CRISPR Therapeutics AG
For the period ended Dec 31, 2024. Filed Feb 11, 2025.
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A company's yearly report to the SEC, with audited financial statements. It is the fullest account a company gives of its business, its finances and the risks it sees.
FY2024 · Filed Feb 11, 2025
CRSP$50.07+3.1%Stored close · as of Nov 6, 2026
What changed in Risk Factors?
Read the current filingPrevious report: 10-K
Period ended 2023-12-31; filed 2024-02-21.
0000950170-24-017571
Item 1A. Risk FactorsCurrent report: 10-K
Period ended 2024-12-31; filed 2025-02-11.
0000950170-25-017899
Item 1A. Risk FactorsThe baseline is this issuer’s latest earlier reporting period of the same form that was filed before the current report. A previous 10-Q is a different quarter, not a year-over-year comparison. Amendments are excluded.
Compared 494 previous paragraphs and 513 current paragraphs.
334 unchanged; 137 reworded; 29 added; 8 removed; 15 previous and 13 current paragraphs rearranged.
Tables are not compared: 0 previous and 0 current tables excluded. Dates, whitespace, punctuation and numbering changes are ignored; changes to financial figures remain significant.
A changed paragraph is not evidence that risk increased or decreased. An unchanged paragraph does not establish that risk stayed the same.
Added paragraphs (29)
Current report
In addition, we and our partner, Vertex, have received marketing approval for CASGEVY in certain jurisdictions. Under the Amended A&R Vertex JDCA, for the years ended December 31, 2022, 2023 and 2024, we had the option to defer and did defer costs on the CASGEVY program in excess of $110.3 million annually, subject to certain adjustments under certain circumstances. Beginning in 2025, we will no longer have the option to defer such costs on the CASGEVY program. We also expect increased development and commercialization expenses for the CASGEVY program and that such expenses will exceed our share of revenue for the foreseeable future.
Current report
ability to obtain and maintain clinical trial participant consent;
Current report
We Expect The Product Candidates We Develop Will Be Regulated Biologics And Therefore They May Be Subject To Competition Sooner Than Anticipated.
Current report
The Biologics Price Competition and Innovation Act of 2009, or BPCIA, was enacted as part of the Affordable Care Act to establish an abbreviated pathway for the approval of biosimilar and interchangeable biological products. The regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable” based on its similarity to an approved biologic. Under the BPCIA, an application for a biosimilar product cannot be approved by the FDA until 12 years after the reference product was approved under a BLA. The law is complex and is still being interpreted and implemented by the FDA. As a result, its ultimate impact, implementation, and meaning are subject to uncertainty. While it is uncertain when processes intended to implement BPCIA may be fully adopted by the FDA, any of these processes could have a material adverse effect on the future commercial prospects for our biological products.
Current report
We believe that any of the product candidates we develop that is approved in the United States as a biological product under a BLA should qualify for the 12-year period of exclusivity. However, there is a risk that this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not consider the subject product candidates to be reference products for competing products, potentially creating the opportunity for generic competition sooner than anticipated. Moreover, the extent to which a biosimilar, once approved, will be substituted for any one of the reference products in a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number of marketplace and regulatory factors that are still developing.
Current report
In addition, the approval of a biologic product biosimilar to one of our products could have a material adverse impact on our business as it may be significantly less costly to bring to market and may be priced significantly lower than our products.
Current report
While We May Seek Accelerated Approval For Some Of Our Product Candidates, We May Not Be Able To Obtain It As The Sufficiency Of Our Clinical Trial Results For Accelerated Approval Are Subject To The FDA’s Discretion.
Current report
We plan to seek approval for some of our product candidates under the FDA’s accelerated approval pathway. A product may be eligible for accelerated approval if it is designed to treat a serious or life-threatening disease or condition and generally provides a meaningful advantage over available therapies upon a determination that the product candidate has an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit. For more information, see the section of this report entitled “Business—Government Regulation—Licensure and Regulation of Biologics in the United States—Accelerated Approval Pathway.
Current report
our and our partners efforts to educate healthcare providers and patients about our products;
Current report
adverse publicity concerning our products or competing products and treatments, including social and ethical controversies in the field of gene editing;
Current report
approval of new products or technologies that are more favorably received than our products, are more cost effective or render our products obsolete.
Current report
We are obligated to share equally the net profits and net losses, as applicable, incurred under the Amended A&R Vertex JDCA with respect to all product candidates and products specified in the A&R Vertex JDCA other than for CASGEVY. With respect to CASGEVY only, beginning in July 2021, the net profits and net losses are allocated 40% to CRISPR and 60% to Vertex. Vertex may have additional expenditures related to the CASGEVY program or other programs under the Amended A&R Vertex JDCA that we cannot predict and that we will be required to pay our portion of or agree to pay a portion of in the future pursuant to the agreement. For example, under certain circumstances, either party can propose to in-license intellectual property that it believes is necessary or commercially reasonable to obtain to develop and commercialize CASGEVY or future hemoglobinopathies product candidates that are subject to the Amended A&R Vertex JDCA, and any costs associated with acquiring such intellectual property rights would be shared by the parties in accordance with the terms of the Amended A&R Vertex JDCA. Moreover, under the Amended A&R Vertex JDCA, for the years ended December 31, 2022, 2023 and 2024, we had the option to defer and did defer costs on the CASGEVY program in excess of $110.3 million annually, subject to certain adjustments under certain circumstances. Beginning in 2025, we will no longer have the option to defer such costs on the CASGEVY program. As a result, our expenses related to the CASGEVY program may be significantly greater than in 2022, 2023 and 2024 as a result of Vertex’s commercialization efforts for CASGEVY.
Current report
Our success depends in large part on our ability to obtain and maintain proprietary or intellectual property protection in the United States and other jurisdictions with respect to our gene editing and other technologies, including CRISPR/Cas9 platform technology, and any proprietary product candidates we develop. We seek to develop, maintain and protect our proprietary position and intellectual property that is important to our business by relying upon a combination of know-how, technological innovation and intellectual property rights, including patent rights and trade secret protection, as well as entering into confidentiality agreements and in-licensing arrangements.
Current report
For example, we cannot be certain that all of the potentially relevant prior art relating to our wholly-owned and in-licensed patents and patent applications has been found. Third parties can raise challenges to the patentability or validity of our owned or in-licensed patents and patent applications, such as third-party observations and oppositions before administrative bodies in the United States or in other jurisdictions, even outside the context of litigation.
Current report
If we or a third party that we are obliged to defend and indemnify are found to infringe a third party’s intellectual property rights, and we are unsuccessful in demonstrating that such patents are invalid or unenforceable, we and our partners may be required to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, cease commercialization of the infringing technology, including our core CRISPR/Cas9 gene editing technology, or the applicable product candidate, or we could be required to obtain one or more licenses under the applicable patents from third parties to continue developing, manufacturing, and marketing any product candidates we may develop and our gene-editing and other technologies until such patents expire or are finally determined to be held invalid or unenforceable. These third parties would be under no obligation to grant to us any such licenses and such licenses may not be available on commercially reasonable terms or at all, or may be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us, and it could require us to make substantial licensing and royalty payments. If we are unable to obtain or maintain a necessary license to a third-party patent on commercially reasonable terms, our ability to commercialize our technologies and product candidates may be impaired or delayed, or we may be required to redesign our infringing products, which may be impossible or require substantial time and monetary expenditure.
Current report
Third-party Claims Of Overlapping Intellectual Property Rights May Prevent Or Delay Our Product Discovery and Development Efforts.
Current report
The effects that any such proceedings and results may have on us and our intellectual property position are currently unknown. In any case, it may be years before there is a final determination on priority with respect to CVC Group’s patents included in the worldwide patent portfolio we have in-licensed from Dr. Charpentier.
Current report
Moreover, under our current and future in-license agreements, including our 2014 exclusive license agreement with Dr. Charpentier, and other technology agreements, we are or may be required to pay milestones and royalties based on our revenues from sales of our products utilizing the technologies acquired, licensed or sublicensed from third parties and these milestones and royalty payments could adversely affect our ability to research, develop and obtain approval of product candidates, as well as the overall profitability for us of any products that we may seek to commercialize. Further, our licensors may dispute the terms, including amounts, that we are required to pay under the respective agreements. If these claims were to result in a material increase in the amounts that we are required to pay to our licensors our ability to research, develop and obtain approval of product candidates, or to commercialize products, could be significantly impaired.
