−Removed: This Quarterly Report on Form 10-Q contains forward-looking statements that involve substantial risks and uncertainties.
−Removed: All statements, other than statements of historical facts, contained herein, including statements regarding our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans and objectives of our management are forward-looking statements.
−Removed: These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.
−Removed: The words “anticipate,” “believe,” “estimate,” “expect,” “goal,” “intend,” “may,” “plan,” “predict,” “project,” “strategy,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” “vision” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
−Removed: We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements.
−Removed: Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make.
−Removed: You should read this Quarterly Report on Form 10-Q completely and with the understanding that our actual future results may be materially different from what we expect.
−Removed: The risks described are not the only risks facing our company.
−Removed: Additional risks and uncertainties not currently known to us or that we currently deem to be immaterial also may materially adversely affect our business, financial condition and/or operating results.
−Removed: We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.
−Removed: These risk factors restate and supersede the risk factors set forth under the heading “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2020.
−Removed: Summary Risk Factors
−Removed: Our business is subject to a number of risks that if realized could materially affect our business, financial condition, results of operations, cash flows and access to liquidity.
−Removed: These risks are discussed more fully below.
−Removed: Our principal risks include the following:
−Removed: • We may not be able to realize the anticipated benefits of the recent sale of our oncology business to Servier, including deploying the proceeds to expand our GDD business, and we may face new challenges as a smaller, less diversified company.
−Removed: • If our existing capital is insufficient to execute our operating plan through major catalysts and to cash-flow positivity, we will need to raise capital, and if we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate our product development programs or commercialization efforts.
−Removed: • We have historically incurred operating losses.
−Removed: We expect to incur losses in the future and may never achieve or maintain profitability.
−Removed: Our net income for the nine months ended September 30, 2021 was $1,699.3 million and our net loss for the nine months ended September 30, 2020 was $229.7 million.
−Removed: The net income we generated in the nine months ended September 30, 2021 was primarily due to the sale of our oncology business to Servier, which was consummated on March 31, 2021.
−Removed: As of September 30, 2021, we had an accumulated deficit of $144.1 million.
−Removed: • The amount of contingent consideration we will receive from the sale of our oncology business to Servier is subject to various risks and uncertainties.
−Removed: • We depend heavily on the success of our clinical product candidates, including our lead product candidate mitapivat.
−Removed: Clinical trials of our product candidates may not be successful for a number of important reasons.
−Removed: If we or our collaborators are unable to commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.
−Removed: • The COVID-19 pandemic has and may continue to affect our ability to initiate or continue our planned, ongoing and future clinical trials, disrupt regulatory activities, or have other adverse effects on our business and operations.
−Removed: • We may not be successful in our efforts to identify or discover potential product candidates or to develop medicines of commercial value and we may not achieve our goals included in our strategic vision.
−Removed: • Even if any of our product candidates receives marketing approval, we or others may later discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.
−Removed: • Even if any of our product candidates receive marketing approval, they may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.
−Removed: • We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.
−Removed: There are a number of large pharmaceutical and biotechnology companies that
−Removed: currently market and sell products or are pursuing the development of products for the treatment of the disease indications for which we are developing our product candidates.
−Removed: • We currently rely, and expect to continue to rely, on third-party manufacturers for the materials and manufacture of our product candidates for preclinical and clinical testing and we expect to rely on third-party manufacturers for commercial supply of any product candidate for which we or our collaborators obtain marketing approval.
−Removed: Any performance failure on the part of our existing or future third-party manufacturers could delay clinical development or marketing approval.
−Removed: • If we are unable to obtain and maintain patent or trade secret protection for our medicines and technology, or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize medicines and technology similar or identical to ours, and our ability to successfully commercialize our medicines and technology may be adversely affected.
−Removed: If we do not, or are unable to, obtain or maintain any issued patents for any of our lead product candidates, it could have a material adverse effect on our competitive position, business, financial condition, results of operations, and prospects.
−Removed: Risks Related to Our Financial Position
−Removed: We may not be able to realize the anticipated benefits of the recent sale of our oncology business to Servier and we may face new challenges as a smaller, less diversified company.
−Removed: We may not be able to realize the anticipated benefits from the recent sale of our oncology business to Servier, including deploying the proceeds from the transaction to expand our GDD business.
−Removed: Our ability to realize the anticipated benefits of the transaction and the success of the GDD business is subject to various risks and uncertainties, including the possibility of adverse clinical and other developments in respect of mitapivat or other pipeline products of the GDD business, the possibility that we may not be able to successfully develop and commercialize products based on PK activation and cellular metabolism and unanticipated changes in applicable laws and regulations that may adversely affect the GDD business.
−Removed: We developed most of our initial products and product candidates for the treatment of various types of cancer.
−Removed: The sale of our oncology business to Servier, including all of our approved products, resulted in us being a smaller, less diversified company with a more limited business concentrated on product candidates for the treatment of GDDs.
−Removed: As a result, we may be more susceptible to changing market conditions, including fluctuations and risks particular to the markets for patients with GDDs, than a more diversified company, which could adversely affect our business, financial condition and results of operations.
−Removed: In addition, the diversification of our revenues, costs and cash flows will diminish following the transaction, such that our results of operations, cash flows, working capital and financing requirements may be subject to increased volatility and our ability to fund capital expenditures and investments or satisfy other financial commitments may be diminished.
−Removed: We may also face new challenges with maintaining employee morale, retaining key management and other employees and attracting new employees and retaining existing business and operational relationships, including with third parties, employees and other counterparties that otherwise prefer to transact with larger companies (or will only transact with smaller companies on less favorable terms).
−Removed: We have broad discretion as to the use of the proceeds from the sale of our oncology business to Servier, and we may not use the proceeds effectively.
−Removed: We have broad discretion with respect to the use of proceeds of the sale of our oncology business to Servier.
−Removed: The results and effectiveness of the use of proceeds, including the repurchase of up to $1.2 billion of our outstanding shares of common stock, are uncertain, and we could spend the proceeds in ways that do not improve our remaining business, financial condition or results of operations.
−Removed: Our failure to apply these funds effectively could have an adverse effect on its business, financial condition and results of operations.
−Removed: Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.
−Removed: Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs primarily through cash on hand, royalty payments from Servier with respect to U.S.
−Removed: net sales of TIBSOVO®, a potential milestone payment from Servier if vorasidenib is approved by the FDA and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
−Removed: In addition, in connection with potential future strategic transactions, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.
−Removed: We do not have any committed potential external source of funds other than the potential milestone and royalty payments that we are eligible to receive under our purchase agreement with Servier.
−Removed: To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our common stockholders.
−Removed: Debt financing, if available, may require us to enter into agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.
−Removed: In addition, securing financing could require a substantial amount of time and
−Removed: attention from our management and may divert a disproportionate amount of their attention away from day-to-day activities, which may adversely affect our management’s ability to oversee the development of our product candidates.
−Removed: If we raise funds through collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or to grant licenses on terms that may not be favorable to us.
−Removed: If our existing capital is insufficient to execute our operating plan through major catalysts and to cash-flow positivity, we will need to raise capital, and if we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate our product development programs or commercialization efforts.
−Removed: We expect to incur significant expenses as we continue to advance our ongoing activities.
−Removed: We expect to execute our operating plan through major catalysts and to cash-flow positivity without the need to raise additional equity.
−Removed: Our estimate as to how long we expect our existing cash, cash equivalents, and marketable securities to be available to fund our operating plan is based on assumptions that may prove to be wrong, and we could use our available capital resources sooner than we currently expect.
−Removed: Further, changing circumstances, some of which may be beyond our control, could cause us to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds.
−Removed: Our future capital requirements will depend on many factors, including:
−Removed: • the amount of contingent consideration we ultimately receive in connection with the sale of our oncology business to Servier;
−Removed: • the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our product candidates;
−Removed: • the costs, timing and outcome of regulatory review of our product candidates;
−Removed: • the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims;
−Removed: • the costs and timing of future commercialization activities, including product manufacturing, sales, marketing and distribution, for any of our product candidates for which we may receive marketing approval;
−Removed: • the amount and timing of revenue, if any, received from commercial sales of our product candidates for which we receive marketing approval;
−Removed: • our ability to establish and maintain collaborations on favorable terms, if at all;
−Removed: • our ability to successfully execute on our strategic plans;
−Removed: • operational delays due to the COVID-19 pandemic;
−Removed: • the extent to which we acquire or in-license, or monitor or out-license, other medicines and technologies.
−Removed: We have historically incurred operating losses.
−Removed: We expect to incur losses in the future and may never achieve or maintain profitability.
−Removed: We have historically incurred operating losses.
−Removed: Our net income for the nine months ended September 30, 2021 was $1.7 billion and our net loss for the nine months ended September 30, 2020 was $229.7 million.
−Removed: The net income we generated in the nine months ended September 30, 2021 was primarily due to the sale of our oncology business to Servier, which was consummated on March 31, 2021.
−Removed: As of September 30, 2021, we had an accumulated deficit of $144.1 million.
−Removed: Prior to the sale of our oncology business to Servier, we had generated only modest revenue from sales of TIBSOVO® and, prior to our sale to Royalty Pharma, or RPI, of our royalty rights to IDHIFA®, royalties on sales of IDHIFA®.
−Removed: Other than the FDA approvals of TIBSOVO® (for the treatment of IDH1 mutant-positive adult patients with relapsed or refractory acute myeloid leukemia, R/R AML, or newly diagnosed AML who are at least 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy) and IDHIFA® (for the treatment of IDH2 mutant-positive adult patients with R/R AML), the rights to both of which we have sold to Servier, we have not obtained marketing approval for any of our product candidates, all of which are in preclinical or clinical development stages.
−Removed: In June 2021, we submitted an NDA to the FDA for mitapivat for the treatment of adults with PK deficiency, which was accepted with priority review and granted a Prescription Drug User Fee Act, or PDUFA, action date of February 17, 2022, and a MAA, for mitapivat in adults with PK deficiency to the EMA.
−Removed: We have financed our operations primarily through public offerings of our common stock and our collaboration agreements with Celgene and have devoted substantially all of our efforts to research and development.
−Removed: Following the sale of our oncology business to Servier on March 31, 2021, we expect to finance our operations primarily through cash on hand, royalty payments from Servier with respect to U.S.
−Removed: net sales of TIBSOVO®, a potential milestone payment from Servier if vorasidenib is approved by the FDA, future potential sales of mitapivat, if approved for marketing by regulatory authorities and successfully launched by us and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
−Removed: We expect to continue to incur significant expenses and net losses until such time as we are able to report
−Removed: profitable results.
