10-K

prld-10k_20201231.htm

10-K

prld-10k_20201231.htm

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2020

Commission File Number 001-39527

PRELUDE THERAPEUTICS INCORPORATED

(Exact name of Registrant as specified in its Charter)

200 Powder Mill Road Wilmington, Delaware 19803

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (302) 467-1280

Securities registered pursuant to Section 12(b) of the Act:

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common Stock, par value $0.0001 per share PRLD The Nasdaq Stock Market LLC

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐ NO ☒

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ NO ☒

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. YES ☒ NO ☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). YES ☒ NO ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). YES ☒ NO ☐

The number of shares of Registrant’s Common Stock outstanding as of March 12, 2021 was 46,585,860

The registrant was not a public company as of the last business day of its most recently completed second fiscal quarter and therefore, cannot calculate the aggregate market value of its voting and non-voting common equity held by non-affiliates as of such date.

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s Definitive Proxy Statement (“Proxy Statement”) relating to the 2021 Annual Meeting of Stockholders will be filed with the Commission within 120 days after the end of the Registrant’s 2020 fiscal year pursuant to Regulation 14A and is incorporated by reference into Part III of this Report.

Table of Contents

Page

PART I

Item 1. Business 2

Item 1A. Risk Factors 59

Item 1B. Unresolved Staff Comments 110

Item 2. Properties 110

Item 3. Legal Proceedings 110

Item 4. Mine Safety Disclosures 110

PART II

Item 6. Selected Financial Data 112

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 121

Item 8. Financial Statements and Supplementary Data 121

Item 9A. Controls and Procedures 140

Item 9B. Other Information 140

PART III

Item 10. Directors, Executive Officers and Corporate Governance 141

Item 11. Executive Compensation 141

Item 14. Principal Accounting Fees and Services 141

PART IV

Item 15. Exhibits, Financial Statement Schedules 142

PART I

This Annual Report on Form 10-K contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements are based on our management’s beliefs and assumptions and on information currently available to our management. All statements other than statements of historical facts are “forward-looking statements” for purposes of these provisions, including those relating to future events or our future financial performance. In some cases, you can identify forward-looking statements by terminology such as “may,” “might,” “will,” “should,” “expect,” “plan,” “anticipate,” “project,” “believe,” “estimate,” “predict,” “potential,” “intend” or “continue,” the negative of terms like these or other comparable terminology, and other words or terms of similar meaning in connection with any discussion of future operating or financial performance. These statements are only predictions. All forward-looking statements included in this Annual Report on Form 10-K are based on information available to us on the date hereof, and we assume no obligation to update any such forward-looking statements. Any or all of our forward-looking statements in this document may turn out to be wrong. Actual events or results may differ materially. Our forward-looking statements can be affected by inaccurate assumptions we might make or by known or unknown risks, uncertainties and other factors. We discuss many of these risks, uncertainties and other factors in this Annual Report on Form 10-K in greater detail under the heading “Item 1A—Risk Factors.” We caution investors that our business and financial performance are subject to substantial risks and uncertainties.

Item 1. Business.

Overview

We are a clinical-stage precision oncology company focused on discovering and developing small molecule therapies optimized to target the key driver mechanisms in cancers with high unmet need. By leveraging our core competencies in cancer biology and medicinal chemistry, combined with our target class- and technology platform-agnostic approach, we have built an efficient, fully-integrated drug discovery engine to identify compelling biological targets and create new chemical entities, or NCEs, that we rapidly advance into clinical development. We believe our approach could result in better targeted cancer therapies. Our discovery excellence has been validated by our rapid progress in creating a wholly-owned, internally developed pipeline. Since our inception in 2016, we have received clearance from the U.S. Food and Drug Administration, or the FDA, for four investigational new drug applications, or INDs, and successfully advanced three of these programs into clinical development with the fourth expected to begin clinical development in the first half of 2021. In addition, we have three unique programs in various stages of preclinical development that we plan to advance into clinical development beginning in 2021.

By focusing on developing agents using broad mechanisms that have multiple links to oncogenic driver pathways in select patients, we have developed a diverse pipeline consisting of six distinct programs spanning methyltransferases, kinases, protein-protein interactions and targeted protein degraders. Our pipeline is geared towards serving patients with high unmet medical need where there are limited or no treatment options. We are exploring therapies in both solid tumors and hematological malignancies such as adenoid cystic carcinoma, or ACC, homologous recombination deficient positive, or HRD+, cancers, myelofibrosis, or MF, and glioblastoma multiforme, or GBM, amongst others. We believe we can best address these diseases by developing therapies that target primary and secondary resistance mechanisms.

Our lead product candidates are designed to be oral, potent and selective inhibitors of protein arginine methyltransferase 5, or PRMT5. The potency and selectivity of our product candidates is supported by preclinical data demonstrating nanomolar inhibition of PRMT5 and no inhibition of related enzymes at 1,000 times higher concentration of our product candidates. We are currently advancing our first clinical candidate, PRT543, in a Phase 1 clinical trial in select solid tumors and myeloid malignancies in patients who are refractory to or intolerant of established therapies. Interim Phase 1 results indicate dose-dependent increases in exposure and target engagement, and we have observed early signs of clinical activity, including an ongoing, confirmed complete response, or CR, in a patient with HRD+ high grade serous ovarian cancer through nine months of therapy. A complete response is defined as the disappearance of all target lesions. While we will need to enroll and demonstrate objective responses in additional patients to support further development and potential approval by the FDA or other regulatory authorities, and while such approval is not guaranteed, we are encouraged by the clinical activity as of the date of this Annual Report on Form 10-K. We recently completed the dose escalation portion of the trial. The dose expansion portion of the Phase 1 trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the

second quarter of 2021. We anticipate presenting initial clinical data from the trial at medical meetings in the second half of 2021.

We are also advancing PRT811, a second PRMT5 inhibitor that we have optimized for high brain exposure, in a Phase 1 clinical trial in solid tumors, including GBM. As of the date of this Annual Report on Form 10-K, the trial has demonstrated early signs of clinical activity and tolerability. The previously disclosed refractory GBM patient whose tumor had demonstrated a 66% reduction on monotherapy PRT811 subsequently underwent a follow-up MRI at week 18 and the regression has improved to 77% from baseline, confirming a partial response, or PR, per RANO (response assessment in neuro-oncology) criteria. We expect to begin enrolling patients in the expansion portion of the Phase 1 clinical trial by mid-2021 and anticipate obtaining initial clinical data from this trial by the end of 2021.

PRT1419, our third clinical candidate, is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. The potency and selectivity of PRT1419 is supported by preclinical data demonstrating nanomolar inhibition of MCL1 and no inhibition of related enzymes at 200 times higher concentration of our product candidate. We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into the Phase 1 clinical trial for the oral formulation of PRT1419. We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial in the second half of 2021. Additionally, the FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors.

Our pipeline is summarized in the figure below:

Prelude Discoveryand DevelopmentApproach

Wecarefullyevaluateandselectourtargetsbasedonthreekeypillars,whichprovideaframeworkfor optimizingour drug discoveryand developmentefforts.

• Identify target mechanisms with compelling biological rationale

• Pursue targets that drive cancers with high unmet need

Once we have identified optimal targets using the three pillars above, we engage our unique discovery engine to rapidly and efficiently invent and develop molecules. We believe our expertise, capabilities and experience to select high value biological targets and invent molecules with an optimized balance of biological and chemical properties differentiates us from others in the precision oncology space. We believe our unique discovery engine will enable us to continue delivering a new IND every 12 to 18 months.

We design our clinical trials to leverage the broad utility of our compounds with a focus on efficient regulatory pathways to enable our potentially transformative medicines to quickly reach patients with high unmet medical need. By focusing on validated cancer signaling pathways and early clinical proof-of-concept, we seek to advance our programs through expedited approval processes.

Our Product Candidates

Our first two candidates, PRT543 and PRT811, are designed to be potent, selective and oral inhibitors of PRMT5. We believe targeting PRMT5 has broad applicability and a strong scientific rationale for the treatment of cancer as it regulates transcription, translation and messenger ribonucleic acid, or mRNA, as well as the splicing of cancer related genes. Inhibition of PRMT5 has been observed to suppress tumor growth and produce synthetic lethality preclinically.

PRT543, our first clinical candidate, is currently in a Phase 1 clinical trial in advanced solid tumors and select myeloid malignancies. We have been encouraged by both the clinical activity and tolerability data that have been seen in 61 patients (42 with advanced solid tumors, one with NHL, 11 with MF and seven with MDS) that have enrolled into the study as of December 16, 2020. We have observed early signs of clinical activity, including a durable confirmed CR per RECIST v1.1, in a patient with HRD+ high grade serous ovarian cancer, in the 35 mg 5x/week (once a day, for five days, with two days off) cohort. This patient has received nine months of study therapy as of December 16, 2020 and remains in CR. We will need to enroll and demonstrate objective responses in additional patients to support further development and potential approval by FDA or other regulatory authorities, and such approval is not guaranteed. In addition, extended duration of therapy and improvements in symptoms have been observed in several patients with MF, with one patient demonstrating a response of clinical improvement and another patient showing an approximately 66% reduction in Total Symptom Score, or TSS, a validated clinical endpoint in MF. Clinical improvement means an achievement in anemia, spleen, or symptom response without progressive disease or increase in the severity of anemia, thrombocytopenia or neutropenia. We have begun enrolling patients into the expansion portion of the Phase 1 clinical trial in select tumor types that are potentially driven by PRMT5 dysregulation. These tumor types include ACC, MF, genomically selected MDS and HRD+ tumors. We have recently completed the dose escalation portion of the ongoing Phase 1 trial for PRT543. The dose expansion portion of the trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the second quarter. We anticipate presenting initial clinical data from the trial at medical meetings in the second half of 2021.

PRT811, our second clinical candidate, is currently advancing in the dose escalation portion of a Phase 1 clinical trial in solid tumors, including GBM and primary central nervous system lymphomas, or PCNSL. PRT811 has been optimized for high brain exposure and hence we believe is uniquely positioned to treat PRMT5 sensitive CNS cancers. We have been encouraged by both the clinical activity and tolerability data that have been seen in 24 patients (eight with GBM, 16 with various advanced solid tumors) that have enrolled into the dose escalation portion of the study as of December 16, 2020. We have observed early signs of clinical activity in a refractory GBM patient whose tumor initially demonstrated a 66% reduction on monotherapy PRT811 at week 6, and subsequently underwent a follow-up MRI at week 18, and the regression has improved to 77% from baseline, confirming a PR per RANO (response assessment in neuro-oncology) criteria. This patient has received five months of study therapy as of December 16, 2020 and remains in PR and is clinically stable. We will need to enroll and demonstrate objective responses in additional patients to support further development and potential approval by FDA or other regulatory authorities, and such approval is not guaranteed. We plan to initially enroll patients in the expansion portion of the clinical trial with GBM, PCNSL and solid tumors with metastatic disease to the CNS once we

have established an expansion dose. We expect these expansions to begin by mid-2021 and anticipate initial clinical results from this trial by the end of 2021.

PRT1419, our third clinical candidate, is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. We believe hematological malignancies are particularly sensitive to MCL1 inhibitors. MCL1 upregulation has been noted as a mechanism of acquired resistance to venetoclax and tyrosine kinase inhibitors, or TKIs. In addition, certain solid tumors are responsive to MCL1 inhibition, informing a potential patient selection strategy. We have enrolled four patients into the Phase 1 clinical trial investigating oral PRT1419 in high risk MDS, AML, NHL and MM. Additionally, the FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors. We believe that the physicochemical and pharmacological properties of PRT1419 allow the optionality of administering PRT1419 by either oral or IV routes.

In addition to our three clinical stage candidates, our two most advanced preclinical programs target cyclin- dependent kinase 9, or CDK9, and Brahma homologue, or BRM, otherwise known as SMARCA2, respectively. PRT2527, designed to be a potent and selective CDK9 inhibitor, has entered IND-enabling studies with an IND submission expected in 2021. We have also identified SMARCA2 protein degraders that appear to be potent based on preclinical data demonstrating degradation of SMARCA2 at sub-nanomolar concentration. Optimization of the lead compound, PRT-SCA2, is progressing, and we expect to initiate IND-enabling studies in 2021. Our sixth program is exploring a kinase target for solid tumors. We are optimizing our lead compound, PRT-K4, and expect to begin IND-enabling studies in 2021.

Our Team

Wewerefoundedin2016byKrisVaddi,Ph.D., afoundingscientistatIncyte,andhaveassembledan experiencedmanagementteamandboardofdirectorswithdeepexpertiseinoncologyanddrugdevelopment. Wehavebuiltfromthe“groundup”ourinternaldiscoveryteam,ledby scientificand medicalteamswith deep expertiseandprovencapabilitiesin inventingand rapidlyadvancingsmallmoleculemedicinesthataddress important gaps in the current precision oncology ecosystem. Members of our management team have successfullydevelopedand commercializednumerousdrugssuch as Jakafi, Olumiant, Velcade, VITRAKVI, Retevmo,Tabrectaand Pemazyre.

Our Strategy

We aimto createbettertargetedand moreeffectivecancertherapies.Our goalisto transformthe lives of patientswithcancerbyleveragingthecorecompetenciesof our experiencedteamin medicinalchemistry,cancer biologyandclinicaldevelopmentto bringnoveldrugsto market.We intendto becomea fullyintegratedpatient- focusedprecisiononcologycompanyby pursuingthefollowingobjectives:

Our Pipeline

Consistentwith our targetclassagnosticapproach,our currentpipelineincludessixdistinctprograms spanningmethyltransferases,kinases,protein-proteininteractionsand targetedproteindegraders.Sinceour inceptionin 2016, we have receivedclearanceforfourINDs and advancedthree of theseprogramsinto clinical development, with the fourth program expected to initiate clinical development in the first half of 2021. Inaddition,we have threeunique programsin variousstagesof preclinical developmentthatwe plan to advance into clinical development beginningin2021.Wehavestructuredandresourcedourresearchanddevelopment,orR&D,organizationwith thegoaland expectationof continuingto delivera new IND every12 to 18 months.

Cancer Background and Treatment

Canceristhesecond-leadingcauseofdeathintheUnitedStates.TheAmericanCancerSocietyestimates thatapproximately1.8millionnewcancercaseswillbediagnosedandmorethan600,000 peopleareexpectedto dieofthediseaseintheUnitedStatesin2020.CancerisadiseaseofthegenomecausedbychangesinDNA that altercellbehavior,growthanddivision.Thesechangescancausecellstoproduceabnormalamountsof certain proteinsand/orto makeaberrantproteinsthatdo not functionproperly.It is widely understood that cancer cells caneventuallyevadetherapiesthroughmutationsor otherresistancemechanisms,limitingthelong-termsuccess of drug therapies.

Historically,cancerhasbeentreatedwithsurgery,radiationanddrugtherapywith patientsoftenreceivinga combinationofthesetreatmentmodalities.Whilesurgeryandradiationcan be effectivein patientswith localized disease,drugtherapiesareoftenrequiredwhenthecancerhasspreadbeyondtheprimarysiteorisnotamenable to resection.

Drugtherapyisintendedtokillor damagemalignantcellsby interferingwith thebiologicalprocessesthat controldevelopment,growthandsurvivalofcancercells.Thistreatmentmodalityhasevolvedovertimefrom theuse of non-specificcytotoxictherapiesto precisiononcologymedicinestargetingmolecularpathwaysor oncogenicdrivers.These precisionmedicinesarebroadlyknown as targetedtherapies.

Era of PrecisionOncology

The first-generationof approvedtargetedtherapieswere largelydirectedat receptortyrosinekinases (e.g., BCR-ABL, VEGF,EGFR),asuperfamilyofcell-surfacereceptorsthatactivategrowthfactors.Manyofthese agentsthatwere initiallyapprovedin refractoryand resistantpopulationshave now becomefront-linetreatments incancersforwhichtheyareindicated.Whilethesetargetedtherapieshave improvedthetreatmentof certain cancers,manyfailto addresstheunderlyinggenomicalterationsthatdriveoncogenesis,leadingto limited responsesorinadequatetherapeuticdurability.Sincenormalcellscanrelyonthesesamesignalingpathways, thereareoftentoxicitiesassociatedwith pathway inhibition.In addition,manyof thesefirst-generationtargeted therapiesaremulti-kinaseinhibitorsthatinterferewith off-targetadjacentpathways,resultingin significant toxicities.

Asecond-generationoftargetedcancertherapieshasevolvedfromthenexus of rapidadvancesin the understandingof tumorbiologyand increasinglysophisticateddiagnosticplatformsthatenableidentificationof subsetsoftumorsbasedon

genomicalterations.Thesetherapiesoftenrequiregenomictestingof tumortissueor bloodtoidentifypotentiallytargetablealterationsin a patient’sindividualcancer.Increasingly,theseprecision medicinesareagnostictotumorsiteoforiginandinsteadtargetspecificoncogenicdriversthatcan occurbroadly acrosstumortypes.In2018,VITRAKVI(larotrectinib)wasapprovedbytheFDA forneurotrophicreceptor tyrosinekinase-drivencancers,makingitthefirstnewdrugtobedevelopedandapprovedto treata specific genomicalterationin a tissue-agnosticfashion.This emergingtrend for tumor-agnosticindicationsrepresentsa significantadvancementindrugdevelopment,clinicaltrialdesigns,drug approvalpatternsand speedto market. Targetedtherapiesgeneratedapproximately$20.1 billionof worldwidesalesin 2019 and have remaineda mainstayof oncologydrug developmentand treatment.

Next GenerationPrecisionOncology

Firstand second-generationprecisiononcologymedicinesdramaticallychangedthelandscapeof available treatmentoptionsforpatientswith cancerand createda paradigmshiftin oncologydrug development.However, therearestillsignificantgapsthatrequirefurtheradvancesto optimizetreatmentoptions.For example,oncology drugdevelopmenthasbeenprimarilyfocusedon readilydruggablegenomicalterationsthatconfernew or enhanced protein activity, known as gain-of-function targets, which represent only a subset of targets in oncology.Additionally,malignantcellsmaypossessoracquireintrinsicresistanceby usingalternativesignaling pathways,enablingthemtosurviveandproliferateandcontributingtoalackofresponseand/orshortdurability ofresponseto thesetypesof precisionmedicines.The nearlyuniversalnatureof thisprimaryor secondary resistancehighlightstheurgentneedtoaddressresistanceusingacellularlevelunderstandingof themechanisms thatdrivetreatmentfailure.

