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Item 1A. Risk Factors

2026-05-06 compared with 2025-11-07 · 428 added, 456 removed, 940 unchanged (48% of the section changed)

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Consequently, you should not consider this summary to be a complete discussion of all potential risks or uncertainties that may substantially impact our business.

Additional discussion of the risks and uncertainties summarized in this risk factor summary, as well as other risks and uncertainties that we face, are described under the heading “Risk Factors” below, and this summary is qualified in its entirety by that more complete discussion of such risks and uncertainties.

Additional discussion of the risks and uncertainties summarized in this risk factor summary, as well as other risks and uncertainties that we face, can be found under “Risk Factors” in Part I, Item 1A of this Report.

The summary below is qualified in its entirety by that more complete discussion of such risks and uncertainties.

Moreover, we operate in a competitive and rapidly changing environment.

New factors emerge from time to time and it is not possible to predict the impact of all of these factors on our business, financial condition or results of operations.

You should consider carefully the risks and uncertainties described under the heading “Risk Factors” below as part of your evaluation of an investment in our common stock.

You should consider carefully the risks and uncertainties described under “Risk Factors” in Part I, Item 1A of this Report as part of your evaluation of an investment in our common stock.

Risks Related to the Commercialization of RYTELO® (Imetelstat)

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for lower-risk MDS, or to expand its indication of use, our ability to generate meaningful revenue or achieve profitability will be materially and adversely affected.

• We have limited experience as a commercial company and our sales, marketing, and distribution of RYTELO may be unsuccessful or less successful than anticipated.

• Although we have established commercial operations and sales, marketing and distribution infrastructure for RYTELO, we have limited experience in sustaining and scaling these operations and our commercialization efforts may be unsuccessful or less successful than anticipated.

• 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.

• If we do not maintain acceptable prices or adequate reimbursement for RYTELO, the use of RYTELO could be severely limited.

• 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.

• If the market opportunities for RYTELO are smaller than we believe, our revenue may be adversely affected, and our business may suffer.

• If competitors develop products, product candidates or technologies that are superior to or more cost-effective than RYTELO, it would significantly impact the development and commercial viability of RYTELO, which would severely and adversely affect our financial results, business and business prospects, and the future of RYTELO, and might cause us to cease operations.

• We rely on a select network of third party distributors, specialty pharmacies and other vendors to distribute RYTELO in the U.S., and any failure by such distributors, specialty pharmacies and vendors could adversely affect our revenues, financial condition, or results of operations.

• We will be subject to pricing, drug marketing, post-market and reimbursement regulations in the European Union, or EU, which may materially affect our ability to commercialize and receive reimbursement coverage for RYTELO in the EU.

• We face competition from existing products, product candidates and technologies, and competitors may develop new products and technologies.

If these products, product candidates or technologies are deemed by the healthcare community to be superior to or more cost-effective than RYTELO, it would significantly impact the development and commercial viability of RYTELO, which would severely and adversely affect our financial results, business and business prospects, and the future of RYTELO, and might cause us to cease operations.

• We will be subject to pricing and reimbursement regulations in the European Union, or EU, which may materially affect our ability to commercialize and receive reimbursement coverage for RYTELO in the EU.

Risks Related to Regulatory Approval of RYTELO

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and in the EU for certain patients with lower-risk MDS is subject to post-marketing requirements and commitments, and we may be subject to penalties or product withdrawal if we fail to comply with these regulatory requirements and commitments, or if we experience unanticipated problems with RYTELO.

• We may be unable to obtain regulatory approval to commercialize RYTELO in any other jurisdictions or for any new indications, or may experience significant delays in doing so, any of which could severely and adversely affect our business and business prospects, and might cause us to cease operations.

Risks Related to Compliance with Healthcare Laws

• The FDA, the Department of Justice, or DOJ, and other regulatory authorities actively enforce regulations related to the promotion and advertisement of pharmaceutical products, and if we were found to have violated the Food, Drug and Cosmetic Act, we could be subject to significant civil, criminal and administrative penalties.

• Our relationships with healthcare providers, including physicians and third-party payors, the methods by which we promote RYTELO, and the content of our promotional materials and programs, are subject to applicable promotional, anti-kickback, fraud and abuse, and other healthcare laws and regulations, and our failure to comply

with these laws could expose us to criminal sanctions, civil penalties, exclusion from federal health care programs, contractual damages, reputational harm and may adversely affect our business and financial results.

Risks Related to the Further Development of Imetelstat

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• RYTELO may cause, or have attributed to it, undesirable or unintended side effects or other adverse events that could halt or limit its further commercialization, delay or prevent its regulatory approval in any other jurisdiction or indication, or cause us to delay or terminate our clinical trials.

• Results and data we disclosed from prior non-clinical studies and clinical trials may not predict success in later clinical trials, and we cannot assure you that any ongoing or future clinical trials of imetelstat, including IMpactMF, will lead to similar results and data that could potentially enable us to obtain any further regulatory approvals.

Risks Related to Manufacturing RYTELO

• Results and data we disclosed from prior non-clinical studies and clinical trials, as well as any data disclosed as a result of an interim analysis, may not predict success in later clinical trials or the final analysis, and we cannot assure you that any ongoing or future clinical trials of imetelstat, including IMpactMF, will lead to similar results and data that could potentially enable us to obtain any further regulatory approvals.

Risks Related to Manufacturing RYTELO (Imetelstat)

• Failure by us to maintain a manufacturing supply chain to appropriately and adequately supply RYTELO for commercial and future clinical uses would adversely affect our ability to commercialize RYTELO and result in a further delay in or cessation of clinical trials, and our business and business prospects could be severely harmed, and we could cease operations.

• If third parties that manufacture RYTELO fail to perform as needed, the commercial and clinical supply of RYTELO could be interrupted or limited, and we may be unable to successfully commercialize RYTELO or conduct or complete current or potential future clinical trials.

Ris ks Related to Our Operating Results, Financial Position and Need for Additional Capital

Risks Related to Our Operating Results, Financial Position and Need for Additional Capital

• We have a history of net losses and may not achieve consistent future profitability for some time, if ever.

• Our operating results are unpredictable and may fluctuate.

If our operating results are below the expect ations of securities analysts or investors, the trading price of our common stock could decline.

• Our failure to obtain additional capital, if and when needed, would force us to further delay, reduce or eliminate the further development of RYTELO, or to halt the commercialization of RYTELO, any of which would severely and adversely affect our financial results, business and business prospects, and might cause us to cease operations.

Risks Related to Our Indebtedness and Royalty Payment Obligations

• 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, including by limiting our operating and financial flexibility.

Risks Related to Protecting Our Intellectual Property

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Risks Related to Managing Our Growth and Other Business Operations

• Our strategic restructuring plan and the associated workforce reduction implemented in December 2025 may not result in anticipated savings and long-term value creation, could result in total costs and operating expenses that are greater than expected and could disrupt our business.

• We and certain of our current and former officers and directors have been named as defendants in securities class action lawsuits and derivative lawsuits.

These lawsuits, and potential similar or related lawsuits, could result in substantial damages, divert management’s time and attention from our business, and have a material adverse effect on our results of operations.

These lawsuits, and any other lawsuits to which we are subject, will be costly to defend or pursue and are uncertain in their outcome.

These lawsuits, and potential similar or related lawsuits, are costly to defend, could result in substantial damages, divert management’s time and attention from our business, and have a material adverse effect on our results of operations.

We operate in a dynamic and rapidly changing environment involving numerous risks and uncertainties that may have a material adverse effect on our business, financial condition or results of operations.

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Additional risks and uncertainties not presently known to us or that we currently believe are immaterial may also significantly impair our business, financial condition or results of operations.

If any of these risks or uncertainties occur, our business, financial condition or results of operations could suffer, the market price of our common stock could decline and you could lose all or part of your investment in our common stock.

RISKS RELATED TO THE COMMERCIALIZATION OF RYTELO® (IMETELSTAT)

If any of these risks or uncertainties occur,

our business, financial condition or results of operations could suffer, the market price of our common stock could decline and you could lose all or part of your investment in our common stock.

RISKS RELATED TO THE COMMERCIALIZATION OF RYTELO

Our near-term prospects are wholly dependent on RYTELO.

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in that indication.

While we have generated revenue from U.S.

sales of RYTELO since mid-2024, the commercialization of RYTELO marks our first effort to commercially launch a product candidate, and our ability to grow revenue on a sustained basis has not yet been proven.

RYTELO is our only product approved for marketing by the FDA, and our ability to generate meaningful revenue from product sales and achieve profitability is wholly dependent on our ability to successfully commercialize RYTELO in the U.S.

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• our limited historical experience in marketing, selling and distributing RYTELO;

• reimbursement and coverage policies of government and private payors such as Medicare, Medicaid, insurance companies, health maintenance organizations and other plan administrators;

• we may not be able to increase physician adoption of RYTELO through our commercialization strategy and plans, including any potential amendments or adjustments to those plans;

• our inability to achieve and maintain revenue growth in the near future under our current commercialization strategy and plans or any potential further amendments or adjustments thereto;

• potential future changes in the reimbursement and coverage policies of government and private payors such as Medicare, Medicaid, insurance companies, health maintenance organizations and other plan administrators;

• the relative position of RYTELO as compared to alternative treatment options in healthcare guidelines and recommendations, such as those developed by the National Comprehensive Cancer Network, or NCCN, and similar guidelines and recommendations outside the U.S.;

• the relative price of RYTELO as compared to alternative treatment options;

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• the market penetration rate of RYTELO across the breadth of eligible patient segments in its approved indication may continue to be lower than our expectations;

• our projections regarding the market opportunities for RYTELO may not be accurate, and the actual market for RYTELO may be smaller than we estimate;

• future competitive or other market factors may adversely affect the commercial potential of RYTELO;

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• the capabilities of third party manufacturers may adversely affect the success of our commercialization of RYTELO;

• we may need additional financial or other resources to successfully commercialize RYTELO;

• we may need additional financial or other resources that might not be available to us to successfully commercialize RYTELO;

• we may not be able to maintain adequate commercial supplies of RYTELO to meet demand or at an acceptable cost or at all.

Moreover, successful commercialization of RYTELO may not generate sufficient revenue from product sales, and we may not become profitable in the near term, or at all.

Moreover, commercialization of RYTELO may not generate sufficient revenue from product sales, and we may not become profitable in the near term, or at all.

In any event, if we are unable to successfully commercialize RYTELO in the U.S.

for lower-risk MDS, or to expand its indications of use, our ability to generate meaningful revenue from product sales and achieve profitability will be materially and adversely affected, which in turn would severely and adversely affect our financial results, business and business prospects, and might cause us to cease operations.

We have limited experience as a commercial company and our sales, marketing, and distribution of RYTELO may be unsuccessful or less successful than anticipated.

Although we have established commercial operations and sales, marketing and distribution infrastructure for RYTELO in the U.S., our commercialization strategy may ultimately be unsuccessful or less successful than anticipated

As a company, we have limited prior experience in selling and marketing or commercializing an approved drug product in the U.S., and we have no experience selling, marketing or commercializing an approved drug outside of the U.S.

The success of our commercialization efforts is subject to, among other things, managing our internal sales, marketing, and distribution capabilities and our ability to navigate the significant expenses and risks involved with the management of such capabilities.

For example, RYTELO sales trends have been and may continue to be variable.

Net product revenue was approximately$47.2 million in the third quarter of 2025, $49.0 million in the second quarter of 2025, and $39.4 million in the first quarter of 2025.

Our priority is to drive new patient starts across the breadth of the eligible patient population in RYTELO’s approved indication in the U.S.

Our strategy to drive sales growth in the U.S.

is currently focused on three key areas:

investing additional resources to increase brand awareness;

refining our marketing and medical efforts to enhance prescribing clarity and confidence with the approved use of RYTELO;

and implementing programs to expand key opinion leader support and advocacy.

In the second quarter of 2025, we increased the size of our sales force by 20% and doubled the size of our medical affairs team.

However, our strategy to drive sales growth and our ongoing commercialization efforts has not to date achieved and may not in the future achieve meaningful sales growth, which may require us to, among other things, further adjust or amend our commercialization strategy and plans and incur significant expenses, and there can be no assurance that we will be able to grow RYTELO net product revenues in future periods.

In particular, our strategy may not drive new patient starts across the breadth of the eligible patient population in RYTELO's approved indication in a timely manner or at all, or the duration of therapy could be shorter than we expect, each of which would limit RYTELO's growth potential and could preclude or delay our ability to generate meaningful revenue from product sales and to achieve profitability.

Further, given our limited historical experience commercializing drug products, we do not have a track record of successfully executing a commercial launch.

If we are unsuccessful in accomplishing our objectives from our commercialization efforts and strategy, or they are not executed as planned, we may not be able to generate meaningful revenues from the commercialization of RYTELO in lower-risk MDS, we may require significant additional capital and financial resources, we may not become profitable, and we may not be able to compete against more established companies in our industry.

Our initial commercialization efforts in the U.S.

have not to date achieved meaningful sales growth.

Our RYTELO sales trends and resulting revenue have been and may continue to be variable.

Net product revenue was approximately $51.8 million in the first quarter of 2026, $48.0 million in the fourth quarter of 2025, $47.2 million in the third quarter of 2025, and $49.0 million in the second quarter of 2025.

In an effort to better execute on our plans to commercialize RYTELO and generate more meaningful product revenue, we decided to focus our commercial execution on targeted engagement with high-volume accounts that treat earlier-line patients, and invest in non-personal promotion and third-party education to reach the full breadth of the eligible patient population, while cross-functionally collaborating for effective account management.

However, our revised strategy to drive RYTELO commercial growth may still not achieve meaningful sales growth, which may require us to, among other things, further adjust or amend our commercialization strategy and plans and incur significant expenses, and there can be no assurance that we will be able to meet or grow projected RYTELO net product revenue in future periods.

In particular, our strategy may not drive new patient starts in lower-risk MDS U.S.

patients, particularly in second-line lower-risk MDS, in a timely manner or at all, or the duration of therapy could be shorter than we expect, each of which would limit RYTELO's growth potential and could preclude or delay our ability to generate meaningful revenue from product sales and to achieve profitability.

If we are unsuccessful in accomplishing our objectives from our commercialization efforts and strategy, we may not be able to generate meaningful revenue from the commercialization of RYTELO in lower-risk MDS, or may require significant additional capital and financial resources to do make further investment in our commercial operations.

Any of these outcomes would severely and adversely affect our financial results, business and business prospects, and might cause us to cease operations.

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.

To successfully commercialize RYTELO in the U.S., we need to continue to execute on our sales, marketing and distribution plans, including on our efforts to drive new patient starts in RYTELO's approved indication.

The ongoing execution of our sales, marketing and distribution plans requires investment of capital and time, and we cannot be certain that we will be able to execute on our plans successfully in a timely manner or at all.

In addition, we compete with many companies that currently have extensive, experienced and well-funded sales, distribution and marketing operations to recruit, hire, train and retain marketing and sales personnel.

If we are unable to recruit as needed, and to retain and effectively train marketing, sales and medical personnel and equip them with compliant and effective materials, our efforts to successfully commercialize RYTELO could be adversely affected.

Although we received marketing authorization for RYTELO in the EU for the treatment of certain adult patients with TD anemia due to lower-risk MDS in March 2025, we currently have no marketing or sales organization outside of the U.S., and as a company, we have no experience selling and marketing approved drugs outside of the U.S.

In December 2025, we announced a strategic restructuring plan designed to position us for long-term value creation and improve our financial discipline.

However, there can be no assurance that our recent restructuring will result in long-term value creation or that our commercialization strategy will result in meaningful improvement in our sales performance.

Additionally, we may determine that we need further changes in the future that require additional hiring or other organizational changes to adequately support our strategy, which could further increase our costs.

As such, we continue to compete with many companies that currently have extensive, experienced and well-funded sales, distribution and marketing operations to recruit, hire, train and retain marketing and sales personnel.

