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If we fail to comply with these regulations or to maintain these approvals our business could be materially harmed.
−Removed: ● Our resources might be adversely affected if we are unable to successfully complete pre-approval inspections required by regulators or meet our supply needs and obligations, which could adversely affect our ability to sufficiently meet our future production needs or regulatory filing or approval timelines.
−Removed: ● We cannot predict when or if we will obtain marketing approval to commercialize any of our product candidates, or whether they will be commercially successful once approved.
−Removed: If we are unable to successfully commercialize our product candidates or experience significant delays in doing so, our business could be materially harmed.
+Added: ● We cannot predict when our partner, CSL Behring, will obtain marketing approval to commercialize the product candidate for Hemophilia B, when or if a first sale of etranacogene dezaparvovec occurs, or whether etranacogene dezaparvovec will be commercially successful once approved.
+Added: If our partner is unable to achieve marketing approval and successfully commercializes etranacogene dezaparvovec or experiences significant delays in doing so, our business could be materially harmed.
● We are exposed to a number of external factors such as competition, insurance coverage of and pricing and reimbursement for our product candidates that may adversely affect our product revenue and that may cause our business to suffer.
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In addition, the Covid pandemic has affected and may continue to affect the operations of the FDA, EMA, and other health authorities, which could result in delays of reviews and approvals, including with respect to our product candidates.
−Removed: As evidenced by the postponement of procedures for two patients in our Phase I/II clinical study of AMT-130 in 2020, the evolving Covid pandemic has impacted the pace of enrollment and procedures in our clinical trials, as well as caused challenges in scheduling follow-up visits and managing other aspects of our clinical trials.
−Removed: We may in the future be affected by similar delays as patients may avoid or may not be able to travel to healthcare facilities and physicians’ offices unless due to a health emergency and clinical trial staff may no longer be able to get to the clinic due to restrictions or illness.
−Removed: Such facilities and offices have been and may continue to be required to focus limited resources on non-clinical trial matters, including treatment of Covid patients, thereby decreasing availability, in whole or in part, for clinical trial services.
−Removed: In addition, employee disruptions and remote working environments related to the Covid pandemic, and federal, state, and local public health measures designed to mitigate the spread of the virus, have impacted, and could continue to negatively impact the efficiency and pace with which we work and develop our product candidates and our manufacturing capabilities.
−Removed: Further, while the potential economic impact brought by, and the duration of, the Covid pandemic is difficult to assess or predict, the impact of the Covid pandemic on global financial markets may reduce our ability to access capital, which could negatively impact our long-term liquidity.
−Removed: The ultimate impact of the Covid pandemic is highly uncertain and subject to change.
−Removed: We do not yet know the full extent of potential delays or impacts on our business, financing, or clinical trial activities or on healthcare systems or the global economy as a whole.
−Removed: However, these negative effects could have a material impact on our liquidity, capital resources, operations, and business and those of the third parties on whom we rely.
Global supply chains have been disrupted, causing shortages, which could further impact our clinical trials.
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For example, we experienced an immaterial but unexpected delay when our clinical trials of etranacogene dezaparvovec were placed on clinical hold by the FDA from December 2020 to April 2021, following a preliminary diagnosis of hepatocellular carcinoma in one patient.
+Added: Similarly, we experienced an unexpected delay in the enrollment of our Phase Ib/II clinical trial for Huntington’s disease as a result of comprehensive safety investigation into suspected unexpected serious adverse reactions in three patients between July and October 2022.
We cannot guarantee that any preclinical tests or clinical trials will be completed as planned or completed on schedule, if at all.
−Removed: In July 2022, we learned that three patients of the 14 patients that were treated with the higher dose of AMT-130 in our Phase Ib/II clinical trial for Huntington’s disease had experienced certain serious adverse reactions that were potentially attributable to AMT-130.
−Removed: The reactions in these three patients each have been classified as suspected unexpected serious adverse reactions (“SUSARs”).
−Removed: Based on the recommendation of the independent Data Safety Monitoring Board for the clinical trial (“DSMB”) after review of these SUSARs, we have postponed further enrollment and dosing of high dose patients until we conduct a comprehensive safety review with the DSMB.
−Removed: We do not currently know what the outcome of this safety review will be.
−Removed: Moreover, in accordance with regulatory requirements, we have reported these adverse reactions, the DSMB’s recommendations, and our implementation of the recommendations to the applicable regulatory authorities.
−Removed: We do not currently know whether the regulatory authorities will require or recommend that we take further actions.
A failure of one or more preclinical tests or clinical trials can occur at any stage of testing.