Byspecificallytargetingadditionalpathwaysofresistance,nextgenerationprecisiononcologymedicines canaddresstheneedsofpatientswhosetumorsdonotharbortargetablegenomicalterationsas wellas patients whoprogressoncurrenttherapies.Thesemedicinesleveragescientificand technologicalbreakthroughsto target newinterventionpointsinoncogenicsignalingpathways,includingtranscriptionalregulationof oncogenesand tumorsuppressorgenes,DNA damagerepairpathwaysandproteinstructure.These approachesaddressprimary and secondaryresistancemechanismsnot targetableby earliergenerationsof precisiononcology medicines. Examplesof thesemechanismsareshown in thefigurebelow.

Webelievehighlyselectiveand potentmoleculesthattargetspecificoncogenicmechanisms,regardlessof target class,canbeaneffective strategy toaddresscancersnotamenable toearlierandcurrenttreatment modalities.These next-generationprecisiontherapiesshouldpossesspharmacological,pharmacokinetic,or PK, andpharmaceuticalpropertiesthatprovideoptimizedinhibitionofthetargetmechanism,withasafetyprofile and therapeuticwindow thatallowsuse in allstagesof cancereitheras a monotherapyor in combination.

Prelude Discoveryand DevelopmentApproach

Weareguidedbyourcoreexpertiseincancerbiologyand medicinalchemistryto createnextgeneration precisiononcologymedicines.We endeavorto discover,developand commercializesmallmoleculedrugsthat selectivelytargetsignalingpathwaysdrivingprimaryor adaptiveresistance.

Ourapproachistargetclass-andtechnologyplatform-agnosticmeaning,wedonotlimitourselectionof programstoadefinedtargetclass(e.g.,kinases)or a technologyplatform(e.g.,proteindegradation).We have builtfromthe“groundup”our internaldiscoveryteam,ledby scientificand medicalteamswith deep expertise andprovencapabilitiesininventingandrapidlyadvancingsmallmoleculeproductcandidatesthathave the potentialtoaddressimportantgaps in thecurrentprecisiononcologyecosystem.We designour discovery programsaroundtargetswith compellingpreclinicaland clinicaldatathathave thepotentialto addresscancersof highunmetmedicalneed. We evaluateexistingclinicalor preclinicalbiologicalrationaleand chemicalspacethat provideimportant“proof-of-concept”validationbutpresentsignificantopportunitiesforimprovementon current therapies.Thisprocesshasenabledus to rapidlycreatea wholly-owned,internallydevelopedpipelineof differentiatedproductcandidatesforpatientpopulationswith cancersthatshow limitedtherapeuticdurabilityor do not respondto currenttreatments.

Asshowninthediagrambelow,ourapproachisdividedintotworelatedprocesses—targetselectionand our uniquediscoveryengine.

Target Selection

Weidentifyvulnerableinterventionpointsincancerswithhighunmetneed,andthenwe seekto design solutionsthatcanbepreciselytailoredtoaddresstheseinatargetclassagnosticfashion.Applying our deep expertisein cancerbiologyand medicinalchemistry,as wellas our in-depthunderstandingof thecurrent landscapeofoncologytreatments,we interrogatetargetableinterventionpointsin thesignalingpathways amenabletosmallmolecule-basedtreatments.Wethendesign,synthesizeandoptimizemoleculesthatwe believebestmeettheneedsofthepatientswe striveto serve.Consistentwith our patient-centricfocus,we take intoaccountanumberofpatientattributes,includingthetypeof cancer,currentstandardof care,causesof treatmentfailure,comorbidities,potentialfordrug-druginteractionsandpropensityforCNS diseaseto be ableto developmoreeffectivetherapies.

Wecarefullyevaluateandselectour targetsbasedon thethreekey pillarsdescribedbelow which providea frameworkforoptimizingour drug discoveryand developmentefforts.Our discoveryprogramsarebuiltupon thesethreepillars:

1) Identifytargetmechanisms with compellingbiologicalrationale

Wefocusontargetclassesthathaveeitheryieldedsuccessfuldrugsorareemergingas validated,druggable approacheswithcompellingdriverpathway-baseddata,asopposedtoapproachesdrivenbydiseaseassociation ornoveltyoftargetclass.Webelieveourinternalcapabilitiesarebestsuitedtorationallydesignanddevelop moleculesthatcanaddressthesemechanismsinatargetclassagnosticmanner.Wemayexpandourfocuson othertargetmechanismsas new biologyemergesand isvalidated.

Our currenttargetmechanismsof focusinclude:

• Transcriptional regulation

• DNA repair pathway

• Cell cycle regulation

• Exploitation of synthetic lethality

• Brain penetrant molecules to address primary or metastatic CNS tumors

PRMT5 isaprimeexampleofatargetwith strongscientificrationalethatwe arewell-suitedto address.We believethetargetcanbeexploitedtoaddressunderservedcancerssuchasACC withanundruggableoncogenic driver(suchas myeloblastosis,or MYB), as wellas to addressresistanceto severalexisting,approved targeted agents,includingruxolitinib,venetoclaxandCDK4/6 inhibitors.Also,PRMT5isapotentialdrivermechanismin GBM,forwhich a differentiatedproductwith high brainexposureisrequired.

2) Leverageour advancedmedicinalchemistrycapabilitiesto createbetterproductcandidates

Wedeployourintegratedmedicinalandprocesschemistryexpertiseto rationallydesignand synthesize complexchemicalentitiesandrapidlyadvancethroughvariousstagesofdevelopment.Weviewalltarget classes,includingenzymeinhibitors(PRMT5,CDK9), protein-proteininteractions(MCL1),targetedprotein degradation(SMARCA2) andthosethatrequirehighlevelsofbrainexposure,withequalinterestand striveto inventclinicalcandidatesthatmeetour desiredtargetproductprofiles.

Ourabilitytodesignanddevelopmoleculeswith potentialhigh brainexposuresallowsus to targetvalidated mechanismsincancerswithCNS metastasis,asmanycurrenttreatmentsdonothaveadequatebrainexposure. Ourdiscoveryprogramsarenotonlydrivenbypotency,selectivityandPK, butalsoincorporateoptimized physicochemicalpropertiesto providewell-balancedclinicalcandidates.

3) Pursue targetsthatdrivecancerswith high unmet need

Webelievetakingapatient-centricapproachtotargetselectionprovidesopportunitiesto generateproof-of- conceptearlyinclinicaldevelopment,canformthebasisforthedesignofpivotalstudieswith potentialfor acceleratedapprovalin themostrelevantpatientpopulationand rapidlyadvanceintoearlierlinesof treatment.

We focuson targetsthatallowus to selectpatientsand cancerswith high medicalunmetneed with no approvedtherapies,orpatientpopulationsunderservedbyapprovedtreatments.Weplanto utilizemultiple approachestopatientselection,whichincludebiomarker-basedenrichment.For example,one cancerof interest withnoapprovedoreffectivetreatmentsisACC, whichispredominantlydrivenby a specificoncogenic mechanismsuch as MYB, where a biomarkerselectionstrategymaynot be needed.Alternatively,SMARCA4 mutatedcancersaremoreamenableto a biomarker-basedselectionstrategy.

Lastly,weinterrogatetargetsinpathwaysthatdriveresistancetoapprovedtreatmentsin clearlydefined patientpopulations.Specificexamplesinclude:AML patientswho progresson venetoclaxin which MCL1 isa knownresistancedriver;andpatientsprogressingonruxolitinibinwhominhibitingPRMT5canpotentially blockalternativepathwaysof resistancesuch as thetranscriptionfactorE2F1.

Our DiscoveryEngine

Oncewehaveidentifiedoptimaltargetsusingthethreepillarsabove,weengageouruniquediscovery enginetorapidlyandefficientlyinventand developmoleculeswith optimizedproperties.Centralto our internal discoverycapabilityistheinterplaybetweenourhighlyexperiencedbiologistsandchemistswhocollaboratein aniterativefashiontorapidlydesign,synthesizeandtestnovelchemicalentities.Bycouplingour synthetic organicchemistryexpertiseandanalyticaltechnologies,ourmedicinalchemistryteamhas rapidlyand efficiently synthesizedthousandsof rationally-designednovelcompoundssinceinception.

Ourdeepunderstandingofcancerbiologyenablesarigorousdrugselectionprocessthathas allowedus to optimizeourleadmoleculestointerrogatevalidatedcancerpathwayswithhightranslationalsuccess.Wefocus onstereochemically-richmoleculeswith a high degreeof 3-dimensionalcharacter,which has been shown to correlatewithsuccessascompoundstransitionfromdiscovery,throughclinicaltesting,todrug.Ourunique abilitytoleveragemedicinalchemistrytolookbeyondclassicdrug-likespaces,suchasthoseinvolvedin protein-proteininteractionandtargetedproteindegradationandtoincorporatecriticalelementsof drug-like propertiesintoourcandidatecompoundsisakeyaspectofouruniquediscoveryengine.Ourinternaland external teams utilize a suite of capabilities in crystallography; absorption, distribution, metabolism and excretion,orADME;PKandpharmacodynamic,orPD, analysis;preclinicalefficacymodelsusingcellline xenograftandpatient-derivedxenograft,orPDX, models;andprocessscalesynthesisandtoxicologytoevaluate and optimizetheleadmoleculeswe inventuntiltheymeetrigorousand pre-specifiedcriteria.

Finally,wedesignourclinicaltrialstoleveragethebroadutilityof our compoundswith a focuson efficient regulatorypathwaysthatenablepotentiallytransformativemedicinesto quicklyreachcancerpatientswith high unmetmedicalneed.Byfocusingonvalidatedcancersignalingpathwaysand earlyclinicalproof-of-concept,we seekto advanceour programsthroughexpeditedapprovalprocesses.

Webelieveourrapidprogressincreatingawholly-owned,internallydevelopedpipelinewith three differentiatedclinical-development-stagecompounds, a fourth program expected to enter clinical development in the first half of 2021,and multipleadditionalmoleculesin various stages of preclinicaldevelopmentacrossarangeoftargetclassesvalidatesourdiscoveryexcellence.Wehave structured andresourcedourR&DorganizationwiththegoalandexpectationofcontinuingtodeliveranewINDevery12 to18months.Webelieveourexpertise,capabilitiesand experienceto selecthigh valuebiologicaltargetsand inventmoleculeswithanoptimizedbalanceofbiologicalandchemicalpropertiesdifferentiatesus fromothersin theprecisiononcologyspace.

Our Product Candidates

PRMT5Inhibitors:PRT543& PRT811

RationalefortargetingthePRMT5 pathway in cancer

Cancerisadiseaseofthegenomeandallcancershavegenomiclesionsthatmustbe addressedto develop effectivetreatments.Thesegenomicchangesareimportantatallstagesof cancerprogression,includinginitial formation,growth,andmetastasis,andresultin theupregulationof genesthatpromotecellgrowth and survival togetherwith thedownregulationof genesthatsuppresstumorgrowth.

PRMT5 controlsanumberofthebiologicalprocessesthatdrivecancerincludingtranscription,translation, DNArepairandcellsignaling.OverexpressionandincreasedenzymaticactivityofPRMT5 areassociatedwith poor outcomeand decreasedsurvivalin multiplehumancancersettings,as outlinedin thetablebelow.

This information is based on published data in peer-reviewed journals and reflects standard therapeutic intervention.

PRMT5 RegulatesTranscriptionand Translationof Cancer-relatedGenes

TheoncogenicprocesscontrolledbyPRMT5 ismediatedthroughthesymmetricdimethylationofarginines onitssubstrateproteins(Figure1).PRMT5, anintracellularenzyme,transferstwo methylgroupsfroma co- factorS-adenosylmethionine,orSAM,anddepositsthemonitssubstrateproteinsresultingin theformationof a symmetricdimethylarginine,or sDMA, mark.This post-translationalmodificationaltersthe protein structure, impactsinteractionswithDNA, andalsogeneratesdockingsitesforeffectormoleculesthatcan promotetumor cellgrowth and survival.PRMT5substrateproteinsinclude:

RNA

Figure 1. PRMT5 Regulates Oncogenesis and Resistance

Throughargininemethylationofhistones,transcription factorsandthespliceosomecomplex,PRMT5regulatestheexpressionofgenes involvedinpromotingcancercellgrowthandsurvival.Theseincludecellcyclegenes,tumorsuppressors, oncogenes,andgenesinvolvedin proliferationand signaling.

PRMT5-regulatedtranscriptionfactors,includingcyclinD1andMYC, haveawell-establishedroleina numberofcancers.Conversely,PRMT5-mediatedmethylationof histonessuch as H3 and H4 repressesa number oftumorsuppressorgenesincludingretinoblastoma,orRB,familymembers,contributingto unchecked proliferationofmalignantcells.Inaddition,PRMT5 symmetricallydimethylatesribosomalbindingproteinsand modulates mRNA translation of internal ribosome entry site-containing mRNAs, further promoting the generationofoncogenicproteins.Consistentwithitsroleinpromotingcancer,PRMT5inhibitionhasbeen showntodecreasetumorgrowthinpreclinicalmodels.Therefore,PRMT5 isbelievedtoserveasanimportant mediatorofcancerprogressionand can be targetedto treata rangeof solidtumorsand hematological malignancies.These attributesmakePRMT5an idealtherapeutictargetforcancer.

TheroleofPRMT5 inregulatinggenetranscriptionandtranslationmaybeparticularlyrelevantin cancers suchasACC whereupto86%ofpatientsharborthegenefusionoftheMYBfamilymembersMYB or MYBL1 withtheNuclearFactor1B,or NFIB, gene. MYB or MYBL1 gene fusionsleadto overexpressionof theMYB/ MYBL1 protein.PublisheddatademonstratethatMYBoverexpressionisimportantfordrivingcellproliferation andtumorgrowthinpreclinicalACCmodels.Inaddition,ourinternaldataillustratethatPRMT5 inhibition decreasedMYBexpressionlevelsinMYB-dependentpreclinicalmodelsandinhibitedtumorgrowthin PDX modelsofACC. RecentevidenceofclinicalactivitywithathirdpartyPRMT5 inhibitorin patientswith ACC furthervalidatesPRMT5as a potentialtargetmechanismin thishighlyunderservedcancer.

PRMT5 RegulatesmRNASplicingin Cancer Cells

Inadditiontoregulatingtranscription,PRMT5 alsomodulatesgeneexpressionbycontrollingmRNA splicing.Splicingisafundamentalcellularprocessthatinvolvestheremovalof noncodingsequencesfromthe precursormRNAtoproducethematureformthatencodesforprotein.IntheabsenceofcorrectmRNA splicing, mutatedor unstableproteinsareproduced,ultimatelyleadingto cellcycledefects,senescenceand apoptosis.The splicingreactioniscarriedoutbyamulti-protein/RNAcomplexcalledthespliceosome.PRMT5 playsan importantroleinthesplicingofmRNA throughmethylationofspliceosomeprotein,whichiscriticalforthe assemblyofthespliceosomecomplexanditsfunction.Inpreclinicalmodels,tumorswithhigh degreesof proliferation,suchasMYC-driventumors,wereassociatedwithincreasedactivityofPRMT5 tomaintainthe fidelityof thespliceosome,demonstratingtheimportanceof PRMT5in thisprocess.

TheroleofPRMT5 inregulatingmRNA splicingmaybemostrelevantin cancerswith spliceosomal mutationsorthosethataredependentonhighsplicingfidelity,suchasGBM. Spliceosomalmutationsalsooccur inmorethan50% of MDS patientsand atlowerfrequenciesin othertumortypesincludingMF, chronic myelomonocyticleukemia,AML,NHL,MM,chroniclymphocyticleukemia,orCLL,anduvealmelanoma. These spliceosomalalterationsareoftencorrelatedwith highermutationalburdenand/orpoor prognosis. In modelsofAML,preclinicaldatademonstratedthatPRMT5 inhibitionresultedinhigherlevelsofsuppressionof thegrowthofcancercellscontainingmutatedspliceosomeproteinscomparedto thosecontainingunmutated spliceosomeproteins.

Syntheticlethalityfrom PRMT5 inhibitionin certainsettings

Syntheticlethalityappliesto specificpairsof genes.A syntheticlethalinteractionoccurswhen a deficiency ineithergenealoneisviablewhereasadeficiencyinbothgenessimultaneouslyresultsincelldeath.In cancer, syntheticlethalitycanbeexploitedtoselectivelykillcancercellsinwhichonegeneinthepairismutatedor deletedinthetumorcellandtheremainingsecondgene istherapeuticallyinhibited.This leadsto deathof the cancercellswhereasnormalcells,whichlackthespecificgeneticalteration,aresparedtheeffectofthedrug. In thecaseofPRMT5, ithasbeendemonstratedthatcertaingenomicalterationsconferaselectivedependenceon PRMT5 sothatPRMT5 inhibitioncanbe utilizedto producea syntheticlethaleffect.For example,PRMT5 inhibitionshows a modestpreferentialimpairmentof cellviabilityin methylthioadenosinephosphorylase,or MTAP,-nullcancercellscomparedtonormalcells,suggestingthatPRMT5 inhibitorscouldproduceasynthetic lethaleffectin GBM,in which nearlyhalfof thepatientscarrytheMTAP deletion.

ThesyntheticlethaleffectofpharmacologicalinhibitorsofDNA repairmechanismssuchaspolyADP- ribosepolymerases,orPARPs,havebeensuccessfullyutilizedinthetreatmentofHRD+cancers.HRD+can occuras a resultof geneticor epigeneticmechanismsthatresultin lossof genessuch as breastcancer genes, or BRCA1 andBRCA2,thatarerequiredforefficientDNA repair.Morerecentdatasupportthepotentialsynthetic lethalityofPRMT5inhibitionintumorsthatareHRD+duetotheroleofPRMT5inDNArepair(Figure2). PRMT5upregulates the transcription of genes involved in HRrepair to regulate the DNAdamage repair response.PRMT5 inhibitionhasbeenshownpreclinicallyto decreaseexpressionof thesegenesto inducecell death,supportingthepotentialof PRMT5inhibitorsin HRD+tumors.

