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Item 1A. Risk Factors

2022-02-24 compared with 2021-02-25 · 323 added, 388 removed, 504 unchanged (59% of the section changed)

4 unchanged sentences

If any of the following risks occur, our business, financial condition, results of operations and future growth prospects could be materially and adversely affected.

Risks Relating to the Proposed Sale to Servier

The transaction is subject to conditions, some or all of which may not be satisfied, or completed on a timely basis, if at all.

Failure to complete, or unexpected delays in completing, the transaction or any termination of the Purchase Agreement could have an adverse effect on us, our financial condition and results of operations.

The completion of the transaction is subject to a number of conditions, including the approval of the transaction by Agios stockholders and the receipt of certain regulatory approvals, which make the completion and timing of the transaction uncertain.

The failure to satisfy all of the required conditions could delay the completion of the transaction for a significant period of time or prevent it from occurring at all.

There can be no assurance that the conditions to the completion of the transaction will be satisfied or waived or that the transaction will be completed.

In addition, either we or Servier may terminate the Purchase Agreement under certain circumstances, including if the transaction is not completed by the outside date.

In certain circumstances, upon termination of the Purchase Agreement, we would be required to pay a termination fee of $45 million to Servier.

If the transaction is not completed, we may be adversely affected and, without realizing any of the benefits of having completed the transaction, will be subject to a number of risks, including the following:

• the trading price of our common stock could decline ;

• if the Purchase Agreement is terminated and our board of directors seeks another strategic transaction, our stockholders cannot be certain that we will be able to find a party willing to enter into a transaction on terms equivalent to or more attractive than the terms that Servier has agreed to in the Purchase Agreement;

• time and resources, financial and otherwise, committed by our management to matters relating to the transaction could otherwise have been devoted to pursuing other beneficial opportunities;

• we may experience negative reactions from the financial markets or from our customers, suppliers, partners or employees;

• we will generally be required to pay our expenses relating to the transaction, such as legal, accounting and financial advisory fees, whether or not the transaction is completed.

In addition, if the transaction is not completed, we could be subject to litigation related to any failure to complete the transaction or related to any enforcement proceeding commenced against us to perform our obligations under the Purchase Agreement.

Any of these risks could materially and adversely impact our business, financial condition, results of operations and the trading price of shares of our common stock.

Similarly, delays in the completion of the transaction could, among other things, result in additional transaction costs, loss of revenue or other negative effects associated with delay and uncertainty about completion of the transaction and could materially and adversely impact our business, financial condition, results of operations and the trading price of shares of our common stock.

The amount of consideration we will receive in the transaction is subject to various risks and uncertainties.

In connection with the transaction, Servier will assume certain liabilities with respect to the oncology business and pay to us:

• $1.8 billion in cash upon the completion of the transaction, subject to certain adjustments for the working capital of the oncology business at the completion of the transaction and amounts for a representation and warranty insurance policy;

• $200 million in cash if, prior to January 1, 2027, vorasidenib is granted approval for an 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);

• a royalty payment of 5% of the U.S.

net sales (as defined in the Purchase Agreement ) of TIBSOVO® (ivosidenib) from the completion of the transaction through loss of exclusivity of TIBSOVO®;

• a royalty payment of 15% of the U.S.

net sales (as defined in the Purchase Agreement ) of vorasidenib from its first commercial sale through loss of exclusivity of vorasidenib.

The consideration described above is subject to various risks and uncertainties.

The purchase price is subject to a working capital adjustment;

specifically the purchase price will increase (or decrease) based on the amount of working capital of the oncology business as of the completion of the transaction relative to a specified working capital target.

It is not possible to determine with precision as of the date of this Annual Report on Form 10-K the amount of working capital the oncology business may have as of the completion of the transaction and, therefore, it is possible that the working capital adjustment may result in a meaningful reduction to the base purchase price.

In addition, 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.

Finally, the parties cannot predict what success, if any, Servier may have in the United States with respect to sales of TIBSOVO® and vorasidenib 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.

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 Annual Report on Form 10-K.

The Purchase Agreement contains provisions that limit our ability to pursue alternatives to the transaction, could discourage a third party from making a favorable alternative transaction proposal, and provide that, in specified circumstances, we would be required to pay a termination fee.

The Purchase Agreement contains provisions that make it more difficult for us to be acquired by, or enter into certain strategic transactions with (including the sale of businesses to), a third party.

The Purchase Agreement contains certain provisions that restrict our ability to, among other things, solicit, initiate or knowingly encourage or knowingly facilitate, or engage in or otherwise participate in any discussions or negotiations, with respect to any alternative transaction.

In addition, following receipt by us of any alternative transaction proposal that constitutes a “superior proposal,” Servier will have an opportunity to offer to modify the terms of the Purchase Agreement before our Board may withdraw, qualify or modify its recommendation with respect to the transaction in favor of such superior proposal.

These provisions could discourage a potential third-party acquiror that might have an interest in acquiring all or a significant portion of us or pursuing an alternative transaction from considering or proposing such a transaction.

In addition, either we or Servier may terminate the Purchase Agreement under certain circumstances, including if the transaction is not completed by the outside date.

In certain circumstances, upon termination of the Purchase Agreement , we would be required to pay a termination fee of $45 million to Servier.

The pendency of the transaction, whether or not consummated, may adversely affect our business and operations.

The announcement and pendency of the transaction, whether or not consummated, may adversely affect the trading price of our common stock as well as our relationships with existing or potential suppliers, customers, vendors, distributors, licensors, licensees, collaboration partners and other business partners, and may have an adverse effect on our business, financial condition and results of operations.

The pending transaction may cause such counterparties to seek to change existing business relationships with us or the oncology business, to forego new relationships or to enter into alternative agreements with our competitors because business partners may perceive that such new relationships are likely to be more stable.

In addition, our current and prospective employees, including of the oncology business, may feel uncertain about their roles with us or within the oncology business prior to and following the completion of transaction, which may have an adverse effect on our ability to attract or retain key management personnel or other key employees.

If key employees depart, our business, financial condition and results of operations may be adversely impacted.

The focus and attention of our management and employee resources may also be diverted from operational matters during the pendency of the transaction to focus on integration matters and the consummation of the transaction.

The parties must obtain certain regulatory approvals in order to complete the transaction;

if such approvals are not obtained or are obtained with conditions, the transaction may be prevented or delayed or the anticipated benefits of the transaction could be reduced.

Completion of the transaction is conditioned upon the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended.

At any time before or after the transaction is completed, any of the DOJ, the FTC or U.S.

state attorneys general could take action under the antitrust laws in opposition to the transaction, including seeking to enjoin completion of the transaction or condition completion of the transaction upon the divestiture of our assets, Servier or their respective subsidiaries or affiliates.

Any such requirements or restrictions may prevent or delay completion of the transaction or may reduce the anticipated benefits of the transaction, which could also have an adverse effect on us, our financial condition and its results of operations.

