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The following is a summary of the principal risks associated with an investment in our ordinary shares:
−Removed: ● Our business, operations and supply chain have been, and may continue to be, materially and adversely affected by the ongoing Covid pandemic.
−Removed: ● We have encountered, and may continue to encounter, delays in, and impediments to the progress of our clinical trials or fail to demonstrate the safety and efficacy of our product candidates.
+Added: ● We have encountered, and may continue to encounter, delays in, and impediments to the progress of our clinical trials or failure to demonstrate the safety and efficacy of our product candidates.
● We may not be successful in our efforts to use our gene therapy technology platform to build a pipeline of additional product candidates, and we may not be successful in our efforts to create innovative programs, platform technologies or other technologies to be competitive with others.
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If we fail to comply with these regulations or to maintain these approvals our business could be materially harmed.
−Removed: ● We cannot predict when our partner, CSL Behring, will obtain marketing approval to commercialize the product candidate for Hemophilia B, when or if a first sale of etranacogene dezaparvovec occurs, or whether etranacogene dezaparvovec will be commercially successful once approved.
−Removed: If our partner is unable to achieve marketing approval and successfully commercializes etranacogene dezaparvovec or experiences significant delays in doing so, our business could be materially harmed.
● We are exposed to a number of external factors such as competition, insurance coverage of and pricing and reimbursement for our product candidates that may adversely affect our product revenue and that may cause our business to suffer.
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● If we are unable to obtain and maintain patent protection for our technology and products, or if the scope of the patent protection is not sufficiently broad, our ability to successfully commercialize our products may be impaired.
−Removed: ● Our reliance on third parties may require us to share our trade secrets, which could increase the possibility that a competitor will discover them or that our trade secrets will be misappropriated or disclosed.
+Added: ● Our reliance on third parties may require us to share our trade secrets and other proprietary technology, which could increase the possibility that a competitor will discover them or that our trade secrets and other proprietary technology will be misappropriated or disclosed.
● We will likely need to raise additional funding, which may not be available on acceptable terms, or at all.
Failure to obtain capital when needed may force us to delay, limit or terminate our product development efforts or other operations which could have a material adverse effect on our business, financial condition, results of operations, and cash flows.
−Removed: ● Our relationships with customers and third-party payers will be subject to applicable anti-kickback, anti-bribery, fraud and abuse and other laws and regulations, which, if we are found in violation thereof, could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.
+Added: The amount of capital required will depend in part on the future payments we receive from CSL Behring related to HEMGENIX® royalties, commercial supply, and
+Added: contractual milestones, including a $75.0 million payment that CSL Behring would owe on the occurrence of a first sale of HEMGENIX® in the European Union prior to July 2, 2023.
+Added: ● Our relationships with employees, customers, and third parties are subject to applicable laws and regulations, the non-compliance of any of which could have a material adverse effect on our business, financial condition, and results of operations.
● We are subject to laws governing data protection in the different jurisdictions in which we operate.
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● If we fail to maintain an effective system of internal controls, we may be unable to accurately report our results of operations or prevent fraud or fail to meet our reporting obligations, and investor confidence and the market price of our ordinary shares may be materially and adversely affected.
−Removed: Risks Related to the Current Covid Pandemic
−Removed: Our business, operations, human resources and supply chain have been, and may continue to be, materially and adversely affected by the ongoing Covid pandemic.
−Removed: On March 11, 2020, the WHO declared the ongoing outbreak of Covid a pandemic.
−Removed: The Covid pandemic is affecting the United States and global economies and has affected and may continue to affect our operations and those of third parties on which we rely.
−Removed: The Covid pandemic has caused and may continue to cause disruptions in our raw material supply, our commercial-scale manufacturing capabilities for AAV-based gene therapies, the development of our product candidates, employee productivity and the conduct of current and future clinical trials.
−Removed: In addition, the Covid pandemic has affected and may continue to affect the operations of the FDA, EMA, and other health authorities, which could result in delays of reviews and approvals, including with respect to our product candidates.
−Removed: Global supply chains have been disrupted, causing shortages, which could further impact our clinical trials.
−Removed: This disruption of our employees, distributors and suppliers has historically impacted and may continue to impact our future operating results.
−Removed: Additionally, to the extent that inspections of facilities by governmental authorities are required, the review of our marketing applications or supplements may further be delayed as regulatory authorities, such as FDA, have significantly limited facility inspections during the pandemic.
−Removed: We may also be subject to further laws, regulations, guidelines, executive orders and other requirements at the federal, state and local levels related to the pandemic, which we may be required to undertake or that we choose to undertake.
−Removed: Any such requirements or guidelines that we adopt could have a material impact on our business operations.
+Added: ● Our business, operations and supply chain have been, and may continue to be, materially and adversely affected by the ongoing Covid pandemic.
Risks Related to the Development of Our Product Candidates
−Removed: None of our product candidates have been approved for commercial sale and they might never receive regulatory approval or become commercially viable.
+Added: Our product candidates in development have not yet been approved for commercial sale and they might never receive regulatory approval or become commercially viable.
We have never generated any significant revenue from product sales and may never be profitable.
−Removed: All of our product candidates are in research or development.
−Removed: We have not generated any revenues from the sale of products or manufacturing of a product for a third party and do not expect to generate any such revenue until this year, at the earliest.
+Added: Our pipeline consists of product candidates in research or development that have not been approved for commercial sale.
+Added: We have not generated any revenues from the sale of products or manufacturing of a product for a third party related to our product candidates in development and do not expect to generate any such revenue this year.
Our product candidates, including AMT-130 and any of our other potential product candidates will require extensive preclinical and/or clinical testing, manufacture development and regulatory approval prior to commercial use.
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Our product candidates are in different stages of clinical or preclinical development, and there is a significant risk of failure or delay in each of these programs.
−Removed: For example, we experienced an immaterial but unexpected delay when our clinical trials of etranacogene dezaparvovec were placed on clinical hold by the FDA from December 2020 to April 2021, following a preliminary diagnosis of hepatocellular carcinoma in one patient.
−Removed: Similarly, we experienced an unexpected delay in the enrollment of our Phase Ib/II clinical trial for Huntington’s disease as a result of comprehensive safety investigation into suspected unexpected serious adverse reactions in three patients between July and October 2022.
+Added: For example, we experienced an immaterial but unexpected delay when our clinical trials of HEMGENIX® were placed on clinical hold by the FDA from December 2020 to April 2021, following a preliminary diagnosis of hepatocellular carcinoma in one patient.
+Added: Similarly, we experienced an unexpected delay in the enrollment of our Phase Ib/II clinical trial for Huntington’s disease between July and October 2022 as a result of our voluntary postponement and comprehensive safety investigation into suspected unexpected serious adverse reactions in three patients.
We cannot guarantee that any preclinical tests or clinical trials will be completed as planned or completed on schedule, if at all.
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● interruptions in manufacturing clinical supply of our product candidates or issues with manufacturing product candidates that meet the necessary quality requirements;
−Removed: ● unanticipated clinical trial costs or insufficient funding, including to pay substantial application user fees;
+Added: ● unanticipated clinical trial costs or insufficient funding, including paying substantial application user fees;
● occurrence of serious adverse events or other undesirable side effects associated with a product candidate that are viewed to outweigh its potential benefits;
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● determinations that there are issues with our manufacturing facility or process;
−Removed: ● changes in regulatory requirements and guidance, as well as new, revised, postponed, or frozen regulatory requirements (such as the forthcoming EU Clinical Trials Regulation), that require amending or submitting new clinical protocols, undertaking additional new tests or analyses, or submitting new types or amounts of clinical data.
+Added: ● changes in regulatory requirements and guidance, as well as new, revised, postponed, or frozen regulatory requirements (such as the EU Clinical Trials Regulation), that require amending or submitting new clinical protocols, undertaking additional new tests or analyses, or submitting new types or amounts of clinical data.
Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the product candidates in humans.
