−Removed: We are a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies.
−Removed: We are deploying Prime Editing technology, which we believe is a versatile, precise, and efficient gene editing technology.
−Removed: The field of genetic medicine has rapidly evolved over the last decade, with groundbreaking advances in gene therapy, cell therapy, ribonucleic acid, or RNA, therapy, and, more recently, gene editing.
−Removed: This includes the approval of the first CRISPR/Cas9-based gene editing therapy by the U.S.
−Removed: Food and Drug Administration, or the FDA, for the treatment of sickle cell disease.
−Removed: These technologies represent significant advancements for genetic medicines but we believe Prime Editing is the only gene editing technology that, by itself, can edit, correct, insert and delete deoxyribonucleic acid, or DNA, sequences in any target tissue.
−Removed: We believe Prime Editing technology has transformative potential that could change the course of how many diseases are treated and overcome the challenges associated with current genetic therapies.
−Removed: Prime Editing can correct mutations across many tissues, organs, and cell types, in both dividing and non-dividing human cells.
−Removed: For example, Prime Editing technology has the ability to repair diverse mutations, including all types of point mutations, deletion mutations, insertion and duplication mutations and insertion-deletion mutations.
−Removed: Our analysis of more than 75,000 pathological, or disease-causing, mutations found in the National Center for Biotechnology Information ClinVar Database shows that those addressable by Prime Editing technology account for approximately 90 percent of genetic variants associated with disease.
−Removed: As such, we believe Prime Editing technology has the theoretical potential to repair approximately 90 percent of known disease-causing mutations across many tissues, organs and cell types.
−Removed: In addition, we believe our Prime Assisted Site-Specific Integrase Gene Editing, or PASSIGE TM technology, may enable Prime Editing to precisely insert gene-sized sequences.
−Removed: PASSIGE uses Prime Editing to insert one or more recombinase recognition sequences at precisely chosen locations in the genome.
−Removed: In our preclinical studies, we have shown that a site-specific recombinase can locate the recombinase recognition sequence and carry out DNA recombination, resulting in the desired large DNA sequence insertion at the desired location in the genome.
−Removed: We believe that such a technology has the potential to precisely insert “gene-sized” pieces of DNA, at a predetermined and specific site in the genome.
−Removed: Taken together, Prime Editing’s versatile gene editing capabilities have the potential to unlock opportunities across thousands of potential indications.
−Removed: Prime Editors have the ability to create permanent modifications at their natural genomic location, resulting in durable edits that retain their native physiological control and are passed on to daughter cells.
−Removed: Our next generation gene editing technology is designed to produce a wide variety of precise, predictable and efficient genetic outcomes at the targeted sequence, while minimizing unwanted bystander edits and off-target edits and avoiding double-stranded DNA breaks.
−Removed: Our Prime Editors are designed to make only the right edit at the right position within a gene.
−Removed: If nuclease gene editing approaches are “scissors” for the genome, and base editors are “pencils,” erasing and rewriting a subset of single letters in the gene, then Prime Editing is a “word processor,” searching for the correct location and replacing or repairing a wide variety of target DNA.
−Removed: Recent highlights of the programs in our portfolio include the following:
−Removed: • In April 2024, the FDA cleared our IND application for PM359 for the treatment of chronic granulomatous disease, or CGD, a serious life-threatening disease that presents in childhood, enabling us to initiate our global Phase 1/2 clinical trial in the United States.
−Removed: The Phase 1/2 clinical trial is a multinational, first-in-human trial designed to assess the safety and efficacy of PM359 in adult and pediatric study participants.
−Removed: PM359, our first product candidate within our hematology, immunology and oncology area of focus, targets the p47phox variant of CGD.
−Removed: PM359 is comprised of autologous hematopoietic stem cells, or HSC, modified ex vivo using Prime Editors that have been designed to correct cells containing the disease-causing mutation.
−Removed: We believe Prime Editing is uniquely well-suited to address this form of CGD.
−Removed: We have received rare pediatric drug designation, or RPDD, and orphan drug designation, or ODD, from the FDA
−Removed: for PM359 in January 2024.
−Removed: We also have received fast track designation from the FDA for PM359 in November 2024.
−Removed: • We have demonstrated Prime Editing of cells in preclinical studies at predicted therapeutically relevant levels for Wilson’s Disease in our liver area of focus.
−Removed: In October 2024, we presented in vivo proof-of-concept data demonstrating successful correction of a disease-causing mutation in Wilson’s Disease in a fully humanized mouse model and precise editing of the genomic site in non-human primate, or NHP, models using our proprietary, universal liver-targeted lipid nanoparticle, or LNP, platform to deliver the Prime Editor.
−Removed: • We continue to advance multiple Prime Editors in our lung area of focus for the treatment of Cystic Fibrosis, or CF.
−Removed: In January 2024, we entered into a therapeutic development agreement with the Cystic Fibrosis Foundation, or CFF, in which CFF agreed to provide Prime Medicine with up to $15 million to support development of hotspot editing with PASSIGE in CF, as well as our ongoing efforts to develop delivery to the lung.
−Removed: Through hotspot editing, we aim to address multiple mutations at mutational hotspots using a small number of Prime Editors, potentially addressing a large percentage of individuals with CF with only a few Prime Editors.
−Removed: In parallel, using PASSIGE, we aim to address nearly all people with CF using a single superexon insertion strategy.
−Removed: • In September 2024, we entered into a strategic research collaboration and license agreement, or the BMS Collaboration Agreement, with Bristol Myers Squibb, or BMS, via its wholly owned subsidiary, Juno Therapeutics, Inc., or Juno, in which BMS agreed to provide us with a $55.0 million upfront payment and a $55.0 million equity investment in exchange for developing reagents for the next generation of ex vivo T-cell therapies.
−Removed: BMS will be responsible for development, manufacturing and commercialization of the next generation cell therapies, with support from us in gene editing strategy and reagent development.
−Removed: We are eligible to receive more than $3.5 billion in milestones, including up to $185.0 million in preclinical milestones, up to $1.2 billion in development milestones and up to $2.1 billion in commercialization milestones, along with royalties on net sales.
−Removed: • To maximize the potential of our Prime Editing technology, in September 2024, we strategically focused our portfolio to a set of high value programs in the following core areas of focus:
−Removed: hematology, immunology and oncology, liver, and lung.
−Removed: We are identifying partnership opportunities to advance our other programs, including those for neurological diseases, cell therapy, ocular diseases and hearing loss.
−Removed: Our goal is to transform the lives of patients with debilitating diseases through the application of our Prime Editing platform and technology.
−Removed: We are committed to developing safe and efficient therapeutics using Prime Editing approaches to address high unmet need across a broad spectrum of diseases, from rare genetic diseases to severe, chronic and acute diseases.
−Removed: Key components of our strategy are as follows:
−Removed: • Maximize the potential of Prime Editing to benefit patients.
−Removed: We believe our Prime Editing technology and capabilities represent the future of gene editing, with broad applications in medicine and life sciences.
−Removed: Through our proprietary rights to and ongoing advancements building upon this ground breaking gene-editing approach, we have established a clear leadership position in the Prime Editing field.
−Removed: We have built a cross-disciplinary team consisting of dedicated employees and other experts in Prime Editing and drug development who are passionate about our common goal of helping patients live longer, healthier lives.
−Removed: • Deploy our technology to extend the application of one time potentially curative therapeutics to areas that we believe were not addressable before.
−Removed: To unlock the full potential of our Prime Editing technology across a wide range of therapeutic applications, we intend to advance multiple therapeutic programs into the clinic.
−Removed: We are currently focused on high-value programs for genetic diseases that we believe have a fast, direct path to treating patients, and those with high unmet need not currently addressable using other gene-editing approaches.
−Removed: Over time, we intend to push new and innovative technological developments to maximize Prime Editing’s versatile therapeutic potential, and unlock broad opportunities beyond the genetic diseases in our strategically focused pipeline, potentially including immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases.
−Removed: • Advance our pipeline while simultaneously enhancing, validating and enabling our modular platform.
−Removed: We are pursuing a diverse pipeline of investigational therapeutic programs organized around a set of high value programs in our core areas of focus:
−Removed: hematology, immunology and oncology, liver, and lung.
−Removed: We have designed a modular platform within each core area, which we believe will accelerate our ongoing efforts and enable rapid generation of new product candidates.
−Removed: We believe the core components, such as Prime Editors, off-target assays, delivery, manufacturing, clinical, and regulatory can be leveraged to accelerate our pipeline to clinical trials and potential approval.
−Removed: To unlock the full potential of our Prime Editing technology across each of our areas of focus, we intend to use the delivery modality with the most compelling biodistribution and Prime Editing efficiency.
−Removed: We are currently focusing on electroporation for delivery to blood cells and immune cells ex vivo , LNP for non-viral in vivo delivery to the liver, lung and potentially other organs in the future and adeno-associated viruses, or AAV, for viral in vivo delivery to the eye, ear, and potentially the central nervous system, lung and muscle.
−Removed: Our goal is to develop highly modular delivery systems that allow us to rapidly develop new products targeting the same cells/tissues/organs by leveraging the approaches and data that precedes them.
−Removed: • Continue to push the frontier of innovation in gene editing by optimizing and expanding our Prime Editing technology and capabilities.
−Removed: We plan to continue investing in our technology, team and intellectual property with a focus on reinforcing our leadership position and making fundamental progress towards better therapies for patients.
−Removed: • Opportunistically evaluate synergistic and value-creating partnerships to maximize the broad potential of our platform.
−Removed: Our pipeline programs have been internally generated, and we retain worldwide development and commercialization rights to all of our programs except for certain ex vivo chimeric antigen receptor T-cell, or CAR T-cell, programs that are partnered with BMS.
−Removed: Given the broad potential of our technology, we intend business development to play an important role in building Prime Medicine, with the goal of accelerating our pipeline, bolstering our financial resources, and maximizing the potential of Prime Editing.
−Removed: Our overall partnership strategy includes:
−Removed: 1) partnering within our core areas to accelerate and globalize our current pipeline programs at the “right” stage of development;
−Removed: 2) outside our core areas, entering into collaboration or license agreements for programs now that we would not otherwise pursue in the near term;
−Removed: and 3) accessing enabling innovations, such as delivery and manufacturing capabilities.
−Removed: In 2024, we executed on this strategy by entering into a therapeutic development agreement with CFF and a collaboration agreement with BMS.
−Removed: • Lead with our culture of integrity, ethics, innovation and respect in everything we do.
−Removed: We believe the potential of Prime Editing can only be achieved through the coordinated effort of our team and the support of our partners across academia and industry.
−Removed: To push the boundaries of where gene editing can go, we are committed to jointly defining and maintaining a culture that is transparent, develops trust, values integrity and ethics, puts patients first, is science and data driven, and encourages innovation.
−Removed: Current Challenges for the Field of Genetic Medicines
−Removed: Despite significant progress within gene therapy, gene editing, cell therapy, and RNA therapeutics, there remain considerable limitations to current genetic medicine approaches that impede their ability to truly deliver on the promise of a curative, one-time therapy to the broadest set of patients.
−Removed: Non-targeted gene therapy includes using viral vectors, such as AAV, retroviruses such as lentiviruses, or mobile gene elements, such as retrotransposons and transposons, to deliver new copies of genes, or transgenes, to cells.
−Removed: These approaches generally do not correct genes but insert new copies of genes or parts of genes into cells in a non-targeted manner.
−Removed: While having some important benefits, non-targeted gene therapy approaches have many key limitations including limited durability, inability to be re-dosed, variable gene expression, and random integration of transgenes into the genome, which carries the risk of insertional mutagenesis.
−Removed: First generation gene editing methods rely on a class of enzymes called nucleases, such as CRISPR, ZFNs, engineered meganucleases and TALENs, to create double-stranded breaks in DNA at a targeted location.
−Removed: While nuclease-based gene editing approaches can be useful to inactivate a gene, they have several key limitations, including random creation of indels, or chromosomal insertions and deletions, low percentage editing efficiency to
−Removed: make corrections, replacements, or insertions in a gene, the ability to edit only in dividing cells, and unwanted DNA modifications associated with double-stranded breaks, including cell death response, genomic instability, off-target editing and the potential for oncogenesis.
−Removed: Base editing is an emerging gene editing technology that can enable C-to-T, T-to-C, G-to-A or A-to-G base substitutions edits using either a Cytosine Base Editor, or CBE, or Adenine Base Editor, or ABE, respectively.
−Removed: However, base editing has several key limitations including the ability to reliably correct only 4 out of 12 possible single base mutations, the inability to make or correct insertion or deletions, unwanted on-target by-products, called bystander edits, near the targeted site, and limited optionality for targeting mutations due to its smaller editing window.
−Removed: Prime Editing:
−Removed: A Next Generation Gene Editing Approach
−Removed: Prime Editing is a next generation gene editing approach that we believe can address the genetic cause of disease and potentially provide patients with long-lasting cures.
−Removed: Although Prime Editing is a developing technology and is not yet validated in clinical studies, it has been extensively validated in vitro and in animal studies, both by our company and in hundreds of papers published in the primary scientific literature to date.
−Removed: Advantages of our Prime Editing Platform
−Removed: We believe Prime Editing is a versatile, precise, efficient and broad gene editing technology with the following key advantages:
−Removed: Deep and highly differentiated toolbox of editing capabilities to enable a wide variety of therapeutic applications
−Removed: • Applicable to a wide range of target mutations or alterations of DNA, including all twelve types of single base pair corrections, as well the ability to insert and delete DNA sequences.
−Removed: • Direct correction of DNA with no requirement for delivery of the corrected DNA sequence in many applications of Prime Editing.
−Removed: • Modular for targeting a broad set of mutations, meaning that by redesigning the Prime Editing guide RNA, or pegRNA, a new mutation can be targeted for correction while leaving the other Prime Editor components largely unchanged.
−Removed: • Multiple potential therapeutic applications, including but not limited to targeted gene correction, gene silencing or activation such as by altering the regulatory regions of genes, inserting or creating premature stop codons, or modifying splicing sequences, hotspot region replacement, multiplex editing of several genes simultaneously, and wild-type variant modification to protect against or modify risk for a disease.
−Removed: • Capable of inserting, deleting or inverting kilobase amounts of genomic DNA by combining Prime Editing with proprietary recombinase technology in an approach we call PASSIGE.
−Removed: Highly specific and predictable gene editing
−Removed: • Designed to specifically make only the directed type of Prime Edit at the desired target location.
−Removed: • Avoids the potential negative impacts associated with double-stranded DNA breaks, which results in minimal to potentially no unwanted on-target or off-target by-products and preservation of cell viability.
−Removed: • Limited potential for bystander editing at the target site, a potential unwanted effect of base editing.
−Removed: Durable gene edits with potential for superior therapeutic activity
−Removed: • Single treatment resulting in permanent correction of disease-causing mutations by restoring the targeted gene back to its wild-type, or non-diseased sequence.
−Removed: • Permanent, durable edits that persist in a cell and are passed along to daughter cells, creating potential for a life-long, “once and done” therapeutic outcome.
−Removed: • Preservation of natural regulation and a normal number of copies of the gene in the cell by modification of genes under endogenous control, or in their native genomic setting.
−Removed: Able to address a wide range of diseases in multiple tissue types
−Removed: • Applicability in a wide range of human cells, including both dividing and non-dividing human cells, a wide range of organs, tissues and cell types, including primary cells such as hepatocytes, HSC and neurons.
−Removed: • Potential ability to repair approximately 90 percent of all types of mutations known to cause genetically driven disease.
−Removed: • Broad therapeutic potential extending beyond rare genetic diseases to also potentially include severe, chronic, and acute diseases.
−Removed: In addition to correcting disease-causing mutations, potential for gene modification to edit naturally occurring variations within genes known to protect against or modify risk for a disease.