−Removed: The net losses we incur may fluctuate significantly from quarter to quarter.
−Removed: We anticipate that we will incur significant expenses if and as we:
−Removed: • initiate and continue clinical trials for our product candidates;
−Removed: continue our research and preclinical development of our product candidates and seek to identify additional product candidates;
−Removed: • seek marketing approvals for our product candidates that successfully complete clinical trials;
−Removed: • establish and maintain a sales, marketing and distribution infrastructure to commercialize any medicines for which we may obtain marketing approval;
−Removed: • require the manufacture of larger quantities of product candidates for clinical development and, potentially, commercialization;
−Removed: • maintain, expand and protect our intellectual property portfolio;
−Removed: • add additional personnel to support our product research and development and planned future commercialization efforts and our operations;
−Removed: • add equipment and physical infrastructure to support our research and development;
−Removed: • acquire or in-license other medicines and technologies.
−Removed: To become and remain profitable, we must develop and eventually commercialize one or more medicines with significant market potential.
−Removed: This will require us to be successful in a range of challenging activities, including completing preclinical testing and clinical trials of our product candidates, obtaining marketing approval for these product candidates, manufacturing, marketing and selling those medicines for which we may obtain marketing approval and satisfying any post-marketing requirements.
−Removed: Notwithstanding the extent to which we may succeed in any of these activities, we may never generate revenues that are significant or large enough to achieve profitability.
−Removed: If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis.
−Removed: Our failure to become and remain profitable would decrease the value of our company and could impair our ability to raise capital, maintain our research and development efforts, expand our business or continue our operations.
−Removed: A decline in the value of our company could also cause our stockholders to lose all or part of their investment.
−Removed: The amount of contingent consideration we will receive from the sale of our oncology business to Servier is subject to various risks and uncertainties.
−Removed: Upon closing of the sale of our oncology business to Servier, Servier assumed certain liabilities with respect to the oncology business and paid to us:
−Removed: approximately $1.8 billion in cash, net of certain adjustments for the working capital of the oncology business at the time of closing of the transaction and amounts for a representation and warranty insurance policy.
−Removed: In addition, Servier will pay to us:
−Removed: • $200 million in cash if, prior to January 1, 2027, vorasidenib is granted approval for a new drug application, or NDA, from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an IDH1 or IDH2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval);
−Removed: • a royalty payment of 5% of the U.S.
−Removed: net sales (as defined in the purchase agreement with Servier) of TIBSOVO® from the completion of the transaction through loss of exclusivity of TIBSOVO®;
−Removed: • a royalty payment of 15% of the U.S.
−Removed: net sales (as defined in the purchase agreement with Servier) of vorasidenib from its first commercial sale through loss of exclusivity of vorasidenib.
−Removed: The contingent consideration described above is subject to various risks and uncertainties.
−Removed: Whether the regulatory approval milestone will be achieved prior to January 1, 2027 is subject to various risks and uncertainties, many of which are outside of the control of the parties, including adverse clinical developments with respect to vorasidenib.
−Removed: In addition, we cannot predict what success, if any, Servier may have in the United States with respect to sales of TIBSOVO® and vorasidenib, if approved, and, therefore, the amount of royalty payments that we can expect to receive from Servier under the terms of the purchase agreement prior to the loss of exclusivity of these products.
−Removed: The royalty payments are also subject to deductions and other adjustments under the terms of the purchase agreement, the amounts of which are uncertain as of the date of this Quarterly Report on Form 10-Q.
−Removed: Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.
−Removed: Changes in tax law may adversely affect our business or financial condition.
−Removed: On December 22, 2017, the U.S.
−Removed: government enacted the Tax Cuts and Jobs Act, or the Tax Act, which significantly reformed the U.S.
−Removed: Internal Revenue Code of 1986, as amended, or the Code.
−Removed: The Tax Act, among other things, contained significant changes to corporate taxation.
−Removed: As part of Congress’ response to the COVID-19 pandemic, the Families First Coronavirus Response Act, or FFCR Act, was enacted on March 18, 2020, the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, was enacted on March 27, 2020, and COVID-19 relief provisions were included in the Consolidated Appropriations Act, 2021, or CAA, which was enacted on December 27, 2020.
−Removed: All contain numerous tax provisions.
−Removed: Regulatory guidance under the Tax Act, the FFCR Act, the CARES Act, and the CAA is and continues to be forthcoming, and such guidance could ultimately increase or lessen impact of these laws on our business and financial condition.
−Removed: It is also possible that Congress will enact additional legislation in connection with the COVID-19 pandemic, some of which could have an impact on our company.
−Removed: In addition, it is uncertain if and to what extent various states will conform to the Tax Act, the FFCR Act, the CARES Act, or the CAA.
−Removed: Risks Related to the Discovery, Development, and Commercialization of our Product Candidates
−Removed: We depend heavily on the success of our clinical product candidates, including our lead product candidate mitapivat.
+Added: The following risk factors and other information included in this Quarterly Report on Form 10-Q should be carefully considered.
+Added: The risks and uncertainties described below are not the only risks and uncertainties we face.
+Added: Additional risks and uncertainties not presently known to us or that we presently deem less significant may also impair our business operations.
+Added: Please see page 1 of this Quarterly Report on Form 10-Q for a discussion of some of the forward-looking statements that are qualified by these risk factors.
+Added: If any of the following risks occur, our business, financial condition, results of operations and future growth prospects could be materially and adversely affected.
+Added: Risks Related to the Discovery, Development, and Commercialization of our Products and Product Candidates
+Added: If we do not successfully commercialize PYRUKYND® and other products for which we receive approval, our prospects may be substantially harmed.
+Added: In February 2022, we obtained marketing approval from the FDA for PYRUKYND® (mitapivat) for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States.
+Added: PYRUKYND® is the first product for which we have received marketing approval following the sale of our oncology business to Servier in March 2021 and PYRUKYND® is the first product in our GDD portfolio that has received marketing approval.
+Added: As of the date of this Quarterly Report on Form 10-Q, we are in the process of commercially launching PYRUKYND ®.
+Added: Our ability to generate revenue from PYRUKYND® will depend heavily on our successful development and commercialization of the product.
+Added: The development and commercialization of PYRUKYND® could be unsuccessful if:
+Added: • the medical community and third-party payors do not accept PYRUKYND® as safe, efficacious and cost-effective for the treatment of hemolytic anemia in adults with PK deficiency;
+Added: • we fail to maintain the necessary financial resources and expertise to manufacture, market and sell PYRUKYND®;
+Added: • we fail to develop, implement and maintain effective marketing, sales and distribution strategies and operations for the development and commercialization of PYRUKYND®;
+Added: • we fail to continue to develop, validate and maintain a commercially viable manufacturing process for PYRUKYND® that is compliant with current good manufacturing practices, or cGMP;
+Added: • we fail to successfully obtain third party reimbursement and generate commercial demand that results in sales of PYRUKYND®;
+Added: • PYRUKYND® or any product candidate that we commercialize, may become subject to unfavorable pricing regulations and third-party reimbursement practices, which would harm our business.
+Added: • our efforts to commercialize PYRUKYND® are impeded by the effects of the COVID-19 pandemic;
+Added: • we encounter any third-party patent interference, derivation, inter partes review, post-grant review, reexamination or patent infringement claims with respect to PYRUKYND®;
+Added: • we fail to comply with regulatory and legal requirements applicable to the sale of PYRUKYND®;
+Added: • competing drug products are approved for the same indications as PYRUKYND®;
+Added: • we fail to approve marketing approval of PYRUKYND® in jurisdictions other than the United States;
+Added: • new significant safety risks are identified;
+Added: • we fail to gain and/or maintain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community;
+Added: • a significant number of eligible patients with PK deficiency do not end up being prescribed PYRUKYND® and, if they are, such patients do not stay on treatment;
+Added: • PYRUKYND® does not demonstrate acceptable safety and efficacy in current or future clinical trials, or otherwise does not meet applicable regulatory standards for approval in indications other than currently approved indications.
+Added: If we experience significant delays or an inability to successfully develop and commercialize PYRUKYND® our business would be materially harmed.
+Added: We depend heavily on the success of our clinical product candidates, including our lead product candidate PYRUKYND® for use in indications other than PK deficiency and in other jurisdictions.
Clinical trials of our product candidates may not be successful for a number of important reasons.
If we or our collaborators are unable to commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.
−Removed: Our ability to generate product revenue will depend heavily on the successful clinical development and eventual commercialization of our current and any future product candidates, including our lead product candidate mitapivat.
−Removed: We have invested a significant portion of our efforts and financial resources in the identification of our product candidates and development of our most advanced programs, including mitapivat, In June 2021, we submitted an NDA to the FDA for mitapivat for the treatment of adults with PK deficiency, which was accepted with priority review and granted a PDUFA action date of February 17, 2022, and a MAA, for mitapivat in adults with PK deficiency to the EMA.
+Added: We have invested a significant portion of our efforts and financial resources in the identification of our product candidates and development of our most advanced clinical programs, including PYRUKYND®.
+Added: Our ability to generate product revenue will depend heavily on the successful clinical development and eventual commercialization of our current and any future product candidates, including PYRUKYND® for use in indications other than PK deficiency and in jurisdictions outside of the United States.
+Added: In February 2022, the FDA approved PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States.
+Added: In June 2021, we submitted a MAA to the EMA for the treatment of adults with PK deficiency the European Union.
We, and any collaborators, are not permitted to commercialize, market, promote or sell any product candidate in the United States without obtaining marketing approval from the FDA.
21 unchanged sentences
• the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be insufficient or inadequate.
−Removed: In December 2016, we withdrew our IND for AG-519, our second PKR activator, following verbal notification of a clinical hold from the FDA relating to a previously disclosed case of drug-induced cholestatic hepatitis which occurred in our phase 1 clinical trial of AG-519 in healthy volunteers.
−Removed: Although these decisions and this hepatic adverse event finding do not affect our ongoing clinical trials for mitapivat, our first PKR activator, we cannot provide any assurances that there will not be similar or other treatment-related severe adverse events in our other clinical trials of mitapivat, that our other trials will not be placed on clinical hold in the future, or that patient recruitment for our other trials will not be adversely impacted.
+Added: In December 2016, we withdrew our IND for AG-519, our second PKR activator, following verbal notification of a clinical hold from the FDA relating to a previously disclosed case of drug-induced cholestatic hepatitis which occurred in our phase 1
+Added: clinical trial of AG-519 in healthy volunteers.