−Removed: Such trials and regulatory review and approval take many years.
+Added: trials and regulatory review and approval take many years.
It is impossible to predict when or if any of our clinical trials will demonstrate that product candidates are effective or safe in humans.
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● obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;
−Removed: ● be subject to changes with the way the product is administered;
+Added: ● be subject to changes in the way the product is administered;
● be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;
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Clinical trial sites may not have the adequate infrastructure established to handle gene therapy products or may have difficulty finding eligible patients to enroll into a trial.
−Removed: In addition, we, or any collaborators we may have may not be able to locate and enroll enough eligible patients to participate in these trials as required by the FDA, the EMA or similar regulatory authorities outside the United States and the European Union.
+Added: In addition, we, or any collaborators we may have may not be able to locate and enroll enough eligible patients to participate in these trials as required by the FDA, the EMA or similar regulatory authorities outside the U.S.
+Added: and the European Union.
This may result in our failure to initiate or continue clinical trials for our product candidates or may cause us to abandon one or more clinical trials altogether.
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A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
−Removed: A RMAT designation is designed to accelerate approval for regenerative advanced therapies.
+Added: An RMAT designation is designed to accelerate approval for regenerative advanced therapies.
Priority review designation is intended to speed the FDA marketing application review timeframe for drugs that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.
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In addition, the FDA may later decide that the products no longer meet the applicable conditions for qualification as either a fast-track product, RMAT, or a breakthrough therapy or, for priority review products, decide that the period for FDA review or approval will not be shortened.
+Added: Moreover, in the U.S., FDA expects that sponsors with products under these programs will be prepared for a more rapid pace of development, including with respect to manufacturing or any combination medical devices, such as companion diagnostics.
+Added: If we are unable to meet these expectations, we may not be able to fully avail ourselves of certain advantages of these programs.
We may not be successful in our efforts to use our gene therapy technology platform to build a pipeline of additional product candidates.
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Even if we are successful in continuing to build our pipeline, the potential product candidates that we identify may not be suitable for clinical development.
−Removed: Research programs to identify new product candidates require substantial technical, financial, and human resources.
+Added: Research programs to
+Added: identify new product candidates require substantial technical, financial, and human resources.
We or any collaborators may focus our efforts and resources on potential programs or product candidates that ultimately prove to be unsuccessful.
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In addition, there is the potential risk of delayed adverse events following exposure to gene therapy products due to persistent biological activity of the genetic material or other components of products used to carry the genetic material.
−Removed: A small number of patients have experienced serious adverse events during our clinical trials of either AMT-060 (our first-generation hemophilia B gene therapy) or etranacogene dezaparvovec.
+Added: A small number of patients have experienced serious adverse events during our clinical trials of either AMT-060 (our first-generation hemophilia B gene therapy), etranacogene dezaparvovec, and AMT-130.
However, adverse events in our clinical trials or those conducted by other parties (even if not ultimately attributable to our product candidates), and the resulting publicity, could result in delay, a hold or termination of our clinical trials, increased governmental regulation, unfavorable public perception, failure of the medical community to accept and prescribe gene therapy treatments, potential regulatory delays in the testing or approval of our product candidates, stricter labeling requirements for those product candidates that are approved and a decrease in demand for any such product candidates.
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Other of our product candidates may also require the use of a companion diagnostic device to confirm the presence of specific genetic or other biomarkers.
−Removed: We currently expect that a diagnostic test will be required to determine the levels of neutralizing antibodies present in a patient seeking treatment with etranacogene dezaparvovec, and that regulatory approval of such a diagnostic test will be required.
−Removed: The approval could adversely affect the timing of a first commercial sale of etranacogene dezaparvovec if it does not occur, or if it occurs after or delays regulatory approval of etranacogene dezaparvovec.
−Removed: Currently, CSL Behring is working directly with a third-party provider to gain regulatory health approval of such a diagnostic test, which is based on the clinical diagnostic test used during the development of etranacogene dezaparvovec.
−Removed: It is also possible that our product candidates would be deemed to be combination products, potentially necessitating compliance with the FDA’s investigational device regulations, separate marketing application submissions for the medical device component, a demonstration that our product candidates are safe and effective when used in combination with the medical devices, cross labeling with the medical device, and compliance with certain of the FDA’s device regulations.
+Added: It is possible that our product candidates would be deemed to be combination products, potentially necessitating compliance with the FDA’s investigational device regulations, separate marketing application submissions for the medical device component, a demonstration that our product candidates are safe and effective when used in combination with the medical devices, cross-labeling with the medical device, and compliance with certain of the FDA’s device regulations.
If we are not able to comply with the FDA’s device regulations, if we are not able to effectively partner with the applicable medical device manufacturers, if we or any partners are not able to obtain any required FDA clearances or approvals of the applicable medical devices, or if we are not able to demonstrate that our product candidates are safe and efficacious when used with the applicable medical devices, we may be delayed in or may never obtain FDA approval for our product candidates, which would materially harm our business.
Moreover, certain of our delivery modalities, such as direct delivery of product candidates to the brain, may require significant physician ability and skill.
−Removed: If physicians are not able to effectively deliver our product candidates to the applicable site of action or if delivery modalities are too difficult, we may never be able to obtain approval for our product candidates, may be delayed in obtaining approval, or, following approval, physicians may not adopt our product candidates, any of which may materially harm our business.
+Added: If physicians are not able to effectively deliver our product candidates
+Added: to the applicable site of action or if delivery modalities are too difficult, we may never be able to obtain approval for our product candidates, may be delayed in obtaining approval, or, following approval, physicians may not adopt our product candidates, any of which may materially harm our business.
Risks Related to Our Manufacturing
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Our manufacturing facility in Lexington is subject to ongoing regulation and periodic inspection by the FDA, EU member state, and other regulatory bodies to ensure compliance with current cGMP requirements.
−Removed: Moreover, before approving a BLA for any product candidate, the FDA will inspect our manufacturing facility and processes.
Any failure to follow and document our adherence to such cGMP regulations or other regulatory requirements may lead to significant delays in the availability of products for commercial sale or clinical study, may result in the termination of or a hold on a clinical study, or may delay or prevent filing or approval of marketing applications for our products.
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Issues with any of our manufacturing processes, even minor deviations from the normal process, could result in insufficient yield, product deficiencies or manufacturing failures that result in adverse patient reactions, lot failures, insufficient inventory, product recalls and product liability claims.
−Removed: Additionally, we may not be able to scale up some or all of our manufacturing processes, that may result in delays in regulatory approvals or otherwise adversely affect our ability to manufacture sufficient amounts of our products.
+Added: Additionally, we may not be able to scale up some or all of our manufacturing processes, which may result in delays in regulatory approvals, inability to produce sufficient amounts of commercial product, or otherwise adversely affect our ability to manufacture sufficient amounts of our products.
Many factors common to the manufacturing of most biologics and drugs could also cause production interruptions, including raw materials shortages, raw material failures, growth media failures, equipment malfunctions, facility contamination, labor problems, natural disasters, disruption in utility services, terrorist activities, war or cases of force majeure and acts of god (including the effects of the Covid pandemic) beyond our control.
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Our development and manufacturing processes involve the use of viruses, chemicals, other (potentially) hazardous materials and produce waste products.
−Removed: Accordingly, we are subject to national, federal, state, and local laws and regulations in the United States and the Netherlands governing the use, manufacture, distribution, storage, handling, treatment, and disposal of these materials.
+Added: Accordingly, we are subject to national, federal, state, and local laws and regulations in the U.S.
+Added: and the Netherlands governing the use, manufacture, distribution, storage, handling, treatment, and disposal of these materials.
In addition to ensuring the safe handling of these materials, applicable requirements require increased safeguards and security measures for many of these agents, including controlling access and screening of entities and personnel who have access to them, and establishing a comprehensive national database of registered entities.
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Our resources might be adversely affected if we are unable to validate our manufacturing processes and methods, or develop new processes and methods to meet our product supply needs and obligations.
