What changed in this filing

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Item 1A. Risk Factors

2025-10-30 compared with 2025-07-31 · 117 added, 86 removed, 727 unchanged (22% of the section changed)

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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, which was accepted with standard review and granted a PDUFA goal date of September 7, 2025.

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 $21.2 million and $16.8 million of net product revenues from sales of PYRUKYND® in the six months ended June 30, 2025 and 2024, respectively.

In connection with our regulatory approval in the EU and Great Britain, we are currently providing access to PYRUKYND® on a for charge and free of charge basis for eligible patients in those jurisdictions through a global managed access program.

We provide access to PYRUKYND® for adult patients with PK deficiency in other jurisdictions upon request through the global managed access program, on either a free of charge or for charge basis.

Beyond the global managed access program, we have entered into the NewBridge Agreement and the Avanzanite Agreement for commercialization of PYRUKYND® in certain regions outside of the United States and we continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities.

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.

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:

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• 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.

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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®.

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.

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, 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;

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;

• 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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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 the 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.

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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 the current armed conflict in the region.

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.

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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• 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;

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

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• 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.

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There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the indications for which we are developing our product or our product candidates, such as PK deficiency, thalassemia, SCD, LR MDS, PKU, and PV.

For example, Merck and Bristol-Myers Squibb Company, or BMS, are marketing a therapy to treat beta thalassemia and LR MDS, and are conducting clinical trials for alpha thalassemia and LR MDS patients that are erythropoeisis-stimulating agent naïve and non-transfusion dependent;

For example, Merck and Bristol-Myers Squibb Company, or BMS, are marketing a therapy to treat beta thalassemia and LR MDS, and are conducting clinical trials for alpha thalassemia and LR MDS patients that are erythropoiesis-stimulating agent naïve and non-transfusion dependent;

Geron Corporation recently announced FDA approval of a treatment for adults with LR MDS with transfusion-dependent anemia;

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is marketing and conducting clinical trials for therapies to treat PKU;

is conducting clinical trials for therapies in SCD;

PTC Therapeutics, Inc.

has a recently approved treatment for PKU;

Pfizer Inc., CSL Behring, and Cellarity, Inc.

are conducting clinical trials for therapies in SCD;

Novo Nordisk A/S is conducting clinical trials for the treatment of alpha and beta thalassemia and SCD;

Sanofi is conducting clinical trials for a therapy in SCD;

bluebird is marketing a gene therapy to treat transfusion-dependent beta-thalassemia and SCD;

Vertex, with CRISPR, is

marketing a gene therapy targeting SCD and transfusion-dependent beta-thalassemia;

Genetix Biotherapeutics Inc.

(formerly bluebird bio) is marketing a gene therapy to treat transfusion-dependent beta-thalassemia and SCD;

Vertex, with CRISPR, is marketing a gene therapy targeting SCD and transfusion-dependent beta-thalassemia;

Disc Medicine, Inc., or Disc, is conducting a clinical trial for a potential treatment for SCD;

Fulcrum Therapeutics Inc.

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BMS is conducting clinical trials for a potential treatment for SCD;

PTC Therapeutics, Inc.

and Otsuka Pharmaceutical Co., Ltd are conducting clinical trials for potential treatments for PKU;

Otsuka Pharmaceutical Co., Ltd, NGGT Inc., and Maze Therapeutics, Inc.

are conducting clinical trials for potential treatments for PKU;

PharmaEssentia Corp and Incyte Corporation are marketing therapies to treat PV, and Protagonist Therapeutics with Takeda, Ionis Pharmaceuticals, Inc.

with Ono Pharmaceutical Co., Ltd, Italfarmaco S.p.A., Disc Medicine, Inc., Merck & Co., Inc., and Silence Therapeutics are developing therapies to treat PV;

with Ono Pharmaceutical Co., Ltd, Italfarmaco S.p.A., Disc, Merck & Co., Inc., GluBio Inc., and Silence Therapeutics are developing therapies to treat PV;

Rocket Pharma LTD is developing a therapy for the treatment of PK deficiency;

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With FDA approval of an NDA, the product covered by the application is specified as a “reference-listed drug” in the FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations,” or the Orange Book.