+Added: Although these decisions and this hepatic adverse event finding do not affect our ongoing clinical trials for PYRUKYND®, our first PKR activator, we cannot provide any assurances that there will not be similar or other treatment-related severe adverse events in our other clinical trials of PYRUKYND®, that our other trials will not be placed on clinical hold in the future, or that patient recruitment for our other trials will not be adversely impacted.
Our failure to successfully begin and complete clinical trials of our product candidates and to demonstrate the efficacy and safety necessary to obtain regulatory approval to market any of our product candidates could result in additional costs to us, or any collaborators, would impair our ability to generate revenue from product sales, regulatory and commercialization milestones and royalties and would significantly harm our business.
9 unchanged sentences
If we are unable to identify suitable compounds for preclinical and clinical development, or any medicines we develop do not effectively correct metabolic pathways or alter the metabolic state of immune cells, we will not be able to achieve our strategic vision and our specific long-term goals and will not be able generate product revenue in future periods, which likely would result in significant harm to our financial position and adversely impact our stock price.
−Removed: The COVID-19 pandemic has and may continue to affect our ability to initiate or continue our planned, ongoing and future clinical trials, disrupt regulatory activities, or have other adverse effects on our business and operations.
+Added: The COVID-19 pandemic has and may continue to affect our ability to initiate or continue our planned, ongoing and future clinical trials, disrupt regulatory activities, disrupt our ability to maintain a commercial infrastructure for our product or have other adverse effects on our business and operations.
In addition, this pandemic may continue to adversely impact economies worldwide, which could result in adverse effects on our business and operations.
−Removed: In response to the COVID-19 pandemic, we were required to close our facilities except for a limited number of essential facilities and laboratory staff.
−Removed: We recently opened our Cambridge office to employees who prefer to work onsite all or some of the time, and our field-based employees engage with healthcare providers and other third parties remotely and, where local regulations allow, on a limited in-person basis.
−Removed: Effective November 8, 2021, we will require all employees, regardless of role or work location, to be fully vaccinated against COVID-19, as defined by CDC guidelines, subject to limited exceptions.
+Added: In response to the COVID-19 pandemic, we were temporarily required to close our facilities except for a limited number of essential facilities and laboratory staff.
+Added: Our Cambridge office reopened, with appropriate safety precautions in place that are aligned with local and CDC guidelines.
+Added: Operations have maintained productivity, while allowing employees who prefer to work onsite to do so all or some of the time.
+Added: Additionally, our field-based employees engage with healthcare providers and other third parties remotely and, where local regulations allow, on a limited in-person basis.
+Added: In November 2021, we began requiring all employees, regardless of role or work location, to be fully vaccinated against COVID-19, as defined by CDC guidelines, subject to limited exceptions.
We may face disruptions that may affect our ability to initiate and complete clinical trials including disruptions in procuring items that are essential for our research and development activities, including, for example, raw materials used in the manufacturing of our product candidates and laboratory supplies for planned and ongoing clinical trials, in each case, for which there may be shortages because of ongoing efforts to address the outbreak.
+Added: We have experienced disruptions to certain research activities at our contract research organizations, or CROs, based in China, due to the recent COVID-19 surge in China.
We have enrolled, and seek to enroll, patients in our clinical trials at sites located both in the United States and internationally.
Site initiation, participant recruitment and enrollment, participant dosing, distribution of clinical trial materials, study monitoring and data analysis has been and may continue to be paused or delayed due to changes in hospital or university policies, federal, state or local regulations, prioritization of hospital resources toward pandemic efforts, or other reasons related to the pandemic.
−Removed: We have faced and expect to continue to face difficulties recruiting or retaining patients in our ongoing clinical trials because of the pandemic.
+Added: We have faced and may continue to face difficulties recruiting or retaining patients in our ongoing clinical trials because of the pandemic.
Patients enrolled in our clinical trials may be unable or unwilling to visit clinical trial sites which may impact the collection of important clinical trial data and has, and may continue to, necessitate remote data verification.
−Removed: In addition, limitations in the ability to visit sites has affected, and may continue to adversely affect, our enrollment timelines for our clinical trials, and may adversely affect the timing of completion of our clinical trials or our ability to complete clinical trials in a fully compliant manner.
+Added: In addition, limitations in the ability to visit sites has affected, and may continue to affect, our enrollment timelines for our clinical trials, and may adversely affect the timing of completion of our clinical trials or our ability to complete clinical trials in a fully compliant manner.
Additionally, the potential suspension of clinical trial activity at clinical trial sites may have an adverse impact on our clinical trial plans and timelines.
−Removed: We have faced and may continue to face disruptions in our ability to prepare and submit applications to regulatory authorities for drug approvals and to build and maintain a commercial infrastructure for our product candidates.
+Added: We have faced and may continue to face disruptions in our ability to prepare and submit applications to regulatory authorities for drug approvals and to build and maintain a commercial infrastructure for our product and product candidates.
We may face manufacturing disruptions or disruptions related to the ability to obtain necessary institutional review board or other necessary site approvals, as well as other delays at clinical trial sites.
2 unchanged sentences
The COVID-19 pandemic may continue to significantly impact economies and financial markets worldwide, which could result in adverse effects on our business and operations, impact our ability to raise additional funds through public offerings and impact the volatility of our stock price and trading in our stock.
−Removed: We cannot be certain what the overall impact of the COVID-19 pandemic will be on our business and it has the potential to adversely affect our business, financial condition, results of operations, and prospects.
+Added: We cannot be certain what the overall impact of the COVID-19 pandemic will be on our business in the future and a continuation of the pandemic has the potential to adversely affect our business, financial condition, results of operations, and prospects.
If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.
−Removed: We or our collaborators may not be able to initiate or continue clinical trials for our product candidates if we or they are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or analogous regulatory authorities outside the United States.
+Added: We or our collaborators may not be able to initiate, continue or complete clinical trials for our product candidates if we or they are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or analogous regulatory authorities outside the United States.
Furthermore, enrollment has been and may continue to be particularly challenging in light of the ongoing COVID-19 pandemic and even more so for some of the orphan diseases we target in our GDD programs.
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Vertex Pharmaceuticals Incorporated, or Vertex, is developing a gene therapy targeting SCD;
−Removed: IMARA Inc., or IMARA, and Forma Therapeutics Holdings, Inc., or Forma, are developing molecules for the treatment of beta thalassemia and SCD;
−Removed: and Global Blood Therapeutics is developing molecules for the treatment of
−Removed: Competition for eligible patients may make it particularly difficult for us to enroll enough patients to complete our clinical trials for our product candidates in a timely and cost-effective manner.
+Added: Forma Therapeutics Holdings, Inc., or Forma, is developing molecules for the treatment of beta thalassemia and SCD;
+Added: Global Blood Therapeutics is developing molecules for the treatment of SCD;
+Added: Fibrogen, Inc.
+Added: is developing Roxadustat for the treatment of anemia in MDS patients;
+Added: and Geron Corporation is developing imetelstat for the treatment of low-risk MDS.
+Added: Roivant Sciences is developing RVT-2001 (licensed from Eisai Co., Ltd.) for the treatment of transfusion-dependent anemia in patients with lower-risk MDS.
+Added: Competition for eligible patients may make it particularly difficult for us to enroll a sufficient number of patients to complete our clinical trials for our product candidates in a timely and cost-effective manner.
We rely on contract research organization, or CROs, and clinical trial sites to ensure the proper and timely conduct of our clinical trials and while we have agreements governing their committed activities, we have limited influence over their actual performance.
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Enrollment delays in our clinical trials may result in increased development costs for our product candidates, which would cause the value of our company to decline and limit our ability to obtain additional financing.
−Removed: Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials.
+Added: Results of preclinical studies and early clinical trials may not be predictive of results of later-stage clinical trials.
The outcome of preclinical studies and early clinical trials may not be predictive of the success of later clinical trials, and interim results of clinical trials do not necessarily predict success in future clinical trials.
−Removed: Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier development, and we could face similar setbacks.
+Added: Many companies in the pharmaceutical
+Added: and biotechnology industries have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier stages of development, and we could face similar setbacks.
The design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced.
−Removed: We have limited experience in designing clinical trials and may be unable to design and execute a clinical trial to support marketing approval.
In addition, preclinical and clinical data are often susceptible to varying interpretations and analyses.
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In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen and other clinical trial protocols and the rate of dropout among clinical trial participants.
+Added: While we obtained marketing approval of PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States, we cannot be certain that we will obtain marketing approval of PYRUKYND® in other indications.
+Added: The results of clinical trials of PYRUKYND® for the treatment of PK deficiency do not predict that PYRUKYND® will be efficacious in our ongoing clinical trials in other indications.
If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced product candidates, and, correspondingly, our business and financial prospects would be negatively impacted.
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If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.
−Removed: If we are unable to successfully develop companion diagnostics for our product candidates, or experience significant delays in doing so, we may not realize the full commercial potential of our therapeutics.
−Removed: Because we are focused on precision medicine, in which predictive biomarkers will be used to identify the right patients for our drug candidates, we believe that our success will depend, in part, on our ability to develop companion diagnostics, which are assays or tests to identify an appropriate patient population for these drug candidates.
−Removed: There has been limited success to date industry-wide in developing these types of companion diagnostics.
−Removed: To be successful, we need to address a number of scientific, technical and logistical challenges.
−Removed: We have little experience in the development of diagnostics and may not be successful in developing appropriate diagnostics to pair with any of our therapeutic product candidates that receive marketing approval.
−Removed: Companion diagnostics are subject to regulation by the FDA and similar regulatory authorities outside the United States as medical devices and require separate regulatory approval prior to commercialization.
−Removed: Given our limited experience in developing diagnostics, we rely and expect to continue to rely in part or in whole on third parties for their design and manufacture.
−Removed: We also may in the future depend on other third parties for the development of other companion diagnostics for
−Removed: our therapeutic product candidates.
−Removed: If we or our collaborators are unable to successfully develop companion diagnostics for our therapeutic product candidates, or experience delays in doing so:
−Removed: • the development of our therapeutic product candidates may be adversely affected if we are unable to appropriately select patients for enrollment in our clinical trials;
−Removed: • our therapeutic product candidates may not receive marketing approval if safe and effective use of a therapeutic product candidate depends on an in vitro diagnostic;
−Removed: • we may not realize the full commercial potential of any therapeutics that receive marketing approval if, among other reasons, we are unable to appropriately select patients who are likely to benefit from therapy with our medicines.
−Removed: As a result of any of these events, our business would be harmed, possibly materially.
Even if any of our product candidates receives marketing approval, we or others may later discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.
