AGIO 10-K & 10-Q changes, risk factors and insider trading

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 $36.5$54.0 million, $26.8$36.5 million and $11.7$26.8 million of net product revenues from sales of PYRUKYND® in the years ended December 31, 2024,2025, 20232024 and 2022,2023, respectively. We commercially launched AQVESME™ in the United States in late January 2026. In connection with our regulatory approvalapprovals in the EUEU, Great Britain and GreatSaudi Britain,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. WeRevenues provide access to PYRUKYND® for adult patientsassociated with PKthe deficiencyNewBridge in other jurisdictions upon request throughAgreement, the Avanzanite Agreement and our global managed access program,program onare eitherincluded ain freethe rest of chargeworld orproduct forrevenue chargeline basis.within BeyondResults theof globalOperations. managed access program, weWe continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities, such as the NewBridge Agreement.opportunities.

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 a commercially viable manufacturing processprocesses for PYRUKYND® or AQVESME™ that isare 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® becomesor 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™;

•PYRUKYND® failsor 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 with PK deficiency are not prescribed PYRUKYND® or AQVESME™ and, if they are, such patients do not stay on treatment; or

•PYRUKYND®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.indications; or

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

•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, inthe JanuaryU.S. 2025,Prescribing Information, or USPI, for PYRUKYND® includes a warning regarding the risk of potential hepatocellular injury, and the USPI for PYRUKYND®AQVESME™ contains a boxed warning regarding the potential for hepatocellular injury. In addition, the treatmentFDA has required and might in the future require the development and submission of hemolyticREMS anemiafor inour adultsproducts. withFor PK deficiency was updatedexample, to includemitigate informationthe regardingrisk of hepatocellular injuryinjury, observedAQVESME™ inis clinicalavailable trialsonly inthrough patientsthe withREMS thalassemiaapproved treatedby withthe PYRUKYND® at a higher dose than recommended for patients with PK deficiencyFDA;

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®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 begin and complete clinical trials of our product candidates,candidates and to demonstrate the efficacy and safety necessary to obtain regulatory approval to market any of our product candidates,candidates could result in additional costs to us, or any collaborators, and would impair our ability to generate revenue from product sales, regulatory and commercialization milestones and royalties, and would significantly harm our business.

We have and may engage in the future enter into additional 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,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 haveare begun preclinical development ofdeveloping a product candidatecandidate, AG-236, for the potential treatment of patients with PV.

Our ability to successfully in-license or acquire assets and develop product candidates following such transactions is unproven. If we do identify additional suitable candidates or assets for in-licensing transactions or acquisitions, we may not be able to make such transactions on favorable terms, or at all. 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 tofor paypaying 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 theour 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. We may decide to incur debt in connection with an acquisition or an in-licensing transaction or issue our common stock or other equity securities to the stockholders of the counterparty, which would reduce the percentage ownership of our existing stockholders. 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. 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 predict the number, timing or size of future transactions or the effect that any such transactions might have on our operating results.

Patient enrollment is also affected by other factors including:

In addition, some of our competitors may have ongoing or planned clinical trials for product candidates that would treat the same indications as our product candidates, and patients who would otherwise be eligible for our clinical trials may instead enroll in clinical trials of our competitors’ product candidates. For example, Rocket Pharma LTD, or Rocket Pharma, is developing a gene therapy targeting PK deficiency; Novo Nordisk A/S, or Novo Nordisk, and Pfizer Inc., or Pfizer, are developing molecules for the treatment of SCD; Fulcrum Therapeutics Inc., or Fulcrum, is developing a treatment for SCD; PTC Therapeutics, Inc., or PTC, and Otsuka Pharmaceutical Co., Ltd., or Otsuka, are developing therapies to treat PKU; and Protagonist Therapeutics, or Protagonist, with Takeda Pharmaceutical Company Limited, or Takeda, Ionis Pharmaceuticals, Inc., or Ionis, Silence Therapeutics, or Silence, Italfarmaco S.p.A., Disc Medicine, Inc., or Disc Medicine, and Merck & Co., Inc., or Merck, are developing therapies to treat PV. 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.

The outcome of our preclinical studies and early clinical trials may not be predictive of the success of our later clinical trials, and positive results of our completed clinical trials do not necessarily predict success in our future clinical trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier stages of development, and we could face similar setbacks. The design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical trial may not become apparent until the clinical trial is well advanced. In addition, preclinical and clinical data are often susceptible to varying interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval for the product candidates. 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. The results of clinical trials of PYRUKYND® for the treatment of PK deficiency and thalassemia are not predictive of results of our ongoing clinical trials of PYRUKYND® in other indications, such as SCD, and the results of our early-stage clinical trials of tebapivat are not predictive of our later stage clinical trial of tebapivat. 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.

In addition, even whereWhere the foreign study data are not intended to serve as the sole basis for approval, the FDA will not accept the data as support for an application for marketing approval unless the study is well-designed and well-conducted in accordance with GCP requirements and the FDA is able to validate the data from the study through an onsite inspection if deemed necessary. Many foreign regulatory authorities have similar approval requirements. In addition, such foreign trials would be subject to the applicable local laws of the foreign jurisdictions where the trials are conducted. There can be no assurance that the FDA or any comparable foreign regulatory authority will accept data from trials conducted outside of the United States or the applicable jurisdiction. If the FDA or any comparable foreign regulatory authority does not accept such data, it would result in the need for additional trials, which could be costly and time-consuming, and may result in current or future product candidates that we may develop not receiving approval for commercialization in the applicable jurisdiction.