Manufacturers may seek approval of generic versions of reference-listed drugs through submission of abbreviated new drug applications, or ANDAs, in the United States.

Manufacturers may

seek approval of generic versions of reference-listed drugs through submission of abbreviated new drug applications, or ANDAs, in the United States.

In support of an ANDA, a generic manufacturer need not conduct clinical trials.

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We could be subject to risks caused by misappropriation, misuse, leakage, falsification or intentional or accidental release or loss of information maintained in the information systems and networks of our company, including personal information of our employees.

We may not be able to anticipate all types of security threats, and we may not be able to implement preventive measures effective against all such security threats.

We may not be able to anticipate all types of

security threats, and we may not be able to implement preventive measures effective against all such security threats.

The techniques used by cyber criminals change frequently, may not be recognized until launched, and can originate from a wide variety of sources, including outside groups such as external service providers, organized crime affiliates, terrorist organizations or hostile foreign governments or agencies.

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Although we develop and maintain processes, systems and controls designed to prevent these events from occurring, and we have a process to assess, identify and manage threats, the development and maintenance of these systems, controls and processes is costly and requires ongoing monitoring and updating as technologies change and efforts to overcome security measures become more sophisticated.

Moreover, despite our efforts, the possibility of these events occurring cannot be

eliminated entirely.

Moreover, despite our efforts, the possibility of these events occurring cannot be eliminated entirely.

We cannot guarantee that the measures we have taken to date, and actions we may take in the future, will be sufficient to prevent any cyber-attacks or security breaches.

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There are also significant privacy and data security laws that apply in Europe and other countries.

The collection, use, disclosure, transfer, or other processing of personal data, including personal health data, regarding individuals who are located in the European Economic Area, or EEA, and the processing of personal data that takes place in the EEA, is regulated by the GDPR.

The GDPR imposes onerous accountability obligations requiring data controllers and processors to maintain a record of their data processing and policies.

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We face challenges as a less diversified company.

The success of the rare disease business is subject to various risks and uncertainties, including the possibility that we may not be able to successfully commercialize PYRUKYND®, the possibility that PYRUKYND® is not approved for thalassemia, the possibility that PYRUKYND® is not approved for SCD, the possibility of adverse clinical and other developments in respect of PYRUKYND®, tebapivat or our other product candidates, and unanticipated changes in applicable laws and regulations that may adversely affect the rare disease business.

We may be more susceptible to changing market conditions, including fluctuations and risks particular to the markets for patients with rare diseases, than a more diversified company, which could adversely affect our business, financial condition and

results of operations.

In addition, even with the FDA approval of PYRUKYND® for PK deficiency, the diversification of our revenues, costs and cash flows has diminished following the sale of our oncology business.

The success of the rare disease business is subject to various risks and uncertainties, including the possibility that we may not be able to successfully commercialize PYRUKYND®, the possibility that PYRUKYND® is not approved for thalassemia in jurisdictions other than Saudi Arabia, the possibility that PYRUKYND® is not approved for SCD, the possibility of adverse clinical and other developments in respect of PYRUKYND®, tebapivat or our other product candidates, and unanticipated changes in applicable laws and regulations that may adversely affect the rare disease business.

In addition, even with the FDA approval of PYRUKYND® for PK deficiency and the Saudi Food and Drug Authority's approval of PYRUKYND® for non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia, the diversification of our revenues, costs and cash flows has diminished following the sale of our oncology business.

Our results of operations, cash flows, working capital and financing requirements may be subject to increased volatility and our ability to fund capital expenditures and investments or satisfy other financial commitments may be diminished.

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Further, changing circumstances, some of which may be beyond our control, could cause us to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds.

If we are unable to raise additional funds when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

If we are unable to raise

additional funds when needed or on attractive terms, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts, or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

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

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We have a history of incurring operating losses.

Our net losses for the six months ended June 30, 2025 and 2024 were $201.3 million million and $177.7 million million, respectively.