−Removed: The manufacture of our AAV gene therapies, including etranacogene dezaparvovec, is complex and requires significant expertise.
+Added: The manufacture of our AAV gene therapies is complex and requires significant expertise.
Even with the relevant experience and expertise, manufacturers of gene therapy products often encounter difficulties in production, particularly in scaling out and validating initial production, and ensuring that the product meets required specifications.
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We cannot predict when or if we will obtain marketing approval to commercialize a product candidate.
−Removed: The development and commercialization of our product candidates, including their design, testing, manufacture, safety, efficacy, purity, recordkeeping, labeling, storage, approval, advertising, promotion, sale, and distribution, are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States, the EMA, and other regulatory agencies of the member states of the European Union, and similar regulatory authorities in other jurisdictions.
+Added: The development and commercialization of our product candidates, including their design, testing, manufacture, safety, efficacy, purity, recordkeeping, labeling, storage, approval, advertising, promotion, sale, and distribution, are subject to comprehensive regulation by the FDA and other regulatory agencies in the U.S., the EMA, and other regulatory agencies of the member states of the European Union, and similar regulatory authorities in other jurisdictions.
Failure to obtain marketing approval for a product candidate in a specific jurisdiction will prevent us from commercializing the product candidate in that jurisdiction.
−Removed: The process of obtaining marketing approval for our product candidates in the United States, the European Union, and other countries is expensive and may take many years, if approval is obtained at all.
+Added: The process of obtaining marketing approval for our product candidates in the U.S., the European Union, and other countries is expensive and may take many years, if approval is obtained at all.
Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application.
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Further, any marketing approval we ultimately obtain may be for only limited indications or be subject to stringent labeling or other restrictions or post-approval commitments that render the approved product not commercially viable.
−Removed: Our partner, CSL Behring, is currently pursuing the approval of etranacogene dezaparvovec for which marketing authorization applications are currently under review in the United States and European Union.
−Removed: If CSL Behring experiences delays in obtaining marketing approval in the United States, the European Union, or other countries, the commercial prospects of etranacogene dezaparvovec and our ability to achieve contractual milestone payments and royalties on net sales may be harmed and our ability to generate revenues might be materially impaired.
The risks associated with the marketing approval process are heightened by the status of our products as gene therapies.
We believe that all our current product candidates will be viewed as gene therapy products by the applicable regulatory authorities.
−Removed: While there are a number of gene therapy product candidates under development, in the United States, the FDA has only approved a limited number of gene therapy products, to date.
+Added: While there are a number of gene therapy product candidates under development, in the U.S., the FDA has only approved a limited number of gene therapy products, to date.
Accordingly, regulators, like the FDA, may have limited experience with the review and approval of marketing applications for gene therapy products.
Both the FDA and the EMA have demonstrated caution in their regulation of gene therapy treatments, and ethical and legal concerns about gene therapy and genetic testing may result in additional regulations or restrictions on the development and commercialization of our product candidates that are difficult to predict.
−Removed: The FDA and the EMA have issued various guidance documents pertaining to gene therapy products, with which we likely must comply to gain regulatory approval of any of our product candidates in the United States or European Union, respectively.
+Added: The FDA and the EMA have issued various guidance documents pertaining to gene therapy products, with which we likely must comply to gain regulatory approval of any of our product candidates in the U.S.
+Added: or EU, respectively.
The close regulatory scrutiny of gene therapy products may result in delays and increased costs and may ultimately lead to the failure to obtain approval for any gene therapy product.
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federal and state level, as well as congressional committees and foreign governments, have sometimes expressed interest in further regulating biotechnology.
−Removed: In the United States, there have been a number of recent changes relating to gene therapy development.
+Added: In the U.S., there have been a number of recent changes relating to gene therapy development.
By example, FDA issued a number of new guidance documents, and continues to issue guidance documents, on human gene therapy development, one of which was specific to human gene therapy for hemophilia, one that was specific to neurodegenerative diseases, and another of which was specific to rare diseases.
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Our failure to obtain or maintain orphan product exclusivity for any of our product candidates for which we seek this status could limit our commercial opportunity, and if our competitors are able to obtain orphan product exclusivity before we do, we may not be able to obtain approval for our competing products for a significant period.
−Removed: Regulatory authorities in some jurisdictions, including the United States and the European Union, may designate drugs for relatively small patient populations as orphan drugs.
+Added: Regulatory authorities in some jurisdictions, including the U.S.
+Added: and the European Union, may designate drugs for relatively small patient populations as orphan drugs.
While certain of our product candidates have received orphan drug designation, there is no guarantee that we will be able to receive such designations in the future.
The FDA may grant orphan designation to multiple sponsors for the same compound or active molecule and for the same indication.
−Removed: If another sponsor receives FDA approval for such product before we do, we would be prevented from launching our product in the United States for the orphan indication for a period of at least seven years unless we can demonstrate clinical superiority.
+Added: If another sponsor receives FDA approval for such product before we do, we would be prevented from launching our product in the U.S.
+Added: for the orphan indication for a period of at least seven years unless we can demonstrate clinical superiority.
Moreover, while orphan drug designation neither shortens the development or regulatory review time, nor gives the product candidate advantages in the regulatory review or approval process, generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the relevant indication, the product is entitled to a period of market exclusivity, which precludes the FDA or the EMA from approving another marketing application for the same drug for the same indication for that period.
−Removed: The FDA and the EMA, however, may subsequently approve a similar drug or same drug, in the case of the United States, for the same indication during the first product’s market exclusivity period if the FDA or the EMA concludes that the later drug is clinically superior in that it is shown to be safer or more effective or makes a major contribution to patient care.
−Removed: Orphan exclusivity in the United States also does not prevent the FDA from approving another product that is considered to be the same as our product candidates for a different indication or a different product for the same orphan indication.
+Added: The FDA and the EMA, however, may subsequently approve a similar drug or same drug, in the case of the U.S., for the same indication during the first product’s market exclusivity period if the FDA or the EMA concludes that the later drug is clinically superior in that it is shown to be safer or more effective or makes a major contribution to patient care.
+Added: Orphan exclusivity in the U.S.
+Added: also does not prevent the FDA from approving another product that is considered to be the same as our product candidates for a different indication or a different product for the same orphan indication.
If another product that is the same as ours is approved for a different indication, it is possible that third-party payors will reimburse for products off-label even if not indicated for the orphan condition.
+Added: Moreover, in the U.S.
+Added: the exact scope of orphan exclusivity is currently uncertain and evolving due to a recent court decision.
Orphan drug exclusivity may be lost if the FDA or the EMA determines that the request for designation was materially defective, or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition or if the incidence and prevalence of patients who are eligible to receive the drug in these markets materially increase.
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Additionally, regulatory criteria with respect to orphan products is evolving, especially in the area of gene therapy.
−Removed: By example, in the United States, whether two gene therapies are considered to be the same for the purpose of determining clinical superiority was recently updated via a final guidance document specific to gene therapies, and depends on a number of factors, including the expressed transgene, the vector, and other product or product candidate features.
−Removed: Depending on the products, whether two products are ultimately considered to be the same may be determined by FDA on a case-by-case basis, making it difficult to make predictions regarding when FDA might be able to make an approval of a product effective and whether periods of exclusivity will effectively block competitors seeking to market products that are the same or similar to ours for the same intended use.
+Added: By example, in the U.S., whether two gene therapies are considered to be the same for the purpose of determining clinical superiority was recently updated via a final guidance document specific to gene therapies, and depends on a number of factors, including the expressed transgene, the vector, and other product or product candidate features.
+Added: Depending on the products, whether two products are ultimately considered to be the same may be determined by FDA on a case-by-case basis, making it difficult to make predictions regarding when the FDA might be able to make an approval of a product effective and whether periods of exclusivity will effectively block competitors seeking to market products that are the same or similar to ours for the same intended use.