It is possible that our clinical trials, or those of any collaborators, may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify undesirable side effects.
−Removed: If, following approval of a product candidate, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur:
+Added: If, following approval of a product candidate, including PYRUKYND®, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur:
• regulatory authorities may withdraw their approval of the product or seize the product;
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• our reputation may suffer.
−Removed: Even if any of our product candidates receive marketing approval, they may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.
−Removed: Even if any of our product candidates receive marketing approval in the future, they may fail to gain and/or maintain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community.
−Removed: If our product candidates do not achieve an adequate level of acceptance, we may not generate significant product revenue and we may not become profitable.
−Removed: The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on a number of factors, including:
+Added: PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.
+Added: PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, may fail to gain and/or maintain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community.
+Added: If PYRUKYND® or any of our product candidates that may receive marketing approval do not achieve an adequate level of acceptance, we may not generate significant product revenue and we may not become profitable.
+Added: The degree of market acceptance of PYRUKYND® and any of our product candidates, if approved for commercial sale, will depend on a number of factors, including:
• efficacy and potential advantages compared to alternative treatments;
−Removed: • the approval, availability, market acceptance and reimbursement for the companion diagnostic;
• the ability to offer our medicines for sale at competitive prices;
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• the prevalence and severity of any side effects.
−Removed: If we are unable to establish and maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing our product candidates if and when they are approved.
+Added: If we are unable to establish and maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing PYRUKYND® or our product candidates if they are approved.
We have limited experience in the sale, marketing or distribution of pharmaceutical products.
To achieve commercial success for approved medicines for which we retain sales and marketing responsibilities, we must either develop a sales and marketing organization or outsource these functions to other third parties.
−Removed: Although we had established sales and marketing capabilities to
−Removed: support our co-promotion efforts for IDHIFA® and our sales of TIBSOVO® prior to the sale of our oncology business to Servier, we are again in the process of building our sales and marketing infrastructure to sell, or participate in sales activities with any collaborators for, our other product candidates if and when they are approved.
+Added: Although we had established sales and marketing capabilities to support our co-promotion efforts for IDHIFA® and our sales of TIBSOVO® prior to the sale of our oncology business to Servier, we are again in the process of building our sales and marketing infrastructure to support our commercial launch and sell PYRUKYND® for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States.
+Added: We may need to further build our sales and marketing infrastructure to commercialize PYRUKYND® in other indications or outside of the United States or to commercialize any of our other product candidates for which we obtain marketing approval.
There are risks involved with both establishing our own sales and marketing capabilities and entering into arrangements with third parties to perform these services.
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We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our medicines effectively.
−Removed: If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing our product candidates.
+Added: If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing PYRUKYND® or any of our product candidates for which we obtain marketing approval.
We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.
−Removed: We face competition with respect to our current product candidates, and we and our collaborators will face competition with respect to any product candidates that we or they may seek to develop or commercialize in the future.
+Added: We face competition with respect to PYRUKYND® and our current product candidates, and we will face competition with respect to any product candidates that we or they may seek to develop or commercialize in the future.
Potential competitors include major pharmaceutical companies, specialty pharmaceutical companies, biotechnology companies, academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization.
−Removed: There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the disease indications for which we are developing our product candidates, such as PK deficiency, thalassemia and SCD.
+Added: There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the disease indications for which we are developing our product or our product candidates, such as PK deficiency, thalassemia, SCD and L-IR MDS.
For example, Acceleron Pharma Inc.
(in collaboration with Bristol-Myers Squibb Company) and bluebird bio, Inc., or bluebird, are each marketing therapies to treat beta thalassemia, Novartis International AG, Emmaus Life Sciences and Global Blood Therapeutics are each marketing therapies to treat SCD, Rocket Pharma is conducting a clinical trial of a gene therapy targeting PK deficiency, and a number of other biotechnology companies have product candidates in clinical development in similar indications as ours.
−Removed: We are developing product candidates to treat patients with GDDs.
There are a variety of treatment options available, including a number of marketed enzyme replacement therapies, for treating patients with GDDs.
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There are also a number of product candidates in preclinical or clinical development by third parties to treat GDDs by targeting similar mechanisms of action as our product candidates.
−Removed: These companies include large pharmaceutical companies, such as Novartis, as well as biotechnology companies of various sizes, such as BioMarin Pharmaceutical Inc., bluebird, Forma, IMARA, PTC Therapeutics, Inc., Rocket Pharma, and Vertex.
−Removed: Our competitors may develop products that are more effective, safer, more convenient or less costly than any that we are developing or that would render our product candidates obsolete or non-competitive.
+Added: These companies include large pharmaceutical companies, such as Novartis, as well as biotechnology companies of various sizes, such as BioMarin Pharmaceutical Inc., bluebird, Forma, PTC Therapeutics, Inc., Rocket Pharma, and Vertex.
+Added: Our competitors may develop products that are more effective, safer, more convenient or less costly than PYRUKYND® or any product candidates that we are developing or that would render PYRUKYND® or our product candidates obsolete or non-competitive.
In addition, our competitors may discover biomarkers that more efficiently measure metabolic pathways than our methods, which may give them a competitive advantage in developing potential products.
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Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.
−Removed: Smaller and other clinical stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
+Added: Smaller and clinical stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.
These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.
−Removed: If the FDA does not grant our products, if and when approved, appropriate periods of data exclusivity before approving generic versions of our products, the sales of our products could be adversely affected.
+Added: If the FDA does not grant our products, if and when approved, appropriate periods of data exclusivity before approving generic or follow-on versions of our products, the sales of our products could be adversely affected.
With FDA approval of an NDA, the product covered by the application is specified as a “reference-listed drug” in the FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations,” or the Orange Book.
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Thus, following the introduction of a generic drug, a significant percentage of the sales of any reference-listed drug may be typically lost to the generic product.
−Removed: The FDA may not approve an ANDA for a generic product until any applicable period of non-patent exclusivity for the reference-listed drug has expired.
−Removed: The Federal Food, Drug, and Cosmetic Act, or FDCA, provides a period of five years of non-patent exclusivity for a new drug containing a new chemical entity.
−Removed: Specifically, in cases where such exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification that a patent covering the reference-listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application four years following approval of the reference-listed drug.
−Removed: The FDCA also provides a period of three years of new clinical investigation data exclusivity in connection with the approval of a supplemental indication for the product for which a clinical trial is essential for approval.
−Removed: In the event that a generic manufacturer is somehow able to obtain FDA approval without adherence to these periods of data exclusivity, the competition that our approved products may face from generic versions could negatively impact our future revenue, profitability and cash flows and substantially limit our ability to obtain a return on our investments in those product candidates.
+Added: A manufacturer may also submit an NDA under section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, or FDCA, that references the FDA’s prior approval of the innovator product or preclinical studies and/or clinical trials that were not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference.
+Added: A 505(b)(2) NDA product, or follow-product, may be for a new or improved version of the original reference listed drug.
+Added: The FDA may not approve an ANDA or 505(b)(2) NDA until any applicable period of non-patent exclusivity for the reference-listed drug has expired.
+Added: The FDCA provides a period of five years of new chemical entity exclusivity for a new drug containing a new active moiety.
+Added: Specifically, in cases where such exclusivity has been granted, an ANDA or a 505(b)(2) NDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification that a patent covering the reference-listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application four years following approval of the reference-listed drug.
+Added: The FDCA also provides a period of three years of new clinical investigation data exclusivity in connection with the approval of a supplemental indication for the product for which a clinical trial is deemed by the FDA as essential for approval.
+Added: In the event that a generic or follow-on manufacturer is somehow able to obtain FDA approval without adherence to these periods of data exclusivity, the competition that our approved products may face from generic and follow-on versions could negatively impact our future revenue, profitability and cash flows and substantially limit our ability to obtain a return on our investments in those product candidates.
+Added: In addition, if there are patents listed for our drug products in the Orange Book, ANDAs and 505(b)(2) NDAs would be required to include a certification as to each listed patent indicating whether the applicant intends to challenge the patent.
+Added: We cannot predict which, if any, patents in our current portfolio or patents we may obtain in the future will be eligible for listing in the Orange Book, how any generic or follow-on competitor would address such patents, whether we would sue on any such patents or the outcome of any such suit.
Product liability lawsuits against us or any collaborators could cause us or our collaborators to incur substantial liabilities and could limit commercialization of any medicines that we or they may develop.
−Removed: We and any collaborators face a risk of product liability exposure related to our product candidates in human clinical trials and will face an even greater risk as we or they commercially sell any medicines.
+Added: We and any collaborators face a risk of product liability exposure related to our product candidates in human clinical trials and face an even greater risk as we or they commercially sell any medicines, including PYRUKYND®.
If we or any collaborators cannot successfully defend ourselves or themselves against claims that our product candidates or medicines caused injuries, we or they could incur substantial costs and liabilities.
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We could be required to expend significant amounts of money and other resources to repair or replace information systems or networks.
−Removed: Although we develop and maintain systems and controls designed to prevent these events from occurring, and we have a process to identify and mitigate threats, the development and maintenance of these systems, controls and processes is costly and requires ongoing monitoring and updating as technologies change and efforts to overcome security measures become more sophisticated.
+Added: Although we develop and maintain systems and controls designed to prevent these events from occurring, and we have a process to identify and mitigate threats, the development and maintenance of these systems, controls and processes is costly and requires ongoing
+Added: monitoring and updating as technologies change and efforts to overcome security measures become more sophisticated.
Moreover, despite our efforts, the possibility of these events occurring cannot be eliminated entirely.
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Globally, virtually every jurisdiction in which we operate has established its own data security and privacy frameworks with which we must comply.
−Removed: For example, the collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the European Union, including personal health data, is subject to EU General Data Protection Regulation, or the GDPR, which applies to all member states of the European Economic Area, or EEA.
+Added: For example, the collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to EU General Data Protection Regulation, or the GDPR, which applies to all member states of the European Economic Area, or EEA.
The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data.
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A broad range of legislative measures also have been introduced at the federal level.
−Removed: Accordingly, failure to comply with
−Removed: current and any future federal and state laws regarding privacy and security of personal information could expose us to fines and penalties.
+Added: Accordingly, failure to comply with current and any future federal and state laws regarding privacy and security of personal information could expose us to fines and penalties.
We also face a threat of consumer class actions related to these laws and the overall protection of personal data.
Even if we are not determined to have violated these laws, government investigations into these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our reputation and our business.
+Added: Risks Related to Our Financial Position
+Added: We face new challenges as a smaller, less diversified company following the sale of our oncology business to Servier.
