−Removed: We are a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies to address the widest spectrum of diseases.
+Added: We are a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies.
We are deploying Prime Editing technology, which we believe is a versatile, precise, and efficient gene editing technology.
−Removed: In the past forty years, the genetic disorders causing many diseases have become more clear.
−Removed: Genetic mutations implicated in disease are diverse and can range from a single base error, which are known as point mutations, to errors that extend from two bases to several to thousands of bases, including multi-base insertions, deletions, duplications, or combinations thereof.
−Removed: Some mutations affect the coding regions of genes while others affect regulatory sequences that control the function of genes and can affect the function of larger biochemical and genetic pathways.
−Removed: Furthermore, as revealed by population-level genomic studies, natural genetic variations are known to protect against or to increase risk of disease.
−Removed: Given these insights, we believe that gene editing has the potential to treat and even cure many human diseases.
−Removed: The field of genetic medicine has evolved tremendously over the last decade, with groundbreaking advances in gene therapy, cell therapy, ribonucleic acid, or RNA, therapy, and, more recently, gene editing.
−Removed: This past year saw the first CRISPR/Cas9-based gene editing therapy (CASGEVY™) approval by the U.S.
+Added: 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.
+Added: This includes the approval of the first CRISPR/Cas9-based gene editing therapy by the U.S.
Food and Drug Administration, or the FDA, for the treatment of sickle cell disease.
−Removed: These technologies represent significant advancements for genetic therapies 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 is treated and overcome the challenges associated with current genetic therapies.
−Removed: Prime Editing, originally developed by Dr.
−Removed: Anzalone and first described in a Nature publication in 2019, has potentially broad therapeutic applications.
−Removed: Prime Editing is the only gene editing technology that can edit, correct, insert and delete DNA sequences in any target tissue.
−Removed: It can correct mutations across many tissues, organs, and cell types, in dividing and non-dividing human cells.
+Added: 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.
+Added: 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.
+Added: Prime Editing can correct mutations across many tissues, organs, and cell types, in both dividing and non-dividing human cells.
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.
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 for repairing 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 insert gene-sized sequences precisely, potentially addressing large patient markets.
+Added: 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.
+Added: 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.
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 carries out DNA recombination, resulting in the desired large DNA sequence insertion at the desired location in the genome.
+Added: 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.
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.
Taken together, Prime Editing’s versatile gene editing capabilities have the potential to unlock opportunities across thousands of potential indications.
−Removed: Prime Editors also have the ability to create permanent modifications at their natural genomic location, resulting in durable edits that are passed on to daughter cells, and retain their native physiological control.
+Added: 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.
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.
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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: To maximize the potential of our Prime Editing technology to provide one-time curative genetic therapies to the broadest set of diseases possible, we have built a diversified portfolio of investigational therapeutic programs organized around core areas of focus:
−Removed: hematology and immunology, liver, lung, ocular, and neuromuscular.
−Removed: We are advancing additional programs as potential partnership opportunities.
Recent highlights of the programs in our portfolio include the following:
−Removed: • PM359, our first product candidate within our hematology area of focus, targets the p47phox variant of chronic granulomatous disease, or CGD, a serious life-threatening disease that presents in childhood.
−Removed: PM359 is comprised of autologous hematopoietic stem cells, or HSC, modified ex vivo using Prime Editors that have been designed to correct a high percentage of cells containing the disease-causing mutation.
−Removed: We plan to submit an investigational new drug, or IND, application with the FDA and/or clinical trial application, or CTA, in the first half of 2024.
+Added: • 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.
+Added: 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.
+Added: PM359, our first product candidate within our hematology, immunology and oncology area of focus, targets the p47phox variant of CGD.
+Added: 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.
We believe Prime Editing is uniquely well-suited to address this form of CGD.
−Removed: We have completed our preliminary clinical trial design and selected global trial sites to maximize access to patients and expedite enrollment for PM359 clinical trials.
−Removed: In August 2023, we received rare pediatric drug designation, or RPDD, from the FDA for PM359.
−Removed: In addition, in January 2024, we received orphan drug designation, or ODD, from the FDA for PM359.
−Removed: • Also in our hematology and immunology area of focus, in June 2023, we entered into a research collaboration with Cimeio Therapeutics, Inc., or Cimeio, to combine our Prime Editing platform and Cimeio’s Shielded Cell and Immunotherapy Pairs, or SCIP, platform to develop Prime Edited SCIP for genetic diseases, acute myeloid leukemia, and myelodysplastic syndrome.
−Removed: The overall goal of the research is to reduce the toxicity of conditioning regimens and introduce new therapeutic options to meaningfully expand the utility of HSC transplant and enable the in vivo selection of edited HSCs to potentially remove the need for transplantation entirely.
−Removed: • We have demonstrated Prime Editing of cells preclinically at predicted therapeutically relevant levels for all of our leading programs, including Wilson’s Disease and Glycogen Storage Disease 1b, or GSD1b, in our liver area of focus, Retinitis Pigmentosa/Rhodopsin, or RHO, in our ocular area of focus, and Friedreich’s Ataxia in our neuromuscular area of focus.
−Removed: In 2023, we presented preclinical research across multiple programs, including proof-of-concept data from in vivo rodent and large animal studies.
−Removed: Specifically:
−Removed: ▪ In October 2023, we reported preclinical data demonstrating the ability of liver-targeted Prime Editors to precisely correct with high efficiency one of the most prevalent disease-causing mutations of GSD1b in non-human primates, or NHPs, and mouse models.
−Removed: These data are the first Prime Editing data in NHPs, which we believe provide further proof-of-concept for our Prime Editing approach to potentially address a wide range of diseases.
−Removed: ▪ We presented additional in vivo data in October 2023, demonstrating that Prime Editors can efficiently and precisely correct the predominant mutations that cause RHO associated autosomal dominant retinitis pigmentosa.
−Removed: These data suggest that our proprietary dual adeno-associated virus, or AAV, platform can effectively deliver Prime Editors to the eye, with the potential to treat a range of retinal diseases.
−Removed: • In our lung area of focus, we have expanded our efforts to develop Prime Editors for the treatment of Cystic Fibrosis, or CF, and 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 and PASSIGE in CF, as well as our ongoing efforts to develop lipid nanoparticles, or LNPs, for delivery to the lung.
+Added: We have received rare pediatric drug designation, or RPDD, and orphan drug designation, or ODD, from the FDA
+Added: for PM359 in January 2024.
+Added: We also have received fast track designation from the FDA for PM359 in November 2024.
+Added: • 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.
+Added: 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.
+Added: • We continue to advance multiple Prime Editors in our lung area of focus for the treatment of Cystic Fibrosis, or CF.
+Added: 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.
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.
In parallel, using PASSIGE, we aim to address nearly all people with CF using a single superexon insertion strategy.
−Removed: • In our chimeric antigen receptor T cell, or CAR-T, program, we presented preclinical data in December 2023, demonstrating that PASSIGE was greater than 80 percent efficient for non-viral, site-specific delivery of chimeric antigen receptor to primary human T-cells to generate CAR-T cells, and can be
−Removed: multiplexed with Prime Editing at other target sites by non-viral one-step delivery with no loss of efficiency.
−Removed: • Lastly, our comprehensive suite of assays used to identify potential off-target events has been expanded to include new, unbiased genome-wide tools.
−Removed: These analyses have continued to demonstrate minimal to no detectable off-target edits, chromosomal rearrangements or translocations.
−Removed: No off-target activity has been detected in any of our leading programs, including CGD, Wilson’s Disease, GSD1b, and RHO.
−Removed: We believe these preliminary analyses, across multiple editing programs, suggest a potentially best-in-class safety profile.
−Removed: • We believe our Prime Editing programs are well-positioned to leverage the clinical, regulatory, and manufacturing advancements made to date across gene therapy, gene editing, and delivery modalities to accelerate progression to clinical trials and potential approval.
−Removed: To unlock the full potential of our Prime Editing technology across a wide range of therapeutic applications, we are pursuing a comprehensive suite of clinically validated delivery modalities in parallel.
−Removed: For a given tissue type, we intend to use the delivery modality with the most compelling biodistribution.
−Removed: Our initial programs rely on three distinct delivery methodologies:
−Removed: (a) electroporation for efficient delivery to blood cells and immune cells ex vivo ;
−Removed: (b) lipid nanoparticle, or LNP, for non-viral in vivo delivery to the liver and potentially other organs in the future;
−Removed: and (c) AAV for viral delivery in vivo to the eye, ear, and the central nervous system, or CNS, and muscle.
−Removed: • We believe the modularity of our platform means that we will be able to accelerate our ongoing efforts and enable rapid generation of new product candidates.
−Removed: We believe the core components, such as Prime Editors, delivery, manufacturing, off-target assays, clinical, and regulatory can be leveraged to drive acceleration, efficiency and execution of our pipeline.
−Removed: We began operations in the summer of 2020, after being co-founded by David Liu, Ph.D., a world-renowned leader in the field of gene editing, along with co-founder Andrew Anzalone, M.D., Ph.D., who conceived of and developed Prime Editing along with Dr.
−Removed: Liu and others.
−Removed: Anzalone joined as our Head of Platform Development with years of experience in Prime Editing.
−Removed: Keith Gottesdiener, M.D., joined in 2020 as our President and Chief Executive Officer.
−Removed: Drawn by the promise of Prime Editing’s ability to transform the field of gene editing, we have since assembled a diverse and growing team that has grown to approximately 230 as of December 31, 2023, with all key functional leadership and employees in place.
−Removed: Our research, technical, and clinical development teams consist of experts in gene editing and Prime Editing, computational biology, automation, data sciences, off-target biology, structural biology, RNA chemistry, protein engineering and molecular evolution, genetics, pharmacology, translational medicine, the manufacturing and delivery of genetic medicines, and clinical medicine and regulatory affairs.
−Removed: Relationship with David Liu, Ph.D.
−Removed: We benefit from a close working relationship with Dr.
−Removed: In addition to being a co-founder, Dr.
−Removed: Liu is the chair of our Scientific Advisory Board and a Board observer, meets regularly with Company representatives, and provides consulting services to us pursuant to a consulting agreement, or the Liu Consulting Agreement, related to gene editing and related technology for human therapeutic or prophylactic uses.
−Removed: We have also licensed certain improvements to Prime Editing from Dr.
−Removed: Liu’s laboratory at Broad Institute and Dr.
−Removed: Liu has entered into an agreement with us pursuant to which he is obligated to assign to us any inventions with respect to the services he performs for us.
−Removed: Our goal is to transform the lives of patients with debilitating diseases through the application of our ground-breaking 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
−Removed: diseases to severe, chronic and acute diseases, and ultimately to prevent disease before it occurs.
+Added: • 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.
+Added: 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.
+Added: 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.
+Added: • 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:
+Added: hematology, immunology and oncology, liver, and lung.
+Added: We are identifying partnership opportunities to advance our other programs, including those for neurological diseases, cell therapy, ocular diseases and hearing loss.
+Added: Our goal is to transform the lives of patients with debilitating diseases through the application of our Prime Editing platform and technology.
+Added: 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.
Key components of our strategy are as follows:
−Removed: • Deliver the broadest potential of Prime Editing in the service of patients.
−Removed: We believe our Prime Editing technology and capabilities represent the future of gene editing and could unlock broad applications in medicine and life sciences.
−Removed: As a result of our access to proprietary rights in groundbreaking technology and our continued investment to enhance this gene-editing approach, we have established a clear leadership position in Prime Editing.
−Removed: We have built a cross-disciplinary team consisting of dedicated, scientifically curious individuals and experts in Prime Editing and drug development who are passionate about our common goal of helping patients live longer, healthier lives.
+Added: • Maximize the potential of Prime Editing to benefit patients.
+Added: We believe our Prime Editing technology and capabilities represent the future of gene editing, with broad applications in medicine and life sciences.
+Added: 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.
+Added: 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.