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● difficulty or delays in patient recruiting into clinical trials or in the addition of new investigators;
−Removed: ● the impact of the COVID-19 pandemic on the healthcare system or any clinical trial sites;
● delays or deviations in the testing, validation, manufacturing, and delivery of our product candidates to the clinical sites;
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Regulatory authorities may also be delayed in completing their review of any marketing applications submitted by us or our partners.
−Removed: By example, due to the ongoing COVID-19 pandemic, regulatory authorities may not be able to complete the pre-approval inspections that are required for approval of a marketing application.
Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application, may decide that our data are insufficient for approval, may require additional preclinical, clinical, or other studies and may not complete their review in a timely manner.
Further, any marketing approval we ultimately obtain may be for only limited indications or be subject to stringent labeling or other restrictions or post-approval commitments that render the approved product not commercially viable.
−Removed: If we experience delays in obtaining marketing approval for any of our product candidates in the United States, the European Union, or other countries, the commercial prospects of our other product candidates may be harmed and our ability to generate revenues will be materially impaired.
+Added: Our partner, CSL Behring, is currently pursuing the approval of etranacogene dezaparvovec for which marketing authorization applications are currently under review in the United States and European Union.
+Added: If CSL Behring experiences delays in obtaining marketing approval in the United States, the European Union, or other countries, the commercial prospects of etranacogene dezaparvovec and our ability to achieve contractual milestone payments and royalties on net sales may be harmed and our ability to generate revenues might be materially impaired.
The risks associated with the marketing approval process are heightened by the status of our products as gene therapies.
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● obtaining and maintaining patent and trade secret protection and non-patent, orphan drug exclusivity for our product candidates;
−Removed: ● obtaining and maintaining regulatory approvals using our manufacturing facility in Lexington, Massachusetts;
+Added: ● maintaining regulatory approvals using our manufacturing facility in Lexington, Massachusetts;
● launch and commercialization of our products, if approved, whether alone or in collaboration with others;
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and EU markets.
+Added: CSL Behring may not receive a conditional marketing authorization based on an accelerated assessment by the EMA for AMT-061 product candidate to facilitate a first commercial sale in the European Union on or before July 1, 2023, and we, thus, may not receive the $75.0 million first commercial sale milestone in any of the five contractually defined European countries as of or prior to July 1, 2023 under the CSL Behring Agreement.
By example, even if our product candidates are approved, they may be subject to limitations that make commercialization difficult.
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A failure to gain market acceptance for any of the above reasons, or any reasons at all, by a gene therapy for which we receive regulatory approval would likely hinder our ability to recapture our substantial investments in that and other gene therapies and could have a material adverse effect on our business, financial condition, and results of operation.
−Removed: If we are unable to expand our commercialization capabilities or enter into agreements with third parties to market and sell any of our product candidates for which we obtain marketing approval, we may be unable to generate any product revenue.
−Removed: To successfully commercialize any products that may result from our development programs, we need to continue to expand our commercialization capabilities, either on our own or with others.
−Removed: The development of our own market development effort is, and will continue to be, expensive and time-consuming and could delay any product launch.
−Removed: Moreover, we cannot be certain that we will be able to successfully develop this capability.
−Removed: We may enter into collaborations regarding our other product candidates with other entities to utilize their established marketing and distribution capabilities, but we may be unable to enter into such agreements on favorable terms, if at all.
−Removed: If any current or future collaborators do not commit sufficient resources to commercialize our products, or we are unable to develop the necessary capabilities on our own, we will be unable to generate sufficient product revenue to sustain our business.
−Removed: We compete with many companies that currently have extensive, experienced and well-funded medical affairs, marketing, and sales operations to recruit, hire, train and retain marketing and sales personnel.
−Removed: We also may face competition in any search for third parties to assist us with the sales and marketing efforts of our product candidates.
−Removed: Without an internal team or the support of a third party to perform marketing and sales functions, we may be unable to compete successfully against these more established companies.
If the market opportunities for our product candidates are smaller than we believe they are, our product revenues may be adversely affected, and our business may suffer.
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Our business development strategy may not produce the cash flows expected or could result in additional costs and challenges.
−Removed: Any business development transaction, including the recent acquisition of Corlieve Therapeutics SAS (“Corlieve”), could expose us to unknown liabilities and risks, and we may incur additional costs and expenses necessary to address an acquired company’s failure to comply with laws and governmental rules and regulations.
+Added: Any business development transaction could expose us to unknown liabilities and risks, and we may incur additional costs and expenses necessary to address an acquired company’s failure to comply with laws and governmental rules and regulations.
We could incur additional costs related to resources to align our business practices and operations.