No assurance can be given that the required regulatory approvals will be obtained or that the required conditions to closing will be satisfied, and, even if all such approvals are obtained and the conditions are satisfied, no assurance can be given as to the terms, conditions and timing of the approvals.

Lawsuits may be filed against us challenging the transaction and an adverse ruling in any such lawsuit may prevent the transaction from being completed or from being completed within the expected time frame.

One of the conditions to the completion of the transaction is the absence of any judgment or law issued or enacted by any governmental entity of competent jurisdiction, in each case that has been entered and remains and effect that prevents, enjoins, renders illegal or prohibits the consummation of the transaction.

Accordingly, if litigation is filed challenging the transaction and a plaintiff is successful in obtaining an order enjoining completion of the transaction, then such order may prevent the transaction from being completed or from being completed within the expected time frame.

We may not be able to realize the anticipated benefits of the transaction.

We may not be able to realize the anticipated benefits from the transaction, including potentially deploying the proceeds from the transaction to expand its GDD business.

Our ability to realize the anticipated benefits of the transaction and the success of the remaining company 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.

We may also face new challenges operating as a smaller company as a result of the completion of the transaction, including:

• maintaining employee morale and retaining key management and other employees;

• retaining existing business and operational relationships, including with third parties, employees and other counterparties, as may be impacted by contracts containing consent and/or other provisions that may be triggered by the transaction, or with counterparties that otherwise prefer to transact with larger companies (or will only transact with smaller companies on less favorable terms);

• raising capital on favorable terms in debt or equity markets.

Following the transaction, we will be a smaller, less diversified company.

The transaction will result in us being a smaller, less diversified company with a more limited business concentrated on GDDs.

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.

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.

We will have broad discretion as to the use of the proceeds from the transaction, and may not use the proceeds effectively.

We will have broad discretion with respect to the use of proceeds of the transaction.

The results and effectiveness of the use of proceeds are uncertain, and we could spend the proceeds in ways that do not improve our remaining business, financial condition or results of operations.

Our failure to apply these funds effectively could have an adverse effect on its business, financial condition and results of operations.

Risks Related to Our Financial Position and Need for Additional Capital

We have incurred significant losses since inception.

We expect to incur losses in the future and may never achieve or maintain profitability.

Since inception, we have incurred significant operating losses.

Our net losses were $327.4 million, $411.5 million and $346.0 million for the years ended December 31, 2020, 2019 and 2018, respectively.

As of December 31, 2020, we had an accumulated deficit of $1,843.5 million.

To date, we have generated only modest revenue from sales of TIBSOVO® and prior to our sale to RPI of our royalty rights to IDHIFA®, royalties on sales of IDHIFA®.

Other than the FDA approvals of TIBSOVO® (for the treatment of IDH1 mutant-positive adult patients with 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), we have not obtained marketing approval for any of our product candidates, all of which are in preclinical or clinical development stages.

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.

We expect to continue to incur significant expenses and net losses until such time as we are able to report

profitable results.

The net losses we incur may fluctuate significantly from quarter to quarter.

We anticipate that we will incur significant expenses if and as we:

• initiate and continue clinical trials for our products and product candidates;

• continue our research and preclinical development of our product candidates and seek to identify additional product candidates;

• seek marketing approvals for our product candidates that successfully complete clinical trials;

• establish and maintain a sales, marketing and distribution infrastructure to commercialize any medicines for which we have or may obtain marketing approval;

• require the manufacture of larger quantities of product candidates for clinical development and, potentially, commercialization;

• maintain, expand and protect our intellectual property portfolio;

• add additional personnel to support our product research and development and planned future commercialization efforts and our operations;

• add equipment and physical infrastructure to support our research and development;

• acquire or in-license other medicines and technologies.

To become and remain profitable, we must develop and eventually commercialize one or more medicines with significant market potential.

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.

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.

If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis.

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.

A decline in the value of our company could also cause our stockholders to lose all or part of their investment.

We will need substantial additional funding.

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.

We expect to incur significant expenses as we continue to advance our ongoing activities.

We expect that our existing cash, cash equivalents and marketable securities as of December 31, 2020, together with anticipated product revenue, anticipated interest income and anticipated expense reimbursements under our collaboration and license agreements, but excluding any additional program-specific milestone payments or the anticipated proceeds from the proposed sale of our oncology business to Servier, will enable us to fund our operating expenses and capital expenditure requirements to the end of 2022.

Following the completion of the transaction with Servier and the subsequent shareholder returns, we expect to have sufficient capital to fund operations through major catalysts and to cash-flow positivity without the need to raise additional equity.

Our estimate as to how long we expect our existing cash, cash equivalents, and marketable securities to be available to fund our operations is based on assumptions that may prove to be wrong, and we could use our available capital resources sooner than we currently expect.

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 sooner than planned.

Our future capital requirements will depend on many factors, including:

• the timing and likelihood of the closing of the sale of our oncology business to Servier and the amount of potential consideration we receive in connection with the sale;

• the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our product candidates;

• the success of, and developments regarding, our collaborations;

• the costs, timing and outcome of regulatory review of our product candidates;

• the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims;

• commercialization expenses relating to approved medicines;

• levels of product revenue from sales of approved medicines;

• the cost associated with preparation for the potential commercial launch of one or more of our product candidates;

• our ability to establish and maintain additional collaborations on favorable terms, if at all;

• our ability to successfully execute on our strategic plans;

• operational delays due to the COVID-19 pandemic;

• the extent to which we acquire or in-license, or monitor or out-license, other medicines and technologies.

Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

Until such time as we can generate positive cash flow, we expect to finance our cash needs through a combination of cash on hand, equity offerings, debt financings, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

We do not have any committed external source of funds, other than agreements with our collaborators, which are limited in scope and duration.

To the extent that we raise additional capital from the issuances and sales of our common stock pursuant to the 2020 sales agreement or through the sale of equity or convertible debt securities, the ownership interests of our common 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.

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.

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.

If we raise funds through additional 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.

For example, in June 2020 we sold our tiered, sales-based royalty rights on worldwide net sales of IDHIFA®, as well as our rights to receive up to $55.0 million in outstanding regulatory milestone payments from BMS to RPI for $255.0 million.

Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.

Changes in tax law may adversely affect our business or financial condition.

On December 22, 2017, the U.S.

government enacted the Tax Cuts and Jobs Act, or the Tax Act, which significantly reformed the U.S.

Internal Revenue Code of 1986, as amended, or the Code.

The Tax Act, among other things, contained significant changes to corporate taxation.

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.

All contain numerous tax provisions.

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.

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.

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.

Risks Related to the Discovery, Development, and Commercialization of our Product Candidates

If we do not successfully commercialize our approved products in indications for which they may be approved our prospects may be substantially harmed.

Until the completion of the proposed sale of our oncology business to Servier, our ability to generate product revenue from TIBSOVO® will depend heavily on our successful development and commercialization of the product.