• 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, initially focused on 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: Within our neuromuscular programs, for example, our initial focus on repeat expansion diseases is one of many potential areas of differentiation from other gene therapy and editing approaches, and was chosen to demonstrate where we believe Prime Editing has a unique genetic approach that could be applied to a large set of related diseases with high unmet need:
−Removed: the precise removal of pathogenic repeats at the natural gene location, returning the patient’s genome to wild-type genetics.
−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 initial pipeline, potentially including immunological diseases, cancers, infectious diseases, and targeting genetic risk factors in common diseases.
+Added: 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.
+Added: 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.
+Added: 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.
• Advance our pipeline while simultaneously enhancing, validating and enabling our modular platform.
−Removed: We have established a diverse pipeline of investigational therapeutic programs organized around core areas of focus:
−Removed: hematology and immunology, liver, lung, ocular, and neuromuscular.
−Removed: In addition, we are advancing additional programs, such as CAR-T, as potential partnership opportunities.
+Added: We are pursuing a diverse pipeline of investigational therapeutic programs organized around a set of high value programs in our core areas of focus:
+Added: hematology, immunology and oncology, liver, and lung.
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.
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 our areas of focus, we are pursuing numerous clinically validated delivery modalities in parallel.
−Removed: For a given tissue type, we intend to use the delivery modality with the most compelling biodistribution and Prime Editing efficiency.
−Removed: We are currently focusing on three delivery modalities:
−Removed: (a) electroporation for delivery to blood cells and immune cells ex vivo ;
−Removed: (b) LNP for non-viral in vivo delivery to the liver, lung and potentially other organs in the future;
−Removed: and (c) AAV for viral in vivo delivery to the eye, ear, and potentially the central nervous system, lung and muscle.
+Added: 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.
+Added: 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.
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.
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• 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.
+Added: 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.
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.
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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,
−Removed: entering into collaboration or license agreements for programs now that we would not otherwise pursue in the near term;
+Added: 2) outside our core areas, entering into collaboration or license agreements for programs now that we would not otherwise pursue in the near term;
and 3) accessing enabling innovations, such as delivery and manufacturing capabilities.
+Added: In 2024, we executed on this strategy by entering into a therapeutic development agreement with CFF and a collaboration agreement with BMS.
• Lead with our culture of integrity, ethics, innovation and respect in everything we do.
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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: Prime Editors:
−Removed: A Next Generation Gene Editing Technology
−Removed: We are developing Prime Editors as a potentially new class of therapeutics with transformative potential to expand the application of curative precision genetic medicines to the broadest spectrum of diseases.
−Removed: Genetic mutations implicated in disease are diverse and can range from errors of a single base, known as point mutations, to errors that extend beyond a single base, such as insertions, deletions, duplications, or combinations thereof.
−Removed: Other mutations can affect regulatory sequences that control the function of genes and can affect the function of larger biochemical and genetic pathways.
−Removed: Furthermore, natural genetic variations, revealed by population-level genomic studies, are known to protect against or to increase risk of disease.
−Removed: To maximize the impact of these genetic insights, we believe the ability to alter the human genome at the foundational level in a versatile, precise, efficient and broad manner may confer the greatest therapeutic impact on human disease.
−Removed: Over the last decade, groundbreaking advances in gene therapy, cell therapy and RNA therapeutics have resulted in several approvals for genetic medicines that have transformed the treatment of certain severe genetic diseases and cancers as well as the prevention of infectious diseases, such as the mRNA vaccine for COVID-19.
−Removed: More recently, the first generation of CRISPR-Cas based gene editing approaches for gene disruption have demonstrated evidence of the ability to address diseases caused by genetic mutations, via either in vivo or ex vivo delivery to humans.
−Removed: In 2023, the first CRISPR/Cas9-based therapy (CASGEVY™) was approved by the FDA for the treatment of sickle cell disease, followed soon after by its approval for use in beta-thalassemia.
−Removed: In addition to first generation CRISPR approaches, several base editing investigational medicines, which enable targeted introduction of certain point mutations, have received IND clearance by the FDA, and clinical trials have begun.
Current Challenges for the Field of Genetic Medicines
−Removed: Despite significant progress within gene therapy, 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
−Removed: Non-targeted gene therapy includes using viral vectors, such as AAV, or retroviruses such as lentiviruses, to deliver new copies of genes, or transgenes, to cells.
−Removed: It also includes the broad field of mobile gene elements, such as retrotransposons and transposons.
+Added: 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.
+Added: 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.
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.
−Removed: Certain non-integrating viral vectors, such as AAV, may have limited durability, and pre-existing immunity to the vectors could limit their use and ability to be re-dosed.
−Removed: For approaches that integrate genes, including transposons, retrotransposons, and retroviral vectors, gene integration may occur randomly at hundreds or thousands of sites in the human genome because it is not currently possible to direct their integration to a specific, desired genetic location.
−Removed: Randomly integrating approaches also carry the risk of insertional mutagenesis.
−Removed: In addition, non-targeted gene therapy approaches do not take advantage of normal endogenous regulation of gene expression, and instead lead to variable gene expression due to an inability to fine tune the vector copy number per cell.
−Removed: Nuclease Gene Editing and Base Editing
+Added: 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.
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: can then be repaired by one of two naturally occurring DNA repair pathways:
−Removed: (1) non-homologous end joining, or NHEJ, which patches the broken ends of the chromosomes back together and randomly creates indels, or insertions and deletions;
−Removed: or (2) homologous directed repair, or HDR, which can more precisely replace DNA at the target cut site with the delivery of a template of corrected DNA.
−Removed: However, given NHEJ is typically the dominant repair pathway in cells and due to the low efficiency of repair and complexity associated with HDR, most nuclease-based editing programs in the clinic have focused on an NHEJ-directed knock out approach to alter or silence gene expression.
−Removed: Nuclease based gene editing approaches have several key limitations.
−Removed: First, there is a lack of predictability in genetic outcomes at the target site in NHEJ, such as randomly creating indels (efficient if the goal is to disrupt or knock out a gene).
−Removed: Using HDR to make corrections, replacements, or insertions has low percentage editing efficiency, does not have the ability to correct genes in non-dividing cells because HDR DNA repair machinery is only expressed in dividing cells, and requires a DNA template with the desired, corrected gene sequence to be delivered simultaneously, which increases complexity.
−Removed: Nuclease editing also leads to unwanted DNA modifications associated with double-stranded breaks, including cell death response, genomic instability, off-target editing and the potential for oncogenesis.
−Removed: Finally, making multiple edits with nucleases that generate double-stranded breaks at multiple genomic locations has the potential to lead to unwanted large scale translocations and rearrangements, potentially limiting applicability to multiplex editing.
−Removed: Base editing is an emerging gene editing technology that harnesses CRISPR-Cas9 to deliver a deaminase to a target DNA site, which can edit a single base efficiently.
−Removed: Base editing avoids double-stranded breaks and the deleterious effects associated with first generation nuclease editing, while enabling C-to-T or A-to-G base substitutions edits using either a Cytosine Base Editor, or CBE, or Adenine Base Editor, or ABE, respectively.
−Removed: Base editing has several key limitations.
−Removed: Currently, base editing can reliably correct only four out of 12 possible single base mutations, and base editing cannot make or correct insertion or deletions, which limits the number of diseases base editing can address.
−Removed: Further, each base editor (CBE or ABE) has the ability to correct or introduce only a single point mutation at a specific location.
−Removed: Base editing also has been shown to make certain types of unwanted on-target by-products, called bystander edits, near the targeted site, e.g., modifying nearby bases which are not being targeted but fall within the editing window.
−Removed: Finally, base editing may have limited optionality for targeting mutations due to its smaller editing window.
+Added: 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
+Added: 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.
+Added: 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.
+Added: 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.
Prime Editing:
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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 was first described in a Nature publication in December 2019 and has since been extensively validated in vitro and in animal studies, both by our company and in over 150 papers published in the primary scientific literature to date.
+Added: 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.
Advantages of our Prime Editing Platform
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• 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 most applications of Prime Editing.
−Removed: • Greater optionality with respect to editing site availability than other approaches due to a larger editing window.
−Removed: • Programmable, which means that both the specified target location in the genome and the directed type of edit can be easily modified by replacing the Prime Editing guide RNA, or pegRNA, element of a Prime Editor.
−Removed: • Modular for targeting a broad set of mutations, meaning that by redesigning the pegRNA a new mutation can be targeted for correction.
−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 by 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.
+Added: • Direct correction of DNA with no requirement for delivery of the corrected DNA sequence in many applications of Prime Editing.
+Added: • 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.
+Added: • 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.
• 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.
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• Designed to specifically make only the directed type of Prime Edit at the desired target location.
−Removed: • Avoidance of the potential negative impacts associated with double-stranded breaks, which results in minimal to potentially no unwanted on-target or off-target by-products and preservation of cell viability.
+Added: • 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.
• Limited potential for bystander editing at the target site, a potential unwanted effect of base editing.
Durable gene edits with potential for superior therapeutic activity
−Removed: • Single treatment resulting in permanent corrections of disease-causing mutations by restoring the targeted gene back to its wild-type sequence.
+Added: • Single treatment resulting in permanent correction of disease-causing mutations by restoring the targeted gene back to its wild-type, or non-diseased sequence.
• 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 in situ, or in their native genomic setting.
−Removed: • Highly efficient, effecting therapeutically relevant levels of precise gene correction generally unachievable by nuclease-based methods.
+Added: • 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.
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 and cell types, as well as in a wide variety of other organisms, as well as including primary cells such as hepatocytes, hematopoietic stem cells and neurons.
+Added: • 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.
• Potential ability to repair approximately 90 percent of all types of mutations known to cause genetically driven disease.
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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: Prime Editing Technology
Prime Editors have at least two major components, a Prime Editor protein and a pegRNA.
Our Prime Editor proteins contain two protein domains.
−Removed: The first domain is a programmable DNA binding domain, often a CRISPR-Cas domain, or Cas domain.
−Removed: Cas proteins 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, for example Cas9 proteins, are modified such that they do not cause a double-stranded break in the DNA.
−Removed: The second protein domain of Prime Editors is a reverse transcriptase enzyme domain, or RT domain.
−Removed: Reverse transcriptases are DNA polymerase enzymes that write new DNA sequences by
−Removed: copying from an RNA template.
+Added: The first domain is a programmable DNA binding domain, often a CRISPR-Cas protein domain, or Cas domain.
+Added: 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.
+Added: 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.
+Added: The second protein domain of Prime Editors is a DNA polymerase domain, often a reverse transcriptase enzyme domain, or RT domain.
+Added: Reverse transcriptases are DNA polymerase enzymes that write new DNA sequences by copying from an RNA template.
In Prime Editing, the RT domain copies the edited DNA sequence directly into the target genomic site where the edit is made.
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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, our Prime Editor protein, exemplified using a Cas protein, and the pegRNA locate the DNA target site using the pegRNA’s search sequence.
−Removed: 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.
+Added: 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.
+Added: 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.
The other DNA strand remains intact and is not cleaved by the Prime Editor, thus avoiding the formation of double-stranded DNA breaks.
−Removed: Next, the 3’ flap binds to a region of the replace sequence in the pegRNA (“edit check 2”) and “primes” the DNA synthesis, which is shown in the third panel below.
−Removed: The Prime Editor’s RT domain copies the pegRNA’s replace sequence, directly writing the corrected DNA sequence into the gene, as shown in the fourth panel.
−Removed: After the corrected sequence is fully copied, cellular DNA repair preferentially incorporates the corrective 3’ flap (“edit check 3”) while removing the excess original DNA sequence.
−Removed: The complementary DNA strand is also corrected, using the Prime-Edited DNA strand as a template.
+Added: 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.
+Added: The Prime Editor’s RT domain copies a portion of the replace sequence, which incorporates the desired edit, as shown in the fourth panel.
+Added: 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.
+Added: The complementary DNA strand is also corrected through cellular DNA repair, using the Prime-Edited DNA strand as a template.
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.
The overall result is a target gene sequence that is corrected on both strands of DNA.
