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Item 1A. Risk Factors

2026-04-29 compared with 2025-10-30 · 237 added, 217 removed, 627 unchanged (42% of the section changed)

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

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

PYRUKYND® (mitapivat) is approved for use by the FDA for the treatment of hemolytic anemia in adults with PK deficiency in the United States and by the European Commission for the treatment of PK deficiency in adult patients in the EU.

Additionally, we received marketing authorization in Great Britain for PYRUKYND® for the treatment of PK deficiency in adult patients under the European Commission Decision Reliance Procedure.

In December 2024, we announced that we submitted an sNDA to the FDA for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.

The FDA accepted the sNDA and granted a PDUFA goal date of September 7, 2025, which the FDA subsequently extended to December 7, 2025 following our submission of a proposed REMS to mitigate the risk of hepatocellular injury that was described in the original PYRUKYND® sNDA.

Also in December 2024, we announced that we submitted an MAA to the EMA and regulatory applications to the Kingdom of Saudi Arabia and United Arab Emirates health authorities for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.

In August 2025, we announced that the Saudi Food and Drug Authority approved PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia.

In October 2025, we announced that the CHMP of the EMA adopted a positive opinion for the new indication for PYRUKYND® in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha- or beta-thalassemia.

The European Commission will now review the CHMP’s opinion, with the final decision expected by early 2026.

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

We generated $34.1 million and $25.8 million of net product revenues from sales of PYRUKYND® in the nine months ended September 30, 2025 and 2024, respectively.

In connection with our regulatory approvals in the EU, Great Britain and Saudi Arabia, we are currently providing access to PYRUKYND® through the Avanzanite Agreement and the NewBridge Agreement, as applicable, and on a for charge and free of charge basis for eligible patients in those jurisdictions and other jurisdictions through a global managed access program.

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

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

We generated $20.7 million and $8.7 million of net product revenues from sales of PYRUKYND® and AQVESME™ in the three months ended March 31, 2026 and 2025, respectively.

We commercially launched AQVESME™ in the United States in late January 2026.

In connection with our regulatory approvals in the EU, Great Britain, Saudi Arabia and the United Arab Emirates, we are currently providing access to PYRUKYND® through the Avanzanite Agreement and the NewBridge Agreement, as applicable, and on a for charge and free of charge basis for eligible patients in those jurisdictions and other jurisdictions through a global managed access program.

Revenues associated with the NewBridge Agreement, the Avanzanite Agreement and our global managed access program are included in the rest of world product revenue line within Results of Operations.

We continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities.

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

• the medical community and third-party payors do not accept PYRUKYND® as safe, efficacious and cost-effective in the approved jurisdictions and indications;

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

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

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

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

• PYRUKYND® becomes subject to unfavorable pricing regulations and third-party reimbursement practices;

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

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

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

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

• the medical community and third-party payors do not accept PYRUKYND® or AQVESME™ as safe, efficacious and cost-effective in the approved jurisdictions and indications;

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

• we fail to develop, implement and maintain effective marketing, sales and distribution strategies and operations for the development and commercialization of PYRUKYND® or AQVESME™, including PYRUKYND® under the NewBridge Agreement and the Avanzanite Agreement;

• we fail to continue to develop, validate and maintain commercially viable manufacturing processes for PYRUKYND® or AQVESME™ that are compliant with current good manufacturing practices, or cGMP;

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

• PYRUKYND® or AQVESME™ become subject to unfavorable pricing regulations and third-party reimbursement practices;

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

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

• competing drug products are approved for the same indications or in the same jurisdictions as PYRUKYND® or AQVESME™;

• significant safety, manufacturing and/or quality risks are identified;

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

• a significant number of eligible patients with PK deficiency are not prescribed PYRUKYND® and, if they are, such patients do not stay on treatment;

• PYRUKYND® does not demonstrate acceptable safety and efficacy in current or future clinical trials, or otherwise does not meet applicable regulatory standards for approval in other indications;

• the requirements of a REMS make it more difficult and/or time-consuming for physicians to prescribe PYRUKYND® and for patients to subsequently use PYRUKYND®.

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

We depend heavily on the success of our clinical-stage product candidates, including the potential approval of PYRUKYND® for the treatment of thalassemia or SCD in the United States and in other jurisdictions.