Because we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific indications. 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 in thalassemia, SCD and pediatric PK deficiency, our phase 2 trial in LR MDS, our phase 1 trial for AG-181, our PAH stabilizer for the potential treatment of PKU, and AG-236, our preclinical development of a product candidate for the potential treatment of patients with PV.programs. Our resource allocation decisions may cause us to fail to capitalize on viable commercial medicines or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable medicines. 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®, 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® 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 require the addition of warnings on the product labellabel, require a REMS or or modify an existing REMS;

In addition, we are currently evaluating PYRUKYND® in Phase 3 clinical trialsmitapivat for the treatment of sickle cell disease, or SCD, and in pediatric patients with PK deficiency. We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and hemolytic anemiasSCD; (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU; and (iii) AG-236, an siRNA in-licensed from Alnylam Pharmaceuticals, Inc., or Alnylam, targeting the transmembrane serine protease 6, or TMPRSS6TMPRSS6, gene for the potential treatment of polycythemia vera, or PV.

In accordance with the license agreement with Alnylam, in the year ended December 31, 2023,agreement, we made an up-front payment to Alnylam and recognized in-process research and development of $17.5 million which was recorded in researchthe andyear developmentended expenseDecember within31, our consolidated statements of operations and classified as investing activities within our consolidated statements of cash flows.2023. We will also pay Alnylam for certain expenses associated with the development of AG-236, an siRNA targeting the TMPRSS6 gene, and these will be recorded in our consolidated statements of operations as incurred. Additionally, 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 licensed products, which may be subject to specified reductions and offsets. In the year ended December 31, 2025, we achieved a regulatory milestone that triggered a $10.0 million payment to Alnylam, which was recorded in research and development expense within our consolidated statements of operations and classified as investing activities within our consolidated statements of cash flows. Because the acquired assets under the license agreement with Alnylam do not meet the definition of a business in accordance with Accounting Standards Codification, or ASC, 805, Business Combinations, we accounted for the agreement as an asset acquisition.

On March 31, 2021, we completed the sale of our oncology business to Servier Pharmaceuticals, LLC, or Servier, which represented a discontinued operation.Servier. The transaction included the sale of our entire oncology business, including TIBSOVO®, our clinical-stage product candidatescandidate vorasidenib, AG-270 and AG-636, and our oncology research programs for a payment of approximately $1.8 billion in cash at the closing, subject to certain adjustments, and a payment of $200.0 million in cash, if, prior to January 1, 2027, vorasidenib is granted new drug application, or NDA, approval from the FDA with an approved label that permits vorasidenib’s use as a single agent for the adjuvant treatment of patients with Grade 2 glioma that have an isocitrate dehydrogenase, or IDH, 1 or 2 mutation (and, to the extent required by such approval, the vorasidenib companion diagnostic test is granted an FDA premarket approval), or the Vorasidenib Milestone Payment, as well as a royalty of 5% of U.S. net sales of TIBSOVO® from the close of the transaction through loss of exclusivity, and a royalty of 15% of U.S. net sales of vorasidenib from the first commercial sale of vorasidenib through loss of exclusivity, or the Vorasidenib Royalty Rights. The Vorasidenib Milestone Payment,Payment and Vorasidenib Royalty Rights and royalty payments related to TIBSOVO® are referred to as contingent payments and recognized as income when realizable. Servier also acquired our co-commercialization rights for Bristol Myers Squibb’s IDHIFA® and the right to receive a $25.0 million potential milestone payment under our prior collaboration agreement with Celgene Corporation, or Celgene, and following the sale Servier agreed to conduct certain clinical development activities within the IDHIFA® development program.

Since inception, our operations have primarily focused on organizing and staffing our company, business planning, raising capital, assembling our core capabilities in cellular metabolism and classical hematology, identifying potential product candidates, undertaking preclinical studies, conducting clinical trials, establishing a commercial infrastructure, preparing for and executing on the commercial launchlaunches of PYRUKYND® and AQVESME™ and, prior to the sale of our oncology business to Servier on March 31, 2021, marketing TIBSOVO® and IDHIFA®. Through March 31, 2021, we financed our operations primarily through proceeds from the sale of our royalty rights, commercial sales of TIBSOVO®, funding received from our collaboration agreements, private placements of our preferred stock, our initial public offering of our common stock and concurrent private placement of common stock to an affiliate of Celgene, and our follow-on public offerings. Following the sale of our oncology business to Servier on March 31, 2021, we have financed and expect to continue to finance our operations primarily through cash on hand, potential royalty payments with respect to the Retained Earn-Out Rights, the actual and potential future sales of PYRUKYND®, the potential future sales of AQVESME™ if successfully launched by us and, potentially, collaborations, strategic alliances, licensing arrangements and other nondilutive strategic transactions. In addition, we may pursue opportunistic debt offerings, and equity or equity-linked offerings.

Additionally, since inception, we have historically incurred significant operating losses. Our net loss for the year ended December 31, 2025 was $412.8 million, our net income for the year ended December 31, 2024 was $673.7 million,million and our net loss for the year ended December 31, 2023 was $352.1 million and our net loss for the year ended December 31, 2022 was $231.8 million. As of December 31, 2024,2025, we had an accumulated deficit of $148.9$561.7 million. The net income we generated in the year ended December 31, 2024 was primarily due to the sale of the Vorasidenib Royalty Rights to Royalty Pharma and our receipt of the Vorasidenib Milestone Payment discussed above in Overview. We expect to continue to incur significant expenses and net losses until such time we are able to report profitable results. OurWe may never achieve or maintain profitability, and our net losses may fluctuate significantly from year to year. We expect that we will continue to incur significant expenses as we continue to advance and expand clinical development andour commercialization activities for PYRUKYND®, including with respect to the review by the FDA and other regulatory authorities of our regulatory submissions made, which we announced in December 2024, for the treatment of thalassemia; continue to advance and expand clinical development of tebapivat, our novelcommercialization PKactivities activatorfor AQVESME™; continue to advance clinical development ofand AG-181,regulatory ouractivities PAHfor stabilizer;mitapivat, continuetebapivat, preclinicalAG-181 developmentand of AG-236, a licensed siRNA development candidate pursuant to our license agreement with AlnylamAG-236; expand and protect our intellectual property portfolio, including by in-licensing or acquiring assets for pipeline growth; and hire additional commercial and development personnel.