−Removed: As highlighted above, there are three distinct steps in the Prime Editing pathway that require exact matches between the target DNA and pegRNA sequences.
−Removed: Thus, the process of Prime Editing efficiently institutes three “edit checks,” or three sequential steps where only if the match is exact does the next step occur.
+Added: 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.
+Added: 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.
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.
Illustration of Editing Mechanism by Prime Editor – No Double-Stranded DNA Breaks
−Removed: Further Enhancing the Prime Editing Platform
−Removed: Over the last four years 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: The versatile nature of Prime Editing allows for the selection of the right tools for a specific gene edit from up to ten thousand potential choices 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: Multiple enhancements to our Prime Editing platform, including engineered 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
−Removed: more efficient and more precise.
+Added: Enhancing the Prime Editing Platform
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
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.
Dual-flap Prime Editing and long-flap Prime Editing
−Removed: We have in-licensed certain dual-flap Prime Editing technology developed by David Liu’s laboratory at Broad Institute, and expanded and improved on its uses.
−Removed: Compared to traditional Prime Editing, dual-flap Prime Editing uses two Prime Editors instead of one.
−Removed: In different places on a target gene, each of the Prime Editors creates a nick in the DNA and creates a flap;
−Removed: the two flaps are often designed to bind tightly to each other.
−Removed: This results in the looping out of the DNA between the Prime Editors, with replacement by new DNA.
−Removed: Dual-flap Prime Editing is designed to achieve efficient editing of a broader range of edit types, including the precise replacement or insertion of DNA sequences that are a hundred bases or more in length with potentially higher efficiency than standard Prime Editing.
−Removed: In addition, dual-flap Prime Editing can precisely delete up to thousands of bases of DNA, as shown in the data for repeat expansion diseases (see below in Portfolio section).
−Removed: In addition to its high efficiency, it achieves the same level of precision, and we believe it results in minimal off-target editing, as shown in preclinical studies, similar to the more standard forms of Prime Editing.
−Removed: Dual-flap Prime Editing could be used to delete expanded repeat sequences like those that occur in repeat expansion diseases, to replace mutation hotspots with corrected sequences, or to insert sequences at safe harbor or other locations in the genome, as can be applied to our PASSIGE approach.
−Removed: Additionally, we have developed a long-flap Prime Editing approach that, compared to standard 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 applied for similar applications as dual-flap Prime Editing, including editing of hotspot regions in DNA, insertions of recombinase sites for PASSIGE, and the excision of expanded repeats.
+Added: We have in-licensed certain dual-flap Prime Editing technology developed by Dr.
+Added: David Liu’s laboratory at Broad Institute, and expanded and improved on its uses.
+Added: Compared to single-flap Prime Editing, dual-flap Prime Editing uses two Prime Editors instead of one.
+Added: 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.
+Added: In addition, dual-flap Prime Editing can precisely delete up to thousands of bases of DNA.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
Together, dual-flap Prime Editing and long-flap Prime Editing broaden the capabilities of our Prime Editing platform.
PASSIGE™ – Precise introduction of gene-sized pieces of DNA into the genome
−Removed: We have in-licensed from the Broad Institute and are 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.
+Added: 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.
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 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: Although site-specific recombinases have been used as biology research tools to perform insertions, deletions or inversions of large pieces of DNA in the genome, their use in therapeutic applications has been limited by the extremely challenging task of engineering site-specific recombinases to be programmable or to target specific sequences in a gene or the genome.
−Removed: PASSIGE technology complements dual-flap Prime Editing, which is able to delete large pieces of DNA up to many kilobases in size, but which currently can only precisely insert a smaller piece of DNA.
−Removed: Therefore, in circumstances where a larger modification is required, this programmable technique can be used to insert or invert multi-kilobase-sized pieces of DNA.
+Added: This proprietary approach expands the versatility of Prime Editing and we believe
+Added: 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.
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.
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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: As shown in the figure below, PASSIGE may be used to insert DNA that contains a therapeutic gene, potentially such as a chimeric antigen receptor, or CAR, or the open reading frame of any other gene.
+Added: 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.
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.
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PASSIGE™ – Extending Prime Editing to insert gene sized sequences precisely in the genome
−Removed: Translating Prime Editors into Product Candidates - Multiple Modalities for Prime Editors
+Added: Translating Prime Editors into Product Candidates - Optimizing Prime Editor Components and Delivery Modalities
The optimal design and efficient generation of our Prime Editors are fundamental for the development of our pipeline.
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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 initial programs rely on three distinct delivery modalities:
+Added: Our current programs rely on two distinct delivery modalities:
(a) electroporation for delivery to blood cells and immune cells ex vivo ;
−Removed: (b) LNPs, for non-viral in vivo delivery to the liver, lung and potentially other organs in the future;
−Removed: and (c) AAVs for viral in vivo delivery to the eye and ear, and potentially the central nervous system, lung and muscle.
+Added: and (b) LNPs, for non-viral in vivo delivery to the liver, lung and potentially other organs in the future.
+Added: 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.
A key feature of Prime Editing and associated delivery methods is the modularity of the technology platforms.
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• 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 optimal pegRNA sequences.
+Added: An important element of our capability is leveraging high throughput automated screening and design algorithms to identify promising pegRNA sequences.
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 oligonucleotides for in vivo studies.
+Added: Internal chemistry capabilities facilitate high-throughput optimization and manufacture of pegRNA for in vivo studies.
We have established internal high-throughput pegRNA synthesis, pegRNA modifications with structure-activity-relationship to improve drug candidate properties, and pegRNA process chemistry.
• 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 mRNA design and optimization, enzymatic chemistry, and process development capabilities to enhance drug candidate properties and characterize the mRNA for efficient, tolerable, and consistent delivery and translation of the Prime Editor protein.
+Added: 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.
• Prime Editing Specificity and Assays:
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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: In the future, we plan to transition to in vivo editing of stem cells and other lymphocytes.
LNP delivery has initially focused on in vivo delivery of Prime Editing to the liver.
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• Viral Delivery:
−Removed: We are using viral delivery to tissues and locations that can currently only be reached with AAV.
+Added: We are able to use viral delivery to tissues and locations that can currently only be reached with AAV.
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.
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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 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 have built a diversified portfolio of investigational therapeutic programs organized around core areas of focus:
−Removed: hematology and immunology, liver, lung, ocular, and
−Removed: neuromuscular.
−Removed: We are advancing additional programs as potential partnership opportunities.
−Removed: The following table summarizes the status of certain of our programs:
−Removed: Our Blood Programs
+Added: We are developing manufacturing processes and analytical methods
+Added: 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.
+Added: 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:
+Added: hematology, immunology and oncology, liver, and lung.
+Added: The following table summarizes our pipeline:
+Added: Our Hematology, Immunology & Oncology Programs
Chronic Granulomatous Disease
−Removed: Chronic granulomatous disease, or CGD, is a rare inherited hematologic disorder characterized by susceptibility to severe, difficult-to-treat infections, and inflammatory/autoimmune complications.
+Added: CGD is a rare inherited hematologic disorder characterized by susceptibility to severe, difficult-to-treat infections, and inflammatory/autoimmune complications.
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.
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 unsual bacteria, fungi and mycobacteria.
+Added: Beginning in childhood, patients with CGD develop infections from a range of both typical and unusual bacteria, fungi and mycobacteria.
These infections may present in various organ systems, and protracted infections can lead to long-term organ damage and failure.
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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.
+Added: X-linked CGD, or X-CGD, is the most common form of CGD, representing approximately 65 percent of cases.
+Added: X-CGD is caused by mutations in the CYBB gene, which encodes the p91-phox protein.
+Added: X-CGD primarily affects male patients because the CYBB gene is located on the X chromosome.
Our Approach and Results:
Direct correction of prevalent CGD mutations or hotspots
−Removed: PM359, our first product candidate within our hematology and immunology area of focus, targets the p47phox variant of CGD.
+Added: PM359, our first product candidate within our hematology, immunology and oncology area of focus, targets the p47phox variant of CGD.
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
−Removed: the disease-causing mutation.
+Added: 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.
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.
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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 complex is delivered to CD34+ HSCs using electroporation.
−Removed: The Prime Editor mRNA is generated by in vitro transcription, and the pegRNA and ngRNA are generated by solid phase RNA synthesis.
−Removed: The Prime Editor complex is delivered by simultaneously electroporating mRNA encoding the Prime Editor protein along with pegRNA and ngRNA.
−Removed: We believe the mRNA is translated into the Prime Editor protein during a period of incubation, then the Prime Editor protein assembles with pegRNA or ngRNA, and the complex enters the nucleus with Prime Editing commencing at the target site in the genome.
−Removed: We have identified a Prime Editor complex that is 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;
+Added: The Prime Editor components, comprised of the Prime Editor mRNA, pegRNA and ngRNA, are delivered to CD34+ HSCs using electroporation.
+Added: 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;
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 as shown in the figure below.
−Removed: Mice are typically followed for 16 weeks in these experiments to allow for engraftment of the long-term HSCs, repopulation of the immune system by long-term HSCs, and evaluate durability of effect.
−Removed: When Prime Edited healthy donor or CGD patient CD34+ cells are administered to NBSGW mice, they were able to engraft, and edited cells proliferated to repopulate the hematopoietic system.
+Added: 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.
+Added: 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.
+Added: 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.
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.
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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 below demonstrates the results of one commonly used measure of NADPH oxidase activity, the dihyrorhodamine (DHR) assay.
+Added: The panel on the right in the figure
+Added: below demonstrates the results of one commonly used measure of NADPH oxidase activity, the dihydrorhodamine (DHR) assay.
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
−Removed: 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.
+Added: 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.
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.
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Data presented at ASGCT and ESGCT 2023.
−Removed: Prime Editing has exhibited a very low level of undesirable genetic changes.
+Added: Prime Edited CD34+ cells exhibited no significant off-target editing and no detectable evidence of deletions or translocations above the level of significance.
Extensive in silico, ex vivo and in vivo analyses have been performed.
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 interrogated for off-targeting editing in Prime Edited healthy donor CD34+ cells;
+Added: 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;
no significant off-target editing was detected.
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 translocation above the level of significance.
+Added: 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.
In the right panel, a human cell line was transfected with spCas9 targeting NCF1 without the Prime Editing machinery.
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3 Positive control.
−Removed: Overall, the data presented in the two figures above strongly support the clinical evaluation of PM359 in patients with p47phox CGD.
−Removed: We believe these data suggest that PM359 has the potential to meet and exceed the projected mutation correction rate sufficient to achieve disease amelioration, and that PM359 has a low probability of safety events potentially associated with ex vivo gene-edited HSC products.
−Removed: Based on these results, we have selected a development candidate, designated PM359 and are in the process of completing IND-enabling studies with this candidate.
−Removed: We plan to submit an IND and/or CTA with the the FDA, in the first half of 2024.
−Removed: We have completed our preliminary clinical trial design and selected leading CGD transplant centers across the United States and other countries as clinical trial sites to maximize access to patients and expedite enrollment for PM359 clinical studies.
−Removed: Study Prime-0101 is a planned, multinational, first-in-human trial designed to assess the safety, biological activity and preliminary efficacy of PM359 in adult 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 by mobilization and apheresis and transferred to a centralized manufacturing facility, where they will be electroporated with Prime Editing reagents, cryopreserved and quality control tested, to generate PM359.
−Removed: PM359 will be infused after myeloablative conditioning, and study participants 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: Initial study participants will be adults with stable disease.
−Removed: Once safety and biological activity has been demonstrated in initial participants, the study will enroll participants with active infection or inflammation, as well as adolescent and pediatric participants, under the supervision of a Data Monitoring Committee.
−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: We believe PM359 is uniquely well-suited to restore immune function and resolve infectious and inflammatory disease in patients with p47phox CGD.
In August 2023, we received RPDD from the FDA for PM359 for the treatment of CGD.
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, it may be used by us or sold to a third party.