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

• a significant number of eligible patients are not prescribed PYRUKYND® or AQVESME™ and, if they are, such patients do not stay on treatment;

• the product does not demonstrate acceptable safety and efficacy in current or future clinical trials, or otherwise does not meet applicable regulatory standards for approval in other indications;

• the requirements of the AQVESME™ REMS make it more difficult and/or time-consuming for physicians to prescribe AQVESME™ and for patients to subsequently use AQVESME™.

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

We depend heavily on the success of our clinical-stage product candidates, including the potential approval of mitapivat for the treatment of thalassemia in the EU, or SCD in the United States and in other jurisdictions.

Clinical trials of our product candidates may not be successful for a number of important reasons.

If we or our collaborators are unable to commercialize our product candidates or experience significant delays in doing so, our business will be materially harmed.

We have invested a significant portion of our efforts and financial resources in the identification of our product candidates and the development of our most advanced clinical programs, including PYRUKYND® and tebapivat.

Our ability to generate meaningful product revenue will depend heavily on the successful clinical development and eventual commercialization of our current and any future product candidates, including PYRUKYND®.

While we have recently received approval from the Saudi Food and Drug Authority for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia, we cannot be certain that we will obtain marketing approval of PYRUKYND® in jurisdictions with pending or potential future marketing applications for thalassemia, nor can we be certain that we will obtain marketing approval of PYRUKYND® for any other indication or in other jurisdictions.

We cannot be certain that we will obtain marketing approval of mitapivat in jurisdictions with pending or potential future marketing applications for thalassemia, nor can we be certain that we will obtain marketing approval of mitapivat for SCD or for any other indication.

We, and any collaborators, are not permitted to commercialize, market, promote or sell any product candidate in the United States without obtaining marketing approval from the FDA.

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

For example, in January 2025, the USPI for PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency was updated to include information regarding hepatocellular injury observed in clinical trials in patients with thalassemia treated with PYRUKYND® at a higher dose than recommended for patients

with PK deficiency.

Additionally, following an information request from the FDA, we submitted a proposed REMS to mitigate the risk of hepatocellular injury that was described in the original PYRUKYND® sNDA for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.

The FDA might require the development and submission of additional REMS for our products;

For example, the U.S.

Prescribing Information, or USPI, for PYRUKYND® includes a warning regarding the risk of potential hepatocellular injury, and the USPI for AQVESME™ contains a boxed warning regarding the potential for hepatocellular injury.

In addition, the FDA has required and might in the future require the development and submission of REMS for our products.

For example, to mitigate the risk of hepatocellular injury, AQVESME™ is available only through the REMS approved by the FDA;

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

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• the number of patients required for clinical trials of our product candidates may be larger than we anticipate;

enrollment in these clinical trials, which may be particularly challenging for some of the orphan diseases we target in our rare disease programs, may be slower than we anticipate;

enrollment in these clinical trials, which may be particularly challenging for some of the orphan diseases we target in

our rare disease programs, may be slower than we anticipate;

or participants may drop out of these clinical trials at a higher rate than we anticipate;

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In December 2016, we withdrew our IND for AG-519, our second PK activator, following verbal notification of a clinical hold from the FDA relating to a previously disclosed case of drug-induced cholestatic hepatitis which occurred in our phase 1 clinical trial of AG-519 in healthy volunteers.

Although these decisions and this hepatic adverse event finding do not affect our ongoing clinical trials for PYRUKYND® or tebapivat, we cannot provide any assurances that there will not be other treatment-related severe adverse events in our other clinical trials, or that our other trials will not be placed on clinical hold in the future.

Although these decisions and this hepatic adverse event finding do not affect our ongoing clinical trials for mitapivat or tebapivat, we cannot provide any assurances that there will not be other treatment-related severe adverse events in our other clinical trials, or that our other trials will not be placed on clinical hold in the future.

Our failure to successfully complete clinical trials of our product candidates and obtain regulatory approval to market any of our product candidates could significantly harm our business.

PYRUKYND®, AQVESME™ or any of our product candidates that may receive marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.

PYRUKYND®, AQVESME™ or any of our product candidates that may receive marketing approval in the future, may fail to gain and/or maintain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community, which could limit our ability to generate product revenue and impact our ability to become profitable.

