Agios Pharmaceuticals : 2025 Annual Report (15676d)

Published: 2026-04-29 12:56:11 ET AGIO

Published on 04/29/2026 at 12:56 pm EDT

Agios Pharmaceuticals, Inc. 2025 Annual Report

Fueled by Connections toTransform Rare DiseasesTM

Educate, Advocate, and Build Community: Madina's Journey with Thalassemia

For most of her life, Madina's doctors called her "lucky" - her thalassemia was considered non-transfusion-dependent. She held onto that word for decades, but a routine scan recently

revealed silent organ damage that had been building for years. This devastating discovery spurred her to seek out information, a search

that led her to Agios' Thal Pals podcast. It was through this that she learned about Cooley's Anemia Foundation, which helped connect her to a thalassemia specialist. Now diagnosed with transfusion-dependent thalassemia, Madina's message is simple: educate yourself, advocate for yourself, and find your community.

Madina, living with thalassemia

2025 marked strong, consistent execution and meaningful progress toward becoming a sustainable rare disease company

Sickle Cell Disease

Reported topline results from the RISE UP Phase 3 study of mitapivat

Completed enrollment for the Phase 2 trial of tebapivat

Lower-Risk MDS

ompleted enrollment for the hase 2b study of tebapivat

P lycythemia Vera

eceived Investigational

ew Drug (IND) clearance for G-236 in polycythemia vera

2025

Thalassemia

AQVESME™ (mitapivat) approved in U.S. for thalassemia1

PYRUKYND® (mitapivat) approved in Saudi Arabia (2025) and the UAE (2026) for thalassemia2

Received positive CHMP opinion for PYRUKYND® (mitapivat) in adults with thalassemia3

Pediatric PK Deficiency

eported topline results from the

CTIVATE-Kids Phase 3 study of mitapivat

1. In the U.S., AQVESME™ is approved for the treatment of anemia in adults with alpha- or beta-thalassemia. 2. In Saudi Arabia (2025) and the UAE (2026), PYRUKYND® is approved for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. 3. In the European Union, PYRUKYND® is under review for a new indication in adults for the treatment of anemia associated with transfusion-dependent and non-transfusion-dependent alpha- or beta-thalassemia. UAE = United Arab Emirates; CHMP = Committee for Medicinal Products for Human Use; MDS = myelodysplastic syndromes; PK = pyruvate kinase.

2025 Annual Report

Dear Shareholders

The profound needs of rare disease communities are the driving force behind our work. Too often, the stories we hear are marked by uncertainty, delayed diagnoses, and limited treatment options - a powerful reminder that many patients, along with their caregivers and physicians, are still waiting for medicines that can meaningfully change their lives.

At Agios, these stories inspire our vision: to redefine the future of rare disease treatment. We took a significant step toward that vision in 2025 with the historic U.S. approval of our first-in-class pyruvate kinase (PK)

activator, AQVESME™ (mitapivat), which became the only medicine approved by the U.S. Food and Drug Administration (FDA) for anemia in adults with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia. This milestone brings an innovative, disease-modifying oral therapy to patients living with this debilitating and life-threatening rare blood disorder.

For more than two decades, Agios has built a strong and enduring foundation rooted in scientific innovation. Now in 2026, we are at a pivotal inflection point, leveraging that foundation as we enter our next phase of commercial-stage growth. Our path forward is centered on three key areas: redefining the standard of care in hemolytic anemias through our PK activator franchise, advancing a diversified pipeline of next-generation medicines, and building a sustainable future.

Redefining Standard of Care in Hemolytic Anemias

Our leadership in PK activation is built on the proven success of mitapivat, which has now demonstrated positive results in six randomized Phase 3 trials across PK deficiency, thalassemia, and sickle cell disease.

The December 2025 approval of AQVESME™ marks a new era in the treatment of thalassemia. It is the first therapy approved for both alpha- and beta-thalassemia, regardless of transfusion burden, the first to demonstrate quality-of-life improvements for non-transfusion-dependent patients, and the first to demonstrate durable reductions in transfusion burden for those who are transfusion-dependent.

Since its approval, the response from the thalassemia community has been overwhelmingly positive, reflecting the medicine's clear clinical value and the focused execution of our high-performing team. Our global reach is also expanding, with mitapivat approved as PYRUKYND® (mitapivat) in Saudi Arabia (August 2025) and the United Arab Emirates (March 2026), and it is currently under review in the European Union - all geographic areas significantly affected by thalassemia.

In sickle cell disease, we reported topline results from the RISE UP Phase 3 trial of mitapivat in November 2025. Treatment for this complex disease remains a challenge, as available options are often limited by

toxicity, administration burden, and the inability to address all aspects of the disease. At the end of March 2026, we announced we will pursue U.S. accelerated approval for mitapivat in sickle cell disease. This FDA pathway expedites the availability of medicines that can fill a medical need for a serious condition, with the requirement of a confirmatory clinical trial to convert to a traditional approval. We have already submitted our proposal for the required confirmatory trial for

the FDA's review, and are actively working with the agency to achieve its alignment. We remain confident in mitapivat's potential in sickle cell disease, with plans to submit a supplemental New Drug Application in the coming months.

Unlocking Value and Expanding Impact with Pipeline

Our robust early- and mid-stage pipeline offers great potential to expand our impact across hematologic and rare diseases.

Building on our foundation in PK activation, we continue to advance tebapivat, a potent, once-daily oral therapy designed to deepen hemoglobin response. In 2026, we expect to report topline results from two key tebapivat studies: a Phase 2b trial in lower-risk myelodysplastic syndromes in the first half of the year and a Phase 2 study in sickle cell disease in the second half.

Beyond our PK activation franchise, our early-stage pipeline programs offer novel mechanisms of action to address significant needs in other rare diseases. Our portfolio includes AG-236, an siRNA-based TMPRSS6 inhibitor for the treatment of polycythemia vera, and AG-181, an oral PAH stabilizer for the treatment of phenylketonuria. Key early-stage data from these programs are expected this year and will inform

plans for future development.

Building a Sustainable Future

Underpinning our strategy is a continued commitment to financial discipline and long-term value creation.

We have a strong financial position, with $1.2 billion in cash, cash equivalents, and marketable securities as of December 31, 2025. This allows us to maximize the

U.S. commercial launch of AQVESME™, prepare for the potential U.S. commercial launch of mitapivat in sickle cell disease, advance our existing clinical programs, and opportunistically expand our pipeline through both internally and externally discovered assets.

Agios is well positioned for its next chapter of growth as we advance a new wave of innovation in rare diseases, where patient need remains significant. Our solid foundation is a testament to the dedication of our

employees, whose unwavering commitment continues to make a meaningful difference for patients and their loved ones.

Thank you for your trust and continued support - it fuels our work every day. Together with rare disease communities, we are redefining what can be achieved.

Best, Brian Goff

Chief Executive Officer, Agios

2026 Anticipated Milestones*:

Strong Flow of Catalysts Across Rare Disease Pipeline

H1 2026

Sickle Cell Disease Mitapivat

Pre-sNDA meeting Q1

Lower-Risk MDS Tebapivat

Phase 2b topline data

Polycythemia Vera AG-236

Phase 1 HV topline data

H2 2026

Sickle Cell Disease Tebapivat

Phase 2 topline data

Phenylketonuria AG-181

Phase 1b PoM data

AQVESME™ U.S. launch underway in thalassemia

*As of April 22, 2026. sNDA = supplemental new drug application; MDS = myelodysplastic syndromes; HV = healthy volunteer; PoM = proof of mechanism; H1 2026 = first half 2026; H2 2026 = second half 2026; Q1 = first quarter.

(M k O )

ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

For the fi al ye ded D ber 31, 2025 OR

TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934

Commissi File Numb

001-36014

AGIOS PHARMACEUTICALS, INC.

(E t f reg s r nt spec fied in i ch r er)

Dela 26-0662915

(S a e r ther j r sdi t o f n rp r t o r rgani tion)

88 Sidney Street Cambridge, MA

(IRS Employer Id tific t on No.)

02139

(Addr f pri ipal tiv ffic ) (Zip Code)

Regi t nt's telephone ber including a de

(617) 649-8600

Se ritie egiste dp t to Section 2(b) of the Act

Title of Cla s

T ding symbol(s) N f Ex hange Which Registe d

Co n Stock, P Value $0.001 pe ha

AGIO Nasdaq Global Sel t M ket

ritie egiste dp t to Section 12(g) of the Act No

Indicate by check rk if th egistr t i a ll-know a n d i as defin

of 1934 during the preceding 12 months (or f ch sh ter p iod that the gi t nt equi d to file

ch filing requi nts f the pa t 90 day Ye No

Indicate by check rk whether the gi t nt ha ubmitted elect nically y Int active Data File qui d to b ubmittedp r ant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or f ch sh ter p iod that the gi t nt a equi d t ubmit

ch files) Y No

Indicate by check rk whether the gi t nt is a l ge a cel ated filer accel ated filer n-accel ated filer a lle ep ting mp y, ging gr th mp y See the definitio of "l ge accele ted f

"e rging g wth c pany" in Rule 12b-2 of the Exch ge Act

Larg accel ated file Accel ated file No -accel ated file ☐ Smalle ep ting mp y

Em ging gr th mp y

If ging gr th mp y, indicate by check rk if th egistr t ha elected not to e the tended t ition p iod f mplying with y n vi d f

Indicate by check rk whether the gi t nt has file

If ritie a gi t ed pur t to Section 12(b) of the Act, indicate by check rk whether the fi ial state nt f the gi t nt included in the filin

Indicate by check rk whethe ny of th r r ti n tate nt that requi d a ry alysis of in tiv -ba d c pe atio cei d by any of th egistr t x tiv ffi s ing the le ant ry period pur t to §240 10D- (b).