−Removed: In addition, in January 2024, we received Orphan Drug designation from the FDA for PM359 for the treatment of CGD.
−Removed: Other Programs in Discovery
−Removed: We continue to make progress in other programs in our hematology and immunology area of focus.
−Removed: We are exploring cell shielding to expand our HSC area of focus beyond rare diseases.
−Removed: In June 2023, we entered into a research collaboration with Cimeio to combine our Prime Editing platform and Cimeio’s SCIP platform to develop Prime Edited SCIP for genetic diseases, acute myeloid leukemia, and myelodysplastic syndrome.
−Removed: The overall goal of the research is to reduce the toxicity of conditioning regimens and introduce new therapeutic options to meaningfully expand the utility of HSC transplant and enable the in vivo selection of edited HSCs to potentially remove the need for transplantation entirely.
−Removed: Additionally, we are also researching Fanconi anemia, a rare and life-threatening DNA repair disorder that arises from loss-of-function mutations in any of 23 genes.
−Removed: Our Liver Programs
−Removed: Non-Viral Delivery In Vivo with Lipid Nanoparticles
−Removed: LNPs are multicomponent and 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 formulations, and in vivo evaluation of LNP delivered Prime Editors.
−Removed: We are integrating automation, analytical quality control, and 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: For our first in vivo Prime Editor programs, we are building upon learnings from existing LNP technologies to develop a Universal Targeted LNP delivery system that is targeted to the liver, and specifically targets the LNP to the hepatocytes.
−Removed: This approach, we believe, will improve biodistribution to the target cell type.
−Removed: The LNP system will be modular in that simply swapping out the pegRNA (and ngRNA where required) will result in a new product.
−Removed: This approach will allow us to move the existing liver programs in to the clinic quickly and establish proof of concept, and potentially bring forward additional liver programs, quickly thereafter.
−Removed: To develop and optimize the LNP platform, Prime has developed a model system in mice to iteratively study and optimize the properties of our LNP formulations and the Prime Editor cargo.
−Removed: In this system, we inactivate the PCSK9 gene by precisely introducing a stop codon into the gene.
−Removed: PCSK9 protein is a factor controlling lipoprotein uptake into cells from the blood.
−Removed: This system enables us to look at levels of PCSK9 protein in the blood in response to editing.
−Removed: Following optimizations in this system, simply swapping the guide RNAs for PCSK9 Prime Editing for program specific guide RNAs will result in test articles that can be evaluated in humanized mice or in NHPs for the liver programs.
−Removed: Optimization of Prime Editors containing three different mRNA lots were formulated with one of our LNP formulations.
−Removed: One of our optimized mRNA lots showed more than 40 percent editing in whole liver, resulting in more than 90 percent reduction in circulating PCSK9 protein levels.
−Removed: Panel shows an experiment delivering LNPs to the liver containing a Prime Editor precisely introducing a stop codon into the mouse PCSK9 gene.
−Removed: The experiment tested 3 different mRNA lots.
−Removed: Left graph shows precise editing of PCSK9 at seven days with optimized lots of mRNA.
−Removed: PCSK9 protein levels in the blood dropped by more than 90% of normal following editing, right graph.
−Removed: Note that LNPs deliver primarily to hepatocytes in liver.
−Removed: Therefore, maximum editing possible is predicted to be no more than 60%.
−Removed: Panel shows a schematic of the Universal targeted LNP encapsulating the Prime Editor drug components (left) and dose responsive whole liver in vivo Prime Editing of the mouse PCSK9 gene using 2 different leading LNP formulations.
−Removed: on experiment delivering LNPs to the liver containing a Prime Editor precisely introducing a stop codon into the mouse PCSK9 gene.
−Removed: Note that the targeted LNPs deliver to hepatocytes in liver.
−Removed: Therefore, maximum editing possible is predicted to be no more than 60%.
−Removed: Leading Prime Editor LNP formulations resulted in dose responsive Prime Editing of whole liver mouse PCSK9.
−Removed: Following optimizations of the components and their formulations in this system, by swapping only the guide RNAs (pegRNA and ngRNA) for PCSK9 Prime Editor for program specific guide RNAs test articles that can be evaluated in humanized mice or in NHPs for the liver programs, Wilson’s Disease and Glycogen Storage Disease.
+Added: If we receive a priority review voucher, or PRV, it may be used by us or sold to a third party.
+Added: In January 2024, we received Orphan Drug designation from the FDA for PM359 for the treatment of CGD.
+Added: We also have received fast track designation from the FDA for PM359 in November 2024.
+Added: 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.
+Added: 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.
+Added: Autologous CD34+ cells will be collected from study participants and edited with Prime Editing reagents to generate PM359.
+Added: 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.
+Added: 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.
+Added: The Phase 1/2 clinical trial is currently enrolling patients, and we anticipate sharing initial clinical data from this trial in 2025.
+Added: 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.
+Added: We also are continuing our preclinical development of Prime Editors to treat X-CGD.
+Added: 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.
+Added: Our Liver Program
Wilson’s Disease
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 1 in 10,000 and 1 in 30,000, it is expected to affect upwards of 35,000 to 100,000 patients in the United States and Europe.
+Added: 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.
It is also understood that there may be significant under-diagnosis of WD.
2 unchanged sentences
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 caused by mutations in both genomic copies of the ATP7B gene, which encodes a copper transporter that removes excess copper.
+Added: 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.
Two predominant mutations have been described in WD:
−Removed: H1069Q, found in approximately 40 percent of all patients in the United States and 18 to 72 percent in Europe;
−Removed: R778L, frequently found in Asian patients and those of Asian ancestry, reported in 46 percent of Chinese, 38 percent of Korean, and 25 percent of Japanese WD patients.
−Removed: Both of these mutations lie adjacent to hotspots or areas with other pathogenic mutations, for which we are currently designing Prime Editors.
−Removed: Genotyping of ATP7B is not routinely performed during diagnosis and is used to confirm the symptomatic diagnosis when necessary.
+Added: 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;
+Added: 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.
+Added: We are currently designing Prime Editors for both of these mutations, which lie adjacent to hotspots or areas with other pathogenic mutations.
Our Approach and Results:
1 unchanged sentence
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 seen in the U.S.
−Removed: We are also evaluating hotspot editors in the ATP7B gene region around R778L that could address additional patients.
+Added: A Prime Editor that corrects R778L will also correct R778W and R778G mutations, rarer mutations that are observed in the U.S.
We have performed pegRNA and ngRNA screens and identified guide combinations that correct the disease-causing point mutations.
−Removed: 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: In a hepatocyte cell line with the human WD mutation, we have identified Prime Editors that demonstrate precise correction of H1069Q ATP7B in approximately 80 percent of cells as shown in the figure below on the left.
−Removed: We have further demonstrated precise correction of approximately 40 percent in primary humanized mouse hepatocytes bearing the human ATP7B gene with the H1069Q mutation, which is shown in the figure below in the middle, and we have also observed approximately 50 percent precise correction using a surrogate Prime Editor in primary NHP hepatocytes, which is shown in the figure below on the right.
−Removed: Note that each data point in the figure on the left represents the result from a different, individual Prime Editor, and the red circle highlights the best performing Prime Editor, with the average percent precise correction of cells shown in the bar graphs.
−Removed: This high level of precise editing in primary hepatocytes meets our threshold of 25 to 50 percent for predicted clinically relevant effects.
−Removed: To support this, we performed a copper toxicity challenge in liver cells that are normal and liver cells with a pathogenic H1069Q mutation with varying degrees of precise editing correction.
−Removed: As shown in the figure below, we observed a marked difference in cell survival in the presence of high levels of copper between healthy cells (WT;
−Removed: left bar) and liver cells with a pathogenic mutation that are unedited (0 percent;
−Removed: The third and fourth bars show that with different degrees of precise correction, such as 14 percent and 55 percent, the ability of Prime Edited cells to survive copper toxicity returns towards normal levels the greater the level of correction.
−Removed: Initial genome-wide studies using patient cells and human hepatocytes have not identified any detectable off-target editing.
−Removed: Leveraging our modular universal targeted LNP delivery platform, we are currently conducting preclinical studies to optimize our H1069Q and R778L Prime Editors in humanized mouse models and NHP.
−Removed: Glycogen Storage Disease 1b
−Removed: In October 2023, we reported new preclinical data demonstrating the ability of liver-targeted Prime Editors to efficiently and precisely correct one of the most prevalent disease-causing mutations of GSD1b in NHPs and mouse models.
−Removed: These data are the first Prime Editing data in NHPs and we believe provide further proof-of-concept for our Prime Editing approach to potentially address a wide range of diseases.
−Removed: GSD1b is a rare, serious progressive and fatal disease affecting approximately 1,500 patients and caused by impaired glycogen metabolism.
−Removed: This autosomal recessive disease is caused by mutations in the glucose-6-phosphate transporter, G6PT also known as SLC37A4.
−Removed: Deficiencies in this transporter result in hypoglycemia or low blood glucose levels which can be fatal if patients do not adhere to a strict regimen of slow-release glucose including overnight feeding.
−Removed: Most patients experience symptoms within the first six months of life presenting with hypoglycemia, lactic acidosis or with a large liver.
−Removed: They also can manifest seizures and low white blood cell levels, resulting in recurrent bacterial infections and oral and intestinal mucosa ulceration.
−Removed: Many patients have liver tumors, which can progress to liver carcinoma.
−Removed: Multiple other serious manifestations can occur.
−Removed: Our Approach and Results:
−Removed: Direct correction of prevalent mutations in SLC37A4
−Removed: Our initial approach to treating patients with GSD1b is to use our Universal Targeted LNP platform to deliver Prime Editor complex to hepatocytes in the liver to correct the two most prevalent mutations that cause the disease, which are located very close to each other in the gene:
−Removed: L348fs, and G339C.
−Removed: In Caucasian populations, these two predominant mutations together are found in 45 percent of patients.
−Removed: Based on prevalence data we estimate there are approximately 650 patients in the United States and 1,450 patients in Europe with GSD1b, and we estimate there are
−Removed: approximately 950 patients with these mutations.
−Removed: While heterozygote carriers have no disease and animal studies of GSD1b suggest that as little as 11 percent of normal activity has the potential to restore normoglycemia, we use an estimate that 20 percent of activity normalizes fasting glucose.
−Removed: As shown in the left figure below, we have identified Prime Editors that demonstrate precise correction of the first mutation with approximately 80 percent efficiency in primary hepatocytes harboring the L348fs mutation.
−Removed: We formulated Prime Editors in our Universal Targeted LNP platform and, as shown in the right figure below, also demonstrated in vivo editing of the first mutation with approximately 80 percent efficiency in the livers of humanized SLC37A4 mice where the mouse gene has been replaced with the human gene harboring the L347fs mutation.
−Removed: The NHP Prime Editor is directed to the same location in the SLC37A4 gene as the human Prime Editor, but the NHP genomic sequence is slightly different from the human sequence, hence the use of a surrogate.
−Removed: To further evaluate our Universal Targeted LNP platform, we were also able demonstrate in vivo editing with approximately 70 percent efficiency in NHPs using surrogate SLC37A4 Prime Editor, as shown in the figure below.
−Removed: In our preliminary safety studies, the Universal Targeted LNPs were well tolerated in both rats and NHPs.
−Removed: Initial genomewide studies using patient cells and human hepatocytes have not identified any detectable off-target editing.
−Removed: We are currently performing lead optimization of our GSD1b Prime Editors, establishing an efficacy and safety data package including genotype-phenotype biomarker response, and off-target, safety.
−Removed: In addition, we have developed a series of Prime Editors that precisely correct the G339C mutation with high levels of editing efficiency and are evaluating them in in vivo humanized mouse studies.
−Removed: Expansion Opportunities in the Liver Pipeline
−Removed: To accelerate our liver programs, we are continuing to develop our proprietary universal targeted LNP platform in liver.