The degree of market acceptance of PYRUKYND®, AQVESME™ and any of our product candidates, if approved for commercial sale, will depend on a number of factors, including:

• efficacy and potential advantages compared to alternative treatments;

• the prevalence and severity of any side effects;

• the ability to offer our medicines for sale at competitive prices;

• convenience and ease of administration compared to alternative treatments;

• the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;

• ensuring uninterrupted product supply;

• the strength of sales, marketing and distribution support, including under any distribution agreement with third parties;

• sufficient third-party coverage or reimbursement;

• product labeling or product insert requirements of the FDA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling, such as the USPI for AQVESME™ containing a boxed warning regarding the potential for hepatocellular injury and the USPI for PYRUKYND® including warning regarding the risk of potential hepatocellular injury;

• a requirement to implement a REMS, such as the REMS required for AQVESME™.

Failure of physicians, prescribers, pharmacies or patients to enroll in our REMS program or to successfully complete and comply with its requirements may result in regulatory action from the FDA or decreased sales of AQVESME™.

If we are unable to maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing PYRUKYND®, AQVESME™ or any of our product candidates if they are approved.

We have limited experience in the sale, marketing and distribution of pharmaceutical products.

To achieve commercial success for approved medicines for which we retain sales and marketing responsibilities, we must either continue to develop our sales and marketing organization or outsource these functions to other third parties.

We have established sales and marketing capabilities to support our commercialization of PYRUKYND® for the treatment of hemolytic anemia in adults with PK

deficiency in the United States and expanded these capabilities to support the commercial launch of AQVESME™ for the treatment of anemia in adults with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia in the United States.

We may need to further build our sales and marketing infrastructure, either directly or with third-party partners to commercialize PYRUKYND® in additional markets outside of the United States, or to commercialize any of our other product candidates for which we obtain marketing approval.

For example, we have entered into distribution agreements with third parties for the commercialization of PYRUKYND® in certain jurisdictions outside of the United States, including the NewBridge Agreement and the Avanzanite Agreement.

There are risks involved with both establishing our own sales and marketing capabilities and entering into arrangements with third parties to perform these services.

For example, recruiting and training a sales force is expensive, time consuming and could delay any product launch.

If the commercial launch of a product candidate for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses.

This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.

Factors that may inhibit our efforts to commercialize our medicines on our own include:

• our inability to recruit and retain adequate numbers of effective sales and marketing personnel;

• the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future medicines;

• the lack of complementary medicines to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines;

• unforeseen costs and expenses associated with creating an independent sales and marketing organization.

If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenue or the profitability of product revenue to us are likely to be lower than if we were to market and sell any medicines that we develop ourselves.

In addition, we may not be successful in entering into such arrangements with third parties or we may be unable to do so on terms that are favorable to us.

We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our medicines effectively.

If we do not establish or maintain sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing PYRUKYND®, AQVESME™ or any of our product candidates for which we obtain marketing approval.

We may engage in in-licensing transactions or acquisitions that could disrupt our business, cause dilution to our stockholders or reduce our financial resources.

We may engage in transactions to in-license products, technologies or assets or to acquire other products, technologies, assets or businesses.

As part of the evolution of our research organization, we plan to prioritize in-licensing or acquiring assets for future pipeline growth.

As part of our strategy, we plan to prioritize in-licensing or acquiring assets for future pipeline growth.

For example, in July 2023, we entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we are developing a product candidate, AG-236, for the potential treatment of patients with PV.

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Such transactions may require us to relinquish rights to develop product candidates in certain indications, limit our ability to pursue certain targets or require us to make significant milestone or royalty payments to third parties upon achievement of certain events.

For example, we are responsible to pay up to $130.0 million in potential development and regulatory milestones, in addition to sales milestones as well as tiered royalties on annual net sales, if any, of any licensed products, under our license agreement with Alnylam.

For example, we are responsible for paying up to $130.0 million in potential development and regulatory milestones, in addition to sales milestones as well as tiered royalties on annual net sales, if any, of any licensed products, under our license agreement with Alnylam.

Further, any in-licensing transaction or acquisitions we undertake may not strengthen our competitive position, and these transactions may be viewed negatively by customers or investors.