Our wholly owned product, PYRUKYND®, received approval from the FDA on February 17, 2022, for the treatment of hemolytic anemia in adults with PK deficiency in the United States. Upon FDA approval of PYRUKYND® in the United States, we began generating product revenue from sales of PYRUKYND®. We sell PYRUKYND® to a limited number of specialty distributors and specialty pharmacy providers, or collectively, the Customers. These Customers subsequently resell PYRUKYND® to pharmacies or dispense PYRUKYND® directly to patients. In addition to distribution agreements with Customers, we enter into arrangements with healthcare providers and payors that provide for government-mandated and/or privately-negotiated rebates, chargebacks and discounts with respect to the purchase of PYRUKYND®. In July 2024, we entered into a distribution agreement, or the NewBridge Agreement, with NewBridge Pharmaceuticals FZ-LLC, or NewBridge, pursuant to which we granted NewBridge the right to commercialize PYRUKYND® in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates, or the GCC region. For further discussion of our revenue recognition policy, see Note 2, Summary of Significant Accounting Polices and Note 8, Product Revenue, to the consolidated financial statements in this Annual Report on Form 10-K.

In the future, we expect to continue to generate revenue from product sales.sales of PYRUKYND®. We commercially launched AQVESME™ in the United States in late January 2026 and we anticipate generating revenue from product sales of AQVESME™ in the future. We may also generate revenue from milestone payments, upfront payments or royalties on product sales under collaborations or licensing agreements that we may enter into in the future.

Research and development activities are central to our business model. Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We expect research and development costs related to our portfolio to increase as our product candidate development programs progress. However, the successful development of our product candidates is highly uncertain. As such, at this time, we cannot reasonably estimate or know the nature, timing and estimated costs of the efforts that will be necessary to complete the development of and to commercialize these product candidates. We are unable to predict the amount of net cash inflows from PYRUKYND® or any of our products or product candidates. This is due to the numerous risks and uncertainties associated with developing medicines, including the uncertainty of:

•launching commercial sales of the products, if and when approved, in the United States or in other jurisdictions, whether alone or in collaboration with others, including pursuant to the NewBridge Agreement; and Avanzanite Agreement;

•maintaining an acceptable safety profile of the products following approval.approval; and

The following summarizes our products and most advanced programs:

PYRUKYND®/AQVESME™ (mitapivat): First-in-Class PK Activator

We are developing PYRUKYND®mitapivat for the treatment of PK deficiency and other hemolytic anemias such as thalassemia and SCD. PYRUKYND®Mitapivat is an orally available small molecule and a potent activator of the wild-type and mutated PK enzymes.

We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the potential commercial launch of PYRUKYND® in thalassemia in the United States. In connection with our regulatory approvals in the EUEU, Great Britain and GreatSaudi Britain,Arabia, we are currently providing access to PYRUKYND® on a free of charge basis for eligible patients in those jurisdictions through a global managed access program. We provide access to PYRUKYND® forto adulteligible patients with PK deficiency in other jurisdictions upon request through the globalAvanzanite managedAgreement accessand program,the NewBridge Agreement, as applicable, and on either a free of charge or for charge basis.basis Ourfor eligible patients in those jurisdictions and other jurisdictions through a global managed access program. Revenues associated with the NewBridge Agreement, the Avanzanite Agreement and the for charge portion of our global managed access program hasare notincluded hadin athe significant impact on our business, financial condition or resultsrest of operations.world Beyondproduct therevenue globalline managedwithin accessResults program,of weOperations. We continue to evaluate other options for the commercialization of PYRUKYND® outside of the United States, including through exploring potential partnership opportunities, such as the NewBridge Agreement.opportunities.

We are evaluating PYRUKYND®mitapivat in numerous clinical trials, including the following:

•An extension study evaluating the long-term safety, tolerability and efficacy of treatment with PYRUKYND®mitapivat in SCD patients who are 16 years of age or older from DRIVERISE PK,UP, our completed globaldouble-blind phase 2,3 first-in-patient,study open-labelevaluating the efficacy and safety and efficacy clinical trial of PYRUKYND®mitapivat inas adult,a notpotential regularlytreatment transfusedfor patients with PK deficiency.SCD.

We are developing tebapivat, a novel PK activator for the potential treatment of LR MDS and hemolytic anemias.SCD. Tebapivat has been granted orphan drug designation for the treatment of MDS by the FDA.

We have completed a phase 1 clinical trial evaluating tebapivat in healthy volunteers and patients with SCD, and we expecthave tocompleted dose the first patientenrollment in athe phase 2 clinical trial of tebapivat in adult patients with SCDSCD. We expect to announce topline data for this trial in mid-2025.the second half of 2026.

In November 2023, we announced that we achieved clinical proof-of-concept in the phase 2a portion of the trial. We observed that four of the 10 patients with low transfusion burden achieved the transfusion independence endpoint, and one of the 22 patients achieved the hemoglobin response endpoint in the 16-week treatment period. The safety profile observed was consistent with data reported in the healthy volunteer study of tebapivat. 19 patients elected to enroll in the extension period of the trial for up to 156 weeks. We evaluated the phase 2a trial results and assessed the impact of those results on the phase 2b portion of the protocol, and based on the data generated in the phase 2a portion of the trial, we plan to increaseincreased the dosage levels evaluated in the phase 2b portion of the trial, which we initiated in the third quarter of 2024. We expect to completecompleted enrollment in thisthe phase 2b portion of the trial in lateSeptember 2025.2025 and expect to announce topline data for this trial in the first half of 2026.