−Removed: Now that we have established the ability to deliver Prime Editors via LNPs to hepatocytes in vivo , we could potentially advance other Prime Editing liver programs more quickly, reflecting the versatility and modularity of our platform, which potentially enables the rapid creation of new product candidates by merely swapping out pegRNAs.
−Removed: Our Lung Programs
+Added: 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.
+Added: 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.
+Added: 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).
+Added: 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).
+Added: No off-target edits or unintended edits at the target site were detected in the in vivo humanized mouse or NHP studies.
+Added: 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.
+Added: Non-Viral Delivery In Vivo with Lipid Nanoparticles
+Added: 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.
+Added: We are investing strategically to build our LNP formulations for delivery as a platform technology to enable target tissue delivery.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: 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.
+Added: This approach, we believe, improves biodistribution to the target cell type.
+Added: 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.
+Added: Our Lung Program
Cystic Fibrosis
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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: Most patients are diagnosed before two years of age through newborn screening or because of symptoms of lung disease, combined by salty skin which can be confirmed using a sweat test.
−Removed: Through supportive care and antibiotic therapies patient median survival has increased to early thirties before lung failure necessitates lung transplantation, if available.
−Removed: Overall CF prevalence in the United States and Europe is
−Removed: 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.
−Removed: Trikaftor), there is no cure and existing treatments are ineffective or not tolerated for approximately 15 percent of patients.
−Removed: The disease is inherited recessively and caused by loss-of-function mutations in a chloride protein transporter called CF transmembrane conductance regulator, or CFTR.
+Added: 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.
+Added: 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.
Approximately 65 to 75 percent of CF patients have a three-nucleotide deletion in the CFTR gene known as F508del.
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: F508del and several other mutations result in misfolding of the CFTR protein which fails to reach the plasma membrane, whereas other mutations lead to complete absence of protein or a protein which does not function even though it is localized at the correct site in the cell.
−Removed: The failure of CFTR to function at the cell surface leads to cell secretions that lack sufficient salt and water, resulting in high viscosity and inability to clear secretions from lung and pancreas.
Our Approach:
3 unchanged sentences
Through hotspot editing, we aim to address multiple mutations at CFTR mutational hotspots with a small number of Prime Editors.
−Removed: This 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.
In parallel, with PASSIGE, we aim to address nearly all people with CF with a single CFTR superexon insertion strategy.
−Removed: Our preliminary screens have identified hotspot Prime Editors that achieve high levels of precise correction.
−Removed: As shown in the figure below, we observed approximately 70 percent precise editing of the G542X mutational hotspot (left bar), and approximately 50 percent precise editing of the hotspot encompassing I507del and prevalent F508del mutations (right bar) in patient cells.
−Removed: 1 G542X and I507del are “high unmet need” mutations;
−Removed: F508del is one of the most prevalent CF mutations;
−Removed: 2 data show correction in patient induced pluripotent stem cells.
−Removed: Each dot shows a different Prime Editor.
−Removed: In initial proof of concept studies, we developed an intestinal organoid swelling assay that enabled us to test the impact of our Prime Editors on CFTR protein function.
−Removed: As shown in the figure below, healthy donor intestinal organoids swell when stimulated as a result of the CFTR channel pumping salt and water into the organoid (top left image).
−Removed: Organoids from CF patients do not swell (top right image).
−Removed: We then edited the organoids from patients with
−Removed: the G542X mutation and demonstrated that our Prime Editors restore swelling to levels seen in healthy donor organoids (bottom right image).
−Removed: With CFF’s support, pursuant to the therapeutic development agreement with the Cystic Fibrosis Foundation, or CFF, we are aiming to deliver one-time, non-viral therapy that offers first cure to all patients living with CF.
−Removed: We will perform optimizations of the hotspot Prime Editors from the early screens to increase efficiency and optimize Prime Editors for additional mutations.
−Removed: In addition, and in parallel we are developing a superexon insertion approach using Prime’s PASSIGE technology.
−Removed: Screening for Prime Editors and superexon templates for PASSIGE is underway and we are building a series of assays to evaluate our Prime Editors on restoration of CFTR protein function.
−Removed: We are testing Prime Editors in patient-derived cells, including iPSCs, intestinal organoids, and human bronchial epithelium.
−Removed: Humanized mice with part of the mouse CFTR gene replaced with human CFTR gene containing the human mutation, have been developed for us to deliver Prime Editors initially to the lung epithelial basal cells which contain a population of lung stem cells.
−Removed: We are developing and optimizing LNP formulations to efficiently deliver our Prime Editors to human bronchial epithelial cells in vitro and to lung basal cells in vivo .
−Removed: Our Ocular Programs
−Removed: Retinitis Pigmentosa Caused by Rhodopsin Mutations:
−Removed: Our first eye indication using AAV delivery technology
−Removed: Retinitis pigmentosa, or RP, is a subset of related inherited retinal diseases, or IRDs, where disease progression is characterized by loss of night vision in childhood or early adulthood, followed by loss of peripheral vision and eventual loss of central vision leading to blindness later in life.
−Removed: One of the most common IRDs is autosomal dominant RP, or adRP, caused by mutations in the RHO gene which encodes the light sensitive Rhodopsin protein, or RhoP, expressed by rod photoreceptors of the retina.
−Removed: The disease is dominant, or manifests even with mutations to just one of the two gene copies in the genome, because mutant RhoP is toxic to rod photoreceptors, resulting in loss of function followed by rod death.
−Removed: Approximately 6,000-7,000 patients have adRP in the United States caused by RHO mutations.
−Removed: We are initially focused on the predominant mutations of P23H and two mutations V345L and P347L which occur in a mutational hotspot.
−Removed: These three mutations are highly prevalent in the United States and have been identified as causing disease in approximately 60 percent of all patients (approximately 3,000-4,000 patients).
−Removed: As we advance our portfolio, we believe that other frequent mutations may also be suitable targets for Prime Editing.
−Removed: Our Approach and Results:
−Removed: Directly correct prevalent mutations in the RHO gene in photoreceptors of the retina
−Removed: Our initial approach to adRP is to develop two Prime Editors to correct the RHO P23H point mutation and a mutational hotspot in RHO in rod photoreceptors of the retina at their natural genomic location.
−Removed: We believe a Prime Editor that corrects the P23H mutation will also correct rarer, nearby P23L and P23A mutations, while a single hotspot editor could correct 18 different pathogenic mutations in that genomic location, including the most prevalent mutations V345L and P347L.
−Removed: Natural history studies suggest that correction of only 25 percent of rod photoreceptors would have an important clinical impact, because when 25 percent or more of rods are preserved, there is full preservation of cone photoreceptors that are critical to central vision.
−Removed: Similarly to the liver programs, we have developed a modular delivery platform for delivery of Prime Editors to the retina.
−Removed: In the case of retina, our modular delivery platform is a dual AAV system.
−Removed: We have optimized the AAV genomes to precisely and efficiently deliver the Prime Editor protein and the Prime Editor guide RNAs, and have optimized the AAV capsid for delivery to photoreceptors.
−Removed: As shown in the figure below, we have identified Prime Editors that demonstrate up to 65 to 70 percent percent precise correction of photoreceptors in vivo and that were generally well-tolerated with no detectable immune response.
−Removed: In regions of the retina delivered to, Prime Editors prevented retinal degeneration in vivo .
−Removed: There were also no off-target edits detected in human photoreceptors and no detectable evidence of viral vector integration into retinal cells.
−Removed: For our ocular programs, we are optimizing the modular dual-AAV system comprised of an optimized AAV capsid to improve transduction of photoreceptors, optimized AAV genome to increase expression of Prime Editor components, and novel AAV production processes that we believe will enable us to efficiently support multiple products.
−Removed: We are evaluating the modular dual-AAV in humanized RHO adRP mice including studies to evaluate preservation of the retina following Prime Editor delivery, and we plan to evaluate our approach in NHP studies where the Prime Editors will be delivered by subretinal injections or suprachoroidal injections to mimic the anticipated route of administration in the clinic.
−Removed: While we are advancing the RHO program with two Prime Editors for P23H and V345L-P347L, we are also identifying additional Prime Editors that can correct other prevalent mutations in the RHO adRP gene.
−Removed: Other Programs in Discovery
−Removed: Additionally, in our ocular area of focus, building on the modularity of our ocular platform and learnings from Rhodopsin program, we are also researching RP caused by mutations in USH2A resulting in Usher syndrome.
−Removed: simply swapping out the pegRNA and ngRNA in our retinal AAV delivery system we have the potential to accelerate the Usher syndrome program as well as advance additional retinal degeneration programs in the future.
−Removed: In addition, we are researching Fuch’s endothelial corneal dystrophy, a common repeat expansion disease affecting the cornea leading to progressive corneal opacification and blindness.
−Removed: We continue to make progress in both of these programs.
−Removed: Our Neuromuscular Programs
−Removed: Friedreich’s Ataxia
−Removed: Friedreich’s Ataxia, or FRDA, is a multisystem, autosomal recessive neurodegenerative disorder affecting the central and peripheral nervous system as well as the heart and other organs.
−Removed: FRDA significantly reduces survival for patients, with the mean age of death being 39 years.
−Removed: FRDA is characterized by progressive ataxia, or lack of muscle control or coordination of voluntary movements, with mean age at onset of approximately five to 16 years.
−Removed: A vast majority of patients progress to loss of unsupported sitting within two years and loss of ambulation on average 10 to 15 years from diagnosis.
−Removed: In addition, patients develop cardiomyopathy, or heart failure or dysfunction, which is the most common cause of premature death.
−Removed: In the United States, it is estimated that around 4,000 individuals are affected by FRDA, while there are estimated to be 15,000 to 19,000 patients globally.
−Removed: FRDA is a repeat expansion disease caused by GAA-repeat nucleotide sequence expansions in the 1st intron of the FXN gene encoding the frataxin protein, which plays important roles in mitochondria.
−Removed: The expanded repeats occur early in the gene, and cause disruptions in transcribing the FXN gene into RNA resulting in low levels of the frataxin protein, the pathogenesis of the clinical disease.
−Removed: Published literature shows that removal of expanded repeats can restore frataxin expression in vitro .
−Removed: Our Approach and Results:
−Removed: Directly and precisely remove the pathogenic GAA repeats in the FXN gene
−Removed: Our Prime Editing technology enables us to precisely remove the expanded repeat sequences that cause FRDA.
−Removed: Our goal is to precisely remove the pathological expanded GAA repeat sequence from intron 1 of the FXN gene to restore normal FXN regulation and normal expression of frataxin using dual-flap and long-flap Prime Editing technologies.
−Removed: The primary target tissues are for areas of the brain and spinal cord, but removal of repeats from FXN in the myocardium is also highly desirable to prevent cardiomyopathy and reduce mortality, and we plan to address cardiomyocytes as well.
−Removed: We have performed screens to identify the pegRNA pairs that achieve highly efficient and precise removal of the expanded repeats.
−Removed: We have demonstrated removal of pathological repeats from healthy donors, who have only a short length of repeats.
−Removed: We show up to 77 percent precise editing which results in the total removal of the pathogenic repeat region, without errors, as shown in the figure below on the left, where each dot represents an individual candidate Prime Editor.
−Removed: In addition, the figure on the right shows up to 66 percent precise editing in FRDA patient-derived induced Pluripotent Stem Cells, or iPSCs, which contain larger numbers of pathological repeats, numbering from 420 to 541 nucleotide triplet repeats.
−Removed: Remarkably, the total length of sequence precisely removed can be more than 7,000 nucleotides, or seven kilobase, using dual-flap Prime Editing.
−Removed: Consistent with the high levels of precise correction observed in patient iPSCs, we have also observed a restoration of frataxin expression to levels that approach those observed in healthy donor iPSCs.
−Removed: This is shown in the figure below which illustrates restoration of frataxin protein expression after delivery of the Prime Editor to patient iPSCs.
−Removed: FRDA = Friedreich’s Ataxia and GAPDH = a control housekeeping protein (glyceraldehyde-3-phosphate dehydrogenase).