Current report
our diligence obligations under our license and collaboration agreements and what activities satisfy those diligence obligations;
Current report
The biotechnology and pharmaceutical industries are characterized by extensive litigation regarding patents and other intellectual property rights. There may be significant intellectual property related litigation and proceedings relating to our owned and in-licensed intellectual property and proprietary rights, as well as other third party intellectual property rights, in the future. See, for example,“Third-party Claims Of Overlapping Intellectual Property Rights May Prevent Or Delay Our Product Discovery and Development Efforts.”
Current report
If We Are Unable To Protect The Confidentiality Of Our Trade Secrets And Other Proprietary Information, Our Business And Competitive Position Would Be Harmed.
Current report
A “U.S. holder” is a beneficial owner of common shares that is (or is treated as), for U.S. federal income tax purposes:
Current report
an individual who is a citizen or resident of the United States;
Current report
a corporation, or other entity that is treated as a corporation for U.S. federal income tax purposes, created or organized in or under the laws of the United States, any state thereof, or the District of Columbia;
Current report
an estate, the income of which is subject to U.S. federal income taxation regardless of its source; or
Current report
a trust, if (a) a court within the United States is able to exercise primary supervision over its administration and one or more U.S. persons have the authority to control all of the substantial decisions of such trust, or (b) the trust has a valid election in effect under applicable U.S. Treasury Regulations to be treated as a United States person.
Current report
Numerous state, federal, and international laws and regulations govern the collection, dissemination, use, privacy, confidentiality, security, availability, integrity, and other processing of personal data or personally identifiable information. In the United States, numerous states have passed comprehensive consumer privacy laws, and several other states have proposed similar legislation. The existence of comprehensive privacy laws in different states in the country would make our compliance obligations more complex and costly and may increase the likelihood that we may be subject to enforcement actions or otherwise incur liability for noncompliance.
Removed paragraphs (8)
Previous report
In particular, gene editing technology is subject to public debate and heightened regulatory scrutiny due to ethical concerns relating to the application of gene editing technology to human embryos or the human germline. For example, in April 2016, a group of scientists reported on their attempts to edit the genome of human embryos to modify the gene for hemoglobin beta. This is the gene in which a mutation occurs in patients with the inherited blood disorder beta thalassemia. Although this research was purposefully conducted in embryos that were not viable, the work prompted calls for a moratorium or other types of restrictions on gene editing of human eggs, sperm, and embryos. Additionally, in November 2018, Dr. Jiankui He, a biophysics researcher who was an associate professor in the Department of Biology of the Southern University of Science and Technology in Shenzhen, China, reportedly claimed he had created the first human genetically edited babies, twin girls. This claim, and another that Dr. He had helped create a second gene-edited pregnancy, was subsequently confirmed by Chinese authorities and was negatively received by the public, in particular by those in the scientific community. News reports indicate that Dr. He was sentenced to three years in prison and fined $430,000 in December 2019 by the Chinese government for illegal medical practice in connection with such activities. In the wake of the claim, the World Health Organization established a new advisory committee to create global governance and oversight standards for human gene editing. The Alliance for Regenerative Medicine in Washington, D.C. has called for a voluntary moratorium on the use of gene editing technologies, including CRISPR/Cas9, in research that involves altering human embryos or human germline cells and has also released principles for the use of gene editing in therapeutic applications endorsed by a number of companies that use gene editing technologies. Similarly, the NIH has announced that it would not fund any use of gene editing technologies in human embryos, noting that there are multiple existing legislative and regulatory prohibitions against such work, including the Dickey-Wicker Amendment, which prohibits the use of appropriated funds for the creation of human embryos for research purposes or for research in which human embryos are destroyed. Laws in the UK prohibit genetically modified embryos from being implanted into women, but embryos can be altered in research labs under license from the Human Fertilisation and Embryology Authority. Research on embryos is more tightly controlled in many other European countries.
Previous report
We seek to protect our proprietary position by in-licensing intellectual property to cover our platform technology and filing patent applications in the United States and in other jurisdictions related to our technologies and product candidates that are important to our business. We also rely on trade secrets, know-how and continuing technological innovation to develop and maintain our proprietary and intellectual property position. If we or our licensors are unable to obtain or maintain patent protection with respect to our CRISPR/Cas9 platform technology and any proprietary products and technology we develop, our business, financial condition, results of operations and prospects could be materially harmed.
Previous report
Third parties may assert that we infringe their patents or that we are otherwise employing their proprietary technology without authorization, and may sue us. There may be third-party patents of which we are currently unaware with claims to compositions, formulations, methods of manufacture or methods of use or treatment that cover product candidates we discover and develop. Because patent applications can take many years to issue, there may be currently pending patent applications that may later result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our technologies or the manufacture, use or sale of our product candidates infringes upon these patents. If any such third-party patents were held by a court of competent jurisdiction to cover our technologies or product candidates, the holders of any such patents may be able to block our ability to commercialize the applicable product candidate unless we obtain a license under the applicable patents, or until such patents expire or are finally determined to be held invalid or unenforceable. Such a license may not be available on commercially reasonable terms or at all. If we are unable to obtain a necessary license to a third-party patent on commercially reasonable terms, our ability to commercialize our product candidates may be impaired or delayed, which could in turn significantly harm our business.
Previous report
Specifically, the Broad Institute and Massachusetts Institute of Technology and, in some instances, the President and Fellows of Harvard College, which we refer to individually and collectively as the “Broad” owns a patent family that includes issued patents in the United States and Europe that claim certain aspects of CRISPR/Cas9 systems to edit DNA in eukaryotic cells, including human cells. In January 2016, the USPTO declared an interference (Interference No. 106,048, or ‘048 interference) between one of the then pending U.S. patent applications (now issued as U.S. Patent No. 10,266,850) included in the Patent Portfolio and twelve issued U.S. patents owned jointly by the Broad to determine which set of inventors invented first and, thus, is entitled to patents on the invention in the United States. The PTAB concluded that the declared interference should be discontinued because the involved claim sets were considered patentably distinct from each other. Following appeal by the CVC Group, on September 10, 2018, the Federal Circuit affirmed the PTAB’s decision to terminate the interference proceeding without determining which inventors actually invented the use of the CRISPR/Cas9 genome editing technology in eukaryotic cells.
Previous report
Third-party owned IP relating to CRISPR/Cas9 or other related technologies necessary to develop, manufacture and commercialize viable CRISPR/Cas9 therapeutics – such as compositions of the products or components, methods of treatment, delivery technologies, chemical modifications, and analytical and manufacturing methods – could adversely impact our ability to ultimately market and sell products. Third parties may own intellectual property, including patents, that cover all or aspects of our technologies and potential products, and may be necessary for us to develop or commercialize viable products. If we are unable to successfully license, avoid or challenge such third-party intellectual property, we may not be able to develop and commercialize viable products in all or certain jurisdictions. In addition, if the intellectual property covering our products or technologies that we own or license were to be legally impaired or lost, we may be unable to realize sufficient financial returns to support the development or commercialization of our products.
Previous report
If we are determined to be a PFIC, a U.S. holder will generally be treated as owning a proportionate amount (by value) of shares owned by us in any of our direct or indirect subsidiaries that are also PFICs, each a lower-tier PFIC, and will be subject to similar adverse rules with respect to distributions from, or dispositions of, such lower-tier PFICs, in each case as if such U.S. holder held such shares directly (even if such U.S. holder does not receive the proceeds of such distributions or dispositions directly). We have not determined whether any of our subsidiaries (including TRACR and CRISPR Therapeutics Ltd.) are or may be lower-tier PFICs for any prior taxable year, the current taxable year or future taxable years, and we do not intend to do so. We also do not intend to make available the information necessary for U.S. holders to make a QEF election with respect to any lower-tier PFICs and therefore you should expect that you will not be able to make a QEF election with respect to them. You are urged to consult your own tax advisors regarding our PFIC status and the tax considerations relevant to an investment in a PFIC, including the availability, and advisability, of, and procedure for making, a QEF election or a mark to market election with respect to us, and the application of the PFIC rules to any of our subsidiaries.