Indicate by check rk whether the gi t nt is a hell mp y (a defi d in Rule 12b-2 of the Act) Y ☐ No

Th aggregat ket val of th oting and n-voting C n Stock held by n-affi

as $1,914,339,201

As of Febr ry 6, 2026, the 58,592,172 sh of Co m n Stock, $0.001 pa al pe ha out t ding

DOCUMENTS INCORPORATED BY REFERENCE

Portio of th gi t nt's definitiv proxy tat t fo its 2026 An al Meeting of St kholde to be filed pur t to Regulatio 14A within 120 days of th d of th gi t nt's fi al ye ded De be 31, 2025 in rp ated by fe into Part III of this An al Report Fo

10-K to th tent tated he in

Tabl of Cont

PART I

Page

Busi

Risk Fact s

Un lved Staf Co

Cybe ity

Properties

Legal Pr dings

Mi Safety Di lo

PART II

Market fo Regi t nt's Co

Equity Related St

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P cha of Equity Se riti

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PART III

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Principal Ac unt t Fe d Se ic

PART IV

Exhibits d Fi ial Stat

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Fo 10-K Su m ry

PART I

Note Regarding Certai Refe in this An l Report Fo 10-K

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Di ct s" fe to th board of di ct

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Cautio ry Note Regarding Fo d-looking Info atio

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Th fo d-looking tat ts in this An al Report Fo 10-K include ong othe things tat ts garding cializatio ef

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the initiation timing, progr d lts of r nt pl d d futu preclinical tudi d clinical trials d

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t tegi vision

the timing, likelihood d ount of yalty paym ts y cei fro Se ie Ph tical LLC with spect to rtai U S t ale of a id ib

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intentio d pectatio di lo d in th fo d-looking tat ts ke We ha included imp tant fact in this An al Report Fo 10-K, particul ly in th "S ry Risk Fact s" d "Risk Fact s" ctio that uld a a tual lts ts to diffe terially fro th fo d-looking tat ts that ke Ou fo d-looking tat ts do not

flect th pot tial impact of y futu acquisitio in-lic sing nge nt rg disp itio joint nt in t nt y ke

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Sum ry Risk Fact

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W ha hi t ically in r d ope ting lo We pect to in lo in th futu d y achie intain profita

ye ded De mb 31, 2024 a $673.7 millio d t lo fo th ye ded De mb 31, 2023 a $352.1 millio Th t in ge ted in th ye ded De mb 31, 2024 a primarily due to th ale of th Vo sidenib Royalty Right to Royalty Ph d ceipt of th Vo sidenib Mile t n Paym t di d belo in It 1 Busi As of De mb 31, 2025, had a lated deficit of $561.7 millio

W r ntly ly d pect to ntin to ly third partie fo th nuf

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mpletio of ch trials ch te ting

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d technology simila id tical to d ability to sful

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th pot tial to tr sf li With foundatio in he tology, mbin biological pertis with al ld insight to ad a gr ing pipeli of di a dici that fl t th prioritie of th peopl

Busi Ov ie

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Drug Administration FDA, unde th br d AQVESME™ fo th treat nt of ia in adults with n-tr sf

In De be 2024, n ed that bmitted rketing a th izatio application MAA, to th Europ a Medici Ag cy EMA, d gulat y applicatio to th United Arab Emirat health a th itie fo PYRUKYND® fo th treat nt of adult patient with n-tr sf

d n-tr sf

We will ha pr - ppl tal Ne Drug Application sNDA, eting with th FDA in th fi t quart of 2026 d intend to bmit U S rketing applicatio fo mitapivat in sickle cell di a e SCD, following that gage nt

In addition luating mitapi at fo th tr atm t of pediatri patient with PK defici cy We al de loping (i) tebapi at, l PK a ti ator fo th pot tial treat nt of lo r-risk myelodyspla tic syndr LR MDS, d SCD; (ii) AG-181, phenylal in hydroxyla e PAH, tabiliz fo th pot tial treat nt of phenylketo ia PKU; d (iii) AG-236, siRNA in-lic d fro Alnyl Ph utical In Alnyl targeting th tr br ri prot a 6, TMPRSS6 ge fo th pot tial treat nt of polycythemia PV

Alnyla Li Ag t

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di a - difying tr atment fo patient with PV

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Codification ASC, 805, Busi Comb n t o a unted fo th ag t a a t acquisiti n

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mp io diag ti te t is gr ted FDA pr ket appr al) th Vo sidenib Mile t n Paym t, d royalty of 15% of U S t ale of a id ib fro th fi t cial ale of a id ib th ugh lo of cl ivity th Vo sidenib Royalty Right Th Vo sidenib Mile t n Paym t d Vo sidenib Royalty Right fe r d to a ntingent paym ts

d gniz d a in wh alizable

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$200.0 millio within th mil to paym t fro gain ale of n ology busin lin ite in olidated tat ts of ope tio fo th ye nded De be 31, 2024 In May 2024, te d into purcha d ale ag t to ll th Vo sidenib Royalty Right to Royalty Ph In t nt 2019 ICAV, Royalty Ph fo $905.0 millio in a h, th Upfront Paym t Th ale a ntingent upon FDA appr al of a id ib d othe t y cl ing nditi n

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millio ($905.0 millio t of fe of $15.9 million) within th gain ale of ntingent paym ts lin it in olidated tat nt of ope tio fo th ye nded De mb 31, 2024 Royalty in lated to th Retained Ea -Out

Right if y, will be gniz d in th period wh alizable

Ou St tegy d Long-te Goal

We building tai ble alu - eating mp y, grounded in pertis in cellula tabolis d cla sical he tology, fo d de loping d deliv ing in ati dici fo patient

We belie pr PK a ti ato fra hi ha th pot tial to be t dard of a a ltiple he lyti ia pported by appr d indi ati n in PK defici cy d thala mia In addition signifi a t opportunity to unl k

furthe alu th ugh bust a ly d mid tage pipelin d belie ha cl a path to profita

ll positio d to tablish lead ship in he tology d ol into tai bl di a mp y

Ou Co Valu

Ou alu ltivat vi t that pr ot llaboration ntribution gage nt d high gard fo othe point of vi This foundatio help peopl push th boundari of ie d eat tr sf tiv dici which belie will provide long-te be fits fo all takeholde Ou n ctio with each othe d with th di a

m nity fuel th de lopm t of dici Ou alu include

Ai High: We t th ba high fo lv d keep rking to is it At 're guided by deep spect fo th ie d mmitment al ays to a t with th ut t integrity

Co Togeth r We gr pportiv lati n hips with patient d a egiv We build tr ting n ctio with llaborat Togeth ke bigge impact th uld al n

Embr D ffer Be a opportuniti d insight fro ywhe d yone honor all voi d ag hone t dialogue We le eq ally fro d failu bringing ope mind d fl ible appr ach

to ything do

Br ng Yo r Whol Self

Bl Ne Trails We sk th tough que tio that a lead to groundbreaking ientific

Cellula Metabolis

Cellula tabolis is invol d in th healthy fu tioning of ly y sy t in th body d fe to the t of lif taining ch ical tr sf tio within th cells of living gani Th io of nutri ts into gy vi zy catalyzed actio allo gani to gr d produce intain thei t ct d spond to thei vi nt

Additio lly tabolit a key gulat of di a pect of cellula biology, d pha a logi targeting of tabolis a th ef ha di a - difying ef

ch ical by que of zy Enzy atalyz quick d effi

Di a typi ally id ed if they affe

Many di a a ry lif th at ing feat In ny of th di rd th defect of singl ltiple ge lead to defici t pr si fu tio in n l ge products which llectively nife t in ga dysfunctio As th nditio by tu ngenital d frequently he ditary they of

Cla sical he tology fe to th tudy d tr atm t of blood di rd that not a including th mbotic d he rrhagic di rd ia th mb ytopenia di rd of ir tabolis d he globi di rd Many of th

di a debilitating, ha gativ impact patients quality of lif d a ciated with mplicatio d/ sh te d lif pect cy Despite th signifi a t ed fo l dici d imp d patient a e th is sh tage of

ch d trai d sp ialists in th field of cla sical he tology, d patient with th di rd of

peri health disp itie d inequity In addition in di a in which progr ha be de larg bset of th di a y in unde d Ou goal is to de lop in ativ dici fo patient with ari cla sical he tological di rd th ugh br ad clinical de lopm t progr to addr th n et ed of larg nge of patient

