

information, and the law also has a private right of action, which further increases the relevant compliance risk.

Connecticut and Nevada have also passed similar laws regulating consumer health data and additional states (including Vermont) are considering such legislation for 2024.

For example, the State of Washington passed the My Health My Data Act in 2023 which specifically regulated health information that is not otherwise regulated by the HIPAA rules, and the law also has a private right of action, which further increases the relevant compliance risk.

Connecticut and Nevada have also passed similar laws regulating consumer health data, and more states are considering such legislation in 2024.

These laws may impact our business activities, including our identification of research subjects, relationships with business partners and ultimately the marketing and distribution of our products.

Plaintiffs’ lawyers are also increasingly using privacy-related statutes at both the state and federal level to bring lawsuits against companies for their data-related practices.

In particular, there have been a significant number of cases filed against companies for their use of pixels and other web trackers.

These cases often allege violations of the California Invasion of Privacy Act and other state laws regulating wiretapping, as well as the federal Video Privacy Protection Act.

Because of the breadth of these laws and the narrowness of the statutory exceptions and regulatory safe harbors available under such laws, it is possible that some of our current or future business activities, including certain clinical research, sales and marketing practices and the provision of certain items and services to our customers, could be subject to challenge under one or more of such privacy and data security laws.

The heightening compliance environment and the need to build and maintain robust and secure systems to comply with different privacy compliance and/or reporting requirements in multiple jurisdictions could increase the possibility that a healthcare company may fail to comply fully with one or more of these requirements.

If our operations are found to be in violation of any of the privacy or data security laws or regulations described above that are applicable to us, or any other laws that apply to us, we may be subject to penalties, including potentially significant criminal, civil and administrative penalties, damages, fines, contractual damages, reputational harm, diminished profits and future earnings, additional reporting requirements and/or oversight if we become subject to a consent decree or similar agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

diminished profits and future earnings, additional reporting requirements and/or oversight if we become subject to a consent decree or similar agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

To the extent that any product candidates we may develop, once approved, are sold in a foreign country, we may be subject to similar foreign laws.

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As of February 1, 2025, we had 246 full-time employees, including 46 employees with M.D.

Of these full-time employees, 130 employees are primarily engaged in research and development activities.

In December 2024, we announced a reduction in our employee workforce by approximately 180 positions (the “Reduction”) in connection with the decision to discontinue clinical development of reni-cel.

The Reduction commenced in December 2024, and we expect it to be substantially complete by the end of June 2025.

Following the Reduction, we expect to have approximately 110 full-time employees, including approximately 30 employees with M.D.

Approximately 80 of the 110 employees will be primarily engaged in research and development activities.

None of our employees are represented by a labor union or covered by a collective bargaining agreement.

We anticipate that we will increase headcount in our manufacturing and clinical organizations as we progress the clinical development of reni-cel toward regulatory approval and commercialization, and in our research organization to support the advancement of our in vivo product pipeline.

At Editas, we seek to unlock the full potential of gene editing technology, and we recognize that our success is driven by our dynamic, passionate and diverse team.

In recognition of the importance of our employees to the success of our mission, we aim to create a best-in-class people experience driven by performance excellence.

In 2024, we continued to build on the culture roadmap we set in 2023, focusing on three key areas.

First, we sought to strengthen our next generation of leaders through a formal development series focused on deepening enterprise leadership capability and building our executive succession pipeline.

Second, we conducted extensive workforce planning to ensure that our workforce capabilities and mastery aligned with our corporate strategy, and we engaged with functional leadership on approaches to develop and execute on an enterprise talent strategy.

Third, we sought to expand on the ways in which we engage with our employee community.

To that end, we created the Editas Medicine Culture Committee, which is comprised of a diverse group of employees from varying levels across all functions of our organization.

This committee is tasked with the goal of creating an exceptional workplace experience that enables employees to work effectively, efficiently and enjoyably with speed to achieving our corporate mission.

The committee is structured into six teams:

Learning and Development, Belonging, Inclusion, Diversity, and Equity, Events, Performance and Recognition, Advocacy and Community, and Decision Making, which meet periodically to review and develop executable plans for the continued progress of our cultural mission.

Our Core Values

We work together with integrity, guided by our distinct culture, to develop transformative medicines for people living with serious diseases around the world.

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We strongly believe that our greatest strength comes from the people who make up our team.

Each employee brings diverse perspectives, backgrounds, and thinking styles, and when we champion belonging, inclusivity, diversity, and equity (“BIDE”), we cultivate a culture where every individual feels valued and included.

Each employee brings diverse perspectives, backgrounds, and thinking styles, and when we champion inclusion, we cultivate a culture where every individual feels valued and can thrive.

Our commitment to embracing and celebrating our differences fuels our drive to excel in scientific innovation, allowing us to harness the power of gene editing to develop groundbreaking and life-changing therapies for people living with serious diseases with the greatest unmet needs.

We have cultivated a diverse and inclusive workforce, including in our senior management team, to ensure an environment where employees feel empowered to achieve their fullest potential.

As of December 31, 2023, approximately 53% of our full-time employees were women and 48% of our senior management (director level and above) were women.

As of December 31, 2023, approximately 57% of our full-time employees identify as racially/ethnically diverse and 53% of our senior management identify as racially/ethnically diverse.

In furtherance of our efforts to strengthen our corporate culture, in 2023 we created a team of employees from varying levels across all functions of our organization to review and develop executable plans for the continued progress of our cultural mission.

This team, referred to as the BIDE team, conducted an extensive review of corporate culture best practices, participated in cross-industry discussions, and engaged with our employees, including through surveys and focus group interviews, to develop a set of recommendations to support our commitment to belonging, inclusion, diversity, and equity.

These recommendations, which will begin to be implemented in 2024, include the establishment of a BIDE Council to oversee our cultural development efforts, the launch of a BIDE campaign to facilitate related communications, the development of related training and education programs, and the formalization of internal metrics and benchmarking to ensure we are achieving our cultural goals.

As of December 31, 2024, 55% of our full-time employees were women and 49% of our senior management (director level and above) were women.

Following the Reduction, we expect our full-time employee workforce to be comprised of approximately 53% women and our senior management to be approximately 44% women.

As of December 31, 2024, 41% of our full-time employees identify as racially/ethnically diverse and 29% of our senior management identify as racially/ethnically diverse.

Following the Reduction, we expect our full-time employee workforce to be comprised approximately 35% of individuals who identify as racially/ethnically diverse and approximately 26% of our senior management to be individuals who identify as racially/ethnically diverse.

Recruitment, Retention and Development

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We maintain an internet website at www.editasmedicine.com and make available free of charge through our website our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act of 1934, or the Exchange Act.

We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the Securities and Exchange Commission (the “SEC”).

We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the U.S.

Securities and Exchange Commission (the “SEC”).

You can review our electronically filed reports and other information that we file with the SEC on the SEC’s web site at http://www.sec.gov.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business