In addition to the aforementioned development programs, we are developing AG-181, a PAH stabilizer for the potential treatment of PKU, for which we filed an INDinvestigational new drug application, or IND, in December 2023. We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024.2024, Also,initiated the multiple ascending dose portion of the trial in Julythe 2023,second wequarter enteredof into2025, aand license agreement with Alnylam forcompleted the developmenttrial andin commercializationDecember of products containing or comprised of an siRNA preclinical development candidate discovered by Alnylam and targeting the TMPRSS6 gene, and we have begun preclinical development of a product candidate, AG-236, for the potential treatment of patients with PV.2025. We expect to fileinitiate ana investigationalphase new1b drugproof application,of ormechanism IND,trial of AG-181 in patients with thePKU FDA for AG-236 forin the treatmentfirst half of PV2026 and confirm proof of mechanism in mid-2025.the second half of 2026.

We anticipate that our selling, general and administrative expenses will increase in the future to support continued research and development activities, and ongoing and future commercialization activities related to our portfolio, including the ongoing commercialization of PYRUKYND®, AQVESME™ and any of our other product candidates, which may include the hiring of additional personnel.

We generate product revenue from sales of PYRUKYND® in the United States to a limited number of specialty distributors and specialty pharmacy providers, and to Avanzanite and NewBridge outside of the United States, or collectively, the Customers. These Customers subsequently resell PYRUKYND® to pharmacies or dispense PYRUKYND® directly to patients. In addition to distribution agreements with Customers, we enter into arrangements with healthcare providers and payors that provide for government-mandated and/or privately-negotiated rebates, chargebacks and discounts with respect to the purchase of PYRUKYND®.

Government Rebates. Government rebates include Medicare, TriCare, and Medicaid rebates, which we estimate using the expected value method, based upon a range of possible outcomes that are probability-weighted for the estimated payor mix. These reserves are recorded in the same period the related revenue is recognized, resulting in a reduction of product revenue. For Medicare, we also estimate the number of patients in the prescription drug coverage gap for whom we will owe an additional liability under the Medicare Part D program.

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$65.5 million and $8.7$21.2 million of net product revenues from sales of PYRUKYND® and AQVESME™ in the threesix months ended MarchJune 31,30, 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.

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 mitapivat and tebapivat.programs. 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 mitapivat. We cannot be certain that we will obtain marketing approval of mitapivat for SCD in jurisdictionsthe withUnited pendingStates or potentialin futureother marketing applications for thalassemia,jurisdictions, nor can we be certain that we will obtain marketing approval of mitapivatany forother SCDproduct orcandidate for any other indication.

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 mitapivat or tebapivat,trials, 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.

We may engage in transactions to in-license products, technologies or assets or to acquire other products, technologies, assets or businesses. 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.PV, and in June 2026, we entered into a license agreement with Oscotec for the development and commercialization of cevidoplenib, a novel, highly selective, oral SYK inhibitor for the potential treatment of ITP and other autoimmune indications.

Our ability to successfully in-license or acquire assets and develop product candidates following such transactions is unproven. If we do identify additional suitable candidates or assets for in-licensing transactions or acquisitions, we may not be able to make such transactions on favorable terms, or at all. 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 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. We are also responsible for paying up to $140.0 million in potential development and regulatory milestone payments, in addition to sales milestone payments as well as tiered royalties on future net sales, if any, of licensed products under our license agreement with Oscotec. 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. We may decide to incur debt in connection with an acquisition or an in-licensing transaction or issue our common stock or other equity securities to the stockholders of the counterparty, which would reduce the percentage ownership of our existing stockholders. 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. 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 predict the number, timing or size of future transactions or the effect that any such transactions might have on our operating results.

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

For example, the USPI for PYRUKYND® includes a warning regarding the risk of potential hepatoceullarhepatocellular injury, and the USPI for AQVESME™ contains a boxed warning regarding the potential for hepatocellular injury. In addition, to mitigate the risk of hepatocellular injury, AQVESME™ is available only through the REMS program approved by the FDA. If we are unable to comply with any REMS imposed on any of our products, we may face additional restrictions, limitations or substantial penalties, any of which may materially adversely affect our business and results of operations. We cannot predict whether the FDA will request, seek to require or ultimately require modifications to, or impose additional requirements on, the AQVESME™ REMS.

We face competition with respect to PYRUKYND®, AQVESME™, mitapivat, AG-181, AG-236, cevidoplenib and our other product candidates, and we will face competition with respect to any product candidates that we may seek to develop or commercialize in the future. Potential competitors may include major pharmaceutical companies, specialty pharmaceutical companies, biotechnology companies, academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization. There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the indications for which we are developing our product or our product candidates, such as PK deficiency, thalassemia, SCD, PKU, PV and ITP. For example, Merck and Bristol-Myers Squibb Company, or BMS, are marketing a therapy to treat beta-thalassemia, and are conducting a clinical trial for alpha thalassemia patients that are erythropoiesis-stimulating agent naïve and non-transfusion dependent; Geron Corporation has an FDA approved treatment for adults with transfusion-dependent anemia; Novartis International AG is marketing therapies for SCD, PV and ITP and has another molecule in clinical trials to treat SCD and ITP; Emmaus Life Sciences is marketing a therapy to treat SCD; BioMarin Pharmaceutical Inc. is marketing and conducting clinical trials for therapies to treat PKU; PTC has an approved treatment for PKU; Pfizer, CSL Behring, Beam Therapeutics, Inc., and Cellarity, Inc. are conducting clinical trials for therapies in SCD; Novo Nordisk A/S is conducting clinical trials for the treatment of alphaalpha- and beta thalassemiabeta-thalassemia and SCD; Sanofi is marketing a therapy to treat ITP and conducting clinical trials for a therapy in SCD; 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;SCD, Fulcrumbeta Therapeuticsthalassemia Inc.and is conducting clinical trials for a potential treatment for SCDPV; BMS is conducting clinical trials for a potential treatment for SCD; Argenx SE is marketing a therapy and conducting clinical trials for a therapy in ITP; Rigel Pharmaceuticals, Inc. is marketing a therapy to treat ITP; Takeda is conducting clinical trials for a potential treatment for ITP; 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 in collaboration with Takeda, Ionis in collaboration with Ono/Deciphera, Italfarmaco S.p.A., DISC, Merck, and Silence Therapeutics are developing therapies to treat PV; and a number of other biotechnology companies have product candidates in clinical development in similar indications as ours.