+Added: Following the sale of our oncology business to Servier in March 2021, we have focused our resources and efforts on product and product candidates for the treatment of GDDs.
+Added: The success of the GDD business is subject to various risks and uncertainties, including the possibility that we may not be able to successfully commercialize PYRUKYND®, which only recently was approved by the FDA for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, the possibility of adverse clinical and other developments in respect of PYRUKYND® or our other product candidates of the GDD business, and unanticipated changes in applicable laws and regulations that may adversely affect the GDD business.
+Added: We developed most of our initial products and product candidates for the treatment of various types of cancer.
+Added: The sale of our oncology business to Servier, including our approved products at the time of sale, TIBSOVO® and IDHIFA®, has resulted in us being a smaller, less diversified company with a more limited business concentrated on products and product candidates for the treatment of GDDs.
+Added: As a result, we may be more susceptible to changing market conditions, including fluctuations and risks particular to the markets for patients with GDDs, than a more diversified company, which could adversely affect our business, financial condition and results of operations.
+Added: In addition, even with the FDA approval of PYRUKYND®, the diversification of our revenues, costs and cash flows has diminished following the transaction.
+Added: Our results of operations, cash flows, working capital and financing requirements may be subject to increased volatility and our ability to fund capital expenditures and investments or satisfy other financial commitments may be diminished.
+Added: We have broad discretion as to the use of the proceeds from the sale of our oncology business to Servier, and we may not use the proceeds effectively.
+Added: We have broad discretion with respect to the use of proceeds of the sale of our oncology business to Servier.
+Added: The results and effectiveness of the use of proceeds, including the repurchase of shares of our common stock, are uncertain, and we could spend the proceeds in ways that do not improve our remaining business, financial condition or results of operations.
+Added: Our failure to apply these funds effectively could have an adverse effect on its business, financial condition and results of operations.
+Added: Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.
+Added: Until such time, if ever, as we can generate substantial product revenue, including from sales of PYRUKYND®, we expect to finance our cash needs primarily through cash on hand, royalty payments from Servier with respect to U.S.
+Added: net sales of TIBSOVO®, a potential milestone payment and royalties from Servier if vorasidenib is approved by the FDA and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
+Added: In addition, in connection with potential future strategic transactions, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.
+Added: We do not have any committed external source of funds other than the potential milestone and royalty payments that we are eligible to receive under our purchase agreement with Servier.
+Added: To the extent that we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our common stockholders.
+Added: Debt financing, if available, may require us to enter into agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.
+Added: In addition, securing financing could require a substantial amount of time and attention from our management and may divert a disproportionate amount of their attention away from day-to-day activities, which may adversely affect our management’s ability to oversee the development of our product candidates.
+Added: If we raise funds through collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or to grant licenses on terms that may not be favorable to us.
+Added: If our existing capital is insufficient to execute our operating plan through major catalysts and to cash-flow positivity, we will need to raise capital, and if we are unable to raise capital when needed, we would be forced to delay, reduce or eliminate our product development programs or commercialization efforts.
+Added: We expect to incur significant expenses as we continue to advance our ongoing activities.
+Added: We expect to execute our operating plan through major catalysts and to cash-flow positivity without the need to raise additional equity.
+Added: Our estimate as to how long we expect our existing cash, cash equivalents, and marketable securities to be available to fund our operating plan is based on assumptions that may prove to be wrong, and we could use our available capital resources sooner than we currently expect.
+Added: Further, changing circumstances, some of which may be beyond our control, could cause us to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds.
+Added: Our future capital requirements will depend on many factors, including:
+Added: • the amount and timing of future revenue received from commercial sales of PYRUKYND® and any of our other product candidates for which we may receive marketing approval;
+Added: • the amount of contingent consideration we ultimately receive in connection with the sale of our oncology business to Servier;
+Added: • the costs and timing of our ongoing commercialization activities, including product manufacturing, sales, marketing and distribution, for PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency;
+Added: • the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our product candidates;
+Added: • the costs, timing and outcome of regulatory review of our product candidates;
+Added: • the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims;
+Added: • the costs and timing of future commercialization activities, including product manufacturing, sales, marketing and distribution, for any of our product candidates for which we may receive marketing approval;
+Added: • our ability to establish and maintain collaborations on favorable terms, if at all;
+Added: • our ability to successfully execute on our strategic plans;
+Added: • operational delays due to the COVID-19 pandemic;
+Added: • the extent to which we acquire or in-license, or monitor or out-license, other medicines and technologies.
+Added: We have historically incurred operating losses.
+Added: We expect to incur losses in the future and may never achieve or maintain profitability.
+Added: We have a history of incurring operating losses.
+Added: Our net loss for the three months ended March 31, 2022 was $94.8 million, and our net income for the three months ended March 31, 2021 was $1,874.3 million, which was due to the sale of our oncology business to Servier on March 31, 2021.
+Added: As of March 31, 2022, we had an accumulated deficit of $333.5 million.
+Added: Prior to the sale of our oncology business to Servier, we had generated only modest revenue from sales of TIBSOVO® and, prior to our sale to Royalty Pharma of our royalty rights to IDHIFA®, from royalties on sales of IDHIFA®.
+Added: We have only recently obtained marketing approval and have begun to commercialize PYRUKYND® for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States.
+Added: PYRUKYND® is the first product we have received marketing approval for following the sale of our oncology business, including approved products TIBSOVO® and IDHIFA®, to Servier in March 2021.
+Added: We have neither obtained marketing approval for PYRUKYND® in any other indications or for any indication outside of the United States nor have we obtained marketing approval for any of our other product candidates, all of which are in preclinical or clinical development stages.
+Added: In June 2021, we submitted a MAA for PYRUKYND® in adults with PK deficiency to the EMA.
+Added: Prior to the sale of our oncology business to Servier, we financed our operations primarily through public offerings of our common stock and our collaboration agreements with Celgene and have devoted substantially all of our efforts to research and development.
+Added: Following the sale of our oncology business to Servier on March 31, 2021, we have financed and expect to finance our operations primarily through cash on hand, royalty payments from Servier with respect to U.S.
+Added: net sales of TIBSOVO®, a potential milestone payment from Servier if vorasidenib is approved by the FDA, potential sales of PYRUKYND® and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.
+Added: We expect to continue to incur significant expenses and net losses until such time as we are able to report profitable results.
+Added: The net losses we incur may fluctuate significantly from quarter to quarter.
+Added: We anticipate that we will incur significant expenses if and as we:
+Added: • commercially launch PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States;
+Added: • continue to establish and maintain a sales, marketing and distribution infrastructure to commercialize PYRUKYND® and other product candidates for which we may obtain marketing approval;
+Added: • initiate and continue clinical trials for our products and product candidates, including PYRUKYND® in other indications;
+Added: continue our research and preclinical development of our product candidates and seek to identify additional product candidates;
+Added: • seek marketing approvals for our product candidates that successfully complete clinical trials;
+Added: • require the manufacture of larger quantities of product candidates for clinical development and commercialization;
+Added: • maintain, expand and protect our intellectual property portfolio;
+Added: • add additional personnel to support our product research and development and planned future commercialization efforts and our operations;
+Added: • add equipment and physical infrastructure to support our research and development;
+Added: • acquire or in-license other medicines and technologies.
+Added: To become and remain profitable, we must develop and successfully commercialize one or more medicines with significant market potential.
+Added: This will require us to be successful in a range of challenging activities, including completing preclinical testing and clinical trials of our product candidates, obtaining marketing approval for these product candidates, manufacturing, marketing and selling those medicines for which we may obtain marketing approval and satisfying any post-marketing requirements.
+Added: Notwithstanding the extent to which we may succeed in any of these activities, we may never generate revenues that are significant or large enough to achieve profitability.
+Added: If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis.
+Added: Our failure to become and remain profitable would decrease the value of our company and could impair our ability to raise capital, maintain our research and development efforts, expand our business
+Added: or continue our operations.
+Added: A decline in the value of our company could also cause our stockholders to lose all or part of their investment.
+Added: The amount of contingent consideration we will receive from the sale of our oncology business to Servier is subject to various risks and uncertainties.
+Added: Upon closing of the sale of our oncology business to Servier, Servier assumed certain liabilities with respect to the oncology business and paid to us:
+Added: approximately $1.8 billion in cash, net of certain adjustments for the working capital of the oncology business at the time of closing of the transaction and amounts for a representation and warranty insurance policy.
+Added: In addition, Servier will pay to us:
+Added: • $200.0 million in cash if, prior to January 1, 2027, vorasidenib is granted approval for a new drug application, or NDA, from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an IDH1 or IDH2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval);
+Added: • a royalty payment of 5% of the U.S.
+Added: net sales (as defined in the purchase agreement with Servier) of TIBSOVO® from the completion of the transaction through loss of exclusivity of TIBSOVO®;
+Added: • a royalty payment of 15% of the U.S.
+Added: net sales (as defined in the purchase agreement with Servier) of vorasidenib from its first commercial sale through loss of exclusivity of vorasidenib.
+Added: The contingent consideration described above is subject to various risks and uncertainties.
+Added: Whether the regulatory approval milestone will be achieved prior to January 1, 2027 is subject to various risks and uncertainties, many of which are outside of the control of the parties, including adverse clinical developments with respect to vorasidenib.
+Added: In addition, we cannot predict what success, if any, Servier may have in the United States with respect to sales of TIBSOVO® and vorasidenib, if approved, and, therefore, the amount of royalty payments that we can expect to receive from Servier under the terms of the purchase agreement prior to the loss of exclusivity of these products.
+Added: The royalty payments are also subject to deductions and other adjustments under the terms of the purchase agreement, the amounts of which are uncertain as of the date of this report.
+Added: Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.
+Added: Changes in tax law may adversely affect our business or financial condition.
+Added: On December 22, 2017, the U.S.
+Added: government enacted the Tax Cuts and Jobs Act, or the Tax Act, which significantly reformed the U.S.
+Added: Internal Revenue Code of 1986, as amended, or the Code.
+Added: The Tax Act, among other things, contained significant changes to corporate taxation.
+Added: As part of Congress’ response to the COVID-19 pandemic, the Families First Coronavirus Response Act, or FFCR Act, was enacted on March 18, 2020, the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, was enacted on March 27, 2020, COVID-19 relief provisions were included in the Consolidated Appropriations Act, 2021, or CAA, which was enacted on December 27, 2020 and the American Rescue Plan Act of 2021, or ARPA, was enacted on March 11, 2021.
+Added: All contain numerous tax provisions.