Figure 2. PRMT5 Inhibition in HRD+ Tumors

PRMT5upregulatestheexpressionofDNArepairgenesincludingBRCA1,BRCA2,RAD51,RAD51DandKu80.Inhibition ofPRMT5 reducesexpressionofthesegenesandpreventsDNArepair,inducingastateof“BRCAness”andleadingtotumorcelldeathaswellas synergyin combinationwith PARPinhibitors.

Together,thesedatasupportthedevelopmentofPRMT5 inhibitorsinselectsolidtumorsandhematologic malignancies.

Our Approach to Designing OptimizedPRMT5Inhibitors

PRMT5 hasstrongscientificrationaleforitstargetinginthetreatmentofcancer,asitsinhibitionhas been showntosuppresstumorgrowthandproducesyntheticlethalitypreclinically.PRMT5containstwo bindingsites, asubstrateandacofactor(SAM),providingtwodistinctmodes-of-inhibitionofPRMT5 (Figure3).Weutilized X-raycrystalstructuresofPRMT5torapidlydesignandsynthesizeSAMcofactormimeticinhibitorsthatare highly selective for PRMT5, distinct from a substrate competitive inhibitor approach. Given that SAM contributesthemethylgrouptoallofthePRMT5 substrates,webelievethisapproachgivesusanopportunityto morebroadlymodulatetheactivityof PRMT5comparedto a substratecompetitiveinhibitor.

Figure 3. Binding Mode of Prelude PRMT5 Inhibitors

Werationallydesignedand synthesizedmorethan600 compoundsduringtheoptimizationof our lead productcandidatestonotonlyimprovepotency,butalsotosimultaneouslybuildinADME andpharmaceutical properties.Theseeffortsledtoselectionofourfirstcompound,PRT543,anovelSAMmimetic,thatisdesigned tobeahighlypotentandselectivePRMT5 inhibitor.Inaddition,tocreateaPRMT5 inhibitorwiththepotential forhighbrainexposure,weoptimizedthemolecularandphysicochemicalpropertiesofourSAMcompetitive leadsusinginvitroassaystoscreen

forcompoundswithloweffluxpotentialfollowedbyconfirmatorybrain exposurestudiesinvivo.Oursecondcompound,PRT811,isanovelbrainpenetrantPRMT5inhibitor.These moleculesaredifferentiatedbytheirmodeofinhibitionandtheirpotency,whichcomparefavorablyto themost advancedPRMT5 inhibitorindevelopment,GSK3326595. PRT543 andPRT811 wereselectedtoadvanceinto clinicaldevelopmentbecausetheyhavewellbalancedproperties,whichwebelievewillleadto an increasein the probabilityof clinicalactivity.

PRT543

Overview

WearecurrentlyadvancingourfirstclinicalcandidatePRT543,anoralinhibitorofPRMT5 inaPhase1 clinicaltrialin advancedsolidtumorsand selectmyeloidmalignancies.Upon establishinga recommended expansiondose,weplantobeginenrollingpatientsin theexpansionportionof thePhase 1 programin select tumortypesthatarepotentiallydrivenbyPRMT5dysregulation.ThesetumortypesincludeACC, MF, genomicallyselectedMDS,andgenomicallyselectedHRD+tumors.We have recently completed the dose escalation portion of the trial. The dose expansion portion of the Phase 1 trial is open for the patient cohort with adenoid cystic carcinoma and we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the second quarter of 2021.Weanticipatepresentinginitialclinicaldatafromthetrialatmedicalmeetingsinthesecondhalfof

2021.

PreclinicalResults—Summary

Invitro,weobservedthatPRT543 ispotentandhighlyselectiveinbiochemicalassays.In cellularassays PRT543 treatmentresultedinadose-dependentreductioninsymmetricdimethylationof arginine,or sDMA, levels,adirectreadoutofPRMT5activity,intumorcelllines.PRT543inhibitedtheproliferationofapanelof celllinesrepresentativeof both hematologicand solidtumortypesboth as monotherapyand in combinationwith othertargetedtherapies.PRT543was activein celllinesthatareresistantto othertargetedagents.

Invivo,PRT543demonstratedhighoralbioavailability(F%>100%inrats;65%,indogs)andalonghalf- life(~5-10hinratsand~20hdogs).PRT543exhibitedactivityinarangeofxenograftandPDXmodelsofsolid tumorsandhematologicmalignancies,includingACC, AMLandMF.Inthesetumormodels,PRT543 demonstratedacleardose-responserelationshipbetweensuppressionofsDMA levelsand tumorgrowth inhibition,or TGI, establishinga linkbetweentargetengagementand preclinicalactivity.These data define the targetplasmadrugconcentrationandsDMAinhibitiongoalsinthedoseescalationportionofhumanclinical trials.

In VitroPotencyand Selectivity

WeinvestigatedtheinvitropotencyofPRT543 toinhibitthemethyltransferaseactivityofhuman recombinantPRMT5 bymeasuringitsIC50.IC50isaquantitativemeasureof how muchof a compoundis neededtoinhibitabiologicalprocessby50%.Inthisassay,weobservedtheIC50ofPRT543 to be 10.8 nM. We alsoinvestigatedtheinvitroselectivityofPRT543 forPRMT5 ascomparedtoapanelof36otherhuman methyltransferases.Whentestedataconcentration1,000timesaboveitsIC50forPRMT5, weobservedthat PRT543exhibitedminimalinhibitionofCARM1(36.5%at10μM) andnoinhibitionofanyotherhuman methyltransferasetested.

PRT543potentlyreducedsDMA levels,a directreadoutof PRMT5 activity,in cells

WedeterminedthepotencyofPRT543 toinhibitPRMT5 incellsbymeasuringlevelsof sDMA, a direct measureofPRMT5activity.TumorcelllinesweretreatedinvitrowithvariousconcentrationsofPRT543 for threedaysandthePRT543IC50valuetoinhibitsDMAdetermined.WeobservedthatPRT543potentlyand dose-dependentlyreducedsDMAlevelsintumorcelllinesinvitrowithnanomolarIC50 values(Figure4). These datademonstrateon-targeteffectsof PRT543in cells.

Figure 4. PRT543 Dose-Dependently Reduced sDMA Levels in Tumor Cell Lines In Vitro

Westernblotdemonstratingconcentration-dependentreductionofsymmetricallydimethylatedSMD3,aknownPRMT5substrate,following

3 days of PRT543treatmentin indicatedcelllines.Granta-519isa MCL celllineand SET-2 isa JAK2V617FmutantAML cellline.

PRT543inhibitstheproliferationof a broad panelof celllinesin vitro

WeinvestigatedthepotencyofPRT543 toinhibittheproliferationofapanelof celllinesrepresentativeof bothhematologicmalignanciesandsolidtumorsinvitro. Tumorcelllineswere treatedwith various concentrationsofPRT543andthenumberofviablecellswasmeasuredaftertendaysinculture.Weobserved thatPRT543 inhibitedthegrowth of celllinesrepresentativeof both solidtumorsand hematologicmalignancies with nanomolarpotencies,demonstratingitsbroadanti-tumoreffectsin vitro(Figure5).

WealsoexploredwhetherPRT543 wasactiveinprimarycellsorcelllinesknown to be resistantto specific targetedtherapies.Invitro,weobservedthatPRT543 inhibitedthegrowthofprimaryAML patientsamples, includingthoseshowntoberesistanttotheBCL2inhibitor,venetoclax,ortheFLT3 inhibitor,gilteritinib,two currently approved therapies for AML patients. Additionally, PRT543 demonstrated activity in a cell line renderedinsensitivetoJAKinhibitors,suggestingthatPRMT5inhibitionmayovercomeresistancetoother targetedtherapies.

Figure 5: Broad Antiproliferative Activity of PRT543 in a Cancer Cell Line Panel

Profileoftheanti-proliferative responsetoPRT543inapanelof85celllinesfollowing10daysoftreatment.BaselinecorrespondstoIC50=

250nM.BarsbelowthebaselinerepresentcelllineswherePRT543demonstratesmorepotentIC50valuesandbarsabovethebaselineare lesspotent.

GiventheroleofPRMT5inDNA repair,weinvestigatedtheeffectsofPRT543 toinhibitthegrowthof HRD+tumorcelllines.TwoHRD+breastcancercelllines,MDA-MB-436andMDA-MB-468,weretreated withvariousconcentrationsofPRT543 andthenumberofviablecellswas measuredafter10 days in culture.We observedthatPRT543 demonstratedpotentactivityinblockingthegrowthofthesecelllinesinvitrowithIC50 valuesof50-150nM(Figure6).Consistentwiththis,PRT543decreasedlevelsofexpressionofanumberof genesinvolvedinDNArepair,includingBRCA1,BRCA2,ATMandATR,andwassynergisticincombination with PARPinhibitors.

Figure 6. PRT543 Inhibits the Growth of HRD+ Breast Cancer Cell Lines.

Two HRD+breast cancer cell lines, MDA-MB-436 and MDA-MB-468, were treated for 10 days with PRT543 and effects on cell proliferationdetermined.Data are plottedrelativeto DMSOcontrol.

In vivo,PRT543demonstrateda correlationbetweensDMA inhibitionand efficacy

Invivo,weinvestigatedtheabilityofPRT543toreducesDMAlevelsintumortissuesandinplasmain severalmodels,includingtheSET2 modelofAML.PRT543 dosesof5mg/kg,15mg/kgor30 mg/kgwere administeredorallytotumor-bearingmice,once daily,for28 days. As shown in Figure7, we observedthat PRT543dose-dependentlyreducedsDMAlevelsinthetumor,indicatingitinhibitedcellularPRMT5 activityin vivo.PRT543 demonstratedapproximately90%inhibitionofsDMAlevelsinthetumoratthe30mg/kgand 15 mg/kgonce-a-day,orq.d.,doses.Itshouldbenotedthatatdosesthatresultin a 90% reductionin tumorsDMA, approximately50%reductionin plasmasDMA levelswas observed,suggestingthattumorsDMA maybe a more sensitive readout. PRT543 at both dose levels demonstrated significant anti-tumor activity (Figure 7). Collectively,resultsfromthesepreclinicalmodelssupporttargeting50% inhibitionof plasmaor serumsDMA in Phase 1 dose escalationto establisha pharmacologicallyactivedose.

Figure 7. PRT543 PD/Efficacy Relationship in Preclinical Models

PD Efficacy

Oraladministration ofPRT543leadstodose-dependentdecreasesintumorsDMAandTGIintheSET-2AMLmodel,Westernblotshowing sDMAreduction inSET-2tumor tissue collected4hours after the last dose,at the endofa 28-day study.Efficacydatarepresentmean±SEM with 8 mice/group.* P <0.05, ** P <0.01 vs. vehicleby Mann-WhitneyU test.

PRT543isactivein models of ACCand MF in vivo

Invitro,weobservedthatPRT543 decreasedtheexpressionof theMYB oncogeneas wellas MYB-regulated genesinheadandneckcancercelllines.BecausetheactivityoftheMYB oncogenemaybeimportantinACC, whereapproximately90%ofpatientshaveMYBalterations,weinvestigatedwhetherPRT543wasactiveina PDXmodelofACC,ACCx9. PRT543 dosesof25mg/kgand35mg/kgwereadministeredorallytotumor- bearingmice,twicedaily,for28days.WeobservedthatbothdosesofPRT543 inhibitedtumorgrowth in this PDXmodelof ACC(Figure8). These datasupporttheclinicaldevelopmentof PRT543in ACC.

Figure 8. PRT543 Demonstrated Activity in PDX Models of ACC In Vivo

PRT543 oral administration decreased tumor growth in the ACCX9 PDX model of ACC. Data represent mean ± SEM with 8 mice/group.

In addition to studies in ACC models, we observed that PRT543 was active in vivo in solid tumor models representative of bladder cancer and small cell lung cancer at well-tolerated doses. PRT543 was also active in vivo in models of hematological malignancies, including AML and mantle cell lymphoma. In the Granta-519 model of mantle cell lymphoma, PRT543 demonstrated single agent activity and was synergistic in combination with the approved BCL2 inhibitor, venetoclax (Figure 9).

Figure 9. PRT543 is Active as Monotherapy and in Combination In Vivo

Oraladministration ofPRT543ledtodose-dependentTGIintheGranta-519MCLxenograftmodel.CombinationofPRT543andvenetoclax resultedinsignificant TGIatdosesthatdidnotshowactivity asmonotherapyforbothagentsintheGranta-519xenograftmodel.Thedoses testedinthecombinationarmofthestudywere20mg/kgQDofPRT543and30mg/kgQDofvenetoclax.Datarepresentmean±SEM.

** P <0.01 vs. Vehicleby Mann-WhitneyU test.

Finally,weinvestigatedtheactivityofPRT543inamodelofJAK2V617F mutantmyeloproliferative neoplasms,orMPN.Inthismodel,weobservedthatPRT543 ledtoareductioninspleensizeandnormalization ofwhiteblood cellsand reticulocytescounts,key phenotypiceffectsof JAK2 dyrsegulationthroughthe JAK2V617Fmutation,bothasmonotherapyandincombinationwiththeapprovedJAK inhibitor,ruxolitinib. Importantly,theobservedlevelofsuppressionofdiseasespecificeffectsfollowingtreatmentwithPRT543 were similarto thoseachievedwith theapprovedtherapy,ruxolitinib(Figure10).

Figure 10. PRT543 Was Active in a Model of JAK2V617F Mutant MPN.

OraladministrationofPRT543asmonotherapyandincombinationwithruxolitinibledtosignificantdecreaseinspleensizeintheJAK2VF

bonemarrowtransplantmodelofMF.Datarepresentmean±SEM.DottedlineindicatesmeanspleenweightofWTtransplantedmice.

* P <0.05, ** P <0.01, *** P <0.001 vs. vehicleby Mann-WhitneyU test.

Together,thesedataprovidestrongrationaleforadvancingPRT543 intopatientswithsolidtumorssuchas ACCandHRD+tumorsaswellasmyeloidmalignanciesincludingMFandMDS,andprovideopportunitiesfor patientselection(ruxolitinibfailuresinMF,patientswithspliceosomalmutations,HRD+ tumors,MYB+ACC) and combination strategies (with ruxolitinib in MF, venetoclax in MDS/AML, PARP inhibitors in HRD+ tumors).

Clinical Experience

All data are reflective of a data cutoff of September 1, 2020 unless otherwise stated.

We are currently enrolling a Phase 1, open-label, multicenter, dose expansion clinical trial of monotherapy PRT543 in patients with advanced solid tumors, MF or MDS. We have been encouraged by both the clinical activity and tolerability data that has been observed in 41 patients (29 with advanced solid tumors, one with NHL, nine with MF and two with MDS) that

have enrolled into the dose escalation portion of the study as of our data cutoff date of September 1, 2020. We have observed early signs of clinical activity, including a confirmed CR per RECIST v1.1, in a patient with HRD+ high grade serous ovarian cancer, at the 35 mg 5x/week dose level. In addition, one MF patient at the 20 mg twice a week, or b.i.w., dose level has demonstrated a best response of clinical improvement per International Working Group, or IWG, criteria as of September 1, 2020. This patient has exceeded one year on study. A second MF patient at the 40 mg three times a week, or t.i.w., dose level demonstrated an approximately 66% reduction in TSS. Improvement in isolated symptoms and extended duration of therapy have been seen in other MF patients. The safety profile has consisted predominantly of Grade 1-2 adverse events and was similar across both solid tumor and myeloid malignancies patients. As of September 1, 2020, the dose-limiting toxicity experienced at the highest dose level evaluated in both groups has been thrombocytopenia, which in all cases has been reversible without sequalae after a one to two week drug holiday. There have been no deaths or study discontinuation attributed to PRT543. PK/PD analysis reveals dose-dependent increases in drug exposure across doses and schedules with associated decreases in serum sDMA levels. We have recently completed the dose escalation portion of the trial. The dose expansion portion of the Phase 1 trial is open for the patient cohort with adenoid cystic carcinomaand we now expect to begin patient enrollment into additional solid tumor and myeloid malignancies expansion cohorts early in the second quarter of 2021. While early in development and there is no guarantee of approval by the FDA or other regulatory authorities, we are encouraged by the clinical activity of PRT543.

Clinical Trial Design and Schema

Our PRT543 Phase 1 clinical trial design seeks to leverage PRT543’s broad potential therapeutic utility to rapidly generate proof-of-concept across multiple solid tumors and myeloid malignancies. Trial enrollment of patients with relapsed/refractory, or R/R, advanced solid tumors, NHL (Group A) or R/R MF or MDS (Group B) commenced in February 2019 and is being conducted at approximately 25 sites throughout the United States. This clinical trial consists of two parts, a dose escalation portion followed by dose expansion into separate tumor-specific cohorts. Enrollment into the additional dose expansion cohorts is expected to begin early in the second quarter of 2021. Total expected enrollment is anticipated to be approximately 160 patients. The schema is shown below in Figure 11.

Figure 11. PRT543 Clinical Trial Schema

Interim and Preliminary Clinical Results

Interim and Preliminary Safety Data: Group A & Group B

The safety profiles of the 41 patients enrolled have been similar between Group A (solid tumor; 30 patients) and Group B (MF and MDS; 11 patients) treated at doses and schedules ranging from 5 mg b.i.w to 50 mg once a day, or q.d,. Nine patient deaths were reported, none of which were related to PRT543. There were no patients that discontinued study

therapy due to an adverse event. A total of 18 SAEs have been reported amongst six patients and of those, only one event (grade 4 thrombocytopenia) in one patient was deemed related to PRT543.

Adverse events were similar between patient groups with the majority of these adverse events (84.6%) being Grades 1-2. The most common adverse events were diarrhea, nausea and fatigue, ranging from 30% to 50% in both groups and were manageable with standard treatment routine amongst patients with cancer.

Dose limiting toxicity of grade 4 thrombocytopenia has been observed in two out of three Group A patients at the 50 mg q.d. dose level and one out of six Group B patients at the 40 mg t.i.w. dose level, one of which was deemed to be a serious adverse event, or SAE. However, in all of these patients, platelets recovered to baseline levels after a one to two week drug holiday and they remained on the study and restarted at a lower dose. At the 35 mg q.d. dose level, three of the four patients have experienced grade 3 thrombocytopenia. Patients had their doses reduced and remained on study. Among the eight patients who either started or were dose reduced to the 35 mg 5x/week dose level, only one experienced any thrombocytopenia (grade 3).