Reworded paragraphs (137)
Previous wording
You should carefully consider the following risk factors, together with all other information in this report, including our financial statements and notes thereto, and in our other filings with the Securities and Exchange Commission. If any of the following risks, or other risks not presently known to us or that we currently believe to not be significant, develop into actual events, then our business, financial condition, results of operations or prospects could be materially adversely affected. If that happens, the market price of our common shares could decline, and shareholders may lose all or part of their investment.
Current wording
You should carefully consider the following risk factors, together with all other information in this report, including our financial statements and notes thereto, and in our other filings with the U.S. Securities and Exchange Commission, or SEC. If any of the following risks, or other risks not presently known to us or that we currently believe to not be significant, develop into actual events, then our business, financial condition, results of operations or prospects could be materially adversely affected. If that happens, the market price of our common shares could decline, and shareholders may lose all or part of their investment.
Previous wording
conduct IND supporting preclinical studies and initiate clinical trials for our product candidates;
Current wording
conduct preclinical studies to support U.S. Investigational New Drug, or IND, applications and initiate clinical trials for our product candidates;
Current wording
further develop our gene editing and other proprietary technologies;
Previous wording
As a result, we expect to continue to incur significant and increasing operating losses for the foreseeable future. Because of the numerous risks and uncertainties associated with developing gene editing product candidates, we are unable to predict the extent of any future losses or when we will become profitable, if at all. Even if we do become profitable, we may not be able to sustain or increase our profitability on a quarterly or annual basis.
Current wording
As a result of all of the foregoing, we expect to continue to incur significant and increasing operating losses for the foreseeable future. Because of the numerous risks and uncertainties associated with developing gene editing product candidates, we are unable to predict the extent of any future losses or when we will become profitable, if at all. Even if we do become profitable, we may not be able to sustain or increase our profitability on a quarterly or annual basis.
Previous wording
The development of gene editing product candidates is capital intensive. We expect our expenses to increase in connection with our ongoing activities, particularly as we continue the research and development of, initiate preclinical studies and clinical trials for and seek marketing approval for our product candidates. In addition, since we and our partner, Vertex, received the first-ever marketing approval of a CRISPR-based gene editing therapy, CASGEVY, in 2023 in certain jurisdictions, and have received a subsequent approval in 2024, and if we obtain marketing approval for any of our product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution to the extent that such sales, marketing, manufacturing and distribution are not the responsibility of Bayer, Vertex or other future collaborators. We may also need to raise additional funds sooner if we choose to pursue additional indications or geographies for our product candidates or otherwise expand more rapidly than we presently anticipate. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate certain of our research and development programs or future commercialization efforts.
Current wording
The development of gene editing product candidates is capital intensive. We expect our expenses to increase in connection with our ongoing activities, particularly as we continue the research and development of, initiate preclinical studies and clinical trials for and seek marketing approval for our product candidates, as well as incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution to the extent that such sales, marketing, manufacturing and distribution are not the responsibility of our collaborators currently or in the future if we obtain marketing approval for any of our product candidates. For example, beginning in 2025, we will no longer have the option to defer certain costs on the CASGEVY program under the Amended A&R Vertex JDCA and expect our share of expenses for the development and commercialization of CASGEVY to increase, and that such expenses will exceed our share of revenue for the foreseeable future. We may also need to raise additional funds sooner if we choose to pursue additional indications or geographies for our product candidates, investigate new technologies, including delivery modalities, or otherwise expand more rapidly than we presently anticipate. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate certain of our research and development programs or future commercialization efforts.
Previous wording
As of December 31, 2023 and 2022, we had cash, cash equivalents and marketable securities of approximately $1,695.7 million and $1,868.4 million, respectively. With our cash, cash equivalents and marketable securities on hand as of December 31, 2023, we expect cash, cash equivalents and marketable securities to be sufficient to fund our current operating plan through at least the next 24 months.
Current wording
As of December 31, 2024 and 2023, we had cash, cash equivalents and marketable securities of approximately $1,903.8 million and $1,695.7 million, respectively. With our cash, cash equivalents and marketable securities on hand as of December 31, 2024, we expect cash, cash equivalents and marketable securities to be sufficient to fund our current operating plan through at least the next 24 months.
Previous wording
the achievement of milestones or occurrence of other developments that trigger payments under any additional collaboration agreements we obtain;
Current wording
the achievement of milestones or occurrence of other developments that trigger payments under any additional collaboration or license agreements we obtain;
Previous wording
the extent to which we are obligated to reimburse, or entitled to reimbursement of, clinical trial costs under future collaboration agreements, if any;
Current wording
the extent to which we are obligated to reimburse, or entitled to reimbursement of various expenses, including clinical trial, development and commercialization costs, under our current or future collaboration agreements, if any;
Previous wording
the extent to which we acquire or in-license other product candidates and technologies;
Current wording
the extent to which we acquire or in-license other product candidates, intellectual property and technologies;
Previous wording
the costs of establishing or contracting for manufacturing capabilities if we obtain regulatory approvals to manufacture our product candidates;
Current wording
the costs of establishing, expanding or contracting for manufacturing capabilities if we obtain regulatory approvals to manufacture our product candidates;
Previous wording
Our overall development efforts are ongoing and the first clinical trial for any of our product candidates was initiated at the end of 2018. In general, our programs require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions; obtaining manufacturing supply, capacity, and expertise; building a commercial organization; substantial investment and significant marketing efforts before we generate any revenue from product sales. Our product candidates must be approved for marketing by the FDA or certain other health regulatory agencies, including the EMA, before we may commercialize any product. Although we and our partner, Vertex, received the first-ever marketing approval of a CRISPR-based gene-editing therapy, CASGEVY, in 2023 in certain jurisdictions, and have received a subsequent approval in 2024, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future. For additional information, see also “Risk Factors —Risks Related to Our Relationships with Third Parties—We Have Partnered With Vertex On Our Lead Program CASGEVY; Vertex Has Significant Control Over The CASGEVY Program” and “Risk Factors —Risks Related to Our Business, Technology and Industry—If We Are Unable To Advance Our Product Candidates To Clinical Development, Obtain Regulatory Approval And Ultimately Commercialize Our Product Candidates, Or Experience Significant Delays In Doing So, Our Business Will Be Materially Harmed.”
Current wording
Our overall development efforts are ongoing and the first clinical trial for any of our product candidates was initiated at the end of 2018. In general, our programs require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions; obtaining manufacturing supply, capacity, and expertise; building a commercial organization; substantial investment and significant marketing efforts before we generate any revenue from product sales. Our product candidates must be approved for marketing by the FDA or certain other regulatory agencies, including the EMA, before we may commercialize any product. Although we and our partner, Vertex, have received marketing approvals for CASGEVY in certain jurisdictions, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future. For additional information, see also “Risk Factors —Risks Related to Our Relationships with Third Parties—We Have Partnered With Vertex On Our Lead Program CASGEVY; Vertex Has Significant Control Over The CASGEVY Program” and “Risk Factors —Risks Related to Our Business, Technology and Industry—If We Are Unable To Advance Our Product Candidates To Clinical Development, Obtain Regulatory Approval And Ultimately Commercialize Our Product Candidates, Or Experience Significant Delays In Doing So, Our Business Will Be Materially Harmed.”
Previous wording
Our development efforts are ongoing and we have focused our research and development efforts to date on CRISPR/Cas9, gene editing technology, and our initial product candidates. Our future success depends heavily on the successful development of our CRISPR/Cas9 gene editing next-generation product candidates. We have invested substantially all of our efforts and financial resources in the identification and development of our current product candidates. Our ability to generate product revenue will depend heavily on the successful development and eventual commercialization of our product candidates, which may never occur. For example, while we and our partner, Vertex, received the marketing approval of CASGEVY in 2023 in certain jurisdictions, and have received a subsequent approval in 2024, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future, and our research programs, including additional programs subject to current and future collaboration agreements with third parties, may fail to identify potential product candidates for clinical development for a number of reasons or may fail to successfully advance any product candidates through clinical development. Our potential product candidates, or our potential product candidates may be shown to have harmful side effects or may have other characteristics or unforeseeable consequences that may make the product candidates impractical to manufacture, unmarketable, or unlikely to receive marketing approval, or that lead to product-related claims or litigation, including without limitation personal injury/product liability claims, adverse or serious adverse events, regulatory enforcement actions, or product recalls or market withdrawals . We currently generate no revenue from sales of any product and we may never be able to again research, develop or commercialize a marketable product.