+Added: Regulatory guidance under the Tax Act, the FFCR Act, the CARES Act, the CAA and the ARPA is and continues to be forthcoming, and such guidance could ultimately increase or lessen impact of these laws on our business and financial condition.
+Added: It is possible that Congress will enact additional legislation in connection with the COVID-19 pandemic.
+Added: Furthermore, as a result of the changes in the U.S.
+Added: presidential administration and control of the U.S.
+Added: Senate, it is possible that additional tax legislation will be enacted.
+Added: Such legislation could have an impact on our company.
+Added: In addition, it is uncertain if and to what extent various states will conform to the Tax Act, the FFCR Act, the CARES Act, the CAA or the ARPA.
Risks Related to Our Dependence on Third Parties
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We cannot assure you a given regulatory authority will determine that any of our clinical trials comply with cGCP regulations.
−Removed: We also are required to register
−Removed: ongoing clinical trials and post the results of completed clinical trials on a U.S.
+Added: We also are required to register ongoing clinical trials and post the results of completed clinical trials on a U.S.
government-sponsored database, clinicaltrials.gov, within certain timeframes.
Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.
+Added: We are exposed to risk of fraud or other misconduct by such third parties.
Furthermore, third parties on whom we rely may also have relationships with other entities, some of which may be our competitors.
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Any performance failure on the part of our distributors could delay clinical development or marketing approval of our product candidates or commercialization of our medicines, producing additional losses and depriving us of potential product revenue.
−Removed: We contract with third parties for the manufacture of our product candidates for preclinical and clinical testing and we expect to contract with third parties for the manufacture of our product candidates for commercialization.
+Added: We contract with third parties for the manufacture of our product candidates for preclinical and clinical testing and for commercialization.
We do not have any manufacturing facilities.
−Removed: We currently rely, and expect to continue to rely, on third-party manufacturers for the materials and manufacture of our product candidates for preclinical and clinical testing and expect to rely on third-party manufacturers for commercial supply of any product candidate for which we or our collaborators obtain marketing approval.
−Removed: Although we expect to complete long-term supply agreements for commercial supply of mitapivat with third-party manufacturers ahead of a potential regulatory approval, we may be unable to establish similar long-term supply agreements with third-party manufacturers with respect to our other GDD product candidates or to do so on acceptable terms.
+Added: We currently rely, and expect to continue to rely, on third-party manufacturers for the materials and manufacture of our product candidates for preclinical and clinical testing and for commercial supply of PYRUKYND® and any product candidate for which we or our collaborators obtain marketing approval.
+Added: Although we have entered into long-term supply agreements for commercial supply of PYRUKYND® with third-party manufacturers, we may be unable to establish similar long-term supply agreements with third-party manufacturers with respect to our other GDD product candidates or to do so on acceptable terms.
Even if we are able to establish agreements with third-party manufacturers, reliance on third-party manufacturers entails additional risks, including:
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• the possible termination or nonrenewal of the agreement by the third party at a time that is costly or inconvenient for us.
−Removed: Third-party manufacturers may not be able to comply with current good manufacturing practices, or cGMP.
+Added: Third-party manufacturers may not be able to comply with cGMPs.
regulations or similar regulatory requirements on a global basis.
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Although global shipping continues to be disrupted due to the pandemic, we have not yet experienced a supply impact.
−Removed: If either we or any third parties on which we rely are adversely impacted by restrictions resulting from the COVID-19 pandemic, our supply chain may be disrupted, limiting our ability to manufacture our product candidates for our clinical trials and research and development operations.
−Removed: Any performance failure on the part of our existing or future manufacturers could delay clinical development or marketing approval.
+Added: If either we or any third parties on which we rely are adversely impacted by restrictions resulting from the COVID-19 pandemic, our supply chain may be disrupted, limiting our ability to manufacture our product candidates for our clinical trials and research and development operations and our product for commercialization.
+Added: Any performance failure on the part of our existing or future manufacturers could delay clinical development, marketing approval or our commercialization efforts.
We do not currently have arrangements in place for redundant supply for drug product.
If any one of our current contract manufacturers cannot perform as agreed, we may be required to replace that manufacturer.
−Removed: Although we believe that there are several potential alternative manufacturers who could manufacture our product candidates, we may incur added costs and delays in identifying and qualifying any such replacement.
+Added: Although we believe that there are several potential alternative manufacturers who could manufacture our product or our product candidates, we may incur added costs and delays in identifying and qualifying any such replacement.
Our current and anticipated future dependence upon others for the manufacture of our product candidates or medicines may adversely affect our future profit margins and our ability to commercialize any medicines that receive marketing approval on a timely and competitive basis.
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It is also possible that we will fail to identify and/or file patent applications on every aspect of our research and development output that is or may be eligible for patent protection.
−Removed: Although we enter into non-disclosure and confidentiality agreements with parties who may have access to 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.
+Added: Although we enter into non-disclosure and confidentiality agreements with parties who may have access to 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
+Added: patent protection.
There is also the possibility that loss or theft of data or records may jeopardize the ability to seek patent protection or impede the progress or drafting of patent applications.
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An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our technology or products and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize medicines without infringing third-party patent rights.
−Removed: Even if our patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other third parties from competing with us or otherwise provide us with any competitive
+Added: Even if our patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other third parties from competing with us or otherwise provide us with any competitive advantage.
Our competitors or other third parties may be able to circumvent our patents by developing similar or alternative technologies or products in a non-infringing manner.
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The biotechnology and pharmaceutical industries are characterized by extensive litigation regarding patents and other intellectual property rights.
−Removed: Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell our product candidates and use our proprietary technologies without infringing the proprietary rights and intellectual property of third parties.
+Added: Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell our product and product candidates and use our proprietary technologies without infringing the proprietary rights and intellectual property of third parties.
We have in the past and may in the future become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our medicines and technology, including opposition, derivation, revocation, reexamination, post-grant and inter partes review or interference proceedings before the USPTO or other patent offices around the world.
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In addition, we or our collaborators could be found liable for monetary damages.
−Removed: A finding of infringement could prevent us or our collaborators from commercializing our product candidates or force us to cease some of our business operations, which could materially harm our business.
+Added: A finding of infringement could prevent us or our collaborators from commercializing our product and product candidates or force us to cease some of our business operations, which could materially harm our business.
Claims that we or our collaborators have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.
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Litigation may be necessary to defend against these claims.
−Removed: If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable
−Removed: intellectual property rights or personnel.
+Added: If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel.
Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to our organization.
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Unpatented proprietary technical information and know-how can be difficult to protect.
−Removed: We seek to protect this proprietary technical information and know-how, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, corporate collaborators, outside scientific collaborators, contract research organizations, contract manufacturers, consultants, advisors and other third parties.
+Added: We seek to protect this proprietary technical information and know-how, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, corporate collaborators, outside
+Added: scientific collaborators, contract research organizations, contract manufacturers, consultants, advisors and other third parties.
We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants.
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Our product candidates and the activities associated with their development and commercialization, including their design, testing, manufacture, safety, efficacy, record keeping, labeling, storage, approval, advertising, promotion, sale and distribution, export and import, are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States and by the EMA and comparable regulatory authorities in other countries.
−Removed: With the exception of the FDA approvals of IDHIFA® and TIBSOVO®, the rights of which we have sold to Servier, we and our collaborators have not received approval to market any of our product candidates from regulatory authorities in any jurisdiction.
+Added: With the exception of the FDA approval of PYRUKYND®, for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, we have not received approval to market any of our current product candidates from regulatory authorities in any jurisdiction.
Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to the various regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy.
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The FDA, EMA and other foreign regulatory authorities have substantial discretion in the approval process.
−Removed: Accordingly, it is possible that the FDA or EMA may refuse to accept for substantive review any NDA, sNDA or MAA that we submit for our product candidates, or may conclude after review of our data that our marketing application is insufficient to obtain marketing
−Removed: approval of our product candidates, including with respect to the NDA and MAA for mitapivat that are each currently under review by the FDA and EMA, respectively.
+Added: Accordingly, it is possible that the FDA or EMA may refuse to accept for substantive review any NDA, sNDA or MAA that we submit for our product candidates, or may conclude after review of our data that our marketing application is insufficient to obtain marketing approval of our product candidates, including with respect to the MAA for PYRUKYND® that is currently under review by the EMA.
If the FDA or EMA does not accept or approve our applications for any of our product candidates, the applicable regulator may require that we conduct additional clinical trials, preclinical studies or manufacturing validation studies and submit that data before reconsidering our applications.
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If a prolonged government shutdown were to occur, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.
+Added: Should the FDA determine that an inspection is necessary for approval of a regulatory submission and an inspection cannot be completed during the review cycle due to restrictions on travel due to COVID-19, and the FDA does not determine a remote interactive evaluation to be adequate, the FDA has stated that it generally intends to issue a complete response letter or defer action on the regulatory submission until an inspection can be completed.
If we or our collaborators experience delays in obtaining approval or if we or they fail to obtain approval of our product candidates, the commercial prospects for our product candidates may be harmed and our ability to generate revenue will be materially impaired.
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We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our medicines in any market.
−Removed: Additionally, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the recent withdrawal of the United Kingdom from the EU on December 31, 2020, commonly referred to as Brexit.
−Removed: On December 24, 2020, the United Kingdom and EU entered into a Trade and Cooperation Agreement, which sets out certain procedures for approval and recognition of medical products in each jurisdiction.
−Removed: Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from commercializing any product candidates in the United Kingdom and/or the EU and restrict our ability to generate revenue and achieve and sustain profitability.
−Removed: If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or EU for any product candidates, which could significantly and materially harm our business.
+Added: Additionally, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the withdrawal of the United Kingdom from the EU on December 31, 2020, commonly referred to as Brexit.
+Added: On December 24, 2020, the United Kingdom and EU entered into a Trade and Cooperation Agreement, which sets out certain procedures for approval and recognition of medical products in each jurisdiction, and the United Kingdom and EU continue to work on the rules for implementation.
+Added: Since the regulatory framework for pharmaceutical products in the United Kingdom covering the quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical products is derived from EU directives and regulations, the consequences of Brexit and the impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom remains unclear.
+Added: Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from commercializing any product candidates in the United Kingdom and/or the EU and restrict our ability to generate revenue and achieve and sustain profitability, which could significantly and materially harm our business.
We expect that we will be subject to additional risks in commercializing any of our product candidates that receive marketing approval outside the United States, including tariffs, trade barriers and regulatory requirements;
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and workforce uncertainty in countries where labor unrest is more common than in the United States.