As of June 30, 2025, we had an accumulated deficit of $350.2 million.

Our net loss for the nine months ended September 30, 2025 was $304.7 million and our net income for the nine months ended September 30, 2024 was $770.2 million.

As of September 30, 2025, we had an accumulated deficit of $453.7 million.

The net income we generated in the nine months ended September 30, 2024 was primarily due to our receipt of the Upfront Payment related to the sale of the Vorasidenib Royalty Rights and our receipt of the Vorasidenib Milestone Payment.

Following receipt of marketing approval in February 2022, we are commercializing PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States.

We are currently providing access to PYRUKYND® on either a free of charge or for charge basis for eligible patients in the EU and Great Britain through a global managed access program, and we provide access to PYRUKYND® for adult patients with PK deficiency in other jurisdictions through the global managed access program on either a free of charge or for charge basis.

Beyond the global managed access program, we have entered into the NewBridge Agreement and the Avanzanite Agreement for commercialization of PYRUKYND® in certain regsions outside of the United States and we continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities.

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

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

We expect to finance our operations primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions.

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The OBBBA contains numerous tax provisions that we are currently in the process of evaluating, and which may affect our business or financial condition.

Regulatory guidance under the IRA, the OBBBA, and other tax-related legislation is and continues to be forthcoming, and such guidance could ultimately

increase or lessen the impact of these laws on our business and financial condition.

Regulatory guidance under the IRA, the OBBBA, and other tax-related legislation is and continues to be forthcoming, and such guidance could ultimately increase or lessen the impact of these laws on our business and financial condition.

In addition, it is uncertain if and to what extent various states will conform to changes to federal tax legislation.

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Furthermore, third parties on whom we rely may also have relationships with other entities, some of which may be our competitors.

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

In addition, these third parties are not our employees, and except for remedies available to us under our agreements

with such third parties, we cannot control whether or not they devote sufficient time and resources to our ongoing clinical, nonclinical, and preclinical programs.

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

If either we or any third parties on which we rely are adversely impacted by geopolitical events, rising global energy costs or energy shortages or rationing, delays may occur in our product development activities, which delays could have a material adverse impact on our business, financial condition and prospects.

If either we or any third parties on which we rely are adversely impacted by geopolitical events, delays may occur in our product development activities, which delays could have a material adverse impact on our business, financial condition and prospects.

Any performance failure on the part of our distributors could delay clinical development or marketing approval of our product candidates or commercialization of our medicines, producing additional losses and depriving us of potential product revenue.

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Even if we are able to establish such agreements, reliance on third-party manufacturers entails additional risks, including:

reliance on the third party for regulatory compliance, quality

assurance, environmental and safety and pharmacovigilance reporting;

reliance on the third party for regulatory compliance, quality assurance, environmental and safety and pharmacovigilance reporting;

the possible breach of the manufacturing agreement by the third party;

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legislation, including sanctions, trade restrictions and other foreign regulatory requirements which could increase the cost or reduce the supply of material or services available to us, delay the procurement or supply of such material or services, or have an adverse effect on our ability to secure significant commitments from governments to purchase our potential therapies.

Moreover, in September 2024, the U.S.

House of Representatives passed the BIOSECURE Act, and the Senate advanced a substantially similar bill, but it did not pass.

If these bills become law, or similar laws are passed, they would have the potential to severely restrict the ability of companies like ours to contract with certain Chinese biotechnology companies of concern without losing the ability to contract with, or otherwise received funding from, the U.S.

government, and it is possible that some of our contractual counterparties could be impacted.

Such disruptions could have adverse effects on the development of our product candidates and our business operations.

In 2024, the U.S.

Congress considered legislation referred to as the BIOSECURE Act, which if it had been enacted into law, would have prohibited, subject to limited exceptions, the direct or indirect use of U.S.

federal government contract, grant, and loan funds for purchasing biotechnology equipment and services from certain Chinese biotechnology companies.

In October 2025, the U.S.

Senate passed a revised version of the BIOSECURE legislation as part of its National Defense Authorization Act for FY 2026.