Current wording
Our development efforts are ongoing and we have primarily focused our research and development efforts to date on gene editing and other technologies, including CRISPR/Cas9 technology, and our initial product candidates. Our future success depends heavily on the successful development of our next-generation product candidates and other future product candidates. We have invested substantially all of our efforts and financial resources in the development of our proprietary technologies and identification and development of our current product candidates. Our ability to generate product revenue will depend heavily on the successful development and eventual commercialization of our product candidates, which may never occur. For example, while we and our partner, Vertex, have received marketing approvals for CASGEVY in certain jurisdictions, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future, and our research programs, including additional programs subject to current and future collaboration agreements with third parties, may fail to identify potential product candidates for clinical development for a number of reasons or may fail to successfully advance any product candidates through clinical development. Our potential product candidates may be shown to have harmful side effects or may have other characteristics or unforeseeable consequences that may make the product candidates impractical to manufacture, unmarketable, or unlikely to receive marketing approval, or that lead to product-related claims or litigation, including without limitation personal injury or product liability claims, adverse or serious adverse events, regulatory enforcement actions, or product recalls or market withdrawals. Our partner, Vertex, generates product sales from CASGEVY, of which we receive 40% through our collaboration arrangement with Vertex. This amount is currently insufficient to cover program expenses and as such, we are responsible for 40% of losses, subject to certain limitations. We currently generate no revenue from sales of any wholly-owned product and we may never be able to again research, develop or commercialize a marketable product.
Previous wording
We must file U.S. Investigational New Drug, or IND, applications, clinical trial applications, or CTAs, or their equivalents with regulatory authorities to commence clinical trials. The filing of CTAs or INDs for any product candidate is subject to the identification and selection of one or more guide RNAs with acceptable efficiency, among other activities. In addition, commencing any future clinical trial is also subject to acceptance by the European regulatory authorities, or its equivalent, of our CTAs, or the FDA of our INDs, and finalizing the trial design based on discussions with the applicable regulatory authorities. In the event that the European regulatory authorities, FDA or their equivalent require us to complete additional preclinical studies or we are required to satisfy other requests, our clinical trials may be delayed. Even after we receive and incorporate guidance from these regulatory authorities, they could disagree that we have satisfied their requirements to commence our clinical trial or change their position on the acceptability of our trial design or the clinical endpoints selected, which may require us to complete additional preclinical studies or clinical trials or impose stricter approval conditions than we currently expect. In addition, there is no certainty that the FDA or other similar health regulatory agencies will continue to apply to all our CRISPR/Cas9 product candidates the same regulatory pathway and requirements it applied to CASGEVY, and is applying to otherex vivo engineered therapeutics andin vivo therapies.
Current wording
We must file IND applications, clinical trial applications, or CTAs, or their equivalents with regulatory authorities to commence clinical trials. The filing of INDs, CTAs or their equivalents for any product candidate is subject to the identification and selection of one or more guide RNAs with acceptable efficiency, among other activities. In addition, commencing any future clinical trial is also subject to acceptance by the European regulatory authorities, or its equivalent, of our CTAs, or by the FDA of our INDs, and finalizing the trial design based on discussions with the applicable regulatory authorities. In the event that the European regulatory authorities, FDA or their equivalent require us to complete additional preclinical studies or we are required to satisfy other requests, our clinical trials may be delayed. Even after we receive and incorporate guidance from these regulatory authorities, they could disagree that we have satisfied their requirements to commence a clinical trial or change their position on the acceptability of our trial design or the clinical endpoints selected, which may require us to complete additional preclinical studies or clinical trials or impose stricter approval conditions than we currently expect. Regulatory authorities have limited experience with the clinical development of CRISPR/Cas9-based therapeutics, includingin vivo therapeutics, which may require additional significant testing or data compared to more traditional therapies or otherwise delay the development of our product candidates. There is no certainty that the FDA or other similar regulatory agencies will continue to apply to all our gene-editing product candidates, including CRISPR/Cas9 product candidates, the same regulatory pathway and requirements it applied to CASGEVY and is applying to otherex vivo engineered therapeutics andin vivo therapies.
Previous wording
To become and remain profitable, we must develop and commercialize product candidates with significant market potential, which will require us to be successful in a range of challenging activities. In general, our product candidates require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions; obtaining manufacturing supply, capacity, and expertise; building of a commercial organization; substantial investment and significant marketing efforts before we generate any revenue from product sales. In addition, our product development programs must be approved for marketing by the FDA, EMA or certain other health regulatory agencies, before we may commercialize our product candidates. We may never succeed in any or all of these activities and, even if we do, we may never generate revenues that are significant or large enough to achieve profitability. Although we and our partner, Vertex, received the first-ever marketing approval of a CRISPR-based gene-editing therapy, CASGEVY, in 2023 in certain jurisdictions, and have received a subsequent approval in 2024, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future, or that CASGEVY, or any other future product candidate we develop, will be profitable. For additional information, see also “Risk Factors—Risks Related to Our Relationships with Third Parties—We Have Partnered With Vertex On Our Lead Program CASGEVY; Vertex Has Significant Control Over The CASGEVY Program.”
Current wording
To become and remain profitable, we must develop and commercialize product candidates with significant market potential, which will require us to be successful in a range of challenging activities. In general, our product candidates require preclinical and clinical development; regulatory and marketing approval in multiple jurisdictions; obtaining manufacturing supply, capacity, and expertise; building a commercial organization; substantial investment and significant marketing efforts before we generate any revenue from product sales. In addition, our product development programs must be approved for marketing by the FDA, EMA or certain other health regulatory agencies before we may commercialize our product candidates. We may never succeed in any or all of these activities and, even if we do, we may never generate revenues that are significant or large enough to achieve profitability. Although we and our partner, Vertex, have received marketing approvals for CASGEVY in certain jurisdictions, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future, or that CASGEVY, or any other future product candidate we develop, will be profitable. For additional information, see also “Risk Factors—Risks Related to Our Relationships with Third Parties—We Have Partnered With Vertex On Our Lead Program CASGEVY; Vertex Has Significant Control Over The CASGEVY Program.”
Previous wording
approval of CTAs or INDs for our product candidates to commence clinical trials;
Current wording
approval of INDs, CTAs or their equivalents for our product candidates to commence clinical trials;
Previous wording
successful data from our clinical program that support an acceptable risk-benefit profile of our product candidates for the intended patient populations;
Current wording
successful data from our clinical programs that support an acceptable risk-benefit profile of our product candidates for the intended patient populations;
Previous wording
establishing and maintaining arrangements with third-party manufacturers for clinical supply and commercial manufacturing and, where applicable, commercial manufacturing capabilities;
Current wording
establishing and maintaining arrangements with third-party manufacturers for clinical and commercial supply and, where applicable, commercial manufacturing capabilities;
Previous wording
successful development of our internal manufacturing processes and transfer to larger-scale facilities operated by either a contract manufacturing organization or by us;
Current wording
successful development of our internal manufacturing processes and transfer to larger-scale facilities operated by either a third-party contract manufacturing organization or by us;
Previous wording
acceptance of the product candidates, if and when approved, by patients, the medical community and third-party payors;
Current wording
acceptance of our product candidates, if and when approved, by patients, the medical community and third-party payors;
Previous wording
maintenance of a continued acceptable safety profile of the product candidates following approval; and
Current wording
maintenance of a continued acceptable safety profile of our product candidates following approval; and
Previous wording
to date, only a limited number of products that involve the genetic modification of patient cells have been approved in the United States and the EU;
Current wording
to date, only a limited number of products that involve the genetic modification of patient cells have been approved in the United States, the European Union, or EU, and globally;
Previous wording
the administration processes or related procedures for our product candidates (e.g., treatment with myeloablative busulfan conditioning prior to receiving CASGEVY or undergoing a lymphodepletion regimen prior to receiving our immunotherapy product candidates);
Current wording
the administration processes or related procedures for certain of our product candidates (e.g., treatment with myeloablative busulfan conditioning prior to receiving CASGEVY or undergoing a lymphodepletion regimen prior to receiving our immunotherapy product candidates);
Previous wording
In addition, if any product candidates encounter safety or efficacy problems, development delays, regulatory issues or other problems, our development plans and business could be significantly harmed. For the reasons described above, among others, regulatory authorities, particularly the FDA, have requested, and may request in the future, additional preclinical studies for genome editing products, such as additional studies related to toxicology, biodistribution or reproductive health, and/or preclinical studies earlier in clinical development compared to other therapeutic modalities. Although to date the FDA has cleared the INDs that we have submitted for certain of our clinical trials, including CTX112 and CTX131, it is possible that the FDA may impose requirements that result in a delay of any of our programs or their regulatory approval. If we are unable to complete any required studies satisfactorily, the FDA or other regulatory authorities could require that we exclude certain patient populations from clinical studies, place our clinical studies on hold, or require us to cease further clinical studies or deny approval of such product candidates. Further, competitors that are developingex vivoorin vivo products with similar technology may experience problems with their product candidates or programs that could in turn cause us to identify problems with our product candidates and programs, or cause the FDA or other regulatory authorities to impose additional requirements, that could cause us to delay or pause development of our product candidates. Any of these occurrences may harm our ability to identify and develop product candidates, and may harm our business, financial condition, results of operations and prospects significantly. We cannot guarantee that the FDA or other regulatory authorities will not change their requirements in the future or approve amendments to our INDs or equivalent regulatory filings, including for CTX310 and CTX320 or our other product candidates on the timeline we expect.