+Added: We are a biotechnology company focused on developing a new class of genetic medicines designed to provide durable, and potentially curative, treatment options for patients with diseases driven by defined genetic alterations, acquired cellular dysfunction, or dysregulated gene expression.
+Added: Our approach is grounded in Prime Editing, a next-generation gene editing technology that enables targeted modifications to genomic DNA without introducing double-stranded breaks.
+Added: We believe Prime Editing represents the most versatile and precise method for rewriting, replacing, or repairing DNA sequences and may allow us to address a broad spectrum of diseases with an improved safety and specificity profile relative to earlier editing technologies.
+Added: We are advancing a pipeline of wholly owned in vivo programs targeting diseases of the liver, Cystic Fibrosis, or CF, programs with the support of the Cystic Fibrosis Foundation, or CFF, and partnered ex vivo programs with Bristol-Myers Squibb, or BMS, supported by our modular delivery and Prime Editor platform.
+Added: Early clinical data from our ex vivo program, PM359 for CGD, have demonstrated restoration of functional protein activity in treated patients, providing clinical validation of Prime Editing and a potentially curative treatment for CGD patients.
+Added: Genetic diseases affecting the liver and lung, as well as hematologic disorders addressed through ex vivo editing, represent our initial development priorities.
+Added: Many of these diseases arise from well-characterized mutations, have established natural histories, and impose meaningful clinical burdens on patients, caregivers and physicians despite available standard-of-care therapies.
+Added: We believe these attributes enable efficient clinical development, clear biomarker-driven readouts, and the potential to demonstrate meaningful patient benefit in early-stage clinical studies.
+Added: Our lead program, PM577 for Wilson Disease, is designed to initially correct the H1069Q mutation in the ATP7B gene and is supported by preclinical data showing targeted correction and restoration of copper homeostasis in animal models.
+Added: We are also developing follow-on Prime Editors capable of addressing additional ATP7B mutations, enabling a modular and efficient expansion of the Wilson franchise.
+Added: In addition, PM647 is being advanced for alpha-1 antitrypsin deficiency, or AATD, another liver targeted disease with substantial unmet need.
+Added: Beyond these efforts, we are progressing a program in CF using Prime Editing delivered via lipid nanoparticles, or LNPs, or adeno-associated viruses, or AAVs.
+Added: We have constructed an integrated Prime Editing platform engineered to support rapid iteration, standardized manufacturing, and shared toxicology and Chemistry, Manufacturing, and Controls, or CMC, pathways across programs, thereby enabling efficient advancement of multiple therapeutic candidates.
+Added: By maintaining core delivery and editor components while altering program-specific guide RNAs and repair templates, we believe we can leverage platform-level knowledge to expedite new candidate identification and streamline IND-enabling activities, especially within common tissues.
+Added: Our organization is intentionally structured to support clinical development and regulatory engagement as we prepare for multiple parallel clinical trials.
+Added: We are investing in scalable manufacturing and quality systems capable of supporting clinical supply for our lead programs.
+Added: Consistent with industry practice, we also seek to augment our internal capabilities through collaborations.
+Added: Our partnership with BMS, focused on applying Prime Editing to ex vivo T-cell engineering, reflects the potential applicability of Prime Editing across therapeutic modalities.
+Added: We believe the insights gained through this collaboration may inform future applications of Prime Editing in immunology and oncology.
+Added: Looking ahead, our strategy is to advance Prime Editing programs through clinical development, leverage our modular platform to expand into additional indications, and pursue disciplined portfolio prioritization anchored in clear scientific, development, and commercial criteria.
+Added: We expect our focus on liver-directed in vivo editing, combined with the modularity of our platform, will allow us to build a pipeline with breadth and depth while maintaining operational efficiency and disciplined capital deployment.
+Added: Ultimately, our goal is to translate Prime Editing into a clinically and commercially validated therapeutic modality for the treatment across an array of severe genetic diseases and tissue types.
Prime Editing Technology
−Removed: Prime Editors have at least two major components, a Prime Editor protein and a pegRNA.
−Removed: Our Prime Editor proteins contain two protein domains.
−Removed: The first domain is a programmable DNA binding domain, often a CRISPR-Cas protein domain, or Cas domain.
−Removed: Cas domains enable targeting of specific DNA sequences, and they have been adapted and engineered to target desired genomic locations in human cells with high specificity.
−Removed: In Prime Editors, programmable DNA binding domains, such as Cas domains, are typically modified such that they do not cause a double-stranded break in the DNA.
−Removed: The second protein domain of Prime Editors is a DNA polymerase domain, often a reverse transcriptase enzyme domain, or RT domain.
−Removed: Reverse transcriptases are DNA polymerase enzymes that write new DNA sequences by copying from an RNA template.
−Removed: In Prime Editing, the RT domain copies the edited DNA sequence directly into the target genomic site where the edit is made.
−Removed: The other main component in Prime Editing is the pegRNA.
−Removed: The pegRNA contains a search sequence, also known as a spacer, which provides a target genomic address for the Prime Editor.
−Removed: This enables the Prime Editor to specifically target a desired gene sequence.
−Removed: The pegRNA also contains a second sequence unique to Prime Editing, a replace sequence, or edit template, which provides a blueprint for the edit that will be made to the target DNA sequence.
−Removed: As shown in the second panel in the figure below, a Prime Editor protein, exemplified using a fusion protein containing a Cas domain and an RT protein domain, and the pegRNA locate the DNA target site using the pegRNA’s search sequence.
−Removed: As exemplified in the figure, when the correct DNA target is found (referred to as “edit check 1,” as described below), the Prime Editor’s Cas domain cleaves, or nicks, one of the two DNA strands, creating a single-stranded 3’ flap.
−Removed: The other DNA strand remains intact and is not cleaved by the Prime Editor, thus avoiding the formation of double-stranded DNA breaks.
−Removed: As shown in the third panel of the figure, the 3’ flap binds to a region of the replace sequence in the pegRNA (“edit check 2”) and “primes” the DNA synthesis.
−Removed: The Prime Editor’s RT domain copies a portion of the replace sequence, which incorporates the desired edit, as shown in the fourth panel.
−Removed: After the desired edit is copied, cellular DNA repair preferentially incorporates the corrected 3’ flap into the gene (“edit check 3”) while removing the excess original DNA sequence.
−Removed: The complementary DNA strand is also corrected through cellular DNA repair, using the Prime-Edited DNA strand as a template.
−Removed: Incorporation of the correction into the complementary DNA strand can be made more efficient by adding a nicking guide RNA, or ngRNA, where the Prime Editor also transiently nicks the complementary strand.
−Removed: The overall result is a target gene sequence that is corrected on both strands of DNA.
−Removed: As highlighted in the figure below, there are three distinct steps in the Prime Editing pathway that require sequence complementarity between the target DNA and pegRNA sequences.
−Removed: Thus, the process of Prime Editing efficiently institutes three “edit checks,” or three sequential steps where the next step occurs when there is sequence complementarity.
−Removed: In addition to the lack of double-stranded DNA breaks, we believe that these “edit checks” are also important in helping to ensure that the right sequence in the genome is precisely edited in the desired manner, thereby minimizing both on- target and off-target mis-editing.
−Removed: Illustration of Editing Mechanism by Prime Editor – No Double-Stranded DNA Breaks
−Removed: Enhancing the Prime Editing Platform
−Removed: The versatile nature of Prime Editing allows for the selection of the right tools for a specific gene edit to optimize for desired effects with high efficiency and precision at the targeted site, while minimizing off-target edits at more distant chromosomal sites.
−Removed: Since Prime Editing was first described, an increase in efficiency as well as an expansion in the scope of applications have been demonstrated and reported in multiple publications and abstracts as well as contributions from our team.
−Removed: Multiple enhancements to our Prime Editing platform, including engineered and chemically modified pegRNAs, enhanced Prime Editors, and DNA mismatch repair modulation, provide us with a versatile toolbox for applying Prime Editing to a wide range of diseases.
−Removed: In addition, our focus on high-throughput screening and machine learning are allowing us to grow our internal technical expertise for Prime Editing optimization and are being used to develop Prime Editors that are both more efficient and more precise.
−Removed: Finally, we are broadening the types of edits that we can make by incorporating recent innovations in Prime Editing, including dual-flap Prime Editing, long-flap Prime Editing, and PASSIGE.
−Removed: Dual-flap Prime Editing and long-flap Prime Editing
−Removed: We have in-licensed certain dual-flap Prime Editing technology developed by Dr.
−Removed: David Liu’s laboratory at Broad Institute, and expanded and improved on its uses.
−Removed: Compared to single-flap Prime Editing, dual-flap Prime Editing uses two Prime Editors instead of one.
−Removed: Dual-flap Prime Editing is designed to achieve efficient editing of a broad range of edit types, including the precise replacement or insertion of DNA sequences that are greater than a hundred bases in length with high efficiency.
−Removed: In addition, dual-flap Prime Editing can precisely delete up to thousands of bases of DNA.
−Removed: Dual-flap Prime Editing has been shown in preclinical studies to achieve similar levels of precision and similarly low off-target editing as single-flap Prime Editing.
−Removed: Dual-flap Prime Editing is being used for PASSIGE™, to replace mutation hotspots with corrected sequences, and could be used to delete expanded repeat sequences, such as those that occur in repeat expansion diseases.
−Removed: Additionally, we have developed a long-flap Prime Editing approach that, compared to our standard single-flap Prime Editing, is designed to more efficiently insert or replace larger stretches of DNA that are a hundred bases or more in length, while also enabling precise deletions of up to thousands of base pairs.
−Removed: Long-flap Prime Editing can be used for editing of hotspot regions in DNA, insertions of recombinase sites for PASSIGE, and the excision of expanded repeats.
−Removed: Together, dual-flap Prime Editing and long-flap Prime Editing broaden the capabilities of our Prime Editing platform.
−Removed: PASSIGE™ – Precise introduction of gene-sized pieces of DNA into the genome
−Removed: We have in-licensed from the Broad Institute and are further internally developing a technology that allows us to expand our gene editing toolbox to include programmable insertion, deletion, or inversion of thousands of bases of DNA.
−Removed: By combining Prime Editing with an integrase or site-specific recombinase enzyme, we can harness the precision of Prime Editing with the ability to introduce large gene-sized cargo into the genome as a potential one-time therapy for patients.
−Removed: This proprietary approach expands the versatility of Prime Editing and we believe
−Removed: broadens the range of permanent genomic edits that Prime Editing can make to encompass the ability to insert entire genes precisely into a patient’s genome to treat disease.
−Removed: PASSIGE leverages the programmability of Prime Editing to insert recombinase recognition sequences at precisely chosen targeted locations in the genome, as shown in the figure below.
−Removed: A site-specific recombinase, either fused to the Prime Editor or transiently delivered as a separate enzyme into target cells, locates the recognition sequence or sequences and carries out DNA recombination at those recognition sequences, resulting in the desired large DNA sequence edit at the desired location in the genome.
−Removed: We believe that such a technology has the potential to precisely insert “gene-sized” pieces of DNA at a predetermined and specific site in the genome.
−Removed: PASSIGE may be used to insert DNA that contains a therapeutic gene, such as a chimeric antigen receptor, or CAR, or the open reading frame of any other gene.
−Removed: Alternatively, using multiplex Prime Editing, two recombinase DNA target sequences can be inserted so that site-specific recombinases can replace, delete, or invert the intervening DNA sequences.
−Removed: These editing capabilities enable therapeutic opportunities to potentially treat genetic mutations occurring across a large region of DNA sequences within a single gene, and enable therapeutic opportunities to engineer cell therapies to treat disease.
−Removed: PASSIGE™ – Extending Prime Editing to insert gene sized sequences precisely in the genome
−Removed: Translating Prime Editors into Product Candidates - Optimizing Prime Editor Components and Delivery Modalities
−Removed: The optimal design and efficient generation of our Prime Editors are fundamental for the development of our pipeline.
−Removed: We have established capabilities to design and optimize our Prime Editors, and to design and develop the components needed for LNPs, vector genomes, Prime Editing of ex vivo cells, as well as to develop the manufacturing processes and analytical assays to ensure robust, scalable production of quality intermediates and products to support our programs.
−Removed: Many of these workflows are automated to allow rapid machine learning and/or artificial intelligence-based data analysis, correlation, visualization, and iterative optimization and innovation.
−Removed: For each program in our pipeline, we determine the best option for delivering the Prime Editor and select the delivery technology with the most compelling biodistribution for a given tissue type.
−Removed: Our current programs rely on two distinct delivery modalities:
−Removed: (a) electroporation for delivery to blood cells and immune cells ex vivo ;
−Removed: and (b) LNPs, for non-viral in vivo delivery to the liver, lung and potentially other organs in the future.
−Removed: We also can deliver Prime Editors using AAVs for viral in vivo delivery to the eye and ear, and potentially the central nervous system, lung and muscle.
−Removed: A key feature of Prime Editing and associated delivery methods is the modularity of the technology platforms.
−Removed: Once the first program for each delivery platform is established, the design algorithms, workflows, non-clinical and CMC data, as well as the manufacturing process and majority of assays can be leveraged and applied to the next program which differs only in the pegRNA.
−Removed: We believe these delivery technologies are foundational to successfully advancing our pipeline programs to the clinic and we are strategically developing our delivery platforms and generating data to accelerate our pipeline progress.
−Removed: Moreover, we continue to assess the many advancements in novel and experimental delivery approaches that are being made in the cell and gene therapy field and intend to license innovative delivery technologies that prove to provide a breakthrough.
−Removed: We are designing Prime Editing product candidates to provide a “once and done” treatment.
−Removed: Our multi-pronged approach to enable our portfolio includes the following:
−Removed: • pegRNA Design, High Throughput Screening and Synthesis:
−Removed: An important element of our capability is leveraging high throughput automated screening and design algorithms to identify promising pegRNA sequences.
−Removed: The data is also used to develop proprietary machine learning algorithms for pegRNA activity prediction.
−Removed: Internal chemistry capabilities facilitate high-throughput optimization and manufacture of pegRNA for in vivo studies.
−Removed: We have established internal high-throughput pegRNA synthesis, pegRNA modifications with structure-activity-relationship to improve drug candidate properties, and pegRNA process chemistry.
−Removed: • Optimization of Prime Editing proteins and recombinase proteins:
−Removed: We have developed internal protein engineering capabilities to optimize the Prime Editor proteins and recombinase proteins (for PASSIGE) for human therapeutic use, and have developed internal messenger RNA, or mRNA, design and optimization, enzymatic chemistry, and process development capabilities to enhance drug candidate properties and characterize the mRNA for efficient, well-tolerated, and consistent delivery and translation of the Prime Editor protein.
−Removed: • Prime Editing Specificity and Assays:
−Removed: A robust and unbiased evaluation of all potential off-target activities is a critical element of our efforts.
−Removed: Our approach to minimizing off-target editing is to start by screening for Prime Editor candidates with very low off-target activity.
−Removed: We then use comprehensive, sensitive, and state-of-the-art methods to identify all putative off-target sites by identifying places where a Prime Editor has a possibility (no matter how small) to nick the DNA.
−Removed: We have developed multiple, complementary, but distinct, methods to measure such possible events.
−Removed: Our approach includes evaluation of:
−Removed: (a) off-target activity in the genome that is specific to the sequence of a particular pegRNA or the ngRNA;
−Removed: (b) similar activity that is independent of the pegRNA or ngRNA sequences;
−Removed: and (c) genomic rearrangements.
−Removed: • Electroporation:
−Removed: Electroporation is a clinically and commercially validated technology for ex vivo delivery to CD34+ cells which utilizes electrical pulses to increase the cell membrane permeability to deliver the Prime Editing components.
−Removed: Electroporation is being used in our CGD program with ex vivo CD34+ cells.
−Removed: We have established a modular cell processing manufacturing platform process that can be used for autologous CD34+ cells, and it can be leveraged for the next ex vivo HSC programs, as well as for allogeneic T-cells with multiplexing.