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

•the costs associated with in-licensing or acquiring assets for pipeline growth, including the amount and timing of future milestone and royalty payments payable to Alnylam and Oscotec pursuant to the respective license agreementagreements;

We have a history of incurring operating losses. Our net loss for the threesix months ended MarchJune 31,30, 2026 was $99.1$199.8 million and for the threesix months ended MarchJune 31,30, 2025 was $89.3$201.3 million. As of MarchJune 31,30, 2026, we had an accumulated deficit of $660.8$761.5 million. We are commercializing PYRUKYND® for the treatment of hemolytic anemia in adults with PK deficiency in the United States. Following the receipt of marketing approval in December 2025, we commercially launched AQVESME™ in the United States in late January 2026.

In December 2025, as part of the National Defense Authorization Act for FY 2026, President Trump signed into law the BIOSECURE Act, which prohibits, 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 of concern, or BCCs. Under the BIOSECURE Act, U.S. government agencies cannot (i) buy or obtain biotechnology equipment or services provided by a BCC, (ii) enter into, extend, or renew a contract with any entity using biotechnology equipment or services provided by a BCC to perform a government contract, or (iii) expend loan or grant funds for biotechnology equipment or services provided by a BCC. Instead of specifying particular Chinese entities as BCCs, the BIOSECURE Act treats any 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 as BCCs. The legislation allows for other biotechnology companies, possibly including WuXi entities,companies to be added to the federal funding prohibitions at a later time. On FebruaryJune 13,8, 2026, the Department of Defense published an updated list, which included WuXi,WuXi but then abruptly withdrew the list. The implications of this action remain unclear.AppTec.

Competitors may infringe our patents and other intellectual property rights. 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 an ANDA containing a Paragraph IV patent certification for our products. An ANDA containing a Paragraph IV certification for mitapivat was submitted on February 17, 2026. We have received notice of such certification and we intend to filefiled a timely infringement suit. We may receive additional notices of paragraph IV certifications in the future and we may take similar actions with respect to those ANDAs.

In addition, a court or a patent office such as the USPTO or European Patent Office 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. An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated or interpreted narrowly. Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

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

The biotechnology and pharmaceutical industries are characterized by extensive litigation regarding patents and other intellectual property rights. Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell our product and product candidates and use our proprietary technologies without infringing the proprietary rights and intellectual property of third parties. We have in the past, are and may in the future become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our medicines and technology, including opposition, derivation, revocation, reexamination, post-grant and inter partes review or interference proceedings before the USPTO or other patent offices around the world. For example, two of the European patents in our mitapivat portfolio, neither being the primary compound patent, have been challenged in opposition proceedings. The revocation of either of these European patents could potentially allow additional competitor drugs, if approved, to enter the European marketplace earlier than anticipated. After separate oral proceedings, both European patents were upheld by the European Opposition Division in written decisions in November 2025 and January 2026, respectively. These decisions have been appealed by the opponents.opponents and we have filed or will be filing timely responses. In addition, a request for Inter Partes Review in connection with US 11,878,049 was filed with the USPTO on May 18, 2026, and we intend to take all necessary steps to defend our patent.

In December 2024, we announced that we submitted an MAA to the EMA for 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 is now reviewing the CHMP’s opinion, with the final decision expected in the first half of 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. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA approval. The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many foreign countries, a product must be approved for reimbursement before the product can be approved for sale in that country. We or our collaborators may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all. 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 and for PYRUKYND® for the treatment of adult patients with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia in the EU, Saudi Arabia and the United Arab Emirates, 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. For instance, in December 2025, the European Parliament and European Council reached a provisional political agreement on the revision of EU pharmaceutical legislation, which is expected to be adopted by mid-2026.late-2026. If the legislation is finalized in line with the provisional political agreement, it will have a significant impact on the EU pharmaceutical industry, which could impact our business.

We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure 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 and the potential commercial launch of mitapivat in SCD in the United States. The commercial success of PYRUKYND®, AQVESME™ 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 are not available, or reimbursement is available only to limited levels, we, or any collaborators, may not be able to successfully commercialize PYRUKYND®, AQVESME™ 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.

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

In April 2025, President Trump issued an executive order which directs HHS to take steps to reduce the prices of pharmaceutical products and repeats many of the proposals advanced during the first Trump administration, including directing the FDA to streamline and improve its existing drug importation program so as to make it easier for states to obtain approval without sacrificing the safety or quality of drug products. Other provisions of the executive order relate to the 340B program. With respect to the IRA’s Medicare drug pricing program, the executive order, among other things, calls for alignment in “the treatment of small molecule prescription drugs with that of biological products, ending the distortion that undermines relative investment in small molecule prescription drugs, coupled with other reforms to prevent any increase in overall costs to Medicare and its beneficiaries.” In May 2025, President Trump issued an additional executive order calling on pharmaceutical manufacturers to voluntarily reduce the prices of medicines in the United States. The executive order directs the Secretary of HHS to communicate MFN price targets to pharmaceutical manufacturers to bring prices in line with comparably developed nations. The executive order further provides that if such actions do not lower the costs of pharmaceuticals, the Secretary of HHS would pursue other actions, including proposing a rulemaking that imposes MFN pricing in the United States. Subsequently, HHS indicated that the proposed MFN pricing will apply only to brand products without generic or biosimilar competition and the referenced foreign countries will include only those in which the branded product similarly does not have generic or biosimilar competition. HHS also indicated that the MFN target price will be the lowest price in a country that is a member of the Organization for Economic Co-operation and Development, or OECD, with a gross domestic product per capita of at least 60% of the U.S. gross domestic product per capita. The implications of these actions remain unclear and our business could be negatively impacted.