Instead of specifying particular Chinese entities, the Senate bill would initially target biotechnology companies that have been identified on the so-called 1260H List by the U.S.

Department of Defense as Chinese Military Companies Operating in the United States.

The legislation would allow for other biotechnology companies, possibly including WuXi entities, to be added to the federal funding prohibitions at a later time.

House of Representatives has passed a version of the bill that does not contain similar biotechnology provisions.

It is not currently known whether the House or Senate language or other language or neither may become law.

If either we or any third parties on which we rely are adversely impacted by restrictions resulting from the emergence of public health epidemics, by rising global energy costs or energy shortages or rationing and/or geopolitical events, our supply chain may be disrupted, limiting our ability to manufacture our product candidates for our clinical trials and research and development operations and our product for commercialization.

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

Collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing, which may result in a need

for additional capital to pursue further development or commercialization of the applicable product candidate.

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

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

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

Pursuant to the NewBridge Agreement and the Avanzanite Agreement, we rely on our partners, in the GCC and the EU and U.K., respectively, to assist with regulatory filings, prepare applications for pricing and reimbursement approval, negotiate with payors, conduct medical affairs activities and import, distribute, promote and commercialize our products in accordance with applicable law.

If our distribution partners do not fulfill their obligations under these arrangements, or if they experience a change in strategic focus or available funding, our ability to generate revenue outside of the United States could be adversely affected.

Risks Related to Our Intellectual Property

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To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive, time consuming and have uncertain outcomes.

For example we may file patent infringement suits against any company that files and ANDA containing a Paragraph IV patent certification for mitapivat.

For example, we may file patent infringement suits against any company that files an ANDA containing a Paragraph IV patent certification for mitapivat.

In addition, a court may decide that a patent of ours is invalid or unenforceable, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question.

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A finding of infringement could prevent us or our collaborators from commercializing our product and product candidates or force us to cease some of our business operations, which could materially harm our business.

that we or our collaborators have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.

Claims that we or our collaborators have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.

We may be subject to claims that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.

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Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing or distribution activities.

We may not have sufficient financial or other resources to adequately conduct such litigation or proceedings.

We may not have sufficient

financial or other resources to adequately conduct such litigation or proceedings.

Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources and more mature and developed intellectual property portfolios.

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The FDA, EMA and other foreign regulatory authorities have substantial discretion in the approval process.

Accordingly, it is possible that the FDA or EMA may refuse to accept for substantive review any NDA, supplemental NDA or MAA that we submit for our product candidates, or may conclude after review of our data that our marketing application is insufficient to obtain marketing approval of our product candidates.

Accordingly, it is possible that the FDA or EMA may refuse to accept for substantive review any NDA, sNDA or MAA that we submit for our product candidates, or may conclude after review of our data that our marketing application is insufficient to obtain marketing approval of our product candidates.

The applicable regulator may require that we conduct additional clinical trials, preclinical studies or manufacturing validation studies and submit that data before reconsidering our applications.

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

transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.

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

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

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Additionally, our ability to develop and market new drug products may be impacted based on current or future litigation in the federal court system challenging the FDA’s approval of other companies' drugs.

Depending on the outcome of this type of

litigation, our ability to develop new drug product candidates and to maintain approval of existing drug products could be at risk and our efforts to develop and market new drug products could be delayed, undermined or subject to protracted litigation.

Depending on the outcome of this type of litigation, our ability to develop new drug product candidates and to maintain approval of existing drug products could be at risk and our efforts to develop and market new drug products could be delayed, undermined or subject to protracted litigation.

If we or our collaborators experience delays in obtaining approval or if we or they fail to obtain approval of our product candidates, the commercial prospects for our product candidates may be harmed and our ability to generate revenue will be materially impaired.

Failure to obtain marketing approval in foreign jurisdictions would prevent our medicines from being marketed in such jurisdictions and any of our medicines that are approved for marketing in such jurisdiction will be subject to risk associated with foreign operations.