The development and commercialization of TIBSOVO® could be unsuccessful if:

• the medical community and third-party payors no longer accept TIBSOVO® as safe, efficacious, and cost-effective;

• we fail to maintain the necessary financial resources and expertise to manufacture, market and sell TIBSOVO®;

• we fail to continue to develop and implement effective marketing, sales and distribution strategies and operations for the development and commercialization of TIBSOVO®;

• we fail to continue to develop, validate and maintain a commercially viable manufacturing process for TIBSOVO® that is compliant with current good manufacturing practices, or cGMP;

• we fail to successfully obtain third party reimbursement and generate commercial demand that results in sales of TIBSOVO®;

• our efforts to commercialize TIBSOVO® are impeded by the effects of the COVID-19 pandemic;

• we encounter any third-party patent interference, derivation, inter partes review, post-grant review, reexamination or patent infringement claims with respect to ivosidenib;

• we fail to comply with regulatory and legal requirements applicable to the sale of TIBSOVO®;

• competing drug products are approved for the same indications as TIBSOVO®;

Risks Related to the Discovery, Development, and Commercialization of our Products and Product Candidates

If we do not successfully commercialize PYRUKYND and other products for which we receive approval, our prospects may be substantially harmed.

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.

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.

Our ability to generate revenue from PYRUKYND® will depend heavily on our successful development and commercialization of the product.

The development and commercialization of PYRUKYND® could be unsuccessful if:

• the medical community and third-party payors do not accept PYRUKYND® as safe, efficacious and cost-effective for the treatment of adults with PK deficiency;

• we fail to maintain the necessary financial resources and expertise to manufacture, market and sell PYRUKYND®;

• we fail to develop, implement and maintain effective marketing, sales and distribution strategies and operations for the development and commercialization of PYRUKYND®;

• 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;

• we fail to successfully obtain third party reimbursement and generate commercial demand that results in sales of PYRUKYND®;

• 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.

• our efforts to commercialize PYRUKYND® are impeded by the effects of the COVID-19 pandemic;

• we encounter any third-party patent interference, derivation, inter partes review, post-grant review, reexamination or patent infringement claims with respect to PYRUKYND®;

• we fail to comply with regulatory and legal requirements applicable to the sale of PYRUKYND®;

• competing drug products are approved for the same indications as PYRUKYND®;

• we fail to approve marketing approval of PYRUKYND® in jurisdictions other than the United States;

• new significant safety risks are identified;

• we fail to gain and/or maintain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community;

• ivosidenib 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.

If we experience significant delays or an inability to successfully develop and commercialize TIBSOVO®, our business would be materially harmed.

We may not be successful in our efforts to identify or discover potential product candidates or to develop additional medicines of commercial value and we may not achieve our goals included in our strategic vision.

A key element of our strategy has been to identify and test compounds that target cellular metabolism and adjacent areas of biology in a variety of different types of hematologic malignancies, solid tumors and GDDs, as well as in immune cells for the treatment of cancer.

A significant portion of the research that we are conducting involves new compounds and drug discovery methods, including our proprietary technology.

The drug discovery that we are conducting using our proprietary technology may not be successful in identifying compounds in our therapeutic areas.

In addition, our research programs may initially show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development for a number of reasons, including:

• the research methodology used may not be successful in identifying appropriate biomarkers or potential product candidates;

• potential product candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are unlikely to be medicines that will receive marketing approval and achieve market acceptance.

Research programs to identify new product candidates require substantial technical, financial and human resources.

We may choose to focus our efforts and resources on a potential product candidate that ultimately proves to be unsuccessful.

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 incremental product revenue in future periods, which likely would result in significant harm to our financial position and adversely impact our stock price.

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 products 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.

The COVID-19 pandemic, which began in December 2019, has spread worldwide, causing many governments to implement measures to slow the spread of the outbreak through quarantines, strict travel restrictions, heightened border scrutiny, and other measures.

The outbreak and government measures taken in response have also had a significant impact, both direct and indirect, on businesses and commerce, as worker shortages have occurred;

supply chains have been disrupted;

facilities and production have been suspended;

and demand for certain goods and services, such as medical services and supplies, has spiked, while demand for other goods and services, such as travel, has fallen.

The future progression of the pandemic and its effects on our business and operations are uncertain.

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.

We recently opened our Cambridge office to an additional, limited number of employees who prefer to work onsite, 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.

In the event of a continuation of shelter-in-place orders and/or other mandated local travel restrictions, our employees conducting research and development activities may not be able to access our research space, and our core activities may be significant limited or curtailed, possibly for an extended period of time.

In light of the pandemic, we may choose to pause certain research programs, delay the start of certain longer-term clinical trials and limit hiring.

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.

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.

We have faced and expect to 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.

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.

For example, due to disruptions related to the COVID-19 pandemic, we have delayed our expectations for completion of enrollment of our phase 3 AGILE clinical trial and the MDS arm of our phase 1 clinical trial of ivosidenib until 2021.

Additionally, the potential suspension of clinical trial activity at clinical trial sites may have an adverse impact on our clinical trial plans and timelines.

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 products and product candidates.

For example, we plan to submit to the FDA an sNDA for TIBSOVO® for previously treated IDH1 mutant-positive cholangiocarcinoma in the first quarter of 2021, which we originally intended to submit in the fourth quarter of 2020.

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.

The response to the COVID-19 pandemic may redirect resources with respect to regulatory and intellectual property matters in a way that would adversely impact our ability to progress regulatory approvals and protect our intellectual property.

In addition, we may face impediments to regulatory meetings and approvals due to measures intended to limit in-person interactions.

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.

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.

We depend heavily on the success of our clinical product candidates.

• 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;

• 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.

If we experience significant delays or an inability to successfully develop and commercialize PYRUKYND® our business would be materially harmed.

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.

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.

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.

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.

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 PYRUKYND®.

In February 2022, the FDA approved PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States.

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.

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Conversely, as a result of the same factors, our clinical trials may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any.

For example, many compounds that initially showed promise in earlier stage testing for treating cancer, GDDs or other diseases have later been found to cause side effects that prevented further development of the compound;

For example, many compounds that initially showed promise in earlier stage testing for treating specific disease indications have later been found to cause side effects that prevented further development of the compound;

• our product candidates may have undesirable side effects or other unexpected characteristics or otherwise expose participants to unacceptable health risks, causing us, our collaborators or our investigators, regulators or institutional review boards or the data safety monitoring board for such trial to halt, delay, interrupt, suspend or terminate the trials or cause us, or any collaborators, to abandon development or limit development of that product candidate to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective;

• if our product candidates have undesirable side effects, it could result in a more restrictive label, such as the “black box” warning for differentiation syndrome on the labels for IDHIFA® and TIBSOVO®, or it could result in the delay or denial of marketing approval by the FDA or comparable foreign regulatory authorities;

• if our product candidates have undesirable side effects, it could result in a more restrictive label, or it could result in the delay or denial of marketing approval by the FDA or comparable foreign regulatory authorities;

• clinical trials of our product candidates may produce negative or inconclusive results, and we, or our collaborators, may decide, or regulators may require us, to conduct additional clinical trials, including testing in more subjects, or abandon product development programs;

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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.