The reciprocal tariffs and the drug trafficking tariffs were imposed pursuant to the International Emergency Economic Powers Act, or the IEEPA. These tariffs were found to be unconstitutional by multiple federal courts in the spring and summer of 2025. On February 20, 2026, the U.S. Supreme Court held that the IEEPA does not authorize the U.S. President to impose tariffs, invalidating both the reciprocal tariffs and the drug trafficking tariffs. Shortly thereafter, President Trump issued a new executive order revoking the IEEPA tariffs and Customs and Border Protection ceased collecting the tariffs on February 24, 2026. At the same time, however, the Trump Administration imposed a new 10% global tariff under Section 122 of the Trade Act of 1974, effective February 24, 2026. Pursuant to the statute, absent an extension by Congress, these tariffs will expire in 150 daysexpired on July 24, 2026. ForHowever, on July 23, 2026, the Office of the U.S. Trade Representative announced final action under Section 301 of the Trade Act of 1974 imposing new tariffs on imports from 60 trading partners based on findings that those countries thathad havefailed concludedto tradeadopt dealsand effectively enforce prohibitions on imports of goods produced with theforced Unitedlabor. States,The new tariffs, set at either 10% or 12.5% depending on the tariffcountry’s rateslevel agreedof to, including with regardcommitment to pharmaceuticalsforced-labor andimport pharmaceuticalrestrictions, ingredients,took haveeffect now reverted to 10% untilon July 24, 2026.2026, Likeand replaced the IEEPAtariffs tariffs,that pharmaceuticalshad andbeen pharmaceuticalimposed ingredients are exempt from theunder Section 122 tariffs along with a list of other products.122. The Trump Administration has announced that it also plans to initiate new investigations related to excess capacity on “most major trading partners” under Section 301 of the same act, which will likely lead to additional tariffs.

As of MarchJune 31,30, 2026, 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. For example, these persons could significantly influence the election of directors and approval of any merger, consolidation or sale of all or substantially all of our assets. This concentration of voting power could delay or prevent an acquisition of our company on terms that other stockholders may desire.

The following discussion of our financial condition and results of operations should be read in conjunction with our unaudited condensed consolidated financial statements as of MarchJune 31,30, 2026 and for the three and six months ended MarchJune 31,30, 2026 and 2025, and related notes included in Part I, Item 1 of this Quarterly Report on Form 10-Q, as well as the audited consolidated financial statements and notes and Management’s Discussion and Analysis of Financial Condition and Results of Operations, included in our Annual Report on Form 10-K for the year ended December 31, 2025 filed with the SEC on February 12, 2026. This Management’s Discussion and Analysis of Financial Condition and Results of Operations contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on current expectations, estimates, forecasts and projections, and the beliefs and assumptions of our management, and include, without limitation, statements with respect to our expectations regarding our research, development and commercialization plans and prospects, results of operations, selling, general and administrative expenses, research and development expenses, and the sufficiency of our cash for future operations. Words such as “aim,” “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “strategy,” “target,” “vision,” “will,” “would” or the negatives of these words and similar expressions are intended to identify these forward-looking statements, although not all forward-looking statements contain these identifying words. Readers are cautioned that these forward-looking statements are predictions and are subject to risks, uncertainties and assumptions that are difficult to predict. Therefore, actual results may differ materially and adversely from those expressed in any forward-looking statements. Among the important factors that could cause actual results to differ materially from those indicated by our forward-looking statements are those discussed under the heading “Risk Factors” in Part II, Item 1A and elsewhere in this report, and in our Annual Report on Form 10-K for the year ended December 31, 2025. We undertake no obligation to revise the forward-looking statements contained herein to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events, except as required by law.

The lead product candidate in our portfolio, mitapivat, is an activator of both wild-type and mutant pyruvate kinase, or PK, enzymes for the potential treatment of hemolytic anemias. Mitapivat is approved in the United States by the U.S. Food and Drug Administration, or FDA, under the brand name AQVESME™ in the United States for the treatment of anemia in adults with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia and in Saudi Arabia and the United Arab Emirates under the brand name PYRUKYND® for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. Mitapivat is also approved under the brand name PYRUKYND®: in the United States by the FDA for the treatment of hemolytic anemia in adults with PK deficiency and; in the European Union, or EU, for the treatment of PK deficiency and for the treatment of non-transfusion dependent and transfusion dependent alpha- or beta-thalassemia in adult patients; in the Kingdom of Saudi Arabia for the treatment of adults with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemia; in the United Arab Emirates for the treatment of non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia in adult patients; and in Great Britain for the treatment of PK deficiency in adults.adult patients.

In addition, we are evaluating mitapivat for the treatment of pediatric patients with PK deficiency. We are also developing (i) tebapivat, a novel PK activator, for the potential treatment of lower-risk myelodysplastic syndromes, or LR MDS, and SCD; (ii) AG-181, our phenylalanine hydroxylase, or PAH, stabilizer for the potential treatment of phenylketonuria, or PKU; and (iiiii) AG-236, an siRNA in-licensed from Alnylam Pharmaceuticals, Inc., or Alnylam, targeting the transmembrane serine protease 6, or TMPRSS6, gene for the potential treatment of polycythemia vera, or PV.PV; and (iii) cevidoplenib, an oral spleen tyrosine kinase, or SYK, inhibitor in-licensed from Oscotec Inc., or Oscotec, for the potential treatment of immune thrombocytopenia, or ITP, and other autoimmune indications.