−Removed: LNP delivery has initially focused on in vivo delivery of Prime Editing to the liver.
−Removed: We have established end-to-end capabilities across our R&D organization consisting of lipid design, lipid synthesis, high throughput LNP discovery from our proprietary lipid library using screening with bar coding technology, LNP formulation process development for tissue targeted delivery, and manufacturing to support our preclinical and IND enabling studies.
−Removed: We are developing a universal liver targeting LNP comprised of 5 components and plan to leverage its modularity for our various programs aimed at Prime Editing in the liver, as well as to address additional mutations within the same indication.
−Removed: Similar approaches are being taken for developing modular LNPs to lung, and HSCs and T-cells.
−Removed: • Viral Delivery:
−Removed: We are able to use viral delivery to tissues and locations that can currently only be reached with AAV.
−Removed: To enable this delivery approach, we have developed capabilities to design and optimize the vector genome to efficiently deliver Prime Editors to the target tissue.
−Removed: We use our internal AAV Reagent Production Core, analytical development team, as well as outsourced resources and partners to generate AAV Prime Editors, quality control test as well as characterize them.
−Removed: • Strategic Manufacturing Partnerships:
−Removed: Our overall strategy is to design manufacturing platforms to make the Prime Editing components and associated delivery systems with high throughput, high quality, high purity, modularity, and scalability.
−Removed: We are developing manufacturing processes and analytical methods
−Removed: both internally and partnering with suppliers to ensure the quality and consistency of the Prime Editor components and Prime Edited drug products needed for preclinical studies, IND application submission, and future clinical studies.
−Removed: To maximize the potential of our Prime Editing technology, we are currently pursuing a diversified portfolio of high value investigational therapeutic programs organized around core areas of focus:
−Removed: hematology, immunology and oncology, liver, and lung.
−Removed: The following table summarizes our pipeline:
−Removed: Our Hematology, Immunology & Oncology Programs
−Removed: Chronic Granulomatous Disease
−Removed: CGD is a rare inherited hematologic disorder characterized by susceptibility to severe, difficult-to-treat infections, and inflammatory/autoimmune complications.
−Removed: CGD is caused by mutations in any one of the subunits comprising the NADPH oxidase complex, which is required for phagocytic cells, in particular neutrophils, to destroy many invasive microorganisms.
−Removed: CGD causative mutations are estimated to occur between one in 100,000 and one in 200,000 births in the United States, and most children are diagnosed within the first three years of life.
−Removed: Beginning in childhood, patients with CGD develop infections from a range of both typical and unusual bacteria, fungi and mycobacteria.
−Removed: These infections may present in various organ systems, and protracted infections can lead to long-term organ damage and failure.
−Removed: In addition, patients have non-infectious inflammatory disease, most commonly presenting as inflammatory bowel disease, soft tissue granulomas, and strictures of the urinary or digestive tract.
−Removed: Undiagnosed or untreated, the infectious manifestations of CGD are rapidly fatal.
−Removed: Approximately 60 percent of patients with CGD reach age 30 and refractory or antimicrobial resistant infection is the leading cause of mortality.
−Removed: The NADPH oxidase complex has five domains encoded by five separate genes.
−Removed: Loss-of-function mutations in any of these genes can present as CGD.
−Removed: The second most common form, which represents approximately 25 percent of cases, is caused by biallelic loss-of-function mutations, in both copies of the NCF1 gene encoding the p47phox protein.
−Removed: More than 78 percent of p47phox CGD patients have a specific, 2-nucleotide deletion, or ΔGT, in the NCF1 gene.
−Removed: The NCF1 gene location is complex, and also contains pseudogenes, or copies of the NCF1 gene that in most healthy individuals, and in individuals with CGD, are inactivated by the ΔGT mutation.
−Removed: Preclinical studies have demonstrated that correcting just one copy of the ΔGT mutation in either the NCF1 gene or any pseudogene restores protein expression and full NADPH oxidase activity.
−Removed: X-linked CGD, or X-CGD, is the most common form of CGD, representing approximately 65 percent of cases.
−Removed: X-CGD is caused by mutations in the CYBB gene, which encodes the p91-phox protein.
−Removed: X-CGD primarily affects male patients because the CYBB gene is located on the X chromosome.
−Removed: Our Approach and Results:
−Removed: Direct correction of prevalent CGD mutations or hotspots
−Removed: PM359, our first product candidate within our hematology, immunology and oncology area of focus, targets the p47phox variant of CGD.
−Removed: We have been able to demonstrate that Prime Editing precisely corrects the ΔGT mutation in the NCF1 gene to restore p47phox protein expression and NADPH oxidase activity.
−Removed: PM359 is comprised of autologous HSCs modified ex vivo using Prime Editors that have been designed to correct a high percentage of cells containing the disease-causing mutation.
−Removed: PM359 is delivered as an autologous HSC transplant, and is designed to restore normal immunologic function in individuals with p47phox CGD, without the risks of graft-versus-host disease, or GVHD, graft rejection and post-transplant immunosuppression associated with allogeneic transplantation.
−Removed: In order to develop PM359, a therapeutic product candidate to treat patients with p47phox CGD, we screened pegRNA and ngRNA to identify Prime Editing guides and guide pairs that have high activity and perform precise editing at the NCF1 locus.
−Removed: Because healthy donors have NCF1 pseudogenes bearing the same ΔGT mutation, we have been able to utilize healthy donor CD34+ HSCs to demonstrate precise editing of the ΔGT mutation.
−Removed: Using healthy donor CD34+ HSCs we also have been able to demonstrate a very low off-target potential, and robust engraftment and hematopoietic functionality of Prime Edited HSCs in mouse models.
−Removed: We have confirmed these findings using p47phox CGD patient-derived HSCs, and in addition have demonstrated that Prime Editing is able to restore NADPH oxidase activity in patient-derived cells.
−Removed: The overall process for generating PM359 follows a similar paradigm to that employed by other investigational ex vivo HSC CRISPR-Cas9 therapeutics that have been validated in the clinic, with a few notable modifications.
−Removed: The Prime Editor components, comprised of the Prime Editor mRNA, pegRNA and ngRNA, are delivered to CD34+ HSCs using electroporation.
−Removed: We have developed Prime Editor components that are able to correct over 80% of healthy donor CD34+ cells or CGD patient CD34+ cells at at least one ΔGT locus (pseudogene in healthy donor;
−Removed: pseudogene or NCF1 in patient).
−Removed: In order to be able to understand the effects of Prime Editing on the functionality of modified CD34+ cells and to determine the ability of Prime Edited cells to persist in vivo , we administered Prime Edited CD34+ cells to a specialized immunocompromised mouse model, the NBSGW mouse, which is capable of supporting engraftment of human HSCs.
−Removed: As shown in the figure below, mice are typically followed for 16 weeks in these experiments to allow for engraftment of the long-term HSCs and repopulation of the immune system by long-term HSCs and then evaluated for durability of effect.
−Removed: When Prime Edited healthy donor or CGD patient CD34+ cells were administered to NBSGW mice, they were able to engraft, and edited cells proliferated to repopulate the hematopoietic system.
−Removed: The left and middle panels in the figure below demonstrate results from a representative experiment in which healthy donor CD34+ cells, either Prime Edited or mock treated, were administered to NBSGW mice.
−Removed: In the left panel of the figure below, human hematopoietic cells, distinguished by the human CD45+ surface marker, were able to successfully engraft at high efficiency, with no differences between mock treated and Prime Edited cells.
−Removed: In the middle panel, after 16 weeks in the mice, long-term engrafted human CD34+ HSCs retained a very high degree of editing:
−Removed: over 80% of cells exhibited correction of the ΔGT mutation at at least one locus, compared to 0% of mock edited cells.
−Removed: Based on natural history studies of carriers of CGD-causative mutations, restoration of p47phox function in a minimum of 20% of neutrophils is believed to be sufficient to confer protection from serious infection with CGD-associated pathogens.
−Removed: Together these data suggest that Prime Editing is able to correct the ΔGT mutation at an efficiency many-fold above the lower bound of the projected threshold for therapeutic benefit, and that Prime Edited cells may effectively home to and stably engraft in the marrow after infusion.
−Removed: CD34+ HSCs from an individual with p47phox CGD were Prime Edited ex vivo , and these cells were differentiated ex vivo to allow assessment of NADPH oxidase activity in myeloid progeny.
−Removed: The panel on the right in the figure
−Removed: below demonstrates the results of one commonly used measure of NADPH oxidase activity, the dihydrorhodamine (DHR) assay.
−Removed: Mock edited CGD patient-derived and differentiated cells produced negligible amounts of NADPH oxidase, reflected in the absence of any DHR positive cells.
−Removed: In contrast, NADPH oxidase activity was restored in approximately 80 percent of Prime Edited CGD patient cells, very closely corresponding to the editing rate observed in healthy donor CD34+ cells in the middle panel.
−Removed: This level significantly exceeds the projected therapeutic minimum threshold of DHR activity in 20 percent of neutrophils thought to be sufficient to prevent serious infection based on natural history studies.
−Removed: Additionally, these results confirm that editing rates in CGD patient derived CD34+ cells are similar to those in healthy donor cells, and that healthy donor cells are a useful proxy for understanding the Prime Editing reagents used to generate PM359.
−Removed: HSC = hematopoietic stem cell;
−Removed: LT-HSC = long term HSC;
−Removed: DHR = dihydrorhodamine;
−Removed: normalized to healthy donor control.
−Removed: Data presented at ASGCT and ESGCT 2023.
−Removed: Prime Edited CD34+ cells exhibited no significant off-target editing and no detectable evidence of deletions or translocations above the level of significance.
−Removed: Extensive in silico, ex vivo and in vivo analyses have been performed.
−Removed: The figure below demonstrates representative analyses.
−Removed: In the left panel, 550 of the most likely candidate off-target sites were nominated based on in silico assessment, and then interrogated for off-targeting editing in Prime Edited healthy donor CD34+ cells;
−Removed: no significant off-target editing was detected.
−Removed: In the middle panel, the marrow of NBSGW mice receiving either mock or Prime Edited human CD34+ cells was assessed for large deletions or translocations 16 weeks after engraftment;
−Removed: there was no difference between mock treated and Prime Edited cells, and neither had any detectable evidence of deletions or translocations above the level of significance.
−Removed: In the right panel, a human cell line was transfected with spCas9 targeting NCF1 without the Prime Editing machinery.
−Removed: Unlike Prime Editing, spCas9 introduces double strand breaks in DNA as part of its expected mechanism of action.
−Removed: In contrast to the Prime Editor, spCas9 by itself introduced a high rate of translocations.
−Removed: 1 Analysis of edited CD34+ cells from CGD program:
−Removed: Targeted in vitro Analysis of 550 potential off-target sites of off-target editing.
−Removed: 2 Data from in vivo analysis from mouse bone marrow harvested 16 weeks after engraftment was complete.
−Removed: 3 Positive control.
−Removed: In August 2023, we received RPDD from the FDA for PM359 for the treatment of CGD.
−Removed: Companies that receive approval for a New Drug Application, or NDA, or Biologics License Application, or BLA, for a rare pediatric disease may be eligible to receive a voucher for priority review of a subsequent marketing application for a different product.
−Removed: If we receive a priority review voucher, or PRV, it may be used by us or sold to a third party.
−Removed: In January 2024, we received Orphan Drug designation from the FDA for PM359 for the treatment of CGD.
−Removed: We also have received fast track designation from the FDA for PM359 in November 2024.
−Removed: In April 2024, the FDA cleared our IND application for PM359 for the treatment of CGD, enabling us to initiate our global Phase 1/2 clinical trial in the United States.
−Removed: The Phase 1/2 clinical trial is a multinational, first-in-human trial designed to assess the safety and efficacy of PM359 initially in adult study participants and then in adolescent and pediatric study participants who have p47phox CGD due to the ΔGT mutation in NCF1, and are medically suitable to undergo autologous HSCT.
−Removed: Autologous CD34+ cells will be collected from study participants and edited with Prime Editing reagents to generate PM359.
−Removed: PM359 is then infused into study participants after myeloablative conditioning, who will be followed for three years in the primary study, and an additional 12 years as part of the long-term follow-up period.
−Removed: Participants will be followed for safety, including engraftment and reconstitution of the hematopoietic system, as well as early biological markers of restored immune function including the DHR assay, and for the long-term resolution and prevention of infectious and inflammatory complications of CGD.
−Removed: The Phase 1/2 clinical trial is currently enrolling patients, and we anticipate sharing initial clinical data from this trial in 2025.
−Removed: After obtaining clinical data from the Phase 1/2 clinical trial and alignment with the FDA, we intend to enroll study participants in a pivotal clinical trial for PM359.
−Removed: We also are continuing our preclinical development of Prime Editors to treat X-CGD.
−Removed: Using PASSIGE, we believe we can address greater than 90 percent of mutations in the CYBB gene and intend to leverage modular elements of our PM359 program to aid in advancement of this program.
−Removed: Our Liver Program
−Removed: Wilson’s Disease
−Removed: Wilson’s disease, or WD, is a devastating rare disease of the liver, with manifestations throughout the body, that is caused by copper accumulation.
−Removed: Most people are diagnosed with WD between ages five and 35 years and with reported prevalence rates ranging between one in 10,000 and one in 30,000, it is expected to affect upwards of 35,000 to 100,000 patients in the United States and Europe.
−Removed: It is also understood that there may be significant under-diagnosis of WD.
−Removed: Normally, excessive copper is excreted through the liver as bile.
−Removed: For patients with WD, copper is not eliminated correctly and accumulates to toxic levels.
−Removed: While the key site of pathology is the liver, and many patients present with liver disease, patients often show persistent neurological problems including involuntary movements, tremor, gait disturbance, and kidney, hematological or psychiatric problems.
−Removed: WD is an autosomal recessive disorder, meaning that there are mutations in both genomic copies of the ATP7B gene, which encodes a copper transporter protein that removes excess copper.
−Removed: Two predominant mutations have been described in WD:
−Removed: H1069Q, found in approximately 30 to 50 percent of all WD patients in the United States and 18 to 72 percent of WD patients in Europe;
−Removed: R778L, frequently found in Asian WD patients and those of Asian ancestry, reported in 46 percent of Chinese WD patients, 38 percent of Korean WD patients, and 25 percent of Japanese WD patients.
−Removed: We are currently designing Prime Editors for both of these mutations, which lie adjacent to hotspots or areas with other pathogenic mutations.
−Removed: Our Approach and Results:
−Removed: Direct correction of prevalent ATP7B mutations
−Removed: Our initial approach to WD is to correct the prevalent mutations ATP7B H1069Q and R778L in hepatocytes of the liver at their genomic location.
−Removed: A Prime Editor that corrects R778L will also correct R778W and R778G mutations, rarer mutations that are observed in the U.S.
−Removed: We have performed pegRNA and ngRNA screens and identified guide combinations that correct the disease-causing point mutations.
−Removed: We believe correction of the gene in the liver should address all aspects of the disease by normalizing the process in which the body removes copper in the liver.
−Removed: We have identified a formulation, PM577, comprising a Prime Editor encapsulated as RNA cargo in a liver-targeted lipid nanoparticle (LNP), as a lead candidate to precisely correct the H1069Q mutation in ATP7B.
−Removed: In vivo administration of PM577 in a fully humanized homozygous p.H1069Q ATP7B mouse model achieved greater than 70 percent precise correction of hepatocytes (left panel, figure below) leading to a greater than 75% reduction of copper in the liver 28 days following treatment (middle panel, figure below).
−Removed: We have also observed up to 51 percent precise correction of NHP hepatocytes in vivo following intravenous administration of an LNP-encapsulated, surrogate Prime Editor (right panel, figure below).
−Removed: No off-target edits or unintended edits at the target site were detected in the in vivo humanized mouse or NHP studies.