Current wording
In addition, if any product candidates encounter safety or efficacy problems, development delays, regulatory issues or other problems, our development plans and business could be significantly harmed. For the reasons described above, among others, regulatory authorities, particularly the FDA, have requested, and may request in the future, additional preclinical studies for genome editing products, such as additional studies related to toxicology, biodistribution or reproductive health, and/or preclinical studies earlier in clinical development compared to other therapeutic modalities. Although to date the FDA has cleared the INDs that we have submitted for certain of our clinical trials, including CTX112 and CTX131, it is possible that the FDA may impose requirements that result in a delay of any of our programs or their regulatory approval. If we are unable to complete any required studies satisfactorily, the FDA or other regulatory authorities could require that we exclude certain patient populations from clinical studies, place our clinical studies on hold, or require us to cease further clinical studies or deny approval of such product candidates. Further, competitors that are developingex vivoorin vivo products with similar technology may experience problems with their product candidates or programs that could in turn cause us to identify problems with our product candidates and programs, or cause the FDA or other regulatory authorities to impose additional requirements, that could cause us to delay or pause development of our product candidates. Any of these occurrences may harm our ability to identify and develop product candidates, and may harm our business, financial condition, results of operations and prospects significantly. We cannot guarantee that the FDA or other regulatory authorities will not change their requirements in the future or approve amendments to our INDs or equivalent regulatory filings on the timelines we expect.
Previous wording
We aim to develop treatments and therapies for people suffering from serious diseases through transformative gene-based medicines, includingex vivo engineered cell therapies andin vivo therapies. Although there have been significant advances in recent years in the fields of gene therapy and genome editing, including CRISPR/Cas9 gene editing technology, such technologies, includingin vivo CRISPR-based genome editing technologies in particular, are relatively new and only a limited number of clinical trials of product candidates based on such gene editing technologies have been commenced and their therapeutic utility is largely unproven. As such it is difficult to accurately predict the developmental challenges we may incur for our product candidates as they proceed through product discovery or identification, preclinical studies and clinical trials. For example, no genome editingin vivo therapy has been approved by the FDA or other regulatory authorities. While we and our partner, Vertex, received the first-ever approval for anex-vivo CRISPR-based gene-editing therapy, CASGEVY, in 2023 in certain jurisdictions, and have received a subsequent approval in 2024, we and Vertex cannot guarantee we will receive additional marketing approvals for CASGEVY or that we will receive marketing approvals for our other product candidates in the future. In addition, because we have only recently commenced clinical trials for certain of our other product candidates, we have not yet been able to fully assess safety in humans. There may be long-term effects from treatment with any product candidates that we develop that we cannot predict at this time. Any product candidates we may develop will act at the level of DNA, and, because animal DNA differs from human DNA, testing of our product candidates in animal models may not be predictive of the results we observe in human clinical trials of our product candidates for either safety or efficacy. Also, animal models may not exist for some of the diseases we choose to pursue in our programs. As a result of these factors, it is more difficult for us to predict the time and cost of product candidate development, and we cannot predict whether the application of our gene editing technology, or any similar or competitive gene editing technologies, will result in the identification, development, and regulatory approval of any products. There can be no assurance that any development problems we experience in the future related to our gene editing technology or any of our research and development programs will not cause significant delays or unanticipated costs, or that such development problems can be solved. Any of these factors may prevent us from completing our preclinical studies or any clinical trials that we may initiate or commercializing any product candidates we may develop on a timely or profitable basis, if at all.
Current wording
CASGEVY in certain jurisdictions, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future. In addition, because we have only recently commenced clinical trials for certain of our other product candidates, we have not yet been able to fully assess safety in humans. There may be long-term effects from treatment with any product candidates that we develop that we cannot predict at this time. Any product candidates we may develop will act at the level of DNA, and, because animal DNA differs from human DNA, testing of our product candidates in animal models may not be predictive of the results we observe in human clinical trials of our product candidates for either safety or efficacy. Also, animal models may not exist for some of the diseases we choose to pursue in our programs. As a result of these factors, it is more difficult for us to predict the time and cost of product candidate development, and we cannot predict whether the application of our gene editing technology, or any similar or competitive gene editing technologies, will result in the identification, development, and regulatory approval of any products. There can be no assurance that any development problems we experience in the future related to our gene editing technology or any of our research and development programs will not cause significant delays or unanticipated costs, or that such development problems can be solved. Any of these factors may prevent us from completing our preclinical studies or any clinical trials that we may initiate or commercializing any product candidates we may develop on a timely or profitable basis, if at all.
Previous wording
The clinical trial requirements of the FDA, the EMA and other regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of the product candidate. Although we and our partner, Vertex, received the marketing approval of CASGEVY in 2023 in certain jurisdictions, and have received a subsequent approval in 2024, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future, and the regulatory approval process for product candidates such as ours remains uncertain and may be more expensive and take longer than the approval process for product candidates based on other, better known or more extensively studied technologies. It is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our future product candidates in either the United States or the EU or how long it will take to commercialize our product candidates. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product candidate to market could decrease our ability to generate sufficient product revenue, and our business, financial condition, results of operations and prospects may be harmed.
Current wording
The clinical trial requirements of the FDA, the EMA and other regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of the product candidate. Although we and our partner, Vertex, have received marketing approvals for CASGEVY in certain jurisdictions, we cannot guarantee we and Vertex will receive additional marketing approvals for CASGEVY or we will receive marketing approvals for our other product candidates in the future, and the regulatory approval process for product candidates such as ours remains uncertain and may be more expensive and take longer than the approval process for product candidates based on other, better known or more extensively studied technologies. It is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our future product candidates in either the United States or the EU or how long it will take to commercialize our product candidates. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product candidate to market could decrease our ability to generate sufficient product revenue, and our business, financial condition, results of operations and prospects may be harmed.
Previous wording
For our immuno-oncology programs, we are developing a pipeline of allogeneic T cell product candidates (including, for example, CTX112 and CTX131) that are engineered from healthy donor T cells to express chimeric antigen receptors, or CARs, and are intended for use in any patient with certain cancers. Unlike for autologous CAR T therapies, for allogeneic CAR T therapies, we are reliant on receiving healthy donor material to manufacture our product candidates. Healthy donor T cells vary in type and quality, and this variation makes producing standardized allogeneic CAR T product candidates challenging and makes the development and commercialization pathway of those product candidates uncertain.
Current wording
For our immuno-oncology programs, we are developing a pipeline of allogeneic T cell product candidates (including, for example, CTX112 and CTX131) that are engineered from healthy donor T cells to express chimeric antigen receptors, or CARs, and are intended for use in any patient with certain cancers. Unlike for autologous chimeric antigen receptor, or CAR T, therapies, for allogeneic CAR T therapies, we are reliant on receiving healthy donor material to manufacture our product candidates. Healthy donor T cells vary in type and quality, and this variation makes producing standardized allogeneic CAR T product candidates challenging and makes the development and commercialization pathway of those product candidates uncertain.
Previous wording
If significant GvHD or other adverse events are observed with the administration of our product candidates, or if any of the product candidates is viewed as less safe or effective than autologous therapies or other allogenic therapies, our ability to develop allogeneic therapies may be adversely affected.