If we are unable to recruit, retain and effectively train marketing, sales and medical personnel as needed and equip them with compliant and effective materials, our efforts to successfully commercialize RYTELO could be adversely affected.

Further, although we received marketing authorization for RYTELO in the EU for the treatment of certain adult patients with TD anemia due to lower-risk MDS in March 2025, we currently have no marketing or sales organization outside of the U.S., and as a company, we have no experience selling and marketing approved drugs outside of the U.S.

To successfully commercialize RYTELO in the EU or in any other regions outside the U.S.

where we might seek marketing authorization in the future, we will need to develop these capabilities, which we plan to do by working with experienced third-party contractors or commercialization partners.

where we might seek marketing authorization in the future, we will need to develop these capabilities, which we plan to do at this time by working with experienced third-party contractors or commercialization partners.

Doing so will require additional investment of capital and time.

Particularly in light of our current priority to drive new patient starts across the breadth of the eligible patient population in RYTELO’s approved indication in the U.S., we currently intend to seek contractual arrangements, strategic partnerships, collaborations, alliances or licensing arrangements with third parties to assist us in the commercialization of RYTELO in the EU and in any other regions outside of the U.S.

where RYTELO may be approved for marketing in the future.

However, we may be unable to enter into and conduct successful contractual arrangements, strategic partnerships,

collaborations, alliances or licensing arrangements with third parties to commercialize RYTELO in the EU or in any other regions where RYTELO may be approved for marketing in the future.

We currently intend to seek contractual arrangements, strategic partnerships, collaborations, alliances or licensing arrangements with third parties to assist us in the commercialization of RYTELO in the EU and in any other regions outside of the U.S.

Any failure or delay in entering into and conducting such contractual arrangements, strategic partnerships, collaborations, alliances or licensing arrangements with third parties would adversely impact the commercialization of RYTELO in the EU or in any other regions outside the U.S.

where RYTELO may be approved for marketing in the future.

Further, given our limited experience in marketing and selling RYTELO, we continue to evaluate and adapt our strategy in response to experience in the marketplace and have expanded the size of our field sales force and medical science liaisons to support our U.S.

commercialization efforts.

However, there can be no assurance that our recent increase to the size of our field sales force and medical science liaisons will result in meaningful improvement in our sales performance.

Additionally, we may determine that we need further changes in the future that require additional hiring to further expand our field sales force and medical science liaisons to adequately support the commercialization of RYTELO in the U.S., which could further increase our costs.

With respect to the EU or any other regions outside the U.S.

where we might seek marketing authorization in the future for RYTELO, we plan to enter into arrangements with other third parties to utilize their local marketing and distribution capabilities, but we may be unable to enter into such arrangements on favorable terms, if at all.

If potential future partners do not commit sufficient resources to commercialize RYTELO, we may be unable to generate sufficient product revenue to sustain our business.

In any event, if we are unable to establish and maintain adequate sales and marketing capabilities for RYTELO, whether on our own or through contractual arrangements, collaborations or other arrangements, our results of operations may be negatively impacted.

Any of the foregoing would negatively impact our business and business prospects, severely and adversely affect our financial results, and might cause us to cease operations.

If we do not maintain acceptable prices or adequate reimbursement for RYTELO, the use of RYTELO could be severely limited.

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The resulting reimbursement payment rates may not be adequate or may require significant restrictions on use or increased co-payments from commercially insured patients that patients may find unacceptably high.

Patients are unlikely to use RYTELO unless coverage is provided, and reimbursement is adequate to cover all or a significant portion of its cost.

Patients are unlikely to use

RYTELO unless coverage is provided, and reimbursement is adequate to cover all or a significant portion of its cost.

Therefore, coverage and adequate reimbursement are critical to market acceptance of RYTELO.

and some jurisdictions outside the U.S., there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could impact our business.

Generally, there has been increasing legislative and enforcement interest in the U.S.

with respect to drug pricing, including specialty drug pricing practices, in light of the rising cost of prescription drugs and biologics.

Specifically, there have been U.S.

Congressional inquiries and federal and state legislative activity designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the price of drugs under Medicare, and reform government program reimbursement methodologies for drugs and biologics.

For details regarding these legislative and regulatory changes and proposed changes regarding the healthcare system that may affect our ability to operate, see Item 1 “Business - Healthcare Reform” in the 2025 Form 10-K.

In addition, government authorities and other third-party payors in the U.S.

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However, the Medicare Drug Pricing Negotiation Program provisions of the law are currently subject to legal challenges.

Further, on July 16, 2025, the Centers for Medicare & Medicaid Services issued the CY 2026 Medicare Physician Fee Schedule proposed rule, which if finalized, would, among other things, restrict whether certain fees should be considered bona fide service fees, increase bona fide service fee documentation requirements, define “bundled arrangement,” require “unbundling” of both contingent and non-contingent discounts and include sales of Part B units at the Maximum Fair Price in average sales price calculations.

These changes, if finalized, could lower reimbursement for Medicare Part B utilization and require manufacturers to comply with new, uncertain or complex reporting obligations and drug pricing documentation practices.

Further, the final CY 2026 Medicare Physician Fee Schedule rule, issued by the Centers for Medicare & Medicaid Services, among other things, increases bona fide service fee documentation requirements, defines “bundled arrangement,” to require “unbundling” of both contingent and non-contingent discounts and includes sales of Part B units at the Maximum Fair Price in average sales price calculations.

These changes could lower reimbursement for Medicare Part B utilization and require manufacturers to comply with new, uncertain or complex reporting obligations and drug pricing documentation practices.

Further, no uniform policy requirement for coverage and reimbursement for drug products exists among third-party payors in the U.S.

As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of RYTELO to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

Although we have received a permanent and product-specific J-Code (J0870) for RYTELO which became effective on January 1, 2025, coverage may significantly change or may be more limited than the purposes for which the drug is approved by the FDA or similar international regulatory authorities.

Coverage and reimbursement may impact the demand for, or the price of RYTELO, and reimbursement policies in the U.S., the EU, and other jurisdictions may evolve

which may adversely impact our ability to successfully commercialize RYTELO.

Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

If coverage and reimbursement are not available or reimbursement is available only to limited levels, we may not be able to successfully commercialize RYTELO, which would negatively impact our business and business prospects.

As a result, the coverage determination process is often time-consuming and costly, and it will require us to provide scientific and clinical support for the use of RYTELO to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

Although we have received a permanent and product-specific J-Code (J0870) for RYTELO which became effective on January 1, 2025, coverage may significantly change or may be more limited than the indications for which the drug is approved by the FDA or similar international regulatory authorities.

Coverage and reimbursement may impact the demand for, or the price of RYTELO, and reimbursement policies in the U.S., the EU, and other jurisdictions may evolve which may adversely impact our ability to successfully commercialize RYTELO.

Even if favorable coverage and reimbursement status is attained for RYTELO in additional indications or jurisdictions for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Moreover, we have in the past increased and may in the future increase the price of RYTELO, and there is no guarantee that price adjustments that we have taken or may take in the future will not negatively affect our ability to secure and maintain coverage and reimbursement for RYTELO, which could limit the price that we charge for RYTELO, limit the commercial opportunities for RYTELO and/or negatively impact our sales volumes and net revenues from sales of RYTELO.

In any event, if coverage and reimbursement are not available or the reimbursement amount is inadequate, we may not be able to successfully commercialize RYTELO, which would negatively impact our business and business prospects.

If future legislation were to impose direct governmental price controls and access restrictions, it could have a significant adverse impact on our business and financial results.

Managed care organizations, as well as Medicaid and other government authorities, continue to seek price discounts.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biologic product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, to encourage importation from other countries and bulk purchasing.

Due to the volatility in the current economic and market dynamics, we are unable to predict the impact of any unforeseen or unknown legislative, regulatory, payor or policy actions, which may include cost containment and healthcare reform measures.

Such policy actions could have a material adverse impact on future sales of RYTELO in the U.S., the EU, and in any other jurisdictions where we may seek approval in the future.

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.

RYTELO may not achieve market acceptance for lower-risk MDS or any other indication that might be approved in the future, or achieve the potential U.S.

or international revenue we believe may be possible for lower-risk MDS, since hospitals, physicians, patients or the medical community in general may decide not to accept and utilize RYTELO at the rate we expect or may not use RYTELO across the breadth of eligible patient segments.

For example, new patient starts in the U.S.

in 2025 have been primarily in the third-line setting.

While our current priority is to drive new patient starts across the breadth of eligible patient segments in RYTELO's approved indication, we may be unable to do so in a timely manner or at all, which would limit RYTELO's growth potential and which could delay or preclude our ability to generate meaningful revenue from product sales and to achieve profitability.

Our strategy to drive sales growth and our ongoing commercialization efforts has not to date achieved and may not in the future achieve the rate of market acceptance by the healthcare community or breadth of eligible patient segments that we expect, which may require us to, among others, further adjust or amend our commercialization strategy and plans and incur significant expenses, and there can be no assurance that we will be able to grow RYTELO net product revenue in future periods.

While our current priority is to drive new patient starts across the breadth of the eligible patient population in RYTELO's approved indication, we may be unable to do so in a timely manner or at all, which would limit RYTELO's growth potential and which could delay or preclude our ability to generate meaningful revenue from product sales and to achieve profitability.

Furthermore, RYTELO competes with a number of conventional and widely accepted drugs and therapies manufactured and marketed by major pharmaceutical companies.

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• the willingness of medical professionals to prescribe, and patients to use, RYTELO, or to continue to use RYTELO;

• the publication of unfavorable safety or efficacy data concerning RYTELO by third parties or us;

• the publication of favorable safety or efficacy data concerning RYTELO by third parties or us;

• restrictions on use of RYTELO alone or in combination with other products;

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• the timing of market introduction of RYTELO for new indications;

• the effectiveness of sales, marketing and distribution support for RYTELO;

• the effectiveness of sales, marketing and distribution infrastructure for RYTELO;

• the ability of the third-party distributors and specialty pharmacies we contract with to process prescriptions and dispense RYTELO and the processes required to place orders with such distributors and specialty pharmacies;

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If the healthcare community does not accept RYTELO for any of the foregoing reasons, or for any other reasons, our ability to commercialize RYTELO in the U.S.

or the EU for lower-risk MDS or for any other

indications for which RYTELO may be approved, may be negatively impacted or precluded altogether, which would seriously and adversely affect our business and business prospects.

or the EU for lower-risk MDS or for any other indications for which RYTELO may be approved, may be negatively impacted or precluded altogether, which would seriously and adversely affect our business and business prospects.

If the market opportunities for RYTELO are smaller than we believe, our revenue may be adversely affected, and our business may suffer.

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Our commercialization of RYTELO in the U.S.

and our planned commercialization in the EU is limited to certain patients with lower-risk MDS, and any future potential commercialization will be limited to the therapeutic indications examined in our clinical trials and as determined by the FDA and similar international regulatory authorities, which would not permit us to market RYTELO for any other indications not expressly approved by those regulatory authorities.

and our planned commercialization in the EU is limited to certain patients with lower-risk MDS, and any future potential commercialization will be limited to the therapeutic indications

examined in our clinical trials and approved by the FDA and similar international regulatory authorities, which would preclude us from marketing RYTELO for any other indications not expressly approved by those regulatory authorities.

Future regulatory approvals for RYTELO, if any, could be conditioned upon label restrictions that materially limit the addressable patient population.

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If any of our estimates prove to be inaccurate, the market opportunities for RYTELO that we or any potential future collaborative partners develop could be significantly diminished, which would have a material adverse impact on our business and business prospects, and would adversely affect our ability to achieve profitability.

If competitors develop products, product candidates or technologies that are superior to or more cost-effective than RYTELO, it would significantly impact the development and commercial viability of RYTELO, which would severely and adversely affect our financial results, business and business prospects, and the future of RYTELO, and might cause us to cease operations.

We face competition from existing products, product candidates and technologies, and competitors may develop new products and technologies.

The pharmaceutical and biotechnology industries are characterized by intense and dynamic competition with rapidly advancing technologies and a strong emphasis on proprietary products.

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clinical data to date indicating potential disease-modifying activity with RYTELO treatment;

and knowledge and expertise around the development of potential treatments for myeloid hematologic malignancies provide us with competitive advantages, we face competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions, governmental agencies, and public and private research institutions.

and knowledge and expertise around the development of potential treatments for myeloid hematologic malignancies may provide us with certain competitive advantages, we face competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions, governmental agencies, and public and private research institutions.

RYTELO competes with other products and therapies that currently exist, are being developed or will in the future be developed, some of which we may not currently be aware of.

A discussion of current and potential future competitors of RYTELO can be found in the sub‑section titled “Competition” in Part I, Item 1, titled “Business” included in our Annual Report on Form 10-K for the year ended December 31, 2024.

Many of our competitors, either alone or with their strategic partners, could have substantially greater financial, technical and human resources than we do and significantly greater experience in obtaining FDA and other regulatory approvals of treatments and commercializing those treatments.

We believe that the commercial success of RYTELO is subject to a number of factors, including:

product efficacy and safety;

method of product administration;

cost of manufacturing;

the timing and scope of regulatory consents;

status of coverage and reimbursement;

the level of generic competition;

and our patent and regulatory exclusivity position.

A discussion of current and potential future competitors of RYTELO can be found in the sub‑section titled “Competition” in Part I, Item 1, titled “Business” in the 2025 Form 10-K.

Many of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources than we do and significantly greater experience in obtaining FDA and other regulatory approvals of treatments and commercializing those treatments.

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

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Academic institutions, government agencies and other public and private research organizations may also conduct research, seek patent protection and establish collaborative arrangements for research, clinical development and marketing of products similar to RYTELO.

These companies and institutions compete with us in recruiting and retaining

qualified development and management personnel as well as in acquiring technologies complementary to the RYTELO program.

As a result of the foregoing, competitors may develop more commercially desirable or affordable products than RYTELO or achieve patent protection or product commercialization earlier than we may be able to achieve with RYTELO.

These companies and institutions compete with us in recruiting and retaining qualified development and management personnel as well as in acquiring technologies complementary to the RYTELO program.

As a result of the foregoing, competitors may develop more commercially desirable or affordable products than RYTELO.

Competitors have developed, or are in the process of developing, technologies that are, or in the future may be, competitive to RYTELO.

Some of these products may have an entirely different approach or means of accomplishing therapeutic effects similar, or superior, to those that may be demonstrated by RYTELO.

Competitors may develop products that are safer, more effective, or less costly than RYTELO, or more convenient to administer to patients and, therefore, present a serious competitive threat to RYTELO.

Competitors may develop products that are safer, more effective, more convenient to administer to patients, or less costly than RYTELO, and, therefore, present a serious competitive threat to RYTELO.

In addition, competitors may price their products below what we may determine to be an acceptable price for RYTELO, may receive better third-party payor coverage and/or reimbursement, or may be more cost effective than RYTELO.

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In the event that such network fails to properly meet our or our patients’ needs, we may need to partner with other distributors, specialty pharmacies or vendors to replace or supplement our current network and there is no guarantee that we will be able to do so on commercially reasonable terms or at all.

We will be subject to pricing, drug marketing, post-market and reimbursement regulations in the EU, which may materially affect our ability to commercialize and receive reimbursement coverage for RYTELO in the EU.

We will be subject to pricing and reimbursement regulations in the EU, which may materially affect our ability to commercialize and receive reimbursement coverage for RYTELO in the EU.

In March 2025, we received marketing authorization for RYTELO in the EU for the treatment of adult patients with TD anemia due to lower-risk MDS without an isolated deletion 5q cytogenic abnormality and who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

In connection with such approval, we are subject to post-marketing requirements to submit final results from certain ongoing non-clinical and clinical studies and the completion of certain quality-related activities and study.

We are also subject to rules and regulations in the EU applicable to the manufacturing, marketing, promotion and sale of medicinal products.