−Removed: Fast track designation and/or priority review designation by the FDA may not actually lead to a faster development or regulatory review or approval process, nor does it assure approval of the product candidate by the FDA.
+Added: In addition, we do not have experience commercializing products outside of the United States and such efforts may depend on our ability to find a suitable collaborator.
+Added: Fast track designation and/or priority review designation by the FDA or PRIME designation in the EU may not actually lead to a faster development or regulatory review or approval process, nor does it assure approval of the product candidate by the FDA or the EMA.
+Added: We may seek fast track designation, priority review designation and/or PRIME designation for our product candidates.
If a product candidate is intended for the treatment of a serious or life-threatening disease or condition and the product candidate demonstrates the potential to address unmet medical needs for this disease or condition, the drug sponsor may apply for FDA fast track designation.
Further, if the FDA determines that a product candidate offers major advances in treatment or provides a treatment where no adequate therapy exists, the FDA may designate the product candidate for priority review.
−Removed: A priority review designation means that the goal for the FDA to review an application is six months, rather than the standard review period of ten months.
+Added: A priority review designation means
+Added: that the goal for the FDA to review an application is six months, rather than the standard review period of ten months.
Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or thereafter.
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The FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program.
−Removed: In August 2021, the FDA accepted our NDA for mitapivat for the treatment of adults with PK deficiency with priority review designation.
−Removed: We may seek fast track designation and/or priority review designation for our other product candidates.
+Added: In addition, in the EU, the PRIME designation program focuses on product candidates that target conditions for which there exists no satisfactory method of treatment in the EU or product candidates that may offer a major therapeutic advantage over existing treatments.
+Added: The benefits of a PRIME designation include, among other things, the potential to qualify product for accelerated review, meaning reduction in the review time for an opinion on approvability to be issued earlier in the application process.
+Added: PRIME designation enables an applicant to request parallel EMA scientific advice and health technology assessment advice to facilitate timely market access.
+Added: Even if our product candidates receive PRIME designation, we may not experience a faster development process, review or approval compared to conventional EMA procedures and it does not assure or increase the likelihood of the EMA’s grant of a marketing authorization.
We, or any collaborators, may not be able to obtain orphan drug designation or orphan drug exclusivity for our drug candidates and, even if we do, that exclusivity may not prevent the FDA or the EMA from approving competing drugs.
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These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to quality control and manufacturing, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distribution of samples to physicians and record keeping.
−Removed: Even if marketing approval of a product
−Removed: candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a risk evaluation and mitigation strategy.
+Added: Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a risk evaluation and mitigation strategy.
The FDA and other agencies, including the Department of Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling.
The FDA and DOJ impose stringent restrictions on manufacturers’ communications regarding off-label use and if we market our medicines for uses other than their respective approved indications, we may be subject to enforcement action for off-label marketing.
−Removed: Violations of the FDCA and other statutes, including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to investigations and enforcement actions alleging violations of federal and state health care fraud and abuse laws, as well as state consumer protection laws, which violations may result in the imposition of significant administrative, civil and criminal penalties.
+Added: Violations of the FDCA and other statutes,
+Added: including the False Claims Act, relating to the promotion and advertising of prescription drugs may lead to investigations and enforcement actions alleging violations of federal and state health care fraud and abuse laws, as well as state consumer protection laws, which violations may result in the imposition of significant administrative, civil and criminal penalties.
Our relationships with healthcare providers, physicians and third-party payors are subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which, in the event of a violation, could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.
−Removed: Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval.
−Removed: Our future arrangements with healthcare providers, physicians and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any medicines for which we obtain marketing approval.
+Added: Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of PYRUKYND® and any product candidates for which we obtain marketing approval.
+Added: Our future arrangements with healthcare providers, physicians and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute PYRUKYND® and any other medicines for which we obtain marketing approval.
Restrictions under applicable federal and state healthcare laws and regulations include the following:
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• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
−Removed: • the federal Physician Payments Sunshine Act requires applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals;
+Added: • the federal Physician Payments Sunshine Act requires applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals and other covered recipients;
• analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws and transparency statutes, may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers.
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Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States.
−Removed: These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the EU Member States.
+Added: These requirements are provided in the
+Added: national laws, industry codes or professional codes of conduct, applicable in the EU Member States.
Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.
−Removed: Even if we or any collaborators are able to commercialize any product candidates, such products may become subject to unfavorable pricing regulations and third-party reimbursement practices, which would harm our business.
−Removed: The commercial success of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third-party payors, including government health administration authorities and private health coverage insurers.
−Removed: If coverage and reimbursement is not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize our product candidates.
+Added: PYRUKYND® or any product candidate that we commercialize may become subject to unfavorable pricing regulations and third-party reimbursement practices, which would harm our business.
+Added: The commercial success of PYRUKYND® or of any of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third-party payors, including government health administration authorities and private health coverage insurers.
+Added: If coverage and reimbursement is not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize PYRUKYND® or our product candidates.
Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us, or any future collaborators, to establish or maintain pricing sufficient to realize a sufficient return on our or their investments.
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Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.
−Removed: Therefore, our ability, and the ability of any collaborators, to commercialize any of our product candidates will depend in part on the extent to which coverage and reimbursement for these products and related treatments will be available from third-party payors.
+Added: Therefore, our ability, and the ability of any collaborators, to commercialize PYRUKYND® or any of our product candidates will depend in part on the extent to which coverage and reimbursement for these products and related treatments will be available from third-party payors.
Third-party payors decide which medications they will cover and establish reimbursement levels.
The healthcare industry is acutely focused on cost containment, both in the United States and elsewhere.
−Removed: Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications, which could affect our ability or that of any collaborators to sell our product candidates profitably.
+Added: Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications, which could affect our ability or that of any collaborators to sell PYRUKYND® or our product candidates profitably.
These payors may not view our products, if any, as cost-effective, and coverage and reimbursement may not be available to our customers, or those of any collaborators, or may not be sufficient to allow our products, if any, to be marketed on a competitive basis.
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In addition, increasingly, third-party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged.
−Removed: We cannot be sure that coverage will be available for any product candidate that we, or any collaborator, commercialize and, if available, that the reimbursement rates will be adequate.
+Added: We cannot be sure that coverage will be available for PYRUKYND® or any product candidate that we, or any collaborator, may commercialize and, if available, that the reimbursement rates will be adequate.
Further, the net reimbursement for drug products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
−Removed: An inability to
−Removed: promptly obtain coverage and adequate payment rates from both government-funded and private payors for any of our product candidates for which we, or any collaborator, obtain marketing approval could significantly harm our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.
+Added: An inability to promptly obtain coverage and adequate payment rates from both government-funded and private payors for PYRUKYND® or any of our product candidates for which we, or any collaborator, may obtain marketing approval could significantly harm our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.
Current and future healthcare reform legislation may increase the difficulty and cost for us and any collaborators to obtain reimbursement and commercialize our drug candidates.
−Removed: In the United States and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any collaborators, to profitably sell any product for which we, or they, obtain marketing approval.
+Added: In the United States and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability, or the ability of any collaborators, to profitably sell PYRUKYND® or any other product for which we, or they, obtain marketing approval.
We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or any collaborators, may receive for any approved products.
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In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.
−Removed: This legislation resulted in aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which will remain in effect through 2030 under the CARES Act.
+Added: This legislation resulted in aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which will remain in effect through 2031.
+Added: However, pursuant to the CARES Act and subsequent legislation, these Medicare sequester reductions were suspended through the end of March 2022 and from April 2022 through June 2022, a 1% cut will be in effect, with the full 2% cut resuming thereafter.
The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
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To those ends, President Trump issued several executive orders intended to lower the costs of prescription drug products.
−Removed: Certain of these orders are reflected in recently promulgated regulations, including an interim final rule implementing President Trump’s most favored nation model, but such final rule is currently subject to a nationwide preliminary injunction.
−Removed: In addition, on August 21, 2021, the Centers for Medicare & Medicaid Services, or CMS, issued a new proposed rule similar to President Trump’s most favored nation model under which Medicare Part B reimbursement for certain drugs would be based on lower prices in other countries.
+Added: Certain of these orders are reflected in recently promulgated regulations, including an interim final rule implementing President Trump’s most favored nation model, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries effective, but such final rule is currently subject to a nationwide preliminary injunction.
+Added: On August 21, 2021, the Centers for Medicare & Medicaid Services, or CMS, issued a proposed rule to rescind President Trump’s interim final rule, following public notice and comment, and CMS stated it will explore all options to incorporate value into payments for Medicare Part B drugs and improve beneficiaries’ access to evidence-based care.
+Added: The Biden Administration has frozen certain of the Trump Administration’s measures to reform drug prices.
It remains to be seen whether the orders and resulting regulations put in place during the Trump Administration will remain in force.
Further, on September 24, 2020, the Trump Administration finalized a rulemaking allowing states or certain other non-federal government entities to submit importation program proposals to the FDA for review and approval.
−Removed: Applicants are required to demonstrate that their importation plans pose no additional risk
−Removed: to public health and safety and will result in significant cost savings for consumers.
+Added: Applicants are required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in
+Added: significant cost savings for consumers.
The FDA has issued draft guidance that would allow manufacturers to import their own FDA-approved drugs that are authorized for sale in other countries (multi-market approved products).
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These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.
−Removed: We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing pressures.
+Added: We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product or product candidates or additional pricing pressures.
+Added: In the European Union, similar political, economic and regulatory developments may affect our ability to profitably commercialize our product candidates, if approved.
We are subject to U.S.
−Removed: and foreign anti-corruption and anti-money laundering laws with respect to our operations and non-compliance with such laws can subject us to criminal and/or civil liability and harm our business.
−Removed: We are subject to the U.S.
+Added: and foreign export control, import, sanctions, anti-corruption and anti-money laundering laws with respect to our operations and non-compliance with such laws can subject us to criminal and/or civil liability and harm our business.
+Added: We are subject to export control and import laws and regulations, including the U.S.
+Added: Export Administration Regulations, U.S.
+Added: Customs regulations, various economic and trade sanctions regulations administered by the U.S.
+Added: Treasury Department’s Office of Foreign Assets Control, the U.S.
Foreign Corrupt Practices Act of 1977, as amended, the U.S.
6 unchanged sentences
We can be held liable for the corrupt or other illegal activities of these third-party intermediaries, our employees, representatives, contractors, partners, and agents, even if we do not explicitly authorize or have actual knowledge of such activities.
−Removed: Noncompliance with anti-corruption and anti-money laundering laws could subject us to whistleblower complaints, investigations, sanctions, settlements, prosecution, other enforcement actions, disgorgement of profits, significant fines, damages, other civil and criminal penalties or injunctions, suspension and/or debarment from contracting with certain persons, the loss of export privileges, reputational harm, adverse media coverage, and other collateral consequences.