Ou De lopm t Progr

We belie that th capabilitie ha built in cla sical he tology-togeth with pertis in cellula tabolis - able to ad a th ap tic a didate d pand pipelin into additio l he tologi nditi n d,

time pot tially othe di a We ha pr tra k rd of de loping l th ap tic appr ach d ltipl proprietary fi t in cla al all le le

Th following iz appr d products d t ad a ed clinical product a didate each of which is de ribed in furthe detail belo

PK Activat Progr

PK is zy invol d in glycolysis th io of gl into lactic acid This zy ha l tis -sp ific isof (PKR PKL, PKM1 d PKM2). Py ate ki -R PKR, is th isof of PK that is pr t in d blood lls RBC Mutatio in PKR a defect in RBC glycolysis d lead to he tological di a know a PK defici cy Glycolysis is th only path ay a ailabl fo RBC to intain th productio of ad in triphosphate ATP, which is

fo of ch ical gy within cells Ac rdingly, belie that activatio of tant fo of PKR a t glycolytic path ay activity d in a RBC health in patient with PK defici cy d activatio of wild type (n n- tated) PKR a in a ATP which a th et th in a ed gy de nds lting fro tabolic t in RBCs of pati ts with he lytic ia cha thala mia d SCD

PK defici cy is ge tic di rd d di a unde tanding is till olving We timate that th pr al of PK defici cy is betw approxi tely 3,000 d 8,000 individuals in th United Stat d EU5, d belie that th di a is likely under-diagnosed PK defici cy lead to sh te d life sp fo RBCs d is th t m fo of n-sphe ytic he lytic ia in hum

Th is r ntly know unique ethni geographi pr tatio of th di a Th di a nife t by mild to

f of ia a d by th si pr at de t ctio of RBCs Th ch ni he lysi a lead to long-te mplicatio d rbiditie gardle of th degr of th ia of

a ciated with ch ni ia d ndary mpli ati n Th preci ch is fo th he lysi is not ll unde tood but is thought to lt fro mb in tability ndary to th tabolic defect a d by th lo le l of PKR zy

Th he lysi is "ext a lar" in that th RBCs de t yed in all capillari ga d do not spont ly br ak ope in th ci ulatio PK defici cy is a to l si di a wh eby all patient inherit tw tatio n from each pa nt Child with th di a produc PKR zy that ha only fractio of th l le l of activity (g ally

<50%). Prio to th appr al of PYRUKYND® th only ge nt t tegi fo PK defici cy included blood tr sf

id tifie

of th long-te di a burde of this ch ni he lytic ia

Thala mia is he ditary bl d di rd in which tatio in th β-globi chai of he globi lead to globi chai precipitate d aggregat that di t b th RBC mb d induc oxidativ t s leading to de a ed ival of RBC pr inef

al know a th Gulf Co n il Countri GCC; d great th n millio individuals rldwid In additio to ia patient with thal mi a peri larged sple bone defo itie ir rl ad, fatig d infectio Prio to th ppr al of AQVESME in th United Stat d PYRUKYND® in Saudi Arabia th only treat nt t tegi for thala mia included blood tr sf

SCD is inherited blood di rd a d by tati n in he globi that able th he globi to fo long polym ic chai unde tain nditi n ch a lo oxyge tion deoxyge tio Poly rizatio of this ir gul he globi lt in RBCs taking sickle shape a sing th to aggregat d obstr t all blood ls tricting blood fl to ga

lting in pain ll death d ga da ge We ti te that th pr al of SCD is betw 120,000 d 135,000 individuals in th United Stat nd EU5, approxi tely 150,000 individuals in th GCC, d great th th milli individuals rldwid RBC deoxyge tio is dulated by l fact including th le ls of 2,3-diphosphoglyc ate 2,3-DPG, which is found to be el ated in sickle ll patient RBCs Cu r nt treat nt t tegi fo ging d pr ting a te RBC sickling, d include hydroxyur a L-glut in d blood tr sf

dici ch a Adak o® Casg y® d Lfygenia® Activatio of wild type PKR in patient with SCD is belie d to duc he globi polym izatio d th sickling pr by at lea t tw ch is Reducing th le l of 2,3-DPG in

RBCs uld in a th oxyge tio tat of he globi to duc sickling, while in a ing th le ls of ATP y imp RBC hydratio tat which y al inhibit th sickling pr

MD is hete ge group of he tologi al lig ie ch act ized by dysfu tio l he topoi is (o fo atio of blood cells), progr si cytopeni (o lo r-tha - l be of blood cells) d in a ed risk of progr si to a te myeloid leuk ia AML Th t type of MD is LR MDS, but ny isting dici d dici unde de lopm t fo high risk MDS Among pati ts with LR MDS, which a unt fo approxi tely 70% of all

MD a d le likely to progr to AML, th prim y is sympto tic ia We timate that th pr al of LR MD in th United Stat d EU is betw 75,000 d 80,000 individuals We belie that activatio of wild type PK in LR MD pati ts y imp defici t PK activity in MD ythr yt Cu r nt treat nt optio fo LR MD of

Othe Progr

PKU, is ge ti di a a d by defici cy of th PAH zy Lack of PAH activity lead to th a lati of phenylal in d dow tr a ognitiv deficits Patient with PKU th ef of

tricted diet in de to minimiz phenylal in intake which a furthe duc patient quality of lif We timat that th pr al of PKU in th United Stat d EU is betw 35,000 d 40,000 individuals

PV is blood di rd with di a - difying tr atm ts that affe

lt in th mb is ardio a ul ts larged sple d death Phlebot y, which is th pr ed of withdra ing blood, is th r nt t dard of a fo patient with PV

PYRUKYND®/AQVESME (mitapivat): Fi t-i Cl PK Activat

We de loping mitapi at fo th treat nt of PK defici cy d othe he lytic ia ch a thala mi d SCD Mitapi at is ally a ailabl all le le d pot t activat of th wild type d tated PK zy

Th FDA appr d mitapi at, unde th br d PYRUKYND® fo th treat nt of he lytic ia in adults with PK defici cy in th United Stat nd by th Eu pe Commissi fo th treat nt of PK defici cy in adult patient in th EU Additio lly ived rketing a th izatio in Gr at Britain fo PYRUKYND® fo th treat nt of PK defici cy in adult patient unde th Eu pe Commissi Decisi Reli Pr ed

In De be 2025, th FDA appr d mitapi at unde th br d AQVESME™ fo th treat nt of ia in adults with n-tr sf

rketed a PYRUKYND® in th United Stat fo th PK defici cy indication which doe not qui REMS Th AQVESME™ REMS qui liv te t prio to th fi t AQVESME dose y fo ek th eaf

In August 2025, n ed that th Saudi Food d Drug Auth ity appr d PYRUKYND® fo th treat nt of adults with n-tr sf

In De be 2024, n ed that bmitted MAA to th EMA d gulat y applicatio to th United Arab Emirat health a th itie fo PYRUKYND® fo th treat nt of adult patient with n-tr sf

We will ha pr -sNDA eting with th FDA in th fi t qu te of 2026 d intend to bmit U S rketing applicatio fo mitapi at in SCD foll ing that gage nt

In addition aluating mitapi at fo th treat nt of pediatri patient with PK defici cy Additio lly mitapi at ha cei d pha drug designati fro th FDA fo th treat nt of thala mia d SCD, d pha dici l product

designatio fro th EMA fo th treat nt of SCD Mitapi at a gr ted pha drug designatio fo th treat nt of PK defici cy by th FDA d EMA

We ha full hip right to PYRUKYND® d AQVESME™ d pect to fund th futu de lopm t d m ializatio t lated to PYRUKYND® d AQVESME™ We built m ial infra t ct to pport th m ializatio of PYRUKYND® in adult PK defici cy in th United Stat d ha panded this infra tr tu to

pport th m ial la n h of AQVESME™ in thala mi in th United Stat In July 2024, te d into di tributio

ag t, th NewBridge Ag t, with NewBridge Ph tical FZ-LLC NewBridge pur t to which gr ted NewBridge th right to m ializ PYRUKYND® in th GCC gi n In Ju 2025, te d into di tributio

ag t, th Av z ite Ag t, with Av z ite Bi ci B V Av z ite pur t to which gr ted Av z ite th right to m ializ PYRUKYND® in th Eu pe Ec n ic Area Switz land, d th United Kingdom Unde th NewBridge Ag t d th Av z ite Ag t, ly NewBridge d Av z ite spectively, to a si t with gulat y filings prep applicatio fo pricing d imb nt appr al, gotiate with payor nduct di al af

In n ctio with gulat y appr als in th EU Great Britain d Saudi Arabia provide a to PYRUKYND® to eligible patient th ugh th Av z ite Ag t d th NewBridge Ag t, a applicable d eith fre of ch ge fo ch ge basi fo eligible patient in th jurisdictio d othe jurisdictio th ugh global ged a progr