−Removed: We have initiated IND enabling studies to develop PM577 for the treatment of WD and are on track to submit an IND and/or Clinical Trial Application, or CTA, in the first half of 2026.
−Removed: Non-Viral Delivery In Vivo with Lipid Nanoparticles
−Removed: LNPs are multicomponent systems that encapsulate the Prime Editor cargo to prevent its degradation by the ubiquitous endonucleases present in biological fluids, thereby enabling the transient delivery and expression of the Prime Editor in cells.
−Removed: We are investing strategically to build our LNP formulations for delivery as a platform technology to enable target tissue delivery.
−Removed: Specifically, we are establishing end-to-end capabilities including design and synthesis of proprietary lipids, high-throughput LNP screening in vivo using complementary and orthogonal approaches such as DNA bar coding and next generation sequencing, LNP formulation process development, manufacturing of preclinical and clinical formulations, and in vivo evaluation of LNP delivered Prime Editors.
−Removed: We are integrating automation, analytical quality control, characterization data, in vitro and in vivo preclinical data, along with data knowledge management tools such as machine learning to develop correlative analyses that we believe can expedite LNP discovery and inform drug product formulation development and drug product specification setting.
−Removed: We believe that building an iterative and integrated system will increase efficiencies in identifying potent and safe LNPs capable of delivering Prime Editors to extra-hepatic tissues.
−Removed: We have developed a Universal LNP delivery system (see schematic in figure below) that is targeted to the liver, and specifically targets the LNP to the hepatocytes.
−Removed: This approach, we believe, improves biodistribution to the target cell type.
−Removed: We expect that the LNP system will be modular in that simply swapping out the pegRNA (and ngRNA where required) will result in a new product, with the potential to accelerate the development of additional liver programs thereafter.
−Removed: Our Lung Program
−Removed: Cystic Fibrosis
−Removed: CF is a progressive lung disease characterized by production of thick mucus lung secretions which lead to blockage of airways, inflammation, and lung infection, progressing ultimately to lung failure.
−Removed: It also affects the pancreas gland and biliary system of the liver in a similar way, leading to exocrine pancreatic failure and mild to moderate cholestatic liver disease in some patients.
−Removed: Overall CF prevalence in the United States and Europe is approximately 70,000 to 90,000 people (~40,000 in the United States), and while significant progress in the last decade has created therapeutic options for many patients (e.g., TRIKAFTOR ® ), there is no cure and existing treatments are ineffective or not tolerated for approximately 15 percent of patients.
−Removed: The disease is an autosomal recessive disorder caused by loss-of-function mutations in a chloride protein transporter called the CF transmembrane conductance regulator, or CFTR.
−Removed: Approximately 65 to 75 percent of CF patients have a three-nucleotide deletion in the CFTR gene known as F508del.
−Removed: The vast majority of remaining patients have one of several prevalent mutations in a small number of genetic hotspots in the CFTR gene, including mutations such as N1303K, W1282X, G542X, or G553X / G551D and I507del.
−Removed: Our Approach:
−Removed: Correct prevalent mutations and mutational hotspots in the CFTR gene
−Removed: We intend to progress two distinct strategies for applying Prime Editing to treat CF:
−Removed: hotspot editing and PASSIGE.
−Removed: Through hotspot editing, we aim to address multiple mutations at CFTR mutational hotspots with a small number of Prime Editors.
−Removed: In parallel, with PASSIGE, we aim to address nearly all people with CF with a single CFTR superexon insertion strategy.
−Removed: The hotspot editing strategy has the potential to address a large percentage of individuals having CF with only a few Prime Editors, with a particular focus on the 15 percent of patients who cannot be treated with current therapy.
−Removed: Preclinical data generated by us suggest that using only eight hotspot Prime Editors could benefit more than 93 percent of all people with CF, including those living with nonsense and rare mutations whose disease is not amenable to treatment with currently approved therapies, as well as those who do not tolerate existing therapies.
−Removed: We have achieved greater than 60% precise editing of the G542X mutational hotspot in human lung progenitor cells and showed phenotypic restoration of CFTR protein in differentiated human lung cells in air-liquid interface culture (see figure below).
−Removed: We believe the human lung progenitor data are the most predictive of in vivo efficacy.
−Removed: Pursuant to our therapeutic development agreement with the Cystic Fibrosis Foundation, or CFF, we are aiming to deliver a one-time therapy that would offer the first cure to patients living with CF, including those with high unmet need mutations.
−Removed: We are continuing preclinical development of our hotspot Prime Editors and a superexon insertion approach using PASSIGE technology, including testing in animal models and developing delivery systems.
+Added: Prime Editing is a gene editing approach that uses a Cas9 nickase fused to a reverse transcriptase and guided by a prime editing guide RNA, or pegRNA, to introduce defined edits at specified genomic locations.
+Added: Unlike CRISPR nuclease systems that rely on double-stranded DNA breaks, or DSBs, and endogenous repair pathways such as non-homologous end joining, Prime Editing creates a single-stranded nick and directs the incorporation of a desired edit through reverse transcription using the pegRNA as a template.
+Added: This method enables the precise correction, insertion, deletion, or replacement of DNA sequences and is capable of addressing a wide range of genetic abnormalities, including those not amenable to base editing or traditional homology-directed repair approaches.
+Added: The pegRNA used in Prime Editing contains three functional components:
+Added: (i) a spacer sequence that directs the Prime Editor to the target genomic locus;
+Added: (ii) a primer binding site that anneals to the nicked target DNA strand;
+Added: and (iii) a reverse transcription template that encodes the desired edit.
+Added: Upon binding to the target site, the Cas9 nickase creates a single-stranded break, enabling hybridization of DNA to the primer binding site of the pegRNA to initiate reverse transcription.
+Added: The reverse transcriptase enzyme then extends the DNA strand using the pegRNA as a template, and the edit-containing DNA strand is incorporated through endogenous repair mechanisms.
+Added: We believe Prime Editing offers several potential advantages.
+Added: Because it does not require DSBs, it eliminates the formation of indels, chromosomal rearrangements, or large-scale genomic disruptions, each of which has been observed with nuclease-based genome editing.
+Added: Prime Editing also enables multi-base edits, transversion base pair edits, and the installation or removal of long DNA sequences, allowing for broad applicability across mutation types.
+Added: Preclinical data across various disease models have demonstrated high editing efficiencies with undetectable off-target activity.
+Added: As a platform, Prime Editing benefits from modular design principles:
+Added: core editing machinery can be paired with disease-specific pegRNAs, enabling rapid adaptation to new targets while maintaining consistent delivery and CMC characteristics.
+Added: We have developed a suite of Prime Editors optimized for different cell types and genomic contexts.
+Added: These include Prime Editor variants with enhanced activity, increased specificity, expanded PAM compatibility, and/or reduced size which can be delivered by LNP or AAV.
+Added: Our platform uses systematic, high-throughput screening of Prime Editor components to identify optimal combinations of guide RNAs, reverse transcriptase templates, Cas9, and reverse transcriptase, or RT, protein variants tailored to specific gene targets and programs.
+Added: We believe continued innovation in editor engineering, guide design, and delivery technologies will support the expansion of Prime Editing across therapeutic areas.
+Added: Differentiation of Prime Editors vs.
+Added: CRISPR Nucleases, Base Editors, and RNA Editors
+Added: The gene editing landscape includes several modalities, each with distinct mechanisms, capabilities, and risk profiles.
+Added: Prime Editing is differentiated from CRISPR nucleases, base editors, and RNA editing tools on multiple dimensions, including precision, versatility, and expected genomic stability.
+Added: CRISPR nucleases, such as Cas9 and Cas12a, introduce DSBs at target sites, triggering endogenous DNA repair mechanisms that can result in unintended insertions or deletions (indels).
+Added: These outcomes can disrupt gene function and may lead to chromosomal rearrangements or translocations.
+Added: While nuclease-based editing has demonstrated clinical efficacy for disruption of genes or regulatory elements through the formation of indels, the risk of DSB-associated genomic instability remains a consideration.
+Added: By contrast, Prime Editing uses a single-strand nick, which reduces reliance on error-prone repair pathways and is associated with a lower frequency of indels or structural variants in preclinical studies.
+Added: Moreover, Prime Editing is capable of making a variety of precise edits including those that directly correct pathogenic variants.
+Added: Base editors primarily perform targeted C•G-to-T•A or A•T-to-G•C conversions without generating DSBs but are constrained to specific substitution types and may introduce bystander edits at adjacent nucleotides within the editing window.
+Added: These unintended edits may alter protein function or introduce novel variants with unknown effects.
+Added: Prime Editing enables broader editing outcomes, including transversions, multi-base corrections, and small insertions and deletions, while eliminating bystander activity through the use of a reverse transcription template that encodes only the intended edit.
+Added: RNA editing technologies, including ADAR-based tools, modify RNA transcripts rather than genomic DNA.
+Added: These approaches enable transient modification of gene expression but do not provide permanent correction and must be repeatedly administered to maintain therapeutic effect.
+Added: Furthermore, RNA editing is typically limited to A-to-I or C-to-U transitions and cannot address many pathogenic variants.
+Added: Prime Editing produces permanent genomic changes and can address mutation types not amenable to RNA editing.
+Added: Across multiple preclinical programs, including Wilson Disease and AATD, Prime Editing has demonstrated high editing efficiencies and favorable specificity profiles.
+Added: For example, our lead Wilson program has shown targeted correction exceeding 80% in humanized mouse models with normalization of disease-relevant biomarkers with no detectable off-target editing.
+Added: In AATD, comparative analyses with other gene editing approaches have highlighted Prime Editing’s ability to restore wild-type protein expression.
+Added: While clinical data will be required to determine the relative benefits of each modality, we believe Prime Editing has the potential to enable precise and durable correction across a broad range of genetically defined diseases.
+Added: Prime Editing Platform Architecture
+Added: The core components of our platform include the Prime Editor enzyme, pegRNAs, and delivery vehicles.
+Added: We use Cas9 nickase-reverse transcriptase fusion proteins engineered for enhanced activity and specificity.
+Added: For pegRNA design, our modular process incorporates computational modeling, high-throughput screening, and empirical testing to identify optimal guide and template configurations.
+Added: This design framework allows us to rapidly adjust pegRNAs for new mutations while maintaining the same underlying editor and delivery system.
+Added: Modularity and Development Efficiency
+Added: Modularity is central to our platform.
+Added: The core editing machinery and delivery system can be held constant while substituting mutation-specific pegRNAs and, frequently, the mRNA.
+Added: Modular design supports several anticipated efficiencies:
+Added: • High-Throughput Modular Editor Screening:
+Added: Our systematic screening of editor variants and pegRNA constructs allows us to identify optimal combinations for each target with reduced development timelines.
+Added: • Shared Toxicology Framework:
+Added: When delivery systems and editors are conserved, toxicology packages may be broadly informative across programs.
+Added: This approach supports the rationale for an umbrella-IND strategy in certain mutation clusters, such as Wilson Disease, where multiple ATP7B mutations may be addressed using editors delivered via the same LNP backbone.
+Added: • Shared CMC and Manufacturing Pathways:
+Added: Retaining common LNP compositions and editor constructs across programs allows us to leverage prior manufacturing experience, reduce analytical complexity, and streamline scale-up.
+Added: • Guide-RNA Swapping and Mutation-Specific Scalability:
+Added: Because only the pegRNA sequence changes to address a new mutation, we can generate follow-on candidates rapidly and evaluate them using standardized in vitro and in vivo assays.
+Added: • Clinical Development:
+Added: Conserved delivery systems and editor architectures across programs enables harmonized clinical trial designs, shared biomarker strategies, and standardized dose-escalation frameworks.
+Added: This modularity has the potential to reduce protocol complexity, support cross-program learning, and improve capital efficiency as multiple mutation-specific candidates advance through clinical development.
+Added: • Regulatory:
+Added: Consistency in editor components, delivery systems, and manufacturing processes may facilitate more efficient regulatory interactions by allowing prior nonclinical, CMC, and clinical experience to inform subsequent submissions.
+Added: We believe this platform-level continuity supports a more predictable regulatory review process, particularly for follow-on candidates targeting distinct mutations within the same gene or disease area.
+Added: Corporate Strategy
+Added: Our corporate strategy is designed to advance Prime Editing as a differentiated therapeutic modality, with a focus on operational discipline, scientific rigor, and development credibility.
+Added: We intend to pursue a sequenced development approach that emphasizes indications with clear genetic etiology, substantial unmet medical need, and well-defined clinical and regulatory pathways.
+Added: Liver-directed diseases represent our initial strategic priority because they are driven by mutations in genes expressed in hepatocytes, generally rely on established biomarkers and imaging modalities for assessing treatment response, and are amenable to LNP-based systemic delivery.
+Added: These characteristics support efficient early clinical development and alignment with regulatory agencies.
+Added: A core strategic objective is to utilize the modularity of our Prime Editing platform to expand our pipeline while maintaining development efficiency.
+Added: By conserving our Prime Editor architecture and LNP delivery system across programs, we aim to reduce CMC and toxicology burden for follow-on candidates and potentially enable umbrella regulatory strategies in diseases with heterogeneous mutation landscapes and across diseases utilizing shared Prime Editing components.
+Added: This approach is particularly relevant for Wilson Disease, where multiple ATP7B mutations account for a large portion of the global patient population.
+Added: Through continued investment in editor optimization and guide design, we intend to develop and advance mutation-specific editors that leverage shared platform components.
+Added: We also seek to maintain disciplined portfolio prioritization.
+Added: As disclosed in prior periods, we narrowed our internal focus from a broader set of early-stage programs to a concentrated pipeline centered on in vivo liver-directed editing, where we believe Prime Editing can offer the most immediate clinical and regulatory impact.
+Added: We intend to evaluate additional indications using a structured framework that considers scientific feasibility, clinical and regulatory tractability, and long-term commercial value.
+Added: Future investments will be guided by a balanced assessment of risk, resource requirements, and strategic value.
+Added: Partnerships represent another core component of our strategy.
+Added: We intend to collaborate with organizations that offer complementary capabilities, such as cell therapy expertise, manufacturing scale, or disease-area specialization.
+Added: Our partnership with BMS exemplifies this approach, enabling the application of Prime Editing to ex vivo T-cell engineering without diverting internal resources from our core in vivo pipeline.
+Added: We will continue to evaluate collaborations that allow us to expand the reach of Prime Editing and bolster our financial resources while focusing internal efforts on areas of highest strategic priority.
+Added: Finally, we are investing in manufacturing, quality systems, and regulatory infrastructure to support the advancement of multiple programs into clinical trials.
+Added: These investments include LNP manufacturing processes, analytical method development, and IND-enabling studies.
+Added: We intend to maintain readiness for multiple IND/Clinical Trial Application, or CTA, submissions and to support the transition to clinical-stage operations, including potential early-phase trial execution and regulatory interactions.
+Added: Pipeline Overview
+Added: Our pipeline includes wholly owned in vivo programs targeting liver genetic diseases - Wilson Disease, AATD - as well as early-stage discovery efforts in CF.
+Added: In addition, our PM359 program in chronic granulomatous disease serves as a validation of Prime Editing in humans and we plan to submit a BLA following final regulatory alignment.
+Added: We also have a collaboration with BMS to apply Prime Editing to ex vivo T-cell engineering for oncology and immunology indications.
+Added: PM359 for Chronic Granulomatous Disease
+Added: Clinical Overview and Data Summary
+Added: PM359 is an ex vivo Prime Editing program designed to correct the ΔGT mutation in the NCF1 gene, the most common cause of CGD.
+Added: We believe this program provides important validation of Prime Editing in human cells.
+Added: In a Phase 1/2 clinical study conducted in patients undergoing autologous hematopoietic stem cell transplantation, PM359 demonstrated rapid and durable restoration of NADPH oxidase activity to levels exceeding established therapeutic thresholds, accompanied by prompt neutrophil and platelet engraftment within two to three weeks post-transplant.