Group A (Solid Tumors)

Pharmacokinetic Data; Group A (Solid Tumors)

Preliminary PK data were available for 30 solid tumor patients administered various regimens of oral doses of PRT543 (mean values are shown in Table 2). We observed that PRT543 demonstrated rapid absorption with the Tmax generally occurring between one to three hours with dose-proportional increases in exposure. Half-life values for different doses ranged from approximately 7-18 hours, consistent with the long half-life predicted by preclinical data. Exposures were generally similar between Day 1 (first dose of cycle) and Day 25 at doses up to 35 mg. However, the 50 mg q.d. dose demonstrated significant accumulation of PRT543, which was likely associated with dose-limiting exposure. The calculated weekly exposure of the 50 mg q.d. dose was >2-fold higher than the 35 mg dose administered 5x/week, with a weekly AUC of 243 μM h versus 96 μM h. Our preliminary PK data showed plasma levels at doses of 22.5 mg and above achieved the concentrations required to inhibit PRMT5 in our preclinical in vitro and in vivo models, and hence support continued clinical development. We believe our optimal dose will be between 22.5 mg and 50 mg.

Table 2. Preliminary Day 1 Pharmacokinetics in Solid Tumor Cohort

Parameter Doses and Schedules

b.i.w b.i.w b.i.w b.i.w b.i.w. 5x /q.d. q.d

Cmax means the observed maximum plasma concentration after dosing. Tmax means the time to reach the Cmax. AUC0-t means the area under the plasma concentration time curve from time 0 to the last measurable time point.

Pharmacodynamic Data: Group A (Solid Tumors)

Serum sDMA levels, a PD measurement of PRMT5 target engagement, were assessed at baseline and on Day 15 of the treatment cycle. Dose-dependent inhibition of PRMT5 as demonstrated by serum sDMA reduction was observed across groups in the solid tumor cohort. The mean reduction in sDMA level was approximately 75% at both the 35 mg q.d. and 50 mg q.d. doses, which are the highest dose groups evaluated as of September 1, 2020, demonstrating maximum inhibition of PRMT5 activity. In the other cohorts where the dosing was intermittent (b.i.w. and 5x/week doses), serum for sDMA analyses was collected at least 72 hours after the last dose of PRT543 was administered. Therefore, the extent of PRMT5 inhibition was likely underestimated due to rebound in sDMA when the compound is no longer present. In preclinical models, 50% inhibition of sDMA was associated with anti-tumor activity in vivo.

Figure 12. PRT543 PD in Solid Tumors

Serum was obtained from patients at various times following administration of PRT543 and analyzed for sDMA levels by LC/MS. The data are shown as % relative to pre-dose levels.

Interim and Preliminary Efficacy Data: Group A (Solid Tumors/NHL)

Thirty patients have been enrolled into Group A (solid tumors/NHL). Thirteen patients have received doses ≥ 35 mg 5x/week and are response evaluable per RECIST 1.1. Of these patients, one patient demonstrated confirmed CR (HRD+ high grade serous ovarian cancer), four patients demonstrated stable disease (including an additional patient with HRD+ ovarian cancer) and four patients showed progressive disease. Seven patients remain on study, of whom four are awaiting their first response assessment. No objective responses were observed in patients that received doses below 35 mg 5x/week. Given that we are still in the dose escalation portion of a Phase 1 clinical trial in a refractory patient population, with the primary objective of evaluating safety and pharmacokinetic properties, and that a majority of patients are likely to be at subtherapeutic doses, we are encouraged by the confirmed CR in the first enrolled biomarker positive patient. The patient, diagnosed in 2014, and subsequently treated with seven prior lines of therapy for metastatic disease, including standards of care such as a PARP inhibitor, as well as experimental therapies, enrolled in the dose escalation portion of the trial at a dose/schedule of 35 mg, 5x/week. Genomic analysis demonstrated mutations in the DNA repair enzymes, RAD51D,ATR and BRCA1. At baseline, the patient was noted to have one target lesion lymph node, per RECIST, measuring 19mm across the shortest axis. Baseline CA-125 tumor marker levels measured 37.8 U/mL. At the first follow up response assessment, occurring eight weeks after enrollment, the patient’s target lesion demonstrated regression to 8mm with an associated drop in CA-125 levels to 2.6 U/mL. At the second follow up scan performed 16 weeks after enrollment, the target lesion regressed in size to 5 mm, confirming the CR. CA-125 levels measured 4.6 U/mL. At the third response assessment, performed 24 weeks after enrollment, the patient’s target lesion remained at 5 mm, further supporting the durability of the CR, and CA-125 levels measured 3.3 U/mL. The patient remains on study. Images from the patient’s computer tomography scans from baseline and 8 weeks, with highlighted target lesions, are shown below in Figure 13.

Figure 13. Baseline and 8 Week Tumor Assessment CT Scans

Group B (MF and MDS)

Pharmacokinetic and Pharmacodynamic Data: Group B (MF and MDS)

As of the data cutoff, preliminary PK data were available for 11 participants in this cohort (mean values shown in Table 3). As of September 1, 2020, the PRT543 PK profiles have been similar between solid tumor and MF and MDS patients demonstrating rapid absorption and dose-proportional increases in exposure. Exposures were generally similar between Day 1 (first dose of cycle) and Day 25 (last dose of cycle). Our preliminary PK data showed plasma levels at doses of 20 mg and above that achieved the concentrations required to inhibit PRMT5 in our preclinical in vitro and in vivo models, and hence support continued clinical development.

Table 3. Preliminary Day 1 Pharmacokinetics in Myeloid Malignancies Cohort

Parameter Doses and Schedules

b.i.w b.i.w b.i.w b.i.w/t.i.w

* Exposures from 40 mg, b.i.w. and t.i.w. dose levels combined.

Similar to the data in the solid tumor cohort, dose-dependent inhibition in sDMA levels was observed in the heme cohort. A maximum inhibition of approximately 40% was observed at the 40 mg doses, but since only intermittent dosing was tested in this cohort, this reduction may be underestimated due to the sample collection 72 hours after the compound was administered.

In addition to changes in sDMA, changes in cytokine levels and other markers of inflammation were measured in the patients in this cohort. Patients with MF have been shown to demonstrate elevated levels of inflammatory markers such as C-reactive protein, serum amyloid A, interleukin-6, tumor necrosis factor, and interleukin-12. PRT543 treatment was associated with reductions in these markers.

Based on the PK and PD data, we anticipate that an additional two to three dose levels, as originally planned, will be required in order to establish a recommended expansion dose in this cohort.

Interim and Preliminary Efficacy Data: Group B (MF and MDS)

Among the 11 patients enrolled into Group B (nine MF and two MDS), all are evaluable for response assessments as per IWG criteria. One MF patient at the 20 mg b.i.w. dose level has demonstrated an objective response of clinical improvement and continues to receive therapy beyond one year to date. A second MF patient at the 40 mg t.i.w. dose level demonstrated an approximately 66% decrease in TSS. Several other MF patients have demonstrated reductions in individual symptoms, notably pruritis, night sweats and fever. Eight patients achieved a best response of SD. We are encouraged by the extended duration of therapy in two additional patients who remained on study for approximately one year.

Clinical Update as of December 16, 2020

As of December 16, 2020, the Phase 1 clinical trial of PRT543 has currently enrolled 61 patients (42 with advanced solid tumors, one with NHL, 11 with MF and seven with MDS). The overall safety profile is unchanged from the September 1, 2020 data cutoff and consistent between both Groups A and B. The majority of drug related adverse events continue to be grade 1-2 with anemia and thrombocytopenia being the most common grade 3-4 adverse events. Thrombocytopenia is the only dose-limiting toxicity. There have been no patients that have discontinued due to adverse events. Amongst the 61 patients, 24 SAEs have been reported amongst 11 patients, with 3 individual SAEs deemed drug related. No drug-related SAEs occurred more than once throughout the study.

We have initiated the ACC expansion cohort of the trial at a dose/schedule of 35mg 5x weekly with the opportunity for intra-patient dose adjustment. Additionally, we have explored both 25mg q.d. and 45mg 5x weekly doses/schedules in the escalation phase, which may enable a dose titration algorithm in expansion. Enrollment into additional solid tumor and myeloid malignancies cohorts is expected to begin early in the second quarter of 2021.

Addressable Oncology Market for PRT543

Our clinical development strategy is to focus first on indications where there is a patient selection strategy along with a high unmet medical need, no approved therapies and opportunity to utilize early clinical data to design registrational trials. Based on these criteria, the following are examples of indications where we believe we have significant opportunity. In addition to the indications outlined below, we believe there may be opportunity in additional indications in patients with genomically defined tumors.

Adenoid Cystic Carcinoma (ACC)

Adenoid cystic carcinoma is a malignant tumor of the secretory glands often presenting in the oral cavity and pharynx (e.g., salivary glands), with approximately 1,200 patients diagnosed in the United States each year and 10-15,000 patients living with this cancer in the United States. ACC is characterized by indolent, locally invasive growth with a high propensity for recurrence and distant metastasis. The disease typically follows a slow course, with five-, ten-, and 15-year survival rates after surgical resection of 77.3%, 59.6%, and 44.9%, respectively. However, once ACC becomes metastatic, the prognosis worsens and most patients ultimately die from the disease. ACC affects a relatively young patient population, with a median age at diagnosis of 50-60 years.

The vast majority of patients are initially treated with surgical resection, if possible, followed by radiation. Approximately 40-50% of patients progress to develop advanced or metastatic disease. Chemotherapy and tyrosine kinase inhibitor therapies are the most common systemic therapies for advanced/metastatic disease, yet have shown low response rates and limited durability of disease control in clinical trials. There are currently no approved therapies for the treatment of ACC.

Homologous Recombinant Deficient Tumors (HRD+)

Homologous recombination deficient positive tumors were described for the first time in cancers with germline mutations of the tumor suppressors BRCA1/2. Other genetic and epigenetic events can also result in inactivation of various homologous recombination repair components, leading to HRD+ in non-BRCA1/2 mutated cancers.

Germline BRCA1/2 mutations resulting in HRD+ occur in 13% and 15% of ovarian and triple negative breast cancers. Furthermore, 50% and 40% of ovarian and TNBC, respectively, are characterized by harboring HRD+ in the absence of germline BRCA1/2 mutations. Additionally, 10–12% of advanced prostate cancer harbor germline or somatic BRCA2 inactivation and up to 25% contain a DNA repair defect.

BRCA1/2-mutant cancers are sensitive to PARP inhibitors, a class of drugs that block single-strand break DNA repair, favoring accumulation of double-strand breaks that tumors harboring HRD+ cannot repair. Several PARP inhibitors have been approved for the treatment of HRD+ ovarian, breast, prostate, and pancreatic cancers and generated over $1.6 billion of revenue in 2019. There are currently no approved therapies for patients who progress on PARP inhibitors.

Myelofibrosis (MF)

Myelofibrosis is part of a group of progressive blood cancers known as MPN. Approximately two-thirds of the 16,000-18,500 MF patients in the United States are classified as intermediate / high risk and are therefore eligible for systemic treatment. MF is associated with significantly reduced quality of life and shortened survival. As the disease progresses and the bone marrow produces fewer red blood cells, patients experience thrombocytopenia (low platelet counts) and anemia (low red blood cell counts) requiring increasing blood transfusions. Patients with MF suffer from multiple physical symptoms including splenic enlargement, excessive sweating, shortness of breath, bone pain, and fatigue. Demonstrated improvement in the Myelofibrosis Symptom Assessment Form TSS, which is comprised of six specific symptoms associated with MF (abdominal discomfort, pain under the left ribs, an early feeling of fullness, night sweats, bone and muscle pain and itching), has served as a key clinical endpoint in MF trials.

The current standard of care therapy for intermediate- and high-risk MF patients is ruxolitinib, a JAK1/JAK2 inhibitor that inhibits dysregulated JAK. Ruxolitinib revenues in MF were $1.6 billion in 2019. However, patients with anemia and/or thrombocytopenia are ineligible to receive ruxolitinib. Additionally, most patients will experience disease progression on ruxolitinib within three to five years.

Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes are a group of blood disorders in which bone marrow becomes dysplastic or defective. The affected bone marrow produces aberrant blood cells, resulting in cytopenias (low healthy blood cell counts) that require transfusions. Bone marrow failure is progressive, and in advanced stages of the disease, blasts (immature blood cells) leave the bone marrow and enter the blood stream, leading to AML in approximately one-third of patients.

The American Cancer Society estimates the annual incidence of MDS to be more than 10,000 cases, and studies suggest the prevalence of MDS to be more than 60,000 cases in the United States. Various risk criteria are used to stratify MDS patients, including the French-American-British classifications and the Revised International Prognostic Scoring System, with higher risk MDS patients having a median survival of less than two years. Approximately one-third of MDS patients in the United States are classified as higher risk.

The standard of care treatment for higher risk MDS includes hypomethylating drugs azacitidine and/or decitabine. A significant number of higher risk MDS patients fail or cannot tolerate treatment with azacitidine or decitabine, and almost all patients who initially respond to therapy eventually relapse. Median survival time of MDS patients who have progressed on hypomethylating drugs is less than six months.

Uveal Melanoma (UM)

Uveal melanoma, or UM, is the most common primary intraocular malignancy in adults and comprises 5% of all melanomas. UM is an orphan disease with an estimated annual incidence in the United States and Europe of 6 per million population per year.

Localized treatment for UM, including radiotherapy, phototherapy, and local tumor resection, aims to preserve the eye and vision while preventing metastases. However, surgical removal of the eye can be indicated depending on the tumor size, position, and risk of metastasis. Almost 50% of patients with uveal melanoma will develop distant metastasis. The liver is the most common site of metastasis and is involved in 90% of patients who develop metastatic disease. The median survival of uveal melanoma patients with liver metastases is reported to be five to six months, with a one-year survival of 10% to 15%.

While there have been numerous recent therapeutic advancements and approvals for patients with metastatic cutaneous melanoma, the situation for patients with metastatic uveal melanoma is quite different. Several targeted therapies and immunotherapies have been studied in patients with uveal melanoma; however, response rates have been low (<10%) with median overall survival ranging from 4 to 15 months.

PRT811

Overview

Our second PRMT5 inhibitor, PRT811 is currently advancing in the dose escalation portion of a Phase 1 clinical trial in solid tumors, including GBM and PCNSL. PRT811 is designed to be a highly potent, selective and orally bioavailable molecule optimized for high brain exposure and hence we believe is uniquely positioned to treat PRMT5-sensitive CNS cancers. Upon characterizing PK, PD and safety profile and selecting a recommended dose, we plan to begin enrolling patients, including patients with GBM and other CNS cancers determined to be sensitive to PRMT5 inhibition, in the expansion portion of the clinical trial. We expect these expansions to initiate by mid-2021 and anticipate initial clinical results from this trial by the end of 2021.

Preclinical

In vitro potency and selectivity

We investigated the in vitro potency of PRT811 to inhibit the methyltransferase activity of human recombinant PRMT5 by measuring its IC50. In this assay, we observed the IC50 of PRT811 to be 3.9 nM. We also investigated the in vitro selectivity of PRT811 for PRMT5 as compared to a panel of 36 other human methyltransferases. When tested at a concentration >1,000 times above its IC50 for PRMT5, we observed that PRT811 exhibited minimal inhibition of PRMT7 (53.9% at 10 μM) and no inhibition of any other human methyltransferase tested.

We determined the potency of PRT811 to inhibit PRMT5 in cells by measuring levels sDMA, a direct measure of PRMT5 activity. Tumor cell lines were treated in vitro with various concentrations of PRT811 for three days and the PRT811 IC50 value to inhibit sDMA determined. We observed that PRT811 potently and dose-dependently reduced sDMA levels in the U87 glioblastoma cell line with an IC50 value of 17 nM (Figure 14). The potency of PRT811 in blocking sDMA levels was confirmed in 11 additional cell lines, with IC50 values in the range of 7-40 nM. These data demonstrate on-target effects of PRT811 in cells.

Figure 14. PRT811 is Highly Selective and Demonstrated Potent Inhibition of sDMA in Cells

Concentration-dependent inhibition of cellular sDMA by PRT811 in U-87 MG cells following three days of treatment in culture. sDMA IC50=17 ± 1 nM (n=12).

We investigated the potency of PRT811 to inhibit the proliferation of a panel of cell lines representative of brain cancers as well as cancers known to have a high rate of brain metastasis (breast, lung, melanoma and hematological malignancies including lymphoma). Tumor cell lines were treated with various concentrations of PRT811 and the number of viable cells was measured after ten days in culture. Consistent with its effects in blocking sDMA levels, PRT811 inhibited the growth of the majority of cell lines in the panel with nanomolar potencies, demonstrating its broad anti-tumor effects in vitro (Figure 15).

Figure 15. Broad Antiproliferative Activity of PRT811 in a Cancer Cell Line Panel

Waterfall plot showing anti-proliferative activity of PRT811 against a panel of 87 cell lines. Cell panel consists of brain cancer cell lines, as well as breast, lung, and melanoma cells lines, the predominant cancer types that metastasize to the brain.

Preclinical pharmacokinetic profile

The PK profile of PRT811 was characterized in vitro and in vivo in multiple preclinical species including rat, dog and monkey. PRT811 was observed to have good oral bioavailability and high permeability and was not a substrate for P-glycoprotein, or P-gp, and other efflux mechanisms that typically result in low brain exposure. These data suggest PRT811 is not likely to have high efflux out of the brain due to transporters such as P-gp, an important feature of brain penetrant compounds. Accordingly, we observed that the brain exposure of PRT811 in rats after an IV infusion was high with an approximate brain/plasma ratio of two (Table 4). Although both compounds have equivalent potency to inhibit GBM cell line U87 proliferation, the brain:plasma ratio was approximately 100x higher for PRT811 compared to the GSK PRMT5 inhibitor currently in development, providing a clear differentiation for PRT811.

Table 4. Comparison of Cellular Potency and Brain to Plasma Ratio of PRT811 vs. GSK3326595

Concentration-dependent inhibition of U87 glioblastoma tumor cell proliferation in vitro following 10 days of treatment with PRT811 or GSK3326595. Concentration (total) of PRT811 and GSK3326595 in rat plasma and brain following a 4-h IV infusion at 5 mL/h/kg. Data are expressed as mean concentration (±SD) in naïve male animals (n = 3 per time point).