Re a ciated with th NewBridge Ag t, th Av z nite Ag t d th fo ch ge portio of global ged a progr included in th t of rld prod t lin within Re lts of Op r t o We ntin to

al ate othe opti n fo th m ializatio of PYRUKYND® outside of th United Stat including th ugh pl ing pot tial part hip opportunitie

We al ating mitapi at in clinical trials including th following

A te io tudy al ating th long-te afety tole bility d effi

RISE UP pha 2/ tudy al ating th effi

tio to iv th m nded (100 mg twic daily) mitapivat dos le l th placeb Th 52- ek doubl -blind treat nt p iod a mpleted by 87.0% (n=120/138) of patient in th mitapi at d 81.2% (n=56/69) of patient in th pla bo All but tw of th pati ts (174/176) opted to te th ongoing 216- ek ope -label te io period of th tudy. Th prim y dpoint of th pha portio of th trial (i) he globi sp n e defi d a ≥1 g/dL in a in a ag he globi fro ek 24 th ugh ek 52 mp ed to ba line d (ii) alized te of SCPC Th ndary dpoint included ch ge fr ba li in he globi tration ch ge fro ba li in indi ct bilirubin ch ge fro ba lin in Pati t Reported Outc Mea t Info atio Sy t Fatig 13a PROMIS Fatig Sh t Fo alized freq y of hospitalizatio fo SCPC d ch ge fro ba lin in pe t ticul yt le ls In No mb 2025, n ed that th pha portio of th trial had a hi ed th primary dpoint of he globi sp n in th mitapivat m with 40.6% of patient in th mitapi at having achie d he globi sp n e mp ed to 2.9% of patient in th placeb m tatistically signifi ant imp nt (2 ided p<0.0001) In patient wh a hi ed he globi sp n in th mitapi at m ch ge fro ba li in a ag he globi tratio fro Week 24 th ugh Week 52 a 1.6 g/dL Th alized te of SCPC defi d a a te pain eding di al ntact a te ch t syndr e priapi hepatic spleni

que t tion a 2.62 in th mitapi at d 3.05 in th placeb (2 ided p=0.1213) with ch ductio of SCPC nota hi ing tatistical signifi a fo that prim y dpoint Treat nt with mitapi at al sh ed tatistically signifi a t imp nt in tw ndary dpoint (a) th a ag ch ge fro ba lin in he globi tratio fro Week 24 th ugh Week 52 a 7.69 g/L in th mitapivat d 0.26 g/L in th placeb m tatistically signifi a t impr nt (2 ided p<0.0001) d (b) th a ag ch ge fro ba lin in indi ct bilirubi fro Week 24 th ugh Week 52 a -16 03 μmol/L in th mitapivat d 0.88 μmol/L in th placeb m tatistically signifi a t imp nt (2 ided p<0.0001) Th a ag ch ge fro ba lin in PROMIS Fatig fr Week 24 th ugh We k 52 a -2 72 in th mitapi at d -2 25 in th placeb (2 ided p=0.7112) indi ating imp nt in fatigue but th PROMIS Fatigue ndary dpoint a not t No lusi n uld be dra

garding th tatisti al signifi a of th foll ing additi nal key ndary dpoint (a) th alized freque y of hospitalizatio fo SCPC with 1.56 in th mitapivat d 1.81 in th placeb (2 ided inal p=0.2498) d

(b) th a ge ch ge fro ba lin in pe t ti locyte le ls fro Week 24 th ugh Week 52, with -0 0236 (fractio of 1) in th mitapi at d -0 0013 (fractio of 1) in th placeb (2 ided inal p=0.0001) We al

n ed that in th bset of patient in th mitapivat achieving th primary dpoint of he globi sp n e th following a obs d (i) th alized te of SCPC a 2.20 fo he globi sponde d 2.98 fo n-he globi sponde (rate tio [RR]=0.74, 95% nfid

ba lin fo PROMIS Fatigue Th afety profil

spectively, id ed treat nt r lated; (iii) li ab litie obs d a th mitapi at d pla eb

not gge tiv of drug-induced hepatocellula injury unlik what a obs d in th mitapi at ENERGIZE d ENERGIZE-T pha trials (iv) TEAEs led to tr atm t di ontin atio in 4.3% (n=6) of patient mitapivat d 2.9% (n=2) pla bo; d (v) th deaths (2 2%) r d in patient mitapi at, d tw (2 9%) placebo n of which de ed lated to tudy treat nt by th trial in tigat

Ext si tudi aluating th long-te afety tole bility d effi

We n ed toplin data fo ACTIVATE-kidsT in August 2024 A total of 49 patient lled in ACTIVATE-kidsT, with 32 ndomized to mitapi at twic -daily d 17 ndomized to tched placeb 30 patient (93 8%) in th mitapi at d 16 (94.1%) in th pla bo mpleted th 32- ek doubl -blind period of th tudy. Th primary dpoint of ACTIVATE-kidsT is tr sf

d l he globi sp n ndary dpoint in this tudy d only obs d in patient in th mitapi at In th 32- ek doubl -blind treat nt period, mitapivat a ge lly afe d ll-tole ted, with afety lts istent with th afety profile

tr sf

We n ed toplin data fo ACTIVATE-kids in Febr ry 2025 A total of 30 patient lled in ACTIVATE kids with 19 ndomized to mitapivat twic -daily d 11 ndomized to tched placeb All patient in both treat nt

mpleted th 20- ek doubl -blind period of th tudy. Th primary dpoint of ACTIVATE-kids is pe tage of patient with he globi sp n e defi d a ≥1.5 g/dL in a in he globi tratio fro ba li that is

tai d at tw heduled a ts at ek 12, 16, d 20 during th doubl -blind period Using Bayesi thodology, th pr pecified tatistical iteri fo th primary dpoint in ACTIVATE-kids a t ing nge of lativ bor wing fro th adult ACTIVATE tudy, fo all possibl bor wing ight (ranging fro 0 to 1) In

addition th pr -specified pportiv alysis ba d traditio l thodology mp ing th he globi sp n te fo mitapi at pla bo pr ided furthe id that th primary dpoint a t Th 31.6% of patient in th mitapi at a hi ing he globi sp n mp ed to 0% of patient in th placeb m th 95%

nfid

th di ontin ati n of tudy treat nt due to AE fo y a n Th afety lts fro th trial istent with th afety profile

gul ly tr sf

A te io tudy al ating th long-te afety tole bility d effi

A te io tudy al ating th long-te effi

dependent alpha beta thala mia

During th doubl -blind periods of ENERGIZE d ENERGIZE-T, tw patient mitapi at peri ced ts of hepatocellula injury In addition during th ope -label te io periods of both trials total of th patient peri d

ts of hepato llul injury afte

ENERGIZE d ENERGIZE-T trials included in gulat y applicatio hepatocellula injury a imp tant pot tial

risk of mitapi at in pati ts with thala mia d proposed nthly nitoring of liv te t fo th fi t si nths of treat nt with mitapi at We updated mitapi at clinical trial prot ol a all indicatio to in rp at nthly

nitoring of liv te t fo th fi t si nths of treat nt

Tebapivat No l PK Activat

We de loping tebapi at, l PK activat fo th pot tial treat nt of LR MD d SCD Tebapi at ha be gr ted pha drug designati fo th treat nt of MD by th FDA

We ha mpleted pha 1 clinical trial al ating tebapi at in healthy volunt d patient with SCD, d ha mpleted llment in th pha 2 clinical trial of tebapi at in adult patient with SCD We pect to n toplin data

fo this trial in th nd half of 2026

We al initiated pha 2a clinical trial of tebapi at in adults with LR MD in th third quart of 2022, d th trial ha mpleted llment with 22 patient including 12 patient cla sified a n-tr sf

tr sf

tiv ek during th 16- ek treat nt period, d he globi sp n e defi d a ≥ 1.5 g/dL in a fro ba lin in th a ge he globi tratio a ed fr ek th ugh ek 16

In No mb 2023, n ed that achie d clinical proof f-c n ept in th pha 2a portio of th trial We obs d that fo of th 10 pati ts with lo tr sf

istent with data ported in th healthy volunt tudy of tebapi at 19 patient elected to ll in th te io period of th trial fo up to 156 ek We al ated th pha 2a trial lts d a d th impact of th lts th pha 2b portio of th prot ol d ba d th data ge ted in th pha 2a portio of th trial, in a ed th dosag le ls

al ated in th pha 2b porti of th trial, which initiated in th third quart of 2024 We mpleted llm t in th pha 2b portio of th trial in Sept be 2025 d pect to n toplin data fo this trial in th fi t half of 2026

Othe Progr

In additio to th af ti n d de lopm t progr de loping AG-181, PAH tabiliz fo th pot tial treat nt of PKU, fo which filed in tigatio l drug application IND, in De mb 2023 We initiated pha