−Removed: One of the hallmarks of Friedreich’s Ataxia is the degeneration of the dorsal root ganglia, or DRGs.
−Removed: These structures of the central nervous system contain sensory neurons transmitting information to the brain cortex.
−Removed: To evaluate the effect of Prime Editing on the ability of DRG sensory neurons to grow and function, we have developed DRG organoids derived from patient stem cells, a model for growth of the sensory nervous system.
−Removed: These DRGs are multicellular 3D structures and model the growth of a patient DRG.
−Removed: In the figure below, unedited patient DRG organoids (Patient) produce many fewer axons, shown as green fibers, than healthy donor organoids (Healthy Donor).
−Removed: We next edited patient DRG organoids with one of our FXN Prime Editors.
−Removed: When we correct 100 percent of the copies of FXN gene there is complete restoration of the sensory axon growth from the patient DRGs (Patient 100% Corrected).
−Removed: Even, when we correct 50 percent of the copies of the FXN gene there is also complete restoration of the sensory axon growth from the DRGs.
−Removed: We believe these in vitro results indicate that Prime Editors may have the potential to restore normal function of patient sensory neurons.
−Removed: Fluorescence microscopy images at low magnification of dorsal root ganglia, or DRG, from healthy donor or patient, showing cell nuclei (blue) and axons (green).
−Removed: Patient DRG shows very few axons compared to healthy donors.
−Removed: Following Prime Editing to remove the expanded repeats and precisely correct the FXN gene, patient DRGs show normal axon growth.
−Removed: We have established a preliminary dual-AAV delivery system for efficient delivery of Prime Editing to neurons and glial cells in viv o, as demonstrated in the figure below where we have observed robust transduction of over 95 percent of neurons within the injection site (left bar), and where we observed precise editing in approximately 80 percent of the transduced neurons (right bar);
−Removed: this high editing efficiency supports the robustness of the dual -AAV system.
−Removed: This system allows us to interrogate promising Prime Editors while we continue to develop an optimized dual-AAV delivery system as described in “Next Steps” below.
−Removed: Tool Prime Editors were packaged into our preliminary dual-AAV system and together with a reporter AAV were injected into the brains of healthy adult mice.
−Removed: Four weeks later, brain tissues were collected and fluorescent regions indicating successful AAV transduction were isolated and evaluated for editing of target site.
−Removed: For our neuromuscular programs, we are establishing a modular dual-AAV system comprised of an optimized AAV capsid to improve transduction across key brain regions using minimally-invasive route of administration, optimized AAV genome to increase safety, specificity and expression of Prime Editor components, and novel AAV production that we believe will enable us to efficiently support multiple products.
−Removed: In addition to the dual-flap technology used in our preliminary experiments, we are also evaluating a long flap approach to precisely correct the expanded GAA repeats in FXN, and the most promising Prime Editors of either approach will be incorporated into our modular dual-AAV system to be further evaluated in humanized FXN mice containing expanded GAA repeats to confirm editing efficiency in vivo .
−Removed: We will also evaluate the modular dual-AAV approach using tool or surrogate Prime Editors in NHPs.
−Removed: Myotonic Dystrophy Type 1
−Removed: Myotonic Dystrophy type I, or DM1, is a common autosomal dominant muscular dystrophy among people of European ancestry and is principally a muscle disease affecting skeletal and cardiac muscle with multisystem manifestations.
−Removed: Recent newborn screening studies indicate that the true prevalence of DM1 is 1 in 2,300 (approximately 140,000 patients in the United States).
−Removed: Patients can be clinically divided into three groups:
−Removed: congenital DM1;
−Removed: childhood/juvenile DM1, and adult-onset DM1.
−Removed: Congenital DM1, where patients typically have more than 800 repeats, presents at birth with severe weakness, hyporeflexia, or lack of reflexes, and respiratory insufficiency, and has a 40 percent mortality, with cardiac conduction abnormalities accounting for approximately 70 percent of that mortality.
−Removed: Survivors have distal weakness, cognitive impairment, and neuropsychological disorders.
−Removed: Childhood/juvenile DM1 is more similar to adult disease presenting at ages of five to 15 years with developmental delays and speech and learning difficulties.
−Removed: In adolescent patients, muscle weakness, myotonia, or the inability for muscles to relax, and gastrointestinal symptoms are most prominent.
−Removed: DM1 is a repeat expansion disease caused by expanded CTG repeats in the 3’ UTR of one copy of the DMPK gene.
−Removed: When transcribed into RNA, the expanded repeat nucleotides form toxic RNA foci in the nucleus that, sequester critical nuclear splicing factors, thereby preventing the correct function of many genes that regulate cell function.
−Removed: Our Approach and Results:
−Removed: Directly and precisely remove the pathological repeats in the DMPK gene
−Removed: Our goal in DM1 is to leverage our Prime Editing technology to precisely remove the repeat sequence from the UTR region of the DMPK gene, to restore DMPK regulation and expression of DMPK protein back to normal levels.
−Removed: The primary target tissues are cardiac and skeletal muscle, which we believe could have a transformative effect on patients;
−Removed: CNS is an important secondary target tissue.
−Removed: We have performed screens to identify pegRNA pairs that achieve highly efficient and precise removal of the expanded repeats and have demonstrated precise removal of pathological repeats from the DMPK gene.
−Removed: In patient-derived iPSCs, which contain approximately 1,600 pathological repeats, we have demonstrated precise removal of repeats, with our best Prime Editors achieving more than 90 percent precise editing and removal of the pathological repeats.
−Removed: These data are shown in the figure below, with each dot representing the data of a different individual Prime Editor.
−Removed: As mentioned above, a hallmark of the disease is toxic RNA foci , formed from the repeats, that sequester key splicing factors in the cells with this disease.
−Removed: For example, muscleblind-1, or MBLN1, is a known splicing factor that is deficient in these patient cells.
−Removed: We have developed assays to identify these toxic RNA repeats.
−Removed: As shown in the left side of the figure below, toxic repeats of repetitive CUG sequence, or (CUG)n, can be identified in nuclei of patient cardiomyocytes (left column, top) but not seen in healthy donor cardiomyocytes (not shown).
−Removed: These toxic (CUG)n repeats sequester MBLN1, as expected (left column, bottom).
−Removed: We edited patient cardiomyocytes to remove the pathological repeats with one of our Prime Editors and evaluated the impact on the formation of toxic RNA repeats.
−Removed: As is also shown in the right side of the figure below, cardiomyocytes that have 100 percent of pathological DMPK gene corrected, RNA foci are no longer detectable (right column, top);
−Removed: nor is MBNL1 staining detectable (right column, bottom) with only background staining detectable.
−Removed: The right side shows a quantification and analysis of the results, with 100 percent correct patient cells showing levels of RNA foci similar to those in healthy donor cells.
−Removed: Left hand panel shows fluorescence microscopy images at high magnification of patient cardiomyocyte nuclei.
−Removed: The cardiomyocytes are co-stained to show the RNA (CUG)n repeats (red) and MBLN1 splicing factor (green) in toxic RNA foci.
−Removed: Cardiomyocytes without Prime Editing shown in far left column images or after Prime Editing shown in right column images.
−Removed: The arrows indicate (CUG)n RNA repeats co-localized with sequestered MBLN1 in the nuclei (blue).
−Removed: After Prime Editing the toxic RNA foci are not visible.
−Removed: The graph, right panel shows results of RNA foci per nucleus from automated high content imaging analysis of the cardiomyocytes.
−Removed: Columns showing patient cardiomyocytes 100% corrected or 0% corrected (unedited) and healthy donors.
−Removed: We have established a preliminary dual-AAV delivery system for efficient delivery of Prime Editing to muscle, as demonstrated in the figures below, left panel, where using tool Prime Editors we have observed precise editing of up to 90 percent in cardiomyocytes, and right panel, where we observed precise editing of up to 50 percent in skeletal myotubes.
−Removed: This system allows us to investigate promising DM1 Prime Editors while we continue to develop an optimized muscle delivery system as described in “Next Steps" below.
−Removed: Human iPSC-derived cardiomyoctes (above left) and mouse skeletal myotubes differentiated from myoblasts (above right) were treated with tool Prime Editors packaged in dual-AAV system at various titers and evaluated for precise editing of target site.
−Removed: We are evaluating the ability of Prime Editing to correct the mis-splicing of a panel of genes that are known to be mis-spliced as a result of the toxic RNA foci.
−Removed: In parallel, we plan to perform similar experiments in patient-derived skeletal muscle cells.
−Removed: To ultimately deliver Prime Editors to heart and skeletal muscle, we expect initially to rely on the tropism of AAV capsids, optimized to deliver our Prime Editors to the heart and skeletal muscle.
−Removed: We have established an AAV system for efficient delivery of Prime Editing in neurons and glial cells in vivo , as demonstrated
−Removed: above in Friedreich’s Ataxia.
−Removed: We are optimizing this system for the DM1 program and planning to evaluate our Prime Editors in a disease model in mice which contain the human DMPK gene with pathological repeats.
−Removed: While AAV delivery is our primary route of delivery for early programs such as this, we are actively determining whether a non-viral delivery system could be used to efficiently deliver the Prime Editor to muscle.
−Removed: Other Programs in Discovery
−Removed: Within our neuromuscular area of focus, we are also exploring other repeat expansion diseases, including amyotrophic lateral sclerosis, a rapidly progressive neurodegenerative disease characterized by progressive motor neuron loss;
−Removed: Huntington’s disease, an autosomal dominant progressive neurodegenerative disease affecting teenagers through middle aged adults;
−Removed: Fragile X syndrome, an X chromosome-linked dominant rare disease that is the most common monogenic cause of childhood intellectual disability and autism;
−Removed: and oculopharyngeal muscular dystrophy, a rare autosomal dominant disease, characterized by progressive weakness in the muscles around the eyelids as well as in the tongue and pharynx.
−Removed: In addition to the repeat expansion diseases, we are also exploring Duchenne muscular dystrophy, an X chromosome-linked recessive disease affecting boys that is characterized by early onset progressive muscle weakness affecting limbs.
−Removed: Additional Programs
−Removed: As one part of our overall partnering strategy, we are advancing the following programs as partnering opportunities:
−Removed: Chimeric Antigen Receptor T-cell program (CAR-T)
−Removed: We are developing investigational CAR-T cell therapies for autoimmune and oncology indications.
−Removed: In combination with multiplex Prime Editing, we believe PASSIGE may be able to overcome existing challenges in developing CAR-T cells for human therapeutic use — such as manufacturing time, cost, yield for autologous cell therapy, cell quality issues, and safety risks associated with semi-random integration and double strand breaks at multiple genomic loci.
−Removed: Multiplex Prime Editing with PASSIGE has the potential to create a best-in-class allogeneic CAR-T cell product.
−Removed: In December 2023, we presented preclinical data suggesting PASSIGE is up to 80 percent efficient for non-viral, site-specific delivery of chimeric antigen receptor to primary human T-cells to generate CAR-T cells, and can be multiplexed with Prime Editing at other target sites by non-viral one-step delivery with no loss of efficiency.
−Removed: PASSIGE-generated CAR-T cells showed potent antigen-specific function and cytotoxicity ex vivo and in vivo against an established human B-cell tumor growing in immunodeficient mice.
−Removed: The potential advantages, we believe, of our CAR-T approach using Prime-Edited are shown in the table below.
−Removed: As shown in the figure below, we have achieved multiplex Prime Editing in T cells to knock out the B2M gene and the endogenous T cell receptor, or TRAC, without loss in efficiency compared to single site editing (left panel).
−Removed: We have also delivered Prime Editing components and DNA recombinase components (PASSIGE components) in a single step to human primary T cells, without the use of viruses.
−Removed: The short recombinase DNA target sequence, used by the site-specific recombinase enzyme known as Bxb1, was inserted into human primary T cells at the TRAC
−Removed: locus with greater than 95 percent efficiency, and a 3.5 kilobase anti-CD19 CAR gene cassette was precisely inserted into that recombinase site location in up to 80 percent of the T cells, resulting in positive expression of the CAR by those T cells (middle panel).