The ability of a compound to effectively achieve high brain exposures has been highlighted most recently by the significantly improved activity of brain penetrant kinase inhibitors compared to their non-brain penetrant counterparts in patients with CNS cancers or with CNS metastasis. In addition, a clear role for PRMT5 inhibition in CNS cancers such as glioblastoma has been demonstrated in preclinical models. Glioblastoma has been shown to be highly dependent on correct mRNA splicing for growth and to have alterations in MTAP and cyclin D1, all markers of enhanced sensitivity to PRMT5

inhibition. High PRMT5 expression has been shown to reduce GBM median survival from over 700 days to approximately 100 days. Together, these data provide a clear rationale for selecting PRT811 for development in CNS cancers.

PRT811 activity in models for GBM

In vivo, we investigated the ability of PRT811 to reduce sDMA levels in tumor tissues in the U-87MG GBM xenograft tumor model. Tumor-bearing mice were dosed orally once daily for 25 days with either 20 or 30 mg/kg of PRT811. PRT811 at both dose levels demonstrated significant anti-tumor activity in the U-87MG model with 91% inhibition at the 20 mg/kg dose and 100% inhibition at the 30 mg/kg dose (Figure 16). At the 20 mg/kg dose, the plasma concentrations of PRT811 were above the protein binding adjusted in vitro IC50 value observed in the sDMA cellular assay for approximately six hours, suggesting that continual enzyme inhibition is not required for activity in the model.

Figure 16. PRT811 Inhibited Tumor Growth in the U-87MG Subcutaneous Xenograft Model

Nude rats bearing subcutaneously implanted U-87 MG tumors were dosed orally with 20 or 30 mg/kg PRT811 q.d.. Significant antitumor activities were observed at both doses (tumor regression for 30 mg/kg). *: P< 0.05; **: P< 0.01. Student’s t test, 2 tailed. N=8/arm mg/kg, milligrams/kilogram; PO, oral; q.d., once daily; SEM, standard error of the mean.

Since PRT811 was shown to have brain penetration, the effects of PRT811 treatment on sDMA levels in an orthotopic U-87MG model were also assessed. In this model, the U87 glioblastoma cells were implanted directly in the brain. This model requires compound penetration into the brain in order for the compound to inhibit tumor growth. PRT811 was dosed orally once daily for seven days at 80 mg/kg and sDMA levels measured by immunohistochemistry in the brain tumor tissues. We observed that PRT811 reduced sDMA levels in brain tumor tissues by approximately 50% (Figure 17), indicating that it effectively penetrated the brain tumor tissue and inhibited cellular PRMT5 activity in the brain tumor.

Figure 17. PRT811 Decreased sDMA Levels in the U87 Orthotopic Model

Mice bearing orthotopic U-87 MG tumors were treated with vehicle or PRT811 (80 mg/kg, BID) for one week. Whole brain sections (FFPE) were stained with H&E or sDMA antibody.

In summary, PRT811 was shown to have high brain exposure, to inhibit PRMT5 activity in a brain tumor model and to demonstrate significant anti-tumor activity in vivo. No evidence of CNS toxicity was observed in preclinical toxicology studies. Together, these data support the exploration of PRT811 in cancers, including in GBM, PCNSL and other CNS cancers.

Clinical Experience

All data are reflective of a data cutoff of September 1, 2020 unless otherwise stated.

Data is available from 17 patients (ten with solid tumors, six with glioma, one with diagnosis pending) from the dose escalation portion of the ongoing Phase 1 clinical trial of monotherapy PRT811. The safety profile consists predominantly of Grades 1-2 adverse events and was similar across both solid tumor and glioma patients. As of September 1, 2020, no dose limiting toxicities have been seen. PK/PD analysis reveals dose-dependent increases in drug exposure across doses and schedules with associated decreases in sDMA levels. The dose escalation portion is ongoing. The dose expansion portion of the study is expected to begin in the second half of the year.

Clinical Trial Design and Schema

This is a multicenter, open-label, dose-escalation, dose-expansion Phase 1 clinical trial of PRT811. Enrollment into the dose escalation portion of the clinical trial includes patients with R/R solid tumors, PCNSL, and /or high-grade gliomas. Enrollment initiated in November 2019 and is being conducted across seven sites in the United States. We anticipate initiating enrollment of the dose expansion portion of the clinical trial in two patient cohorts consisting of patients with GBM and R/R PCNSL, respectively, by mid-2021. The total expected enrollment is approximately 60 patients.

Figure 18. PRT811 Clinical Trial Schema

Interim and Preliminary Clinical Data

Interim and Preliminary Results: Dose Escalation

As of September 1, 2020, the safety profile among 17 patients demonstrated that PRT811 has been well tolerated at the doses and schedule ranging from 15 mg to 200 mg (q.d. two weeks on/one week off). There were no deaths or study discontinuations related to PRT811. A total of five SAEs have been reported amongst five patients and of those, none were deemed related to PRT811.

The most commonly reported adverse events, regardless of causality, include constipation (29.4%), nausea (23.5%), vomiting (11.8%) and hyponatremia (11.8%). When examining drug-related adverse events, nausea (17.6%) was most reported. It should be noted that the vast majority, 91.8%, of these adverse events were Grades 1-2 and adverse effects of this type and grade are routine amongst cancer patients and can be medically managed with relative ease.

No dose limiting toxicities have been observed as of September 1, 2020.

Of the 17 patients including six GBM patients evaluated as of September 1, 2020, one patient has demonstrated evidence of tumor size reduction by MRI evaluation. This patient with recurrent GBM, who was originally diagnosed and treated with surgery and chemoradiation with Temodar in July 2019, presented with progressive disease in June 2020. The

patient initiated study therapy with PRT811 in July 2020 and was placed into the 200 mg (q.d. two weeks on/one week off) dose cohort. The patient’s tumor is positive for IDH1(R132H) mutation and negative for methylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter. Baseline MRI scans revealed a single target lesion, per response assessment in neuro-oncology (RANO) criteria, measuring 23 mm by 10 mm. In September 2020, we were notified that at the patient’s first follow-up scan performed on week seven, the lesion measured 13 mm by 6 mm, representing a 66% decrease from baseline. T2/FLAIR (fluid-attenuated inversion recovery) sequence, measured as a standard part of GBM MRI evaluation, was stable. The patient has not been treated with steroids or Avastin and their clinical status is stable. The patient remains on study with follow-up MRI evaluations to be conducted approximately every eight weeks. Figure 18.1 below shows baseline and the first follow up MRI images of the patient’s lesion.

Figure 18.1

Pharmacokinetic and Pharmacodynamic Data

As of the data cutoff, preliminary PK data were available for 17 patients administered PRT811 at one schedule (q.d. two weeks on/one week off). Mean data are shown in Table 5.

We observed that PRT811 demonstrated rapid absorption with dose-proportional increases in exposure. Half-life values for different doses are similar, ranging from two to four hours, as predicted by preclinical data. The maximum plasma concentration, or Cmax, at the 120 and 200 mg doses reached the estimated IC50 for PRMT5 inhibition. Consistent with the PK, the maximum sDMA inhibition observed, as an indicator of target engagement, was approximately 50% at the 120 and 200 mg dose levels. Based on the current PK and PD, two to three additional cohorts are anticipated, as originally planned, to reach the recommended expansion dose. Our preliminary PK data showed plasma levels at doses of 120 mg and above achieved the concentrations required to inhibit PRMT5 in our preclinical in vitro and in vivo models, and hence support continued clinical development.

Table 5. Preliminary Day 1 PRT811 Pharmacokinetics

Parameter Doses

Clinical Update as of December 16, 2020

As of December 16, 2020, the Phase 1 clinical trial of PRT811 has enrolled 24 patients (eight with GBM, and 16 with advanced solid tumors). The overall safety profile is unchanged from the September 1, 2020 data cutoff. Four patients have each experienced one SAE, none of which were attributed to study therapy. No dose limiting toxicities have been observed as of December 16, 2020. There has been one patient that has discontinued study therapy due to transient Grade 2 nausea occurring immediately after ingestion of study therapy.

The 300mg q.d. dose cohort is currently ongoing. We expect to initiate the expansion portion of the trial in cancers including GBM, PCNSL, and CNS metastatic solid tumors by mid-2021.

Addressable Oncology Market for PRT811

Our clinical development strategy for PRT811 is to initially focus on CNS indications where there is a patient selection strategy along with a high unmet need, no approved therapies and opportunity to utilize early clinical data to design registrational trials. Based on these criteria, the following are examples of indications where we believe we have significant opportunity. Additionally, we may explore the activity of PRT811 in CNS metastatic disease, which impacts approximately 200,000 patients annually in the United States.

Glioblastoma multiforme (GBM)

Glioblastoma multiforme is the most common malignant primary brain tumor making up 54% of all gliomas and 16% of all primary brain tumors. It is the most aggressive diffuse glioma tumor of astrocytic lineage and under WHO classification is considered a grade IV glioma. Each year, there are approximately 10,000 patients diagnosed with GBM in the United States. GBM remains an incurable tumor with a median survival of only 15 months. Fewer than five percent of GBM patients live beyond five years.

GBMs can be classified into primary and secondary GBMs. Primary GBM occurs de novo without evidence of a less malignant precursor, whereas secondary GBM develops from initially low-grade diffuse astrocytoma (WHO grade II diffuse astrocytoma) or anaplastic astrocytoma (Grade III). The majority of GBMs (90%) are primary and patients with primary GBM tend to be older (mean age = 55 years) than those with secondary GBM (mean age = 40 years).

Treatment is mainly palliative, initially consisting of surgical resection followed by radiation therapy and concurrent chemotherapy. Current therapies include GLIADEL Wafers (carmustine implant), TEMODAR (temozolomide) and AVASTIN (bevacizumab), which show virtually no overall survival benefit for recurrent tumors.

Primary CNS Lymphoma (PCNSL)

Primary central nervous system lymphoma is a type of NHL in which malignant lymphatic cells form in the brain and/or spinal cord. PCNSL can also start in the eye (ocular lymphoma) and/or can involve the cerebrospinal fluid (leptomeningeal lymphoma).

PCNSL is a rare malignancy with an annual incidence rate of seven cases per 1,000,000 people in the United States. PCNSL is relatively more common in immunosuppressed populations, particularly among people with human immunodeficiency virus, or HIV, infection or in solid organ transplant recipients. The median age of diagnosis is 55; the median age of HIV-infected patients with PCNSL is 35.

From 1998 through 2011, survival was poor for PCNSL cases, with just 15.8% of HIV-infected cases and 28.9% of HIV-uninfected cases alive five years after diagnosis. There is no standard treatment for PCNSL, however patients often receive a combination of Rituxan (rituximab), temozolomide, and high-dose methotrexate.

MCL1 Inhibitor: PRT1419

Overview

PRT1419 is designed to be a potent and selective inhibitor of the anti-apoptotic protein, MCL1. PRT1419 has been optimized to have the PK properties to allow for either oral or IV administration, providing maximal coverage of the target while maintaining an adequate tolerability window. We believe that the physicochemical and pharmacological properties of PRT1419 allow the optionality of administering PRT1419 by either oral or IV route. Based on our preclinical data, as well as

published third-party data, we believe that hematological malignancies are particularly sensitive to MCL1 inhibitors. MCL1 upregulation has been noted as a mechanism of acquired resistance to venetoclax and TKIs. In addition, certain solid tumors are responsive to MCL1 inhibition, informing a potential patient selection strategy. Based on data demonstrating that MCL1 is a primary resistance mechanism to BCL2 inhibitors like venetoclax, a combination study with azacitidine or venetoclax in MDS/AML is planned. We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into a Phase 1 clinical trial for the oral formulation of PRT1419. We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial in the second half of 2021. Additionally, the FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors.

Background

The ability to evade cell death is a hallmark of cancer because it is one of the unique acquired abilities that allows malignant transformation of a normal cell. MCL1 and BCL2 are both members of a family of proteins that regulate cell survival versus cell death. Under normal circumstances, MCL1 and BCL2 exert their pro-survival function by binding to and sequestering the pro-death proteins, BAK and BAX, and prevent the activation of a downstream cascade leading to apoptosis (Figure 19). In normal cells, cellular stressors such as DNA damage disrupt this interaction and result in cell death. Cancer cells, however, frequently upregulate pro-survival proteins to prevent activation of the apoptotic pathway, thus evading death. MCL1 has been shown to have a critical role in promoting cancer cell survival and is frequently found to be amplified or overexpressed in both solid tumors and hematologic cancers.

Figure 19. MCL1 Promotes Tumor Cell Survival by Inhibiting Apoptosis

Members of the BCL2 protein family control cell survival and cell death. MCL1, a member of the family, acts to suppress cell death and has emerged as a target for anti-cancer therapy and as a resistance mechanism to the BCL2 inhibitor, venetoclax.

Inhibition of MCL1 expression and/or function is therefore of considerable therapeutic interest in cancer. The importance of blocking the protein-protein interaction between pro-survival and pro-death proteins as a therapy to promote tumor cell death has been clinically validated with the BCL2 inhibitor, venetoclax. Venetoclax was approved in 2016 for R/R patients with CLL and in 2018 for patients with AML. MCL1 is upregulated in response to BCL2 inhibition and has been implicated in mediating resistance to venetoclax, as well as to chemotherapeutic agents and other targeted therapies including TKIs. These studies have demonstrated the potentially broad clinical benefits of targeting cell survival through MCL1 inhibition in cancer.

Small molecule MCL1 inhibitors have been shown to be remarkably efficacious as monotherapy in preclinical models of MM, AML and lymphoma. Treatment with these inhibitors leads to robust activation of apoptosis markers including cleaved caspase-3 and cleaved PARP in vivo and in vitro. Objective clinical responses were demonstrated in a Phase 1

multiple myeloma clinical trial with AMG176, a third-party MCL1 inhibitor, providing clinical validation of the pathway. MCL1 inhibitors have also demonstrated potent synergistic activity in combination with approved standard of care therapies, including venetoclax, in preclinical models of AML. Although these inhibitors show limited efficacy as monotherapy in solid tumor models, combination with TKIs has resulted in potent anti-tumor effects in triple negative breast cancer, melanoma and non-small cell lung cancer.

Although the data on the importance of MCL1 in driving tumor growth and survival are compelling, complete ablation of Mcl1 has been shown to result in cardiomyocyte apoptosis in mice. Mice with heterozygous deletion of Mcl1 resulting in a 50% reduction in MCL1 protein did not demonstrate cardiac abnormalities. These results suggest that an optimized profile for a pharmacological inhibitor of MCL1 should allow for maximal but limited duration of target engagement rather than prolonged coverage to maximize the therapeutic window of MCL1 inhibition in clinical development.

Our Approach to Designing Optimized MCL1 Inhibitors

We used structure-based design to identify PRT1419 as an inhibitor of human MCL1 that is designed to induce tumor cell death by apoptosis. It has been optimized to have high permeability and adequate solubility to provide suitable PK that allows for oral and IV dosing. We believe these features have the potential to maximize the therapeutic window and overcome some of the limitations of current MCL1 inhibitors, as well as provide the convenience and flexibility associated with oral dosing both as monotherapy and potentially in combination with other oral therapies.

PRT1419

In Vitro Potency and Selectivity

We investigated the in vitro potency of PRT1419 to inhibit the protein-protein interaction of human recombinant MCL1 with the pro-death protein, BIM, by measuring its IC50. In this assay, we observed the IC50 of PRT1419 to be 6.6 nM. We also investigated the in vitro selectivity of PRT1419 for MCL1 as compared to related family members, BCL-2 and BCLXL. We observed that PRT1419 showed >200 times weaker inhibition of BCL-2 and BCLXL compared to MCL1.

Tumor cells undergo apoptosis in response to MCL1 inhibition. Therefore, we investigated the potency of PRT1419 to inhibit the proliferation of cell lines representing both solid tumors and hematologic malignancies. Tumor cell lines were treated with various concentrations of PRT1419 and the number of viable cells was measured after two days in culture. We observed that cell lines representing multiple myeloma, lymphomas and leukemias were particularly sensitive to PRT1419 with IC50 values in the nanomolar range.

Since most MCL1 inhibitors have been shown to be highly bound to proteins in the blood, which reduces their effective concentration, PRT1419 was tested in an assay in the presence of human whole blood and shown to retain its potency to activate markers of apoptosis. In this human whole blood assay, we observed that PRT1419 was significantly more potent (9 times) than other MCL1 inhibitors such as AMG176. Consistent with its improved potency, PRT1419 demonstrated anti-tumor activity in vivo at lower doses than those required for activity with AMG176. These data are summarized in Table 6.

Table 6. In Vitro Properties of PRT1419 Compared to Other MCL1 Inhibitors

Inhibition of cell proliferation was determined in the OPM2 cell line. Whole blood IC50 represents the half maximal concentration required to induce markers of apoptosis in OPM2 cells cultured in human blood. Permeability was assessed in Caco-2 cells. Intrinsic clearance was determined in human hepatocytes. All competitor compounds were obtained from commercial sources.

Pharmacokinetics

In preclinical assays, PRT1419 demonstrated favorable ADME and PK properties. PRT1419 had high oral bioavailability in mice and dogs, adequate solubility, high permeability, and high intrinsic clearance in human hepatocytes which taken together should favor an optimized PK profile for an oral MCL1 inhibitor in patients.

Anti-tumor Activity in Preclinical Models

In vivo, the pharmacological activity of PRT1419 to induce apoptosis in tumor tissue from the subcutaneous multiple myeloma xenograft tumor model (OPM2) was evaluated. Oral administration of a single dose of PRT1419 led to a dose-dependent activation of apoptosis markers including cleaved caspase-3 and cleaved-PARP in tumor tissue. Consistent with these effects, once weekly administration of PRT1419 demonstrated potent and dose-dependent anti-tumor activity in this model (Figure 20), resulting in tumor regressions. Similar activity was also observed with once weekly dosing of PRT1419 in subcutaneous cell line derived xenograft mouse models of AML (MV4-11) and DLBCL (OCI-Ly7).