Current wording
If significant GvHD or other adverse events are observed with the administration of our product candidates, or if any of the product candidates are viewed as less safe or effective than autologous therapies or other allogenic therapies, our ability to develop allogeneic therapies may be adversely affected.
Previous wording
CD19-directed genetically modified autologous T cell immunotherapies. FDA’s investigation into CAR T therapies and other similar actions could result in increased government regulation, unfavorable public perception and publicity, and, although we are developing allogeneic CAR T candidates, the FDA’s investigation could result in potential impacts on enrollment in our clinical trials, 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.
Current wording
Further, in November 2023, the FDA announced that it would be conducting an investigation into reports of T-cell malignancies following B-cell maturation antigen, or BCMA, directed or CD19-directed autologous CAR T cell immunotherapies following reports of T cell lymphoma in patients receiving these therapies. In January 2024, the FDA determined that new safety information related to T cell malignancies should be included in the labeling with boxed warning language on these malignancies for all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. FDA’s investigation into CAR T therapies and other similar actions could result in increased government regulation, unfavorable public perception and publicity, and, although we are developing allogeneic CAR T candidates, the FDA’s investigation could result in potential impacts on enrollment in our clinical trials, 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.
Previous wording
The FDA, The NIH 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, Which May Be Difficult To Predict.
Current wording
The FDA, MHRA 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, Which May Be Difficult To Predict.
Previous wording
The FDA, NIH and the EMA have each expressed interest in further regulating biotechnology, including gene therapy and genetic testing. For example, the EMA advocates a risk-based approach to the development of a gene therapy product. Agencies at both the federal and state level in the United States, as well as the U.S. congressional committees and other governments or governing agencies, have also expressed interest in further regulating the biotechnology industry. Such action may delay or prevent commercialization of some or all of our product candidates.
Current wording
The FDA, MHRA and the EMA have each expressed interest in further regulating biotechnology, including gene therapy and genetic testing. For example, the EMA advocates a risk-based approach to the development of a gene therapy product. Agencies at both the federal and state level in the United States, as well as the U.S. congressional committees and other governments or governing agencies, have also expressed interest in further regulating the biotechnology industry. Such action may delay or prevent commercialization of some or all of our product candidates.
Previous wording
Regulatory requirements in the United States and in other jurisdictions governing gene therapy products have changed frequently and may continue to change in the future. The FDA has issued several guidance documents on gene therapy products. The FDA established the Office of Therapeutic Products within its Center for Biologics Evaluation and Research to consolidate the review of gene therapy and related products, and established the Cellular, Tissue and Gene Therapies Advisory Committee to advise this review. In addition to the government regulators, the IBC and IRB of each institution at which we conduct clinical trials of our product candidates, or a central IRB if appropriate, would need to review the proposed clinical trial to assess the safety of the trial. In addition, adverse developments in clinical trials of gene therapy product candidates conducted by others may cause the FDA or other oversight authorities to change the requirements for approval of any of our product candidates. Similarly, the EMA governs the development of gene therapies in the EU and may issue new guidelines concerning the development and marketing authorization for gene therapy products and require that we comply with these new guidelines. These regulatory review agencies and committees and the new requirements or guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies or trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates or lead to significant post-approval limitations or restrictions. As we advance our product candidates and seek regulatory approval, we will be required to consult with these regulatory agencies and committees and comply with applicable requirements and guidelines. If we fail to do so, we may be required to delay or discontinue development of such product candidates. These additional processes may result in a review and approval process that is longer than we otherwise would have expected. Delays as a result of an increased or lengthier regulatory approval process or further restrictions on the development of our product candidates can be costly and could negatively impact our or our collaborators’ ability to complete clinical trials and commercialize our current and future product candidates in a timely manner, if at all.
Current wording
Regulatory requirements in the United States and in other jurisdictions governing gene therapy products have changed frequently and may continue to change in the future. The FDA has issued several guidance documents on gene therapy products. The FDA established the Office of Therapeutic Products within its Center for Biologics Evaluation and Research to consolidate the review of gene therapy and related products, and established the Cellular, Tissue and Gene Therapies Advisory Committee to advise this review. In addition to the government regulators, institutional biosafety committees and institutional review boards of each institution at which we conduct clinical trials of our product candidates, or a central institutional review board if appropriate, would need to review the proposed clinical trial to assess the safety of the trial. In addition, adverse developments in clinical trials of gene therapy product candidates conducted by others may cause the FDA or other oversight authorities to change the requirements for approval of any of our product candidates. Similarly, the EMA governs the development of gene therapies in the EU and may issue new guidelines concerning the development and marketing authorization for gene therapy products and require that we comply with these new guidelines. These regulatory review agencies and committees and the new requirements or guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies or trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our product candidates or lead to significant post-approval limitations or restrictions. As we advance our product candidates and seek regulatory approval, we will be required to consult with these regulatory agencies and committees and comply with applicable requirements and guidelines. If we fail to do so, we may be required to delay or discontinue development of such product candidates. These additional processes may result in a review and approval process that is longer than we otherwise would have expected. Delays as a result of an increased or lengthier regulatory approval process or further restrictions on the development of our product candidates can be costly and could negatively impact our or our collaborators’ ability to complete clinical trials and commercialize our current and future product candidates in a timely manner, if at all.
Previous wording
If Any Of The Product Candidates We May Develop Or Administration Processes We Rely On Cause Undesirable Side Effects, It Could Delay Or Prevent Their Regulatory Approval, Limit The Commercial Potential Or Result In Significant Negative Consequences Following Any Potential Marketing Approval.
Current wording
If Any Of The Product Candidates We May Develop Or Administration Processes And Delivery Modalities We Rely On Cause Undesirable Side Effects, It Could Delay Or Prevent Their Regulatory Approval, Limit The Commercial Potential Or Result In Significant Negative Consequences Following Any Potential Marketing Approval.
Previous wording
Immunotherapy, and its method of action of harnessing the body’s immune system, is powerful and could lead to serious side effects that we only discover in clinical trials. Unforeseen side effects could arise either during clinical development or, if such side effects are rare, after our product candidates have been approved by regulatory authorities and the approved product has been marketed, resulting in the exposure of additional patients. If our CRISPR/Cas9 gene editing technology demonstrates a similar effect, we may decide or be required to halt or delay preclinical development, clinical development or commercialization of our product candidates.
Current wording
Immunotherapy, and its method of action of harnessing the body’s immune system, is powerful and could lead to serious side effects that we only discover in clinical trials. Unforeseen side effects could arise either during clinical development or, if such side effects are rare, after our product candidates have been approved by regulatory authorities and the approved product has been marketed, resulting in the exposure of additional patients. If our CRISPR/Cas9 gene editing technology or delivery modalities we utilize demonstrate a similar effect, we may decide or be required to halt or delay preclinical development, clinical development or commercialization of our product candidates. For example, through internal efforts and external collaborations, we are pursuing the development of multiple delivery technologies, including LNPs, to support our current and futurein vivo product candidates. Possible adverse side effects that could occur with treatment with a product or product candidate utilizing such delivery modalities could include an immunologic reaction early after administration which, while not necessarily adverse to the patient’s health, could substantially limit the effectiveness of the treatment. While we have designed our proprietary LNP platform to minimize any LNP vehicle-related toxicities with repeat administrationin vivo by engineering amino lipids to avoid the immune system and to be rapidly biodegradable relative to prior LNP formulations, we cannot provide assurances that our product candidates utilizing our proprietary LNP platform or similar other delivery modalities will not activate one or more immune responses giving rise to potential immune reaction related adverse events, like liver toxicities or enzyme elevations.
Previous wording
In addition to serious adverse events or side effects caused by any product candidate we may develop, the administration process or related procedures also can cause undesirable side effects. For example, patients who receive CASGEVY or enroll in the ongoing CASGEVY clinical trials have their own CRISPR/Cas9 edited-hematopoietic stem and progenitor cells, CASGEVY, infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of a product candidate. Patients who enroll in our immunotherapy trials undergo a lymphodepletion regimen, which generally includes fludarabine and cyclophosphamide that may cause serious adverse events. Because these regimens will cause a transient and sometimes prolonged immune suppression, patients will have an increased risk of certain infections that may be unable to be cleared by the patient and could ultimately lead to death. Any side effects may not be appropriately recognized or managed by the treating medical staff. We or our collaborators expect to have to educate medical personnel using any product candidates we may develop to understand the side effect profiles for our clinical trials and upon any commercialization of such product candidates. Inadequate recognition or management of the potential side effects of such product candidates could result in patient injury or death. If any undesirable or unacceptable side effects, unexpected characteristics or other serious adverse events occur, our clinical trials or commercial distribution of any product candidates or products we develop alone or with collaborators could be suspended or terminated, and our business and reputation could suffer substantial harm.