+Added: Both patients remained free of new CGD-related complications or significant intercurrent illness during follow-up, with one patient showing improvement in inflammatory markers, supporting the potential for clinically
+Added: meaningful disease modification rather than biomarker correction alone.
+Added: No serious adverse events attributable to Prime Editing were reported as of disclosed data cutoffs.
+Added: Scientific Importance
+Added: The PM359 clinical data support the feasibility of Prime Editing in human cells, providing evidence of on-target correction, restoration of protein function, and clinically meaningful cellular activity.
+Added: These results contribute to the validation of Prime Editing as a therapeutic modality and inform our ongoing development of in vivo programs.
+Added: Regulatory and Clinical Development Plans
+Added: Given the severity of CGD, its limited patient population and encouraging initial clinical data, we believe there may be an expedited path forward to ensure patient access to PM359.
+Added: Discussions are underway with the FDA to explore a potential accelerated path to approval in the United States.
+Added: PM577 for Wilson Disease
+Added: Disease Background and Prevalence
+Added: Wilson Disease is a rare autosomal recessive disorder caused by loss-of-function mutations in ATP7B, a copper-transporting ATPase expressed in hepatocytes.
+Added: This commonly results in impaired biliary copper excretion and copper accumulation in the liver, brain, and other tissues.
+Added: The condition affects an estimated 1 in 30,000 individuals across the United States, Europe, and Japan.
+Added: The H1069Q mutation is the most prevalent variant in North America and Europe, accounting for approximately 30% to 50% of affected individuals in the United States.
+Added: Six of the most common mutations – including H1069Q and R778L – account for up to 26,000 patients across the United States, Europe, and Japan.
+Added: Clinical manifestations range from hepatic steatosis and compensated cirrhosis to acute liver failure and neurological impairment.
+Added: Existing standard-of-care therapies include copper chelators and zinc salts, which require lifelong adherence, are associated with significant pill burden, have tolerability issues, and reflect a disease paradigm with a continued high unmet need.
+Added: Prime Medicine’s Therapeutic Approach
+Added: PM577 is an in vivo Prime Editing candidate designed to correct the H1069Q mutation and restore ATP7B function in hepatocytes.
+Added: Because only a single nucleotide is altered in the H1069Q variant, PM577 is designed to rewrite this specific position to restore expression of the wild-type ATP7B protein and reestablish copper transport and excretion.
+Added: PM577 comprises a Prime Editor enzyme delivered with a mutation-specific pegRNA via our universal liver-targeted LNP.
+Added: We have optimized our liver-targeted LNP for hepatocyte delivery with a goal of high on-target editing, and no detectable off-target activity in pre-clinical models.
+Added: Key Preclinical Data
+Added: Preclinical studies of PM577 have demonstrated efficient correction of the H1069Q mutation in vitro and in vivo .
+Added: In a partially humanized homozygous H1069Q mouse model, Prime Editing achieved greater than 80% correction of hepatocytes at clinically relevant doses.
+Added: Importantly, copper-64 PET imaging showed restoration of physiological copper distribution, including normalization of hepatic copper metabolism by eight weeks post-treatment and increased fecal copper excretion consistent with wild-type animals.
+Added: Histological and biochemical analyses confirmed reductions in hepatic copper concentrations, and no off-target edits were detected in initial assessments.
+Added: Regulatory and Clinical Development Plans
+Added: We plan to submit an IND/CTA for PM577 in 1H 2026.
+Added: The planned Phase 1/2 clinical trial is expected to enroll adult patients with H1069Q-variant Wilson Disease who are maintained on standard-of-care therapies at baseline.
+Added: Consistent with regulatory precedent in metabolic liver diseases, primary endpoints will focus on safety and tolerability, with secondary endpoints including changes in ceruloplasmin, serum copper, urinary copper, and imaging-based assessment of copper distribution.
+Added: We expect to obtain initial clinical data in 2027, subject to regulatory clearance and trial execution.
+Added: Follow-on Wilson Editors (R778L and other variants)
+Added: Variant Background and Prevalence
+Added: In addition to H1069Q, multiple ATP7B mutations contribute to Wilson Disease pathogenicity.
+Added: The R778L variant is particularly prevalent in Asian populations, accounting for up to 35% of individuals with Wilson Disease in Japan and representing up to 10% of cases in the United States.
+Added: Similar to H1069Q, these variants impair ATP7B trafficking and copper transport, leading to progressive hepatic and neurological disease.
+Added: Modular Development Approach
+Added: Our follow-on Wilson Disease candidates are designed to correct R778 variants using the same LNP and editor architecture as PM577, with only the pegRNA template varied.
+Added: This modular design has enabled us to identify multiple editors capable of achieving >90% correction of R778L in fully humanized mouse models, supported by modular editor-component screening and guide-RNA optimization.
+Added: Umbrella-IND Implications
+Added: Given the shared delivery system, editor backbone, and manufacturing processes across H1069Q and R778 programs, we are evaluating an umbrella-IND strategy that could allow multiple ATP7B-targeting candidates to be advanced under a single regulatory framework.
+Added: This approach, if aligned with regulatory feedback, could streamline development and reduce incremental toxicology and CMC requirements for follow-on editors.
+Added: The modularity of our Prime Editing platform, including guide swapping and standardized LNP formulations, underpins this potential regulatory efficiency.
+Added: PM647 for AATD
+Added: Disease Background and Unmet Need
+Added: AATD is a genetic disorder caused by mutations in the SERPINA1 gene, resulting in production of misfolded Z-AAT protein (PiZZ genotype) that accumulates in the liver and leads to hepatocellular injury, cirrhosis, and increased risk of hepatocellular carcinoma.
+Added: AATD also causes progressive lung disease due to insufficient circulating AAT.
+Added: In the United States, approximately 100,000 individuals – many of whom are undiagnosed - have AATD, with PiZZ patients representing the most severe form.
+Added: Currently available treatments primarily address pulmonary manifestations and do not correct the underlying hepatic pathology.
+Added: Liver transplantation is the only curative option for advanced disease.
+Added: Prime Medicine’s Therapeutic Approach
+Added: PM647 is designed to correct the Z-AAT mutation in hepatocytes via in vivo Prime Editing delivered with our universal liver-targeted LNP.
+Added: By rewriting the disease-causing E342K substitution to restore wild-type M-AAT protein sequence, PM647 aims to reduce accumulation of toxic Z-AAT polymers in hepatocytes and reestablish systemic AAT levels.
+Added: The biology of AATD, including the relationship between genotype and hepatic burden, makes it an attractive candidate for precise allele correction.
+Added: Importantly, we believe that Prime Editing offers a potential best-in-class approach given the lack of bystander edits, off-target editing profile and ability for patients’ normal physiology to modulate AAT levels under native transcriptional control – which is critical for protection of the lung from acute inflammatory insults, such as viral infection.
+Added: Key Preclinical Data
+Added: In preclinical in vivo studies, PM647 demonstrated efficient and dose-dependent correction of the disease-causing mutations in SERPINA1 in hepatocytes, resulting in near complete restoration of wild-type M-AAT protein expression at clinically relevant dose levels.
+Added: This correction translated into robust production of corrected M-AAT protein, with M-AAT representing the majority of total human AAT isoforms detected in treated animals.
+Added: Consistent with these findings, circulating serum M-AAT concentrations increased into or above the normal human reference range following PM647 administration, while untreated control animals showed no detectable M-AAT protein.
+Added: believe these data support a direct relationship between in vivo Prime Editing–mediated correction, restoration of wild-type protein expression, and systemic exposure to functional AAT at levels associated with clinical relevance.
+Added: Regulatory and Clinical Development Plans
+Added: We expect to submit an IND/CTA for PM647 in mid-2026 with initial clinical data anticipated in 2027.
+Added: Cystic Fibrosis Program
+Added: Disease Background and Genetic Heterogeneity
+Added: CF is caused by mutations in the CFTR gene, which impair chloride transport and lead to progressive pulmonary, gastrointestinal, and pancreatic disease.
+Added: More than 2,000 CFTR variants have been identified, with a subset of mutational clusters accounting for the majority of clinical cases.
+Added: While small-molecule modulators have transformed CF care, a substantial portion of patients either cannot tolerate modulators or harbor mutations that are not responsive to current therapies.
+Added: We believe gene editing approaches hold the potential to restore CFTR function at the genomic level.
+Added: Prime Editing Approach for CF
+Added: We are evaluating Prime Editing strategies to correct CFTR mutations through in vivo delivery to airway epithelial cells focusing on direct delivery to the airway.
+Added: To enable delivery to the lung, we are assessing both LNP and AAV delivery modalities in parallel.
+Added: Our early research initially focuses on mutation clusters where Prime Editing may restore full-length CFTR function.
+Added: Development Stage
+Added: The program is currently in the lead optimization phase.
+Added: Key activities include identification of mutation-specific editing strategies, optimization of editor variants for airway tissue, and characterization of delivery performance in epithelial models.
+Added: We expect to progress toward IND-enabling activities following completion of preclinical proof-of-concept studies, with initial candidates anticipated to leverage platform learnings from our liver-directed programs.
Our License and Collaboration Agreements
+Added: Research Collaboration and License Agreement with BMS
+Added: In September 2024, we entered into a research collaboration and license agreement, or the BMS Collaboration Agreement, with Juno Therapeutics, Inc., a wholly owned subsidiary of BMS, or Juno.
+Added: Under the terms of the BMS Collaboration Agreement, we granted to BMS an exclusive worldwide license to certain Prime Editing technology for developing, manufacturing and commercializing ex-vivo T-cell therapeutic products directed to select targets.
+Added: We are responsible for designing the Prime Editing reagents to be used by BMS.
+Added: We received a $55.0 million upfront payment under the BMS Collaboration Agreement and a $55.0 million equity investment under a Securities Purchase Agreement with BMS.
+Added: We are also eligible to receive more than $3.5 billion in milestones, including up to $185.0 million in preclinical milestones, up to $1.2 billion in development milestones and up to $2.1 billion in commercialization milestones, along with royalties on net sales.
+Added: Unless earlier terminated, the term of the BMS Collaboration Agreement continues until expiration of the last royalty term for the applicable product in the applicable country.
+Added: The BMS Collaboration Agreement is subject to customary termination provisions, including termination by a party for the other party’s uncured, material breach.
+Added: Cystic Fibrosis Foundation
+Added: 2024 Agreement
+Added: In January 2024, we entered into an agreement with CFF, or the 2024 CFF Agreement, under which CFF agreed to provide up to $15.0 million, payable in multiple tranches, to support the development of Prime Editors for the
+Added: treatment of CF.
+Added: We are obligated to return any of the funding not used in development of the program covered by the 2024 CFF Agreement.
+Added: In return, we have agreed to pay to CFF royalties on future sales of any products covered under the 2024 CFF Agreement, to be determined based on the aggregate annual net sales of products and net amount of funding received by us.
+Added: In addition, in the event of a sale, license or transfer to a third-party of rights in the technology developed under the 2024 CFF Agreement, or a change of control transaction, we will pay a percentage of the proceeds received to CFF, up to 2.5 times the net funding received.
+Added: 2025 Agreement
+Added: In July 2025, we entered into an agreement with CFF, or the 2025 CFF Agreement and together with the 2024 CFF Agreement, the CFF Agreements, under which CFF agreed to provide up to $24.0 million in additional funding to accelerate the development of Prime Editors designed to permanently correct CF-related lung disease.
+Added: The $24.0 million funding includes two equal tranches, subject to certain closing conditions and scientific milestones.
+Added: The first tranche included a $6.0 million cash funding, or Royalty Funding, and a $6.0 million equity investment in our company.
+Added: Any proceeds under the second tranche are payable subject to achieving specific milestones which have not been achieved to date.
+Added: We are obligated to return any of the Royalty Funding not used in development of the program covered by the 2025 CFF Agreement.
+Added: In return, we have agreed to pay to CFF royalties on future sales of any products covered under the 2025 CFF Agreement, to be determined based on the aggregate annual net sales of products and net amount of Royalty Funding received by us.
+Added: In addition, in the event of a sale, license or transfer to a third-party of rights in the technology developed under the 2025 CFF Agreement, or a change of control transaction, we will pay a percentage of the proceeds received to CFF, up to 2.5 times the net Royalty Funding received.
+Added: CFF’s additional investment builds on initial funding received under the 2024 CFF Agreement.
License agreements with Broad Institute
−Removed: In September 2019, we entered into a license agreement with Broad Institute, and in May 2020, February 2021, December 2022, and September 2024 we entered into amendments to that license agreement.
−Removed: We refer to this amended license agreement as the Broad License Agreement.
+Added: In September 2019, we entered into a license agreement with Broad Institute, or the Broad License Agreement, and in May 2020, February 2021, December 2022, September 2024, and September 2025 we entered into amendments to that Broad License Agreement.
Under the Broad License Agreement, Broad Institute grants to us certain rights and licenses under certain patent rights it owns or controls related to editing of DNA sequences using a Prime Editor.
−Removed: Certain of the licensed patent rights are co-owned by Broad Institute with MIT and Harvard and certain are co-owned by Broad Institute with Harvard.
−Removed: In December 2022, following the timely exercise of an option under an existing option agreement with Broad Institute we entered into a second license agreement
−Removed: with Broad Institute, which we refer to as the 2022 Broad License Agreement.
+Added: Certain of the licensed patent rights are co-owned by Broad Institute with the Massachusetts Institute of Technology, or MIT, and Harvard University, or Harvard, and certain are co-owned by Broad Institute with Harvard.
+Added: In December 2022, following the timely exercise of an option under an existing option agreement with Broad Institute we entered into a second license agreement with Broad Institute, or the 2022 Broad License Agreement.
Under the 2022 Broad License Agreement, Broad Institute grants to us certain rights and licenses under certain patent rights it owns or controls related to MMR inhibition and prime editing improvements.
3 unchanged sentences
We refer to this field as the Prime Broad Field.
−Removed: Under the Broad License Agreement, Broad Institute grants to us (i) an exclusive, worldwide license under the licensed patent rights solely to offer for sale, sell, have sold and import products covered by such licensed patent rights, or licensed products, solely for use within the Prime Broad Field (subject to certain specified limitations and exclusions with respect to certain applications), (ii) a non-exclusive, worldwide license under the licensed patent rights solely to make, have made, offer for sale, sell, have sold, and import licensed products solely for use in the Prime Broad Field, (iii) a non-exclusive, worldwide license under the licensed patent rights solely to make, have made, offer for sale, sell, have sold and import other products that are enabled by (a) the licensed patent rights or (b) the use of certain materials transferred to us by Broad Institute, solely for the prevention or treatment of human diseases, which we refer to as enabled products, and (iv) a non-exclusive, worldwide license solely for internal research.
+Added: Under the Broad License Agreement, Broad Institute grants to us (i) an exclusive, worldwide license under the licensed patent rights solely to offer for sale, sell, have sold and import products covered by such licensed patent rights, or licensed products, solely for use within the Prime Broad Field (subject to certain specified limitations and exclusions with respect to certain applications), (ii) a non-exclusive, worldwide license under the licensed patent rights solely to make, have made, offer for sale, sell, have sold, and import licensed products solely for use in the Prime Broad Field, (iii) a non-exclusive, worldwide license under the licensed patent rights solely to make, have made, offer for sale, sell, have sold and import other products that are enabled by (a) the licensed patent rights or (b)
+Added: the use of certain materials transferred to us by Broad Institute, solely for the prevention or treatment of human diseases, which we refer to as enabled products, and (iv) a non-exclusive, worldwide license solely for internal research.
All of the above license grants specifically exclude human germline modification, the stimulation of biased inheritance of particular genes or traits within a plant or animal population, and certain modifications of the tobacco plant, and are subject to certain retained rights of Broad Institute, MIT and Harvard and the U.S.
1 unchanged sentence
Broad Institute also retains certain rights for itself, MIT and Harvard and for other non-for-profit research organizations and government agencies to practice the licensed patent rights for research, teaching, educational and scholarly purposes.
−Removed: In addition, because an employee of HHMI was an inventor on certain of the licensed patent rights, the licenses granted to us with respect to such patent rights are subject to a non-exclusive, irrevocable, worldwide license to HHMI to exercise any such patent rights for research purposes.
+Added: In addition, because an employee of the Howard Hughes Medical Institute, or HHMI, was an inventor on certain of the licensed patent rights, the licenses granted to us with respect to such patent rights are subject to a non-exclusive, irrevocable, worldwide license to HHMI to exercise any such patent rights for research purposes.
We are permitted to sublicense the licensed patent rights to our affiliates and third parties, subject to certain requirements, including that any such sublicense agreement be in compliance with and be consistent with the terms of the Broad License Agreement.
7 unchanged sentences
We must continue to use commercially reasonable efforts to continue to progress such activities.
−Removed: If we notify Broad
−Removed: Institute that we have a good faith interest in sublicensing our rights to such third party or another third party, we have a specified period of time to negotiate and enter into a sublicense agreement with a third party.
+Added: If we notify Broad Institute that we have a good faith interest in sublicensing our rights to such third party or another third party, we have a specified period of time to negotiate and enter into a sublicense agreement with a third party.
If we (i) notify Broad Institute that we are not interested in developing such product (internally or with another third party) or do not respond to the proposed product notice, or (ii) notify Broad Institute of our interest as outlined above and do not complete or, for an internal program, commence, those activities within the specified time periods, Broad Institute has the right, subject to certain conditions, to terminate our rights to such gene target and may grant to such proposing third party an exclusive or non-exclusive license under the patent rights to exploit products covered by the licensed patent rights and directed to such gene target, which we refer to as a march-in license.
3 unchanged sentences
If Broad Institute notifies us that it desires to exercise such right for a given gene target, and we do not, within a specified time period, evidence that we (ourselves or through an affiliate or sublicensee) have an on-going program or good faith interest in pursuing a program for Prime Editor products for such gene target, Broad Institute may terminate our license with respect to such gene target, with such gene target becoming a reserved Broad Institute target.
−Removed: We have a right to negotiate a sublicense with a third-party for-profit company interested in licensing the rights to such reserved Broad Institute targets, which we must complete within a specified period of time, after which Broad Institute may grant such rights to such third party.
+Added: We have a right to negotiate a sublicense with a third-party for-profit company interested in licensing the rights to such reserved Broad Institute targets, which we must complete within a
+Added: specified period of time, after which Broad Institute may grant such rights to such third party.
Broad Institute has not yet exercised its right to designate any reserved gene targets.
5 unchanged sentences
If we are successfully able to gain regulatory approval for any licensed product, we are required to use commercially reasonable efforts to introduce any such licensed product into the commercial market and to commercialize and make such licensed products reasonably available to the public.
−Removed: As partial consideration for the rights granted to us under the Broad License Agreement, we paid Broad Institute an upfront fee of $0.5 million, and issued Broad Institute an aggregate of 623,529 shares of our common stock.
−Removed: Under the February 2021 and December 2022 amendments, as partial consideration for the addition of licensed patent rights relating to prime editing improvements, we paid Broad Institute amendment fees of approximately $0.1 million and $0.1 million, respectively.
We also are obligated to pay to Broad Institute an annual license maintenance fee in the low six-figures for the term of the Agreement.
5 unchanged sentences
Royalties payable to Broad Institute are subject to customary offsets and reductions with respect to a product in a given country, to a floor.
−Removed: On a country-by-country and product-
−Removed: by-product basis, the royalty term for a product in a country will terminate on the latest of:
+Added: On a country-by-country and product-by-product basis, the royalty term for a product in a country will terminate on the latest of:
(i) the expiration of the last to expire valid claim of an issued patent or pending patent application within the licensed patent rights covering such product in such country, (ii) the period of regulatory exclusivity for such product in such country or (iii) ten (10) years after the first commercial sale of such product in such country.
7 unchanged sentences
Broad Institute may also immediately terminate the Broad License Agreement (i) to the extent we (or our affiliates or sublicensees) challenge a licensed patent right, (ii) upon our bankruptcy or insolvency or (iii) if we fail to procure and maintain insurance.
−Removed: 2024 Amendment to The Broad License Agreement
−Removed: In connection with the BMS Collaboration Agreement, we entered into a Letter Agreement, or the 2024 Amendment, with Broad Institute in September 2024, which amends the Broad License Agreement to modify certain of our obligations and rights of Broad Institute in relation to the BMS Collaboration Agreement as a sublicense under the Broad License Agreement.
−Removed: The 2024 Amendment, among other things, modifies the royalty and certain commercial milestones that we are obligated to pay to Broad Institute on net sales of products under the BMS Collaboration Agreement.
+Added: Amendment No.
+Added: 4 and Amendment No.
+Added: 5 to The Broad License Agreement
+Added: In September 2025, we entered into a Fourth Amendment to License Agreement, or the Fourth Amendment, and Fifth Amendment to License Agreement, or the Fifth Amendment and, together with the Fourth Amendment, the 2025 Amendments, with Broad Institute, which amended the Broad License Agreement, to, among other things, modify certain licensed patent applications listed therein.
+Added: Except as expressly stated in the 2025 Amendments, all other terms and provisions of the Broad License Agreement shall remain in full force and effect.
+Added: Side Letter No.
+Added: 2 to The Broad Institute License Agreement
+Added: In connection with the 2025 Amendments, we also entered into a second letter agreement, or the Second Letter Agreement, with Broad Institute in September 2025, which amends the Broad License Agreement.
+Added: The Second Letter Agreement, among other things, modifies certain development milestones and related payment obligations under the BMS Collaboration Agreement.
+Added: Except as expressly stated in the Second Letter Agreement, all other terms and provisions of the Broad License Agreement shall remain in full force and effect.
+Added: Side Letter No.
+Added: 1 to The Broad License Agreement
+Added: In connection with the BMS Collaboration Agreement, we entered into a Letter Agreement, or the First Letter Agreement, with Broad Institute in September 2024, which amends the Broad License Agreement to modify certain of our obligations and rights of Broad Institute in relation to the BMS Collaboration Agreement as a sublicense under the Broad License Agreement.
+Added: The First Letter Agreement, among other things, modifies the royalty and certain commercial milestones that we are obligated to pay to Broad Institute on net sales of products under the BMS Collaboration Agreement.
2022 License Agreement with Broad Institute
8 unchanged sentences
Broad Institute is entitled to lower payments to the extent the clinical and regulatory milestones or sales-based milestones are achieved by royalty-bearing products that are enabled products, rather than royalty-bearing products that are licensed products.
−Removed: Broad Institute is entitled to receive royalties of less than 0.2%
−Removed: on net sales of royalty-bearing products that are licensed products and lower royalties on net sales of for royalty-bearing products that are enabled products.
+Added: Broad Institute is entitled to receive royalties of less than 0.2% on net sales of royalty-bearing products that are licensed products and lower royalties on net sales of for royalty-bearing products that are enabled products.
Royalties payable to Broad Institute are subject to limited customary offsets and reductions.
6 unchanged sentences
In August 2022, we amended and restated the Pledge to clarify that the funds may be used by the laboratory of David Liu, who is a member of Broad Institute and a faculty member at Harvard.
−Removed: Collaboration and License Agreement with Beam Therapeutics
−Removed: In September 2019, we entered into a collaboration and license agreement, which we refer to as the Beam Collaboration Agreement, with Beam Therapeutics Inc., or Beam.
+Added: Collaboration and License Agreement with Beam
+Added: In September 2019, we entered into a collaboration and license agreement, which we refer to as the Beam Collaboration Agreement, with Beam.
One of our founders, David Liu, is also a founder of Beam.
4 unchanged sentences
Under the Beam Collaboration Agreement, Beam grants to us certain non-exclusive, worldwide licenses under certain technology, know-how and patent rights, including under certain CRISPR or delivery-related technology, know-how and patent rights, that it controls during the initial term, and improvements thereto that Beam controls for a specified number of years following the initial term, solely to develop, make, have made, use, offer for sale, sell, import and commercialize products only in the Prime field, which is limited to the prevention, modification, improvement, amelioration or treatment of human disease (excluding sickle cell disease), including cell-based therapies and the creation of one or more protective mutations, through administration of a product or service containing or incorporating a Prime Editing agent that is not a qualifying Prime Editing agent, but excluding (a) the Beam field, (b) the administration of any product or service containing or incorporating a base editor and (c) a field related to microbial cells in the human flora in certain Asia territories and the development of products targeting four named gene targets.
−Removed: For clarity, the Prime field includes products or services that contain or incorporate (x) at least one Prime Editing agent that is not a qualifying Prime Editing agent and (y) any other gene-editing approach,
−Removed: including other Prime Editing agents, which may include one or more qualifying Prime Editing agents, subject to the aforementioned exclusions.
+Added: For clarity, the Prime field includes products or services that contain or incorporate (x) at least one Prime Editing agent that is not a qualifying Prime Editing agent and (y) any other gene-editing approach, including other Prime Editing agents, which may include one or more qualifying Prime Editing agents, subject to the aforementioned exclusions.
The licenses granted to us by Beam under the Beam Collaboration Agreement are subject to the terms of certain third-party agreements and certain rights retained by third parties.
19 unchanged sentences
We are entitled to receive development milestone payments from Beam on Beam’s development of protected products (which, for clarity, includes any licensed product for which we have not exercised our profit share option) and collaboration products.
−Removed: For protected products, we are entitled to receive up to a total of $35.5 million on a protected product-by-protected product basis based on Beam’s development of such protected product and, for
−Removed: collaboration products, up to a total of approximately $17.8 million on a collaboration product-by-collaboration product basis based on Beam’s development of such collaboration product outside of the United States, in each case, with such amounts lowered if such licensed product achieves a given milestone for use in treating an orphan disease.
+Added: For protected products, we are entitled to receive up to a total of $35.5 million on a protected product-by-protected product basis based on Beam’s development of such protected product and, for collaboration products, up to a total of approximately $17.8 million on a collaboration product-by-collaboration product basis based on Beam’s development of such collaboration product outside of the United States, in each case, with such amounts lowered if such licensed product achieves a given milestone for use in treating an orphan disease.
We are also entitled to receive sales-based milestone payments from Beam based on net sales of licensed products.
14 unchanged sentences
Beam is responsible for prosecution and maintenance of the patent rights it licenses to us, while keeping us reasonably informed and providing us the opportunity to provide comments and make requests of us, in each case with respect to any patent rights that Beam exclusively licenses to us in the field of the exclusive license.
−Removed: Beam has the first right to enforce any patent rights we exclusively license to Beam in the Beam field against any third party developing a product in the Beam field that is competitive with a licensed product Beam is developing
−Removed: under the Beam Collaboration Agreement.
+Added: Beam has the first right to enforce any patent rights we exclusively license to Beam in the Beam field against any third party developing a product in the Beam field that is competitive with a licensed product Beam is developing under the Beam Collaboration Agreement.
We have a step-in right on any such enforcement to the extent Beam declines or fails to initiate such enforcement action.
Unless earlier terminated in accordance with its terms, the Beam Collaboration Agreement will expire on the later of (a) expiration of the last royalty term for a product on which a party is obligated to pay royalties to the other party or (b) with respect to any collaboration product, the date on which neither party is developing or commercializing any such collaboration product in the United States.
−Removed: After expiration of the initial term, Beam can terminate the Beam Collaboration Agreement for convenience in its entirety, or on a licensed product-by-licensed product or subfield-by-subfield basis, with ninety (90) days’ prior written notice to Prime.
+Added: After expiration of the initial term, Beam can terminate the Beam Collaboration Agreement for convenience in its entirety, or on a licensed product-by-licensed product or subfield-by-subfield basis, with ninety (90) days’ prior
+Added: written notice to Prime.
Each party may terminate the Beam Collaboration Agreement for (a) the other party’s uncured material breach within ninety (90) days of notice of such breach, (b) upon the insolvency or bankruptcy of the other party if such proceeding is not dismissed within ninety (90) days after the filing thereof or (c) immediately to the extent the other party (or its affiliates or sublicensees) challenges a patent right licensed to such party.
−Removed: Research Collaboration and License Agreement with BMS
−Removed: In September 2024, we entered into the BMS Collaboration Agreement with Juno, a wholly owned subsidiary of BMS.
−Removed: Under the terms of the BMS Collaboration Agreement, we granted to BMS an exclusive worldwide license to certain Prime Editing technology for developing, manufacturing and commercializing ex-vivo T-cell therapeutic products directed to select targets.
−Removed: We are responsible for designing the Prime Editing reagents to be used by BMS.
−Removed: We received a $55.0 million upfront payment under the BMS Collaboration Agreement and a $55.0 million equity investment under a Securities Purchase Agreement with BMS.
−Removed: We are also eligible to receive more than $3.5 billion in milestones, including up to $185.0 million in preclinical milestones, up to $1.2 billion in development milestones and up to $2.1 billion in commercialization milestones, along with royalties on net sales.
−Removed: Unless earlier terminated, the term of the BMS Collaboration Agreement continues until expiration of the last royalty term for the applicable product in the applicable country.
−Removed: The BMS Collaboration Agreement is subject to customary termination provisions, including termination by a party for the other party’s uncured, material breach.
Our Business Development and Partnering Strategy
1 unchanged sentence
The potential therapeutic applications of our Prime Editing technology are broad, and we aspire to fully develop that potential.
−Removed: To achieve our vision, and in addition to independently discovering, developing, and commercializing Prime Editing products, we will seek to selectively enter strategic collaborations to maximize the potential of the Prime Editing platform.
+Added: To achieve our vision, and in addition to independently discovering, developing, and commercializing Prime Editing products, we will seek to selectively enter strategic collaborations to maximize the potential of the Prime Editing platform, such as our Beam Collaboration Agreement and BMS Collaboration Agreement.
Such collaborations may also facilitate our entry into additional therapeutic or geographic areas by leveraging the established capabilities of our partners as well as by funding the development of new Prime Editing platform or corporate capabilities which we can then utilize for additional Prime Medicine products outside such partnerships.
2 unchanged sentences
In each case, we expect to receive value in the form of upfront payments and milestones which will provide us with additional capital in the nearer term as well as royalties and where applicable, profit sharing, to participate in the value created through commercializing Prime Editing products.
−Removed: We may also seek to access or develop enabling technologies or specific capabilities through licenses or partnerships.
−Removed: We will evaluate partnerships with both academic and corporate entities, and these potential collaborations may vary in both structure and scope.
+Added: We may also seek to access or develop enabling technologies or specific capabilities through licenses or partnerships, such as the CFF Agreements.
+Added: We will evaluate partnerships with various types of entities, including academia, corporations, and foundations, and these potential collaborations may vary in both structure and scope.
Technologies that may enable the application of Prime Editing may include viral and non-viral delivery modalities, manufacturing, and technologies that may be synergistic with Prime Editing or Prime Editing products.
−Removed: The pharmaceutical and biotechnology industries, including the gene therapy and gene editing fields, are characterized by rapidly advancing technologies, intense competition and a strong defense of intellectual property.
−Removed: We believe that our Prime Editing technology is highly differentiated and that our considerable expertise in Prime Editing and our expansion of its capabilities, as well as our team’s extensive drug development and manufacturing experience, together with exclusive licenses to this technology have positioned us at the forefront of the field of advanced precision genetic medicines and provided us with significant competitive advantages.
−Removed: Nevertheless, we face potential competition from a variety of companies.
−Removed: There are several companies utilizing CRISPR/Cas9 nuclease technology, including Caribou Biosciences, Inc., Editas Medicine, Inc., CRISPR Therapeutics AG, Intellia Therapeutics, Inc.
−Removed: and Kamau Therapeutics, Inc., among others.
−Removed: Several additional companies such as Sangamo Therapeutics, Inc., Precision BioSciences, Inc.
−Removed: and bluebird bio, Inc.
−Removed: utilize alternative nuclease-based genome editing technologies, including ZFNs, engineered meganucleases and TALENs.
−Removed: Beam Therapeutics Inc.
−Removed: utilizes base editing technology.
−Removed: In addition, other private companies such as Tessera Therapeutics, Inc.
−Removed: have announced their work in recombinase DNA and RNA gene writers, although little is known publicly about their science or portfolio.
−Removed: Other companies have announced intentions to enter the gene editing field, such as Moderna, Inc.
−Removed: and Pfizer Inc.
−Removed: Most recently, new epigenetic editing companies have emerged, such as nChroma Bio, Inc.
−Removed: and Tune Therapeutics, Inc.
−Removed: In addition, we face competition from companies utilizing gene therapy, oligonucleotides and cell therapy therapeutic approaches.
−Removed: Several companies such as Arbor Biotechnologies, Inc., Scribe Therapeutics Inc., Mammoth Biosciences, Inc.
−Removed: and Metagenomi, Inc.
−Removed: are actively searching for novel genome editing components, have reported the discovery of new DNA-cutting enzymes, and have announced gene editing programs.
−Removed: Other companies are active in LNP delivery technologies and advancing those into therapeutics using genetic therapies, including Recode Therapeutics, Inc., Verve Therapeutics, Inc., Generation Bio Co.
−Removed: and Beam Therapeutics Inc., among others.
−Removed: Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future that are approved to treat the same diseases for which we may obtain approval for our product candidates.
−Removed: This may include gene editing companies with other approaches to editing, as well as other types of therapies, such as small molecule, RNAi, antibody and/or protein therapies.
−Removed: In addition, many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials and approved products than we do today.
−Removed: Mergers and acquisitions in the pharmaceutical, biotechnology and gene therapy industries may result in resources becoming increasingly concentrated among a smaller number of our competitors.
−Removed: Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
−Removed: We also compete with these companies in recruiting, hiring and retaining qualified scientific and management talent, establishing clinical trial sites and patient registration for clinical trials, obtaining manufacturing slots at contract manufacturing organizations and in acquiring technologies complementary to, or necessary for, our programs.
−Removed: Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, particularly if they represent cures, have fewer or less severe side effects, are more convenient, or are less expensive than any products that we may develop.
−Removed: Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.
−Removed: The key competitive factors affecting the success of all of our programs are likely to be their efficacy, safety, convenience and availability of reimbursement.
+Added: The development of genetic medicines is highly competitive and rapidly evolving, with multiple companies pursuing therapeutic approaches across gene editing, RNA-based therapies, and gene replacement modalities.
+Added: Several companies, including CRISPR Therapeutics, Editas Medicine, Intellia Therapeutics, and Caribou Biosciences, among others, are advancing CRISPR nuclease–based genome editing technologies, which introduce double-stranded DNA breaks to disrupt, delete, or modify target genes.
+Added: These approaches have demonstrated clinical activity in certain settings, particularly ex vivo hematologic applications.
+Added: However, they rely on endogenous DNA repair pathways that can result in heterogeneous editing outcomes, including insertions, deletions, and structural variants.
+Added: Other companies, including Beam and Verve Therapeutics, recently acquired by Eli Lilly and Company, are developing base editing technologies that enable targeted single-nucleotide transitions without double-stranded breaks.
+Added: However, base editors are generally limited to specific substitution types and may introduce bystander edits within the editing window.
+Added: In contrast, Prime Editing is designed to enable precise rewriting of DNA sequences, including transversions, small insertions and deletions, and multi-base edits, while avoiding double-stranded DNA breaks.
+Added: Other companies, including Tessera Therapeutics, CRISPR Therapeutics, Metagenomi Therapeutics, Scribe Therapeutics and Arbor Biotechnologies, among others, are developing proprietary genome editing or gene writing technologies that may also enable precise genomic modifications without reliance on double-stranded DNA breaks, and which could compete with Prime Editing across overlapping therapeutic indications.
+Added: In addition to genome editing approaches, companies including Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Sarepta Therapeutics, Wave Life Sciences, and Moderna are developing RNA-based therapies, including antisense oligonucleotides, small interfering RNAs, messenger RNA therapies, and RNA editing technologies.
+Added: These modalities typically do not alter genomic DNA and may require chronic or repeated administration to maintain
+Added: therapeutic effect.
+Added: Gene replacement therapies, most commonly delivered via adeno-associated viral vectors and being developed by companies such as Ultragenyx, Genetix Biotherapeutics, 4D Molecular Therapeutics, and others, seek to introduce functional copies of genes but may be limited by vector payload constraints, durability of expression, immunogenicity, and challenges associated with redosing.
+Added: For diseases such as AATD and CF, multiple companies including Vertex Pharmaceuticals, Arrowhead Pharmaceuticals, and others are pursuing combinations of gene editing, RNA-based suppression or augmentation, and gene therapy approaches.
+Added: Competition may also arise from existing and emerging small-molecule therapies, supportive care regimens, or future technologies that are currently unknown.
+Added: We believe that the precision, versatility, and modularity of Prime Editing represent potential differentiating attributes, but the ultimate competitive position of our programs will depend on several factors such as clinical outcomes, regulatory considerations, manufacturing scalability, and commercial execution.
Manufacturing
We currently have no commercial manufacturing capabilities.
−Removed: For our initial wave of clinical programs, we intend to use qualified third-party contract manufacturing organizations, or CMOs, with relevant manufacturing experience in genetic medicines to make our clinical candidates using current good manufacturing practices, or cGMP.
−Removed: We plan to partner with suppliers to produce critical raw materials, bulk compounds, formulated compounds, viral vectors or engineered cells for early-stage clinical trials.
−Removed: At the appropriate time in the product development process, we will determine whether to establish in-house cGMP manufacturing capabilities for some core technologies or continue to rely on third parties to manufacture commercial quantities for any products that we may successfully develop.
+Added: For our initial wave of clinical programs, we have established a robust manufacturing supply chain network for making our clinical candidates using current good manufacturing practices, or cGMP.
+Added: This includes both qualified third-party contract manufacturing organizations and contract testing organizations with relevant manufacturing and/or testing experience in genetic medicines, as well as in-house cGMP manufacturing and testing capabilities for some core technologies to produce early-stage clinical genetic medicine supplies.
+Added: At the appropriate time in the product development process, we will determine whether to establish in-house cGMP manufacturing capabilities for some core technologies or continue to rely on third parties for manufacturing and/or testing commercial products that we may successfully develop.
Intellectual Property
We achieved many major milestones in 2025, including the issuance of two in-licensed U.S.
−Removed: patents, the allowance of another in-licensed U.S.
−Removed: patent application that has since issued as a U.S.
−Removed: patent, the issuance of five ex-U.S.
−Removed: patents, and the allowance of another two ex-U.S.
−Removed: patent applications, one of which has since issued as an ex-U.S.
−Removed: As of February 20, 2025, we have six in-licensed U.S.
−Removed: patents or allowed patent applications and seven in-licensed ex-U.S.
+Added: patents, the allowance of an additional three in-licensed U.S.
+Added: patent applications, the issuance of eight ex-U.S.
+Added: patents, and the allowance of another seven ex-U.S.
+Added: patent applications.
+Added: As of February 27, 2026, we hold 10 in-licensed U.S.
+Added: patents or allowed patent applications and 20 in-licensed ex-U.S.
patents or allowed patent applications, all of which cover Prime Editing methods and its components and systems.
2 unchanged sentences
and certain foreign patent applications and issued patents and filing patent applications related to our platform technology, existing and planned programs and improvements that are important to the development of our business, where patent protection is available.
−Removed: While we in-license four issued patents, we do not currently own any issued patents in any jurisdiction covering our Prime Editing technology or product candidates.
+Added: While we in-license 30 issued patents or allowed applications, we do not currently own any issued patents in any jurisdiction covering our Prime Editing technology or product candidates.
For information regarding the risks related to our intellectual property, please see “ Risk Factors—Risks Related To Our Intellectual Property.
11 unchanged sentences
Owned Patents
−Removed: As of February 20, 2025, we owned approximately 13 pending U.S.
−Removed: provisional patent applications, 16 pending PCT applications, 21 pending U.S.
+Added: As of February 27, 2026, we owned approximately eight pending U.S.
+Added: provisional patent applications, seven pending PCT applications, 29 pending U.S.
non-provisional patent applications and 99 pending ex-U.S.
patent applications.
−Removed: The patent applications outside of the United States were filed in the European Patent Office, Japan, China and certain other foreign jurisdictions.
+Added: Patent applications have been filed outside of the United States in the European Patent Office, Japan, China, and certain other foreign jurisdictions.
Our owned patent applications are generally related to our Prime Editing technology, including claims to modified pegRNAs;
4 unchanged sentences
methods for synthesizing pegRNAs;
−Removed: and novel lipids and LNPs for delivery of Prime Editors.
+Added: novel lipids and LNPs for delivery of Prime Editors;
+Added: and compositions of matter covering officially declared drug candidates.
The provisional patent applications are not eligible to become issued patents until, among other things, we file non-provisional patent applications within 12 months of filing one or more of our related provisional patent applications.
non-provisional patent applications timely filed based on any of these U.S.
−Removed: provisional patent applications, if issued, and if the appropriate maintenance or annuity fees are paid, are expected to expire as
−Removed: early as 2045, excluding any additional term for patent term adjustments or patent term extensions or similar provisions in foreign jurisdictions.
+Added: provisional patent applications, if issued, and if the appropriate maintenance or annuity fees are paid, are expected to expire as early as 2047, excluding any additional term for patent term adjustments or patent term extensions or similar provisions in foreign jurisdictions.
Our current owned U.S.
1 unchanged sentence
In-licensed Patents
−Removed: As of February 20, 2025, we have in-licensed five issued U.S.
−Removed: patents, six granted ex-U.S.
−Removed: patents, approximately 16 pending U.S.
−Removed: non-provisional patent applications, one pending PCT application, and 80 pending ex-U.S.
+Added: As of February 27, 2026, we have in-licensed 10 issued U.S.
+Added: patents or allowed U.S.
+Added: patent applications, 20 granted ex-U.S.
+Added: patents or allowed ex-U.S.
+Added: patent applications, approximately eight pending U.S.
+Added: non-provisional patent applications, and 90 pending ex-U.S.
patent applications, in each case, related to Prime Editing, from Broad Institute.
−Removed: The patent applications outside of the United States were filed in the European Patent Office, Japan, China and certain other foreign jurisdictions.
+Added: Patent applications have been filed outside of the United States in the European Patent Office, Japan, China, and certain other foreign jurisdictions.
The issued patents and patent applications from our in-licensed portfolio for Prime Editing are generally related to Prime Editors, pegRNAs, Prime Editing complexes and systems;
44 unchanged sentences
A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation.
−Removed: A partial clinical hold is a delay or suspension of only part of the clinical investigation
−Removed: conducted under the IND.
+Added: A partial clinical hold is a delay or suspension of only part of the clinical investigation conducted under the IND.
No more than 30 days after imposition of a full or partial clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold.
2 unchanged sentences
Information about certain clinical trials, including clinical trial results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.
+Added: Although sponsors are obligated to disclose the results of their clinical trials after completion, disclosure of the results can be delayed in some cases for up to two years after the date of completion of the trial.
+Added: Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to public notification of noncompliance, civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.
A sponsor may choose, but is not required, to conduct a foreign clinical trial under an IND.
9 unchanged sentences
This group provides advice to the sponsor as to whether or not a trial may move forward at designated check points based on pre-specified criteria and access to unblinded data from the study.
−Removed: In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety committees, or IBCs, as set forth in the National Institutes of Health, or NIH, Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.
+Added: In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of
+Added: institutional biosafety committees, or IBCs, as set forth in the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines.
Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.
9 unchanged sentences
Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.
−Removed: These clinical trials are used to gather additional data from the treatment of patients in the intended
−Removed: therapeutic indication, particularly for long-term safety follow-up.
+Added: These clinical trials are used to gather additional data from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up.
The FDA generally recommends that sponsors of human gene therapy products integrating vectors such as gammaretroviral and lentiviral vectors and transposon elements as well as gene editing product sponsors observe subjects for potential gene therapy-related delayed adverse events for up to a 15-year period, including five years of annual examinations followed by ten years of annual queries, either by telephone or by questionnaire, of study subjects.
−Removed: Both the FDA and the European Medicines Agency, or the EMA, provide expedited pathways for the development of drug product candidates for treatment of rare diseases, particularly life-threatening diseases with high unmet medical need.
+Added: Both the FDA and the EMA provide expedited pathways for the development of drug product candidates for treatment of rare diseases, particularly life-threatening diseases with high unmet medical need.
Such drug product candidates may be eligible to proceed to registration following a single clinical trial in a limited patient population, sometimes referred to as a Phase 1/2 trial, but which may be deemed a pivotal or registrational trial following review of the trial’s design and primary endpoints by the applicable regulatory agencies.
−Removed: Determination of the requirements to be deemed a pivotal or registrational trial is subject to the applicable regulatory authority’s scientific judgement and these requirements may differ in the U.S.
+Added: Determination of the requirements to be deemed a pivotal or registrational trial is subject to the applicable regulatory authority’s scientific judgment and these requirements may differ in the U.S.
and the European Union, or EU.
19 unchanged sentences
In most cases, the submission of a BLA is subject to a substantial application user fee, although the fee may be waived under certain circumstances.
−Removed: Under the performance goals and policies implemented by the FDA under the Prescription Drug User Fee Act, or PDUFA, for original BLAs, the FDA targets 10 months from the filing date in which to complete its initial review of a standard application and respond to the applicant, and six
−Removed: months from the filing date for an application with priority review.
+Added: Under the performance goals and policies implemented by the FDA under the Prescription Drug User Fee Act, or PDUFA, for original BLAs, the FDA targets 10 months from the filing date in which to complete its initial review of a standard application and respond to the applicant, and six months from the filing date for an application with priority review.
The FDA does not always meet its PDUFA goal dates, and the review process is often significantly extended by FDA requests for additional information or clarification.
14 unchanged sentences
FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, when applicable, to evaluate donors through appropriate screening and testing.
−Removed: Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements.
+Added: Additionally, before approving a BLA, the
+Added: FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements.
To assure cGMP, CGTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control.
9 unchanged sentences
If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, including to subpopulations of patients, which could restrict the commercial value of the product.
−Removed: Further, the FDA may require that certain contraindications, warnings precautions
−Removed: or interactions be included in the product labeling.
+Added: Further, the FDA may require that certain contraindications, warnings precautions or interactions be included in the product labeling.
The FDA may impose restrictions and conditions on product distribution, prescribing or dispensing in the form of a REMS, or otherwise limit the scope of any approval.
17 unchanged sentences
If a PRV is received, it may be sold or transferred an unlimited number of times.
−Removed: The FDA’s rare pediatric disease priority voucher program began to sunset on December 20, 2024, on failure to pass a continuing resolution package that included its reauthorization.
−Removed: Under the amended statutory sunset provisions, after December 20, 2024, the FDA may award a PRV for an approved rare pediatric disease product application only if the sponsor has rare pediatric disease designation for the drug and if that designation was granted by December 20, 2024.
−Removed: After September 30, 2026, the FDA may not award any rare pediatric disease PRVs.
−Removed: Congress may vote to reauthorize this program, but its future remains unknown at this time.
+Added: Congress has extended the PRV program through September 30, 2029.
Expedited Development and Review Programs
−Removed: The FDA has various programs, including fast track designation, breakthrough therapy designation, accelerated approval and priority review, that are intended to expedite or simplify the process for the development and FDA
−Removed: review of drugs and biologics that are intended for the treatment of serious or life-threatening diseases or conditions.
+Added: The FDA has various programs, including fast track designation, breakthrough therapy designation, accelerated approval and priority review, that are intended to expedite or simplify the process for the development and FDA review of drugs and biologics that are intended for the treatment of serious or life-threatening diseases or conditions.
These programs do not change the standards for approval but may help expedite the development or approval process.
11 unchanged sentences
As a condition of approval, the FDA may require that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials with due diligence, and, under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the FDA is permitted to require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.
−Removed: Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a product or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.
+Added: Under FDORA, the FDA has increased authority for
+Added: expedited procedures to withdraw approval of a product or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.
In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination or publication be submitted to the agency for review, which could adversely affect the timing of the commercial launch of the product.
7 unchanged sentences
RMAT do not include those HCT/Ps regulated solely under section 361 of the PHS Act and 21 CFR Part 1271.
−Removed: This program is intended to facilitate efficient development and expedite review of regenerative medicine
−Removed: therapies, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify for RMAT designation.
+Added: This program is intended to facilitate efficient development and expedite review of regenerative medicine therapies, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify for RMAT designation.
A drug sponsor may request that FDA designate a drug as a RMAT concurrently with or at any time after submission of an IND.
16 unchanged sentences
The FDA also may perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer.
−Removed: In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency and effectiveness of biological products.
+Added: In addition, the FDA
+Added: conducts laboratory research related to the regulatory standards on the safety, purity, potency and effectiveness of biological products.
We also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling, or off-label use, industry-sponsored scientific and educational activities, and promotional activities involving the internet.
5 unchanged sentences
Biological product manufacturers and other entities involved in the manufacture and distribution of approved biological products, and those supplying products, ingredients, and components of them, are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.
−Removed: Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP
+Added: Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP compliance.
Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved BLA, including withdrawal of the product from the market.
10 unchanged sentences
In addition, only those claims covering the approved product, a method for using it, or a method for manufacturing it may be extended, and a patent can only be extended once and only for a single product.
−Removed: The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.
+Added: Patent and Trademark Office, or USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.
In the future, we may apply for restoration of patent term for one of the patents that may issue from our pending patent applications, if and as applicable, to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA.
10 unchanged sentences
“First licensure” typically means the initial date the particular product at issue was licensed in the United States.
−Removed: Date of first licensure does not include the date of
−Removed: licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.
+Added: Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.
Therefore, one must determine whether a new product includes a modification to the structure of a previously licensed product that results in a change in safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of exclusivity.
16 unchanged sentences
EU Clinical Trials Regulation
−Removed: In April 2014, the EU overhauled the system of approvals for clinical trials in the EU.
−Removed: The transitory provisions of the new Clinical Trials Regulation provide that, by January 31, 2025, all ongoing clinical trials must have transitioned to the new Regulation.
−Removed: Specifically, the new Regulation, which is directly applicable in all Member States (meaning that no national implementing legislation in each EU Member State is required), aims at simplifying and streamlining the approval of clinical trials in the EU.
−Removed: In the EU, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014, or CTR.
−Removed: The CTR provides for a streamlined application procedure via a single entry point (the Clinical Trials Information System) and strictly defined deadlines for the assessment of CTAs.
+Added: In April 2014, the EU adopted the Clinical Trials Regulation, (EU) No 536/2014, which replaced the previous Clinical Trials Directive 2001/20/EC on 31 January 2022.
+Added: The Clinical Trials Regulation is directly applicable in all EU Member States meaning no national implementing legislation in each EU Member State is required.
+Added: The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.
+Added: The main characteristics of the Regulation include:
+Added: a streamlined application procedure via a single-entry point through the Clinical Trials Information System, or CTIS;
+Added: a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;
+Added: and a harmonized procedure for the assessment of applications for clinical trials.
EU Drug Review and Approval
7 unchanged sentences
Where the CHMP gives a positive opinion, it provides the opinion together with supporting documentation to the European Commission, who make the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.
−Removed: Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.
+Added: Accelerated assessment may be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.
The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.
8 unchanged sentences
During the additional two-year period of market exclusivity, a generic or biosimilar marketing authorization can be submitted and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed until the expiration of the market exclusivity period.
−Removed: 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.
+Added: 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, are held to bring a significant clinical benefit in comparison with existing therapies.
Even if an innovative medicinal product gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained a marketing authorization based on an MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.
−Removed: however, no guarantee that a product will be considered by the EU’s regulatory authorities to be an innovative medicinal product, and products may therefore not qualify for data exclusivity.
+Added: There is, however, no guarantee that a product will be considered by the EU’s regulatory authorities to be an innovative medicinal product, and products may therefore not qualify for data exclusivity.
Orphan Drug Designation and Exclusivity
4 unchanged sentences
Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.
−Removed: Products with an orphan designation in the EU can receive 10 years of market exclusivity, during which time no “similar medicinal product” for the same indication may be placed on the market.
+Added: Products with an orphan designation in the EU can receive 10 years of market exclusivity, during which time, subject to limited exceptions, no “similar medicinal product” for the same indication may be placed on the market.
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.
15 unchanged sentences
In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist.
−Removed: The PRIority MEdicines, or PRIME, scheme is intended to encourage product development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation, where the MAA will be made through the centralized procedure.
−Removed: products must target conditions for which there is an unmet medical need (there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if there is, the new medicine will bring a major therapeutic advantage) and they must demonstrate the potential to address the unmet medical need by introducing new methods of therapy or improving existing ones.
+Added: The PRIority MEdicines, or PRIME, scheme is intended to encourage product development in areas of unmet medical need and accelerated assessment of products representing substantial innovation, where the MAA will be made through the centralized procedure.
+Added: Eligible products must target conditions for which there is an unmet medical need (there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if there is, the new medicine will bring a major therapeutic advantage) and they must demonstrate the potential to address the unmet medical need by introducing new methods of therapy or improving existing ones.
Applicants will typically be at the exploratory clinical trial phase of development and will have preliminary clinical evidence in patients to demonstrate the promising activity of the medicine and its potential to address, to a significant extent, an unmet medical need.
Products from small- and medium-sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies if the applicant has compelling non-clinical data and tolerability data from initial clinical trials of the product.
−Removed: Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements and accelerated MAA assessment once a dossier has been submitted.
+Added: Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements and the opportunity for accelerated MAA assessment once a dossier has been submitted.
Importantly, a dedicated Agency contact and rapporteur from the CHMP or CAT are appointed early in the PRIME scheme, facilitating increased understanding of the product at EMA’s Committee level.
5 unchanged sentences
• The holder of a marketing authorization must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance, who is responsible for oversight of that system.
−Removed: Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.
+Added: obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.
• All new MAAs must include a risk management plan, or RMP, describing the risk management system that the company will put in place to prevent or minimize the risks associated with the product.
8 unchanged sentences
The European Commission introduced legislative proposals in April 2023 that, if implemented, will replace the current regulatory framework in the EU for all medicines (including those for rare diseases and for children).
−Removed: The European Commission has provided the legislative proposals to the European Parliament and the European Council for their review and approval, and, in April 2024, the European Parliament proposed amendments to the legislative proposals.
−Removed: Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.
−Removed: Brexit and the Regulatory Framework in the United Kingdom
−Removed: The United Kingdom, or UK, formally left the EU on January 31, 2020.
−Removed: The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, and the medicines aspects of the Windsor Framework have applied since January 1, 2025.
−Removed: The MHRA is responsible for approving all medicinal products destined for the UK market
−Removed: (i.e., Great Britain and Northern Ireland).
+Added: In April 2024, the European Parliament adopted its position on the legislative proposals and, in June 2025, the Council of the European Union adopted its position.
+Added: A common position on the text has been agreed upon on December 11, 2025, in the context of subsequent inter-institutional trilogue negotiations.
+Added: The proposed revisions remain to be adopted, and are not expected to become applicable before 2028.
+Added: Regulatory Framework in the United Kingdom
+Added: Following the end of the Brexit transition period on January 1, 2021 and the implementation of the Windsor Framework on January 1, 2025, the UK is not generally subject to EU laws in respect of medicines.
+Added: The EU laws that have been transposed into UK law through secondary legislation remain applicable in the UK, however, new legislation such as the EU Clinical Trials Regulation is not applicable in the UK.
+Added: As a result of the Northern Ireland protocol, different rules applied in Northern Ireland than in England, Wales, and Scotland (together, Great Britain, or GB) for a period following Brexit, which continued to follow the EU regulatory regime.
+Added: However, on January 1, 2025 a new arrangement called the Windsor Framework came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products.
+Added: The Windsor Framework removes EU licensing processes and EU labeling and serialization requirements in relation to Northern Ireland and introduces a UK-wide licensing process for medicines.
+Added: The MHRA is responsible for approving all medicinal products destined for the UK market (i.e., Great Britain and Northern Ireland).
A single UK-wide marketing authorization will be granted by the MHRA for all novel 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.
+Added: In addition, the new arrangements require, for packs placed on the UK market on or after January 1, 2025, a "UK Only" label, indicating they are not for sale in the EU.
Although a separate authorization is now required to market medicinal products in the UK, under an international recognition procedure which was put in place by the MHRA on January 1, 2024, the MHRA may take into account decisions on the approval of a marketing authorization from the EMA (and certain other regulators) when considering an application for a UK marketing authorization.
+Added: There is no pre-marketing authorization orphan designation in the UK.
+Added: Instead, the MHRA reviews applications for orphan designation with the corresponding marketing authorization application.
+Added: The criteria are essentially the same, but have been tailored for the market, i.e., the prevalence of the condition in the UK, rather than the EU, must be more than five in 10,000.
+Added: Should an orphan designation be granted, the period of market exclusivity will be set from the date of first approval of the product in the UK.
Other Healthcare Laws and Compliance Requirements
24 unchanged sentences
Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs.
−Removed: Net prices for drugs may be also reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by
−Removed: any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
+Added: Net prices for drugs may be also reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
Other healthcare laws
15 unchanged sentences
Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation;
−Removed: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which impose requirements on certain covered healthcare providers, health plans, and healthcare
−Removed: clearinghouses as well as their respective business associates that perform services for them that involve the use, or disclosure of, individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information.
+Added: • HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which impose requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses as well as their respective business associates that perform services for them that involve the use, or disclosure of, individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information.
HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions;
17 unchanged sentences
Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.
−Removed: The shifting compliance environment and the need to build and maintain a robust system to comply with
−Removed: multiple jurisdictions with different compliance and reporting requirements increases the possibility that a healthcare company may violate one or more of the requirements.
+Added: The shifting compliance environment and the need to build and maintain a robust system to comply with multiple jurisdictions with different compliance and reporting requirements increases the possibility that a healthcare company may violate one or more of the requirements.
Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial cost.
10 unchanged sentences
For example, on March 22, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminated the statutory Medicaid drug rebate cap, currently set at 100 percent of a drug’s average manufacturer price, for single source and innovator multiple source drugs.
−Removed: Further, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress that include aggregate reductions of Medicare payments to providers of up to two percent per fiscal year, which will remain in effect through 2031.
−Removed: The American Taxpayer Relief Act of 2012 further 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.
−Removed: These laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.
+Added: Such laws and regulations may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.
Further, in 2018, the Right to Try Act, was signed into law.
7 unchanged sentences
Further, under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but only if they have one orphan designation and for which the only approved indication is for that disease or condition.
−Removed: If a product receives multiple orphan designations or has multiple approved indications, it may not qualify for the orphan drug exemption.
−Removed: The implementation of the IRA is currently subject to ongoing litigation
−Removed: challenging the constitutionality of the IRA’s Medicare drug price negotiation program.
−Removed: The effects of the IRA on our business and the healthcare industry in general is not yet known.
+Added: Under the One Big Beautiful Bill Act of 2025, or the OBBBA, this restriction was eliminated;
+Added: and effective for the 2028 initial price applicability year, all orphan drugs, regardless of the number of orphan drug designations or indications, are exempt from the Medicare drug price negotiation program.
+Added: The implementation of the IRA is currently subject to ongoing litigation challenging the constitutionality of the IRA’s Medicare drug price negotiation program.
+Added: Although the effects of the IRA on our business and the healthcare industry in general is not yet known, we are taking into consideration the potential impact of the IRA on our development and commercialization activities.
In addition to pricing regulations, reforms of regulatory approval frameworks may adversely affect our pricing strategy.
−Removed: At a federal level, President Trump reversed some of President Biden’s executive orders including rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans.” President Trump may issue new executive orders designed to impact drug pricing.
+Added: At a federal level, President Trump reversed some of President Biden’s executive orders including rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans.” President Trump
+Added: may issue new executive orders designed to impact drug pricing.
A number of these and other proposed measures may require authorization through additional legislation to become effective.
Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.
+Added: On December 19, 2025, CMS released two proposed rules that would incorporate most‑favored nation, or MFN, pricing principles into federal reimbursement for prescription drugs.
+Added: The first proposal, the Global Benchmark for Efficient Drug Pricing Model, or GLOBE, for Medicare Part B, would require manufacturers of specified single‑source drugs and sole‑source biologics to pay incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility criteria.
+Added: The second proposal, the Guarding U.S.
+Added: Medicare Against Rising Drug Costs, or GUARD, model for Medicare Part D, would similarly mandate manufacturer rebates for qualifying sole‑source drugs where the Medicare net price exceeds an MFN benchmark derived from international reference pricing methodologies.
+Added: As proposed, GLOBE would begin a five‑year performance period on October 1, 2026 and GUARD would begin its performance period in 2027.
+Added: These proposals will likely be subject to legal challenges that could delay their implementation or modify their impact on manufacturer pricing and revenue.
+Added: Additionally, in November 2025, CMS introduced the GENErating cost Reductions for U.S.
+Added: Medicaid, or GENEROUS, Model, a voluntary MFN framework for manufacturers participating in the Medicaid Drug Rebate Program.
+Added: Although it is voluntary, the GENEROUS Model could also impact the drug pricing landscape for manufacturers.
Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
4 unchanged sentences
Employees and Human Capital Resources
−Removed: As of December 31, 2024, we had 214 full-time employees, of which 101 have M.D.
+Added: As of December 31, 2025, we had 146 full-time employees, of whom 63 have M.D.
Within our workforce, 119 employees are engaged in research and development and 27 are engaged in business development, finance, legal, and general management and administration.
9 unchanged sentences
Available Information
−Removed: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to these reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, are available free of charge on our website located at www.primemedicine.com as soon as reasonably practicable after they are filed with or furnished to the Securities and Exchange Commission, or SEC.
+Added: Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to these reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act, are available free of charge on our website located at www.primemedicine.com as soon as reasonably practicable after they are filed with or furnished to the Securities and Exchange Commission, or the SEC.
These reports are also available at the SEC’s website at www.sec.gov.
−Removed: Our Code of Business Conduct and Ethics is posted on our website located at https://investors.primemedicine.com/corporate-governance/documents-charters.
−Removed: A copy of our Corporate Governance Guidelines, and the charters of the Audit Committee, Compensation Committee, and Nominating and Corporate Governance Committee are posted on our website, www.primemedicine.com, under the heading “Investors—Corporate Governance” and are available in
−Removed: print to any person who requests copies by contacting us by calling (617) 465-0013 or by writing to Prime Medicine, Inc., 60 First Street, Cambridge, Massachusetts 02141.
+Added: Our Code of Business Conduct and Ethics is posted on our website located at investors.primemedicine.com/corporate-governance/documents-charters.
+Added: A copy of our Corporate Governance Guidelines, and the charters of the audit committee, compensation committee, and nominating and corporate governance committee are posted on our website, www.primemedicine.com, under the heading “Investors—Corporate Governance” and are available in print to any person who requests copies by contacting us by calling (617) 465-0013 or by writing to Prime Medicine, Inc., 60 First Street, Cambridge, Massachusetts 02141.
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.