Figure 20. Anti-Tumor Activity in Preclinical Models of Hematologic Malignancies

PRT1419 was administered orally to tumor-bearing mice (n=8 animals/group). Data represents mean ± SEM (standard error of the means), QW – once weekly, p.o – oral administration, *** P value<0.001 vs. Vehicle by Mann-Whitney U test

Since MCL1 is known to be a resistance mechanism in patients treated with the BCL2 inhibitor venetoclax, PRT1419 was studied in combination with venetoclax in the MV411 model of AML. As shown in Figure 22, PRT1419 demonstrated enhanced inhibition in combination with venetoclax, resulting in tumor regression in mice.

Figure 21. PRT1419 Demonstrates Enhanced Activity in Combination with Venetoclax

PRT1419 and venetoclax were administered orally as single agents and in combination to tumor-bearing mice (n=8/group). Data represents mean ± SEM (standard error of the means), Venetoclax was dosed at 50 mg/kg; PRT1419 was dosed at 15 mg/kg; *** P value<0.001 vs. Vehicle by Mann-Whitney U test

In summary, PRT1419 demonstrated potent and selective inhibition of MCL1 in vitro and in vivo that resulted in tumor regressions in preclinical models following once weekly oral dosing. PRT1419 was well-tolerated in 28-day toxicology studies in rats and dogs and showed no evidence of cardiac toxicity. Taken together, these studies support the advancement of PRT1419 into clinical trials in patients with hematologic malignancies.

Clinical Trial Design and Study Schema – Oral Formulation

We have begun enrolling patients with hematologic malignancies, including patients with myelodysplastic syndrome, or MDS, acute myeloid leukemia, or AML, non-Hodgkin’s lymphoma, or NHL, and multiple myeloma, or MM, into a Phase 1 clinical trial for the oral formulation of PRT1419. We expect to add dose expansion and combination cohorts to this Phase 1 clinical trial in the second half of 2021.

Figure 22. PRT1419 Clinical Trial Schema

Clinical Update as of December 16, 2020 – Oral Formulation

As of December 16, 2020, the Phase 1 clinical trial of PRT1419 has enrolled four patients with various hematological malignancies. No adverse events above Grades 1 or 2 and no serious adverse events have been observed.

We are currently enrolling AML and high-risk MDS patients into the second dose escalation cohort (200mg 1x weekly).

PRT1419 – IV Formulation

The FDA recently cleared our IND for an intravenous (IV) formulation of PRT1419. A Phase 1 trial of the IV formulation, which leverages the optimized physicochemical properties of PRT1419, is expected to commence in the first half of 2021 in patients with solid tumors.

Addressable OncologyMarketforPRT1419

Acute MyeloidLeukemia(AML)

AMLisablood cancerwhereinmyeloidstemcellsproliferateand failto properlydifferentiateintomature myeloid cells. AML is the second most common leukemia in adults, with the American Cancer Society estimatingan annualincidenceof nearly20,000 patientsin theUnitedStates.

AMLisparticularlydifficulttotreatin adultsolderthan60 years,who accountformorethan60% of patients;thus,fewerthan29%of AML patientslivebeyond fiveyears.Therearesignificantdifferencesin the treatmentofAMLbasedonageandfitness.Foryounger,fitpatientscurrentfirst-lineAML treatmenttypically involvesaggressivechemotherapyfollowedbystemcelltransplantationifpossible.For older,unfitpatientsfirst- lineAMLtreatmenttypicallyinvolveslowdosecytarabineorazacytidine,potentiallyin combinationwith VENCLEXTA(venetoclax)or otheragents.

OtherapprovedtherapiesforAMLincludeMYLOTARG (gemtuzumabozogamicin),anantibody-drug conjugate,aswellas a numberof targetedtherapiesforsubsetsof patientswhose tumorsharborspecific alterations. These include RYDAPT (midostaurin) and XOSPATA (gilteritinib) for FLT3-mutated AML, IDHIFA(enasidenib)forIDH2-mutatedAML, and TIBSOVO(ivosidenib)forIDH-1 mutatedAML.

Despitetheserecentadvances,webelievethereremainsaneedforawell-toleratedandeffectivetherapy thatcan broadlyaddressAML patients,especiallythoseprogressingon front-linetherapiesand/orvenetoclax.In theregistrational

studyforvenetoclaxin combinationwith azacitidineor decitabine,a compositecomplete remission,orCRc, of67% was observed,with a responsedurationof 11.3 monthsand a medianoverallsurvival, or OS,of 17.5 months.

Non-Hodgkin Lymphoma(NHL)

NHLisagroupofbloodcancersoriginatingineitherB-cells(approximately85%ofallNHL)orT-cells (approximately15%ofallNHL).TheAmericanCancerSocietyestimatestheincidenceofNHLtobeover 77,000 patientsannuallyin theUnitedStates.

NHL ischaracterizedintosubtypesaccordingtothenaturalcourseof diseaseprogression.Aggressive lymphomas,whichaccountfor60%ofallNHL cases,progressrapidly.DiffuselargeB-celllymphoma,or DLBCL, isthemostcommonoftheseaggressivesubtypes.Indolentlymphomas,whichaccountfor40%ofall NHL cases,progressmoreslowlywithfewersymptomsupondiagnosis.Follicularlymphoma,orFL,isthemost commonof theseindolentsubtypes.

ThetreatmentofNHL variesbysubtypeandcanincludeoneofmoreofthefollowingmodalities: chemotherapy,immunotherapy,radiationtherapy,stemcelltransplantation,targetedtherapy,and celltherapy, or CAR-T. Despiterecenttherapeuticadvancesandapprovals,thereremainsahighunmetneedfornew NHL treatments,particularlyformoreaggressivesubtypesandforpatientswhohaveprogressedon standardtherapies. Forexample,approximately50%ofpatientswithDLBCLwillberefractorytoorrelapseonstandardtherapy. The prognosisforpatientswith DLBCLwho relapseispoor, with mediansurvivalof lessthanone year.

MultipleMyeloma(MM)

MMisabloodcanceroriginatinginthebonemarrowthatischaracterizedbyexcessproliferationof aberrantantibody-producingplasmacells.MMisthethirdmostcommonblood cancer,and theAmericanCancer Societyestimatesanincidenceofover32,000patientsannuallyintheUnitedStates.MMisprimarilyadisease of theelderlyand has a five-yearsurvivalrateof 54%.

ThetreatmentofMMdependsontheaggressivenessof diseaseand patientfitness.For patientsin good healthandwithactivedisease,first-linetreatmenttypicallyinvolveshigh-dosechemotherapyfollowedby stem celltransplantationifpossible.ForpatientswhodonotachieveaCRorwhoarenotcandidatesforstemcell transplantation,systemicchemotherapyisindicated.The pasttwo decadeshave seensignificantadvancesin systemictreatmentforMM,includingtheintroductionof immunomodulatoryagents,such as REVLIMID (lenalidomide);monoclonalantibodies,suchasDARZALEX (daratumumab);andproteasomeinhibitors, includingVELCADE(bortezomib)andKYPROLIS (carfilzomib).MMtherapiesgeneratedapproximately$19.4 billionin world-widesalesin 2019.

Despitethesetherapeuticadvances,MM remainsincurable.Patientstypicallyreceivemultiplelines of therapybutultimatelyprogress.ThemedianOS forpatientswhoarerefractorytoboth an immunomodulatory drug and proteasomeinhibitorisonly 13 months.

CDK9 Program

Overview

CDK9 has emergedas an essentialregulatorof cancer-promotingtranscriptionalprograms,includingthose drivenbyMCL1,MYCandMYB.InhibitionofCDK9 isthusanattractivetherapeuticapproachto produce syntheticlethalityingenomicallyselectedcancers.WehaveappliedourinternalexpertisetodesignPRT2527as apotentinhibitorofCDK9thatexhibitshighkinomeselectivity,PKpropertiesandsolubilitythatwebelieve maybroadenthetherapeuticwindowofCDK9 inhibition.PRT2527 has enteredIND-enablingstudies,with IND submissionexpectedin 2021.

Background

Cyclindependentkinases,orCDKs, area familyof closelyrelatedserine/threoninekinasesthathave demonstratedactivityinmultiplecancers.Thefirstinhibitorsoftwoofthefamilymembers,CDK4 andCDK6, gainedFDAapprovalforHR+ metastaticbreastcancerin2015andarenowbroadlyused.IncontrasttoCDK4 andCDK6,whichregulatecellcycleprogressionandproliferation,itisnowappreciatedthatothermembersof theCDKfamilyplayimportantrolesin

regulatingtranscription.CDK9 specificallyphosphorylatesRNA polymeraseIItogeneratematuremRNA.Givenitsfundamentalroleintranscription,CDK9 hasemergedasa centralnode in thetranscriptionaladdictionof cancer.

Importantly,inhibitionofCDK9 in cancerhas been shown to preferentiallydepleteshort-livedtranscripts includingkeyanti-apoptoticgenessuchasMCL1andoncogenictranscriptionfactorssuchasMYCandMYB. PreclinicalevidencedemonstratesthatCDK9 inhibitionrepressesMCL1 and therebyovercomesresistanceto the BCL2inhibitorvenetoclax.Additionally,preclinicalstudiessuggestthatCDK9 inhibitionperturbsMYC- mediatedsignalingandproducessyntheticlethalityinnuclearproteinof thetestismidlinecarcinoma, hepatocellularcarcinomaandadditionalsolidtumors.Our patientselectionstrategyin clinicaltrialswould strive toexploitthesesyntheticlethalityrelationshipsbyidentifyingcancerswith molecularevidenceof MCL1 and/or MYC dysregulation.

Our CDK9Inhibitor:PRT2527

Althoughvariousnon-selectiveCDK9 inhibitorshaveprogressedthroughclinicaldevelopment,theyhave beensignificantlylimitedby narrowtherapeuticwindows due to adverseeffects,includingbone marrow suppression,nauseaandGIeffects.Wehave utilizedstructure-baseddesignto identifya novel,structurally differentiatedseriesofCDK9 inhibitors.Iterativesynthesisand testingof over600 compoundsallowedthe identificationofPRT2527,whichhasimprovedpotencyandkinaseselectivitycomparedtoAZ4573, themost advancedCDK9-selectiveinhibitorcurrentlyindevelopment.ThePK andphysicalpropertiesofPRT2527 are suitableforIV or SCdosing.

Inpreclinicalmodels,PRT2527 reducedMCL1andMYC proteinlevelsandwashighlyactivein theMYC- amplifiedMV4-11 xenograftmodelatwell-tolerateddoses.Our preclinicalstudies suggest that PRT2527 demonstrateshighselectivityandhighpotency,providingopportunityfora widertherapeuticindexcomparedto lessselectiveCDK9inhibitors.

SMARCA2targeteddegrader program

Background

SMARCA2(alsoknownasBRM)anditsrelatedfamilymember,SMARCA4(alsoknownasBRG1),are theenzymaticsubunitsoftheSWI/SNFcomplexthatregulatesgeneexpressionbyallowingtheDNA tobe accessiblefortranscriptiontomatureRNA,aprocessknownaschromatinremodeling.SMARCA4 ismutatedin multiplecancers,including10-12%ofNSCLC,resultinginlossofSMARCA4protein.Becausetheactivityof eitherSMARCA2 orSMARCA4 isrequiredforchromatinremodelingtooccur,theSMARCA4-deficientcancer cellsbecomehighlydependentonSMARCA2fortheirsurvival.Therefore,webelievetargetingSMARCA2 in SMARCA4-deficientcancerswillproduceastrongsyntheticlethality,resultinginSMARCA4 mutanttumorcell deathwhilesparingnormalcellsthatexpressSMARCA4protein.

Our SMARCA2Degrader Program

DuetothehighhomologybetweenSMARCA2 andSMARCA4, therearefewstructuraldifferencesinthe bindingsitesbetweenthetwoproteinsandthusselectiveSMARCA2 degradationhasbeenachallengefor medicinalchemistry.Targetedproteindegradationisarelativelynewapproachtodegradeoncogenicproteins andhasbeenshowntoprovideselectivedegradationofhighlyhomologousproteins.A moleculecapableof targetingaproteinfordegradation(degrader)typicallycontainsabindingelementtoa targetedproteinof interest (SMARCA2), a chemicallinkerand an E3 ligasebindingelementwhich allowsfortheformationof a ternary complex between the target, the degrader and the E3 ligase that induces ubiquitination and subsequent degradationofthetargetedprotein.Selectivitycanbeachieved,not only by theselectivebindingto thetarget (SMARCA2), butalsothroughtheoptimizationof theuniqueternarycomplexesformedby thetarget (SMARCA2)versusitshomologousprotein(SMARCA4).

Weusedstructure-baseddrugdesigntoidentifyanovelseriesofpotentSMARCA2 degradersthatare outsidethetypicaldrug-likechemicalspace,beingsignificantlylargerand structurallymorecomplex.Extensive structureactivityrelationshipsgeneratedbytheiterativesynthesisandtestingof>250compoundsasofthedate of thisAnnual Report on Form 10-K has allowedtheidentificationof specificstructuralmotifsthat provide >20-fold selectivityfor SMARCA2degradationoverSMARCA4whilemaintainingpotentSMARCA2 degradation,DC50<10nM. DC50isaquantitativemeasureofhowmuchofacompoundisneededtoinhibitthedegradationofaproteinby 50%.Wehavedesignedour

SMARCA2 degraderstobepotentandselectivetospecificallyinhibitSMARCA4- deficienthumanNSCLCcelllinesandprimarypatientderivedsamples.OptimizationofthePKandphysical propertiessuitablefororal,IV or SCdosingison-goingwith thegoalof initiatingIND-enablingstudiesin 2021.

KinaseProgramin Solid Tumors

Weareevaluatingakinasethathasbeenshowninpreclinicalstudiestobeanoncogenicdriverin cancer. Genomicalterationsin thiskinasehave been identifiedin multipletumortypesand thesetumorsare sensitive inhibitorsof thiskinasein preclinicalmodels.Currentinhibitorsof thiskinasein developmentlackoptimalPK andbiodistributionproperties.Ourgoalistoidentifynovel,potent,selective,oralinhibitorsof thiskinasethat haveanoptimizedPK profileforclinicaldevelopmentin patientswith solidtumors.Optimizationof our lead kinaseinhibitor,PRT-K4,isongoing with thegoalof initiatingIND-enablingstudiesin 2021.

IntellectualProperty

Westrivetoprotecttheproprietarytechnologiesthatwebelieveareimportanttoourbusiness,including seeking and maintaining patent protection intended to cover the compositions of matter of our product candidates,theirmethodsof use, relatedtechnology,and otherinventionsthatareimportantto our business.

Oursuccesswilldependsignificantlyon our abilityto obtainand maintainpatentand otherproprietary protectionforcommerciallyimportanttechnology,inventions,and know-how relatedto our business,to defend andenforceourpatents,topreservetheconfidentialityofourtradesecrets,andtooperatewithoutinfringing validandenforceablepatentsand otherproprietaryrightsof thirdparties.We alsorelyon know-how and continuingtechnologicalinnovationto develop,strengthen,and maintainour proprietarypositionin thefieldof precisiononcology.

As morefullydescribedbelow, our patentportfolioincludespatentfamilieswith claimsdirectedto compositionsofmatterfor,andmethodsofusing,compoundsPRT543,PRT811PRT1419,PRT2527,and compoundsthatdegradeSMARCA2. AU.S.patentdirectedtoPRT543hasissuedandisexpectedtoexpireno earlierthanAugust9,2038.Inaddition,aU.S. patentdirectedtoPRT811 hasissuedandisexpectedtoexpireno earlierthanMarch14, 2039.

InadditiontoourfilingsintheUnitedStates,we own patentapplicationsthatarependingin Australia, Brazil,Canada,China,Eurasia,Europe,Israel,HongKong,India,Japan,Korea,Mexico,New Zealand,Ukraine, andSouthAfrica.IncludedintheseapplicationsareclaimsdirectedtothePRT543 compositionandmethodsof usingthesametherapeutically.Thepatentsfromtheseapplications,ifissued,areexpectedtoexpireinAugust

2038, subjectto any disclaimersor extensions.

The patentportfoliosforour mostadvancedprogramsaresummarizedbelow.

PRT543

OurPRT543patentportfolioiswhollyownedbyus.TheportfolioincludesoneissuedU.S. patent,which claims,amongotherthings,PRT543,pharmaceuticalcompositionscomprisingPRT543,methodsofinhibiting PRMT5 usingPRT543, andmethodsoftreatingcertaincancers,includingbreastand ovariancancers,using PRT543.ThisU.S. patentisexpectedtoexpirenoearlierthanAugust9,2038,subjecttoanydisclaimersor extensionsavailableundertheHatch-WaxmanAct.Correspondingpatentapplicationsarependinginseveral othercountriesandregions,includingAustralia,Brazil,Canada,China,Eurasia,Europe,HongKong,Israel, India,Japan,Korea,Mexico,New Zealand,Ukraine,andSouthAfrica.Anypatentsresultingfromthesepatent applications,ifissued,arealsoexpectedtoexpireno earlierthanAugust 9, 2038, subjectto any disclaimersor extensions.

ThePRT543patentportfolioalsoincludesthreependingU.S.andtwopendingPCTpatentapplications, whichclaim,amongotherthings,agenusofcompoundsthatencompassPRT543, PRT543 saltsandcrystalline forms,methodsofpreparingPRT543,andadditionalmethodsoftreatmentusingPRT543.AnyU.S. patents issuingfromtheseapplicationswouldbeexpectedtoexpirenoearlierthanAugust9,2038,February13,

2040, April3, 2040, and December10, 2041 respectively,subjectto any disclaimersor extensions.

PRT811

OurPRT811patentportfolioiswhollyownedbyus.TheportfolioincludesoneissuedU.S. patent,which claims,amongotherthings,PRT811,pharmaceuticalcompositionscomprisingPRT811,methodsofinhibiting PRMT5usingPRT811,andmethodsoftreatingcertaincancers,includingglioblastoma,usingPRT811. The patentisexpectedtoexpirenoearlierthanMarch14, 2039, subjectto any disclaimersor extensionsavailable under the Hatch-Waxman Act. A related PCT application was filed, and corresponding national phase applicationswerefiledinAustralia,Brazil,Canada,China, Eurasia,Europe, India,Israel,Japan,Korea, Mexico, New Zealand,UkraineandSouthAfrica.Anypatentsresultingfromthesenationalpatentapplications,ifissued, areexpectedto expireno earlierthanMarch14, 2039, subjectto any disclaimersor extensions.