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.

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.

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.

A key element of our strategy is to identify and test compounds that target cellular metabolism and adjacent areas of biology in a variety of different types of GDDs.

A significant portion of the research that we are conducting involves new compounds and drug discovery methods, including our proprietary technology.

The drug discovery that we are conducting using our proprietary technology may not be successful in identifying compounds in our therapeutic areas.

• the research methodology used may not be successful in identifying appropriate biomarkers or potential product candidates;

Research programs to identify new product candidates require substantial technical, financial and human resources.

We may choose to focus our efforts and resources on a potential product candidate that ultimately proves to be unsuccessful.

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.

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.

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.

Our Cambridge office reopened, with appropriate safety precautions in place that are aligned with local and CDC advisements.

Operations have maintained productivity, while allowing employees who prefer to work onsite all or some of the time.

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.

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 have enrolled, and seek to enroll, patients in our clinical trials at sites located both in the United States and internationally.

We have faced and may continue to face difficulties recruiting or retaining patients in our ongoing clinical trials because of the pandemic.

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.

In addition, we may face impediments to regulatory meetings and approvals due to measures intended to limit in-person interactions.

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.

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.

For example, in the first quarter of 2020, we made the decision to halt internal development of AG-636 for the treatment of hematologic malignancies, including lymphoma due to limited enrollment in our phase 1 trial in lymphoma.

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.

For example, due to disruptions related to the COVID-19 pandemic, we delayed our expectations for completion of enrollment of our phase 3 AGILE clinical trial and the MDS arm of our phase 1 clinical trial of ivosidenib until 2021.

Patient enrollment is also affected by other factors including:

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In addition, some of our competitors may have ongoing or planned clinical trials for product candidates that would treat the same indications as our product candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors’ product candidates.

For example, Daiichi Sankyo Company, Ltd., or Daiichi Sankyo, with DS-1001b, Bayer AG, or Bayer, with BAY1436032, and Forma Therapeutics Holdings, LLC, or Forma, with FT-2102, are conducting clinical trials that are targeted specifically towards patients with IDH1 mutant positive-cancers and/or include IDH mutant positive populations;

Rocket Pharma LTD, or Rocket Pharma, developing a gene therapy targeting PK deficiency;

Vertex is developing a gene therapy targeting SCD;

Forma is developing a PKR activator for the treatment of hemolytic anemias, including PK deficiency and SCD;

and IDEAYA Biosciences, Inc., or IDEAYA, is developing a MAT2A inhibitor for the treatment of MTAP-deleted cancers.

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.

For example, Rocket Pharma LTD, or Rocket Pharma, is developing a gene therapy targeting PK deficiency;

Vertex Pharmaceuticals Incorporated, or Vertex, is developing a gene therapy targeting SCD;

IMARA Inc., or IMARA, and Forma Therapeutics Holdings, Inc., or Forma, are developing molecules for the treatment of beta thalassemia and SCD;

Global Blood Therapeutics is developing molecules for the treatment of SCD;

Fibrogen, Inc.

is developing Roxadustat for the treatment of anemia in MDS patients;

and Geron Corporation is developing imetelstat for the treatment of low-risk MDS.

Roivant Sciences is developing RVT-2001 (licensed from Eisai Co., Ltd.) for the treatment of transfusion-dependent anemia in patients with lower-risk MDS.

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.

Results of preclinical studies and early clinical trials may not be predictive of results of future clinical trials.

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.

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.

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.

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.

Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval for the product candidates.

Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have

nonetheless failed to obtain marketing approval for the product candidates.

Even if we, or any collaborators, believe that the results of clinical trials for our product candidates warrant marketing approval, the FDA or comparable foreign regulatory authorities may disagree and may not grant marketing approval of our product candidates.

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.

While we obtained marketing approval of PYRUKYND® for the treatment of [adults with PK deficiency] in the United States, we cannot be certain that we will obtain marketing approval of PYRYKYND® in other indications.

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.

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.

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.

There has been limited success to date industry-wide in developing these types of companion diagnostics.

To be successful, we need to address a number of scientific,

technical and logistical challenges.

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.

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.

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.

We also depend on Abbott Laboratories for the development of the FDA approved diagnostic for TIBSOVO®, and may in the future depend on other third parties for the development of other companion diagnostics for our cancer therapeutic product candidates.

If we or our collaborators are unable to successfully develop companion diagnostics for our therapeutic product candidates, or experience delays in doing so:

• 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;

• 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;

• 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.

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.

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:

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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• we may be subject to fines, injunctions or the imposition of civil or criminal penalties;

• regulatory authorities may require the addition of labeling statements, such as a “black box” warning or a contraindication, including, for example, the black box warning for differentiation syndrome on the labels for IDHIFA® and TIBSOVO®;

• regulatory authorities may require the addition of labeling statements;

• we, or any collaborators, may be required to create a Medication Guide outlining the risks of the previously unidentified side effects for distribution to patients;

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• our reputation may suffer.

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.

Our approved products, or any of our product candidates that 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.

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.

The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on a number of factors, including:

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.

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.

If PYRUKYND® or any of our product candidates, if approved, do not achieve an adequate level of acceptance, we may not generate significant product revenue and we may not become profitable.

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;

• 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.

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.

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.

Although we have established sales and marketing capabilities to support our co-promotion efforts for IDHIFA® and our sales of TIBSOVO®, we will need to further build our sales and marketing infrastructure to sell, or participate in sales activities with our collaborators for, our other product candidates if and when they are approved, including, for example, to support the potential approval of one or more product candidates in the EU.

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 commercially launch and sell PYRUKYND® for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States.

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.

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.

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.

We face competition with respect to our current products and 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.

We face competition with respect to PYRUKYND® and 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.

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.

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 AML, high risk myelodysplasia, PK deficiency, thalassemia and SCD.

For example, BMS, Jazz Pharmaceuticals plc, AbbVie Inc.

(in collaboration with Roche Holdings Inc.), Novartis International AG, or Novartis, Pfizer, Inc., or Pfizer, and Astellas Pharma Inc.

are each marketing therapies to treat AML, Acceleron Pharma Inc.

and bluebird bio, Inc., or bluebird, are each marketing therapies to treat beta thalassemia, Novartis 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.

Some competitive products and therapies are based on scientific approaches that are the same as or similar to our approach, and others are based on entirely different approaches, for example, in the area of GDDs.

We are developing most of our initial product candidates for the treatment of various types of cancer.

There are a variety of available drug therapies marketed for cancer.

In many cases, these drugs are administered in combination to enhance efficacy, and cancer drugs are frequently prescribed off-label by healthcare professionals.

Some of the currently approved drug therapies are branded and subject to patent protection, and others are available on a generic basis.

Many of these approved drugs are well established therapies and are widely accepted by physicians, patients and third-party payors.

Insurers and other third-party

payors may also encourage the use of generic products.

We expect that our product candidates, if approved, will be priced at a significant premium over competitive generic products, as is the case with TIBSOVO® and IDHIFA®.

This may make it difficult for us to achieve our business strategy of using our product candidates in combination with existing therapies or replacing existing therapies with our product candidates.

We are also pursuing product candidates to treat patients with GDDs.

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.

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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As a result, they may provide significant competition for any of our product candidates for which we obtain marketing approval.

There are also a number of product candidates in preclinical or clinical development by third parties to treat hematologic malignancies, solid tumors and GDDs by targeting similar mechanisms of action as our product candidates.

These companies include large pharmaceutical companies, such as Bayer, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc, and Merck, as well as biotechnology companies of various sizes, such as bluebird, Forma, IDEAYA, IMARA, Rocket Pharma, and Vertex.

In addition, there are several companies developing immunotherapies, including metabolic immunotherapies, targeting cancer, including AstraZeneca plc;

BeiGene, Ltd.;

Bristol-Myers Squibb Company;

GlaxoSmithKline plc;

Genentech Inc.;

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.

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.

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.

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.

Smaller and other clinical stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

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.

If the FDA does not grant our products appropriate periods of data exclusivity before approving generic versions of our products, the sales of our products could be adversely affected.

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.

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.

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.

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.

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.

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.

Product liability lawsuits against us or our collaborators could cause us or our collaborators to incur substantial liabilities and could limit commercialization of any medicines that we or they may develop.

We and our 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.

If we or our 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.

Regardless of merit or eventual outcome, liability claims may also result in, among other things:

• decreased demand for any product candidates or medicines that we may develop, reputational harm and lost revenue.

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.

A 505(b)(2) NDA product, or follow-product, may be for a new or improved version of the original reference listed drug.

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.

The FDCA provides a period of five years of new chemical entity exclusivity for a new drug containing a new active moiety.

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.

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.

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.

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.

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.

Regardless of merit or eventual outcome, liability claims may also result in, among other thing, decreased demand for any product candidates or medicines that we may develop, reputational harm and lost revenue.

Although we maintain product liability insurance coverage, it may not be adequate to cover all liabilities that we may incur.

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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.

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.

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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In addition, the GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the United States and, as a result, increases the scrutiny that clinical trial sites located in the EEA should apply to transfers of personal data from such sites to countries that are considered to lack an adequate level of data protection, such as the United States.

to lodge complaints with supervisory authorities, seek judicial remedies and obtain compensation for damages resulting from violations of GDPR.

The GDPR also permits data protection authorities to require destruction of improperly gathered or used personal information and/or impose substantial fines for violations of GDPR, and it also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies and obtain compensation for damages resulting from violations of GDPR.

In addition, the GDPR provides that EU member states may make their own further laws and regulations limiting the processing of personal data, including genetic, biometric or health data.

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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.

Risks Related to Our Financial Position

We face new challenges as a smaller, less diversified company following the sale of our oncology business to Servier.

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.

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.

We developed most of our initial products and product candidates for the treatment of various types of cancer.

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.

In addition, even with the FDA approval of PYRUKYND® the diversification of our revenues, costs and cash flows has diminished following the transaction.

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.

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.

We have broad discretion with respect to the use of proceeds of the sale of our oncology business to Servier.

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.

Our failure to apply these funds effectively could have an adverse effect on its business, financial condition and results of operations.

Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

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.

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.

In addition, in connection with potential future strategic transactions, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.

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.

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.

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.

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.

We expect to incur significant expenses as we continue to advance our ongoing activities.

We expect to execute our operating plan through major catalysts and to cash-flow positivity without the need to raise additional equity.

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.

Our future capital requirements will depend on many factors, including:

• the amount and timing of revenue received from commercial sales of PYRUKYND® and any of our other product candidates for which we may receive marketing approval;

• the amount of contingent consideration we ultimately receive in connection with the sale of our oncology business to Servier;

• the costs and timing of our ongoing commercialization activities, including product manufacturing, sales, marketing and distribution, for PYRUKYND® for the treatment of [adults with PK deficiency];

• the scope, progress, results and costs of drug discovery, preclinical development, laboratory testing and clinical trials for our product candidates;

• the costs, timing and outcome of regulatory review of our product candidates;

• the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims;

• 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;

• our ability to establish and maintain collaborations on favorable terms, if at all;

• our ability to successfully execute on our strategic plans;

• operational delays due to the COVID-19 pandemic;

• the extent to which we acquire or in-license, or monitor or out-license, other medicines and technologies.

We have historically incurred operating losses.

We expect to incur losses in the future and may never achieve or maintain profitability.

We have a history of incurring operating losses.

Our net income for the year ended December 31, 2021 was $1,604.7 million and our net losses for the years ended December 31, 2020 and 2019 were $327.4 million and $411.5 million, respectively.

As of December 31, 2021, we had an accumulated deficit of $238.8 million.

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®.

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.

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.

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.

In June 2021, we submitted a MAA for PYRUKYND® in adults with PK deficiency to the EMA.

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.

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.

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.

We expect to continue to incur significant expenses and net losses until such time as we are able to report profitable results.

The net losses we incur may fluctuate significantly from quarter to quarter.

We anticipate that we will incur significant expenses if and as we:

• commercially launch PYRUKYND® for the treatment of [adults with PK deficiency] in the United States;

• 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;

• initiate and continue clinical trials for our products and product candidates, including PYRUKYND® in other indications;

continue our research and preclinical development of our product candidates and seek to identify additional product candidates;

• seek marketing approvals for our product candidates that successfully complete clinical trials;

• require the manufacture of larger quantities of product candidates for clinical development and commercialization;

• maintain, expand and protect our intellectual property portfolio;

• add additional personnel to support our product research and development and planned future commercialization efforts and our operations;

• add equipment and physical infrastructure to support our research and development;

• acquire or in-license other medicines and technologies.

To become and remain profitable, we must develop and successfully commercialize one or more medicines with significant market potential.

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.

If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis.

A decline in the value of our company could also cause our stockholders to lose all or part of their investment.

The amount of contingent consideration we will receive from the sale of our oncology business to Servier is subject to various risks and uncertainties.

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:

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.

In addition, Servier will pay to us:

• $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);

• a royalty payment of 5% of the U.S.

net sales (as defined in the purchase agreement with Servier) of TIBSOVO® from the completion of the transaction through loss of exclusivity of TIBSOVO®;

• a royalty payment of 15% of the U.S.

net sales (as defined in the purchase agreement with Servier) of vorasidenib from its first commercial sale through loss of exclusivity of vorasidenib.

The contingent consideration described above is subject to various risks and uncertainties.

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.

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.

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.

Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.

Changes in tax law may adversely affect our business or financial condition.

On December 22, 2017, the U.S.

government enacted the Tax Cuts and Jobs Act, or the Tax Act, which significantly reformed the U.S.

Internal Revenue Code of 1986, as amended, or the Code.

The Tax Act, among other things, contained significant changes to corporate taxation.

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.

All contain numerous tax provisions.

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.

It is possible that Congress will enact additional legislation in connection with the COVID-19 pandemic.

Furthermore, as a result of the changes in the U.S.

presidential administration and control of the U.S.

Senate, it is possible that additional tax legislation will be enacted.

Such legislation could have an impact on our company.

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

We depend on our collaborations and may depend on collaborations with additional third parties for the development and commercialization of our product candidates.

We may depend on collaborations with third parties for the development and commercialization of our product candidates.

If those collaborations are not successful, we may not be able to capitalize on the market potential of these product candidates.

We are party to several collaboration agreements that provide for milestone payments to us based on the achievement of specified clinical development, regulatory and commercial milestones, provide us with royalty-based revenue if certain product candidates are successfully commercialized and provide for cost reimbursements of certain development activities.

We cannot predict the success of these collaborations.

We may seek other collaborations for the development and commercialization of our product candidates with large and mid-size pharmaceutical companies and biotechnology companies.

We may seek collaborations for the development and commercialization of our product candidates with large and mid-size pharmaceutical companies and biotechnology companies.

We face significant competition in seeking appropriate collaborators.

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We may not be able to negotiate collaborations on a timely basis, on acceptable terms, or at all.

Collaborators may have rights that restrict us from entering into future agreements on certain terms with potential collaborators.

If we enter into any such arrangements with collaborators, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of our product candidates.

Our ability to generate revenue from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements.

Collaborations involving our product candidates, including our collaborations with Celgene and CStone, pose the following risks to us:

• Collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations.

Under the 2010 Agreement, and the CStone Agreement, development and commercialization plans and strategies for licensed programs, such as enasidenib, or in the CStone Territory, ivosidenib, will be conducted in accordance with a plan and budget approved by a joint committee comprised of equal numbers of representatives from each of us and Celgene or CStone, as to which Celgene or CStone, as applicable, may have final decision-making authority.

Collaborators may not pursue development and commercialization of our product candidates or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborator’s strategic focus or available funding or external factors such as an acquisition that diverts resources or creates competing priorities.

For example, in March 2020, Celgene notified us of its decision to decline its option to enter into a development and commercialization agreement with respect to MAT2A and provided notice of its decision to decline its right to extend the research term of the 2016 Agreement.

Further, in April 2020, Celgene notified us that BMS has declined to elect any program for continued development and opt-in rights under the 2016 Agreement.

Collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing, which may result in a need for additional capital to pursue further development or commercialization of the applicable product candidate.

For example, under the 2010 Agreement, it is possible for Celgene to terminate the agreement, upon 90 days prior written notice, with respect to any product candidate at any point in the research, development and clinical trial process, without triggering a termination of the remainder of the collaboration arrangement.

• Collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our medicines or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours.

• Collaborators may have rights that restrict us from entering into future agreements on certain terms with potential collaborators.

Following the discovery phase until termination or expiration of the 2010 Agreement, either in its entirety or with respect to the relevant program, we may not directly or indirectly develop, manufacture or commercialize, outside of the collaboration, any medicine or product candidate with specified activity against any collaboration target that is within a licensed program or against any former collaboration target against which Celgene is conducting an independent program under the agreement.

• Collaborators with marketing and distribution rights to one or more medicines may not commit sufficient resources to the marketing and distribution of such medicine or medicines.

Collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our proprietary information or expose us to potential litigation.

For example, under specified circumstances Celgene has the first right to maintain or defend our intellectual property rights with respect to enasidenib under the 2010 Agreement and, although we may have the right to assume the maintenance and defense of our intellectual property rights if Celgene does not, our ability to do so may be compromised by Celgene’s actions.

• Disputes may arise between the collaborators and us that result in the delay or termination of the research, development or commercialization of our medicines or product candidates or that result in costly litigation or arbitration that diverts management attention and resources.

• We may lose certain valuable rights under circumstances identified in our collaborations, if we undergo a change of control.

• Collaborations may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization of the applicable product candidates.

For example, in September 2018, we and Celgene agreed to terminate the AG-881 Agreements, as a result of which we became responsible for future development costs of vorasidenib.

• Collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner or at all.

• If present or future collaborators of ours were to be involved in a business combination, the continued pursuit and emphasis on our product development or commercialization program under such collaboration could be delayed, diminished or terminated.

The failure to maintain the CStone Agreement or the failure of CStone to perform its obligations under the CStone Agreement, could negatively impact our business prospects in the CStone Territory.

In June 2018, we entered into the CStone Agreement, for the development and commercialization of ivosidenib, either as monotherapy or in combination with other therapies, in the CStone Territory.

Until the completion of the sale of our oncology business to Servier, our ability to generate royalty and milestone revenue under the CStone Agreement is dependent on CStone’s performance of its obligations under the CStone Agreement.

We cannot control the amount and timing of resources that CStone will dedicate to these efforts.

We are subject to a number of other risks associated with our dependence on the CStone Agreement with respect to ivosidenib in the CStone Territory, including:

• CStone may fail to comply with applicable regulatory guidelines with respect to developing, manufacturing or commercializing ivosidenib, which could adversely impact future development or potential sales of ivosidenib in the CStone Territory or elsewhere;

• There may be disputes between CStone and us, including disagreements regarding the CStone Agreement and as to future development plans, that may result in the delay of or failure to achieve developmental, regulatory and sales objectives that would result in milestone or royalty payments, the delay or termination of any future development or commercialization of ivosidenib in the CStone Territory, and/or costly litigation or arbitration that diverts our management’s attention and resources;

• CStone may fail to provide us with timely and accurate information regarding development, sales and marketing activities or supply forecasts, which could adversely impact our ability to comply with our obligations to CStone, as well as our ability to generate accurate financial forecasts;

• Business combinations, significant changes in CStone’s business strategy, or the impact of public health epidemics, such as the COVID-19 pandemic, may adversely affect CStone’s ability or resources available to perform its obligations under the CStone Agreement;

• During the term of the CStone Agreement, we are prohibited from developing or commercializing, in the CStone Territory and in specified indications, other compounds or products that inhibit IDH1 mutations at specified levels of binding.

The CStone Agreement is also subject to early termination, including through CStone’s right under certain circumstances to terminate upon advance notice to us.

If the CStone Agreement is terminated early, we may not be able to find another collaborator for the further development and commercialization of ivosidenib in the CStone Territory on acceptable terms, or at all, and we may be unable to pursue continued development and commercialization of ivosidenib in the CStone Territory on our own.

Disputes may arise between the collaborators and us that result in the delay or termination of the research, development or commercialization

of our medicines or product candidates or that result in costly litigation or arbitration that diverts management attention and resources.

Our ability to generate revenue from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements.

We rely and expect to continue to rely on third parties to conduct our clinical trials and some aspects of our research and preclinical testing, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials, research or testing.

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For example, we are responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol and legal, regulatory and scientific standards, and our reliance on third parties does not relieve us of our responsibility to comply with any such standards.

We and these third parties are required to comply with current good clinical practices, or cGCP, which are regulations and guidelines enforced by the FDA, the Competent Authorities of the Member States of the European Economic Area and comparable foreign regulatory authorities for all of our products in clinical development.

Regulatory authorities enforce these cGCPs through periodic inspections of trial sponsors, principal investigators and trial sites.

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Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.

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.

In addition, these third parties are not our employees, and except for remedies available to us under our agreements with such third parties, we cannot control whether or not they devote sufficient time and resources to our on-going clinical, nonclinical and preclinical programs.

delayed or terminated and we may not be able to obtain, or may be delayed in obtaining, marketing approvals for our product candidates and will not be able to, or may be delayed in our efforts to, successfully commercialize our medicines.

If these third parties do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need to be replaced or if the quality or accuracy of the clinical data they obtain is compromised, our clinical trials may be extended, delayed or terminated and we may not be able to obtain, or may be delayed in obtaining, marketing approvals for our product candidates and will not be able to, or may be delayed in our efforts to, successfully commercialize our medicines.

We also rely and expect to continue to rely on other third parties to store and distribute drug supplies for our clinical trials.

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.

We contract with third parties for the manufacture of our product candidates for preclinical and clinical testing and for commercialization.

We contract with third parties for the manufacture of our product candidates for preclinical and clinical testing for commercialization.

We do not have any manufacturing facilities.

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 any product candidate for which we or our collaborators obtain marketing approval.

Although we have long-term supply agreements in place for commercial supply of TIBSOVO® with third-party manufacturers, we may be unable to establish any further long-term supply agreements with respect to other product candidates with third-party manufacturers or to do so on acceptable terms.

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.

Although we have entered into long-term supply agreements for commercial supply of PYRUKYND® with third-party manufacturers ahead of its commercial launch, 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.

Third-party manufacturers may not be able to comply with cGMP regulations or similar regulatory requirements on a global basis.

Third-party manufacturers may not be able to comply with current cGMPs.

regulations or similar regulatory requirements on a global basis.

Our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates or medicines, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our medicines and harm our business and results of operations.

We have been monitoring our supply chain network for any disruptions due to the COVID-19 pandemic, and our manufacturers have remained largely unaffected, with any campaign delays experienced to date being limited to a few days in duration.

Although global shipping continues to be disrupted due to the pandemic, we have not yet experienced a supply impact and we have accrued additional stock of TIBSOVO® in order to further mitigate risk.

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.

Any performance failure on the part of our existing or future manufacturers could delay clinical development or marketing approval.

We do not currently have arrangements in place for redundant supply for bulk drug substance or drug product.

Although global shipping continues to be disrupted due to the pandemic, we have not yet experienced a supply impact.

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.

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.

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.

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.

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.

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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As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are highly uncertain.

Our pending and future patent applications may not result in patents being issued that protect our technology or medicines or that effectively prevent others from commercializing competitive technologies and medicines.

Our pending and future patent applications may

not result in patents being issued that protect our technology or medicines or that effectively prevent others from commercializing competitive technologies and medicines.

Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents or narrow the scope of our patent protection.

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An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated or interpreted narrowly.

because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

Third parties may initiate legal proceedings alleging that we or our collaborators are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.

The biotechnology and pharmaceutical industries are characterized by extensive litigation regarding patents and other intellectual property rights.

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.

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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Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future.

If we or one of our collaborators are found to infringe a third party’s intellectual property rights, we or they could be required to obtain a license from such third party to continue developing and marketing our medicines and technology.

If we or one of our collaborators are found to infringe a third party’s intellectual property rights, we or they could be required to

obtain a license from such third party to continue developing and marketing our medicines and technology.

However, we or our collaborators may not be able to obtain any required license on commercially reasonable terms or at all.

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In addition, we or our collaborators could be found liable for monetary damages.

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.

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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Even if we complete necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain and may prevent us from obtaining approvals for the commercialization of some or all of our product candidates.

If we or our collaborators are not able to obtain, or if there are delays in obtaining, required regulatory approvals, we or they will not be able to commercialize, or will be delayed in commercializing, our product candidates, and our ability to generate revenue will be materially impaired.

If we or our collaborators are not able to obtain, or if there are delays in obtaining, required regulatory

approvals, we or they will not be able to commercialize, or will be delayed in commercializing, our product candidates, and our ability to generate revenue will be materially impaired.

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.

With the exception of the FDA approvals of IDHIFA® and TIBSOVO®, we and our collaborators have not received approval to market any of our product candidates from regulatory authorities in any jurisdiction.

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.

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.

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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It is also possible that additional trials or studies, if performed and completed, may not be considered sufficient by the FDA or EMA to approve any marketing applications.

For example, Celgene submitted an MAA to the EMA for IDHIFA® for IDH2 mutant-positive AML which it subsequently withdrew in December 2019, and we submitted an MAA to the EMA for TIBSOVO® for the treatment of adult patients with IDH1 mutant-positive R/R AML, which we subsequently withdrew in October 2020.

Celgene or we may not be successful in obtaining EMA approval of IDHIFA® or TIBSOVO®, respectively, on a timely basis, or ever.

We have limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party contract research organizations to assist us in this process, and failure to obtain marketing approval for our products or product candidates will prevent us from commercializing the product or product candidate in the applicable jurisdictions.

We may not be successful in obtaining FDA or EMA approval of our product candidates on a timely basis, or ever.

We have limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party contract research organizations to assist us in this process, and failure to obtain marketing approval for our product candidates will prevent us from commercializing the product candidate in the applicable jurisdictions.

Further, the process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years if additional clinical trials are required, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved.

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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.

The Trump Administration also took several executive actions that could impose significant burdens on, or otherwise materially delay, the FDA’s ability to engage in routine regulatory and oversight activities.

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.

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.

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.

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.

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.

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.

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.

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.

A fast track 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 FDA.

In the United States, enasidenib and ivosidenib received fast track designation for treatment of patients with AML that harbor an IDH2 and IDH1 mutation, respectively.

If a drug is intended for the treatment of a serious or life-threatening disease or condition and the drug demonstrates the potential to address unmet medical needs for this disease or condition, the drug sponsor may apply for FDA fast track designation.

The FDA has broad discretion whether or not to grant fast track designation, so even if we believe a particular product candidate is eligible for such designation, the FDA may decide not to grant it.

Even if our product candidates receive fast track designation, we may not experience a faster development process, review or approval, if at all, compared to conventional FDA procedures.

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.

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.

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.

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.

Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or thereafter.

The FDA has broad discretion on whether to grant fast track designation and/or priority review designation to a product candidate, so even if we believe a particular product candidate is eligible for such designation or status, the FDA may decide not to grant it.

Even if our product candidates receive fast track designation and/or priority review designation, we may not experience a faster development process, review or approval, if at all, compared to conventional FDA procedures.

The FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program.

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.

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.

PRIME designation enables an applicant to request parallel EMA scientific advice and health technology assessment advice to facilitate timely market access.

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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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.

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.

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.

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.

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;

• 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;

• 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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Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

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.

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.

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.

PYRUKYND® or any product candidate that we commercialize, such products may become subject to unfavorable pricing regulations and third-party reimbursement practices, which would harm our business.

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.

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.

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.

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.

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.

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.

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.

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.

An inability to 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.

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.

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.

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.

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.

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.

However, pursuant to the CARES Act and subsequent legislation, these Medicare sequester reductions are 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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For example, in 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.

November 10, 2020, the Supreme Court heard oral arguments as to whether the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

On November 10, 2020, the Supreme Court heard oral arguments as to whether the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

On February 10, 2021, the Biden Administration withdrew the federal government’s support for overturning the ACA.

A ruling by the Supreme Court is expected sometime this year.

On June 17, 2021, the Supreme Court struck down the lower court rulings, finding that the plaintiffs did not have standing to challenge the ACA’s minimum essential coverage provision at issue in the case.

The Trump Administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.

On January 28, 2021, however, President Biden issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access.

On January 28, 2021, however, President Biden revoked these Orders and issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access.

This Executive Order also directs the U.S.

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We cannot predict how federal agencies will respond to such Executive Orders.

The costs of prescription pharmaceuticals in the United States and foreign jurisdictions is subject to considerable legislative and executive actions and could impact the prices we obtain for our drug products, if and when approved.

The costs of prescription pharmaceuticals in the United States and foreign jurisdictions are subject to considerable legislative and executive actions and could impact the prices we obtain for our drug products, if and when approved.

The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.

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To those ends, President Trump issued several executive orders intended to lower the costs of prescription drug products.

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.

It remains to be seen whether these orders and resulting regulations will remain in force during the Biden Administration.

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.

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.

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.

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These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing.

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.

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.

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.

We are subject to the U.S.

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.

We are subject to export control and import laws and regulations, including the U.S.

Export Administration Regulations, U.S.

Customs regulations, various economic and trade sanctions regulations administered by the U.S.

Treasury Department’s Office

of Foreign Assets Control, the U.S.

Foreign Corrupt Practices Act of 1977, as amended, the U.S.

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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.

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.

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

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.

In addition, responding to any action will likely result in a materially significant diversion of management’s attention and resources and significant defense and compliance costs and other professional fees.

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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.

We also cannot be sure of the effect the announcement of our proposed sale of our oncology business to Servier will have on our ability to retain and hire key personnel.

Our current and prospective employees, including of the oncology business, may feel uncertain about their roles with us or within the oncology business prior to and following the completion of transaction, 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 associated work from home policy may make it difficult for us to maintain our corporate culture.

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.

We expect to continue to experience growth in the number of our employees as we expand our development, regulatory and future sales and marketing capabilities.

To manage our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel.

To manage our anticipated future growth, we must continue to implement and improve

our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional qualified personnel.

Any inability to manage growth could delay the execution of our business plans or disrupt our operations.

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We are exposed to the risk of employee fraud or other misconduct.

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.

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.

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.

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.

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.

If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business and results of operations, including the imposition of significant fines or other sanctions.

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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.

While the full extent of the economic impact and the duration of the

COVID-19 pandemic may be difficult to assess or predict, it has already caused, and is likely to result in further, significant disruption of global financial markets, which may reduce our ability to access capital either at all or on favorable terms.

While the full extent of the economic impact and the duration of the COVID-19 pandemic may be difficult to assess or predict, it has already caused, and is likely to result in further, significant disruption of global financial markets, which may reduce our ability to access capital either at all or on favorable terms.

The market price for our common stock may be influenced by many factors, including:

• perceived likelihood of the consummation of our proposed sale of our oncology business to Servier;

• regulatory actions with respect to our product candidates or our competitors’ products and product candidates;

• our success in launching and commercializing PYRUKYND®;

• 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;

• announcements by us or our competitors of significant acquisitions, strategic partnerships, joint ventures, collaborations or capital commitments;

• the timing and results of clinical trials of product candidates;

• the timing and results of clinical trials of product candidates, or our competitors’ product candidates;

• 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;

• failure or discontinuation of any of our development programs;

• results of clinical trials of product candidates of our competitors;

• regulatory or legal developments in the United States and other countries;

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• the recruitment or departure of key personnel;

• the level of expenses related to any of our product candidates or clinical development programs;

• the results of our efforts to develop additional product candidates or products;

• the level of expenses related to any of our products, product candidates or development programs;

• 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;

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• sales of our common stock by us, our insiders or other stockholders, including shares issuable upon exercise of outstanding stock options and upon vesting of stock units under our stock incentive plans;

• variations in our financial results, including fluctuations in levels of sales of TIBSOVO® or results of companies that are perceived to be similar to us;

• whether an active trading market for our shares is sustained;

• variations in our financial results or results of companies that are perceived to be similar to us;

• 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;

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• the other factors described in this “Risk Factors” section.

In the past, following periods of volatility in the market price of a companies securities, securities class-action litigation often has been instituted against that company.

In the past, following periods of volatility in the market price of a company's securities, securities class-action litigation often has been instituted against that company.

Such litigation, if instituted against us, could cause us to incur substantial costs to defend such claims and divert managements' attention and resources, which could seriously harm our business, financial condition, results of operations and prospects.

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This concentration of voting power could delay or prevent an acquisition of our company on terms that other stockholders may desire.

Future sales and issuances of our common stock or rights to purchase common stock could result in additional dilution of the percentage ownership of our stockholders and could cause our stock price to fall.

We expect that significant additional capital will be needed in the future to continue our planned operations.

To raise capital, we may sell common stock, convertible securities or other equity securities in one or more transactions at prices and in a manner we determine from time to time.

If we sell common stock, convertible securities or other equity securities in more than one transaction, investors may be materially diluted by subsequent sales.

Such sales may also result in material dilution to our existing stockholders, and new investors could gain rights, preferences and privileges senior to those of holders of our common stock.

Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.

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Moreover, these rules and regulations increase our legal and financial compliance costs and make some activities more time-consuming and costly.

There can be no assurance that we will repurchase shares of our common stock or that we will repurchase shares at favorable prices.

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.

On March 31, 2021, in connection with the Repurchase Program, we entered into a definitive share repurchase agreement with BMS to repurchase 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.

This repurchase was completed on April 5, 2021.

Further, on April 2, 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.

In total, as of December 31, 2021, we have repurchased 16.2 million shares of common stock for $802.5 million under the Repurchase Program.

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.

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.

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.

A reduction in repurchases under, or the completion of, our Repurchase Program could have a negative effect on our stock price.

We can provide no assurance that we will repurchase shares at favorable prices, if at all.

Because we do not anticipate paying any cash dividends on our capital stock in the foreseeable future, capital appreciation, if any, will be the sole source of gain for our stockholders.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1A. Risk Factors