If we, or a regulatory authority, discover previously unknown problems with RYTELO, such as adverse events of unanticipated severity or frequency, or problems with a facility where RYTELO is manufactured, a regulatory authority may impose restrictions relative to RYTELO or the manufacturing facility, including requiring recall or withdrawal of RYTELO from the market or suspension of manufacturing.

Moreover, product labeling, advertising and promotion for RYTELO will be subject to regulatory requirements and continuing regulatory review.

Failure to comply with EU and EU Member State laws that apply to the conduct of clinical trials, manufacturing approval, marketing authorization of medicinal products and marketing of such products, both before and after grant of the marketing authorization, or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.

These penalties could include delays or refusal to authorize the conduct of clinical trials, or to grant marketing authorization, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the marketing authorization, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

In addition, the pricing of RYTELO will be subject to governmental control and other market regulations which could put pressure on the pricing and usage of RYTELO.

In the EU, pricing negotiations with governmental authorities can take considerable time after obtaining marketing approval of a product candidate and market acceptance and

sales of RYTELO will depend significantly on the availability of adequate coverage and reimbursement from third-party payors for RYTELO and may be affected by existing and future healthcare reform measures.

The pricing of RYTELO will be subject to governmental control and other market regulations which could put pressure on the pricing and usage of RYTELO.

In the EU, pricing negotiations with governmental authorities can take considerable time after obtaining marketing approval of a product candidate and market acceptance and sales of RYTELO will depend significantly on the availability of adequate coverage and reimbursement from third-party payors for RYTELO and may be affected by existing and future healthcare reform measures.

The requirements governing drug pricing and reimbursement vary widely from country to country.

For example, the EU provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

For example, within the EU member states may restrict the range of medicinal products for which their national health insurance systems provide reimbursement and may control the prices of medicinal products for human use.

Reference pricing used by various EU Member States and parallel distribution, or arbitrage between low-priced and high-priced EU Member States, can further reduce prices.

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If pricing is set at unsatisfactory levels or if reimbursement of RYTELO is unavailable or limited in scope or amount, our revenues from sales and the potential profitability of RYTELO in those countries would be negatively affected.

Much like the federal Anti-Kickback Statute prohibition in the U.S., the provision of benefits or advantages to physicians and other healthcare professionals to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the EU.

Interactions between pharmaceutical companies and health care professionals are governed by strict laws, such as national anti-bribery laws of European countries, national sunshine rules, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct.

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

Infringement of related laws could result in substantial fines and imprisonment.

Payments made to physicians and other healthcare professionals in certain EU Member States must be publicly disclosed.

Moreover, agreements with physicians may require prior notification or approval by the physician’s or healthcare professional’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States.

These requirements are provided in the national laws, industry codes or professional codes of conduct, applicable in the EU Member States.

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

RISKS RELATED TO REGULATORY APPROVAL OF RYTELO

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We do not currently have regulatory approval for RYTELO in any other jurisdictions or for any other indication, and governments in other jurisdictions have significant regulations that may limit or prevent us from successfully commercializing RYTELO in other jurisdictions.

The regulatory frameworks and practices of the FDA, EMA/EC and comparable authorities in other countries may change over time, and we cannot predict the nature, timing, or impact of any such developments.

We cannot project with certainty if or when we might submit or gain regulatory approval for RYTELO for other indications or in other jurisdictions.

The FDA, EMA/EC and other regulatory authorities exercise broad discretion throughout the product review and approval process, including in determining the specific conditions for submission, including the requirement for a pre-approval inspection of RYTELO’s listed manufacturing facility.

As a result, the FDA, EMA/EC and other authorities may delay or extend application review, may decline to accept an application for substantive review, or may conclude, after review, that the information provided is inadequate to obtain or maintain approval of RYTELO.

Any such decision could materially and adversely affect the timing of potential approval and our business prospects.

If the FDA, for instance, determines that an NDA is not sufficiently complete for filing or issues a complete response letter, or CRL, requiring additional data or clarification, we may be required to resubmit the application and any such resubmission or CRL‑driven delays could significantly postpone review and potential approval RYTELO for other indications.

Even if we resubmit an NDA, it remains uncertain whether the FDA will ultimately accept the completed application or additional data, and any such outcome could delay or prevent approval of RYTELO for other indications.

Failure to maintain regulatory approval for RYTELO from the FDA in the U.S.

and from the EC in the EU for lower-risk MDS, or delays in obtaining, failure to obtain, or limitations in the scope of such approvals in any other jurisdictions or for any other indications, could:

and from the EC in the EU for lower-risk MDS, or delays in obtaining, failing to obtain, or limitations in the scope of such approvals in any other jurisdictions or for any other indications, could:

• result in a withdrawal of RYTELO from the market or could otherwise delay, limit or preclude any revenue we may receive from the commercialization of RYTELO for lower-risk MDS;

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• delay or preclude any revenue we may receive from the future commercialization of RYTELO in any other jurisdictions or for any other indications, if any.

In addition, approved products and their manufacturers, together with other vendors involved in the commercialization process, are subject to continual review, and discovery of previously unknown problems with a product or its manufacturer may result in restrictions on the product or manufacturer, including import restrictions, seizure and withdrawal of the product from the market.

Commercialization and sales of RYTELO are subject to government regulations related to numerous matters, including the processes of:

• manufacturing;

• advertising and promotion;

• selling and marketing;

• medical information;

• distribution.

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.

In addition, approved products and their manufacturers, together with other vendors involved in the commercialization process, are subject to continual review, and discovery of previously unknown problems with a product or its manufacturer, including if regulatory inspectors identify regulatory noncompliance by third-party manufacturers requiring remediation, may result in restrictions on the product or manufacturer, including import restrictions, seizure, and withdrawal of the product from the market, or may otherwise cause manufacturing delays and supply disruptions.

Further, if RYTELO causes serious or unexpected side effects, or if other safety risks are observed as a result of our commercialization efforts for RYTELO in the U.S.

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• regulatory authorities may withdraw approval of RYTELO;

• we may be required to recall RYTELO, seek to change the way it is administered, conduct additional clinical trials or change the labeling of the product;

• we may be required to recall RYTELO, seek to change the way it is administered, conduct additional costly, time-consuming and burdensome clinical trials or change the labeling of the product;

• regulatory authorities may require revisions to the labeling of RYTELO, including limitations on approved uses or the addition of further warnings, contraindications or other safety information, or may impose restrictions on distribution in the form of additional requirements in a risk evaluation and management plan or risk management plan;

• we may experience manufacturing delays and supply disruptions if regulatory inspectors identify regulatory noncompliance by third-party manufacturers requiring remediation;

• RYTELO may be rendered less competitive and sales, if any, may decrease;

• our reputation may suffer generally both among clinicians and patients;

• our reputation may suffer generally among clinicians and patients;

• we may be exposed to potential lawsuits and associated legal expenses, including costs of resolving claims;

• regulatory authorities may refuse to approve supplements to approved applications filed by us, or may suspend or revoke license approvals;

• we may be required to change or stop ongoing clinical trials of RYTELO (imetelstat), which would negatively impact the development of RYTELO (imetelstat) for other potential indications.

• we may be required to change or stop ongoing clinical trials of RYTELO, which would negatively impact the development of RYTELO for other potential indications.

Any of these events could prevent us from achieving or maintaining market acceptance for RYTELO, could substantially increase the costs and expenses of commercializing RYTELO, or could limit its commercial potential, which in turn could delay or prevent us from generating any meaningful revenues from the sale of the RYTELO.

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Our regulatory approval for RYTELO in lower-risk MDS in the U.S.

is subject to non-clinical, clinical and manufacturing post-marketing requirements and commitments, including the requirement of continuing to assess long-term safety of RYTELO (imetelstat) in the Phase 3 IMerge trial and a clinical trial to evaluate alternative dosing regimens in lower-risk MDS, with timelines for completion and reporting established by the FDA.

In the EU, our regulatory approval for RYTELO in certain patients with TD anemia due to lower-risk MDS is subject to our commitment to submit the results from certain ongoing non-clinical and clinical studies required by the FDA, including the assessment of the long-term safety of RYTELO in the Phase 3 IMerge trial, as well as results from an ongoing substudy within the Phase 3 IMerge trial and the completion of certain quality-related activities and study.

and EU are subject to non-clinical, clinical and manufacturing post-marketing requirements and/or commitments, including the requirement to assess the long-term safety of RYTELO (imetelstat) in the Phase 3 IMerge trial and a clinical trial to evaluate alternative dosing regimens in lower-risk MDS, with timelines for completion and reporting established by the FDA.

In addition, RYTELO and the manufacturing processes and facilities, post-approval clinical data, labeling, advertising and promotional activities related to RYTELO will be subject to continual requirements of, and review by, the FDA and comparable regulatory authorities.

These requirements include submissions of safety and other post-marketing information and reports, compliance with good pharmacovigilance practices, registration requirements, current Good Manufacturing Practice, or cGMP, requirements relating to quality control, quality assurance and corresponding maintenance of records and documents, and requirements regarding promotional interactions with healthcare professionals.

Failure to comply with these post-marketing requirements and commitments or any other regulatory requirements, or later discovery of previously unknown problems with RYTELO, or our manufacturers, or manufacturing processes for RYTELO, may result in actions such as:

Failure to comply with these post-marketing requirements and commitments on the timeline required or at all, or any other regulatory requirements, including the FDA’s regulation of promotional claims, or later discovery of previously unknown problems with RYTELO, or our manufacturers, or manufacturing processes for RYTELO, may result in actions such as:

• adverse regulatory inspection findings;

• restrictions on RYTELO manufacturing, distribution or use;

• restrictions on labeling or marketing;

• restrictions on, or prohibitions against, marketing, importing or exporting RYTELO;

• additional post-marketing requirements or commitments;

• warning letters or the withdrawal of RYTELO from the market;

• product recalls;

• fines, untitled letters, warning letters or the withdrawal of RYTELO from the market;

• voluntary or mandatory product recalls or public notification or medical product safety alerts to healthcare professionals;

• suspension or termination of ongoing clinical trials of imetelstat in other indications;

• suspension of review or refusal to approve pending applications or supplements to approved applications;

• exclusion from participation in government-funded healthcare programs and/or eligibility for the award of government contracts for RYTELO;

suspension or withdrawal of regulatory approval for RYTELO;

• significant civil, criminal and administrative penalties, including fines, restitutions or disgorgement of profits or revenues;

• refusal to permit the import or export of RYTELO;

• product seizure or detentions;

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• adverse publicity.

Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could generate negative publicity.

In addition, the regulations, policies or guidance of the FDA, EC or any other regulatory authority may change and new or additional statutes or government regulations may be enacted that could prevent or delay regulatory approval of our product candidates or further restrict or regulate post-approval

The imposition of any of these penalties or other commercial limitations, including equivalent penalties or commercial limitations imposed by foreign regulatory authorities, could severely and adversely affect our financial results, business and business prospects, including the commercialization of RYTELO, and might cause us to cease operations.

Similar requirements and related consequences apply outside the U.S.

Any government investigation of alleged violations of law could require us to spend significant time and resources in response and could generate negative publicity.

We also cannot predict the likelihood, nature, or extent of adverse government regulation that may arise from pending or future legislation or administrative action, either in the U.S.

If we are unable to fulfill the post-marketing requirements and commitments established by the FDA or the EC for RYTELO in lower-risk MDS, or that may be applied to the approval and commercialization of RYTELO by any regulatory authority, or are unable to adapt to changes in existing regulatory requirements or adoption of new regulatory requirements or policies, there may be a negative impact to our business and continued regulatory approval of RYTELO.

If we are unable to fulfill the post-marketing requirements and commitments established by the FDA, or that may be or are applied to the approval and commercialization of RYTELO by any regulatory authority, or are unable to adapt to changes in existing regulatory requirements or adoption of new regulatory requirements or policies, there may be a negative impact to our business and continued regulatory approval of RYTELO.

Under such circumstances, we or our respective service providers may be subject to the actions listed above, including losing marketing approval for RYTELO, which would severely and adversely affect our business and business prospects, and might cause us to cease operations.

Furthermore, in connection with our marketing authorization for RYTELO in the EU for certain patients with TD anemia due to lower-risk MDS, we are subject to post-marketing requirements to submit final results from certain ongoing non-clinical and clinical studies and the completion of certain quality-related activities and study.

We are also subject to rules and regulations in the EU applicable to the manufacturing, marketing, promotion, and sale of medicinal products.

Moreover, product labeling, advertising and promotion for RYTELO will be subject to regulatory requirements and continuing regulatory review.

Failure to comply with EU and EU Member State laws that apply to the conduct of clinical trials, manufacturing approval, marketing authorization of medicinal products and marketing of such products, both before and after grant of the marketing authorization, or with other applicable regulatory requirements, or failure to complete post-marketing requirements on the timeline required, may result in administrative, civil or criminal penalties.

This could also result in delays or refusal to authorize the conduct of clinical trials, or to grant marketing authorization, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the marketing authorization, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties, among others.

If RYTELO is approved outside the U.S.

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Of the large number of drugs in development, only a small percentage complete the development and regulatory approval process and are successfully commercialized.

In addition, the lengthy review process and the unpredictability of future or ongoing clinical trials may result in a delay in obtaining, or our failure to obtain, regulatory approval for RYTELO in lower-risk MDS in any jurisdictions other than the U.S.

and the EU, or our inability to obtain regulatory approval for RYTELO for relapsed/refractory MF or for any other indications, which could significantly harm our business and business prospects, and might cause us to cease operations.

In addition, the lengthy review process and the unpredictability of ongoing or future clinical trials may result in a delay in obtaining, or our failure to obtain, regulatory approval for RYTELO in lower-risk MDS in any jurisdictions other than the U.S.

and the EU, or for other indications, such as relapsed/refractory MF, in any jurisdictions.

Failure to obtain approval could significantly harm our business and business prospects, render our significant clinical development expenditures unrecoverable, and might cause us to cease operations.

Securing marketing approval requires the submission of extensive non-clinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy to the satisfaction of such regulatory authorities, as well as information about the product manufacturing process and any inspections of manufacturing facilities conducted by regulatory authorities through the filing of a New Drug Application, or NDA, in the U.S.

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Although RYTELO is approved in the U.S.

and the EU in lower-risk MDS, there can be no assurance that we will receive regulatory approval for the commercialization of RYTELO for lower-risk MDS in any other jurisdiction or for any new indications.

Any marketing approval that we may receive for RYTELO in any other jurisdiction or for any other indication may also be limited or subject to restrictions or post-approval commitments that increase our costs or render RYTELO not commercially viable, which would harm our business and business prospects.

Any marketing approval that we may receive for RYTELO in any other jurisdiction or for any other indication may also be limited or subject to restrictions or post-approval commitments and requirements that increase our costs or render RYTELO not commercially viable, which would harm our business and business prospects.

Regulatory authorities may also not approve the labeling claims that are necessary or desirable for the successful commercialization of a drug, such as RYTELO.

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Any delay in obtaining or failure to obtain required approvals of RYTELO in any other jurisdictions or for any other indications, or limitations on any regulatory approval that we might receive in the future, if any, could reduce the potential commercial use of RYTELO, and potential market demand for RYTELO and therefore result in decreased revenue for us from any commercialization of RYTELO in any other jurisdictions or for any other indications, any of which could severely and adversely affect our financial results and ability to raise additional capital, if needed, the price of our common stock, our business and business prospects, and might cause us to cease operations.

The commercialization efforts we plan to undertake for RYTELO in the EU for lower-risk MDS may cause us to experience additional risks related to operating outside of the U.S.

that could materially adversely affect our business.