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

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

In order to market and sell our medicines in the EU and many other foreign jurisdictions, we or our collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements.

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Moreover, approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA.

Although we have received marketing authorization for PYRUKYND® for the treatment of adults with PK deficiency in the EU and Great Britain, we may not be able to file for additional marketing approvals and may not receive necessary approvals to commercialize our medicines in any other foreign market.

Although we have received marketing authorization for PYRUKYND® for the treatment of adults with PK deficiency in the EU and Great Britain and for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia in Saudi Arabia, we may not be able to

file for additional marketing approvals and may not receive necessary approvals to commercialize our medicines in any other foreign market.

In addition, foreign regulatory authorities may change their approval policies and new regulations may be enacted.

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Regulatory authorities in some jurisdictions, including the United States and the EU, may designate drugs and biologics for relatively small patient populations as orphan drugs.

Generally, if a product with an orphan drug designation subsequently

receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the EMA or the FDA from approving another marketing application for the same product for that time period, except in certain limited circumstances.

Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the EMA or the FDA from approving another marketing application for the same product for that time period, except in certain limited circumstances.

Orphan drug exclusivity may be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.

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These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to quality control and manufacturing, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distribution of samples to physicians and record keeping.

Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a REMS.

Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the medicine may be marketed

or to the conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a REMS.

The FDA and other agencies, including the Department of Justice, or DOJ, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling.

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Disruptions at the FDA and other government agencies from funding cuts, personnel losses, regulatory reform, government shutdowns and other developments could hinder our ability to obtain guidance from the FDA regarding our clinical development program and develop and secure approval of our product candidates in a timely manner, which would negatively impact our business.

If oversight and review activities by the FDA and comparable foreign regulatory authorities are disrupted, then our ability to develop and/or secure timely approval of our product candidates could be impacted in a negative manner.

If oversight and review activities by the FDA and comparable foreign regulatory authorities are disrupted due to the ongoing government shutdown, then our ability to develop and/or secure timely approval of our product candidates could be impacted in a negative manner.

For example, the recent loss of FDA leadership and personnel could lead to disruptions and delays in FDA guidance, review and approval of our product candidates.

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The commercial success of PYRUKYND® or of any of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third-party payors, including government health administration authorities and private health coverage insurers.

If coverage and reimbursement is not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize PYRUKYND® or our product candidates.

If coverage and reimbursement are not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize PYRUKYND® or our product candidates.

Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us, or any future collaborators, to establish or maintain pricing sufficient to realize a sufficient return on our or their investments.

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Pricing and reimbursement for new drug products vary widely from country to country.

countries require approval of the sale price of a drug before it can be marketed.

Some countries require approval of the sale price of a drug before it can be marketed.

In many countries, the pricing review period begins after marketing or product licensing approval is granted.

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Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications, which could affect our ability or that of any collaborators to sell PYRUKYND® or our product candidates profitably.

These payors may not view our products as cost-effective, and coverage and reimbursement may not be available to our customers, or those of any collaborators, or may not be sufficient to allow our products to be marketed on a competitive basis.

These payors may not view our products as cost-effective, and coverage and reimbursement

may not be available to our customers, or those of any collaborators, or may not be sufficient to allow our products to be marketed on a competitive basis.

Cost-control initiatives could cause us, or any collaborators, to decrease the price we, or they, might establish for products, which could result in lower than anticipated product revenue.

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Since enactment of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act, or collectively, the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

President Trump recently revoked numerous executive orders issued by

President Biden, including at least two executive orders which where were designed to further implement the ACA.

President Trump recently revoked numerous executive orders issued by President Biden, including at least two executive orders which where were designed to further implement the ACA.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.

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We can be held liable for the corrupt or other illegal activities of these third-party intermediaries, our employees, representatives, contractors, partners, and agents, even if we do not explicitly authorize or have actual knowledge of such activities.

injunctions, suspension and/or debarment from contracting with certain persons, the loss of export privileges, reputational harm, adverse media coverage, and other collateral consequences.