Current wording
In addition to serious adverse events or side effects caused by any product candidate we may develop, the administration process or related procedures also can cause undesirable side effects. For example, patients who receive CASGEVY or enroll in the ongoing CASGEVY clinical trials have their own CRISPR/Cas9 edited-hematopoietic stem and progenitor cells, CASGEVY, infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of a product candidate. Patients who enroll in our immunotherapy trials undergo a lymphodepletion regimen, which generally includes fludarabine and cyclophosphamide that may cause serious adverse events. Because these regimens will cause a transient and sometimes prolonged immune suppression, patients will have an increased risk of certain infections that may be unable to be cleared by the patient and could ultimately lead to death.
Previous wording
If in the future we are unable to demonstrate that such adverse events were caused by factors other than our product candidate or approved products, the FDA, EMA or other comparable health regulatory authorities could order us to cease further clinical studies of, or deny approval of, any product candidates we are able to develop for any or all targeted indications or cease the sale of approved products. Even if we are able to demonstrate that all future serious adverse events are not product-related, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the trial. Moreover, if we elect, or are required, to delay, suspend or terminate any clinical trial of any product candidate, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated. Any of these occurrences may harm our ability to identify and develop product candidates, and may harm our business, financial condition, result of operations and prospects significantly.
Current wording
If in the future we are unable to demonstrate that such adverse events were caused by factors other than our product candidate or approved products, the FDA, EMA or other comparable regulatory authorities could order us to cease further clinical studies of, or deny approval of, any product candidates we are able to develop for any or all targeted indications or cease the sale of approved products. Even if we are able to demonstrate that all future serious adverse events are not product-related, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the trial. Moreover, if we elect, or are required, to delay, suspend or terminate any clinical trial of any product candidate, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated. Any of these occurrences may harm our ability to identify and develop product candidates and may harm our business, financial condition, result of operations and prospects significantly.
Previous wording
Additionally, if we successfully develop a product candidate and it receives marketing approval, the FDA could require us to adopt a Risk Evaluation and Mitigation Strategy, or REMS, to ensure that the benefits of treatment with such product candidate outweighs the risks for each potential patient, which may include, among other things, a medication guide outlining the risks of the product for distribution to patients, a communication plan to health care practitioners, extensive patient monitoring, or distribution systems and processes that are highly controlled, restrictive, and more costly than what is typical for the industry. Furthermore, if we or others later identify undesirable side effects caused by any product candidate that we develop alone or with our collaborators, several potentially significant negative consequences could result, including:
Current wording
Additionally, if we successfully develop a product candidate and it receives marketing approval, the FDA could require us to adopt a Risk Evaluation and Mitigation Strategy, or REMS, to ensure that the benefits of treatment with such product candidate outweighs the risks for each potential patient, which may include, among other things, a medication guide outlining the risks of the product for distribution to patients, a communication plan to health care practitioners, extensive patient monitoring, or distribution systems and processes that are highly controlled, restrictive, and more costly than what is typical for the industry. Furthermore, if we or others later identify undesirable side effects caused by any approved product or product candidate that we develop alone or with our collaborators, several potentially significant negative consequences could result, including:
Previous wording
regulatory authorities may revoke licenses or suspend, vary or withdraw approvals of such product candidate;
Current wording
regulatory authorities may revoke licenses or suspend, vary or withdraw approvals of such product or product candidate;
Previous wording
we may be required to change the way a product candidate is administered or conduct additional clinical trials;
Current wording
we may be required to change the way a product or product candidate is administered or conduct additional clinical trials;
Previous wording
Moreover, gene therapy product candidates investigated by other parties have resulted in serious adverse events, including deaths, and it is possible that the FDA or other regulatory authorities could impose a clinical hold on clinical trials of our product candidates after becoming aware of adverse events with products or product candidates in the same class as our product candidates.
Current wording
Moreover, gene therapy product candidates investigated by other parties have resulted in serious adverse events, including deaths, and it is possible that the FDA or other regulatory authorities could impose a clinical hold on clinical trials of our product candidates after becoming aware of adverse events with products or product candidates in the same class as our products or product candidates.
Previous wording
Any of these events could prevent us from achieving or maintaining market acceptance of our gene editing technology and any product candidates we may identify and develop and could have a material adverse effect on our business, financial condition, results of operations and prospects.
Current wording
Any of these events could prevent us from achieving or maintaining market acceptance of our gene editing technology and any products or product candidates we may identify and develop and could have a material adverse effect on our business, financial condition, results of operations and prospects.
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Current report — wording carried from elsewhere
We aim to develop treatments and therapies for people suffering from serious diseases through transformative gene-based medicines, includingex vivo engineered cell therapies andin vivo therapies. Although there have been significant advances in recent years in the fields of gene therapy and genome editing, including CRISPR/Cas9 gene editing technology, such technologies, includingin vivo CRISPR-based genome editing technologies in particular, are relatively new and only a limited number of clinical trials of product candidates based on such gene editing technologies have been commenced and their therapeutic utility is largely unproven. As such it is difficult to accurately predict the developmental challenges we may incur for our product candidates as they proceed through product discovery or identification, preclinical studies and clinical trials. For example, no genome editingin vivo therapy has been approved in the United States, EU or other key jurisdictions. While we and our partner, Vertex, have received marketing approvals for
Current report — wording carried from elsewhere
Any side effects may not be appropriately recognized or managed by the treating medical staff. We or our collaborators expect to have to educate medical personnel using any product or product candidates we may develop to understand the side effect profiles for our clinical trials and upon any commercialization of such product or product candidates. Inadequate recognition or management of the potential side effects of such product or product candidates could result in patient injury or death. If any undesirable or unacceptable side effects, unexpected characteristics or other serious adverse events occur, our clinical trials or commercial distribution of any product candidates or products we develop alone or with collaborators could be suspended or terminated, and our business and reputation could suffer substantial harm.
Current report — wording carried from elsewhere
There can be no assurance that the FDA would allow any of the product candidates we may develop to proceed on an accelerated approval pathway, and even if the FDA did allow such pathway, there can be no assurance that such submission or application will be accepted or that any expedited development, review or approval will be granted on a timely basis, or at all.. Moreover, the FDA is empowered to take action, such as issuing fines, against companies that fail to conduct with due diligence any post-approval confirmatory study or submit timely reports to the agency on their progress. The FDA may further withdraw approval of a drug or biologic granted accelerated approval on an expedited basis if the sponsor fails to conduct such studies in a timely manner, send the necessary updates to the FDA, or if such post-approval studies fail to verify the drug’s predicted clinical benefit. Accordingly, even if we received accelerated approval, any post-approval studies required to confirm and verify clinical benefit may not show such benefit, which could lead to withdrawal of any approvals we have obtained. Receiving accelerated approval does not assure that the product’s accelerated approval will eventually be converted to a traditional approval.
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In particular, gene editing technology is subject to public debate and heightened regulatory scrutiny due to ethical concerns relating to the application of gene editing technology to human embryos or the human germline. Public attitudes may be influenced by claims that gene editing is unsafe, unethical, or immoral, and, consequently, our product candidates may not gain the acceptance of the public or the medical community. Adverse public attitudes may adversely impact our ability to enroll clinical trials. Moreover, our success will depend upon physicians prescribing, and their patients being willing to receive, treatments that involve the use of product candidates we may develop in lieu of, or in addition to, existing treatments with which they are already familiar and for which greater clinical data may be available.