Accordingly, whether any of our product candidates will be deemed to be the same as another product or product candidate is uncertain.
−Removed: As appropriate, we intend to seek all available periods of regulatory exclusivity for our product candidates.
+Added: As appropriate, we intend to seek available periods of regulatory exclusivity for our product candidates.
However, there is no guarantee that we will be granted these periods of regulatory exclusivity or that we will be able to maintain these periods of exclusivity.
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If we do not obtain or maintain periods of market exclusivity, we may face competition sooner than otherwise anticipated.
−Removed: For instance, in the United States, this could mean that a competing biosimilar product may be able to submit an application to the FDA and obtain approval either as a biosimilar to one of our products or even as an interchangeable product.
+Added: For instance, in the U.S., this could mean that a competing biosimilar product may be able to apply to the FDA and obtain approval either as a biosimilar to one of our products or even as an interchangeable product.
This may require that we undertake costly and time-consuming patent litigation, to the extent available, or defend actions brought by the biosimilar applicant for declaratory judgment.
1 unchanged sentence
It is also possible that, at the time we obtain approval of our product candidates, regulatory laws and policies around exclusivities may have changed.
−Removed: For instance, there have been efforts to decrease the United States period of exclusivity to a shorter timeframe.
+Added: For instance, there have been efforts to decrease the U.S.
+Added: period of exclusivity to a shorter timeframe.
Future proposed budgets, international trade agreements and other arrangements or proposals may affect periods of exclusivity.
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Moreover, if a company obtains FDA approval for a product via the accelerated approval pathway, the company would be required to conduct a post-marketing confirmatory trial to verify and describe the clinical benefit in support of full approval.
−Removed: An unsuccessful post-marketing study or failure to complete such a study could result in the expedited withdrawal of the FDA’s marketing approval for a product.
+Added: FDA can require that this confirmatory trial be commenced prior to FDA granting a product accelerated approval.
+Added: An unsuccessful post-marketing study or failure to complete such a study could result in the expedited withdrawal of the FDA’s marketing approval for a product using a statutorily defined streamlined process.
Changes to some of the conditions established in an approved application, including changes in labeling, indications, manufacturing processes or facilities, may require a submission to and approval by the FDA or the EMA, as applicable, before the change can be implemented.
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However, as we will not control the actions of the applicable third parties, we will be reliant on them to meet their contractual and regulatory obligations.
−Removed: By example, the decisions associated with regulatory filings and approvals for AMT-061 have been, and will continue to be, largely controlled by CSL Behring, and we will not have final decision-making authority in that regard.
Accordingly, actions taken by any of our partners could materially and adversely impact our business.
1 unchanged sentence
If we, or our commercial partner, are unable to successfully commercialize our product candidates or experience significant delays in doing so, our business could be materially harmed.
−Removed: Our ability to generate product revenues will depend on the successful development and eventual commercialization of our product candidates.
−Removed: The success of our product candidates will depend on many factors, including:
−Removed: ● successful execution of our contractual relationship with CSL Behring for the commercialization of etranacogene dezaparvovec;
+Added: Our ability to generate revenues from HEMGENIX® or any other product will depend on the successful development and eventual commercialization of our product candidates.
+Added: The success of HEMGENIX® or other product candidates will depend on many factors, including:
+Added: ● successful execution of our contractual relationship with CSL Behring for the commercialization of HEMGENIX®;
● successful completion of preclinical studies and clinical trials, and other work required by regulators;
● receipt and maintenance of marketing approvals from applicable regulatory authorities;
−Removed: ● our ability to timely manufacture sufficient quantities of our products according to required quality specifications;
−Removed: ● obtaining and maintaining patent and trade secret protection and non-patent, orphan drug exclusivity for our product candidates;
+Added: ● our ability to timely manufacture sufficient quantities of HEMGENIX® and other products according to required quality specifications;
+Added: ● obtaining and maintaining patent and trade secret protection and non-patent, exclusivities for our product candidates;
● maintaining regulatory approvals using our manufacturing facility in Lexington, Massachusetts;
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● the relative convenience and ease of administration of our products;
−Removed: ● obtaining and maintaining healthcare coverage and adequate reimbursement;
+Added: ● obtaining and maintaining healthcare coverage and adequate reimbursement of HEMGENIX® and other products;
● any price concessions, rebates, or discounts we may need to provide;
−Removed: ● complying with any applicable post-approval requirements and maintaining a continued acceptable overall safety profile;
+Added: ● complying with any applicable post-approval commitments and requirements, and maintaining a continued acceptable overall safety profile;
● obtaining adequate reimbursement for the total patient population and each subgroup to sustain a viable commercial business model in U.S.
and EU markets.
−Removed: CSL Behring may not receive a conditional marketing authorization based on an accelerated assessment by the EMA for AMT-061 product candidate to facilitate a first commercial sale in the European Union on or before July 1, 2023, and we, thus, may not receive the $75.0 million first commercial sale milestone in any of the five contractually defined European countries as of or prior to July 1, 2023 under the CSL Behring Agreement.
−Removed: By example, even if our product candidates are approved, they may be subject to limitations that make commercialization difficult.
+Added: CSL Behring may not facilitate a first commercial sale in the European Union prior to July 2, 2023, and we may not receive the $75.0 million first commercial sale milestone in any of the five contractually defined European countries prior to July 2, 2023 under the CSL Behring Agreement unless the CSL Behring Agreement is amended.
+Added: Even if our product candidates are approved, they may be subject to limitations that make commercialization difficult.
There may be limitations on the indicated uses and populations for which the products may be marketed.
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Patients that have pre-existing antibodies to a particular capsid may not be eligible for administration of a gene therapy that includes this particular capsid.
−Removed: For example, etranacogene dezaparvovec, the gene therapy candidate for hemophilia B patients, incorporates an AAV5 capsid.
−Removed: In our Phase I/II clinical study of AMT-060, we screened patients for pre-existing anti-AAV5 antibodies to determine their eligibility for the trial.
−Removed: Three of the ten patients screened for the study tested positive for anti-AAV5 antibodies on reanalysis.
−Removed: Although we did not observe any ill-effects or correlation between the level of anti-AAV5 antibodies and clinical outcomes in these three patients, suggesting that patients who have anti-AAV5 antibodies may still be eligible for AAV5-based gene therapies, since we only have been able to test a limited number of patients and have limited clinical and pre-clinical data, we do not know if future clinical studies will confirm these results.
−Removed: This may limit the addressable market for etranacogene dezaparvovec and any future revenues derived from the sale of the product, if approved.
Any approved gene therapy we seek to offer may fail to achieve the degree of market acceptance by physicians, patients, third party payers and others in the medical community necessary for commercial success.
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These estimates may prove to be incorrect and new studies may reduce the estimated incidence or prevalence of these diseases.
−Removed: The number of patients in the United States, the EU and elsewhere may turn out to be lower than expected, may not be otherwise amenable to treatment with our products or patients may become increasingly difficult to identify and access, any of which could adversely affect our business, financial condition, results of operations and prospects.
+Added: The number of patients in the U.S., the EU and elsewhere may turn out to be lower than expected, may not be otherwise amenable to treatment with our products or patients may become increasingly difficult to identify and access, any of which could adversely affect our business, financial condition, results of operations and prospects.
Further, there are several factors that could contribute to making the actual number of patients who receive other potential products less than the potentially addressable market.
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For example, concerns have been expressed that insurance carriers and employers may use these tests to discriminate on the basis of genetic information, resulting in barriers to the acceptance of genetic tests by consumers.
−Removed: This could lead to governmental authorities restricting genetic testing or calling for limits on or regulating the use of genetic testing, particularly for diseases for which there is no known cure.
+Added: This could lead to governmental authorities restricting genetic testing or
+Added: calling for limits on or regulating the use of genetic testing, particularly for diseases for which there is no known cure.
Any of these scenarios could decrease demand for any products for which we obtain marketing approval.