1 clinical trial of AG-181 in healthy volunt in th fi t quart of 2024, initiated th ltiple a ding dos portio of th trial in th nd quart of 2025, d mpleted th trial in De be 2025 We pect to initiate pha 1b proof of

ch is trial of AG-181 in patient with PKU in th fi t half of 2026 d nfir

Al in July 2023, te d into lic ag t with Alnyl fo th de lopm t d m ializatio of prod ts ntaining mpri d of siRNA preclinical de lopm t a didate di d by Alnyl d targeting th TMPRSS6 ge d de loping product a didate AG-236, fo th pot tial treat nt of patient with PV We filed IND with th FDA fo AG-236 fo th treat nt of PV which cl a ed in Ju 2025, d initiated pha 1 clinical trial

al ating AG-236 in healthy volunt in July 2025 We pect to n toplin data fo this trial in th fi t half of 2026

Intellect l Prop ty

Ou m ial depends in part ability to obtai d intain proprietary intellect l property prot tio fo product a didate d technologi including l bi ke d diag tic di ri d othe know-how

to ope te without infringing th proprietary right of othe d to pr t othe fro infringing propriet y intellect l property right Ou policy is to ek to protect proprietary d intellect l property positio by, ong othe

thods filing United Stat d fo ig patent applicatio lated to proprietary technology, in ntio d imp nt that important to th de lopm t d impl tatio of busin We al ly nfid

We file y llab at with third partie to file patent applicatio di cted to key products d product andidate including mitapi at, tebapi at, AG-181, d AG-236, in additi to lated mpounds d pot tial back p mpounds in

th apie with product andidate

Th patent portfolio fo PK activat progr ntai is ed patent d pending patent applicatio di cted to mp itio of tte fo mitapi at, a ll a to lated mpounds ari lid tat fo of mitapi at, mp iti n of tte fo additio l PKR a ti ato ch a tebapi at, a ll a ari lid tat fo thods of d thods of nuf

447 is ed fo ig patent d ha pending patent applicatio in th United Stat d in ari fo ig jurisdicti n Th patent that ha is ed y is fo mitapi at will ha tatut y pi tio date of at lea t 2030 to 2042, d th patent that ha is ed y is fo tebapi at will ha tatut y pi tio date of at lea t 2038 to 2045 Patent te adju t nt patent te te io uld lt in late pi tio date In a th te of United Stat patent a be sh te d by th filing of te inal di laime which ope te to duc th te of patent to that of arlie piring patent We ha is ed patent d pending patent applicatio pertaining to products/p duct a didate in PK activat progr in be of fo ig jurisdictio including Argentina Au t lia Au tria Belgium Brazil, Ca da China th Czech Republic De k, Finl d, Fr ce Ge y, Gr ce Hungary Ireland, Italy, Japan Lebanon Lith nia Mexi

th Neth lands No ay Poland, Portugal, Ro nia Russia Saudi Arabia Sl akia Sl nia Spain Swed Switz land, Taiw Turkey d th United Kingdom Pr utio is lengthy pr during which th ope of th clai initially bmitted fo inatio a be signifi a tly r d by th time they is e if they is at all We pect this uld be th

a with spect to of pending patent applicatio fe r d to ab We al r ntly invol d in ad ial pr eedings befo th Eu pe Patent Offi

spectively Th decisi n a be appealed d pect that appeal will be filed fo both of th opposed Eu pe patent

Th patent portfolio fo PAH tabiliz progr ntai is ed patent d pending patent applicatio di cted to mp itio of tte d thods of fo AG-18 d othe l PAH tabiliz As of Febr ry 1, 2026, d n

is ed United Stat patent d tw is ed fo ig patent d ha pending patent applicatio in th United Stat d in ari fo ig jurisdicti n Th patent that ha is ed y is fo PAH tabiliz progr will ha tatut y pi tio date of at lea t 2043 to 2044 Patent te adju t nt patent te te io uld lt in late pi tio date

In a th te of United Stat patent a be sh te d by th filing of te inal di laime which ope te to duc th te of patent to that of a lie piring patent We ha is ed patent d pending patent applicatio pertaining to products/p duct a didate in PAH tabiliz progr in be of fo ig jurisdictio including Argentina Au t lia Br zil, Ca da China Eu pe Japan Lebanon Mexi Eu sia Saudi Arabia d Taiw Pr utio is lengthy pr during which th ope of th clai initially bmitted fo inatio a be signifi a tly r ed by

th time they is e if they is at all We pect this uld be th a with spect to of pending patent applicatio fe r d to ab

We ha cl ively li ed rld-wide patent right fro Alnyl di cted to mp itio of tte d thods of for AG-236 Th cl ively li ed patent that ha is ed y is will ha tatut y pi tio date of at lea t 2032 to 2042 Patent te adju t nt patent te te io uld lt in late pi tio date

Th te of individual patent depends upon th legal te fo patent in th untri in which they obtai d In t untri including th United Stat th patent te is 20 ye fro th a lie t filing date of n-provisi nal patent

application although te te io y be a ailabl In th United Stat patent's te y be lengthe d by patent te adju t nt which mp ate patent fo admini t tiv delays by th United Stat Patent d Trad k Offi

to obtai ppl tary prot tio tific

ducing y ad antag of y ch patent

In th futu if d wh product a didate iv appr al by th FDA fo ig gulat y a th itie pect to apply fo patent te te io is ed patent ring th products depending upon th length of th clinical trials for

each product a didate d othe fact Th a be a that y of pending patent applicatio will be is ed that will be fit fro y patent te te io fa able adju t nt to th te of y of patent

As with othe bi technology d pha a tical mp ie ability to intain d lidify proprietary d intellect l property positio fo product, product a didate d technologi will depend in obtaining ef

y ha to participat in legal pr eedings te into li ing nge nt which uld lt in bstantial t to

if th tual out is fa able to In additi to patent protection al ly upon unpatented nfid

with llaborat third-party ic provide ientific

ultant ientific

protect In particul ticipate that at lea t of technical info atio d know-h will, ti be know within th industry th ugh independent de lopm t, th publicatio of jo l ticle d th nt of pe nn l skilled in th t fro a ad ic to industry ientific

Competitio

Th pha a tical nd biot hnology industrie ch act ized by pidly ad a ing technologi inte mpetiti d t ng phasi proprietary products Whil belie that technology, de lopm t peri d ientific knowledge provide with mpetitiv ad antag fa pot tial mpetitio fro ny diffe nt including jo pha a ti al, sp ialty pha a tical d biot hnology mp ie acad ic in titutio d gove ntal

ag ci d public d privat ch in tituti n PYRUKYND® AQVESME™ d y product a didate that

sful

We mpet in pha a tical biotechnology d othe lated rket that addr di a particul ly he lytic ia PKU d PV Th othe mp ie rking to de lop di a th apie including divisi n of large

pha a tical mp ie d biotechnology mp ie of ari siz

Ou mpetito include but not limited to BioM in Ph tical In BioM in Bristol-My Squibb Comp y, BMS; Cellarity In Cellarity CRISPR Th ap tic AG CRISPR DISC Medici In DISC Em Life Scie In Em Fulc Th ap tic In Fulc m Ge tix Biothe peutic In Ge tix (f r ly

bl bird bio In ); Ge Corp ation Ge n Halia Th ap tic Inc Or Halia Incyte Corp ation Incyte Ioni Ph tical In Ioni in llaboratio with On Ph tical Co Ltd./Deciphe Ph tical In Ono/ Deciphe Italfa a S p.A Italfa a Maz Th ap ti In Maze Me k & Co In Me k; NGGT In NGGT No artis Inte atio l AG, No artis No Nordisk A/S, Novo Ot ka Ph tical Co Ltd., Ot ka Pfiz

llaboratio with Takeda Ph tical Comp y Limited Takeda PTC Th ap tic In PTC; Sanofi

Th t m thods fo treating patient with di a include diet y triction diet y ppl tati

pla t, treat nt of sympto d mplicatio ge th apy, blood tr sf

ple tly appr d tr atment fo thala mia SCD, LR MDS, PKU d PV include Rebl zyl® fro Me k/BM (fo ly Accel on/BMS) Revlimid® fro BMS; Zynteglo® d Lyfg ia® fro Ge tix Adak o® fro No artis Casg y® fro Vert /CRISPR; Ku an® d Paly ziq® fro BioM in Endari® fro Em Be i® fr Ph Es ntia Jakafi® fro Incyte Sephi fro PTC, d Rytelo® fro Ge While product d product a didate y mpet with isting dici d othe th apie to th tent they ultimately ed in mbinatio with

a adju t to th th apie product prod t andidate y not be mpetitiv with th In additio to r ntly

rketed th apie th al l products that eith all le le biologi ERTs ge th apie in ari tag of de lopm t to tr at he lytic ia PKU d PV Fo ple No is de loping eta opi at (a PKR a tivat ) f th treat nt of he lytic ia including SCD; Pfiz

mp ie including Ot ka de loping th apie to tr at PKU; d be of mp ie including Sile e Protagoni t with Takeda Italfa a S p.A DISC Me k, d Ioni in llaboratio with Ono/Deciphe de loping th apie to treat PV Th products y provide effi