Noncompliance with such laws could subject us to whistleblower complaints, investigations, sanctions, settlements, prosecution, other enforcement actions, disgorgement of profits, significant fines, damages, other civil and criminal penalties or injunctions, suspension and/or debarment from contracting with certain persons, the loss of export privileges, reputational harm, adverse media coverage, and other collateral consequences.

If any subpoenas, investigations, or other enforcement actions are launched, or governmental or other sanctions are imposed, or if we do not prevail in any possible civil or criminal litigation, our business, results of operations and financial condition could be materially harmed.

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Later, the U.S.

and China reached a framework agreement that resulted in the suspension of the higher reciprocal tariffs on China until August 10, 2025.

Three other countries, the United Kingdom, Vietnam and Indonesia, have also reached deals with the U.S.

and China reached a framework agreement that resulted in the suspension of the higher reciprocal tariffs on China until November 11, 2025.

Several countries, the United Kingdom, Japan, South Korea, European Union, among others, have reached deals with the U.S.

that include reduced tariff rates and other measures.

The administration has not indicated the effective date for these deals.

Recently, the administration announced an extension of the deadline for the effective date of the country-specific tariffs for all remaining countries until August 1, 2025.

Currently, the 10% baseline reciprocal tariff announced in April remains in effect, in addition to the other tariffs on China (a minimum of an additional 20% as of July 15, 2025) and Canada and Mexico (25% as of July 15, 2025 for goods that are not covered by the USMCA).

President Trump also issued an Executive Order detailing new reciprocal tariff rates for individual countries that took effect on August 7, 2025.

The new reciprocal rates, which are consistent with the rates reflected in the trade deals already announced, range from 10% to 41%.

The new rates do not apply to Canada, China, Mexico and a few other countries.

For China, the 10% baseline reciprocal tariff announced in April remains in effect, in addition to a minimum of an additional 20%.

For Mexico, the rate remains 25% for goods that are not covered by the USMCA, and for Canada, the rate is 35% for goods that are not covered by the USMCA.

Sustained uncertainty about, or the further escalation of, trade and political tensions between the United States and China could result in a disadvantageous research and manufacturing environment in China, particularly for U.S.

based companies, including retaliatory restrictions that hinder or potentially inhibit our ability to rely on contract development and manufacturing organizations and other service providers that operate in China.

Separately, on April 16, 2025, the U.S.

Department of Commerce announced an investigation under Section 232 of the Trade Expansion Act of 1962 into imports of pharmaceuticals and pharmaceutical ingredients, including finished drug products, medical countermeasures, critical inputs such as active pharmaceutical ingredients, and key starting materials, and derivative products of those items.

The investigation will examine the impact of these imports on U.S.

national security culminating in a decision by the President whether to take action to remedy any identified threats, including by imposing additional tariffs.

The statute provides that the Commerce Department report must be completed within 270 days of initiation of the investigation and that the President must decide whether to act within 90 days of receiving the report.

Certain countries, including the European Union, Japan, South Korea and the United Kingdom, have reached agreements with the U.S.

that cap pharmaceutical tariffs at 15%.

Separately, in April 2025, the U.S.

Department of Commerce announced an investigation under Section 232 of the Trade Expansion Act of 1962 into the impact on U.S.

national security of the imports of pharmaceuticals and pharmaceutical ingredients, including finished drug products, medical countermeasures, critical inputs such as active pharmaceutical ingredients, and key starting materials, and derivative products of those items.

On September 25, 2025, via a post on Truth Social, the President announced that, beginning October 1, 2025, all branded or patented drugs imported in the U.S.

would face a 100% tariff.

The President indicated that the tariffs could be avoided by building pharmaceutical manufacturing facilities in the U.S.

Thereafter, the President delayed the October 1st effective date of the tariffs and announced that the administration had “begun preparing” tariffs on manufacturers that do not build in the U.S.

or enter into a most-favored-nation drug pricing agreement with the administration.

As a result of changes in tariffs that have been announced and/or implemented, and the underlying uncertainty currently surrounding international trade, we could experience a negative impact to our costs of materials and production processes, and supply chain disruptions and delays as a result of any new tariff policies or trade restrictions.