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We could incur losses resulting from undiscovered liabilities of the acquired business, product or technology that are not covered by the indemnification we may obtain from the seller.

In addition, we may not be able to successfully integrate the acquired personnel, technologies and operations into our existing business in an effective, timely and

non-disruptive manner.

In addition, we may not be able to successfully integrate the acquired personnel, technologies and operations into our existing business in an effective, timely and non-disruptive manner.

Such transactions may also divert management attention from day-to-day responsibilities, increase our expenses and reduce our cash available for operations and other uses.

We cannot ensure that following any transaction we would achieve the expected synergies to justify the transactions.

We cannot ensure that following any

transaction we would achieve the expected synergies to justify the transactions.

We cannot predict the number, timing or size of future transactions or the effect that any such transactions might have on our operating results.

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Competition for eligible patients may make it particularly difficult for us to enroll a sufficient number of patients to complete our clinical trials for our product candidates in a timely and cost-effective manner.

In addition, we have a small number of clinical trial sites for certain clinical trials in the Middle East that could be affected by armed conflicts in the region.

Ongoing or unanticipated geopolitical events in countries where we may have clinical trial sites could also negatively impact our ability to initiate, enroll and retain patients in, and conduct clinical trials.

We rely on CROs and clinical trial sites to ensure the proper and timely conduct of our clinical trials, and while we have agreements governing their committed activities, we have limited influence over their actual performance.

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

In some instances, there can be significant variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors, including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes in and adherence to the dosing regimen and other clinical trial protocols and the rate of dropout among clinical trial participants.

rate of dropout among clinical trial participants.

If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced product candidates, and, correspondingly, our business and financial prospects would be negatively impacted.

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As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential.

We are prioritizing investment in advancing our late lead-optimization research, while continuing to progress our registration-enabling clinical programs.

Our resource allocation decisions may cause us to fail to capitalize on viable commercial medicines or profitable market opportunities.

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If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

We or others may later discover that PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.

We or others may later discover that PYRUKYND®, AQVESME™ or any of our product candidates that may receive marketing approval in the future, is less effective than previously believed or causes undesirable side effects that were not previously identified, which could compromise our ability, or that of any collaborators, to market the product.

It is possible that our clinical trials, or those of any collaborators, may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify undesirable side effects.

If, following approval of a product candidate, including PYRUKYND®, we, or others, discover that the product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur:

If, following approval of a product candidate, including PYRUKYND® and AQVESME™, we, or others, discover that the

product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following adverse events could occur:

• regulatory authorities may withdraw their approval of the product or seize the product;

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

• regulatory authorities may require the addition of warnings on the product label, or require or modify a REMS;

• regulatory authorities may require the addition of warnings on the product label, require a REMS or or modify an existing REMS;

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

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• our reputation may suffer.

For example, in January 2025, the USPI for PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency was updated to include information regarding liver injury observed in patients with thalassemia treated with PYRUKYND® at a higher dose than recommended for patients with PK deficiency.

In September 2025, we announced that, following an information request from the FDA, we submitted a proposed REMS to mitigate the risk of hepatocellular injury that was described in the original PYRUKYND® sNDA for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.

PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.

PYRUKYND®, or any of our product candidates that may receive marketing approval in the future, may fail to gain and/or maintain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community, which could limit our ability to generate product revenue and impact our ability to become profitable.

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

• efficacy and potential advantages compared to alternative treatments;

• the prevalence and severity of any side effects;

• the ability to offer our medicines for sale at competitive prices;

• convenience and ease of administration compared to alternative treatments;

• the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;

• ensuring uninterrupted product supply;

• the strength of sales, marketing and distribution support, including under any distribution agreement with third parties;

• sufficient third-party coverage or reimbursement;

• product labeling or product insert requirements of the FDA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling;

• a requirement to implement a REMS.

If we are unable to maintain sales and marketing capabilities or enter into agreements with third parties to sell and market our product candidates, we may not be successful in commercializing PYRUKYND® or any of our product candidates if they are approved.

We have limited experience in the sale, marketing and distribution of pharmaceutical products.

We have established sales and marketing capabilities to support our commercialization of PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States and have expanded these capabilities to support the potential commercial launch of PYRUKYND® in thalassemia in the United States.