Many of mpetit y ha signifi a tly great fi ial d pertis in ch d de lopm t, nuf

being trated ong alle be of mpetito Th mpetito al mpet with

in uiting d taining qualifie

y al

to be signifi a t

mpetito particul ly th

ugh

llab ativ

progr Smalle arly- tag mp nge nt with larg d tablished

Th key mpetitiv fact affe

Ou m ial opportunity uld be duced eliminated if mpetito de lop d m ializ dici that afer ef

y de lop Ou mpetit al y obtai FDA othe gulat y appr al fo thei dici pidly th

y obtai appr al fo which uld lt in mpetito tablishing t ng rket positio befo able to te th rket In addition ability to mpet y be affe

indicatio that pur ing, d additio l dici pected to be a ailabl ge ri basi th ming ye We pect that PYRUKYND® AQVESME™ d y of product a didate that y cei rketing appr al in th futu will be priced at signifi a t pr iu mpetiti ge ri dici

Manuf turing d Supply Chai

Mitapi at, tebapi at, d AG-181 gani mpounds of lo le la ight ge lly called all le le d dosed ally Ou siRNA progr AG-236, targeting th TMPRSS6 ge is olig n leotid intended fo a t il pa nt al administratio Each a be nuf

pr We pect to ntin to de lop product a didate that a be produced t ffectively at nt ct nuf

We do not ope te d r ntly ha pl to tablish, y in-h nuf

mplia e quality d liability of third-party nuf

Fo PYRUKYND® d AQVESME™ ha long-te m ial nuf

Du to th volatility of th pply tw ks globally ha gained gulat y appr al fo dundant pply of terial d activ pha a ti al ingredient API, fo PYRUKYND® d AQVESME™ d ha ongoing progr to nito pply, including tablishing afety t ks While intain br ad afety t k of drug bsta d drug product, do

not r ntly ha nge nt in pla fo dundant pply of drug bsta d drug product As ha done fo PYRUKYND® d AQVESME™ fo pr - cial progr intend to id tify d qualify additi nal

nuf

Go nt Regulati d Prod t Approval

Go nt a th itie in th United Stat at th fede l, tat d local le l, d in othe untri d jurisdictio including th EU te ively gulate ong othe things th ch de lopm t, te ting, nuf

nt l, appr al, packaging, t age rdkeeping, labeling, ad rtising, pr otion di tribution rketing, post-appr al nitoring d porting, d imp t d port of biopha a tical products Th pr fo obtaining rketing appr als in th United Stat d in fo ig untri d jurisdictio along with mplia with applicable tatut d

gulatio d othe gulat y a th itie qui th penditu of bstantial time d fi ial

Approval d Regulati of Drug in th United Stat

In th United Stat drug products gulated unde th Fede l Food, Drug d Co etic Act, FDCA d applicable imple nting gulatio d guida A mp y, in titution ganizatio sp n ible fo initiating d ging clinical de lopm t progr fo ch products d fo thei gulat y appr al, is typically fe r d to a sp n

A sp n eking appr al to rket d di tribut drug in th United Stat ge lly t atisfact ily mplete ach of th following tep befo th product a didate will be appr d by th FDA

p clinical te ting including laborat y te t imal tudi d fo ulatio tudi which t be perf ed in a rd with th FDA good laborat y practice GLP, gulatio d t dard

d ig of clinical prot ol d bmissi to th FDA of IND fo hum clinical te ting, which t be ef

ppr al by independent in titutio l vi board IRB, pr ting each clinical site befo each clinical trial y be initiated

p fo of adeq ate d ll- nt lled hum clinical trials to tablish th afety d effi

p pa tio d bmissi to th FDA of NDA, sNDA fo ch ge to pr io ly appr d drug product, which bmissi n include not only th lts of th clinical trials but al detailed info atio th ch istry

nuf

atisfact y mpleti of FDA inspectio of th nuf

pr th product id tity, t ngth, quality d purity

atisfact y mpletio of y FDA a dits of th n-clinical d clinical trial site to a mplia with GCP d th integrity of clinical data in pport of th NDA;

pay nt of fe pur t to PDUFA;

ppr al of NDA fo th drug product a th izing rketing of th drug product fo particul indicatio in th United Stat d

plia with y appr al post-appr al qui nt including th pot tial qui nt to imple nt REMS d th pot tial qui nt to nduct y post-appr al tudi qui d by th FDA

Befo sp n begi te ting product a didate with pot tial th ap tic alu in hum th product a didate te th preclinical te ting tag Pr linical te t include laborat y al atio of product ch istry fo ulatio d tability d othe tudi to al ate ong othe things th toxicity of th product a didate Th nduct of th preclinical te t d fo ulatio of th mpounds fo te ting t mply with fede l gulatio d qui nt including GLP gulatio

d t dard d th United Stat Depart nt of Agri ltu 's Animal Welfa Act, if applicable Th lts of th preclinical te t togeth with nuf

typically fe r d to a IND- abling tudi So long-te preclinical te ting, ch a imal te t of productiv ad ts d a inogenicity d long-te toxicity tudi y ntin afte

With pa age of th FDA Mode izatio Act 2.0 in De mb 2022, Congr eliminated provisi n in both th FDCA d th Public Health Se ic Act, PHSA that qui d imal te ting in pport of NDA While imal te ting y till be nducted, th FDA a a th ized to ly alte ativ n-clinical te t including cell-ba d a ays mic physiologi al sy t bioprinted mput dels In April 2025, th FDA lea ed ad p to pla imal te ting in pr linical afety tudi with ientific

deling, d ad a ed n vi r a ays

An IND is mptio fro th FDCA that allo ppr d product a didate to be shipped in inte tate fo in in tigatio l clinical trial d que t fo FDA a th izatio to administe ch in tigatio l product to hum

Such a th izatio t be d prio to inte tate ship nt d administratio of y product a didate that is not th bject of appr d NDA In additio to vi ing IND to a th afety d right of patient th FDA al fo

th quality of th in tigatio d whethe it will be adeq ate to pe it al atio of th drug' afety d effi

each IND befo clinical trials y begi This aiting period is designed to allo th FDA to vi th IND to dete in whethe hum ch bject will be posed to n a bl health risk At y time during this 30-day period,

th eaf

a begi

Following m t of clinical trial unde IND, th FDA y al pla clinical partial clinical hold that trial A clinical hold is de is ed by th FDA to th sp n to delay proposed clinical trial to sp d ongoing in tigatio A partial clinical hold is delay sp si of only part of th clinical rk que ted unde th IND Fo

ple specifi prot ol part of prot ol is not allo d to pr eed while othe prot ol y do No th 30 days afte

A sp n y ch e but is not qui d, to nduct fo ig clinical trial unde IND Wh fo ig clinical trial is nducted unde IND, all FDA IND qui nt t be t unl aived Wh fo ig clinical trial is not nducted unde IND, th sp n t that th tudy mplie with tain gulat y qui nt including GCP

qui nt of th FDA to th tudy a pport fo IND applicatio fo rketing appr al Th GCP qui nt mpa both ethi al d data integrity t dard fo clinical tudi Th FDA gulatio intended to help th

protectio of hum bj ts lled in n-IND fo ig clinical tudi a ll a th quality d integrity of th lting data They furthe help that n-IND fo ig tudi nducted in n mp able to that quired for IND tudi

In additio to th fo going IND qui nt IRB pr ting each in titutio participating in th clinical trial t vi d appr th pl fo y clinical trial befo it at that in titution d th IRB t nduct ntinuing vi d appr th tudy at lea t ally Th IRB t vi d appr ong othe things th tudy prot ol d info ed t info atio to be provided to tudy bj ts An IRB t ope te in mplia with FDA gulatio An IRB a sp d te inat appr al of clinical trial at it in titution in titutio it pr ts if th clinical trial is not being nducted in a da with th IRB qui nt if th product a didate ha be a ciated with n xpected

ri ha to patient

Additio lly trials by independent gr p of qualifie

te inatio of de lopm t during y pha of clinical trials a if it is dete ined that th particip ts pati ts being posed to na eptabl health risk Othe a n fo sp si te inatio y be de ba d olving busin objectiv nd/ mpetitiv climate

Unde th PHSA sp n of tain clinical trials of tain FDA- gulated products including pr ipti drugs d biologi qui d to gi t d di lo rtai clinical trial info atio public gi try (clinicaltrials.gov) intained by th Nati nal In titute of Health Info atio lated to th product, patient population pha of in tigation tudy site d in tigat d othe a pect of th clinical trial is de public a part of th gi t tio of th clinical trial

Th PHSA gr ts the Se et y of Health d Hu Se ic HHS th a th ity to is notic of n plia to sp n ible party to fail to bmit clinical trial info atio a qui d Th sp n ible party, how is allo d 30 days

to r ct th n plia d bmit th qui d info atio As of De be 30, 2025, th FDA ha is ed eight notic of n- mplia e signaling th gove nt's willingne to fo th qui nt agai t n- mpliant clinical trial sp n While th notic of n- mplia did not lt in civil tary pe ltie th failu to bmit clinical trial info atio to clinicaltrials gov is prohibited act unde th FDCA with violatio bject to pot tial civil tary pe ltie of up to $10,000 fo ach day th violatio ntin Violatio y al lt in inju tio d/ iminal pr utio disq alific