We have employees located outside of the U.S., conduct clinical trials outside of the U.S., and are preparing to commercialize RYTELO in select EU markets beginning in 2026, which may subject us to additional risks, including risks related to operating outside of the U.S., such as:

• we may experience unexpected changes in tariffs, trade barriers, price and exchange controls and other regulatory requirements;

• risks of potential noncompliance by us or by any third parties we engage with legal requirements applicable to privacy, data protection, information security and other matters;

• risks of potential noncompliance with tax, employment, immigration and labor laws for employees living or traveling abroad;

• increased taxes outside of the U.S., including withholding and payroll taxes;

• significant foreign currency fluctuations, which could result in increased operating expenses and reduced revenue, and other obligations incident to doing business in another country;

• difficulties staffing and managing operations outside of the U.S.;

• complexities associated with managing multiple payor reimbursement regimes and government payors in foreign countries;

• workforce uncertainty in countries where labor unrest is more common than in the U.S.;

• potential liability under the Foreign Corrupt Practices Act of 1977 or comparable regulations outside of the U.S.;

• business interruptions resulting from geopolitical actions, including war and terrorism.

For example, the current administration in the U.S.

has called for substantial changes to foreign trade policy and has recently proposed and imposed significant increases in tariffs on international trade and the renegotiation of international trade agreements.

We cannot predict what effects these and potential additional tariffs or renegotiation of existing international trade agreements will have on our business, including in the context of escalating global trade and political tensions.

However, such tariffs and other trade restrictions could increase our cost of doing business, reduce our gross margins or otherwise negatively impact our financial results.

See the risk factor titled, “ Global trade issues and changes in and uncertainties with respect to trade policies and export regulations, including import and export license requirements, trade sanctions, tariffs and international trade disputes, could increase our costs and negatively impact net revenues from sales of RYTELO .”

These and other risks associated with international operations may materially adversely affect our ability to attain or maintain profitable operations.

Uncertainty in the regulatory framework and future legislation could lead to disruption in the execution of international multi-center clinical trials, the monitoring of adverse events through pharmacovigilance programs, the evaluation of the benefit-risk profiles of new medicinal products, and determination of marketing authorization across different jurisdictions.

Changes to existing regulations may add considerably to the time from clinical development to marketing authorization and commercialization of products in foreign jurisdictions and increase our costs.

We cannot predict the impact of such changes and future regulation on our business or the results of our operations.

Global trade issues and changes in and uncertainties with respect to trade policies and export regulations, including import and export license requirements, trade sanctions, tariffs and international trade disputes, could increase our costs and negatively impact net revenues from sales of RYTELO.

There is inherent risk, based on the complex relationships among the U.S.

and the countries in which we now conduct or may in the future conduct our business, that political, diplomatic, and national security factors can lead to global trade restrictions and changes in trade policies and export regulations that may adversely affect our business and operations.

Compliance with applicable regulatory requirements regarding the export of products may create delays in the introduction of RYTELO in international markets, including in the EU, or, in some cases, prevent the export of RYTELO to some countries altogether.

Furthermore, U.S.

export control laws and economic sanctions prohibit the provision of certain products and services to countries, governments and persons targeted by U.S.

and other countries have imposed and may continue to impose new trade restrictions and export regulations, have levied tariffs and taxes on certain goods, and could continue to significantly increase tariffs on a broad array of goods, including pharmaceutical and biological products.

The ongoing trade tensions between the U.S.

and other jurisdictions have resulted in multiple rounds of tariffs and anticipated tariffs affecting pharmaceuticals and pharmaceutical ingredients, including finished drug products, manufacturing equipment, and related supplies.

In April 2025, the U.S.

government imposed a 10% baseline global tariff and in August 2025, the U.S.

imposed higher “reciprocal” tariffs on numerous other territories, including EU Member States and South Korea, with the potential for future increases or revisions.

The Bureau of Industry and Security, U.S.

Department of Commerce, has initiated an investigation to determine whether pharmaceutical ingredients, including finished drug product, manufactured outside the U.S.

pose a national security risk and should be subject to additional tariffs.

Unlike consumer goods, pharmaceuticals face unique regulatory constraints that make rapid supply chain adjustments particularly difficult and costly .

Although a significant portion of our supply chain for imetelstat is currently based in the U.S., the active pharmaceutical ingredient, or API, for imetelstat is manufactured in South Korea and our 47mg vial of RYTELO drug product is currently manufactured in Italy.

In addition, in the future we may choose to utilize other contract manufacturers for different presentations of imetelstat and source materials for our supply chain from other international jurisdictions.

Accordingly, such global or industry-specific tariffs, or the renegotiation of current international trade agreements, or other trade restrictions could result in additional costs on our business, including generally increasing our manufacturing costs, and may decrease our gross margins and increase our supply chain complexity.

Moreover, other governments have imposed and may continue to impose retaliatory tariffs, trade restrictions or trade barriers impacting RYTELO, which could impose additional costs and complexity on our business, including with respect to our planned commercialization of RYTELO in select EU markets in 2026 or restrict our ability to sell RYTELO in the EU or in other international markets where we may obtain approval of RYTELO.

Further, the continued threats of new or increased tariffs, sanctions, trade restrictions and trade barriers as well as ongoing changes in U.S.

and foreign government trade policies, including potential modifications to existing international trade agreements, have had and may continue to have a generally disruptive impact on the global economy and, therefore, could negatively impact revenues from sales of RYTELO.

Given the volatility and uncertainty regarding the scope and duration of such tariffs and other aspects of U.S.

and foreign government trade policies, the ultimate impact on our operations and financial results is uncertain and could be significant in the future.

Although orphan drug designation has been granted to RYTELO for the treatment of MDS and MF in the U.S.

and in the EU, these designations may not be maintained, which would eliminate the benefits associated with orphan drug

designation, including market exclusivity, which could limit the period of exclusivity we are able to maintain for the commercialization of RYTELO, and would likely harm our business and business prospects.

and in the EU, these designations may not be maintained, which would eliminate the benefits associated with orphan drug designation, including market exclusivity, which could limit the period of exclusivity we are able to maintain for the commercialization of RYTELO, and would likely harm our business and business prospects.

The FDA granted orphan drug designation to RYTELO in June 2015 for the treatment of MF and for the treatment of MDS in December 2015, and the EC granted orphan drug designation in December 2015 to RYTELO for the treatment of MF and in July 2020 for the treatment of MDS.

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and EU, respectively, following approval, subject to satisfying regulatory requirements.

The FD A has confirmed seven years of orphan drug exclusivity for RYTELO following its approval on June 6, 2024 for its approved indication in lower-risk MDS.

In connection with the EC's approval of RYTELO in the EU, the EMA's Committee of Orphan Medicinal Products reviewed and issued a positive opinion to maintain RYTELO's orphan drug designation in the EU for the treatment of certain patients with MDS.

Designation as an orphan drug does n ot guarantee that any regulatory authority will accelerate regulatory review of, or ultimately approve, RYTELO for any indication, or at all, in the U.S., EU or any other country, nor does it limit the ability of any regulatory authority to grant orphan drug designation to product candidates of other companies that treat the same indications as RYTELO prior to RYTELO receiving any exclusive marketing approval.

We may lose orphan drug exclusivity for certain reasons, including if the FDA or the European Medicines Agency, or EMA, determines that the request for orphan drug designation was materially defective or if we cannot ensure sufficient quantities of RYTELO to meet the needs of patients with lower-risk MDS or MF.

Failure to maintain orphan designation status, or failure to agree to and complete any agreed upon pediatric plan, would lead to the inability to obtain or the loss of such regulatory exclusivity.

Even if we maintain orphan drug exclusivity for RYTELO, the exclusivity may not effectively protect RYTELO from all competition because different drugs with different active moieties can be approved for the same condition.

The FDA has confirmed seven years of orphan drug exclusivity for RYTELO following its approval on June 6, 2024 for its approved indication in lower-risk MDS.

On March 7, 2025, the EC granted marketing authorization for RYTELO as an orphan medicinal product indicated for the treatment of adult patients with TD anemia due to very low, low or intermediate risk MDS without an isolated deletion 5q cytogenetic (non-del 5q) abnormality and who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.

Designation as an orphan drug does n ot guarantee that any regulatory authority will accelerate regulatory review of, or ultimately approve, RYTELO for any indication, or at all, in the U.S., EU or any other country, nor does it limit the ability of any regulatory authority to grant orphan drug designation to product candidates of other companies that treat the same indications as RYTELO if such products are able to demonstrate superiority to RYTELO.

We may lose orphan drug exclusivity in the U.S.

for certain reasons, including if the FDA determines that the request for orphan drug designation was materially defective or if we cannot ensure sufficient quantities of RYTELO to meet the needs of patients.

In the EU, orphan designation may be lost before marketing authorization if it is established that the criteria for orphan designation are no longer met.

Failure to maintain orphan designation status would lead to the inability to obtain or the loss of associated regulatory exclusivity.

Even if we maintain orphan drug exclusivity for RYTELO in the U.S., the exclusivity may not effectively protect RYTELO from all competition because different drugs with different active moieties can be approved for the same condition or a drug containing the same active moiety or principal molecular structure can be approved for a different indication.

Even after an orphan drug product is approved, such as the approval of RYTELO in the U.S.

in June 2024 and by the EC in March 2025 for certain patients with lower-risk MDS, the FDA or the EC can subsequently approve a different drug with the same active moiety for the same condition, if the FDA or the EC concludes that the later drug is safer, more effective, or makes a major contribution to patient care.

The occurrence of any of these events could limit the period of exclusivity we are able to maintain for RYTELO, and may harm our business and business prospects.

In addition, for any other indication that we are currently or may in the future seek to develop or obtain regulatory approval for RYTELO, orphan drug designation will neither shorten the development time nor regulatory review time for RYTELO, and it does not give RYTELO any advantage in the regulatory review or approval process.

in June 2024 for certain patients with lower-risk MDS, the FDA can subsequently grant orphan designation to a different drug with the same active moiety for the same condition, if the FDA concludes that the later drug is safer, more effective, or makes a major contribution to patient care.

The occurrence of any of these events could limit the period of exclusivity we are able to maintain for RYTELO, allow competitive products to enter the market, and harm our business and business prospects.

In addition, for any other indication that we are currently or may in the future seek to develop or obtain regulatory approval

for RYTELO, orphan drug designation will neither shorten the development time nor regulatory review time for RYTELO in the US and other comparable jurisdictions, and it does not give RYTELO advantages in the regulatory review or approval process.

Notably, there have been legal challenges to aspects of FDA’s regulations and policies concerning the exclusivity provisions of the Orphan Drug Act, including whether two drugs are the same drug product.

Future challenges could lead to changes that affect the protections potentially afforded to our products in ways that are difficult to predict.

Similarly, in the EU, orphan market exclusivity may not effectively protect RYTELO from all competition.

Following the authorization of RYTELO as an orphan medicinal product by the EC in March 2025 for certain patients with lower-risk MDS, the EC can subsequently approve similar orphan medicinal products for the same therapeutic indication or if we are unable to supply RYTELO in sufficient quantities or if a similar medicinal product with the same orphan indication is shown to be safer, more effective or otherwise clinically superior to the original orphan medicinal product.

If it is established that the criteria for orphan designation are no longer met inter alia where it is shown that the product is sufficiently profitable, EU orphan market exclusivity may be reduced to six instead of 10 years, allowing similar medicinal products for the same therapeutic indication to the market sooner.

In the EU, orphan drug designation for any additional indication we may pursue for RYTELO does confer certain regulatory advantages—such as protocol assistance—but it does not shorten development timelines or accelerate the EMA’s overall review process.

In April 2023, the EC published a proposal to reform the current pharmaceutical framework, including revision of orphan market exclusivity.

The new legislation, if adopted, is expected to start to apply from mid-2028.

The proposal to reform the current pharmaceutical framework intends to revise the orphan drug designation and exclusivity regime.

In the latest version of the proposal, orphan market exclusivity will be reduced from the current 10 years to 9 years.

Extension by another two years will be possible for so-called “breakthrough orphan medicinal products”.

Previous drafts also included the concept of “global orphan marketing authorization”, which would no longer grant additional separate orphan market exclusivity for second or further orphan therapeutic indications.

Although the final text has not yet been published and RYTELO for the treatment of MDS is and remains regulated under the current regulatory framework, authorization of future indications may be affected by the new legislation.

Even though we reported positive top-line results from IMerge Phase 3 in January 2023 and received regulatory approval from the FDA in June 2024 to commercialize RYTELO in the U.S.

for lower-risk MDS, the top-line results from IMerge Phase 3 are not necessarily predictive of RYTELO’s activity in other indications, such as from IMpactMF.

Even though we reported positive top-line results from IMerge Phase 3 in January 2023 and received regulatory approval from the FDA in June 2024 and the EC in March 2025 to commercialize RYTELO in lower-risk MDS, the top-line results from IMerge Phase 3 are not necessarily predictive of RYTELO’s activity in other indications and for other pivotal trials that may be needed to support any application to the FDA or similar international regulatory authorities for such other indications, such as from IMpactMF.

In addition, with respect to the trial design for IMpactMF, the FDA urged us to consider adding a third dosing arm to the trial to assess a lower dose and/or a more frequent dosing schedule that might improve the trial’s chance of success by identifying a less toxic regimen and/or more effective spleen response, one of the trial’s secondary endpoints.

for lower-risk MDS, the top-line results from IMerge Phase 3 are not necessarily predictive of RYTELO’s activity in other indications, such as in relapsed/refractory MF.

In addition, with respect to the trial design for IMpactMF, our Phase 3 trial in relapsed/refractory MF, the FDA urged us to consider adding a third dosing arm to the trial to assess a lower dose and/or a more frequent dosing schedule that might improve the trial’s chance of success by identifying a less toxic regimen and/or more effective spleen response, one of the trial’s secondary endpoints.

Based on data from IMbark, our Phase 2 clinical trial that evaluated two doses of imetelstat in relapsed/refractory MF and the results of which our IMpactMF trial is based on, we believe that testing a lower dose regimen would likely result in a lower median OS, which is the trial’s primary endpoint, in the imetelstat treatment arm.

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RISKS RELATED TO COMPLIANCE WITH HEALTHCARE LAWS

The FDA, DOJ and other regulatory authorities actively enforce regulations related to the promotion and advertisement of pharmaceutical products, and if we were found to have violated the Food, Drug and Cosmetic Act, we could be subject to significant civil, criminal and administrative penalties.

Our relationships with healthcare providers, including physicians and third-party payors, the methods by which we promote RYTELO, and the content of our promotional materials and programs, are subject to applicable promotional, anti-kickback, fraud and abuse, and other healthcare laws and regulations, and our failure to comply with these laws could expose us to criminal sanctions, civil penalties, exclusion from federal health care programs, contractual damages, reputational harm and may adversely affect our business and financial results.

The FDA strictly regulates the promotional claims that may be made about drug products.

In particular, a product may not be promoted for uses that are not approved by the FDA as reflected in the product’s approved labeling.

In particular, FDA asserts that a product may not be promoted for uses that are not approved by the FDA as reflected in the product’s approved labeling.

The FDA, DOJ and other agencies actively enforce regulations related to the promotion and advertisement of pharmaceutical products.

If we were found to have violated the Food, Drug, and Cosmetic Act, we could be subject to significant civil, criminal and administrative penalties, which could inhibit our ability to commercialize RYTELO and generate revenue, require us to expend significant time and resources in response, and generate negative publicity.

Enforcement actions include, among others:

• adverse regulatory inspection findings;

• fines, warning letters, or untitled letters;

• voluntary or mandatory product recalls or public notification or medical product safety alerts to healthcare professionals;

• restrictions on, or prohibitions against, marketing RYTELO;

• restrictions on, or prohibitions against, importing or exporting RYTELO;

• suspension of review or refusal to approve pending applications or supplements to approved applications;

• exclusion from participation in government-funded healthcare programs;

• exclusion from eligibility for the award of government contracts for RYTELO;

• suspension or withdrawal of regulatory approval for RYTELO;

• product seizures;

• injunctions;

• civil and criminal penalties and fines.

Similar requirements and related consequences apply outside the U.S.

Enhanced governmental and private scrutiny over, or investigations or litigation involving, pharmaceutical manufacturer donations to patient assistance programs offered by charitable foundations may require us to modify our programs and could negatively impact our business practices, harm our reputation, divert the attention of management and increase our expenses.