Moreover, we cannot assure that the anticipated benefits of any acquisition would be realized in a timely manner, if at all.
−Removed: Additionally, the product candidate and intellectual property rights that we acquired in the acquisition of Corlieve were developed and owned by Corlieve and its licensors and we have not yet demonstrated an ability to develop, advance, or run clinical trials with this product candidate.
−Removed: As a result, we cannot ensure that we will be able to successfully advance this product candidate going forward.
+Added: Additionally, the product candidate and intellectual property rights that we acquired in the acquisition of Corlieve were developed and owned by Corlieve and its licensors and we cannot ensure that we will be able to continue to successfully advance this product candidate going forward.
Risks Related to Pricing and Reimbursement
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Risks Related to Our Financial Position and Need for Additional Capital
−Removed: We had a gain in the year ended December 31, 2021, but incurred significant losses in previous years and expect to incur losses over the next several years and may never achieve or maintain profitability.
−Removed: We had a net loss of $85.7 million in the six months ended June 30, 2022, and a net gain of $329.6 million in the full year 2021.
−Removed: As of June 30, 2022, we had an accumulated deficit of $540.9 million.
+Added: We had a gain in the year ended December 31, 2021, but incurred significant losses in previous years and expect to incur losses during the current and over the next several years and may never achieve or maintain profitability.
+Added: We had a net loss of $133.6 million in the nine months ended September 30, 2022, and a net gain of $329.6 million in the full year 2021.
+Added: As of September 30, 2022, we had an accumulated deficit of $588.7 million.
In the past, we have financed our operations primarily through the sale of equity securities and convertible debt, venture loans, upfront payments from our collaboration partners and, to a lesser extent, subsidies and grants from governmental agencies and fees for services.
−Removed: We expect to finance our operations in 2022 and 2023 primarily from payments we collected and expect to collect in relation to the CSL Behring Agreement.
+Added: We expect to finance our operations in 2022 and 2023 primarily from our existing cash resources including payments we collected and expect to collect in relation to the CSL Behring Agreement.
We have devoted substantially all our financial resources and efforts to research and development, including preclinical studies and clinical trials.
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Our existing and any future indebtedness could adversely affect our ability to operate our business.
−Removed: As of June 30, 2022, we had $100.0 million of outstanding principal of borrowings under the 2021 Restated Facility, which we are required to repay in equal installments between December 2024 and December 2025 or in full in December 2025 if, prior to June 30, 2024, either (a) the BLA for AMT-061 is approved by the FDA or (b) AMT-130 is advanced into a pivotal trial.
+Added: As of September 30, 2022, we had $100.0 million of outstanding principal of borrowings under the 2021 Restated Facility, which we are required to repay in equal installments between December 2024 and December 2025 or in full in December 2025 if, prior to June 30, 2024, either (a) the BLA for AMT-061 is approved by the FDA or (b) AMT-130 is advanced into a pivotal trial.
We could in the future incur additional debt obligations beyond our borrowings from Hercules.
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Our share price has been and may in the future be volatile.
−Removed: From the start of trading of our ordinary shares on the Nasdaq Global Select Market on February 4, 2014 through August 3, 2022, the sale price of our ordinary shares ranged from a high of $82.49 to a low of $4.72.
−Removed: The closing price on August 3, 2022, was $24.59 per ordinary share.
+Added: From the start of trading of our ordinary shares on the Nasdaq Global Select Market on February 4, 2014 through October 28, 2022, the sale price of our ordinary shares ranged from a high of $82.49 to a low of $4.72.
+Added: The closing price on October 28, 2022, was $19.04 per ordinary share.
The stock market in general and the market for smaller biopharmaceutical companies in particular, have experienced extreme volatility that has often been unrelated to the operating performance of particular companies.
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Our directors, executive officers, and major shareholders, if they choose to act together, will continue to have a significant degree of control with respect to matters submitted to shareholders for approval.
−Removed: Our directors, executive officers and major shareholders holding more than 5% of our outstanding ordinary shares, in the aggregate, beneficially own approximately 54.3% of our issued shares (including such shares to be issued in relation to exercisable options to purchase ordinary shares) as of June 30, 2022.
+Added: Our directors, executive officers and major shareholders holding more than 5% of our outstanding ordinary shares, in the aggregate, beneficially own approximately 55.4% of our issued shares (including such shares to be issued in relation to exercisable options to purchase ordinary shares) as of September 30, 2022.
As a result, if these shareholders were to choose to act together, they may be able, as a practical matter, to control many matters submitted to our shareholders for approval, as well as our management and affairs.
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.