+Added: Noncompliance with such laws could subject us to whistleblower complaints, investigations, sanctions, settlements, prosecution, other enforcement actions, disgorgement of profits, significant fines, damages, other civil and criminal penalties or injunctions, suspension and/or debarment from contracting with certain persons, the loss of export privileges, reputational harm, adverse media coverage, and other collateral consequences.
If any subpoenas, investigations, or other enforcement actions are launched, or governmental or other sanctions are imposed, or if we do not prevail in any possible civil or criminal litigation, our business, results of operations and financial condition could be materially harmed.
23 unchanged sentences
Our consultants and advisors, including our scientific co-founders, who assist us in formulating our research and development and commercialization strategy may be employed by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their availability to us.
−Removed: We also cannot be sure of the effect that the recent sale of our oncology business to Servier will have on our ability to retain and hire key personnel.
−Removed: Our current and prospective employees may feel uncertain about their roles with us now that we are a smaller company focused on GDDs, which may have an adverse effect on our ability to attract or retain key management personnel or other key employees.
Furthermore, the ongoing COVID-19 pandemic and our flexible workplace policy allowing employees to work from home may make it difficult for us to maintain our corporate culture.
4 unchanged sentences
We are exposed to the risk of employee fraud or other misconduct.
−Removed: Misconduct by employees could include intentional failures to comply with FDA regulations, provide accurate information to the FDA, comply with manufacturing standards we have established, comply with federal and state healthcare fraud and abuse laws and regulations, report financial information or data accurately, disclose unauthorized activities to us, or comply with securities laws.
−Removed: Employee misconduct could also involve the improper use of information obtained in the course of clinical trials, including for illegal insider trading activities, which could result in regulatory sanctions and serious harm to our reputation.
+Added: Misconduct by employees could include intentional failures to comply with FDA regulations or regulations in other jurisdictions, provide accurate information to the FDA or other regulatory authorities, comply with manufacturing standards we have established, comply with federal and state healthcare fraud and abuse laws and regulations, report financial information or data accurately, disclose unauthorized activities to us, or comply with securities laws.
+Added: Employee misconduct could also involve the improper use of information obtained in the course of clinical trials or interactions with the FDA or other regulatory authorities, including for illegal insider trading activities, which could result in regulatory sanctions and serious harm to our reputation.
We have adopted a Code of Business Conduct and Ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.
27 unchanged sentences
The trading price of our common stock has been, and may continue to be, volatile and could be subject to wide fluctuations in response to various factors, some of which are beyond our control.
−Removed: For example, since January 1, 2015 the price of our common stock on the Nasdaq Global Select Market has ranged from $27.77 per share to $138.85 per share.
+Added: For example, since January 1, 2015 the closing price of our common stock on the Nasdaq Global Select Market has ranged from $22.70 per share to $138.85 per share.
The stock market in general and the market for biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies.
1 unchanged sentence
The market price for our common stock may be influenced by many factors, including:
−Removed: • the impacts of the recent sale of our oncology business to Servier on our business;
+Added: • our success in launching and commercializing PYRUKYND®;
+Added: • the impact of the sale of our oncology business to Servier on our business;
• the impact of our repurchases of shares of common stock from our stockholders;
1 unchanged sentence
• the timing and results of clinical trials of product candidates, or our competitors’ product candidates;
−Removed: • regulatory actions with respect to our product candidates or our competitors’ products and product candidates;
+Added: • regulatory actions with respect to our product or product candidates or our competitors’ products and product candidates;
• commencement or termination of collaborations for our development programs;
3 unchanged sentences
• the recruitment or departure of key personnel;
−Removed: • the level of expenses related to any of our product candidates or clinical development programs;
−Removed: • the results of our efforts to develop additional product candidates;
+Added: • the level of expenses related to any of our products, product candidates or development programs;
+Added: • the results of our efforts to develop additional product candidates and products;
• actual or anticipated changes in estimates as to financial results or development timelines;
2 unchanged sentences
• variations in our financial results or results of companies that are perceived to be similar to us;
−Removed: • whether an active trading market for our shares is sustained;
• changes in estimates, evaluations or recommendations by securities analysts, that cover our stock or the failure by one or more securities analysts to continue to cover our stock;
11 unchanged sentences
Our executive officers, directors and principal stockholders maintain the ability to significantly influence all matters submitted to stockholders for approval.
−Removed: As of September 30, 2021, our executive officers, directors and principal stockholders, in the aggregate, beneficially owned shares representing a significant percentage of our capital stock.
+Added: As of March 31, 2022, our executive officers, directors and principal stockholders, in the aggregate, beneficially owned shares representing a significant percentage of our capital stock.
As a result, if these stockholders were to choose to act together, they would be able to significantly influence all matters submitted to our stockholders for approval, as well as our management and affairs.
15 unchanged sentences
As a result, our effective tax rate is derived from a combination of applicable tax rates in the various places that we operate.
−Removed: In preparing our financial statements, we estimate the amount of tax that will become payable in each of such places.
−Removed: Nevertheless, our effective tax rate may be different from previous periods or our current expectations due to numerous factors, including as a result of changes in the mix of our
−Removed: profitability from state to state, the results of examinations and audits of our tax filings, our inability to secure or sustain acceptable agreements with tax authorities, changes in accounting for income taxes and changes in tax laws.
+Added: In preparing our financial statements, we estimate the
+Added: amount of tax that will become payable in each of such places.
+Added: Nevertheless, our effective tax rate may be different from previous periods or our current expectations due to numerous factors, including as a result of changes in the mix of our profitability from state to state, the results of examinations and audits of our tax filings, our inability to secure or sustain acceptable agreements with tax authorities, changes in accounting for income taxes and changes in tax laws.
Any of these factors may result in tax obligations in excess of amounts accrued in our financial statements.
7 unchanged sentences
On March 25, 2021, we announced that our Board of Directors authorized the Repurchase Program for the repurchase of up to $1.2 billion of our outstanding shares of common stock.
−Removed: On March 31, 2021, in connection with the Repurchase Program, we entered into a definitive share repurchase agreement with BMS to repurchase 7,121,658 shares of our common stock held by certain subsidiaries of BMS for an aggregate purchase price of $344.5 million, or $48.3785 per share.
−Removed: This repurchase was completed on April 5, 2021.
−Removed: Further, on April 2, 2021, in connection with the Repurchase Program, we entered into a Rule 10b5-1 repurchase plan to which we repurchased approximately 8.7 million shares of common stock for $438.9 million, or $50.57 per share, under the plan.
−Removed: In total, as of September 30, 2021, we have repurchased 15.8 million shares of common stock for $783.4 million under the Repurchase Program.
−Removed: On October 5, 2021, we terminated our Rule 10b5-1 share repurchase program and on October 13, 2021 entered into a Rule 10b-18 repurchase plan that allows us to conduct open market repurchases over time up to our remaining authorization.
−Removed: The amount and timing of share repurchases are subject to capital availability, our cash balances and future capital requirements and our determination that share repurchases are in the best interest of our stockholders and are in compliance with all respective laws and our applicable agreements.
+Added: In April 2021, in connection with the Repurchase Program, we repurchased from BMS 7.1 million shares of our common stock held by certain subsidiaries of BMS for an aggregate purchase price of $344.5 million, or $48.38 per share.
+Added: Further, in April 2021, in connection with the Repurchase Program, we entered into a Rule 10b5-1 repurchase plan pursuant to which we repurchased approximately 9.1 million shares of common stock for $458.0 million, or $50.35 per share, under the plan.
+Added: In total, as of December 31, 2021, we repurchased 16.2 million shares of common stock for $802.5 million under the Repurchase Program.
+Added: In October 2021, we terminated our Rule 10b5-1 share repurchase program and entered into a Rule 10b-18 repurchase plan that allows us to conduct open market repurchases over time up to our remaining authorization.
We have paused our share repurchases and for the foreseeable future, we expect that our capital allocation will be prioritized towards opportunities to accelerate programs in our development pipeline and/or pursue potential complementary business development opportunities.
+Added: The amount and timing of share repurchases are subject to capital availability, our cash balances and future capital requirements and our determination that share repurchases are in the best interest of our stockholders and are in compliance with all respective laws and our applicable agreements.
A reduction in repurchases under, or the completion of, our Repurchase Program could have a negative effect on our stock price.
4 unchanged sentences
As a result, capital appreciation, if any, of our common stock will be the sole source of gain for our stockholders for the foreseeable future.
+Added: Incorporated by Reference
+Added: Description of Exhibit
+Added: Date of Filing
+Added: 3.1 Restated Certificate of Incorporation
+Added: July 30, 2013 3.1
+Added: 3.2 Second Amended and Restated By-Laws
+Added: December 19, 2018 3.1
+Added: 31.1 Certification of principal executive officer pursuant to Rule 13a 14(a)/15d 14(a) of the Securities Exchange Act of 1934, as amended
+Added: 31.2 Certification of principal financial officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as amended.
+Added: 32.1* Certification of principal executive officer pursuant to 18 U.S.C.
+Added: §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.
+Added: 32.2* Certification of principal financial officer pursuant to 18 U.S.C.
+Added: §1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002.
+Added: XBRL Instance Document - the instance document does not appear in the Interactive Data File because its XBRL tags are not embedded within the Inline XBRL document
+Added: XBRL Taxonomy Extension Schema Document
+Added: XBRL Taxonomy Calculation Linkbase Document
+Added: XBRL Taxonomy Extension Definition Linkbase Document
+Added: XBRL Taxonomy Label Linkbase Document
+Added: XBRL Taxonomy Presentation Linkbase Document
+Added: 104 Cover Page Interactive Data File (formatted as Inline XBRL and contained in Exhibit 101.INS) X
+Added: * This certification will not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or the Exchange Act, or otherwise subject to the liability of that section.
+Added: Such certification will not be deemed to be incorporated by reference into any filing under the Securities Act of 1933, as amended, or the Exchange Act, except to the extent specifically incorporated by reference into such filing.
+Added: Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
+Added: AGIOS PHARMACEUTICALS, INC.
+Added: May 5, 2022 By:
+Added: /s/ Jacqualyn A.
+Added: Chief Executive Officer
+Added: (principal executive officer)
+Added: May 5, 2022 By:
+Added: /s/ Jonathan Biller
+Added: Jonathan Biller
+Added: Chief Financial Officer and Head of Corporate Affairs
+Added: (principal financial officer)
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.