To help patients afford our products, we have a patient assistance program and also occasionally make donations to independent charitable foundations that help financially needy patients.

These types of programs designed to assist patients in affording pharmaceuticals have become the subject of scrutiny.

In recent years, some pharmaceutical manufacturers were named in class action lawsuits challenging the legality of their patient assistance programs and support of independent charitable patient support foundations under a variety of federal and state laws.

At least one insurer also has directed its network pharmacies to no longer accept manufacturer co-payment coupons for certain specialty drugs the insurer identified.

Our patient assistance program and support of independent charitable foundations could become the target of similar litigation.

In addition, there has been regulatory review and enhanced government scrutiny of donations by pharmaceutical companies to patient assistance programs operated by charitable foundations.

For example, the Office of Inspector General of the U.S.

Department of Health & Human Services, or OIG, has established specific guidelines

permitting pharmaceutical manufacturers to make donations to charitable organizations who provide co-pay assistance to Medicare patients, provided that such organizations are bona fide charities, are entirely independent of and not controlled by the manufacturer, provide aid to applicants on a first-come basis according to consistent financial criteria, and do not link aid to use of a donor’s product.

If our promotional materials or methods were found to have violated the Food, Drug, and Cosmetic Act, or False Claims Act, we could be subject to Warning or Untitled Letters, or to significant civil, criminal, or administrative penalties, which could inhibit our ability to commercialize RYTELO and generate revenue, require us to expend significant time and resources in response, and generate negative publicity.

Healthcare professionals, including but not limited to physicians, nurses, medical directors, hospitals, pharmacies, pharmacy benefit managers, group purchasing organizations, wholesalers, insurers, and all individuals employed by such entities (collectively, HCPs), and patients, caregivers, patient advocacy organizations, or medical societies, may influence the recommendation and prescription of RYTELO.

There is ongoing government focus on the relationships between the pharmaceutical industry and HCPs or others who can influence the prescription or recommendation of products, and common industry activities that we may engage in such as speaker programs, advisory boards, consulting agreements with HCPs, relationships with charitable foundations providing copayment assistance, and relationships with patient organizations and patients continue to receive increased governmental attention.

Our arrangements with HCPs and others who have the ability to influence the recommendation and prescription of RYTELO may expose us to broadly applicable federal and state fraud and abuse and other healthcare laws and regulations, including anti-kickback and false claims laws;

data privacy and security laws, including the Health Insurance Portability and Accountability Act, or HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH;

and transparency laws related to payments and/or other transfers of value made to physicians, other healthcare professionals and teaching hospitals.

Additionally, some state and local laws require certain regulatory licenses to manufacture or distribute our products commercially and/or the registration of pharmaceutical sales representatives in the jurisdiction.These laws may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we market, sell and distribute RYTELO.

For details regarding the restrictions under applicable federal and state healthcare laws and regulations that may affect our ability to operate, see Item 1 “Business-Government Regulation- Fraud and Abuse, and Transparency Laws and Regulations” of the 2025 Form 10-K.

Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible that some of our business activities could be subject to challenge under one or more of such laws.

For example, to help patients afford our products, we have a patient assistance program and also occasionally make donations to independent charitable foundations that help financially needy patients.

These types of programs designed to assist patients in affording pharmaceuticals have become the subject of scrutiny under the AKS and other federal and state laws in recent years.

If we or our vendors or donation recipients are deemed to fail to comply with laws or regulations in the operation of these programs, we could be subject to damages, fines, penalties or other criminal, civil or administrative sanctions or enforcement actions.

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A government investigation could negatively impact our business practices, harm our reputation, divert the attention of management and increase our expenses.

If our business activities become subject to challenge under supranational, national, federal, state or international healthcare laws, including fraud and abuse, transparency, and health information privacy and security laws, we could face substantial penalties and our business, results of operations, financial condition and prospects could be adversely affected.

Our business operations and current and future arrangements with investigators, healthcare professionals, consultants, third-party payors and customers, may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations, including federal and state fraud and abuse laws, including anti-kickback and false claims laws;

and transparency laws related to payments and/or other transfers of value made to physicians, other healthcare professionals and teaching hospitals.

These laws may constrain the business or financial arrangements and relationships through which we conduct our operations, including how we market, sell and distribute RYTELO.

Federal and state enforcement bodies have increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

While we maintain a comprehensive compliance program designed with the goal of ensuring that our practices and the activities of our third party contractors and employees fall within the scope of available statutory exceptions and regulatory safe harbors whenever possible, and otherwise comply with applicable laws, it is possible that government authorities may disagree with our assessment, find fault with the conduct of our employees or contractors or conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.

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, or could result in related shareholder lawsuits, any of which would adversely affect our business, financial condition, results of operations and prospects.

Foreign, federal and state enforcement bodies have increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

If our operations are found to be in violation of any of these or any other healthcare and privacy-related regulatory laws that may apply to us, our ability to operate our business and our results of operations could be adversely affected by:

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Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

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.

and some jurisdictions outside the U.S., there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could impact our business.

Generally, there has been

increasing legislative and enforcement interest in the U.S.

with respect to drug pricing, including specialty drug pricing practices, in light of the rising cost of prescription drugs and biologics.

Specifically, there have been U.S.

If future legislation were to impose direct governmental price controls and access restrictions, it could have a significant adverse impact on our business and financial results.

Managed care organizations, as well as Medicaid and other government authorities, continue to seek price discounts.

Such policy actions could have a material adverse impact on future sales of RYTELO in the U.S.

the EU, and in any other jurisdictions where we may seek approval in the future.

RISKS RELATED TO THE FURTHER DEVELOPMENT OF IMETELSTAT

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Our ability to further develop imetelstat and to expand its indications of use to other myeloid hematologic malignancies is subject to significant risks and uncertainties, including, among other things, our ability to:

• generate sufficient safety and efficacy data from the IMpactMF clinical trial to support any application for regulatory approval in relapsed/refractory MF, without clinically meaningful safety issues, side effects or dose-limiting toxicities related to imetelstat that may negatively impact its benefit-risk profile;

• generate sufficient safety and efficacy data from the IMpactMF, IMproveMF, IMpress and IMAGINE clinical trials, as well as our studies in frontline MF and acute myeloid leukemia or high-risk MDS, to support any application for regulatory approval, without clinically meaningful safety issues, side effects or dose-limiting toxicities related to imetelstat that may negatively impact its benefit-risk profile;

• ascertain that the use of imetelstat does not result in significant systemic or organ toxicities, including hepatotoxicity, or other safety issues resulting in an unacceptable benefit-risk profile;

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• obtain and maintain required regulatory clearances and approvals to enable continued clinical development of imetelstat;

• enter into and maintain commercially reasonable arrangements with third parties to provide services needed to further research, develop and commercialize RYTELO, including maintaining the agreements with our contract research organizations, or CROs, and third-party manufacturers;

• recruit and retain sufficient qualified and experienced personnel to support the development and commercialization of RYTELO in potential other approved indications and other jurisdictions outside of the U.S.

• enter into and maintain arrangements with third parties to provide services needed to support the commercialization of RYTELO for territories outside of the U.S.

in compliance with applicable laws;

• achieve acceptance of RYTELO treatment by patients and the relevant medical communities;

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• patient recruitment, enrollment and retention challenges and operational delays, including in connection with opening new clinical trial sites, while also competing with clinical trials for other investigational drugs in the same patient population;

• use of trial endpoints such as OS, that inherently require prolonged periods of clinical observation or analysis of the resulting data to determine trial outcomes, including the need for a certain number of events, or deaths, to occur in IMpactMF prior to the interim or final analysis in that trial of OS;

• use of OS as a trial endpoint, which inherently requires prolonged periods of clinical observation and follow-up, including the need for a certain number of events, or deaths, to occur in IMpactMF prior to the interim or final analysis in that trial of OS;

• use of trial endpoints, including patient-reported outcomes, that necessitate a comprehensive analysis of the resulting data to determine trial outcomes;

• obtaining and/or maintaining regulatory clearances in the U.S.

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RYTELO may cause, or have attributed to it, undesirable or unintended side effects or other adverse events that could halt or limit its further commercialization, delay or prevent its regulatory approval in any other jurisdiction or indication, or cause us to delay or terminate our clinical trials.

RYTELO (imetelstat) has been administered only to a limited number of patients in clinical trials.

While the FDA and the EC granted approval of RYTELO based on the data included in our NDA and MAA, respectively, including data from the Phase 3 IMerge trial, we do not know whether the results when a larger number of patients receive RYTELO from commercial use, including results related to safety, will be consistent with the results from earlier clinical trials that served as the basis for its approval.

While the FDA and the EC granted approval of RYTELO based on the data included in our NDA and MAA, respectively, including data from the Phase 3 IMerge trial, we cannot be certain whether the results as a larger number of patients receive RYTELO from commercial use, including results related to safety, will be consistent with the results from earlier clinical trials that served as the basis for its approval.

In addition, because remaining patients in ongoing clinical trials continue to receive imetelstat, additional or more severe toxicities or safety issues may be observed, and the benefit-risk profile of imetelstat will continue to be assessed, including the risk of hepatotoxicity, severe cytopenias, fatal bleeding with or without any associated thrombocytopenia, patient injury or death.

New data relating to imetelstat, including from adverse event reports and our post-marketing requirements in the U.S., and from ongoing clinical trials of imetelstat, may result in changes to the product label and may adversely affect sales, or result in withdrawal of imetelstat from the market.

The FDA and regulatory authorities in other jurisdictions may also consider the new data in reviewing our marketing applications for additional indications and/or in other jurisdictions, or impose post-approval requirements.

The FDA and regulatory authorities in other jurisdictions may also consider the new data in reviewing our marketing applications for additional

indications and/or in other jurisdictions, or impose post-approval requirements.

If any of these actions were to occur, it could result in significant expense and delay or limit our ability to generate sales revenues.

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• infusion-related reactions.

If patients who receive RYTELO as a result of commercialization or in any clinical trials experience similar or more severe adverse events, or new or unusual adverse events, or if the FDA or other similar international regulatory authorities determine that efficacy and safety data from our commercialization efforts or in clinical trials do not support an adequate benefit-risk profile to justify continued treatment of patients, then the FDA or other similar international regulatory authorities may halt or restrict the commercialization of RYTELO or place one or more of our INDs on clinical hold, as occurred in March 2014.

If patients experience similar or more severe adverse events, or new or unusual adverse events, or if the FDA or other similar international regulatory authorities determine that efficacy and safety data from our commercialization efforts or in clinical trials do not support an adequate benefit-risk profile to justify continued treatment of patients, then the FDA or other similar international regulatory authorities may halt or restrict the commercialization of RYTELO or place one or more of our INDs on clinical hold, as occurred in March 2014.

If this were to occur, there could be a significant delay in, or possible termination of, one or more of our clinical trials, and our commercialization efforts could be halted, which might cause us to cease operations.

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The occurrence of any of these events could interrupt, further delay, or halt our commercialization of RYTELO or its further development, and as a result, could preclude the commercialization of RYTELO in any additional indications, as well as increase costs for continued development in additional indications, which would have a severe adverse effect on our results of operations, financial condition and ability to raise additional capital, business and business prospects, any of which might cause us to cease operations.

Results and data we disclosed from prior non-clinical studies and clinical trials may not predict success in later clinical trials, and we cannot assure you that any ongoing or future clinical trials of imetelstat, including IMpactMF, will lead to similar results and data that could potentially enable us to obtain any further regulatory approvals.

Results and data we disclosed from prior non-clinical studies and clinical trials, as well as any data disclosed as a result of an interim analysis, may not predict success in later clinical trials or the final analysis, and we cannot assure you that any ongoing or future clinical trials of imetelstat, including IMpactMF, will lead to similar results and data that could potentially enable us to obtain any further regulatory approvals.

The design of a clinical trial can determine whether its results will support regulatory approval of a product, and flaws in the trial design may not become apparent until the clinical trial is well advanced or during the approval process after the trial is completed.

A clinical trial design that is considered appropriate for regulatory approval includes a sufficiently large sample size with appropriate statistical power, as well as proper control of bias, to allow a meaningful interpretation of the results.

meaningful interpretation of the results.

The preliminary results of imetelstat clinical trials with smaller sample sizes can be disproportionately influenced by the impact the treatment had on a few individuals, which limits the ability to generalize the results across a broader community, making the trial results of clinical trials with smaller sample sizes less reliable than trials with a larger number of patients.

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Many companies in the biopharmaceutical industry have frequently suffered significant setbacks in later clinical trials, even after achieving promising results in earlier non-clinical studies or clinical trials.

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 the results observed in IMbark, and if this were to occur with IMpactMF, this would adversely affect future development prospects of imetelstat, and as a result, impact the potential commercialization of imetelstat in relapsed/refractory MF, which would have a severe adverse effect on our results of operations, financial condition and ability to raise additional capital, if needed, business and business prospects, any of which might cause us to cease operations.

Furthermore, non-clinical and clinical data are often susceptible to varying interpretations and analyses.

In some instances, there can be significant variability between different clinical trials of imetelstat due to numerous factors, including changes in trial procedures set forth in trial protocols, differences in the size and type of patient populations, and changes in and adherence to the dosing regimens.

For example, although the statistical analyses comparing IMbark data to closely matched real world data, or RWD, published in the September 2021 issue of the Annals of Hematology, suggest potentially favorable OS in relapsed/refractory MF patients treated with imetelstat, compared to BAT using closely matched patients’ RWD, such comparative analyses between RWD and our clinical trial data have several limitations.

For example, although the statistical analyses comparing IMbark data to closely matched real world data, or RWD, published in the September 2021 issue of the Annals of Hematology, suggest potentially favorable OS in relapsed/refractory MF patients treated with imetelstat, compared to bipolar androgen therapy using closely matched patients’ RWD, such comparative analyses between RWD and our clinical trial data have several limitations.

For instance, the analyses create a balance between treatment groups with respect to commonly available covariates, but do not take into account the unmeasured and unknown covariates that may affect the outcomes of the analyses.

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Thus, reported data should be considered carefully and with caution, and not relied upon as indicative of future clinical results.

Such additional data could result in a lower benefit-risk profile than initially expected, which could halt the commercialization of RYTELO, hinder the potential success of IMpactMF, IMproveMF or IMpress, or cause us to abandon further development of imetelstat entirely.

Top-line results and data may differ from future results of the same study, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated.

Such additional data could result in a lower benefit-risk profile than initially expected, which could halt the commercialization of RYTELO, hinder the potential success of IMpactMF, IMproveMF, IMpress or IMAGINE, or cause us to abandon further development of imetelstat entirely.

Top-line or interim results and data may differ from future results of the same study, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated.

Moreover, as remaining patients in IMerge Phase 3 continue to be treated and followed under the extension phase of the trial and longer-term outcomes are assessed, these additional and more mature data may alter the benefit-risk profile of imetelstat in an adverse manner, including with respect to OS.

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We do not have the ability to independently conduct clinical trials.

Therefore, we rely on medical institutions, clinical investigators, contract laboratories and other third parties, such as CROs, service providers, vendors,

suppliers and consultants, to conduct clinical trials of imetelstat.

Therefore, we rely on medical institutions, clinical investigators, contract laboratories and other third parties, such as CROs, service providers, vendors, suppliers and consultants, to conduct clinical trials of imetelstat.

The third parties we contract with for execution of our current and potential future clinical or investigator-sponsored trials of imetelstat play a critical role in the conduct of these trials and the subsequent collection and analysis of data.

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If we or any of our CROs fail to comply with applicable GCP requirements, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, or similar international regulatory authorities, may require us to perform additional clinical trials.

We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with GCP or other applicable regulations.

We cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine whether any of our clinical trials comply with GCP or other applicable regulations.

In addition, our clinical trials must be conducted with imetelstat produced under applicable GMP regulations.