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The strength of patents in the biotechnology and pharmaceutical field generally, and the gene-editing field in particular, involves complex legal and scientific questions and can be uncertain. Changes in either the patent laws or their interpretation in the United
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The patent prosecution process is expensive, time-consuming, and complex, and we may not be able to file, prosecute, maintain, enforce, or license all necessary or desirable patent applications at a reasonable cost or in a timely manner. Given the amount of time required for the development, testing and regulatory review of new product candidates, or if we encounter delays in our clinical trials, patents protecting our product candidates might expire before or shortly after such candidates are commercialized. It is also possible that we will fail to identify patentable aspects of our research and development output in time to obtain patent protection. Although we enter into non-disclosure and confidentiality agreements with parties who have access to confidential or patentable aspects of our research and development output, such as our employees, corporate collaborators, outside scientific collaborators, contract research organizations, contract manufacturers, consultants advisors, and other third parties, any of these parties may breach the agreements and disclose such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection. See, for example,“Risk Factors —Risks Related to Intellectual Property—If We Are Unable To Protect The Confidentiality Of Our Trade Secrets And Other Proprietary Information, Our Business And Competitive Position Would Be Harmed.”
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Competitors may claim that they invented the inventions claimed in such issued patents or patent applications prior to our inventors, or may have filed patent applications before our inventors did. Competitors may also claim that our products and technology infringe its patents and that we therefore cannot practice our technology as claimed under our patent applications, if issued.
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The outcome following legal assertions of invalidity and unenforceability is unpredictable, and such challenges, after exhausting available appeals, may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, revoked, withdrawn, invalidated or held unenforceable, in whole or in part, which could limit our ability to practice the invention or 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.
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Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar material adverse effect on our business, financial condition, results of operations, and prospects.
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Any of these outcomes could materially harm our business and could prevent us from further developing and commercializing such products or future product candidates, thereby causing us significant harm. In addition, third parties asserting their patent rights against us may seek and obtain injunctive or other equitable relief, which could effectively limit or block our ability to further develop and commercialize our product candidates.
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In order to successfully challenge the validity of any such third party U.S. patent in federal court, we would need to overcome a presumption of validity. As this burden is a high one requiring us to present clear and convincing evidence as to the invalidity of any such U.S. patent claim, there is no assurance that a court of competent jurisdiction would invalidate the claims of any such U.S. patent and such court could hold that any such third-party patents are valid, enforceable, and infringed, which could materially and adversely affect our ability to commercialize any product candidates we may develop and any other product candidates or technologies covered by the asserted third-party patents.
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If any third party were to succeed in its interference and prevail in their claims of being first-to-invent, or obtain patent claims that cover our product candidates or related activities through these various legal proceedings, such party could seek to assert its issued patents against us based on our business activities, including commercialization of any CRISPR/Cas9-based product or product candidate. Moreover, in such event, we may be required to obtain licenses from such third parties, which may not be available on commercially reasonable terms or at all. See, for example,“Risk Factors —Risks Related to Intellectual Property—The Intellectual Property Landscape Around Gene Editing Technology, Including CRISPR/Cas9, Is Highly Dynamic, And Third Parties May Initiate And Prevail In Legal Proceedings Alleging That The Patents That We In-License Or Own Are Invalid Or That We Are Infringing, Misappropriating, Or Otherwise Violating Their Intellectual Property Rights, The Outcome Of Which Would Be Uncertain And Could Have A Material Adverse Effect On The Success Of Our Business.”and“We May Not Be Successful In Obtaining Or Maintaining Necessary Rights To Any Product Candidates or Other Technologies We May Develop Through Acquisitions And In-Licenses.”
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We are unable to predict the outcome of any of these matters and are unable to make a meaningful estimate of the amount or range of loss, if any, that could result from an unfavorable outcome in any current or future proceeding related to our intellectual property position. Any of these events could have a material adverse effect on our competitive position, business, financial conditions, results of operations, and prospects, and limit our ability to research, develop and obtain approval of product candidates, or to commercialize products.
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successful completion of clinical trials and preclinical studies;
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Further, in November 2023, the FDA announced that it would be conducting an investigation into reports of T-cell malignancies following BCMA-directed or CD19-directed autologous chimeric antigen receptor, or CAR T cell immunotherapies following reports of T cell lymphoma in patients receiving these therapies. In January 2024, the FDA determined that new safety information related to T cell malignancies should be included in the labeling with boxed warning language on these malignancies for all BCMA- and
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Be Able To Have Competing Products Approved By The Applicable Regulatory Authority For A Significant Period Of Time.
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the willingness of physicians to prescribe new therapies;
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Parties—We Have Partnered With Vertex On Our Lead Program CASGEVY; Vertex Has Significant Control Over The CAGEVY Program.”
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We have entered into strategic collaborations and licenses, including, for example, with Vertex, and may enter into additional collaborations and licenses with other third parties in the future. For some programs, we also depend on, or may in the future depend on, third-party collaborators and strategic partners to design and conduct our clinical trials, and for any approved products, the commercialization of such products. Some of these collaborations provide us with important technologies in order to more fully develop our product candidates and we may enter into collaborations with other companies to provide us with important technologies or funding for our programs. The success of these arrangements will depend heavily on the efforts and activities of our collaborators and licensing partners.
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Although we expect all of our employees and consultants to assign their inventions to us, and all of our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information or technology to enter into confidentiality agreements, we cannot provide any assurances that all such agreements have been duly executed or that our trade secrets and other confidential proprietary information will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially equivalent information and techniques. Misappropriation or unauthorized disclosure of our trade secrets could impair our competitive position and may have a material adverse effect on our business. Additionally, if the steps taken to maintain our trade secrets are deemed inadequate, we may have insufficient recourse against third parties for misappropriating the trade secret. In addition, others may independently discover our trade secrets and proprietary information. For example, the FDA, as part of its Transparency Initiative, is currently considering whether to make additional information publicly available on a routine basis, including information that we may consider to be trade secrets or other proprietary information, and it is not clear at the present time how the FDA’s disclosure policies may change in the future, if at all.
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Further, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result, we may encounter significant problems in protecting and defending our intellectual property both in the United States and abroad. If we are unable to prevent material disclosure of the non-patented intellectual property related to our technologies to third parties, and there is no guarantee that we will have any such enforceable trade secret protection, we may not be able to establish or maintain a competitive advantage in our market, which could materially adversely affect our business.
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Our commercial success depends in part on our avoiding infringement of the valid patents and proprietary rights of third parties.
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Third-party Claims Of Intellectual Property May Prevent Or Delay Our Product Discovery and Development Efforts.
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Further, in June 2019, the USPTO declared a second interference (Interference No. 106,115, or ‘115 interference) between fourteen (14) pending U.S. patent applications co-owned by the CVC Group and thirteen (13) patents and a patent application co-owned by the Broad. The Broad patents include those that were the subject of the ‘048 interference. In September 2020, the PTAB issued an order that, among other matters, advanced the proceeding to the priority phase. In February 2022, PTAB issued a Decision of Priority and Judgment finding that Broad has priority over CVC Group with respect to the subject matter of the interference. The CVC Group has appealed this decision to the Federal Circuit. Any final decision by the Federal Circuit can be further appealed to the Supreme Court.
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Each of the CVC Group, the Broad, ToolGen, Vilnius University, MilliporeSigma and Harvard University can pursue existing or new patent applications in the United States and elsewhere. Because the CVC Group and these other third parties all allege owning intellectual property claiming overlapping aspects of CRISPR/Cas9 systems and methods to edit DNA in eukaryotic cells, including human cells, our ability to market and sell CRISPR/Cas9-based human therapeutics may be adversely impacted depending on the scope and actual ownership over the inventions claimed in the competing patent portfolios.
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In any case, it may be years before there is a final determination on priority. Pursuant to the terms of the license agreement with Dr. Charpentier, we are responsible for covering or reimbursing Dr. Charpentier’s patent prosecution, defense and related costs associated with our in-licensed technology.
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In addition to seeking patents for some of our technology and product candidates, we also rely on trade secrets and confidentiality agreements to protect our unpatented know-how, technology, and other proprietary and confidential information and to maintain our competitive position. Trade secrets and know-how can be difficult to protect. In particular, we anticipate that with respect to our technology platform, these trade secrets and know-how will over time be disseminated within the industry through independent development, the publication of journal articles describing the methodology, and the movement of personnel from academic to industry scientific positions.
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In addition, we must also ensure that we maintain adequate safeguards to enable the transfer of personal data outside of the EEA or the UK, in particular to the United States, in compliance with European data protection laws. In some cases, we rely upon the recently updated standard contractual clauses (new standard contractual clauses) to legitimize transfers of personal data out of the