Expanded a tim alled "compa si nate e is th of in tigatio l drug products outside of clinical trials to treat pati ts with ri immediately lif th at ing di a nditio wh th mp able atisfact y alte ativ tr atment optio Th le d gulatio lated to panded a intended to impr a

to in tigatio l drugs fo patient wh y be fit fro in tigatio l th apie FDA gulatio allo a to in tigatio l drugs unde IND by th mp y th tr ating physicia fo treat nt purpos a -by- a basi for individual patient (singl -patient IND applicatio fo tr atment in ge y ttings d n- ge y ttings); inte ediate iz pati t populatio d larg populatio fo of th drug unde treat nt prot ol Tr atment IND Applicatio

While th is obligatio to ke in tigatio l products a ailabl fo panded a sp n qui d to ke policie fo al ating d sponding to que t fo panded a publicly a ailabl upon th a lie of initiatio of Pha 2 Pha clinical trial, 15 days afte

In addition th Right to Try Act, ong othe things provide fede l fra rk fo tain patient to a tain in tigatio l drug product that ha mpleted Pha 1 clinical trial d undergoing in tigatio for FDA appr al Unde rtai ci t eligible patient a ek treat nt without lling in clinical trials d without obtaining FDA pe issi unde th FDA panded a progr Th is obligatio fo drug nuf

Clinical trials invol th administratio of th in tigatio l product a didate to hum bject unde th pervisi of qualifie

ch bject provide thei info ed t in iting befo thei participatio in y clinical trial Clinical trials nducted unde itte clinical trial prot ol detailing, ong othe things th objectiv of th tudy, incl io d cl io it ia th pa te to be ed in nitoring afety d th ef

Hu clinical trial typi ally nducted in th quential pha but th pha y rlap be mbined

Ph clinical trials initially nducted in limited populatio to te t th product a didate fo afety including AE dos tole e ab rption tabolism di tribution etio d pha a dynamic in healthy hum in pati ts During Pha 1 clinical trial info atio about th in tigatio l drug product pha a ki tic d pha a logi al ef

Ph 2 clinical trials ge lly nducted to id tify possibl AE d afety risk al ate th effi

clinical trials ll nt lled cl ely nito d d nducted in limited patient populatio

Ph 3 clinical trials pr eed if th Pha 2 clinical trials de trat that dos nge of th product a didate is pot tially ef

mp y' designatio of th pha of trial is not arily indicativ that th trial will be ffici t to atisfy th FDA qui nt of that pha

In De mb 2022, with th pa age of th Food d Drug Omnibus Refo Act, FDORA, Congr qui d sp n to de lop d bmit di ity actio pl fo ach Pha clinical trial y othe "pivotal tudy" of drug biologi al product Th pl t to ag th ll nt of di patient populatio in late tage clinical trials of FDA- gulated products Specifically a ti pl t include th sp n 's goals fo llment th underlying

tio le fo th goals d pl atio of how th sp n intends to et th In additio to th quir ts th legislatio di ct th FDA to is guida di ity actio pl In Ju 2024, th FDA is ed draf

n fo bmissi of di ity actio pl specified in FDA guida

In Ja ary 2025, in sp n to tiv de is ed by Pr id t Tr p Di ity Equity d Incl io progr th FDA d th draf

de d imple nted in a da with applicable la Ac rdingly, th is id able n tainty r unding th draf

In Sept be 2025, th FDA is ed fi l guida with updated m ndatio fo GCPs ai d at de izing th design d nduct of clinical trials Th update intended to help pa th ay fo effi

de lopm t of di al products Th fi l guida is adopted fro th Inte atio l Co n il fo Ha oni ation updated E6(R3) draf

In Octobe 2025, th FDA is ed fi l guida that fo patient-fo d drug de lopm t Th guida outlin how takeholde ch pati ts a egiv ch d dical product de lope a bmit patient peri data in pport of th de lopm t d appr al of drug products To that d, th guida provide ie of clinical out

a ts in clinical trials d th le that clinical out a ts y play in in al ating th clinical be fit of dical product

In a th FDA y appr NDA fo product a didate but qui th sp n to nduct additi nal clinical trials to furthe a th product a didate's afety d ef

patient in th intended tr atm t group d to furthe doc t clinical be fit in th a of drugs appr d unde accel ated appr al gulatio Failu to hibit due dilig with gard to nducting Pha 4 clinical trials uld lt in withdra al of appr al fo products

Progr ports detailing th lts of clinical trials t be bmitted ally to th FDA within 60 days of th ni y date that th IND nt into ef

posed to th product; d y clinically imp tant in a in th a of ri spected ad actio that listed in th prot ol in tigat br hur Pha 1, Pha 2 d Pha clinical trials y not be mpleted sful

y specified period, at all Th FDA will typi ally insp t n clinical site to a mplia with GCP d th integrity of th clinical data bmitted

Following th cl a of IND d th m t of clinical trials sp n will ntin to ha inte ctio with th FDA d th sp n y et with th FDA at rtai point in th clinical de lopm t progr Specifically sp n

y et with th FDA prio to th bmissi of IND, pr -IND eting, at th d of Pha 2 clinical trial,

EOP2 eting, d befo NDA is bmitted, pr -NDA eting Meetings at othe time y al be que ted Th etings provide opportunity fo th sp n to sh info atio about th data gath ed to date with th FDA d fo th

FDA to provide advi th xt pha of de lopm t

Th fi type of etings that betw sp n d th FDA Type A etings th ary fo othe is talled product de lopm t progr to pr eed to addr imp tant afety is Type B etings include pr -IND d pr -NDA etings a ll a d of pha etings ch a EOP2 etings A Type C eting is y eting othe th Type A Type B eting garding th de lopm t d vi of product, including, fo ple etings to facilitat arly ultatio th of bi ke a r gate dpoint that ha be pr io ly ed a th primary basi fo product appr al in th proposed nt t of A Type D eting is fo d r t of is (typi ally limited to th tw fo d topi ) d should not qui input fro th th di ipli

divisi n Fi lly INitial Targeted Engage nt fo Regulat y Advi CBER products INTERACT, etings intended fo l products d de lopm t progr that pr t unique challenge in th a ly de lopm t of in tigatio l product

Such etings y be nducted in pe on vi tele nf ce/vide onf ce itte sp n only with minut flecting th que tio that th sp n posed to th FDA d th FDA sp n Th FDA ha indicated that its sp n

a yed in eting minut nd advi lette only titut m ndatio d/ advi de to sp n d, a ch sp n not bound by ch m ndatio d/ advi No thel fro practical pe pective sp n 's

failu to foll th FDA m ndatio fo design of clinical progr y put th progr at signifi a t risk of failu In Sept be 2023, th FDA is ed draf

Unde th Pediatri Re ch Equity Act of 2003, PREA NDA ppl t th et t ntai data that adeq ate to a th afety d ef

al bmit pediatri tudy pl prio to th a t data Th pl t ntai outlin of th proposed pediatri tudy tudi th sp n pl to nduct, including tudy objectiv d design, y defe r l aiv que t d othe info atio qui d by gulatio Th sp n th FDA, d th FDA inte al vi mmitte t th vi th info atio bmitted, ult with each othe d ag upon fi l pl Th FDA th sp n y que t dm t to th pl at y ti

Fo drugs intended to tr at ri lif th at ing di a ndition th FDA t upon th que t of sp n et to di prep atio of th initial pediatri tudy pl to di defe r l aiv of pediatri a ts In addition th FDA will et a ly in th de lopm t pr to di pediatri tudy pl with sp n d th FDA t et with sp n by late th th d-of-pha 1 eting fo ri lif th at ing di a d by late th ni ty (90) days afte

Th FDA y, its initiativ at th que t of th sp n gr t defe r ls fo bmissi of all pediatri data until afte

adults befo pediatri trials mplete that additio l afety ef

tatut y ptio in PREA by n ing that it doe not intend to gr t y additio l pha drug designati n fo pediatri bpopulatio of what is othe is m di a Th FDA intain list of di a that pt fr th

qui

nt of th PREA In May 2023, th

FDA is ed

draf guida

that furthe de

ribe th pediatri

tudy

qui

nt unde PREA

To obtai appr al to rket drug product in th United Stat rketing applicatio t be bmitted to th FDA that provide ffici t data tablishing th afety d effi

biguous lts a ll a positiv findings togeth with detailed info atio lating to th product ch istry nuf

in tigat To pport rketing appr al, th data bmitted t be ffici t in quality d quantity to tablish th afety d effi

Th NDA is hicl th ugh which sp n fo ally propos that th FDA appr product fo rketing d ale in th United Stat fo n indicatio Ev y drug product a didate t be th bject of appr d NDA befo it y be cialized in th United Stat Unde fede l law th bmissi of t NDAs is bj t to applicatio fee which fo fed al fi al ye 2026 is approxi tely $4.7 millio Th sp n of appr d NDA is al

bject to al progr fee which fo fi al ye 2026 is $442,213 pe product Certai ceptio d aiv

a ailabl fo of th fe ch a ptio fro th applicatio fe fo products with pha designatio d aiv fo tain all busin