−Removed: As a result, the T cells acquired CD19+ tumor cell killing activity that was dependent on cell dose in a cell assay, indicating that the integrated CAR was functional (right panel).
−Removed: PASSIGE and Multiplex Prime Editing Could Create Potentially Best-in-Class Allogenic CAR-T Cell Product
−Removed: This exploratory program is approaching lead optimization.
−Removed: Additional optimization of the Prime Editor and PASSIGE components is ongoing, and the scalable cell therapy process is being developed.
−Removed: A suite of assays to evaluate cell potency and cell fitness are currently being developed and we plan to evaluate CAR-T cell leads in vivo in established tumor killing studies.
−Removed: Other Programs in Discovery
−Removed: In addition to CAR-T, we are also exploring genetic hearing loss, including Usher’s syndrome type III, which is characterized by progressive post-lingual hearing loss, variable vestibular dysfunction, as well as adolescent-onset progressive vision loss due to retinitis pigmentosa caused by mutations in the Clarin 1 protein encoded by the CLRN1 gene;
−Removed: and non-syndromic hearing loss due to mutations in GJB2, the most commonly mutated gene in non-syndromic hearing loss, which accounts for two thirds of genetic hearing loss.
+Added: 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.
+Added: 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.
+Added: 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).
+Added: We believe the human lung progenitor data are the most predictive of in vivo efficacy.
+Added: 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.
+Added: 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.
Our License and Collaboration Agreements
License agreements with Broad Institute
−Removed: In September 2019, we entered into a license agreement with Broad Institute, and in May 2020, February 2021 and December 2022, we entered into amendments to that license agreement.
+Added: 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.
We refer to this amended license agreement as the Broad License Agreement.
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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 with Broad Institute, which we refer to as the 2022 Broad License Agreement.
+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
+Added: with Broad Institute, which we refer to as 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.
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We must continue to use commercially reasonable efforts to continue to progress such activities.
−Removed: 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.
−Removed: 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
−Removed: 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.
+Added: If we notify Broad
+Added: 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 (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.
Broad has not yet granted any march-in license to a third party.
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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-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-
+Added: 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.
−Removed: Broad Institute is also entitled to a percentage of consideration that we receive from our sublicensees, with such percentage at low double-digits and
−Removed: decreasing to high single digits, dependent on the development stage of products under the Broad License Agreement at the time of sublicense execution.
+Added: Broad Institute is also entitled to a percentage of consideration that we receive from our sublicensees, with such percentage at low double-digits and decreasing to high single digits, dependent on the development stage of products under the Broad License Agreement at the time of sublicense execution.
Broad Institute is responsible for the prosecution and maintenance of all licensed patent rights, although we are entitled to certain consultation, comment and review rights with respect to such prosecution and maintenance activities of the exclusively licensed patent rights.
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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.
+Added: 2024 Amendment to The Broad License Agreement
+Added: 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.
+Added: 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.
2022 License Agreement with Broad Institute
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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% 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%
+Added: 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.
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The Pledge is intended to be used for research and development related to new genome editing technologies, for example Prime Editing, improve on existing genome-editing technologies, identify delivery mechanisms for these technologies and apply these technologies to the understanding and treatment of rare genetic diseases.
−Removed: We can terminate the Pledge at our discretion, subject to providing one year of funding from the
−Removed: date of termination.
+Added: We can terminate the Pledge at our discretion, subject to providing one year of funding from the date of termination.
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.
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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, 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,
+Added: 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.
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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 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
+Added: 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.
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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 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
+Added: 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.
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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.
+Added: Research Collaboration and License Agreement with BMS
+Added: In September 2024, we entered into the BMS Collaboration Agreement with Juno, a wholly owned subsidiary of BMS.
+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.
Our Business Development and Partnering Strategy
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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 expanding 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.
+Added: 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.
Nevertheless, we face potential competition from a variety of companies.
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In addition, other private companies such as Tessera Therapeutics, Inc.
−Removed: and Tome Biosciences, Inc.
have announced their work in recombinase DNA and RNA gene writers, although little is known publicly about their science or portfolio.
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and Pfizer Inc.
−Removed: Most recently, new epigenetic editing companies have emerged, such as Chroma Medicine, Inc.
+Added: Most recently, new epigenetic editing companies have emerged, such as nChroma Bio, Inc.
and Tune Therapeutics, Inc.
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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
−Removed: genetic therapies, including Recode Therapeutics, Inc., Verve Therapeutics, Inc., Generation Bio Co.
+Added: 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.
and Beam Therapeutics Inc., among others.
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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.
−Removed: We plan to partner with suppliers and CMOs to produce or process critical raw materials, bulk compounds, formulated compounds, viral vectors or engineered cells for IND-supporting activities and early-stage clinical trials.
−Removed: At the appropriate time in the product development process, we will determine whether to establish in-house GMP 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 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.
+Added: 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.
+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 to manufacture commercial quantities for any products that we may successfully develop.
Intellectual Property
We achieved many major milestones in 2024, including the issuance of two in-licensed U.S.
−Removed: patents and the allowance of another in-licensed U.S.
−Removed: patent application, which has since issued as a U.S.
−Removed: patent, in addition to the U.S.
−Removed: patent issued in 2022, all of which cover Prime Editing methods and its components and systems.
+Added: patents, the allowance of another in-licensed U.S.
+Added: patent application that has since issued as a U.S.
+Added: patent, the issuance of five ex-U.S.
+Added: patents, and the allowance of another two ex-U.S.
+Added: patent applications, one of which has since issued as an ex-U.S.
+Added: As of February 20, 2025, we have six in-licensed U.S.
+Added: patents or allowed patent applications and seven in-licensed ex-U.S.
+Added: patents or allowed patent applications, all of which cover Prime Editing methods and its components and systems.
Our success depends in large part on our ability to obtain and maintain additional intellectual property protection for our platform technology, our programs and know-how related to our business, defend and enforce our intellectual property rights, in particular, our patent rights, preserve the confidentiality of our trade secrets and other confidential or proprietary information and operate without infringing, misappropriating or otherwise violating any intellectual property rights of others.
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• Prime Editors
−Removed: • Prime Editing guide RNA, or pegRNA, and modified pegRNAs
+Added: • pegRNA, and modified pegRNAs
• Prime Editing complexes and methods
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As of February 20, 2025, we owned approximately 13 pending U.S.
−Removed: provisional patent applications, 20 pending PCT applications, nine pending U.S.
+Added: provisional patent applications, 16 pending PCT applications, 21 pending U.S.
non-provisional patent applications and 39 pending ex-U.S.
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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 early as 2044, 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
+Added: early as 2045, excluding any additional term for patent term adjustments or patent term extensions or similar provisions in foreign jurisdictions.
Our current owned U.S.
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In-licensed Patents
−Removed: As of February 28, 2024, we have in-licensed four issued U.S.
−Removed: patents, one granted ex-U.S.
−Removed: patent, approximately 12 pending U.S.
−Removed: non-provisional patent applications, three pending PCT applications, one pending U.S.
−Removed: provisional applications and 83 pending ex-U.S.
+Added: As of February 20, 2025, we have in-licensed five issued U.S.
+Added: patents, six granted ex-U.S.
+Added: patents, approximately 16 pending U.S.
+Added: non-provisional patent applications, one pending PCT application, and 80 pending ex-U.S.
patent applications, in each case, related to Prime Editing, from Broad Institute.
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and delivery modalities for Prime Editing systems, including the use of AAV, in a split AAV system for viral delivery of a Prime Editor.
−Removed: The in-licensed issued patents and patent applications cover various aspects related to the Prime Editing platform technology, including Prime Editors that employ CRISPR-Cas protein domains, such as Cas9 nickases and DNA polymerase domains, such as reverse transcriptase domains.
+Added: The in-licensed issued patents and patent applications cover various aspects related to the Prime Editing platform technology, including Prime Editors that employ Cas domains, such as Cas9 nickases and DNA polymerase domains, such as RT domains.
The exclusive in-licensed patents and patent applications also cover dual-flap Prime Editing technology, including dual-flap Prime Editing compositions and methods of using such technology for therapeutic indications, and engineered pegRNAs, including compositions and methods comprising such pegRNAs.
Our current in-licensed U.S.
−Removed: and foreign patents and patent applications, if issued and if the appropriate maintenance or annuity fees are paid, are expected to
−Removed: expire as early as 2040, excluding any additional term for patent term adjustments or patent term extensions or similar provisions in foreign jurisdictions.
+Added: and foreign patents and patent applications, if issued and if the appropriate maintenance or annuity fees are paid, are expected to expire as early as 2040, excluding any additional term for patent term adjustments or patent term extensions or similar provisions in foreign jurisdictions.
Additional Intellectual Property
5 unchanged sentences
Both the FD&C Act and the PHS Act and their corresponding regulations govern, among other things, the research, development, clinical trials, testing, manufacturing, safety, efficacy, labeling, packaging, storage, record keeping, distribution, reporting, advertising and other promotional practices involving biological products.
−Removed: Each clinical trial protocol for a gene therapy product must be reviewed and approved by the FDA before initiating clinical trials.
+Added: Each clinical trial protocol for a gene therapy or gene editing product must be reviewed and approved by the FDA before initiating clinical trials in the United States.
In addition, FDA approval must be obtained before the marketing of biological products in the United States.
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• submission to the FDA of a BLA for marketing approval that includes sufficient evidence of establishing the safety, purity and potency of the proposed biological product for its intended indication, including from results of nonclinical testing and clinical trials;
−Removed: • satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with current good manufacturing practices, or cGMP, to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity and, if applicable, the FDA’s current good tissue practices, or CGTPs, for the use of human cellular and tissue products;
+Added: • satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with cGMP to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity and, if applicable, the FDA’s current good tissue practices, or CGTPs, for the use of human cellular and tissue products;
• potential FDA audit of the nonclinical study and clinical trial sites that generated the data in support of the BLA;
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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 conducted under the IND.
+Added: A partial clinical hold is a delay or suspension of only part of the clinical investigation
+Added: 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.
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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
−Removed: 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 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.
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.
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While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding for recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.
+Added: Regulatory requirements governing the development of gene therapy products have also changed frequently and may continue to change in the future.
Clinical trials typically are conducted in three sequential phases that may overlap or be combined:
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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 therapeutic indication, particularly for long-term safety follow-up.
−Removed: 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 genome editing products 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.
+Added: These clinical trials are used to gather additional data from the treatment of patients in the intended
+Added: therapeutic indication, particularly for long-term safety follow-up.
+Added: 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.
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.
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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 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
+Added: 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.
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The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
−Removed: For a gene therapy product, the FDA also will not approve the product if the manufacturer is not in compliance with the CGTPs.
+Added: For a gene therapy or gene editing product, the FDA also will not approve the product if the manufacturer is not in compliance with the CGTPs.
These are FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues and cellular and tissue-based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient.
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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
−Removed: 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 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.
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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 or interactions be included in the product labeling.
+Added: Further, the FDA may require that certain contraindications, warnings precautions
+Added: 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.
9 unchanged sentences
If a drug or biological product designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan product exclusivity.
−Removed: Orphan drug status in the EU has similar, but not identical, benefits.
+Added: Orphan drug designation status in the EU has similar, but not identical, benefits.
Rare Pediatric Disease Designation and Priority Review Vouchers
Under the FD&C Act, the FDA incentivizes the development of drugs and biological products that meet the definition of a “rare pediatric disease,” defined to mean a serious or life-threatening disease in which the serious of life-threatening manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals in the United States or affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making in the United States a drug or biological product for such disease or condition will be received from sales in the United States of such drug or biological product.
−Removed: The sponsor of a product candidate for a rare pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug or biological product application after the date of approval of the rare pediatric disease drug or biological product, referred to as a priority review voucher, or PRV.
+Added: The sponsor of a product candidate for a rare pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug or biological product application after the date of approval of the rare pediatric disease drug or biological product, referred to as a PRV.
