▸ If we are unable to continue to execute on our sales, marketing and distribution plans to commercialize RYTELO, we may be unable to generate meaningful product revenue.· · · · ● 1 ▸ If we fail to successfully implement or upgrade our enterprise resource planning and other information systems, our business and results of operation could be adversely impacted.· · · · ● 1 ▸ In general, Phase 3 clinical trials with larger numbers of patients or longer durations of therapy may fail to replicate efficacy and safety results observed in earlier clinical trials, such as IMbark, and if this were to occur with· · · · ● 1 ▸ Our business could be negatively impacted by environmental, social and corporate governance, or ESG, matters or our reporting of such matters.· · · · ● 1 ▸ Our financial projections and estimates are subject to significant risks, assumptions, and uncertainties, and our actual results may differ materially.· · · · ● 1 ▸ group RISKS RELATED TO COMPLIANCE WITH HEALTHCARE LAWS· · · · ● 1 ▸ group RISKS RELATED TO REGULATORY APPROVAL OF RYTELO· · · · ● 1 ▸ RYTELO may not receive or maintain regulatory clearances and approvals required to enable its continued development.· · · · ● 1 ▸ group Risks Related to Our OPERATING RESULTS AND Financial Position· · · · ● 1 ▸ group Risks Related to THE Commercialization of RYTELO· · · · ● 1 ▸ group Risks Related to our Indebtedness and ROYALTY PAYMENT OBLIGATIONS· · · · ● 1 ▸ The Royalty Pharma Agreement places certain restrictions on our operational flexibility.· · · · ● 1 ▸ The requirements of Section 404 are ongoing and also apply to future years. We expect that our internal control over financial reporting will continue to evolve as our business develops, including in connection with our· · · · ● 1 ▸ The validity, scope and enforceability of any patents listed in the Orange Book that cover RYTELO or its methods of use can be challenged by third parties and may not protect us from generic or innovator competition.· · · · ● 1 ▸ We are exposed to the risk that our employees, independent contractors, principal investigators, clinical trial sites, CROs, consultants or vendors may engage in fraudulent or other illegal activity. Misconduct by these parties· · · · ● 1 ▸ We have a history of net losses and may not achieve consistent future profitability for some time, if ever.· · · · ● 1 ▸ We have a registered trademark, RYTELO, for our product and failure to maintain such trademark could adversely affect our business.· · · · ● 1 ▸ We have limited experience as a commercial company and our sales, marketing, and distribution of RYTELO may be unsuccessful or less successful than anticipated.· · · · ● 1 ▸ We may be involved in lawsuits to protect or enforce our patents or other intellectual property rights, which could be expensive, time consuming and unsuccessful, and which could result in the invalidity or unenforceability of· · · · ● 1 ▸ We may be unable to maintain regulatory approval for RYTELO in the U.S. for lower-risk MDS, which would severely and adversely affect our business and business prospects, and might cause us to cease operations.· · · · ● 1 ▸ We may experience additional risks related to operating outside of the U.S. that could materially adversely affect our business.· · · · ● 1 ▸ We periodically implement or upgrade new or enhanced enterprise resource planning, or ERP, and other business systems in order to better manage our business operations. Implementation or upgrade of new business· · · · ● 1 ▸ Our clinical trials of imetelstat could be interrupted, delayed, terminated or abandoned for a variety of reasons which could severely and adversely affect our financial results, business and business prospects.· · · ● ● 2 rw ▸ The U.S. has enacted and implemented wide-ranging patent reform legislation, including the Leahy-Smith America Invents Act, or the AIA, signed into law on September 16, 2011. The U.S. Supreme Court has ruled on· · · ● ● 2 ▸ Historically, our stock price has been extremely volatile and your investment may suffer a decline in value.· · ● ● ● 3 ▸ If the market opportunities for RYTELO are smaller than we believe, our revenue may be adversely affected, and our business may suffer.· · ● ● ● 3 rw ▸ If, and to the extent that, we are unable to comply with these regulations, our ability to earn revenue from the commercialization of RYTELO will be materially and adversely impacted.· · ● ● ● 3 rw ▸ These and other risks associated with international operations may materially adversely affect our ability to attain or maintain profitable operations.· · ● ● ● 3 ▸ Any of these events may result in a failure to further develop, obtain regulatory approval for or commercialize imetelstat, which would severely and adversely affect our business and business prospects, and might cause us to cease operations.· · · ● · 1 ▸ European Commission and other foreign regulatory approvals, if any, may take longer and be more costly to obtain than approvals in the U.S., due to differing regulatory requirements in foreign countries;· · · ● · 1 ▸ If we are unable to obtain regulatory approval for and successfully commercialize imetelstat, or experience significant delays in doing so, our business will be severely harmed.· · · ● · 1 ▸ In the U.S., the Hatch-Waxman Act permits one patent per approved product to receive a patent term extension of up to five years beyond its normal expiration. The length of the patent term extension is typically· · · ● · 1 ▸ The occurrence of any such event would significantly harm our business, business prospects, including any potential commercialization of imetelstat, and the future value of imetelstat and might cause us to cease operations.· · · ● · 1 ▸ We are seeking regulatory approval to market imetelstat in Europe, and as a result, we may experience additional risks related to marketing outside of the U.S. that would materially adversely affect our business.· · · ● · 1 ▸ Although we reported positive top-line results from IMerge Phase 3 in January 2023, retaining remaining patients in the treatment or follow-up phase would allow us to continue to assess the longer-term durability of· · ● · · 1 ▸ As of March 9, 2023, 508,722,486 shares of common stock are issued and outstanding, and we had reserved 166,207,514 shares of our common stock for future issuance pursuant to our stock option and equity incentive plans and outstanding warrants.· · ● · · 1 ▸ FibroGen, Inc; Onureg (oral azacytidine) by BMS; and Hengqu (hetrombopag), an oral nonpeptide thrombopoietin receptor agonist, by Jiangsu Hengrui Pharmaceuticals Co., Ltd.· · ● · · 1 ▸ If, in the future, we seek regulatory approval to market imetelstat internationally, we may experience a variety of risks that would materially adversely affect our business.· · ● · · 1 ▸ Regulatory authorities may also not approve the labeling claims that are necessary or desirable for the successful commercialization of a drug, such as imetelstat. For example, future regulatory clearances, if any, that we· · ● · · 1 ▸ Requirement that drug companies pay rebates to Medicare if prices rise faster than inflation for drugs used by Medicare beneficiaries, beginning in 2023.· · ● · · 1 ▸ Requirement that the federal government negotiate prices for certain single-source drugs covered under Medicare Part B and D with the highest total spending, beginning in 2026; and· · ● · · 1 ▸ The consolidated shareholder derivative actions filed in the U.S. District Court for the District of Delaware have been stayed pending the ruling on our motion to dismiss the Chancery Court Derivative· · ● · · 1 ▸ Business disruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.· ● ● · · 2 ▸ group DATA SECURITY AND DATA PRIVACY· ● · ● · 2 ▸ Other therapies currently in Phase 3 development in lower risk MDS, some of which may obtain regulatory approval earlier than imetelstat include roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, by· ● ● · · 2 rw ▸ Success in non-clinical testing and early clinical trials, including Phase 2 clinical trials, such as IMerge Phase 2 and IMbark, does not ensure that later clinical trials will be successful, nor does it predict final clinical trial results. We· ● · · · 1 ▸ The Innovation Passport designation from the United Kingdom regulatory authorities does not guarantee marketing approval and may not lead to a faster development, regulatory review or approval process.· ● ● · · 2 ▸ We are seeking registered trademarks for a commercial trade name for imetelstat in the U.S. and jurisdictions outside of the U.S. and failure to secure and maintain such registrations could adversely affect our business.· ● ● ● · 3 rw ▸ Although imetelstat has received Fast Track designation by the FDA for MDS and MF, this does not guarantee marketing approval and may not lead to a faster development, regulatory review or approval process.● ● ● ● · 4 rw ▸ Challenges to our owned or licensed patent rights would result in costly and time-consuming legal proceedings that could prevent or limit development of imetelstat.● ● ● · · 3 ▸ Changes in and failures to comply with United States federal and state as well as foreign privacy and data protection laws, regulations and standards may adversely affect our business, operations and financial performance.● · · · · 1 ▸ Failure to achieve continued compliance with government regulations could delay or halt potential commercialization of imetelstat.● ● ● ● · 4 ▸ Further delay, suspension or abandonment of the development of imetelstat in hematologic myeloid malignancies, including resulting from our inability to successfully enroll, conduct and complete IMerge Phase 3 and● · · · · 1 ▸ Historically, our stock price has been extremely volatile.● ● · · · 2 ▸ IMpactMF, and to plan for, commence, conduct and complete potential future clinical trials of imetelstat, could have a material adverse effect on the future of imetelstat and our business prospects, and we might cease operations.● · · · · 1 ▸ If imetelstat is approved for marketing and commercialization and we are unable to establish sales, marketing and distribution capabilities, we will be unable to successfully commercialize imetelstat if and when it is approved.● ● · · · 2 ▸ If we are unable to establish potential future collaborative arrangements for imetelstat, we may have to delay, alter or abandon our imetelstat development and commercialization plans.● · · · · 1 ▸ It may not be possible to manufacture imetelstat at costs or scales necessary to conduct clinical trials or potential future commercialization activities.● ● ● · · 3 ▸ Obtaining potential future regulatory clearances to market imetelstat in the U.S. and other countries is a costly and lengthy process, and we cannot predict when or if regulatory authorities will approve imetelstat for commercial sale.● ● · · · 2 rw ▸ Our undesignated preferred stock may inhibit potential acquisition bids; this may adversely affect the market price of our common stock and the voting rights of holders of our common stock.● ● ● · · 3 ▸ Provisions in our charter, bylaws and Delaware law may inhibit potential acquisition bids for us, which may prevent holders of our common stock from benefiting from what they believe may be the positive aspects of acquisitions and takeovers.● ● ● · · 3 ▸ group RISKS RELATED TO COVID-19● ● ● · · 3 ▸ group Risks Related to Competitive Factors● ● ● ● · 4 ▸ Risks Related to Our Financial Position and Need For Additional Financing● ● ● ● · 4 ▸ Risks Related to Regulatory APPROVAL and Commercialization of Imetelstat● ● ● ● · 4 rw ▸ group Risks Related to our Indebtedness● ● ● ● · 4 ▸ Significant disruptions of information technology systems, including cloud-based systems, or breaches of data security could adversely affect our business.● · · · · 1 ▸ The imposition of any of these penalties or other commercial limitations would severely and adversely affect our financial results, business and business prospects, and the future of imetelstat, and might cause us to cease operations.● ● · · · 2 ▸ The research and development of imetelstat is subject to numerous risks and uncertainties.● ● ● · · 3 ▸ The sale of a substantial number of shares may adversely affect the market price of our common stock.● ● ● · · 3 ▸ To the extent additional debt is added to our current debt levels, the risks described above could increase.● ● ● · · 3 ▸ We cannot assure you that our existing capital resources, future interest income, and potential future sales of our● · · · · 1 ▸ We currently have no products approved for commercial sale, and we have not yet demonstrated an ability to obtain marketing approvals for any product candidates, which makes it difficult to assess our future viability.● ● ● · · 3 ▸ We currently have no source of product revenue and may never become profitable.● ● ● ● · 4 ▸ We may fail to continue to meet the listing standards of Nasdaq, and as a result our common stock may be delisted, which could have a material adverse effect on the liquidity of our common stock.● ● · · · 2 ▸ We may not be able to protect our intellectual property rights throughout the world.● ● ● · · 3 ▸ Changes in U.S. or international patent law or interpretations of such patent laws could diminish the value of our patents in general, thereby impairing our ability to protect our technologies and RYTELO.● ● ● ● ● 5 rw ▸ Changes in tax laws or regulations that are applied adversely to us or our customers may have a material adverse effect on our business, cash flow, financial condition or results of operations.● ● ● ● ● 5 ▸ Failure to achieve and maintain effective internal controls in accordance with Section 404 of the Sarbanes-Oxley Act of 2002 could have a material adverse effect on our business and stock price.● ● ● ● ● 5 ▸ If we do not obtain acceptable prices or adequate reimbursement for RYTELO, the use of RYTELO could be severely limited.● ● ● ● ● 5 rw ▸ Much of the information and know-how that is critical to our business is not patentable, and we may not be able to prevent others from obtaining this information and establishing competitive enterprises.● ● ● ● ● 5 ▸ Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.● ● ● ● ● 5 ▸ Our level of indebtedness and debt service obligations could adversely affect our financial condition and may make it more difficult for us to fund our operations.● ● ● ● ● 5 rw ▸ Patent terms may be inadequate to protect our competitive position on RYTELO for an adequate amount of time.● ● ● ● ● 5 rw ▸ RISKS RELATED TO INFORMATION TECHNOLOGY SYSTEMS, DATA SECURITY AND DATA PRIVACY● ● ● ● ● 5 rw ▸ group RISKS RELATED TO THE FURTHER DEVELOPMENT OF RYTELO (IMETELSTAT)● ● ● ● ● 5 rw ▸ group Risks Related to Managing Our Growth and Other Business Operations● ● ● ● ● 5 ▸ group Risks Related to Manufacturing RYTELO (IMETELSTAT)● ● ● ● ● 5 rw ▸ group Risks Related to Our Common Stock and Financial Reporting● ● ● ● ● 5 ▸ group Risks Related to Protecting Our Intellectual Property● ● ● ● ● 5 ▸ The adoption of health policy changes and healthcare reform both in the U.S. and outside the U.S. may adversely affect our business and financial results.● ● ● ● ● 5 rw ▸ The terms of the Pharmakon Loan Agreement place restrictions on our operating and financial flexibility.● ● ● ● ● 5 rw ▸ To be commercially successful, RYTELO must be accepted by the healthcare community, which can be slow to adopt or unreceptive to new technologies and products.● ● ● ● ● 5 rw ▸ We do not intend to pay cash dividends on our common stock in the foreseeable future.● ● ● ● ● 5 ▸ We may be subject to infringement claims that are costly to defend, and such claims may limit our ability to use disputed technologies and prevent us from pursuing research, development, manufacturing or commercialization of RYTELO.● ● ● ● ● 5 rw ▸ We may be subject to third-party litigation, and such litigation would be costly to defend or pursue and uncertain in its outcome.● ● ● ● ● 5 ▸ We may be unable to successfully retain or recruit key personnel to support the commercialization and further development of RYTELO or to otherwise successfully manage our growth.● ● ● ● ● 5 rw ▸ We may not have cash available in an amount sufficient to enable us to make interest or principal payments on our indebtedness when due.● ● ● ● ● 5 