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The Creating and Restoring Equal Access to Equivalent Samples Act of 2019, or the CREATES Act, authorizes sponsors of ANDAs and 505(b)(2) applications to file lawsuits against companies holding NDAs that decline to provide sufficient quantities of an approved reference drug on commercially reasonable, market-based terms, subject to certain exemptions.

If a sponsor were to bring an action under the statute and prevail in litigation, it is entitled to a court order directing the NDA holder to provide, without delay, sufficient quantities of the applicable product on commercially reasonable, market-based

terms, plus reasonable attorney fees and costs.

Additionally, the statutory provisions authorize a federal court to award the sponsor an amount “sufficient to deter” the NDA holder from refusing to provide sufficient product quantities on commercially reasonable, market-based terms if the court finds, by a preponderance of the evidence, that the NDA holder did not have a legitimate business justification to delay providing the product or failed to comply with the court’s order.

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We generally contract with third parties for the disposal of these materials and wastes.

We cannot eliminate the risk of contamination or injury from these materials.

cannot eliminate the risk of contamination or injury from these materials.

In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.

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Misconduct by employees could include intentional failures to comply with FDA regulations or regulations in other jurisdictions, provide accurate information to the FDA or other regulatory authorities, comply with manufacturing standards we have established, comply with federal and state healthcare fraud and abuse laws and regulations, report financial information or data accurately, disclose unauthorized activities to us, or comply with securities laws.

Employee misconduct could also involve the improper use of information obtained in the course of

clinical trials or interactions with the FDA or other regulatory authorities, including for illegal insider trading activities, which could result in regulatory sanctions and serious harm to our reputation.

Employee misconduct could also involve the improper use of information obtained in the course of clinical trials or interactions with the FDA or other regulatory authorities, including for illegal insider trading activities, which could result in regulatory sanctions and serious harm to our reputation.

We have adopted a Code of Business Conduct and Ethics, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws or regulations.

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Provisions in our corporate charter documents and under Delaware law could make an acquisition of us, which may be beneficial to our stockholders, more difficult and may prevent attempts by our stockholders to replace or remove our current management.

Provisions in our corporate charter and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of us that stockholders may consider favorable, including transactions in which stockholders might otherwise receive a premium for their shares.

premium for their shares.

These provisions could also limit the price that investors might be willing to pay in the future for shares of our common stock, thereby depressing the market price of our common stock.

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The stock market in general and the market for biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies.

already caused, and are likely to result in further, significant disruption of global financial markets, which may reduce our ability to access capital either at all or on favorable terms.

While the full extent of the economic impact of the recent increases in inflation rates (particularly as it relates to clinical- or manufacturing-related costs) may be difficult to assess or predict, such impacts have already caused, and are likely to result in further, significant disruption of global financial markets, which may reduce our ability to access capital either at all or on favorable terms.

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

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Our executive officers, directors and principal stockholders maintain the ability to significantly influence all matters submitted to stockholders for approval.

As of June 30, 2025, our executive officers, directors and principal stockholders, in the aggregate, beneficially owned shares representing a significant percentage of our capital stock.

As of September 30, 2025, our executive officers, directors and principal stockholders, in the aggregate, beneficially owned shares representing a significant percentage of our capital stock.

As a result, if these stockholders were to choose to act together, they would be able to significantly influence all matters submitted to our stockholders for approval, as well as our management and affairs.

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As a result, our effective tax rate is derived from a combination of applicable tax rates in the various places that we operate.

In preparing our financial statements, we estimate the amount of tax that will become payable in each of such places.

In preparing our financial statements, we estimate the

amount of tax that will become payable in each of such places.

Nevertheless, our effective tax rate may be different from previous periods or our current expectations due to numerous factors, including as a result of changes in the mix of our profitability from state to state, the results of examinations and audits of our tax filings, our inability to secure or sustain acceptable agreements with tax authorities, changes in accounting for income taxes and changes in tax laws.

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

What changed 10-Q

Item 1A. Risk Factors