A sponsor may request rare pediatric disease designation from the FDA prior to the submission of its BLA.
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If a PRV is received, it may be sold or transferred an unlimited number of times.
−Removed: Congress has extended the PRV program through September 30, 2024, with the potential for PRVs to be granted through September 30, 2026.
+Added: 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.
+Added: 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.
+Added: After September 30, 2026, the FDA may not award any rare pediatric disease PRVs.
+Added: Congress may vote to reauthorize this program, but its future remains unknown at this time.
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 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
+Added: 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.
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Drug or biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means that they may be approved on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on an intermediate clinical endpoint other than survival or irreversible morbidity.
−Removed: 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
−Removed: date of approval for a product granted accelerated approval.
+Added: 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.
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.
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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 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
+Added: 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.
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If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot.
−Removed: The FDA also may perform certain confirmatory
−Removed: tests on lots of some products before releasing the lots for distribution by the manufacturer.
+Added: The FDA also may perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer.
In addition, the FDA conducts laboratory research related to the regulatory standards on the safety, purity, potency and effectiveness of biological products.
−Removed: 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 (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.
+Added: 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.
Discovery of previously unknown problems or the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market as well as possible civil or criminal sanctions.
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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 compliance.
+Added: Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP
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.
In addition, changes to the manufacturing process or facility generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval.
+Added: From time to time, legislation is drafted, introduced, passed in Congress and signed into law that could significantly change the statutory provisions governing the approval, manufacturing, and marketing of products regulated by the FDA.
+Added: In addition to new legislation, FDA regulations, guidance, and policies are often revised or reinterpreted by the agency in ways that may significantly affect the manner in which pharmaceutical products are regulated and marketed.
Patent Term Restoration and Marketing Exclusivity
19 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 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
+Added: 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.
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Foreign Corrupt Practices Act
−Removed: Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
+Added: Foreign Corrupt Practices Act, or FCPA, to which we are subject, prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
It is illegal to pay, offer to pay or authorize the payment of anything of value to any foreign government official, government staff member, political party or political candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official capacity.
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The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.
−Removed: In all cases, the clinical trials must be conducted in accordance with GCP and the
−Removed: applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
+Added: In all cases, the clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.
If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.
3 unchanged sentences
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: For instance, the new Clinical Trials Regulation provides for a streamlined application procedure via a single entry point and strictly defined deadlines for the assessment of clinical trial applications.
+Added: In the EU, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014, or CTR.
+Added: 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.
EU Drug Review and Approval
20 unchanged sentences
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: 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.
+Added: 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
7 unchanged sentences
An orphan medicinal product can also obtain an additional two years of market exclusivity in the EU where an agreed pediatric investigation plan for pediatric studies has been complied with.
−Removed: No extension to any supplementary protection certificate, or SPC, can be granted on the basis of pediatric studies for orphan indications.
+Added: No extension to any supplementary protection certificate, or SPC, can be granted on the basis of pediatric studies for products with an orphan designation.
The 10-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.
−Removed: Otherwise, orphan medicinal product marketing exclusivity may be revoked only in very select cases, such as if:
−Removed: • a second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior;
−Removed: • the marketing authorization holder of the authorized orphan medicinal product consents to a second orphan medicinal product application;
+Added: Otherwise, an orphan medicinal product marketing exclusivity may be revoked only in very select cases, such as if:
+Added: • a second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior to the authorized orphan medicinal product;
+Added: • the marketing authorization holder of the authorized orphan medicinal product consents to a second medicinal product application;
• the marketing authorization holder of the authorized orphan medicinal product cannot supply enough orphan medicinal product.
2 unchanged sentences
The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the product for which marketing authorization is being sought.
−Removed: The marketing authorization application for the product must include the
−Removed: results of pediatric clinical trials conducted in accordance with the PIP, unless a waiver applies or a deferral has been granted by the PDCO of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults, in which case the pediatric clinical trials must be completed at a later date.
+Added: The marketing authorization application for the product must include the results of pediatric clinical trials conducted in accordance with the PIP, unless a waiver applies or a deferral has been granted by the PDCO of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults, in which case the pediatric clinical trials must be completed at a later date.
Products that are granted a marketing authorization with the results of the pediatric clinical trials conducted in accordance with the PIP are eligible for a six month extension of the protection under an SPC, even where the trial results are negative, provided an application for such extension is made at the same time as filing the SPC application for the product, or at any point up to two years before the SPC expires.
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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: 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 EEA 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: 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.
9 unchanged sentences
Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.
−Removed: • All new MAAs must include a risk management plan, or RMP, describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.
+Added: • 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.
The regulatory authorities may also impose specific obligations as a condition of the marketing authorization.
3 unchanged sentences
Direct-to-consumer advertising of prescription medicines is also prohibited in the EU.
−Removed: Although general requirements for advertising and
−Removed: promotion of medicinal products are established under EU directives, the details are governed by regulations in each EU Member State and can differ from one country to another.
−Removed: The aforementioned EU rules are generally applicable in the EEA.
+Added: Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each EU Member State and can differ from one country to another.
+Added: All the aforementioned EU rules are generally applicable in the EEA.
Reform of the Regulatory Framework in the EU
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.
−Removed: In October 2023, the European Parliament published draft reports proposing amendments to the legislative proposals, which will be debated by the European Parliament.
+Added: 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.
Once the European Commission’s legislative proposals are approved (with or without amendment), they will be adopted into EU law.
Brexit and the Regulatory Framework in the United Kingdom
−Removed: The United Kingdom, or UK, formally left the EU on January 31, 2020, and the EU and the UK have concluded a trade and cooperation agreement, or TCA, which has been formally applicable since May 1, 2021.
−Removed: The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products, and GMP documents issued, but does not foresee wholesale mutual recognition of UK and EU pharmaceutical regulations.
−Removed: At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework continues to apply in Northern Ireland).
−Removed: Except with respect to the new EU Clinical Trials Regulation, the regulatory regime in Great Britain therefore aligns in many ways with current EU medicines regulations, although it is possible that these regimes will diverge more significantly in the future now that Great Britain’s regulatory system is independent from the EU, and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.
−Removed: However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under a new framework by the Medicines and Healthcare Products Regulatory Agency, or MHRA, the MHRA has stated that it will take into account decisions on the approval of marketing authorizations from the EMA (and certain other regulators) when considering an application for a Great Britain marketing authorization.
−Removed: The UK and the European Commission announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework,” to be effective as of January 1, 2025.
−Removed: This new framework fundamentally changes the existing system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.
−Removed: In particular, the MHRA will be responsible for approving all medicinal products destined for the UK market (i.e., Great Britain and Northern Ireland), and the EMA will no longer have any role in approving medicinal products destined for Northern Ireland.
−Removed: A single UK-wide marketing authorization will be granted by the MHRA for all medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.
+Added: The United Kingdom, or UK, formally left the EU on January 31, 2020.
+Added: 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.
+Added: The MHRA is responsible for approving all medicinal products destined for the UK market
+Added: (i.e., Great Britain and Northern Ireland).
+Added: 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: 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.
Other Healthcare Laws and Compliance Requirements
5 unchanged sentences
The availability of coverage and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford treatments such as gene therapy products.
−Removed: Sales of these or other product candidates that we may identify will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by health
−Removed: maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, private health coverage insurers and other third-party payors.
+Added: Sales of these or other product candidates that we may identify will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, private health coverage insurers and other third-party payors.
If coverage and adequate reimbursement is not available, or is available only to limited levels, we may not be able to successfully commercialize our product candidates.
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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 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.
−Removed: Other healthcare laws and compliance requirements
+Added: Net prices for drugs may be also reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by
+Added: 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: Other healthcare laws
In the United States, our current and future operations are subject to regulation by various federal, state and local authorities in addition to the FDA, including but not limited to, CMS, other divisions of HHS (such as the Office of Inspector General, Office for Civil Rights and the Health Resources and Service Administration), the U.S.
5 unchanged sentences
Violations are subject to civil and criminal fines and penalties for each violation, plus up to three times the remuneration involved, imprisonment, and exclusion from government healthcare programs.
−Removed: In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim
−Removed: for purposes of the federal False Claims Act or federal civil monetary penalties.
+Added: In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act or federal civil monetary penalties.
This statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand, and prescribers, purchasers and formulary managers, among others, on the other.
6 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 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
+Added: 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;
3 unchanged sentences
• analogous state and foreign law equivalents of each of the above federal laws, such as anti-kickback and false claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers or patients;
−Removed: state laws that require pharmaceutical companies to comply with the industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government or
−Removed: otherwise restrict payments that may be made to healthcare providers and other potential referral sources;
+Added: state laws that require pharmaceutical companies to comply with the industry’s voluntary compliance guidelines and the applicable compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;
state and local laws that require the licensure of sales representatives;
state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures and pricing information;
−Removed: data privacy and security laws and regulations in foreign jurisdictions that may be more stringent than those in the United States (such as the EU, which adopted the General Data Protection Regulation, which became effective in May 2018);
−Removed: state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect;
+Added: data privacy and security laws and regulations in foreign jurisdictions some of which may be more stringent than those in the United States (such as the EU, which adopted the General Data Protection Regulation, which became effective in May 2018);
+Added: and numerous state laws governing the privacy and security of health information, many of which differ from each other in significant ways regarding their applicability, compliance requirements and enforcement;
• state laws related to insurance fraud in the case of claims involving private insurers.
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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 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
+Added: 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.
9 unchanged sentences
In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted.
−Removed: For example, on March 22, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates 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, beginning January 1, 2024.
−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 2 percent per fiscal year, which will remain in effect through 2031.
+Added: 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.
+Added: 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.
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: Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.
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.
Further, in 2018, the Right to Try Act, was signed into law.
−Removed: The law, among other things, provides a federal framework for certain patients to access certain investigational new drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.
+Added: The law, among other things, provides a federal framework for certain patients to access certain IND products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval.
Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.
6 unchanged sentences
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 challenging the constitutionality of the IRA’s Medicare drug price negotiation program.
+Added: The implementation of the IRA is currently subject to ongoing litigation
+Added: challenging the constitutionality of the IRA’s Medicare drug price negotiation program.
The effects of the IRA on our business and the healthcare industry in general is not yet known.
In addition to pricing regulations, reforms of regulatory approval frameworks may adversely affect our pricing strategy.
−Removed: For example, the current administration has issued multiple executive orders that have sought to reduce prescription drug costs.
−Removed: In February 2023, HHS also issued a proposal in response to an October 2022 executive order from the current administration that includes a proposed prescription drug pricing model that will test whether targeted Medicare payment adjustments will sufficiently incentivize manufacturers to complete confirmatory trials for drugs approved through the FDA’s accelerated approval pathway.
−Removed: Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the current administration may reverse or otherwise change these measures, both the current administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.
+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 may issue new executive orders designed to impact drug pricing.
+Added: A number of these and other proposed measures may require authorization through additional legislation to become effective.
+Added: Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.
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.
In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.
−Removed: State legislatures have also been increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints,
−Removed: 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.
+Added: State legislatures have also been increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological 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.
It is difficult to predict the future legislative landscape in healthcare and the effect on our business, results of operations, financial condition and prospects.
9 unchanged sentences
We were incorporated under the laws of the state of Delaware in September 2019 under the name Prime Medicine, Inc.
−Removed: Our principal executive offices are located at 21 Erie Street, Cambridge, MA 02139.
+Added: Our principal executive offices are located at 60 First Street, Cambridge, MA 02141.
Our telephone number is (617) 465-0013 and our website is located at www.primemedicine.com.
1 unchanged sentence
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 Securities Exchange Act of 1934, as amended, 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 SEC.
These reports are also available at the SEC’s website at www.sec.gov.
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 print to any person who requests copies by contacting us by calling (617) 564-0013 or by writing to Prime Medicine, Inc., 21 Erie Street, Cambridge, Massachusetts 02139.
+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
+Added: 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.