Additionally, since inception, we have historically incurred significant operating losses. Our net loss for the threesix months ended MarchJune 31,30, 2026 was $99.1$199.8 million and for the threesix months ended MarchJune 31,30, 2025 was $89.3$201.3 million. As of MarchJune 31,30, 2026, we had an accumulated deficit of $660.8$761.5 million. We expect to continue to incur significant expenses and net losses until such time we are able to report profitable results. We may never achieve or maintain profitability, and our net losses may fluctuate significantly from year to year. We expect that we will continue to incur significant expenses as we continue to advance and expand our commercialization activities for PYRUKYND® and AQVESME™; continue to advance clinical development and regulatory activities for mitapivat, tebapivat,AG-181, AG-181AG-236 and AG-236cevidoplenib; expand and protect our intellectual property portfolio, including by in-licensing or acquiring assets for pipeline growth; and hire additional commercial and development personnel.

Cost of sales consists primarily of manufacturing costs for sales of PYRUKYND® and AQVESME™. Based on our policy to expense costs associated with the manufacturing of our products prior to regulatory approval, certain of the manufacturing costs associated with product shipments of PYRUKYND® and AQVESME™ recorded during the three and six months ended MarchJune 31,30, 2026 and 2025 were expensed prior to applicable regulatory approval, and, therefore, are not included in costs of sales during the three and six months ended MarchJune 31,30, 2026 and 2025. The amounts excluded from cost of sales were not significant during the three and six months ended MarchJune 31,30, 2026 and 2025.

Inventories are reviewed periodically to identify excess or obsolete inventory based on projected sales activity as well as product shelf-life. Expired inventory is disposed of, and the related costs are recognized as cost of sales in our consolidated statements of operations, when, based on the expiry date, we do not believe we are able to sell the inventory. We have not reserved for excess or obsolete inventory during the three and six months ended MarchJune 31,30, 2026 and 2025.

InMitapivat Decemberis 2025,an orally available small molecule and a potent activator of the FDAwild-type and mutated PK enzymes. Mitapivat is approved mitapivat under the brand name AQVESME™ in the United States for the treatment of anemia in adults with non-transfusion dependent and transfusion-dependent alpha- or beta-thalassemiabeta-thalassemia, in the United States. AQVESME™and is the only FDA-approved medicine for anemia in both non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. We commercially launched AQVESME™ in the United States in late January 2026 following our implementation of a Risk Evaluation and Mitigation Strategy, or REMS, to mitigate the risk of hepatocellular injury. Mitapivat will continue to be marketed as PYRUKYND® in the United States for the PK deficiency indication, which does not require a REMS. The AQVESME™ REMS requires liver tests prior to the first AQVESME™ dose, every four weeks thereafter for 24 weeks, and then as clinically indicated. It also includes education and certification requirements for patients, prescribing physicians, and pharmacists, which are common components of REMS.

In addition, we are evaluating mitapivat for the treatment of pediatric patients with PK deficiency. Additionally, mitapivatMitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and SCD, and orphan medicinal product designation from the EMA for the treatment of SCD. MitapivatAdditionally, mitapivat was granted orphan drug designation for the treatment of PK deficiency by the FDA and EMA.

We have full ownership rights to PYRUKYND® and AQVESME™ and expect to fund the future development and commercialization costs related to PYRUKYND® and AQVESME™. We built our commercial infrastructure to support the commercialization of PYRUKYND® in adult PK deficiency in the United States, and have expanded this infrastructure to support the commercial launch of AQVESME™ in thalassemia in the United States and the potential commercial launch of mitapivat in SCD in the United States. In July 2024, we entered into the NewBridge Agreement with NewBridge,Agreement, pursuant to which we granted NewBridge the right to commercialize PYRUKYND® in the GCC region. In June 2025, we entered into the Avanzanite Agreement with Avanzanite,Agreement, pursuant to which we granted Avanzanite the right to commercialize PYRUKYND® in the European Economic Area, Switzerland, and the United Kingdom. Under the NewBridge Agreement and the Avanzanite Agreement, we rely on NewBridge and Avanzanite, 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 in the applicable jurisdictions.

In addition to the aforementioned development programs, weWe are developing AG-181, a PAH stabilizer for the potential treatment of PKU, for which we filed an IND in December 2023. We initiated a phase 1 clinical trial of AG-181 in healthy volunteers in the first quarter of 2024, initiated the multiple ascending dose portion of the trial in the second quarter of 2025, and completed the trial in December 2025. We expect to initiateinitiated a phase 1b trial of AG-181 in patients with PKU in the first half of 2026 and expect to confirm proof of mechanism in the second half of 2026.

Also, in July 2023, weWe entered into a license agreement with Alnylam for the development and commercialization of products containing or comprised of an siRNA preclinical 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. We filed an IND with the FDA for AG-236 for the treatment of PV, which cleared in June 2025, and initiated a phase 1 clinical trial evaluating AG-236 in healthy volunteers in July 2025. In June 2026, we announced topline results from the phase 1 clinical trial, which demonstrated dose-dependent hepcidin induction, sustained activity across doses, rapid and sustained biomarker changes and no dose-limiting toxicities. We expect to announceinitiate toplinethe dataphase for2 thisportion of a phase 2/3 trial of AG-236 in patients with PV in the firstsecond half of 2026.

Our critical accounting estimates are those which require the most significant judgments and estimates in the preparation of our condensed consolidated financial statements. We have determined that our most critical accounting estimates are those relating to revenue recognition, accrued research and development expenses and stock-based compensation. As of MarchJune 31,30, 2026, there have been no material changes to our existing critical accounting estimates discussed in Part II, Item 7 of our Annual Report on Form 10-K for the year ended December 31, 2025.