ThePRT811 patentportfolioalsoincludestwopendingU.S. non-provisionalapplications,a firstPCT applicationthatclaimscompositionsofmatter,andasecondPCT applicationthatclaimsmethodsoftreatment. Anypatentsissuingfromthetwo pendingU.S.non-provisionalapplicationswould be expectedto expirein 2039, andanypatentsissuingfromthetwoPCT applicationswouldbeexpectedtoexpirein2040,subjecttoany disclaimersor extensions.

PRT1419

OurPRT1419 patentportfolio,whichiswhollyownedbyus,includespendingU.S. patentapplications claiming,amongotherthings,PRT1419 and othercompounds,pharmaceuticalcompositionscomprising PRT1419,andmethodsofusingPRT1419.Anypatentsissuedfromthisapplicationwouldbeexpectedtoexpire noearlierthanNovember8,2039,subjecttoanydisclaimersorextensions.ArelatedPCT applicationwas filed andnationalpatentapplicationsbasedon thatapplicationareplannedforfilingin non-U.S. countriesin May and June2021.Anypatentsresultingfromthesenationalpatentapplications,ifissued,would expireno earlierthan November8, 2039, subjectto any disclaimersor extensions.

ThePRT1419patentportfolioalsoincludesapendingU.S.provisionalapplicationthatclaimsadditional compositionsof matter.Any patentsgrantedthatclaimpriorityto thisprovisionalapplicationcouldexpireas late as 2041.

PRT2527

OurPRT2527 patentportfolio,whichiswhollyownedbyus,includesoneU.S. non-provisionalpatent applicationandonePCT applicationclaiming,amongotherthings,PRT2527 andothercompounds, pharmaceuticalcompositionscomprisingPRT2527,and methodsof usingPRT2527.Any patentsthatissuebased upontheseU.S.non-provisionalandPCTapplicationswouldbeexpectedtoexpirenoearlierthan2040,subject to any disclaimersor extensions.

SMARCA2Degraders

TheSMARCA2 degraderpatentportfolioincludesonependingnon-provisionalU.S. application,onePCT application,andtwoU.S. provisionalapplicationswhich claim,amongotherthings,generaof compoundsthat encompassSMARCA2 and/orrelatedinhibitors,pharmaceuticalcompositionscomprisingthoseinhibitors,and methodsof treatingcancerwith thoseinhibitors.

Other

Inaddition,we have patentportfoliosthataredirectedto a numberof differentcompoundsotherthan PRT543,PRT811,PRT1419,PRT2527,andSMARCA2 degraders.Wehavepatentapplicationsdirectedto compoundsthattargetresistancemechanismsin cancer.We expectto maintainsomeof theseapplicationsin the UnitedStatesand to alsofilein foreigncountries.In additionto theapplicationsdescribedabove, we wholly-own 11applicationsincludingU.S. provisionalpatentapplications,U.S. non-provisionalpatentapplications,foreign applications,andPCTapplications,coveringcompositionsandmethodsofmakingandusingthosecompounds to treatcancerand otherdiseases.

The termof individualpatentsdependsupon thelegaltermof thepatentsin thecountriesin which theyare obtained.Inthecountriesinwhichwefile,thepatenttermis20yearsfromtheearliestnon-provisionalfiling date,subjecttoanydisclaimersorextensions.ThetermofapatentintheUnitedStatescanbeadjusteddueto anyfailureoftheUnitedStatesPatentandTrademarkOfficefollowingcertainstatutoryand regulationdeadlines forissuinga patent.

In theUnitedStates,thepatenttermof a patentthatcoversan FDA-approved drug mayalsobe eligiblefor patenttermextension,whichpermitspatenttermrestorationascompensationfora portionof thepatenttermlost duringtheFDAregulatoryreviewprocess.TheHatch-WaxmanActpermitsapatenttermextensionofupto fiveyearsbeyondtheoriginalexpirationofthepatent.Theprotectionprovidedby a patentvariesfromcountryto country,andisdependentonthetypeofpatentgranted,thescopeofthepatentclaims,and thelegalremedies availablein a givencountry.

Obtainingpatentprotectionisnottheonlymethodthatwe employto protectour proprietaryrights.We also utilizeotherformsofintellectualpropertyprotection,includingtrademark,copyright,and tradesecrets,when thoseotherformsarebettersuitedtoprotectaparticularaspectofourintellectualproperty.Our beliefisthatour proprietaryrightsarestrengthenedby our comprehensiveapproachto intellectualproperty protection.It is our policytorequireouremployees,consultants,outsidescientificcollaborators,sponsoredresearchersandother advisorstoexecuteconfidentialityagreementsuponthecommencementofemploymentor consulting relationshipswithus.Theseagreementsprovidethatallconfidentialinformationconcerningour businessor financialaffairsdevelopedormadeknowntotheindividualduringthecourseoftheindividual’srelationship withusistobekeptconfidentialandnotdisclosedto thirdpartiesexceptin specificcircumstances.In thecaseof employees,theagreementsprovidethatallinventionsconceivedby theindividual,and which arerelatedto our currentorplannedbusinessorresearchanddevelopmentormadeduringnormalworkinghours,onour premises or usingour equipmentor proprietaryinformation,areour exclusiveproperty.

Manufacturing

Wedonotownoroperate,andcurrentlyhavenoplansto establish,any manufacturingfacilities.We currentlyrely,andexpecttocontinuetorelyfortheforeseeablefuture,on thirdpartiesforthemanufactureof our productcandidatesforpreclinicaland clinicaltesting,includingpharmaceuticalingredientsand clinicaldrug supply,aswellasforcommercialmanufactureofany drugsthatwe maycommercialize.We obtainour supplies fromthesemanufacturersonapurchaseorderbasisanddonot have long-termsupplyarrangementsin place.We donotown in-housewarehousefacilities.We relyon thirdpartiesforstorageand distributionof drug substance and drug product.We do not currentlyhave arrangementsin placeforredundantsupplyforactivepharmaceutical ingredientsanddrugproduct.Asour developmentprogramsprogressand we buildnew processefficiencies,we expecttocontinuallyevaluatethisstrategywiththeobjectiveof satisfyingdemandforregistrationtrialsand, if approved,themanufacture,saleand distributionof commercialproducts.

Commercialization

Givenourstageofdevelopment,we have not yetestablisheda commercialorganizationor distribution capabilities.Ifwearesuccessfulinobtainingnecessaryregulatoryapproval,wemaypursuecommercialization on our own or seekto collaboratewith a thirdpartyforcommercialization,particularlyoutsidetheUnitedStates.

Thebiotechnologyandpharmaceuticalindustriesarecharacterizedbytherapidevolutionoftechnologies and understandingof diseaseetiology,intensecompetitionand a strongemphasison intellectualproperty. We believethatourapproach,strategy,scientificcapabilities,know-howandexperienceprovideus with competitive advantages.However, we expectsubstantialcompetitionfrommultiplesources,includingmajor pharmaceutical, specialtypharmaceutical,and existingor emergingbiotechnologycompanies,academicresearchinstitutionsand governmentalagenciesand publicand privateresearchinstitutionsworldwide.Many of our competitors,either aloneorthroughcollaborations,have significantlygreaterfinancialresourcesand expertisein researchand development,manufacturing,preclinicaltesting,conducting clinicaltrials,obtaining regulatoryapprovals and marketingapprovedproductsthanwe do. Smalleror early-stagecompaniesmayalsoproveto be significant competitors,particularlythroughcollaborativearrangementswithlargeand establishedcompanies.These competitorsalsocompetewith us in recruitingand retainingqualifiedscientificand managementpersonneland establishingclinicaltrialsitesand patientenrollmentin clinicaltrials,as wellas in acquiringtechnologies complementaryto, or necessaryfor,our programs.As a result,our competitorsmay discover, develop, licenseor commercializeproductsbeforeor moresuccessfullythanwe do.

Competition

We facecompetitionfromsegmentsof thepharmaceutical,biotechnologyand other relatedmarketsthat pursuethedevelopmentofprecisiononcologytherapiesoptimizedtotargetthekey drivermechanismsin cancers withhighunmetneed.

Severalbiopharmaceuticalcompanies,includingBlack DiamondTherapeutics,Inc., ConstellationPharmaceuticals,Inc.,Kronos Bio, Inc.,RepareTherapeuticsInc.,RevolutionMedicines,Inc., Relay Therapeutics,Inc.,Vincerx Pharma, Inc. and ZentalisPharmaceuticals,Inc.,aredevelopingprecisiononcologymedicines.In addition,wemayfacecompetitionfromcompaniesdevelopingproductcandidatesthatarebasedontargeting pathwaysofadaptiveresistance,includingAmgen, AbbVie, AstraZeneca,GlaxoSmithKline,Johnson & Johnson, Pfizer,Bayer and Novartis.

Furthermore,we also face competitionmore broadly across the oncology marketfor cost-effectiveand reimbursable cancertreatments. The most common methods of treating patients with cancer are surgery, radiationanddrugtherapy,includingchemotherapy,hormonetherapy,biologictherapy,such as monoclonaland bispecificantibodies,immunotherapy,cell-basedtherapyand targetedtherapy,or a combinationof any such methods.Therearea varietyof availabledrug therapiesmarketedforcancer.In manycases,thesedrugsare administered incombinationtoenhanceefficacy.Whileourproductcandidates,ifanyareapproved,may competewiththeseexistingdrugsandothertherapies,to theextenttheyareultimatelyused in combinationwith orasanadjuncttothesetherapies,ourproductcandidatesmaynotbecompetitivewiththem.Someofthese drugsarebrandedandsubjectto patentprotection,and othersareavailableon a genericbasis.Insurersand other third-partypayorsmayalsoencouragetheuseofgenericproductsorspecificbrandedproducts.Asa result, obtainingmarketacceptanceof,andgainingsignificantshareofthemarketfor,anyofourproductcandidates thatwe successfullyintroduceto themarketmaypose challenges.In addition,many companiesare developing newoncologytherapeutics,andwecannotpredictwhatthestandardofcarewillbe as our productcandidates progressthroughclinicaldevelopment.

With respect to our PRMT5 programs, PRT543 and PRT811, several companies are developing PRMT5 inhibitors with clinical trials ongoing, including GlaxoSmithKline (GSK3326595), Johnson & Johnson (JNJ-64619178) and Pfizer (PF-06939999). For our product candidate PRT1419, other companies are developing MCL1 inhibitors with monotherapy and/or combination trials ongoing, including Amgen (AMG176), AstraZeneca (AZD5991) and Novartis (MIK665). For our preclinical CDK9 program, both AstraZeneca and Bayer have CDK9 programs in Phase 1 clinical trials.

Wecouldseeareductionor eliminationin our commercialopportunityifour competitorsdevelopand commercializedrugsthataresafer,moreeffective,have feweror lesssevereside effects,are more convenient to administer,arelessexpensiveorwithmorefavorablelabelingthanourproductcandidates.Our competitorsalso mayobtainFDA orotherregulatoryapprovalfortheirdrugsmorerapidlythanwemayobtainapprovalforours, whichcouldresultinourcompetitorsestablishingastrongmarketpositionbeforeweareabletoenterthe market.The key competitivefactorsaffectingthesuccessof allof our productcandidates,if approved, are likely tobe theirefficacy,safety,convenience,price,thelevelof genericcompetitionand theavailabilityof reimbursementfromgovernmentand otherthird-partypayors.

GovernmentRegulation

GovernmentauthoritiesintheUnitedStates,atthefederal,stateandlocallevel,and in othercountriesand jurisdictionsextensivelyregulate,among other things, the research,development,testing,manufacture, quality control, approval, packaging, storage, recordkeeping,labeling,advertising,promotion,distribution,marketing, post-approvalmonitoringandreporting,andimportandexportof pharmaceuticalproducts.The processesfor obtainingregulatoryapprovalsin theUnitedStatesand in foreigncountriesand jurisdictions,alongwith subsequentcompliancewithapplicablestatutesand regulationsand otherregulatoryauthorities,requirethe expenditureof substantialtimeand financialresources.

FDAApproval Process

IntheUnitedStates,pharmaceuticalproductsaresubjecttoextensiveregulationby theFood and Drug Administration,orFDA, TheFederalFood,Drug,andCosmeticAct,orFD&C Act,andotherfederalandstate statutesand regulationsgovern,amongotherthings,theresearch,development,testing,manufacture,storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting,samplingandimportand exportof pharmaceuticalproducts.Failureto complywith applicableU.S. requirementsmaysubjectacompanyto a varietyof administrativeor judicialsanctions,such as clinicalhold, FDArefusaltoapprovependingNDAs, warningoruntitledletters,productrecalls,productseizures,totalor partialsuspensionof productionor distribution,injunctions,fines,civilpenaltiesand criminalprosecution.

Pharmaceuticalproductdevelopmentforanewproductorcertainchangestoanapprovedproductinthe U.S. typicallyinvolvespreclinicallaboratoryandanimaltests,thesubmissiontoFDA ofaninvestigationalnew drugapplication,orIND,whichmustbecomeeffectivebeforeclinicaltestingmaycommence,and adequateand well-controlledclinicaltrialstoestablishthesafetyand effectivenessof thedrug foreachindicationforwhich FDA approvalissought.SatisfactionofFDA pre-marketapprovalrequirementstypicallytakesmanyyearsand theactualtimerequiredmayvarysubstantiallybasedupon thetype,complexityand noveltyof theproductor disease.

Preclinicaltestsincludelaboratoryevaluationof productchemistry,formulationand toxicity,as wellas animaltrialstoassessthecharacteristicsand potentialsafetyand efficacyof theproduct.The conductof the preclinicaltestsmustcomplywith federalregulationsand requirements,includinggood laboratorypractices.The resultsofpreclinicaltestingaresubmittedtoFDA aspartofanINDalongwithotherinformation,including informationaboutproductchemistry,manufacturingand controls,and a proposedclinicaltrialprotocol.Long- termpreclinicaltests,suchasanimaltestsofreproductivetoxicityand carcinogenicity,maycontinueafterthe INDissubmitted.A30-daywaitingperiodafterthesubmissionof eachIND isrequiredpriorto the commencementofclinicaltestinginhumans.IfFDA hasneithercommentedonnorquestionedtheIND within this30-dayperiod,theclinicaltrialproposedin theIND may begin. Clinicaltrialsinvolve the administrationof theinvestigationalnewdrugtohealthyvolunteersorpatientsunderthesupervisionof a qualifiedinvestigator. Clinicaltrialsmustbeconducted:(i)in compliancewith federalregulations;(ii)in compliancewith good clinical practice,orGCP,aninternationalstandardmeanttoprotecttherightsandhealthofpatientsandtodefinethe roles of clinical trial sponsors, administrators and monitors; as well as (iii) under protocols detailing the objectives ofthetrial, theparameters tobeusedinmonitoring safetyandtheeffectiveness criteria tobe evaluated.EachprotocolinvolvingtestingonU.S. patientsandsubsequentprotocolamendmentsmustbe submittedto FDAas partof theIND.

FDA mayorderthetemporary,orpermanent,discontinuationofaclinicaltrialatany time,or imposeother sanctions,ifitbelievesthattheclinicaltrialeitherisnotbeingconductedinaccordancewithFDArequirements orpresentsanunacceptablerisktotheclinicaltrialpatients.Impositionofaclinicalholdmaybe fullor partial. Thestudyprotocolandinformedconsentinformationforpatientsin clinicaltrialsmustalsobe submittedto an institutionalreviewboard,or IRB, and ethicscommitteeforapproval.The IRB willalso monitorthe clinicaltrial untilcompleted.An IRB mayalsorequiretheclinicaltrialatthesiteto be halted,eithertemporarilyor permanently,forfailureto complywith theIRB’s requirements,or mayimposeotherconditions.Additionally, someclinicaltrialsareoverseenbyanindependentgroup of qualifiedexpertsorganizedby theclinicaltrial sponsor,knownasadatasafetymonitoringboardor committee.This group providesauthorizationforwhethera trialmaymoveforwardatdesignatedcheckpointsbasedon accessto certaindatafromthetrial.

ClinicaltrialstosupportNDAsformarketingapprovalaretypicallyconductedinthreesequentialphases, butthephasesmayoverlap.InPhase1,theinitialintroductionofthedrugintohealthyhumansubjectsor patients,thedrugistestedto assessmetabolism,pharmacokinetics,pharmacologicalactions,sideeffects associatedwithincreasingdoses,and,ifpossible,earlyevidenceof effectiveness.Phase 2 usuallyinvolvestrials in a limitedpatientpopulationto determinetheeffectivenessof thedrug fora particularindication,dosage toleranceandoptimumdosage,andtoidentifycommonadverseeffectsandsafetyrisks.Ifa drug demonstrates evidenceofeffectivenessandanacceptablesafetyprofileinPhase 2 evaluations,Phase 3 trialsareundertakento obtaintheadditionalinformationaboutclinicalefficacyandsafetyinalargernumberofpatients,typicallyat geographicallydispersedclinicaltrialsites,topermitFDA toevaluatetheoverallbenefit-riskrelationshipofthe drugandtoprovideadequateinformationforthelabelingofthedrug.InmostcasesFDA requirestwoadequate andwell-controlledPhase3clinicaltrialstodemonstratetheefficacyofthedrug.AsinglePhase3trialmaybesufficientinrareinstances, including (1) wherethestudyisalargemulticenter trialdemonstratinginternalconsistencyandastatisticallyverypersuasivefindingofaclinicallymeaningful effectonmortality,irreversiblemorbidityor preventionof a diseasewith a potentiallyseriousoutcomeand confirmationof theresultin a secondtrialwould be practicallyor ethicallyimpossible or (2) when in conjunction with other confirmatory evidence.

ThesePhasesmayoverlaporbecombined.Forexample,aPhase1/2clinicaltrialmaycontainbotha dose- escalationstageandadose-expansionstage,thelatterofwhichmayconfirmtolerabilityattherecommended doseforexpansioninfutureclinicaltrials(asintraditionalPhase1clinicaltrials)andprovideinsightintothe anti-tumoreffectsof theinvestigationaltherapyin selectedsubpopulation(s).