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This could result in a delay in approval, or rejection, of any future applications for regulatory approval of imetelstat, including in any additional indications by the FDA.

unfavorable benefit-risk assessment that could materially and adversely impact our ongoing clinical trials, or our development program as a whole.

We do not control the conduct of current or any potential future investigator-led clinical trials, and data from such trials could show marginal efficacy and/or clinically relevant safety concerns related to imetelstat resulting in an unfavorable benefit-risk assessment that could materially and adversely impact our ongoing clinical trials, or our development program as a whole.

We do not control the design or administration of investigator-led clinical trials, nor the submission, approval or maintenance of any IND or international equivalent filings required to conduct these clinical trials.

In addition, we do not have control over the timing and reporting of the data from any such investigator-led clinical trials.

A delay in the timely completion of or reporting of data from any current or potential future investigator-led clinical trial could have a material adverse effect on our ability to maintain regulatory approval for RYTELO in lower-risk MDS, or to further develop or advance it in clinical trials, as such delays may impede our ability to generate necessary supplemental clinical evidence, fulfill post-marketing commitments or requirements, or provide regulatory authorities with timely safety and efficacy data needed to support ongoing approval or future development.

Investigator-led clinical trials may be conducted under less rigorous clinical standards than those used in company-sponsored clinical trials.

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Safety concerns arising from future investigator-led clinical trials could result in withdrawal of approval of RYTELO, partial or full clinical holds being placed on our INDs by the FDA or other similar international regulatory authorities, as occurred in March 2014, which would further delay or prevent us from commercializing RYTELO or advancing it into further clinical development.

Any of the foregoing would delay or preclude any future marketing approvals for RYTELO and could cause us to discontinue our development of it, which would severely harm our business and prospects and could potentially cause us to cease operations.

RISKS RELATED TO MANUFACTURING RYTELO

Any of the foregoing would delay or preclude any future marketing approvals for RYTELO and could cause us to discontinue our development, which would severely harm our business and prospects and could potentially cause us to cease operations.

RISKS RELATED TO MANUFACTURING RYTELO (IMETELSTAT)

Failure by us to maintain a manufacturing supply chain to appropriately and adequately supply RYTELO for commercial and future clinical uses would adversely affect our ability to commercialize RYTELO and result in a further delay in or cessation of clinical trials, and our business and business prospects could be severely harmed, and we could cease operations.

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• reliance on third-party manufacturers and suppliers, whose efforts we do not control;

• supply chain issues, including the timely availability of product and management of shelf-life, including raw materials, active pharmaceutical ingredient, or API, and drug product and other supplies, and the cost of procuring the foregoing, any of which may be impacted by a number of factors, including the effects of macroeconomic or other global conditions, such as increased tariffs, renegotiation of existing international trade agreements, escalating trade tensions and other trade restrictions;

• supply chain issues, including the timely availability of product and management of shelf-life, including raw materials, active pharmaceutical ingredient, or API, and drug product and other supplies, and the cost of procuring the foregoing, any of which may be impacted by a number of factors, including the effects of macroeconomic or other global conditions, such as ongoing military conflicts, increased tariffs, renegotiation of existing international trade agreements, escalating trade tensions and other trade restrictions;

• shortage of qualified personnel at any of our third party suppliers;

• regulatory acceptance and compliance with regulatory requirements, which are less well-defined for oligonucleotide products than for small molecule drugs and vary in each country.

In addition, the ongoing Russia-Ukraine military conflict and the ongoing military conflict involving the U.S., Israel and Iran have had and may continue to have further global economic consequences, including continued disruptions of the global supply chain and energy markets.

For example, disruptions or perceived risks to energy supply routes, including shipping through key transit points, have resulted in increased fuel and energy prices and could continue to do so for an extended period, which could disrupt our existing supply chain and increase our cost of doing business, reduce our gross margins or otherwise negatively impact our financial results.

See also the risk factor entitled “ Global trade issues and changes in and uncertainties with respect to trade policies and export regulations, including import and

export license requirements, trade sanctions, tariffs and international trade disputes, could increase our costs and negatively impact net revenues from sales of RYTELO.

As a result of these and other risks, we may be unable to maintain a manufacturing infrastructure and supply chain capable of providing RYTELO for clinical and commercial use, which would delay or adversely affect our RYTELO commercialization efforts;

result in lost sales;

delay or result in a cessation of our current or potential future

clinical trials;

delay or result in a cessation of our current or potential future clinical trials;

delay or preclude potential future regulatory approvals of RYTELO in other jurisdictions or indications;

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Failure by such third-party manufacturers to perform in a timely manner and in compliance with all regulatory requirements, or at all, or the termination of one of our supply agreements before we have retained and established an acceptable alternative supplier, could lead to delays or shortages in drug supply, perhaps substantially, that are necessary for our clinical activities and commercialization of RYTELO.

In this regard, a recent FDA inspection of one of our third-party manufacturers identified certain deficiencies in the manufacturer’s processes and facilities which, while not related to the production of RYTELO, could impact the manufacturer’s ability to produce and deliver products, including RYTELO, if not remediated by the manufacturer, and could lead to delays or shortages in drug supply, or the inability to manufacture or ship drug supply necessary for non-clinical and clinical activities, and commercialization.

For example, one of our third-party manufacturers received a warning letter from the FDA due to certain deficiencies in the manufacturer’s process and facilities that were not in compliance with FDA requirements and regulations governing the manufacturing, processing, packing and holding of drug product.

While not related to the production of RYTELO, if the warning letter is not timely remediated by the manufacturer, it could lead to delays or shortages in drug supply, or the inability to manufacture or ship drug supply necessary for non-clinical and clinical activities, and commercialization.

In addition, we plan to retain additional third-party manufacturers to provide redundancy in our supply chain;

however, we may be unable to do so on a timely basis on terms that are acceptable to us, or at all.

Any of the foregoing could increase our costs, result in lost sales and delays in our clinical trials, and otherwise have a material adverse effect on our financial results, business and business prospects.

We expect to rely on third-party manufacturers to produce and deliver sufficient quantities of RYTELO and other materials to support our commercialization of RYTELO and clinical trials on a timely basis and to comply with applicable regulatory requirements.

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• the possible mislabeling by third-party manufacturers of finished drug product for both commercial and clinical use, potentially resulting in product recall and harm to our business;

• decisions by third-party manufacturers to exit the contract manufacturing business during the time required to supply clinical trials or to successfully produce, store and distribute RYTELO to meet our commercial needs or before we have established an acceptable alternative supplier;

• compliance by third-party manufacturers with GMP standards mandated by the FDA and state agencies and other government regulations, including foreign governing regulations, corresponding to similar international regulatory authorities, including any deficiencies identified during regulatory inspections, such as those identified in a recent FDA inspection of one of our third-party manufacturers;

• compliance by third-party manufacturers with GMP standards mandated by the FDA and state agencies and other government regulations, including foreign governing regulations, corresponding to similar international regulatory authorities, including any deficiencies identified during regulatory inspections, such as those identified in the warning letter issued to one of our third-party manufacturers;

• breach or termination of manufacturing or supply contracts;

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We are incurring and have incurred net losses every year since our operations began in 1990, except for one.

As of September 30, 2025, our accumulated deficit was approximately $1.8 billion.

As of March 31, 2026, our accumulated deficit was approximately $1.9 billion.

Losses have resulted principally from costs incurred in connection with our research and development activities and from general and administrative costs associated with our operations.

Although we have recently begun to commercialize RYTELO, our revenue and profit potential is unproven and our limited operating history as a commercial company makes our future operating results difficult to predict.

Although we began commercializing RYTELO in June 2024, the commercial potential of and our ability to successfully commercialize RYTELO remains unproven, and our limited operating history as a commercial company makes our future operating results difficult to predict.

We expect that our sales revenue may continue to vary from period to period as a result of the evolving effects of our commercialization strategy and as our commercialization efforts otherwise progress.

If we do not generate sufficient revenue from commercial sales of RYTELO, or if we experience unforeseen events or choose to make other investments in our business, we may continue to experience negative cash flow as we fund our operations and imetelstat clinical development activities and research programs, and continue with the commercialization of RYTELO, including as a result of our obligation to pay royalty payments under the Royalty Pharma Agreement and service our debt obligations.

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To the extent that we do not meet our guidance, our financial projections or estimates, or the expectations of analysts or investors, our stock price may be adversely impacted, perhaps significantly.

For example, following our release of earnings for the quarter and year ended December 31, 2024, our stock price declined significantly.

For example, following releases of earnings for both of the quarters and years ended December 31, 2025 and 2024, our stock price declined significantly both times.

As a result of this volatility, our stockholders may not be able to sell their common stock at or above the price they paid for their common stock.

We believe that our quarterly and annual results of operations may be affected by a variety of factors, including:

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• the extent to which coverage and reimbursement for RYTELO is available from government and health administration authorities, private health insurers, managed care programs and other third-party payors;

• changes in the amount of deductions from gross sales, including government-mandated rebates, chargebacks and discounts that can vary because of changes to the government discount percentage, including increases in the government discount percentage resulting from price increases we may take in the future, or due to different levels of utilization by entities entitled to government rebates and discounts and changes in patient demographics;

• changes in the amount of deductions from gross sales, including government-mandated rebates, chargebacks and discounts that can vary because of changes to the government discount percentage, including increases in the government discount percentage resulting from price increases we have taken or may take in the future, or due to different levels of utilization by entities entitled to government rebates and discounts and changes in patient demographics;

• increases in the scope of eligibility for customers to purchase RYTELO at the discounted government price or to obtain government-mandated rebates on purchases of RYTELO;

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For these and other reasons, it is difficult for us to accurately forecast future sales of RYTELO, operating expenses or future profits or losses.

As a result, our operating results in future periods could be below our guidance or the expectations of securities analysts or investors, which could cause the trading price of our common stock to decline, perhaps significantly.

Our financial projections and estimates are subject to significant risks, assumptions, and uncertainties, and our actual results may differ materially.

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Successful drug development and commercialization requires significant amounts of capital.

As of September 30, 2025, we had approximately $421.5 million in cash, cash equivalents, restricted cash and marketable securities.

While we believe that, based on our current operating plans and assumptions, our existing cash, cash equivalents, and marketable securities, together with anticipated net revenues from sales of RYTELO, will be sufficient to fund our projected operating requirements for the foreseeable future, if we do not generate net revenues from commercial sales of RYTELO at the levels we anticipate, if we experience unforeseen events or choose to make other investments in our business, or our assumptions regarding our projected operating expenses are otherwise incorrect, we may require additional funding, which could include a combination of public or private equity offerings, debt financings (including additional tranches under the Pharmakon Loan Agreement, if available), collaborations, strategic alliances, licensing arrangements or marketing and distribution arrangements, which may not be possible.

As of March 31, 2026, we had approximately $341.0 million in cash, cash equivalents, restricted cash and marketable securities.

regarding our projected operating expenses are otherwise incorrect, we may require additional funding, which could include a combination of public or private equity offerings, debt financings (including additional tranches, if available, under the Pharmakon Loan Agreement (as defined below), collaborations, strategic alliances, licensing arrangements or marketing and distribution arrangements, which may not be possible.

For example, changes in our operations, such as increased development, manufacturing and clinical trial expenses, or our undertaking of additional programs, business activities, or entry into strategic transactions, including potential future acquisitions of products, technologies or businesses, may cause our operating expenses to increase, perhaps significantly, which could require us to raise additional funding.

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• the costs of manufacturing, developing, commercializing and marketing RYTELO, including with respect to third-party vendors and service providers and our ability to achieve any meaningful reduction in manufacturing costs;

• the sales price for RYTELO;

• the availability of coverage and adequate third-party reimbursement for RYTELO;

• the sales price for RYTELO, including the availability of coverage and adequate third-party reimbursement for RYTELO;

• the extent to which we acquire or in-license other drugs and technologies, or invest in businesses, products or technologies, although we currently have no commitments or agreements relating to any of these types of transactions, or to which we out-license RYTELO;

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• the costs of enabling our personnel to work remotely, including providing supplies, equipment and technology necessary for them to perform their responsibilities.

In the event we need to raise additional capital to fund our business, including pursuant to the 2023 Sales Agreement with B.

Riley Securities, Inc., the Tranche B Loan and the Tranche C Loan under the Pharmakon Loan Agreement, which are subject to certain funding conditions;

In the event we need to raise additional capital to fund our business, including pursuant to the 2026 Sales Agreement with TD Cowen (as defined below), the Tranche B Loan and the Tranche C Loan under the Pharmakon Loan Agreement, which are subject to certain funding conditions;

capital lease transactions or other financing sources, such additional capital may not be available on acceptable terms, or at all.

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These effects have increased market volatility and could result in a significant long-term disruption of global financial markets, which could reduce or eliminate our ability to raise additional funds through financings, and could negatively impact the terms upon which we may raise those funds.

Similarly, these macroeconomic conditions have created extreme volatility and disruption in the capital markets and are expected to have further global economic consequences.

If the equity and credit markets deteriorate, including as a result of macroeconomic or other global conditions, such as further changes in tariffs and other trade restrictions and uncertainty around further escalation of trade tensions and renegotiation of existing international trade agreements, inflation, fluctuations in interest rates, prospects of a recession, government shutdowns, bank failures and other disruptions to financial systems, civil or political unrest, military conflicts, pandemics or other health crises and supply chain and resource issues, it may make any necessary debt or equity financing more difficult to obtain in a timely manner or on favorable terms, more costly or more dilutive.

Similarly, these macroeconomic conditions have created extreme volatility and disruption in the equity and credit markets and are expected to have further global economic consequences.

For example, the ongoing Russia-Ukraine military conflict and the ongoing military conflict involving the U.S., Israel and Iran have created extreme volatility and disruption in the equity and credit markets and have had and may continue to have further global economic consequences, including continued disruptions of the global supply chain and energy markets, which could continue to drive inflationary pressures and increase global recession risk.If the equity and credit markets deteriorate, it may make any necessary debt or equity financing more difficult to obtain in a timely manner or on favorable terms, more costly or more dilutive.

If we are unable to effectively commercialize RYTELO, or raise additional capital, if needed, or establish alternative collaborative arrangements with third-party collaborative partners for RYTELO when needed, the development and commercialization of RYTELO may be further delayed, altered or abandoned, which might cause us to cease operations.

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To the extent that we raise additional capital through the sale of equity or convertible debt securities, including pursuant to the 2026 Sales Agreement, our stockholders may be diluted, and the terms may include liquidation or other preferences that could materially and adversely affect the rights of our existing stockholders.

In addition, we have borrowed, and in the future may borrow, additional capital from institutional and commercial banking sources to fund development and our future growth, including pursuant to our Pharmakon Loan

Agreement or potentially pursuant to new arrangements with different lenders.

We may borrow funds on terms under agreements, such as our Pharmakon Loan Agreement, that include restrictive covenants, including covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.

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RISKS RELATED TO OUR INDEBTEDNESS AND ROYALTY PAYMENT OBLIGATIONS

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.

On November 1, 2024, we entered into the Pharmakon Loan Agreement.

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, including by limiting our operating and financial flexibility.

On November 1, 2024, we entered into the Pharmakon Loan Agreement, which we amended on January 5, 2026.

We drew the Tranche A Loan of $125.0 million on November 1, 2024 and as of November 1, 2024, the total outstanding principal amount under the Pharmakon Loan Agreement was $125.0 million.

The tranches for the remaining $125.0 million available to us under the Pharmakon Loan Agreement are as follows:

(a) a Tranche B Loan of $75.0 million, which is available until December 31, 2025 and is available at our option, subject to certain customary and limited conditions;

and (b) a Tranche C Loan of $50.0 million, which is available until December 31, 2025, subject to certain conditions including achieving a certain revenue milestone on or prior to November 30, 2025.

(a) a Tranche B Loan of $75.0 million, which is available for us to request at our option until July 30, 2026, subject to certain customary and limited conditions;

and (b) a Tranche C Loan of $50.0 million, which is available for us to request until July 30, 2026, subject to certain conditions, including us reaching a specified trailing twelve-month RYTELO revenue milestone on or prior to June 30, 2026.