Comparison of the three and six months ended MarchJune 31,30, 2026 and 2025

Total Revenue - Three Months Ended MarchJune 31,30, 2026 vs. Three Months Ended MarchJune 31,30, 2025 – The increase in total revenue of $12.0$32.3 million for the three months ended MarchJune 31,30, 2026 compared to the three months ended MarchJune 31,30, 2025 was primarily due to an increase of $10.1$28.8 million in United States product revenuerevenue, and an increase of $1.9 million in rest of world product revenue. The increase in United States product revenuewhich was primarily due to increased volume associated with AQVESME™, sales, which launchedwe onbegan December 23, 2025, and increased volume associated with PYRUKYND®. The increase in rest of worldrecognizing product revenue wasfor primarily due to increased volume associated within the Newbridgefirst Agreementquarter discussedof above in Overview.2026.

Total Operating Expenses - Three Months Ended MarchJune 31,30, 2026 vs. Three Months Ended MarchJune 31,30, 2025 – The increase in total operating expenses of $15.4$15.8 million for the three months ended MarchJune 31,30, 2026 compared to the three months ended MarchJune 31,30, 2025 was primarily due to an increase in research and development expenses of $8.4$8.8 million, which is described below under Research and Development Expenses, and an increase in selling, general and administrative expenses of $6.8$5.7 million, driven by an increase in commercial-related activities as we execute our launch of AQVESME™ in thalassemia, and an increase in stock compensation expense.thalassemia.

Total Research and Development Expenses - Three Months Ended MarchJune 31,30, 2026 vs. Three Months Ended MarchJune 31,30, 2025 – The increase in total research and development expenses of $8.4$8.8 million for the three months ended MarchJune 31,30, 2026 compared to the three months ended MarchJune 31,30, 2025 was primarily due to aan $4.7 million increase in our indirect expenses and a $3.7$8.0 million increase in our direct expenses. The increase in our indirect expenses was primarily due to higher compensation and related expenses driven principally by workforce-related expenses. The increase in direct expenses was primarily due to an increase in in-process research and development of $15.0 million, driven by the $25.0 million up-front payment associated with the agreement with Oscotec discussed above under Overview, partially offset by a decrease in PYRUKYND®/AQVESME™ costs drivenof by$4.0 highermillion primarily due to lower process development expenses.

Other Income and Expense - Three Months Ended MarchJune 31,30, 2026 vs. Three Months Ended MarchJune 31,30, 2025 – The decrease in interest income, net was due to a lower investment balance in the three months ended MarchJune 31,30, 2026 compared to the three months ended MarchJune 31,30, 2025.

Net Loss - Three Months Ended MarchJune 31,30, 2026 vs. Three Months Ended MarchJune 31,30, 2025 – The increasedecrease in net loss for the three months ended MarchJune 31,30, 2026 compared to the three months ended MarchJune 31,30, 2025 was primarily driven by the increase in product revenue discussed above under Revenues, partially offset by the increase in research and development expenses discussed above under Research and Development Expenses, the increase in selling, general and administrative expenses discussed above under Total Operating Expenses and the decrease in interest income, net discussed above in Other Income and Expense, partially offset by the increase in product revenue discussed above under Revenues.Expense.

In May 2024, we entered into a purchase and sale agreement to sell the Vorasidenib Royalty Rights to Royalty Pharma Investments 2019 ICAV, or Royalty Pharma. The sale was contingent upon FDA approval of vorasidenib and other customary closing conditions.

Our cash, cash equivalents and marketable securities balance was $1.0 billion at MarchJune 31,30, 2026. The Retained Earn-Out Rights discussed above are our only committed potential external sources of funds. We cannot predict what success, if any, Servier may have in the United States with respect to the sale of vorasidenib, and consequently, we cannot estimate the amount of payments, if any, we may receive on account of the Retained Earn-Out Rights.

The following table provides information regarding our cash flows for the threesix months ended MarchJune 31,30, 2026 and 2025:

Net cash used in operating activities. Cash used in operating activities of $118.9$176.2 million during the threesix months ended MarchJune 31,30, 2026 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received from product revenues of $16.9$56.2 million and interest income of $12.4$22.1 million.

Cash used in operating activities of $111.5$188.6 million during the threesix months ended MarchJune 31,30, 2025 was primarily due to operating expenses driven by research and development costs described above under Research and Development Expenses, partially offset by cash received from interest income of $16.1$31.5 million and product revenues of $10.4$22.0 million.

Net cash provided by investing activities. Cash provided by investing activities of $141.3$181.5 million during the threesix months ended MarchJune 31,30, 2026 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

Cash provided by investing activities of $112.6$191.6 million during the threesix months ended MarchJune 31,30, 2025 was primarily due to higher proceeds from maturities and sales of marketable securities than purchases of marketable securities.

Net cash provided by financing activities. Cash provided by financing activities of $2.1$5.2 million during the threesix months ended MarchJune 31,30, 2026,2026 was due to net proceeds received from stock option exercises and purchases made pursuant to our Amended and Restated 2013 Employee Stock Purchase Plan, or 2013 ESPP.

Cash provided by financing activities of $1.6$1.7 million during the threesix months ended MarchJune 31,30, 2025, was due to net proceeds received from stock option exercises and purchases made pursuant to our 2013 ESPP.

We expect that our existing cash, cash equivalents and marketable securities as of MarchJune 31,30, 2026, together with anticipated product revenue and interest income, will provide the financial independence to execute the U.S. commercial launch of AQVESME™ in thalassemia, prepare for the potential U.S. commercial launch of mitapivat in SCD, advance our existing clinical programs, and opportunistically expand our pipeline through both internally and externally discovered assets. Our expectations regarding our long-term funding requirements are based on assumptions that may prove to be wrong, and we may need additional capital resources to fund our operating plans and capital expenditure requirements.

•the costs associated with in-licensing or acquiring assets for pipeline growth, including the amount and timing of future milestone and royalty payments potentially payable to Alnylam and Oscotec pursuant to the respective license agreementagreements;

During the three months ended March 31, 2026, thereThere were no other material changes to our contractual obligations and commitments described under Management's Discussion and Analysis of Financial Condition and Results of Operations in our Annual Report on Form 10-K for the year ended December 31, 2025.