−Removed: If we, or our commercial partner, obtain approval to commercialize any of our product candidates outside of the United States, a variety of risks associated with international operations could materially adversely affect our business.
−Removed: We expect that we will be subject to additional risks in commercializing any of our product candidates outside the United States, including:
+Added: If we, or our commercial partner, obtain approval to commercialize any of our product candidates outside of the U.S., a variety of risks associated with international operations could materially adversely affect our business.
+Added: We expect that we will be subject to additional risks in commercializing any of our product candidates outside the U.S., including:
● different regulatory requirements for approval of drugs and biologics in foreign countries;
● reduced protection for intellectual property rights;
−Removed: ● unexpected changes in tariffs, trade barriers and regulatory requirements which may make it more difficult or expensive to export or import products and supplies to or from the United States;
+Added: ● unexpected changes in tariffs, trade barriers and regulatory requirements which may make it more difficult or expensive to export or import products and supplies to or from the U.S.;
● economic weakness, including inflation, or political instability in particular foreign economies and markets;
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● foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to doing business in another country;
−Removed: ● workforce uncertainty in countries where labor unrest is more common than in the United States;
+Added: ● workforce uncertainty in countries where labor unrest is more common than in the U.S.;
● production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad;
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It is not possible to predict the broader consequences of this conflict, which could include further sanctions, embargoes, regional instability, geopolitical shifts and adverse effects on macroeconomic conditions, currency exchange rates and financial markets, all of which could impact our business, financial condition and results of operations.
+Added: We may be adversely affected by the effects of inflation.
+Added: Inflation has the potential to adversely affect our liquidity, business, financial condition and results of operations by increasing our overall cost structure.
+Added: The existence of inflation in the economy has resulted in, and may continue to result in, higher interest rates and capital costs, shipping costs, supply shortages, increased costs of labor, weakening exchange rates and other similar effects.
+Added: As a result of inflation, we have experienced and may continue to experience, cost increases.
+Added: Although we may take measures to mitigate the impact of this inflation, if these measures are not effective our business, financial condition, results of operations and liquidity could be materially adversely affected.
+Added: Even if such measures are effective, there could be a difference between the timing of when these beneficial actions impact our results of operations and when the cost inflation is incurred.
We face substantial competition, and others may discover, develop, or commercialize competing products before or more successfully than we do.
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We face worldwide competition from larger pharmaceutical companies, specialty pharmaceutical companies and biotechnology firms, universities and other research institutions and government agencies that are developing and commercializing pharmaceutical products.
−Removed: Our key competitors focused on developing therapies in various indications, include among others, Pfizer, Freeline Therapeutics, Intellia Therapeutics, Sangamo Biosciences, Voyager Therapeutics, Passage Bio, Roche, PTC Therapeutics, Prilenia Therapeutics, Triplet Therapeutics, CombiGene, AvroBio, Caritas Therapeutics, and 4D Molecular Therapeutics.
+Added: Our key competitors focused on developing therapies in various indications, include among others, Pfizer, Freeline Therapeutics, Intellia Therapeutics, Sangamo Biosciences, Voyager
+Added: Therapeutics, Passage Bio, Roche, PTC Therapeutics, Prilenia Therapeutics, CombiGene, Caritas Therapeutics, Alnylam, Wave Life Sciences, Bayer AG, Amicus Therapeutics and 4D Molecular Therapeutics.
Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than the products that we develop.
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To the extent we are unable to successfully identify and manage the performance of third-party service providers in the future, our business may be materially and adversely affected.
−Removed: Our third-party service providers may also have relationships with other entities, some of which may be our competitors, for whom they may also be conducting trials or other therapeutic development activities that could harm our competitive position.
+Added: Our third-party service
+Added: providers may also have relationships with other entities, some of which may be our competitors, for whom they may also be conducting trials or other therapeutic development activities that could harm our competitive position.
Our reliance on these third parties for development activities will reduce our control over these activities.
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For example, we will remain responsible for ensuring that each of our trials is conducted in accordance with the general investigational plan and protocols for the trial.
−Removed: We must also ensure that our preclinical trials are conducted in accordance with good laboratory practices, as appropriate.
−Removed: Moreover, the FDA and comparable foreign regulatory authorities require us to comply with good clinical practices (“GCPs”) for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial participants are protected.
+Added: We must also ensure that our preclinical trials are conducted in accordance with GLPs, as appropriate.
+Added: Moreover, the FDA and comparable foreign regulatory authorities require us to comply with GCPs for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of trial participants are protected.
Regulatory authorities enforce these requirements through periodic inspections of trial sponsors, clinical and preclinical investigators, and trial sites.
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We also rely on other third parties to store and distribute our products for the clinical and preclinical trials that we conduct.
−Removed: Any performance failure on the part of our distributors could delay development, marketing approval, or commercialization of our product candidates, producing additional losses and depriving us of potential product revenue.
+Added: Any performance failure on the part of our distributors could delay the development, marketing approval, or commercialization of our product candidates, producing additional losses and depriving us of potential product revenue.
We rely on third parties for important aspects of our development programs.
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We rely, in part, upon a combination of forms of intellectual property, including in-licensed and owned patents to protect our intellectual property.
−Removed: Our success depends in a large part on our ability to obtain and maintain this protection in the United States, the European Union, and other countries, in part by filing patent applications related to our novel technologies and product candidates.
+Added: Our success depends in large part on our ability to obtain and maintain this protection in the U.S., the European Union, and other countries, in part by filing patent applications related to our novel technologies and product candidates.
Our patents may not provide us with any meaningful commercial protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage.
−Removed: For example, patents we own currently are and may become subject to future patent opposition or similar proceedings, which may result in loss of scope of some claims or the entire patent.
+Added: Patents we own currently are and may become subject to future patent opposition or similar proceedings.
+Added: For example, we are currently defending a patent case in each of Canada, the United Kingdom, and the US and have filed Notices of Appeal at the CAFC contesting three FWDs.
+Added: These oppositions and future patent oppositions may result in loss of scope of some claims or the entire patent.
Our competitors may be able to circumvent our owned or licensed patents by developing similar or alternative technologies or products in a non-infringing manner.
−Removed: Successful challenges to our patents may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated, or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products.
+Added: Successful challenges to our patents may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated, or held unenforceable, in whole or in part, which could limit our ability to stop others
+Added: from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products.
The patent prosecution process is expensive, time-consuming, and uncertain, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner.
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The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation.
−Removed: In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the United States.
+Added: In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the U.S..
For example, EU patent law with respect to the patentability of methods of treatment of the human body is more limited than U.S.
−Removed: Publications of discoveries in the scientific literature often lag the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after their priority date, or in some cases at all.
+Added: Publications of discoveries in the scientific literature often lag the actual discoveries, and patent applications in the U.S.
+Added: and other jurisdictions are typically not published until 18 months after their priority date, or in some cases at all.
Therefore, we cannot know with certainty whether we were the first to make the inventions or that we were the first to file for patent protection of the inventions claimed in our owned or licensed patents or pending patent applications.
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Our pending and future patent applications may not result in patents being issued that protect our technology or products, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products.
−Removed: Changes in either the patent laws or interpretation of the patent laws in the European Union, the United States or other countries may diminish the value of our patents or narrow the scope of our patent protection.
+Added: Changes in either the patent laws or interpretation of the patent laws in the European Union, the U.S.
+Added: or other countries may diminish the value of our patents or narrow the scope of our patent protection.
Our inability to obtain and maintain appropriate patent protection for any one of our products could have a material adverse effect on our business, financial condition, and results of operations.
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Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.
−Removed: For example, outside of the United States two of the patents we own are subject to patent opposition.
+Added: For example, outside of the U.S.
+Added: two of the patents we own are subject to patent opposition.
If these or future oppositions are successful or if we are found to otherwise infringe a third party's intellectual property rights, we could be required to obtain a license from such third party to continue developing and marketing our products and technology.
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Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.