Typically,duringthedevelopmentof oncologytherapies,allsubjectsenrolledin Phase 1 clinicaltrialsare disease-affectedpatientsand, as a result,considerablymoreinformationon clinicalactivitymaybe collected duringsuchtrialsthan

duringPhase1clinicaltrialsfornon-oncologytherapies.Asinglepivotaltrialmaybe sufficientinrareinstancestoprovidesubstantialevidenceofeffectiveness(generallysubjecttotherequirement of additionalpost-approvalstudies).

ThemanufacturerofaninvestigationaldruginaPhase2or3clinicaltrialfora seriousor life-threatening diseaseisrequiredtomakeavailable,suchasbypostingonitswebsite,itspolicyonevaluatingandresponding to requestsforexpandedaccess.

Aftercompletionoftherequiredclinicaltesting,anNDA ispreparedandsubmittedtoFDA. FDA approval oftheNDAisrequiredbeforemarketingoftheproductmaybeginintheU.S. TheNDA mustincludetheresults ofallpreclinical,clinicalandothertestinganda compilationof datarelatingto theproduct’spharmacology, chemistry,manufactureand controls.

ThecostofpreparingandsubmittinganNDAissubstantial.ThesubmissionofmostNDAs isadditionally subjecttoasubstantialapplicationuserfee.Fee waiversor reductionsareavailablein certaincircumstances, includingawaiveroftheapplicationfeeforthefirstapplicationfiledby a smallbusiness.Additionally,no user feesareassessedonNDAsforproductsdesignatedasorphandrugs,unlesstheproductalsoincludesanon-orphanindication.TheapplicantunderanapprovedNDA isalsosubjectto annualprogramfees.The FDA adjuststheuserfeeson an annualbasis,and thefeestypicallyincreaseannually.

FDA reviewseachsubmittedNDA beforeitdetermineswhethertofileit, based on the agency’s threshold determination that it is sufficiently complete to permit substantive review, and FDA mayrequestadditional information.TheFDA mustmakeadecisiononwhethertofileanNDA within60daysofreceipt,andsuch decisioncouldincludearefusaltofilebytheFDA.Oncethesubmissionisfiled,FDA beginsanin-depthreview oftheNDA.FDA hasagreedtocertainperformancegoalsinthereviewofNDAs. Mostapplicationsforstandard reviewdrug productsarereviewedwithintento twelve months; most applicationsfor priorityreview drugs are reviewedinsixtoeightmonths.PriorityreviewcanbeappliedtodrugsthatFDAdeterminesoffermajor advancesintreatmentorprovideatreatmentwherenoadequatetherapyexists.The reviewprocessforboth standardandpriorityreviewmaybeextendedbyFDA forthreeadditionalmonthstoconsidercertainlate- submittedinformation,orinformationintendedtoclarifyinformationalreadyprovidedinthesubmission.The FDAdoesnotalwaysmeetitsgoaldatesforstandardandpriorityNDAs, andthereviewprocesscanbeextended by FDArequestsforadditionalinformationor clarification.

FDA mayalsoreferapplicationsfornoveldrugproducts,ordrugproductsthatpresentdifficultquestionsof safetyorefficacy,toanoutsideadvisorycommittee—typicallyapanelthatincludescliniciansand other experts—forreview,evaluationand a recommendationas to whethertheapplicationshouldbe approved and underwhatconditions,ifany.FDA isnot bound by therecommendationof an advisorycommittee,but it generallyfollowssuch recommendations.

BeforeapprovinganNDA,FDAwillconductapre-approvalinspectionofthemanufacturingfacilitiesfor thenewproducttodeterminewhethertheycomplywithcGMPrequirements.FDA willnotapprovetheproduct unlessitdeterminesthatthemanufacturingprocessesand facilitiesarein compliancewith cGMP requirements and adequate to assure consistent production of the product within required specifications. The FDAalso typicallyinspectsoneormoreclinicaltrialsitestoensurecompliancewithGCP requirementsandtheintegrityof thedatasupportingsafetyand efficacy.

AfterFDA evaluatestheNDA andthemanufacturingfacilities,itissueseitheranapprovalletteror a complete response letter. A complete response letter, or CRL, generally outlines the deficiencies in the submissionandmayrequiresubstantialadditionaltesting,orinformation,inorderforFDA toreconsiderthe application,suchasadditionalclinicaldata,additionalpivotalclinicaltrial(s),and/orothersignificantand time- consumingrequirementsrelatedtoclinicaltrials,preclinicalstudiesormanufacturing.IfaCRLisissued,the applicantmayresubmittheNDA addressingallofthedeficienciesidentifiedin theletter,withdrawthe application,engageinformaldisputeresolutionorrequestanopportunityforahearing.FDA hascommittedto reviewingresubmissionsintwo or sixmonthsdependingon thetypeof informationincluded.Even ifsuch data and informationaresubmitted,theFDAmaydecidethattheNDAdoes not satisfythecriteriaforapproval.

If,orwhen,thedeficienciesidentifiedintheCRL havebeenaddressedtoFDA’ssatisfactionina resubmissionoftheNDA, FDA willissueanapprovalletter.Anapprovalletterauthorizescommercialmarketing ofthedrugwithspecificprescribinginformationforspecificindications.AsaconditionofNDA approval,FDA mayrequireariskevaluationand

mitigationstrategy,orREMS, tohelpensurethatthebenefitsof thedrug outweighthepotentialriskstopatients.AREMS canincludemedicationguides,communicationplansfor healthcareprofessionals,andelementstoassuresafeuse,orETASU. ETASU caninclude,butarenotlimitedto, specialtrainingorcertificationforprescribingordispensing,dispensingonlyundercertaincircumstances, specialmonitoring,andtheuseofpatientregistries.TherequirementforaREMS canmateriallyaffectthe potentialmarketandprofitabilityof thedrug. Moreover,productapprovalmayrequiresubstantialpost-approval testingand surveillanceto monitorthedrug’ssafetyor efficacy.Once granted,productapprovalsmay be withdrawnifcompliancewith regulatorystandardsisnot maintainedor problemsareidentifiedfollowing initial marketing.

Changestosomeoftheconditionsestablishedinanapprovedapplication,includingchangesin indications, labeling,ormanufacturingprocessesorfacilities,requiresubmissionandFDA approvalofanNDA supplement or,insomecase,anewNDA, beforethechangecanbeimplemented.AnNDA supplementfora new indication typicallyrequiresclinicaldatasimilartothatintheoriginalapplication,andFDA usesthesameproceduresand actionsin reviewingNDAsupplementsas itdoes in reviewingNDAs.

Disclosureof ClinicalTrialInformation

SponsorsofclinicaltrialsofFDA regulatedproducts,includingdrugs,arerequiredtoregisteranddisclose certainclinicaltrialinformation.Informationrelatedtotheproduct,patientpopulation,phaseofinvestigation, studysitesandinvestigators,andotheraspectsof theclinicaltrialisthenmadepublicas partof theregistration. Sponsorsarealsoobligatedtodiscusstheresultsoftheirclinicaltrialsaftercompletion.Disclosureof theresults ofthesetrialscanbe delayedin certaincircumstancesforup to two yearsafterthedateof completionof thetrial. Competitors may use this publicly available information to gain knowledge regarding the progress of developmentprograms.

ExpeditedDevelopmentand Review Programs

Fast Track Designation

Fasttrackdesignationmaybe grantedfora productthatisintendedto treata seriousor life-threatening diseaseor conditionforwhich thereisno effectivetreatmentand preclinicalor clinicaldata demonstratethe potentialtoaddressunmetmedicalneedsforthecondition.Thesponsorofan investigationaldrug productmay requestthatFDA designatetheproductcandidateforaspecificindicationasa fasttrackdrug concurrentwith, or after,thesubmissionoftheINDfortheproductcandidate.FDAmustdetermineiftheproductcandidate qualifiesforfasttrackdesignationwithin60daysofreceiptofthesponsor’srequest.Forfasttrackproducts, sponsorsmayhavegreaterinteractionswiththeFDA andtheFDA mayinitiatereviewofsectionsofa fasttrack product’sNDAbeforetheapplicationiscomplete.This“rollingreview”isavailableiftheFDA determines,after preliminaryevaluationofclinicaldatasubmittedbythesponsor,thatafasttrackproductmaybeeffective.The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining informationandthesponsormustpayapplicableuserfees.AtthetimeofNDA filing,theFDA willdetermine whethertograntpriorityreviewdesignation.FDA willgrantsuchdesignationiftheproposeddrugwouldbea significantimprovementinthesafetyor effectivenessof thetreatment,prevention,or diagnosisof a serious condition.Additionally,fasttrackdesignationmaybewithdrawnifFDAbelievesthatthedesignationisno longersupportedby dataemergingin theclinicaltrialprocess.

AcceleratedApproval

Acceleratedapprovalmaybegrantedforaproductthatisintendedtotreata seriousor life-threatening conditionandthatgenerallyprovidesa meaningfultherapeuticadvantageto patientsoverexistingtreatments.A producteligibleforacceleratedapprovalmaybe approvedon thebasisof eithera surrogateendpointthatis reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversiblemorbidityormortality,thatisreasonablylikelytopredictaneffecton irreversiblemorbidityor mortalityorotherclinicalbenefit,takingintoaccounttheseverity,rarityorprevalenceoftheconditionand the availabilityorlackofalternativetreatments.The acceleratedapprovalpathway ismostoftenused in settingsin whichthecourseofadiseaseislongandan extendedperiodof timeisrequiredto measuretheintendedclinical benefitofaproduct,eveniftheeffecton thesurrogateor intermediateclinicalendpointoccursrapidly.Thus, acceleratedapprovalhasbeenusedextensivelyin thedevelopmentand approvalof productsfortreatmentof a varietyof cancersin which thegoalof therapyisgenerallyto improvesurvivalor decreasemorbidityand the durationof thetypicaldiseasecourserequireslengthyand sometimeslargestudiesto demonstratea clinicalor survivalbenefit.The acceleratedapprovalpathway iscontingenton a sponsor’sagreementto conduct additional post-approvalconfirmatorystudiestoverify

anddescribetheproduct’sclinicalbenefit.These confirmatorytrials mustbecompletedwithduediligenceand,inmostcases,theFDAmayrequirethatthetrialbedesigned, initiated,and/orfullyenrolledpriortoapproval.Failuretoconductrequiredpost-approvalstudies,ortoconfirm aclinicalbenefitduringpost-marketingstudies,wouldallowtheFDAtowithdrawtheproductfromthemarket onanexpeditedbasis.Allpromotionalmaterialsforproductcandidatesapprovedunderacceleratedregulations aresubjectto priorreviewby theFDA.

BreakthroughTherapy Designation

FDA isalsorequiredtoexpeditethedevelopmentandreviewofapplicationsforapprovalofdrugsthatare intendedtotreata seriousor life-threateningdiseaseor conditionwhere preliminaryclinicalevidenceindicates thatthedrugmaydemonstratesubstantialimprovementoverexistingtherapiesonone or moreclinically significantendpoints.Under thebreakthroughtherapyprogram,thesponsorof a new productcandidatemay requestthatFDA designatetheproductcandidateforaspecificindicationasabreakthroughtherapyconcurrent with,orafter,thefilingoftheINDfortheproductcandidate.FDA mustdetermineiftheproductcandidate qualifiesforbreakthroughtherapydesignationwithin60daysofreceiptofthesponsor’srequest.TheFDA may takecertainactionswith respectto breakthroughtherapies,includingholdingmeetingswith thesponsor throughoutthedevelopmentprocess,providingtimelyadviceto theproductsponsorregardingdevelopmentand approval,involvingmoreseniorstaffinthereviewprocess,assigningacross-disciplinaryprojectleadforthe reviewteamand takingotherstepsto designtheclinicalstudiesin an efficientmanner.

OrphanDrugs

UndertheOrphanDrugAct,FDAmaygrantorphandrugdesignationtodrugsintendedtotreatarare diseaseorcondition,whichisgenerallyadiseaseor conditionthataffectsfewerthan200,000 individualsin the UnitedStates,ormorethan200,000 individualsin theUnitedStatesbut forwhich thereisno reasonable expectationthatthecostofdevelopingandmakingtheproductforthistypeof diseaseor conditionwillbe recoveredfromsalesof theproductin theUnitedStates.

OrphandrugdesignationmustberequestedbeforesubmittinganNDA. AfterFDA grantsorphandrug designation,theidentityofthedruganditspotentialorphanusearedisclosedpubliclybyFDA.Orphandrug designationdoesnotconveyanyadvantagein,orshortenthedurationof,theregulatoryreviewandapproval process.

ThefirstNDAapplicanttoreceiveFDA approvalforaparticularactivemoietytotreatararediseasefor whichithassuchdesignationisentitledtoaseven-yearexclusivemarketingperiodintheU.S. forthatproduct, forthatindication.Duringtheseven-yearexclusivityperiod,FDA maynotapproveanyotherapplicationsto marketthesamedrugforthesamedisease,exceptinlimitedcircumstances,suchas a showing of clinical superioritytotheproductwith orphandrug exclusivityby meansof greatereffectiveness,greatersafety,or providingamajorcontributiontopatientcare,orininstancesofdrugsupplyissues.Orphandrugexclusivity doesnotpreventFDA fromapprovingadifferentdrugforthesamediseaseor condition,or thesamedrug fora differentdiseaseorcondition.Otherbenefitsoforphandrug designationincludetaxcreditsforcertainresearch and an exemptionfromtheNDAuserfee.

PediatricInformation

UnderthePediatricResearchEquityAct,orPREA,NDAsorsupplementstoNDAs mustcontaindatato assessthesafetyand effectivenessof thedrug fortheclaimedindicationsin allrelevantpediatricsubpopulations andtosupport dosing andadministration foreachpediatric subpopulation forwhichthedrugissafeand effective.FDAmaygrantfullorpartialwaivers,ordeferrals,forsubmissionofdata.Unlessotherwiserequired byregulation,PREA does not applyto any drug foran indicationforwhich orphandesignationhas been granted exceptthatPREAwillapplytoanoriginalNDA foranewactiveingredientthatisorphan-designatedifthedrug isamolecularlytargetedcancerproductintendedforthetreatmentofanadultcancerandisdirectedata moleculartargetthatFDA determinestobesubstantiallyrelevanttothegrowthorprogressionofapediatric cancer.

TheBestPharmaceuticalsforChildrenAct,orBPCA, providesNDA holdersasix-monthextensionofany exclusivity—patentor nonpatent—fora drug ifcertainconditionsare met. Conditions for exclusivityinclude FDA’sdeterminationthatinformationrelatingtotheuse of a new drug in thepediatricpopulationmayproduce healthbenefitsinthatpopulation,FDA makingawrittenrequestforpediatricstudies,and theapplicantagreeing toperform,andreportingon, therequestedstudieswithinthestatutorytimeframe.ApplicationsundertheBPCA aretreatedas priorityapplications,with allof thebenefitsthatdesignationconfers.

Post-ApprovalRequirements

OnceanNDAisapproved,aproductwillbesubjecttocertainpost-approvalrequirements.Forinstance, FDA closelyregulatesthepost-approvalmarketingandpromotionofdrugs,includingstandardsand regulations fordirect-to-consumeradvertising,off-labelpromotion,industry-sponsoredscientificandeducationalactivities andpromotionalactivitiesinvolvingtheinternet.Drugsmaybemarketedonlyfortheapprovedindicationsand in a mannerconsistentwith theapprovedlabeling.

AdverseeventreportingandsubmissionofperiodicreportsarerequiredfollowingFDAapprovalofan NDA.FDAalsomayrequirepost-marketingtesting,knownasPhase4testing,riskevaluationandmitigation strategies, or REMS, and surveillance to monitor the effects of an approved product, or FDA may place conditionsonanapprovalthatcouldrestrictthedistributionoruseoftheproduct.Inaddition,qualitycontrol, drugmanufacture,packagingandlabelingproceduresmustcontinuetoconformto cGMPs afterapproval.Drug manufacturersandcertainoftheirsubcontractorsarerequiredtoregistertheirestablishmentswithFDA and certainstateagencies.RegistrationwithFDA subjectsentitiesto periodicunannouncedinspectionsby FDA, duringwhichtheAgency inspectsmanufacturingfacilitiesto assesscompliancewith cGMPs. Accordingly, manufacturersmustcontinuetoexpendtime,moneyandeffortintheareasof productionand quality-controlto maintaincompliancewith cGMPs. Regulatoryauthoritiesmaywithdrawproductapprovalsor requestproduct recallsifa companyfailsto complywith regulatorystandards,if it encountersproblemsfollowing initial marketing,or ifpreviouslyunrecognizedproblemsaresubsequentlydiscovered.

The Hatch-WaxmanAmendments

Orange Book Listing

UndertheDrugPriceCompetitionandPatentTermRestorationActof1984,commonlyreferredto as the HatchWaxmanAmendments,NDAapplicantsarerequiredtoidentifytoFDAeachpatentwhoseclaimscover theapplicant’sdrugorapprovedmethodofusingthedrug.Uponapprovalofadrug,theapplicantmustupdate itslistingofpatentstotheNDA intimelyfashionandeachofthepatentslistedintheapplicationforthedrugis thenpublishedin theFDA’s Approved Drug Productswith TherapeuticEquivalenceEvaluations,commonly known as theOrange Book.

DrugslistedintheOrangeBookcan,inturn,becitedbypotentialgenericcompetitorsinsupportof approvalofanabbreviatednewdrugapplication,orANDA. AnANDA providesformarketingofadrugproduct thathasthesameactiveingredient(s),strength,routeofadministration,anddosageformasthelisteddrugand hasbeenshownthroughbioequivalencetestingtobetherapeuticallyequivalentto thelisteddrug. An approved ANDA productisconsideredtobetherapeuticallyequivalenttothelisteddrug.Otherthantherequirementfor bioequivalencetesting,ANDA applicantsarenotrequiredtoconduct,orsubmitresultsof,pre-clinicalorclinical teststoprovethesafetyoreffectivenessoftheirdrugproduct.DrugsapprovedundertheANDApathwayare commonlyreferredtoas“genericequivalents”tothelisteddrugandcanoftenbesubstitutedbypharmacists underprescriptionswrittenfortheoriginallisteddrug pursuantto eachstate’slaws on drug substitution.

PRLD US Equity

PRLD · 10-K · period ended 2020-12-31

Item 1. Business.

PRLD US Equity☆

PRLD · 10-K · period ended 2020-12-31

Item 1. Business.

PRLD US Equity