Following bmissi of NDA, th FDA nducts prelimi ry vi of th applicatio ge lly within 60 alenda days of its ipt d t info th sp n at that tim befo whethe th applicatio is ffici tly mplete to pe it bstantiv vi In th t that th FDA dete in that applicatio doe not atisfy this t dard it will is Refusal

to File dete inatio to th sp n In this t, th applicatio t be bmitted with th additio l info atio Th bmitted applicatio is al bject to vi befo th FDA accepts it fo filing In Octobe 2025, th FDA is ed inte al

guida cl ifying that "mat ially in mplete inadeq ately ganized applicatio that uld not pe it timely effi

inatio

Th inte al guida

lie

singl adeq ate d

ll-

ined th

ed fo

d mplete vi will be th bject of Refu al to File dete will is Refu al to File dete inatio fo applicatio that

pport appr al if prio unicatio with th FDA dete ju tific

provide that th ag cy nt lled in tigatio to clinical tudy d y

On th bmissi is a epted fo filing, th FDA begi in-depth bstantiv vi Unde th goals d policie ag ed to by th FDA unde th PDUFA, applicatio eking appr al of Ne Mole la Entitie NMEs t to be vi ed within te nths fro th date which th FDA a epts th applicatio fo filing Th vi pr d th PDUFA goal date y be tended by th FDA fo th additio l nths to id info atio cl ific

A sp n is qui d to bmit sNDA if it wish to ke ch ge to product that ha al ady be appr d unde NDA Such ch ge y include visi of th labeling fo th appr d product, additio of indication ch ge in th dosage t ngth fo ulatio of th drug product, dificatio of th n in which th drug is nuf

Befo approving pplication th FDA typi ally will inspect th facility facilitie wh th product is will be nuf

applicatio unl it dete in that th nuf

nditio id tif

Mo r th FDA will vi sp n 's fi ial lati n hip with th principal in tigat wh nducted th clinical trials in pport of th NDA That is be a unde tain ci t principal in tigat at clinical trial site y al

a ientific

y be qui d to port th latio hips to th FDA Th FDA will th al ate that fi ial latio hip d dete in whethe it eat nfli

In addition a nditi of appr al, th FDA y qui sp n to de lop REMS REMS risk minimizatio t tegi beyond th prof si nal labeling to that th be fits of th product out igh th pot tial risk REMS uld include dicatio guide m nicatio pl fo health a prof si nals d el ts to a afe e including special training rtific

Th FDA y fe applicatio fo l product which pr ts diffi lt que tio of afety effi

mmittee but it id ch m ndatio wh king decisi n

Th FDA is a th ized to designate tain products fo pedited vi if they intended to addr n et di al ed in th tr atment of ri lif th at ing di a nditio No of th following pedited progr ch ge th t dard fo appr al but they y help pedite th de lopm t appr al pr of product a didate

Fast Tr k Designat o Th FDA y designate prod t fo Fa t Tra k vi if it is intended, eith al n in mbinatio with n othe products fo th tr atm t of ri lif th at ing di a ndition d it de trat th pot tial to addr n et di al ed fo ch di a nditio Fo Fa t Tra k products sp n y ha gr ate inte ctio with th FDA d th FDA y initiate vi of ctio of Fa t Tra k product applicatio befo th applicatio is mplete This lling vi pr y be a ailabl if th FDA dete in afte

belie that th designatio is longe pported by data ging in th clinical trial pr

Br kthrough Th rapy Designat o A product y be designated a Breakth ugh Th apy if it is intended, eith al n in mbinatio with othe prod ts to treat ri lif th at ing di a nditio d prelimin y clinical vide indicat that th product y de trat bstantial imp nt isting th apie

n clinically signifi a t dpoint Th FDA y take tain actio with spect to Br akthrough Th apie including holding etings with th sp n th ughout th de lopm t pr providing timely advi to th product sp n garding de lopm t d appr al; involving ni taf

-di iplin y proj t lead fo th vi te d taking othe tep to design th clinical trials in effi

Pr ority Revi Th FDA y designate prod t fo priority vi if it is product that tr ats ri nditi d, if appr d, uld provide signifi a t imp nt in afety ef

th apie Signifi ant imp nt y be ill trated by id of in a ed ef

patient mplia that y lead to imp nt in ri out d id of afety d ef

applicatio d to sh te th FDA goal fo vi of rketing applicatio fro te nths to si nths

ad a

ed th

apie designati

if it

lif

th at ing di a

Rege r tiv Ad ed Th rapy Designat o A product is eligible fo is ge tiv dici th apy that is intended to tr at, dify

ndition d prelimin y clinical id indicat that th product ha th pot tial to addr n et di al ed fo ch di a nditio Th be fits of ge ti ad a ed th apy designatio include a ly inte ctio with FDA to pedite de lopm t d vi be fits a ailabl to breakth ugh th apie pot tial eligibility fo priority

vi d a el ated appr al ba d ogat inte ediate dpoint

Commissi r' National Pr ority o her In Ju 2025, th FDA eated he progr called th Commissi n r's Nati nal Priority Vo her CNPV to pedite th de lopm t d appr al of drug products Vo he y portedly be de ed by sp n to sh te th vi time of NDA fro approxi tely 10-12 nths to 1-2 nths Th FDA ha indicated that th CNPV pr will pert fro th FDA offi

fo te -ba ed vi th th ing th t dard vi sy t of drug applicatio being nt to FDA offi

vi th bmitted info atio d fo 1-day eting

Ev if product andidate qualifie

Drug biologi products tudied fo thei afety d ef

that product a didate y be appr d th basi of adeq ate d ll nt lled clinical trials tablishing that th product a didate ha ef

With th pa age of FDORA in De be 2022, Congr dified tain provisi n gove ing accel ated appr al of drug d biologi products Specifically th legislatio a th ized th FDA to (i) qui sp n to ha its nfir

to bmit progr ports it post-appr al tudi to th FDA y si nths until th tudy is mpleted; d (iii) pedited pr ed to withdra accel ated appr al of NDA biologi lic applicatio if tain nditio not t, including wh nfir

product is not sh to be afe ef

pl atio fo proposed withdra al d opportuniti fo eting with th FDA Commissi n th Commissi n r's designe d itte appeal ong othe things

In Ma h 2023, th FDA is ed draf

mp is n to a ailabl th apy To that d, th FDA outlined id atio fo designing, nducting, d alyzing data fo trials intended to pport accel ated appr als of n ology th ap tic Subseq ntly in De be 2024 d Ja ary 2025, th FDA is ed additi nal draf

what it to nduct nfir

products qualify fo a le ted appr al

Ba d its al ati of th applicatio d a panying info ation including th lts of th insp tio of th nuf

lette ge lly indi ate that th vi cycl is mplete d outlin th defici ci in th bmission d y qui bstantial additio l te ting info atio in de fo th FDA to id th applicatio A sp n ha n ye to spond to th defici ci id tified in th mplete sp n lette Th FDA ha mmitted to vi ing ch bmissi n

in tw si nths depending th type of info atio included Ev with bmissi of this additio l information th FDA ultimately y decide that th applicatio doe not atisfy th gulat y iteri fo appr al

If th FDA appr prod t, it y limit th appr d indicatio fo of th product Th FDA y al qui nt indi atio a ings pr a tio be included in th prod t labeling, qui post-appr al trials qui te ting d

eilla progr to nito th product afte

out igh th pot tial risk Th FDA y pr t limit furthe rketing of product ba d th lts of post-rketing trials eilla progr Afte

indicatio nuf

Unde th En ring In atio Act, signed into la in 2021, th FDA t publish actio packag m rizing it decisi n to appr drugs within 30 days of appr al of ch drugs While mplete sp n lette pr io ly tr ated by th FDA a nfid

If gulat y appr al fo rketing of product indicatio fo isting product is obtai d, th sp n will be qui d to mply with all gul post-appr al gulat y qui nt a ll a y post-appr al qui nt that th FDA y ha imp ed a part of th appr al pr Th sp n will be qui d to port, ong othe things rtai ad actio d nuf

qui d to gi t thei tablishm ts with th FDA d tain tat ag ci d bject to periodi na n n ed inspectio by th FDA d rtai tat ag ci fo mpli with ongoing gulat y qui nt including cGMP

gulatio Ac rdingly, th sp n d its third-party nuf

In May 2025, th FDA di lo d pl to pand its of na n n ed inspectio of fo ig nuf

A product y al be bject to offi

lots of pr d ct befo lea ing th lots fo di tributio Fi lly th FDA will nduct laborat y ch lated to th afety purity pot cy d ef

On appr al is gr ted, th FDA y withdra th appr al if mplia with gulat y qui nt is not intained if probl afte

Disclaimer

Agios Pharmaceuticals Inc. published this content on April 29, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 29, 2026 at 16:55 UTC.