+Added: In addition, legal proceedings relating to intellectual property claims, with or without merit, are unpredictable and generally expensive and time-consuming and is likely to divert significant resources from our core business, including distracting our technical and management personnel from their normal responsibilities.
+Added: Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.
For example, we are aware of patents owned by third parties that relate to some aspects of our programs that are still in development.
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Enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive, and time consuming, and the outcome is unpredictable.
−Removed: In addition, some courts in and outside of the United States are less willing or unwilling to protect trade secrets.
+Added: In addition, some courts in and outside of the U.S.
+Added: are less willing or unwilling to protect trade secrets.
If any of our trade secrets were to be lawfully obtained or independently developed by a competitor or other third party, we would have no right to prevent them from using that technology or information to compete with us.
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We also conduct joint research and development programs that may require us to share trade secrets under the terms of our research and development partnerships or similar agreements.
−Removed: Some courts inside and outside the United States are less willing or unwilling to protect trade secrets.
+Added: Some courts inside and outside the U.S.
+Added: are less willing or unwilling to protect trade secrets.
If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them, or those with whom they communicate, from using that technology or information to compete with us.
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Moreover, we cannot assure that the anticipated benefits of any acquisition would be realized in a timely manner, if at all.
−Removed: Additionally, the product candidate and intellectual property rights that we acquired in the acquisition of Corlieve were developed and owned by Corlieve and its licensors and we cannot ensure that we will be able to continue to successfully advance this product candidate going forward.
Risks Related to Pricing and Reimbursement
−Removed: We face uncertainty related to insurance coverage of, and pricing and reimbursement for product candidates for which we may receive marketing approval.
+Added: We, and our commercial partner, face uncertainty related to insurance coverage of, and pricing and reimbursement for HEMGENIX® and other product candidates for which we may receive marketing approval.
We anticipate that the cost of treatment using our product candidates will be significant.
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Increasingly, third party payers require drug companies to provide them with predetermined discounts from list prices, are exerting influence on decisions regarding the use of particular treatments and are limiting covered indications.
−Removed: Additionally, in the United States and some foreign jurisdictions, pending or potential legislative and regulatory changes regarding the healthcare system and insurance coverage could result in more rigorous coverage criteria and downward pressure on drug prices, and may affect our ability to profitably sell any products for which we obtain marketing approval.
+Added: Additionally, in the U.S.
+Added: and some foreign jurisdictions, pending or potential legislative and regulatory changes regarding the healthcare system and insurance coverage could result in more rigorous coverage criteria and downward pressure on drug prices, and may affect our ability to profitably sell any products for which we obtain marketing approval.
For example, on November 27, 2020, CMS issued an interim final rule implementing a Most Favored Nation (“MFN”) payment model under which reimbursement for certain Medicare Part B drugs and biologicals will be based on a price that reflects the lowest per capita GDP-adjusted price of any non-U.S.
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GDP per capita.
−Removed: While this rule now has been rescinded, government negotiation of certain Medicare drug pricing continues to be the focus of recent proposed legislation.
+Added: While this rule has now been rescinded, government negotiation of certain Medicare drug pricing continues to be the focus of recent proposed legislation.
The pricing review period and pricing negotiations for new medicines take considerable time and have uncertain results.
−Removed: Pricing review and negotiation usually begins only after the receipt of regulatory marketing approval, and some authorities require approval of the sale price of a product before it can be marketed.
+Added: Pricing review and negotiation usually begin only after the receipt of regulatory marketing approval, and some authorities require approval of the sale price of a product before it can be marketed.
In some markets, particularly the countries of the European Union, prescription pharmaceutical pricing remains subject to continuing direct governmental control and to drug reimbursement programs even after initial approval is granted and price reductions may be imposed.
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If we fail to obtain and sustain an adequate level of coverage and reimbursement for our products by third party payers, our ability to market and sell our products could be adversely affected and our business could be harmed.
−Removed: Due to the generally limited addressable market for our target orphan indications and the potential for our therapies to offer therapeutic benefit in a single administration, we face uncertainty related to pricing and reimbursement for these product candidates.
+Added: Due to the generally limited addressable market for our target orphan indications and the potential for our therapies to offer therapeutic benefit in a single administration, we face uncertainty related to pricing and reimbursement for HEMGENIX® and other product candidates.
The relatively small market size for orphan indications and the potential for long-term therapeutic benefit from a single administration present challenges to pricing review and negotiation of our product candidates for which we may obtain marketing authorization.
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Risks Related to Our Financial Position and Need for Additional Capital
−Removed: We had a gain in the year ended December 31, 2021, but incurred significant losses in previous years and expect to incur losses during the current and over the next several years and may never achieve or maintain profitability.
−Removed: We had a net loss of $133.6 million in the nine months ended September 30, 2022, and a net gain of $329.6 million in the full year 2021.
−Removed: As of September 30, 2022, we had an accumulated deficit of $588.7 million.
+Added: We had a loss in the year ended December 31, 2022, incurred significant losses in previous years and expect to incur losses during the current and over the next several years and may never achieve or maintain profitability.
+Added: We had a net loss of $77.2 million in the three months ended March 31, 2023, and a net loss of $126.8 million in the full year 2022.
+Added: As of March 31, 2023, we had an accumulated deficit of $659.2 million.
In the past, we have financed our operations primarily through the sale of equity securities and convertible debt, venture loans, upfront payments from our collaboration partners and, to a lesser extent, subsidies and grants from governmental agencies and fees for services.
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● advancing AMT-130 for our Huntington’s disease gene therapy program into phase III clinical study;
−Removed: ● advancing our gene therapy programs for temporal lobe epilepsy and Fabry into Phase I/II clinical studies;
−Removed: ● advancing preclinical research and development for gene therapy product candidates targeting other diseases;
−Removed: ● continuing to invest in expanding, developing and optimizing our manufacturing capabilities and other enabling technologies, such as next-generation viral vectors, promoters and re-dosing;
+Added: ● advancing our gene therapy programs for rTLE, SOD1-ALS and Fabry disease into Phase I/II clinical studies;
● potentially acquiring or in-licensing rights to new therapeutic targets, product candidates and technologies;
● making potential future milestone payments related to the acquisition of Corlieve, if any
+Added: ● advancing preclinical research and development for gene therapy product candidates targeting other diseases;
+Added: ● continuing to invest in expanding, developing and optimizing our manufacturing capabilities and other enabling technologies, such as next-generation viral vectors, promoters and re-dosing.
We may never succeed in these activities and, even if we do, may never generate revenues that are sufficient to achieve or sustain profitability.
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Failure to obtain capital when needed may force us to delay, limit or terminate our product development efforts or other operations which could have a material adverse effect on our business, financial condition, results of operations and cash flows.
−Removed: We expect to incur significant expenses in connection with our on-going activities and that we will likely need to obtain substantial additional funding in connection with our continuing operations.
−Removed: In addition, we have based our estimate of our financing requirements on assumptions that may prove to be wrong, and we could use our capital resources sooner than we currently expect.
+Added: We expect to incur significant expenses in connection with our ongoing activities and we will likely need to obtain substantial additional funding in connection with our continuing operations.
+Added: In addition, we have based our
+Added: estimate of our financing requirements on assumptions that may prove to be wrong, and we could use our capital resources sooner than we currently expect.
Adequate capital may not be available to us when needed or may not be available on acceptable terms.
−Removed: Our ability to obtain debt financing may be limited by covenants we have made under our 2021 Restated Facility with Hercules and our pledge to Hercules of substantially all our assets as collateral.
+Added: Our ability to obtain debt financing may be limited by covenants we have made under our 2021 Restated Facility with Hercules Capital Inc.
+Added: (“Hercules”) that we entered into on December 15, 2021 when the Company and Hercules amended and restated the 2021 Amended Facility (the “2021 Restated Facility”) and our pledge to Hercules of substantially all our assets as collateral.
If we raise additional capital through the sale of equity or convertible debt securities, our shareholders' ownership interest could be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of holders of our ordinary shares.
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Our existing and any future indebtedness could adversely affect our ability to operate our business.
−Removed: As of September 30, 2022, we had $100.0 million of outstanding principal of borrowings under the 2021 Restated Facility, which we are required to repay in equal installments between December 2024 and December 2025 or in full in December 2025 if, prior to June 30, 2024, either (a) the BLA for AMT-061 is approved by the FDA or (b) AMT-130 is advanced into a pivotal trial.
+Added: As of March 31, 2023, we had $100.0 million of outstanding principal of borrowings under the 2021 Restated Facility, which we are required to repay in full in December 2025.
We could in the future incur additional debt obligations beyond our borrowings from Hercules.
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Risks Related to Other Legal Compliance Matters
−Removed: Our relationships with customers and third-party payers will be subject to applicable anti-kickback, anti-bribery, fraud and abuse and other laws and regulations, which, if we are found in violation thereof, could expose us to criminal sanctions, civil and administrative penalties, contractual damages, reputational harm and diminished profits and future earnings.
+Added: Our relationships with employees, customers and third parties are subject to applicable laws and regulations, the non-compliance of any of which could have a material adverse effect on our business, financial condition, and results of operations.
Healthcare providers, physicians, other practitioners, and third-party payers will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval.
−Removed: Our future arrangements with third party payers and customers may expose us to broadly applicable anti-bribery laws, including the Foreign Corrupt Practices Act, as well as fraud and abuse and other US and international healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we would be able to market, sell and distribute any products for which we obtain marketing approval.
+Added: Our future arrangements with third party payers and customers may expose us to broadly applicable anti-bribery laws, including the Foreign Corrupt Practices Act, as well as fraud and abuse and other U.S.
+Added: and international healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we would be able to market, sell and distribute any products for which we obtain marketing approval.
Efforts to ensure that our business arrangements with third parties will comply with applicable laws and regulations could involve substantial costs.
If our operations, or the activities of our collaborators, distributors or other third-party agents are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal, and administrative penalties, damages, fines, imprisonment, exclusion from participation in government funded healthcare programs and the curtailment or restructuring of our operations.
−Removed: The costs associated with any of these actions could be substantial and could cause irreparable harm to our reputation or otherwise have a material adverse effect on our business, financial condition, and results of operations.
+Added: Additionally, we are subject to various labor and employment laws and regulations.
+Added: These laws and regulations relate to matters such as employment discrimination, wage and hour laws, requirements to provide meal and rest periods or other benefits, family leave mandates, employee and independent contractor classification rules, requirements regarding working conditions and accommodations to certain employees, citizenship or work authorization and related requirements, insurance and workers’ compensation rules, healthcare laws, scheduling notification requirements and anti-discrimination and anti-harassment laws.
+Added: Complying with these laws and regulations, including ongoing changes thereto, subjects us to substantial expense and non-compliance could expose us to significant liabilities.
+Added: In particular, we are subject to allegations of Sarbanes-Oxley whistleblower retaliation and employment discrimination and retaliation, and we may in the future be subject to additional claims of non-compliance with similar or other Laws and regulations.
+Added: The costs associated with a violation of any of the foregoing could be substantial and could cause irreparable harm to our reputation or otherwise have a material adverse effect on our business, financial condition, and results of operations.
We are subject to laws governing data protection in the different jurisdictions in which we operate.
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For instance, the EU has adopted a comprehensive data protection law called the General Data Protection Regulation (“GDPR”) that took effect in May 2018.
−Removed: The GDPR, together with the national legislation of the EU member states governing the processing of personal data, impose strict obligations and restrictions on the ability to collect, analyze and transfer personal data, including health data from clinical trials and adverse event reporting.
+Added: The GDPR, together with the national legislation of the EU member states governing the processing of personal data, imposes strict obligations and restrictions on the ability to collect, analyze and transfer personal data, including health data from clinical trials and adverse event reporting.
In particular, these obligations and restrictions concern the consent of the individuals to whom the personal data relates, the information provided to the individuals, the transfer of personal data out of the EU, security breach notifications, security and confidentiality of the personal data, and imposition of substantial potential fines for breaches of the data protection obligations.
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● the inability to further develop or commercialize any products that we develop.
−Removed: Dependent upon the country where the clinical trial is conducted, we currently hold coverages ranging from EUR 500,000 to EUR 6,500,000 per occurrence and per clinical trial.
+Added: Dependent upon the country where the clinical trial is conducted, we currently hold coverages ranging from EUR 500,000 to EUR 10,000,000 per occurrence.
Such coverage may not be adequate to cover all liabilities that we may incur.
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Our industry is highly regulated and changes in law may adversely impact our business, operations, or financial results.
−Removed: The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or the PPACA, is a sweeping measure intended to, among other things, expand healthcare coverage within the United States, primarily through the imposition of health insurance mandates on employers and individuals and expansion of the Medicaid program.
+Added: The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, or the PPACA, is a sweeping measure intended to, among other things, expand healthcare coverage within the U.S., primarily through the imposition of health insurance mandates on employers and individuals and expansion of the Medicaid program.
Several provisions of the law may affect us and increase certain of our costs.
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The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our products.
+Added: Our future growth may depend, in part, on our ability to penetrate foreign markets, where we would be subject to additional regulatory burdens and other risks and uncertainties.
+Added: Our future profitability may depend, in part, on our ability to commercialize current or future drug candidates in foreign markets for which we may rely on collaboration s with third parties.
+Added: We are not permitted to market or promote any of our drug candidates before we receive regulatory approval from the applicable regulatory authority in that foreign market.
+Added: To obtain separate regulatory approval in many other countries we must comply with numerous and varying regulatory requirements of such countries regarding safety and efficacy and governing, among other things, clinical trials, manufacturing, commercial sales, pricing and distribution of our drug candidates, and we cannot predict success in these jurisdictions.
Our internal computer systems, or those of our collaborators or other contractors or consultants, may fail or suffer security breaches, which could result in a material disruption of our product development programs.
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While we have implemented security measures to protect our information technology systems and infrastructure, there can be no assurance that such measures will prevent service interruptions or security breaches that could adversely affect our business and the further development and commercialization of our product and product candidates could be delayed.
+Added: Climate change, environmental, social and governance and sustainability initiatives may result in regulatory or structural industry changes that could require significant operational changes and expenditures, reduce demand for the Company’s products and adversely affect our business, financial condition, and results of operations.
+Added: Greenhouse gases may have an adverse effect on global temperatures, weather patterns, and the frequency and severity of extreme weather and natural disasters.
+Added: Such events could have a negative effect on our business.
+Added: Concern over climate change may result in new or additional legislative and regulatory requirements to reduce or mitigate the effects of climate change on the environment, which could result in future tax, transportation cost, and utility increases.
+Added: Moreover, natural disasters and extreme weather conditions may impact the productivity of our facilities, the operation of our supply chain, or consumer buying patterns.
+Added: Any of these risks could have a material adverse effect on our business.
+Added: Climate change, environmental, social and governance and sustainability initiatives may result in regulatory or structural industry changes that could require significant operational changes and expenditures, reduce demand for the Company’s products and adversely affect our business, financial condition, and results of operations.
+Added: Climate change, environmental, social and governance and sustainability are a growing global movement.
+Added: Continuing political and social attention to these issues has resulted in both existing and pending international agreements and national, regional and local legislation, regulatory measures, reporting obligations and policy changes.
+Added: Also, there is increasing societal pressure in some of the areas where we operate, to limit greenhouse gas emissions as
+Added: well as other global initiatives.
+Added: These agreements and measures, including the Paris Climate Accord, may require, or could result in future legislation, regulatory measures or policy changes that would require operational changes, taxes, or purchases of emission credits to reduce emission of greenhouse gases from our operations, which may result in substantial capital expenditures.
+Added: Furthermore, increasing attention to climate change, ESG and sustainability has resulted in governmental investigations, and public and private litigation, which could increase our costs or otherwise adversely affect our business or results of operations.