If we do not achieve such revenue milestone within the required timeline, we will not be eligible to draw down the Tranche C Loan.

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Further, the terms of the Pharmakon Loan Agreement place restrictions on our operating and financial flexibility, and limit or prohibit our ability to dispose of certain assets, change our line of business, and engage in other significant transactions.

This indebtedness may create additional financing risk for us, particularly if our business or prevailing financial market conditions are not conducive to paying off or refinancing the outstanding debt obligations at maturity.

If we draw down any of the remaining tranches under the Pharmakon Loan Agreement, our indebtedness will increase, which would further increase our risk of being unable to pay off or refinance our outstanding debt obligations at maturity.

Our indebtedness could also have important negative consequences, including:

• we will need to repay the indebtedness by making payments of interest and principal, which will reduce the amount of cash available to finance our operations, our research and development efforts and other general corporate activities;

• our failure to comply with the obligations of our affirmative and restrictive covenants in the Pharmakon Loan Agreement could result in an event of default that, if not cured or waived, would permit the Lenders to accelerate our obligation to repay this indebtedness, and the Lenders could seek to enforce their security interest in the assets securing such indebtedness.

In addition, we may borrow additional capital in the future to fund clinical development and our future growth, including pursuant to the Pharmakon Loan Agreement or potentially pursuant to new arrangements with different lenders.

To the extent additional debt is added to our current debt levels, the risks described above could increase.

The terms of the Pharmakon Loan Agreement place restrictions on our operating and financial flexibility.

The Pharmakon Loan Agreement imposes operating and other restrictions on us.

Such restrictions will affect, and in many respects limit or prohibit, our ability and the ability of our subsidiaries to, among other things:

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• engage in certain transactions with affiliates.

Our indebtedness could also have important negative consequences, including:

To the extent additional debt is added to our current debt levels, the risks described above could increase.

We may not have cash available in an amount sufficient to enable us to make interest or principal payments on our indebtedness when due.

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Under such circumstances, we may not have enough available cash or be able to raise additional funds through equity or debt financings to repay such indebtedness at the time of such acceleration.

In that case, we may be required to delay, limit, reduce or terminate our RYTELO development or commercialization efforts or grant to others rights to develop and market RYTELO.

We may be required to delay, limit, reduce or terminate our RYTELO development or commercialization efforts or grant to others rights to develop and market RYTELO.

The lenders could also exercise their rights to take possession and dispose of the collateral securing the Pharmakon Loan Agreement, which collateral includes substantially all of our property including, without limitation, our intellectual property, subject to certain exceptions.

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and in other countries.

As a result of the Leahy-Smith America Invents Act, or the AIA, in March 2013, the U.S.

transitioned to a first-inventor-to-file system under which, assuming the other requirements for patentability are met, the first inventor to file a patent application is entitled to the patent.

However, since the publication of discoveries in scientific or patent literature tends to lag behind actual discoveries by at least several months and sometimes several years, we are not able to be certain upon filing a patent application that the persons or entities that we name as inventors or applicants in our patent applications were the first to invent the inventions disclosed therein, or the first to file patent applications for these inventions.

Thus, our ability to protect our patentable intellectual property depends, in part, on our ability to be the first to file patent applications with respect to our inventions, or inventions that were developed by our former collaboration partner and assigned to us, for the future development, commercialization and manufacture of RYTELO.

As a result, if we are not the first inventor-to-file, we may not be able to obtain patents for discoveries that we otherwise would consider patentable and that we consider to be significant to the future success of RYTELO.

Delay in the filing of a patent application for any purpose, including further development or refinement of an invention, may result in the risk of loss of patent rights.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our patents may be challenged in the courts or patent offices in the U.S.

and in other countries.

Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated, or held unenforceable, which could limit our ability to stop others from using or commercializing RYTELO or our technology and/or limit the duration of the patent protection for RYTELO and our technology.

In the event that we are unsuccessful in obtaining, maintaining, enforcing and extending our patents and other intellectual property rights or having our licensors maintain the intellectual property rights we have licensed, the value of RYTELO and/or our technologies will be adversely affected, and we may not be able to further develop or commercialize RYTELO.

Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated, or held unenforceable, which could limit our ability to

stop others from using or commercializing RYTELO or our technology and/or limit the duration of the patent protection for RYTELO and our technology.

While we have method-of-use patents that protect the use of RYTELO for the treatment of certain diseases, this type of patent does not prevent a generic competitor from making and marketing a product that is identical to RYTELO for an indication that is outside the scope of our approved use after our composition-of-matter patents or their patent term extensions, and any regulatory exclusivities have expired.

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Our request for NCE exclusivity is still pending with FDA, and might not be awarded or could be awarded and then later withdrawn.

In Europe, New Active Substance, or NAS, exclusivity is expected to entitle us to eight years of data exclusivity and two years of market exclusivity, for a total of ten years of NAS

exclusivity for the first-approved indication, but as with other forms of regulatory exclusivity, NAS exclusivity could be limited or withdrawn.

Loss or impairment of our intellectual property rights related to RYTELO might further delay or halt ongoing or potential future clinical trials of RYTELO and any applications for regulatory approval, and might further delay or preclude any future development or commercialization of RYTELO by us.

In the EU, imetelstat is designated as a New Active Substance, or NAS.

For this NAS, regulatory data protection entitles us to eight years of data exclusivity and two years of market exclusivity, for a total of ten years in parallel to orphan market exclusivity.

Furthermore, such loss of intellectual property rights could impair our ability to exclude others from commercializing products similar or identical to RYTELO and therefore result in decreased sales for us.

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As a result, our intellectual property may not provide us with sufficient patent rights to exclude others from commercializing products similar or identical to RYTELO.

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 calculated as one half of the clinical trial period plus the entire period of time during the review of the NDA by the FDA, minus any time of delay by us during these periods.

In the U.S., the Hatch-Waxman Act permits one patent per approved product to receive one patent term extension of up to five years beyond its normal expiration.

The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

The length of the patent term extension is typically calculated as one half of period between the effective date of an IND and the submission date of an NDA less any time the

sponsor did not act with due diligence during the period, plus the time between the submission date of an NDA and the approval of that application less any time the sponsor did not act with due diligence during the period.

There is also a limit on the patent term extension to a term that is no greater than fourteen years from drug approval.

Only one U.S.

patent may receive patent term extension under the Hatch-Waxman Act.

We have applied to the USPTO for patent term extension of some of our patents.

Once the USPTO and the FDA determine the extension period for each proposed eligible patent, we will select the one patent to be extended.

Currently, communication of patent term extension approval and the length of the granted extension period by the USPTO may occur up to several years from filing of an application for patent term extension.

If the USPTO and the FDA determine the extension period for each proposed eligible patent, we will select the one patent to be extended.

We expect to apply any patent term extension that is granted in the U.S.

to our method of treatment patent for MDS and MF that expires on March 15, 2033.

If such patent term extension is granted, we expect the term of the patent to extend through August 2037, although such timing is subject to approval by the USPTO as part of its review of our application for patent term extension and could differ from our calculation.

Accordingly, we will decide on the specific patent to be extended only after such communication from the USPTO.

If such patent term extension is granted, we expect the term of the patent to extend through August 2037, although such timing is subject to approval by the USPTO and could differ from our calculation.

Similar extensions are also available in certain countries and territories outside the U.S., such as in Japan, and in Europe as Supplementary Protection Certificates, or SPCs.

However, we might not be granted a patent term extension at all because of failure to satisfy any of the numerous applicable requirements.

However, we might not be granted a patent term extension at all because of failure to satisfy any of the numerous applicable requirements, including:

• failure to adhere to the required filing deadlines;

• submission of a patent term extension application after the underlying patents have expired;

• failure to exercise due diligence during clinical development or regulatory review;

• failure to otherwise meet the applicable criteria.

Moreover, the applicable authorities, including the FDA and the USPTO in the U.S., and any equivalent regulatory authorities and patent offices in other countries, may not agree with our assessment of whether such extensions are available, may refuse to grant extensions to our patents, or may grant more limited extensions than we request and could be less than five years.

If we select and are granted a patent term extension on a recently filed and issued patent, we may not receive the full benefit of a possible patent term extension, if at all.

Moreover, in some countries, the scope of protection for claims under patent term extension, if any, is limited to the product composition as approved and, for a method of treatment patent, to the approved indications.

If we do not have sufficient patent life and regulatory exclusivity to protect RYTELO, our financial results, business and business prospects would be materially and adversely affected, which might cause us to cease operations.

In Europe and other countries, our composition of matter patent coverage expired in September 2024, and our method of treatment patent rights for MDS and MF expire in November 2033.

In Europe and other jurisdictions, our composition of matter patent coverage expired in September 2024, and our method of treatment patent rights for MDS and MF expire in November 2033.

Our method of treatment patents may be eligible for patent term extension of up to five years under an SPC, permitted under European Council (EC) Regulation No.

469/2009, or the European SPC Regulation, upon receipt of marketing authorization, such as, for example, our method of treatment patent for MDS.

In Europe, we have separate method of treatment patents covering MDS and MF, and a SPC may only be applied to one patent.

In Europe, we have separate method of treatment patents covering MDS and MF, and an SPC may only be applied for once with respect to a product.

Accordingly, in countries of the European Economic Area, or EEA, we must rely on regulatory exclusivity and our method of treatment patents.

If regulatory approval of RYTELO occurs after a patent has expired in a country that does not allow interim patent term extensions, as is the case in many countries and territories including Europe, we will be unable to obtain any patent term extension of that expired patent, and the duration of our patent rights may be limited.

Accordingly, in Europe and such other similar countries and territories, we will not be able to seek patent term extension of our composition of matter patent, as it expired in September 2024.

If regulatory approval of RYTELO occurs after a patent has expired in a country that does not allow interim patent term extensions, as is the case in many jurisdictions and territories including in Europe, we will be unable to obtain any patent term extension of that expired patent, and the duration of our patent rights may be limited.

Accordingly, in Europe and such other similar jurisdictions and territories, we will not be able to seek patent term extension of our composition of matter patent, as it expired in September 2024.

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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.

If a third party files an application under Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act or an abbreviated new drug application, or ANDA, under Section 505(j) to obtain permission to sell a generic or follow-on version of RYTELO, and relies in whole or in part on studies conducted by or for us, the third-party will be required to certify to the FDA that either:

If a third party files an application under Section 505(b)(2) of the FDCA or an abbreviated new drug application, or ANDA, under Section 505(j) to obtain permission to sell a generic or follow-on version of RYTELO, and relies in whole or in part on studies conducted by or for us, the third-party will be required to certify to the FDA that either:

(1) there is no patent information listed in the Orange Book with respect to our NDA for RYTELO;

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We may then initiate a lawsuit to defend the patents identified in the notice.

The filing of a patent infringement lawsuit within 45 days of receipt of the notice automatically prevents the FDA from approving the third-party’s ANDA until the earliest of 30 months or the date on which the patent expires, the lawsuit is settled, or the court reaches a decision in the infringement lawsuit in favor of the third-party.

The filing of a patent infringement lawsuit within 45 days of receipt of the notice automatically prevents the FDA from approving the third-party’s ANDA until the earliest of 30 months after the NDA holder’s receipt of the notice of Paragraph IV Certification, the expiration of the patent, certain settlements of the lawsuit, or the court reaches a decision in the infringement lawsuit in favor of the third-party.

If the product has NCE exclusivity and the notice is given and the suit filed in the fifth year of exclusivity, the regulatory stay extends until 7.5 years after approval of the reference product.

If we do not file a patent infringement lawsuit within the required 45-day period, the third-party’s ANDA will not be subject to the 30-month stay of FDA approval.

However, if an appropriate patent covering RYTELO is not listed in the Orange Book or is subsequently removed from the Orange Book, a manufacturer of generic drugs would not be required to provide advance notice to us of any abbreviated NDA filed with the FDA to obtain permission to sell a generic version of RYTELO.

Any of the foregoing could harm our competitive position, business, financial condition, results of operations and prospects.

Our issued U.S.

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If the patents covering RYTELO or its methods of use are successfully challenged or designed around, or if we are unsuccessful in enforcing our patents against generics, we could face competition prior to the expiration of these patents, which could have a material adverse effect on our business, financial condition, results of operations and prospects.

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.

The patent positions of pharmaceutical and biopharmaceutical companies, including ours, are highly uncertain and involve complex legal and technical questions.

In particular, legal principles for biotechnology and pharmaceutical patents in the U.S.

and in other countries are evolving, and the extent to which we will be able to obtain patent coverage to protect our technologies and RYTELO, or enforce or defend issued patents, is uncertain.

For instance, the U.S.

has enacted and implemented wide-ranging patent reform legislation, including AIA, signed into law on September 16, 2011.

Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection available in certain circumstances or weakening the rights of patent owners in certain situations.

Depending on actions by Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents or patents that we might obtain in the future.

Similarly, changes in patent law, regulations in other jurisdictions or the governmental bodies that enforce them or changes in how the relevant governmental authority enforces patent laws or regulations may weaken our ability to obtain new patents or to enforce our existing patents or patents that we may obtain in the future.

Occurrence of these events and/or significant impairment of our RYTELO patent rights could severely and adversely affect our financial results, business and business prospects, which might cause us to cease operations.

In 2012, the European Patent Package, or EU Patent Package, was approved and included regulations with the goal of providing for the possibility of a single Unitary Patent covering the Contracting Member States, and a new Unified Patent Court, or UPC, for litigation of Unitary Patents and as well as European patents not opted out from the UPC system.

The EU Patent Package entered into force fully in June 2023 and currently covers 18 EU Member States.

As of June 1, 2023, all European patents, including those issued prior to June 1, 2023 in principle fall under the jurisdiction of the UPC and allow for the possibility of obtaining injunctions for the UPC Member States and are at risk of central revocation at the UPC in participating UPC Member States.

Under the EU Patent Package, patent holders are permitted to “opt out” their European patents (but not their Unitary Patents) from the UPC on a patent-by-patent basis during an initial seven year

transitional period after June 1, 2023.

Owners of European patent applications who receive notice of grant after the EU Patent Package came into effect could, for the UPC Member States, either obtain a Unitary Patent or validate the European patent nationally and optionally file an opt-out demand.

The EU Patent Package may increase the uncertainties and costs surrounding the enforcement or defense of our issued European patents and pending applications.

The full impact on future European patent filing strategy and the enforcement or defense of our issued European patents in European jurisdictions and/or the UPC is not fully known.

Filing, prosecuting, maintaining, defending and enforcing patents for RYTELO and our technologies in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the U.S.

are less extensive than those in the U.S.

The requirements for patentability may differ in certain countries, particularly in developing countries;

thus, even in countries where we do pursue patent protection, there can be no assurance that any patents will be issued with claims that cover RYTELO and our technologies.

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 our patents covering RYTELO or its methods of use.

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could result in substantial costs and divert our efforts and attention from other aspects of our business, and could put our patents at risk of being invalidated or interpreted narrowly.

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.

The patent positions of pharmaceutical and biopharmaceutical companies, including ours, are highly uncertain and involve complex legal and technical questions.

In particular, legal principles for biotechnology and pharmaceutical patents in the U.S.

and in other countries are evolving, and the extent to which we will be able to obtain patent coverage to protect our technologies and RYTELO, or enforce or defend issued patents, is uncertain.

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.

Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection available in certain circumstances or weakening

the rights of patent owners in certain situations.

Similarly, changes in patent law and regulations in other countries or jurisdictions or changes in the governmental bodies that enforce them or changes in how the relevant governmental authority enforces patent laws or regulations may weaken our ability to obtain new patents or to enforce our existing patents or patents that we may obtain in the future.

As a result of the AIA, in March 2013, the U.S.

transitioned to a first-inventor-to-file system under which, assuming the other requirements for patentability are met, the first inventor to file a patent application is entitled to the patent.