+Added: In addition, organizations that provide information to investors on corporate governance and related matters have developed ratings processes for evaluating companies on their approach to ESG matters.
+Added: Such ratings are used by some investors to inform their investment and voting decisions.
+Added: Unfavorable ESG ratings may lead to increased negative investor sentiment toward us, which could have a negative impact on the price of our securities and our access to and costs of capital.
+Added: Any or all of these ESG and sustainability initiatives may result in significant operational changes and expenditures, reduced demand for our products, cause us reputational harm, and could materially adversely affect our business, financial condition, and results of operations.
Risks Related to Employee Matters and Managing Growth
16 unchanged sentences
Our share price has been and may in the future be volatile.
−Removed: From the start of trading of our ordinary shares on the Nasdaq Global Select Market on February 4, 2014 through October 28, 2022, the sale price of our ordinary shares ranged from a high of $82.49 to a low of $4.72.
−Removed: The closing price on October 28, 2022, was $19.04 per ordinary share.
+Added: From the start of trading of our ordinary shares on the Nasdaq Global Select Market on February 4, 2014 through May 4, 2023, the sale price of our ordinary shares ranged from a high of $82.49 to a low of $4.72.
+Added: The closing price on May 4, 2023, was $21.15 per ordinary share.
The stock market in general and the market for smaller biopharmaceutical companies in particular, have experienced extreme volatility that has often been unrelated to the operating performance of particular companies.
4 unchanged sentences
● regulatory delays and greater government regulation of potential products due to adverse events;
−Removed: ● regulatory or legal developments in the European Union, the United States, and other countries;
+Added: ● regulatory or legal developments in the EU, the U.S., and other countries;
● developments or disputes concerning patent applications, issued patents or other proprietary rights;
9 unchanged sentences
Our directors, executive officers, and major shareholders, if they choose to act together, will continue to have a significant degree of control with respect to matters submitted to shareholders for approval.
−Removed: Our directors, executive officers and major shareholders holding more than 5% of our outstanding ordinary shares, in the aggregate, beneficially own approximately 55.4% of our issued shares (including such shares to be issued in relation to exercisable options to purchase ordinary shares) as of September 30, 2022.
+Added: Our directors, executive officers and major shareholders holding more than 5% of our outstanding ordinary shares, in the aggregate, beneficially own approximately 38.8% of our issued shares (including such shares to be issued in relation to exercisable options to purchase ordinary shares) as of March 31, 2023.
As a result, if these shareholders were to choose to act together, they may be able, as a practical matter, to control many matters submitted to our shareholders for approval, as well as our management and affairs.
9 unchanged sentences
We have not paid any dividends since our incorporation.
−Removed: Even if future operations lead to significant levels of distributable profits, we currently intend that earnings, if any, will be reinvested in our business and that dividends will not be paid until we have an established revenue stream to support continuing dividends.
+Added: Even if future operations lead to significant levels of distributable profits, we currently intend those earnings, if any, will be reinvested in our business and that dividends will not be paid until we have an established revenue stream to support continuing dividends.
Accordingly, shareholders cannot rely on dividend income from our ordinary shares and any returns on an investment in our ordinary shares will likely depend entirely upon any future appreciation in the price of our ordinary shares.
7 unchanged sentences
We have in the past qualified and in the future may qualify as a passive foreign investment company, which may result in adverse U.S.
−Removed: federal income tax consequence to U.S.
+Added: federal income tax consequences to U.S.
Based on our average value of our gross assets, our cash and cash equivalents as well as the price of our shares, we qualified as a passive foreign investment company (“PFIC”) for U.S.
−Removed: federal income tax for 2016 but not for 2017 through 2021.
−Removed: A corporation organized outside the United States generally will be classified as a PFIC for U.S.
+Added: federal income tax for 2016 and 2022 but not for 2017 through 2021.
+Added: A corporation organized outside the U.S.
+Added: generally will be classified as a PFIC for U.S.
federal income tax purposes in any taxable year in which at least 75% of its gross income is passive income or on average at least 50% of the gross value of its assets is attributable to assets that produce passive income or are held to produce passive income.
12 unchanged sentences
or other foreign judgments may be difficult to enforce against us in the Netherlands.
−Removed: Although we now report as a U.S.
+Added: Although we report as a U.S.
domestic filer for SEC reporting purposes, we are incorporated under the laws of the Netherlands.
−Removed: Some of the members of our board and senior management reside outside the United States.
−Removed: As a result, it may not be possible for shareholders to effect service of process within the United States upon such persons or to enforce judgments against them or us in U.S.
−Removed: courts, including judgments predicated upon the civil liability provisions of the federal securities laws of the United States.
+Added: Some of the members of our board and senior management reside outside the U.S.
+Added: As a result, it may not be possible for shareholders to effect service of process within the U.S.
+Added: upon such persons or to enforce judgments against them or us in U.S.
+Added: courts, including judgments predicated upon the civil liability provisions of the federal securities laws of the U.S.
In addition, it is not clear whether a Dutch court would impose civil liability on us or any of our Board members in an original action based solely upon the federal securities laws of the United States brought in a court of competent jurisdiction in the Netherlands.
−Removed: The United States and the Netherlands currently do not have a treaty providing for the reciprocal recognition and enforcement of judgments, other than arbitration awards, in civil and commercial matters.
−Removed: Consequently, a final judgment for payment given by a court in the United States, whether or not predicated solely upon U.S.
+Added: and the Netherlands currently do not have a treaty providing for the reciprocal recognition and enforcement of judgments, other than arbitration awards, in civil and commercial matters.
+Added: Consequently, a final judgment for payment given by a court in the U.S, whether or not predicated solely upon U.S.
securities laws, would not automatically be recognized or enforceable in the Netherlands.
11 unchanged sentences
Therefore U.S.
−Removed: shareholders may not be able to enforce against us or our board members or senior management who are residents of the Netherlands or countries other than the United States any judgments obtained in U.S.
+Added: shareholders may not be able to enforce against us or our board members or senior management who are residents of the Netherlands or countries other than the U.S.
+Added: any judgments obtained in U.S.
courts in civil and commercial matters, including judgments under the U.S.
7 unchanged sentences
jurisdictions).
−Removed: As a result of these considerations our directors may take action that would be different than those that would be taken by a company organized under the law of some U.S.
+Added: As a result of these considerations, our directors may take actions that would be different than those that would be taken by a company organized under the law of some U.S.
jurisdictions.
+Added: Risks Related to the Current Covid Pandemic
+Added: Our business, operations, human resources and supply chain have been, and may continue to be, materially and adversely affected by the ongoing Covid pandemic.
+Added: On March 11, 2020, the World Health Organization (“WHO”) declared the ongoing outbreak of coronavirus disease (“Covid”) a pandemic.
+Added: The Covid pandemic is affecting the U.S.
+Added: and global economies and has affected and may continue to affect our operations and those of third parties on which we rely.
+Added: The Covid pandemic has caused and may continue to cause disruptions in our raw material supply, our commercial-scale manufacturing capabilities for AAV-based gene therapies, the development of our product candidates, employee productivity and the conduct of current and future clinical trials.
+Added: In addition, the Covid pandemic has affected and may continue to affect the operations of the FDA, EMA, and other health authorities, which could result in delays of reviews and approvals, including with respect to our product candidates.
+Added: Global supply chains have been disrupted, causing shortages, which could further impact our clinical trials.
+Added: This disruption of our employees, distributors and suppliers has historically impacted and may continue to impact our future operating results.
+Added: Additionally, to the extent that inspections of facilities by governmental authorities are required, the review of our marketing applications or supplements may further be delayed as regulatory authorities, such as FDA, have significantly limited facility inspections during the pandemic.
+Added: Any such requirements or guidelines that we adopt could have a material impact on our business operations.
Unregistered Sales of Equity Securities and Use of Proceeds
3 unchanged sentences
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.