Delay in the filing of a patent application for any purpose, including further development or refinement of an invention, may result in the risk of loss of patent rights.

In 2012, the European Patent Package, or EU Patent Package, was approved and included regulations with the goal of providing for a single pan-European Unitary Patent, and a new European Unified Patent Court, or UPC, for litigation of European patents.

The EU Patent Package was ratified in February 2023 and currently covers certain EU states.

As of June 1, 2023, all European patents, including those issued prior to ratification, by default automatically fall under the jurisdiction of the UPC and allow for the possibility of obtaining pan-European injunctions and are at risk of central revocation at the UPC in participating UPC states.

Under the EU Patent Package, patent holders are permitted to “opt out” of the UPC on a patent-by-patent basis during an initial seven year transitional period after June 1, 2023.

Owners of European patent applications who receive notice of grant after the EU Patent Package came into effect could, for the UPC contracting states, either obtain a Unitary Patent or validate the patent nationally and file an opt-out demand.

The EU Patent Package may increase the uncertainties and costs surrounding the enforcement or defense of our issued European patents and pending applications.

The full impact on future European patent filing strategy and the enforcement or defense of our issued European patents in member states and/or the UPC is not known.

are less extensive than those in the U.S.

The requirements for patentability may differ in certain countries, particularly in developing countries;

thus, even in countries where we do pursue patent protection, there can be no assurance that any patents will issue with claims that cover RYTELO and our technologies.

We may not be able to protect our intellectual property rights in the U.S or worldwide and challenges to our owned or licensed patent rights would result in costly and time-consuming legal proceedings that could prevent or limit development or commercialization of RYTELO.

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Patent interferences are typically complex, highly contested legal proceedings, subject to appeal.

They are usually expensive and prolonged and can cause significant delay in the issuance of patents.

They are usually expensive and prolonged and can cause significant delays in the issuance of patents.

Our pending patent applications or our issued patents, or those we have licensed and may license from others, may be drawn into interference proceedings or be challenged through post-grant review procedures or litigation, any of which could delay or prevent the issuance of patents, or result in the loss of issued patent rights.

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Significant impairment of our RYTELO patent rights could severely and adversely affect our financial results, business and business prospects, which might cause us to cease operations.

Certain jurisdictions, such as Europe, China, Japan, New Zealand and Australia, permit third parties to file oppositions or invalidation trials against granted patents or patents proposed to be granted.

Certain jurisdictions, such as Europe, China, Japan, New Zealand and Australia, permit third parties to file third party observations, oppositions or invalidation trials against granted patents and/or patent applications.

Because we seek to enable potential global commercialization of RYTELO, securing both proprietary protection and freedom to operate outside of the U.S.

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• causing us to lose patent rights in the relevant jurisdiction(s);

• subjecting us to litigation, or otherwise preventing us from commercializing RYTELO in the relevant jurisdiction(s);

• requiring us to obtain licenses to the disputed patents;

• subjecting us to litigation, or other types of proceedings aimed at preventing us from commercializing RYTELO in the relevant jurisdiction(s);

• requiring us to obtain licenses to certain patents and patent applications;

• forcing us to cease using the disputed technology;

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The commercial success of RYTELO will depend upon our ability to research, develop, manufacture, market and sell RYTELO without infringing or otherwise violating the intellectual property and other proprietary rights of third parties.

There is considerable intellectual property litigation in the biotechnology and pharmaceutical industries, and many pharmaceutical companies, including potential competitors, have substantial patent portfolios.

There is considerable intellectual property litigation in the biotechnology and pharmaceutical industries, and

many pharmaceutical companies, including potential competitors, have substantial patent portfolios.

Since we cannot be aware of all intellectual property rights potentially relating to RYTELO and its uses, we do not know with certainty that RYTELO, or the commercialization thereof, does not and will not infringe or otherwise violate any third party’s intellectual property.

For example, we are aware that certain third parties have or may be prosecuting patents and patent estates that may relate to RYTELO, and while these patents have expired, or we believe that a reasonable court should find they are invalid and/or would not be infringed by the manufacture, use or sale of RYTELO, it is possible that the owner(s) of these patents will assert claims against us in the future.

alternative non-infringing technologies, which we may not be able to do at an acceptable cost or on acceptable terms, or at all, or cease the commercialization and continued development of RYTELO.

In the event our technologies infringe the rights of others or require the use of discoveries and technologies controlled by third parties, we may be prevented from pursuing research, development, manufacturing or commercialization of RYTELO, or may be required to obtain unblocking licenses from such third parties, develop alternative non-infringing technologies, which we may not be able to do at an acceptable cost or on acceptable terms, or at all, or cease the commercialization and continued development of RYTELO.

If we are unable to resolve an infringement claim successfully, we could be subject to an injunction that would prevent us from commercializing RYTELO and could also require us to pay substantial damages.

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We have a registered trademark, RYTELO, which is the commercial trade name for imetelstat, in a number of countries and regions, including in the U.S.

Our product trademark, RYTELO, is approved for use as name of the imetelstat medicinal product by the FDA and the EC.

Opposition or cancellation proceedings, however, may be filed against our trademarks, and our trademarks may not survive such proceedings.

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We may be unable to maintain or enforce our current and future trademarks, and if we fail to satisfy the applicable regulatory requirements, we may not have enforceable trademark rights or registrations in such jurisdictions.

Our product trademark, RYTELO, is approved by the FDA and the EMA.

We may become involved in disputes with past or future collaborator(s) over intellectual property inventorship, ownership or use, and publications by us, or by investigators, scientific consultants, research collaborators or others.

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Under some circumstances, it may be difficult to determine who invents and owns a particular invention, or whether it is jointly owned, and disputes can arise regarding inventorship, ownership and use of those inventions.

These disputes could be costly and time-consuming, and an unfavorable outcome could have a significant adverse effect on our business if we are not able to protect or license rights to these inventions.

disputes could be costly and time-consuming, and an unfavorable outcome could have a significant adverse effect on our business if we are not able to protect or license rights to these inventions.

In addition, clinical trial investigators, scientific consultants and research collaborators generally have contractual rights to publish data and other proprietary information, subject to review by the trial sponsor.

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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.

We rely on trade secrets to protect our proprietary technology, especially in circumstances in which we believe patent protection is not appropriate or available.

In addition to patent and trademark protection, we rely on trade secrets to protect our proprietary technology, especially in circumstances in which we believe patent protection is not appropriate or available.

We attempt to protect our proprietary technology in part by entering into confidentiality agreements with our employees, consultants, collaborators and contractors.

However, we cannot provide assurance that these agreements will not be breached, that we would have adequate remedies for any breach, or that our trade secrets will not otherwise become known or be independently discovered by competitors, any of which would harm our business significantly.

In May 2016, the Defend Trade Secrets Act of 2016, or the DTSA, was enacted, providing a federal cause of action for misappropriation of trade secrets.

Under the DTSA, an employer may not collect enhanced damages or attorney fees from an employee or contractor in a trade secret dispute brought under the DTSA, unless certain advanced provisions are observed.

We cannot provide assurance that our existing agreements with employees and contractors contain notice provisions that would enable us to seek enhanced damages or attorneys’ fees in the event of any dispute for misappropriation of trade secrets brought under the DTSA.

However, certain consultants and third parties with whom we have business relationships, and to whom in some cases we have disclosed trade secrets and other proprietary knowledge, may also provide services to other parties in the medical device/pharmaceutical industry, including companies, universities and research organizations that are developing competing products.

In addition, some of our former employees who were exposed to certain of our trade secrets and other proprietary knowledge in the course of their employment may seek employment with, and become employed by, our competitors.

We cannot provide assurance that these agreements will not be breached, that we would have adequate remedies for any breach, or that our trade secrets will not otherwise become known or be independently discovered by competitors, any of which would harm our business significantly.

Trade secret protection does not prevent independent discovery of the technology or proprietary information or use of the same.

Competitors may independently duplicate or exceed our technology in whole or in part.

If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us in countries where we do not have patent protection.

RISKS RELATED TO MANAGING OUR GROWTH AND OTHER BUSINESS OPERATIONS

Our strategic restructuring plan and the associated workforce reduction implemented in December 2025 may not result in anticipated savings and long-term value creation, could result in total costs and operating expenses that are greater than expected and could disrupt our business.

In connection with our strategic restructuring plan announced in December 2025, we implemented a workforce reduction, representing approximately one-third of our workforce prior to the reduction in headcount.

We may not realize, in full or in part, the anticipated benefits on our 2026 operating expenses from our restructuring efforts due to unforeseen difficulties, delays or unexpected costs.

We incurred approximately $17.0 million in restructuring and restructuring-related charges for the year ended December 31, 2025, primarily consisting of one-time employee severance payments, healthcare and related benefits, and other employee-related costs.

The workforce reduction was substantially completed in the first quarter of 2026.

If we are unable to realize the expected operational efficiencies and cost savings from the restructuring, our operating results and financial condition could be adversely affected.

We also cannot guarantee that we will not have to undertake additional workforce reductions or restructuring activities in the future.

Furthermore, our workforce reduction may be disruptive to our operations, or could yield unanticipated consequences, such as attrition beyond planned staff reductions, or disruptions in our day-to-day operations.

Our workforce reductions could also harm our ability to attract and retain qualified management, scientific, clinical, and manufacturing personnel who are critical to our business.

Any failure to attract or retain qualified personnel could prevent us from successfully developing and commercializing our product candidates in the future, if approved.

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.

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and in the EU for lower-risk MDS, and to continue to develop RYTELO in other myeloid hematologic malignancies depends to a significant extent on the skills, experience and efforts of our executive officers and key members of our staff.

In addition, we need to recruit, maintain, motivate and integrate additional personnel with expertise and experience in sales, marketing, market access, commercial operations, pricing, clinical science, biostatistics, clinical operations, pharmacovigilance, quality, manufacturing, regulatory affairs, medical affairs, legal affairs, and compliance to enable us to further commercialize and further develop RYTELO.

In addition, we need to recruit, maintain, motivate and integrate additional personnel with expertise and experience in sales, marketing, market access, commercial

operations, pricing, clinical science, biostatistics, clinical operations, pharmacovigilance, quality, manufacturing, regulatory affairs, medical affairs, legal affairs, and compliance to enable us to further commercialize and further develop RYTELO.

We face intense competition for qualified individuals from numerous pharmaceutical, biopharmaceutical and biotechnology companies, as well as academic and other research institutions, and competition in our geographic regions is particularly intense.

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In addition, in October 2025, we appointed a new EVP, Chief Commercial Officer and in November 2024, we appointed a new EVP of Research and Development.

Changes to company strategy, which can often times occur with the appointment of new executives, can

create uncertainty, may negatively impact our ability to execute quickly and effectively, and may ultimately be unsuccessful.

Additionally, in connection with our strategic restructuring plan announced in December 2025, we implemented a workforce reduction, representing approximately one-third of our workforce prior to the reduction in headcount.

Changes to company strategy, which can often times occur with the appointment of new executives and departure of prior executives, can create uncertainty, may negatively impact our ability to execute quickly and effectively, and may ultimately be unsuccessful.

In addition, executive leadership transition periods are often difficult as the new executives gain detailed knowledge of our operations, and friction can result from changes in strategy and management style.

Management transition inherently causes some loss of institutional knowledge, which can negatively affect strategy and execution.

Management transition inherently causes some loss of institutional knowledge, which may have a disruptive impact on our ability to implement our strategy and could have a material adverse effect on our financial condition and our business and business prospects can negatively affect strategy and execution.

Until we integrate new personnel, and unless they are able to succeed in their positions, we may be unable to successfully manage and grow our business, and our results of operations and financial condition could suffer as a result.

In any event, changes in our organization as a result of executive management transition may have a disruptive impact on our ability to implement our strategy and could have a material adverse effect on our financial condition and our business and business prospects.

We may be unable to establish potential future collaborative arrangements for RYTELO on acceptable terms, or at all, and as a result, may have to delay, alter or abandon commercialization or further development of RYTELO.

We intend to develop RYTELO broadly for hematologic malignancies, and to commercialize, market and sell RYTELO in the U.S.

and in the EU for certain patients with lower-risk MDS.

At this time, we do not plan to commercialize R YTELO independently in the EU or in any other regions outside the U.S.

where RYTELO may be approved for marketing in the future.

Accordingly, we currently intend to seek contractual arrangements, strategic partnerships, collaborations, alliances or licensing arrangements with a third-party partner or partners to assist us in the commercialization of RYTELO in the EU and in any other regions outside the U.S.

Although we intend to establish potential future collaborative arrangements for RYTELO, we may be unable to establish such collaborative arrangements on acceptable terms, or at all, and may have to delay, alter or abandon commercialization or further development of RYTELO.

We intend to develop RYTELO broadly for hematologic malignancies, and to continue to commercialize, market and sell RYTELO in the U.S.

for certain patients with lower-risk MDS ourselves.

At this time, we do not plan to commercialize RYTELO independently in the EU (or in any other regions outside of the U.S.

where RYTELO may be approved for marketing in the future).

Accordingly, we plan to work with experienced third parties for the commercialization and marketing of RYTELO in the EU, including on critical path activities for the planned launch of RYTELO in the EU, such as reimbursement, Health Technology Assessment, or HTA, submissions, market access and distribution, and we may otherwise seek collaborative partners, at an appropriate time, to assist us in the potential development and commercialization of RYTELO outside the U.S., and to provide funding for such activities.

We face significant competition in seeking appropriate collaborative partners, and these potential collaborative arrangements are complex and time consuming to negotiate, document and implement.

In addition, the terms of our Pharmakon Loan Agreement may limit our ability to enter into certain collaborative arrangements and any future debt agreements may continue or further limit our ability to enter into such agreements.

We may not be able to establish collaborative arrangements on acceptable terms, or at all.

We may not be able to establish collaborative

arrangements on acceptable terms, or at all.

In this regard, collaborative arrangements with third parties may require us to relinquish material rights, including revenue from commercialization, or assume material ongoing development obligations that we would have to fund or otherwise support.

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• increase our expenditures and undertake development or commercialization activities at our own expense, which will require additional capital than our current resources.

We have established subsidiaries in the United Kingdom, or UK, and the Netherlands, which exposes us to additional costs and risks.

The wholly-owned subsidiaries we have established in the UK, and the Netherlands subject us to certain additional costs and risks associated with doing business outside the U.S., including:

We have established subsidiaries in the United Kingdom and the Netherlands, which exposes us to additional costs and risks.

The wholly-owned subsidiaries we have established in the U.K.

and the Netherlands subject us to certain additional costs and risks associated with doing business outside the U.S., including:

• the increased complexity and costs inherent in managing international operations in geographically disparate locations;

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• potentially adverse tax consequences, including changes in applicable tax laws and regulations;

• potentially costly trade laws, further increases to tariffs, renegotiation of existing international trade agreements, and changes to export quotas, custom duties or other trade restrictions, including as a result of recent changes implemented by the current administration in the U.S.;

• potentially costly trade laws, tariffs, export quotas, custom duties or other trade restrictions, and any changes to them, including in connection with new Trump administration changes;

• compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;

• challenges inherent in efficiently managing employees in diverse geographies, including the need to adapt systems, policies, benefits and compliance programs to differing labor and other regulations;

• natural disasters, political and economic instability, including terrorism and civil and political unrest, outbreak of health epidemics, and the resulting global economic and social impacts;

• natural disasters, political and economic instability, including terrorism and civil and political unrest, military conflicts, outbreak of health epidemics, and the resulting global economic and social impacts;

• workforce uncertainty in countries where labor unrest is more common than in the U.S.

We may experience additional risks related to operating outside of the U.S.

that could materially adversely affect our business.

We have employees located outside of the U.S., conduct clinical trials outside of the U.S., and are pursuing paths to make RYTELO available to LR-MDS patients outside of the U.S., including in the EU, which may subject us to additional risks, including risks related to operating outside of the U.S., such as: