Item 1A. Risk Factors

Investing in our common stock involves significant risks, some of which are described below. In evaluating our business, investors should carefully consider the following risk factors. These risks and uncertainties summarized above and described below are not intended to be exhaustive and are not the only ones we face. Additional risks and uncertainties not presently known to us or that we presently deem immaterial may also impair our business operations. Please see page 2 of this Annual Report for a discussion of some of the forward-looking statements that are qualified by these risk factors. If any of the following risks actually occur, our business, financial condition, results of operations and future growth prospects could be materially and adversely affected.

Summary of the Material and Other Risks Associated with Our Business

Our business is subject to numerous risks and uncertainties that you should be aware of in evaluating our business, including those described in Part I, Item 1A. “Risk Factors” in this Annual Report. These risks include, but are not limited to, the following:

• Our stock price is expected to be volatile.

Risks Relatedto Our Business, FinancialCondition and CapitalRequirements

We arean early commercialstagebiopharmaceuticalcompany,have a limitedoperatinghistory,have not initiatedor completedany large-scaleclinicaltrials,and have a single productapprovedforcommercialsale,which maymake itdifficultforyou to evaluateourcurrentbusinessand likelihoodof successand viability.

We arean early commercial-stagebiopharmaceuticalcompanywith a limitedoperatinghistoryupon which you can evaluateourbusinessand prospects.We have a single product, FYARRO,approvedforcommercialsale by the FDA in November 2021and have not generated any revenue as of December 31, 2021, and we continue to

incur significant research and development and other expenses related to our ongoing operations. We have not yet demonstrated an ability to overcome many of the risks and uncertainties frequently encountered by companies in new and rapidly evolving fields, particularly in the biopharmaceutical area.Consequently, any predictions about our future performance may not be as accurate as they would be if we had a history of successfully developing and commercializing biopharmaceutical products.

To date, we have devotedsubstantiallyallof ourresourcesto researchand developmentactivities,businessplanning, establishingand maintainingourintellectualpropertyportfolio, preparing for commercialization of FYARRO, hiringpersonnel,raisingcapitaland providing generaland administrativesupportfortheseoperations. OurPhase 2 registrationalstudyof ourdrug FYARRO (nab-sirolimus)(the“AMPECT trial”)foradvanced(metastaticor locallyadvanced)malignantperivascularepithelioidsarcoma(“PEComa”)has been completed.A rollingNewDrug Application(an “NDA”)submissionforour leadproductcandidate,FYARRO, was completedin May 2021, and the U.S.Food and Drug Administration(the“FDA”) accepted our NDA in July 2021 and approved FYARRO for the treatment of advanced malignant PEComa in November 2021. Based on theAMPECTtrialand emergingdataforFYARRO in othersolidtumorswith tumor-agnosticTuberousSclerosisComplex1 and 2 (“TSC1& TSC2”) alterations,and followingdiscussionswith theFDA,we opened enrollment for our tumor-agnosticregistration-directedtrialin cancersharboringTSC1& TSC2 inactivatingalterationsin the first quarter of 2022. Ourotherprogramsarein earlyclinicalresearchstages.

We have not yetdemonstratedourabilityto successfullymanufacturea commercial-scaleproduct, although we have arrangedfora thirdpartyto do so on ourbehalf, or conductedsalesand marketing activitiesnecessaryforsuccessfulproductcommercialization.As a result,itmaybe moredifficultforyou to accuratelypredictourlikelihoodof successand viabilitythanitcouldbe if we had a longeroperatinghistory.

In addition,we mayencounterunforeseenexpenses,difficulties,complications,delaysand otherknown and unknown factorsand risksfrequentlyexperiencedby early commercial-stagebiopharmaceuticalcompaniesin rapidly evolvingfields.We alsoare transitioningto a companycapableof supportingcommercialactivities.We have not yetdemonstratedan abilityto successfully overcomesuch risksand difficulties,or to makesuch a transition.Ifwe do not adequatelyaddresstheserisks and difficultiesor successfullymakesuch a transition,ourbusinesswillsuffer.

We have incurredsignificantnet lossessinceour inception,and weexpectto continueto incur significantnet lossesforthe foreseeablefuture.

We have incurred significant net losses since our inception, have not generated any revenue from product sales to date and have financed our operations principally through private placements of our convertible preferred stock, federal grants and proceeds from licenses. Our net losses were $110.1 million for the year ended December 31, 2021, and $3.5 million for the year ended December 31, 2020. We had an accumulated deficit of $142.7 million as of December 31, 2021, and $32.6 million as of December 31, 2020. These losses have resulted primarily from a non-cash impairment charge of $74.2 million related to an acquired contract intangible asset, costs incurred in connection with research and development activities, costs incurred in connection with commercializing FYARRO and general and administrative costs associated with our operations. We have only one product approved for commercial sale and have not generated any product revenue as of December 31, 2021, and we continue to incur significant research and development and other expenses related to our ongoing operations. As a result, we expect to continue to incur significant operating expenses for the foreseeable future due to the cost of commercializing FYARRO, research and development, including identifying and designing additional product candidates and conducting preclinical studies and clinical trials, and the regulatory approval process for our product candidates. We expect our expenses, and the potential for losses, to increase substantially as we commercialize FYARRO, continue to conduct clinical trials of our product candidates and seek to expand our pipeline. The amount of our future expenses and potential losses is uncertain.

Even if we succeed in commercializing FYARRO for its approved PEComa indication, and if we succeed in receiving regulatory approval for and commercializing one or more of our future product candidates, we expect to continue to incur significant expenses and increasing operating losses over the next several years and for the foreseeable future. The net losses we incur may fluctuate significantly from quarter to quarter such that a period-to-period comparison of our results of operations may not be a good indication of our future performance. The size of our future net losses will depend, in part, on the rate of future growth of our expenses and our ability to generate revenue. Our prior losses and expected future losses have had, and will continue to have, an adverse effect on our

working capital, our ability to fund the commercialization of FYARRO, the development of our other product candidates, our ability to achieve and maintain profitability and the performance of our stock.

Ourabilityto generaterevenueand achieveprofitabilitydepends significantlyon ourabilityto achieve severalobjectivesrelatingto the discovery,developmentand commercializationof ourproductcandidates.

We have one product approved for commercialization in the U.S., FYARRO, for the treatment of advanced malignant PEComa, which was approved by the FDA in November 2021 and launched commercially in the U.S. in February 2022. Ourabilityto generate substantial productrevenuesufficientto achieveprofitabilitydepends on our ability, alone or with strategic collaboration partners, to obtain the regulatory and marketing approvals necessary to commercialize FYARRO in foreign jurisdictions and to successfully complete discovery,developmentand eventualcommercializationof additional indications or one or moreof our other currentand futureproduct candidates.We do not anticipategeneratingrevenuefromproductsales significant enough to achieve profitability for the foreseeable future.Ourabilityto generate future revenueand achieveprofitabilitydependssignificantlyon ourability,or any currentor futurecollaborator’sability,to achieveseveralobjectives,including,but not limitedto:

• identifying, assessing and developing new product candidates;

• protecting our rights in our intellectual property portfolio;

• defending against third-party interference or infringement claims, if any;

• attracting, hiring and retaining qualified personnel.

We mayneverbe successfulin achievingourobjectivesand, even ifwedo, maynevergeneraterevenue thatissignificantor largeenough to achieveprofitability.Ifwe do achieveprofitability,wemaynot be ableto sustainor increaseprofitabilityon a quarterlyor annualbasis.Ourfailureto becomeand remainprofitable would decreaseourvalueand couldimpairourabilityto maintainor furtherourresearchand developmentefforts, raiseadditionalnecessarycapital,grow ourbusinessor continueouroperationsand couldcausea declinein the valueof ourcommonstock.

We willrequireadditionalcapitalto financeouroperations. Ifwe areunable to raisesuch capitalwhenneeded, or on acceptableterms,wemaybe forcedto delay,reduceand/or eliminateone or moreof ourresearchand drug developmentprogramsor futurecommercializationefforts.

Developing pharmaceutical products, including conducting preclinical studies and clinical trials, is a very time-consuming, expensive and uncertain process that takes years to complete. Our operations have consumed substantial amounts of cash since inception, and we expect our expenses to increase in connection with our ongoing and planned activities, particularly as we seek additional regulatory approval of FYARRO for additional indications, and the commercialization of FYARRO for its approved indications. Our expenses could increase beyond our current expectations if we are required by the FDA, the European Medicines Agency (the “EMA”) or other regulatory agencies to perform clinical trials or preclinical studies in addition to those that we currently anticipate, or if there are any delays in any of our clinical trials or the development of any of our product candidates. Other unanticipated costs may also arise. In addition, even if we obtain regulatory approval for any of our other product candidates, including additional indications for FYARRO, we expect to incur significant commercialization expenses related to sales, marketing, manufacturing and distribution activities and ongoing compliance activities. We cannot reasonably estimate the actual amount of resources and funding that will be necessary to successfully complete the development and commercialization of FYARRO for the PEComa indication, or for any other additional indications, if approved, or any other product candidates or other indications we may develop. Upon receiving regulatory approval for FYARRO from the FDA in November 2021, we are only permitted to market or promote FYARRO for the PEComa indication, and not for any other indication, or any other product candidate, in the United States. In addition, we will incur additional costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in order to continue our operations.

As of December 31, 2021, we had $149.0 million in cash and cash equivalents. Based on our current operating plan, we believe that our cash and cash equivalents will enable us to fund our planned operating expenses and capital expenditures into 2024. Our estimate as to how long we expect our cash and cash equivalents to be able to continue to fund our operations is based on assumptions that may prove to be wrong, and we could exhaust our available capital resources sooner than we currently expect. Changing circumstances, some of which may be beyond our control, could cause us to consume capital significantly faster than we currently anticipate, and we may need to seek additional funds sooner than planned.

We plan to use our cash and cash equivalents to fund the commercialization of FYARRO for the PEComa indication, ongoing and planned clinical trials of FYARRO for other indications such as the TSC1 & TSC2 indications, for manufacturing operations and to fund our other research for other product candidates and development activities, as well as for working capital and other general corporate purposes. Advancing the development of FYARRO and any other product candidate will require a significant amount of capital. Our existing cash and cash equivalents will not be sufficient to fund all of the activities that are necessary to complete the development of FYARRO.

We willbe requiredto obtainfurtherfundingto supportourcontinuingoperationsthroughpublicor private equityofferings,debtfinancings,third-partyfunding,marketingand distributionarrangements,collaborations with thirdpartiesand licensingarrangementsor othersourcesor a combinationof theseapproaches,which may diluteourstockholdersor restrictouroperatingactivities.Any additionalfundraisingeffortsmaydivertour managementfromtheirday-to-dayactivities,which mayadverselyaffectourabilityto developand commercializeFYARRO or

any other product candidates we may develop in the future, if approved.Adequateadditionalfinancingmaynot be availableto us in sufficient amountsor on acceptableterms,or atall.To theextentthatwe raiseadditionalcapitalthroughthesaleof equityor convertibledebtsecurities,your ownershipinterestwillbe diluted,and thetermsmayinclude liquidationor otherpreferencesthatadverselyaffectyour rightsas a stockholderand thepossibilityof such issuancemaycausethemarketpriceof oursharesto decline.Debt financingmayresultin impositionof debt covenants,increasedfixedpaymentobligationsor otherrestrictionsthatmayaffecttheconductof our business.Ifwe raiseadditionalfundsthroughup-frontpaymentsor milestonepaymentspursuantto strategic collaborationswith thirdparties,wemayhave to relinquishvaluablerightsto certainof ourtechnologiesor our productcandidates,or grantlicenseson termsthatarenot favorableto us,which mayhave a materialadverse effecton ourbusiness,operatingresultsand prospects.Ourabilityto raiseadditionalfundswilldepend on financial,economicand otherfactors,manyof which arebeyond our control.In addition,we mayseek additionalcapitaldue to favorablemarketconditionsor strategicconsiderationseven ifwebelievewehave sufficientfundsforourcurrentor futureoperatingplans.

Ourfailureto raisecapitalas and when neededor on acceptabletermswould have a negativeimpacton ourfinancialconditionand ourabilityto pursueourbusinessstrategy,and we mayhave to significantlydelay, reducethescopeof, suspendor eliminateone or moreof ourresearchor developmentprograms,clinicaltrialsor futurecommercializationefforts.

Risks Relatedto the Discovery,Developmentand Commercializationof Our Product Candidates

We are early in our development efforts and have only one product which has completed development and obtained regulatory approval by the FDA for a single indication, FYARRO. We are substantiallydependenton the successof FYARRO.Ifwe areunable to commercializeFYARRO for the PEComa indication or complete development of, obtain approval for and commercialize FYARRO forone or more otherindicationsin a timelymanner, ourbusinesswillbe harmed.

We are early in our development efforts and have only one product that has completed development and been approved by the FDA, FYARRO, our lead product. Ourfuturesuccessisdependenton ourabilityto commercialize FYARRO, and to timelyand successfullyobtainregulatoryapprovalfor additional indications for FYARRO.We areinvestingthemajorityof our effortsand financialresources to commercialize FYARRO for the PEComa indication andin theresearchand developmentof FYARRO formultiple additionalindications.FYARRO (sirolimus protein-boundparticles for injectable suspension (albumin-bound)), aformof sirolimusbound to albumin,forthetreatmentof malignant PEComa, as wellas othercancertypeswith mTORpathway alterationsin theTSC1& TSC2genesthatare mostlikelyto respondto mTORtreatment.

In May 2021, we completed the filing of a rolling NDA for FYARRO to the FDA for approval to treat patients with advanced malignant PEComa, and the FDA accepted our NDA in July 2021 and approved FYARRO for advanced malignant PEComa in November 2021. Our NDA was based on results from our AMPECT trial, involving patients for whom there were no approved therapies in the United States. In November 2019, we announcedtop-line resultsfromtheAMPECTtrial,includingthatthestudyachieveditsprimaryendpointofobjectiveresponserate (the“ORR”)asdeterminedbyblindedindependentcentralradiologicreviewusingmodifiedResponse EvaluationCriteriainSolidTumors(“RECIST”).FYARRO willrequireadditionalclinicaldevelopment, expansionofmanufacturingcapabilities,regulatoryapproval from foreign regulatoryauthoritiesin jurisdictions outside of the U.S. where we plantomarketFYARRO for malignant PEComa and potentially in additional indications, if approved,substantialinvestmentandsignificantmarketingeffortsbeforewe cangenerateanyrevenuesfromproductsales.WearenotpermittedtomarketorpromoteFYARRO for non-PEComa indications,before we receiveregulatoryapprovalfromtheFDAandcomparableforeignregulatoryauthorities, andwemayneverreceivesuchregulatoryapprovals.

The successof FYARRO willdepend on severalfactors,includingthefollowing:

• the prevalence and severity of adverse side effects;

• the potential and perceived value and relative cost of FYARRO;

• the type, frequency and severity of adverse events in clinical trials;

• the protection of our rights in our intellectual property portfolio;

• our ability to compete with other therapies.

In additionto advancedmalignantPEComa, basedon datafromthecompletedAMPECTtrialand our ongoing expandedaccessprogram,we have initiateda registration-directed tumor-agnostic Phase 2 study,PRECISION1, of FYARRO in patients with TSC1& TSC2alterations.We completeda Type B meetingwith theFDAin which wediscussedtheinitialtrial design. The PRECISION 1 trial is now open for enrollment in the United States. Ourproductdevelopmentcostscouldincreaseifwe experiencedelays.Significanttrialdelaysalsocouldshortenany periodsduringwhich we mayhave the exclusiverightto commercializeFYARRO or allowourcompetitorsto bringproductsto marketbeforewe do, which would impairourabilityto successfullycapitalizeon FYARRO and mayharmourbusiness,results of operationsand prospects.Eventsthatmayresultin a delayor unsuccessfulcompletionof additional clinicaldevelopment of FYARRO include,amongotherthings:

• failure to demonstrate the efficacy of FYARRO in this clinical trial;

An inabilityby us to timelycompleteclinicaldevelopmentcouldresultin additionalcoststo us or impairour abilityto generate substantial productrevenuesor development,regulatory,commercializationand salesmilestone paymentsand royaltieson productsales.

We do not have completecontrolovermanyof thesefactors,includingcertainaspectsof clinical developmentand theregulatorysubmissionprocess,potentialthreatsto ourintellectualpropertyrightsand the manufacturing,marketing,distributionand saleseffortsof ourcurrentor any futurecollaborators.Ifwe arenot successfulwith respectto one or moreof thesefactorsin a timelymanneror atall,wecouldexperiencesignificant delaysor an inabilityto successfullycommercializeFYARRO for multiple indications, which would materiallyharmourbusiness.Ifwe do not receiveregulatoryapprovalsforFYARRO in additional indications or for otherproductcandidates,we maynot be ableto continue ouroperations.

In additionto FYARRO, ourprospectsdepend in partupon discovering,developingand commercializing additionalproductcandidates,which mayfailin developmentor sufferdelaysthatadverselyaffecttheir commercialviability.

Our future operating results are dependent on our ability to successfully discover, develop, obtain regulatory approval for and commercialize product candidates other than FYARRO. All of our current product candidates other than FYARRO are in research or preclinical development. Prior to initiating clinical trials with our other product candidates, we will need to file an IND or similar application to the FDA or regulatory authorities in other jurisdictions. We may not be able to file future INDs for our product candidates on the timelines we expect. For example, we may experience manufacturing delays or other delays with IND-enabling studies. Moreover, we cannot be sure that submission of an IND will result in the FDA allowing further clinical trials to begin, or that, once begun, issues will not arise that result in the suspension or termination of clinical trials. Additionally, even if such regulatory authorities agree with the design and implementation of the clinical trials set forth in an IND, we cannot guarantee that such regulatory authorities will not change their requirements in the future. These considerations also apply to new clinical trials we may submit as amendments to existing INDs or to a new IND. Any failure to file INDs on the timelines we expect or to obtain regulatory clearance for our trials may prevent us from developing our product candidates on a timely basis, if at all. A product candidate can unexpectedly fail at any stage of preclinical and clinical development. The historical failure rate for product candidates is high due to risks relating to safety, efficacy, clinical execution, changing standards of medical care and other unpredictable variables. The results from preclinical studies or early clinical trials of a product candidate may not be predictive of the results that will be obtained in later stage clinical trials of the product candidate.

The successof otherproductcandidateswe maydevelopwilldepend on manyfactors,includingthe following:

•generatingsufficientpreclinicaldatato supporttheinitiationof clinicaltrials;

•obtainingregulatorypermissionto initiateclinicaltrials;

•contractingwith thenecessarypartiesto conductpreclinicalstudiesand clinicaltrials;

•successfulenrollmentof patientsin, and thecompletionof, clinicaltrialson a timelybasis;

•thetimelymanufactureof sufficientquantitiesof a productcandidateforuse in clinicaltrials;and

Even ifwe successfullyadvanceany otherproductcandidatesintoclinicaldevelopment,theirsuccess willbe subjectto allof theclinical,regulatoryand commercialrisksdescribedelsewherein this“Risk Factors” section.Accordingly,we cannotassureyou thatwewilleverbe ableto discover,develop,obtainregulatory approvalof, commercializeor generatesignificantrevenuefromany additional productcandidates beyond FYARRO for advanced malignant PEComa.

FYARRO or any otherproductcandidates we may develop in the futuremaynot achieveadequatemarketacceptanceamong physicians,patients, healthcarepayorsand othersin the medicalcommunitynecessaryforcommercialsuccess,which would limit the revenuethatwe generatefromoursales.

Even though FYARRO has been approved for advanced malignant PEComa, and even ifany otherproductcandidates that we may develop in the futurereceiveregulatoryapproval,suchapprovedproductcandidatesmaynot gainadequatemarketacceptanceamongphysicians,patients,third-partypayorsand othersin themedical community.The degreeof marketacceptanceof any of ourapprovedproductcandidateswilldepend on a numberof factors,including,amongothers:

• the clinical indications for which a product candidate is approved;

• the cost of treatment in relation to alternative treatments;

• relative convenience and ease of administration;

• the effectiveness of sales and marketing efforts;

• unfavorable publicity relating to our product candidates; and

• the approval of other new therapies for the same indications.

Even though FYARRO isapproved for advanced malignant PEComa, it maynever achievean adequatelevelof acceptanceby physicians,hospitals,healthcarepayorsand patients, and we maynot generateor derivesufficientrevenuefrom thatproductand ourfinancialresultscouldbe negativelyimpacted.Beforegrantingreimbursement approval,healthcarepayorsmayrequireus to demonstratethatourproductcandidates,in additionto treating targetindications,alsoprovideincrementalhealthbenefitsto patients.Oureffortsto educatethemedical communityand third-partypayorsaboutthebenefitsof ourproductcandidatesmayrequiresignificantresources and mayneverbe successful.

The marketopportunitiesforFYARRO and any otherproductcandidateswe may develop in the future,ifapproved,maybe limitedto certainsmallerpatientsubsets.

Cancertherapiesaresometimescharacterizedby lineof therapy(first-line,second-line,third-line,etc.)and theFDAoftenapprovesnew therapiesinitiallyonly fora particularlineor linesof use. When cancerisdetected earlyenough, first-linetherapy,such as chemotherapy,hormonetherapy,surgery,radiationtherapyor a combinationof these,issometimesadequateto curethecanceror prolonglifewithouta cure. FYARRO for malignant PEComa

has been approved as a first-line therapy. Second line therapiesoftenconsistof morechemotherapy,radiation,antibodydrugs,tumor-targetedsmallmolecules,or a combinationof these.Thirdlinetherapiescan includechemotherapy,antibodydrugsand smallmoleculetumor- targetedtherapies,moreinvasiveformsof surgeryand new technologies.Ourcompletedand plannedclinical trialsforFYARRO arewith patientswho mayhave receivedone or morepriortreatments.Thereisno guarantee thatproductcandidatesthatwe develop,even ifapproved,would be approvedforfirst-lineor second-line therapy and, priorto any such approvals, we mayhave to conductadditionalclinicaltrialsthatmaybe costly,time-consumingand subjectto risk.

The numberof patientswho have thecancerswe aretargetingmayturnout to be lowerthanexpected. Ourprojectionsof addressablepatientpopulationsthatmaybenefitfromtreatmentwith ourproductcandidates arebasedon ourestimates,which mayproveto be incorrect.Additionally,thepotentiallyaddressablepatient populationforFYARRO and otherproductcandidatesmaybe limitedor maynot be amenableto treatmentwith ourproductcandidates.Regulatoryapprovalmaylimitthemarketof a productcandidateto targetpatient populationswhen such biomarker-drivenidentificationand/orhighlyspecificcriteriarelatedto thestageof diseaseprogressionareutilized.Ifany of ourestimatesproveto be inaccurate,themarketopportunityforany productcandidatethatweor ourstrategicpartnersdevelopcouldbe significantlydiminishedand have an adverse materialimpacton ourbusiness.

Even ifwe obtainsignificantmarketshareforany approvedproduct,ifthepotentialtargetpopulations aresmall,we mayneverachieveprofitabilitywithoutobtainingregulatoryapprovalforadditionalindications.

Any productcandidateswe developmaybecomesubjectto unfavorablethird-partycoverageand reimbursementpractices,as wellas pricingregulations.

The availabilityand extentof coverageand adequatereimbursementby third-partypayors,including governmenthealthadministrationauthorities,privatehealthcoverageinsurers,managedcareorganizationsand otherthird-partypayorsisessentialformostpatientsto be ableto affordexpensivetreatments.Salesof FYARRO or any otherproductcandidate we may develop in the futurethatreceivesregulatoryapprovalwilldepend substantially,both in theUnitedStates and internationally,on theextentto which thecostsof such productcandidatewillbe coveredand reimbursed by third-partypayors.Ifreimbursementisnot available,or isavailableonly to limitedlevels,we maynot be ableto successfullycommercialize FYARRO or any otherproductcandidates that we may develop in the future.Even ifcoverageisprovided,theapproved reimbursementamountmaynot be high enough to allowus to establishor maintainpricingsufficientto realizean adequatereturnon ourinvestment.Coverageand reimbursementmayimpactthedemandfor,or the priceof, FYARRO or any other productcandidate that we may develop in the futureforwhich we obtainregulatoryapproval.Ifcoverageand reimbursementare not availableor reimbursementisavailableonly to limitedlevels,we maynot successfullycommercialize FYARRO or any other productcandidate that we may develop in the futureforwhich weobtainregulatoryapproval.

Thereissignificantuncertaintyrelatedto third-partypayorcoverageand reimbursementof newly approved products,which would include FYARRO and any other productcandidate we may develop in the futureforwhich we mayobtainregulatoryapproval.Market acceptanceand salesof FYARRO or any other productcandidates we may develop in the future for which we obtain regulatory approvalwilldepend on reimbursementpoliciesand maybe affectedby healthcarereformmeasures.Coverageand adequatereimbursementfromgovernmentalhealthcareprograms, such as Medicareand Medicaidin theUnitedStates,and commercialpayorsarecriticalto new product acceptance.Third-partypayorsdecidewhich drugstheywillpay forand establishreimbursementlevels.In the UnitedStates,forexample,principaldecisionsaboutreimbursementfornew productsaretypicallymadeby the CentersforMedicare& MedicaidServices(“CMS”),an agencywithintheU.S.Departmentof Healthand Human Services(“HHS”).CMS decideswhetherand to what extenta new productwill be coveredand reimbursedunderMedicare,and privatethird-partypayorsoftenfollowCMS’s decisions regardingcoverageand reimbursementto a substantialdegree.However, one third-partypayor’sdetermination to providecoveragefora productcandidatedoes not assurethatotherpayorswillalsoprovidecoverageforthe productcandidate.As a result,thecoveragedeterminationprocessisoftentime-consumingand costly.Factors thatpayorsconsiderin determiningreimbursementarebasedon whethertheproductis:(i)a coveredbenefit underthehealthplan;(ii)safe,effectiveand medicallynecessary;(iii)appropriateforthespecificpatient; (iv)cost-effective;and (v)neitherexperimentalnor investigational.This processwillrequireus to provide scientificand clinicalsupportfortheuse of ourproductsto eachthird-partypayorseparately,with no assurance thatcoverageand adequatereimbursementwillbe appliedconsistentlyor obtainedin thefirstinstance.

Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. Further, such payors are increasingly challenging the price, examining the medical necessity and reviewing the cost effectiveness of medical product candidates. There may be especially significant delays in obtaining coverage and reimbursement for newly approved drugs such as FYARRO. Third-party payors may limit coverage to specific product candidates on an approved list, known as a formulary, which might not include all FDA-approved drugs for a particular indication. In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price (an “ASP”) and best price. Penalties may apply in some cases when such metrics are not submitted accurately and timely. Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs. We may need to conduct expensive pharmaco-economic studies to demonstrate the medical necessity and cost effectiveness of our products. Nonetheless, FYARRO or any other product candidate we may develop in the future may not be considered medically necessary or cost effective. We cannot be sure that coverage and reimbursement will be available for FYARRO or any other product that we commercialize and, if reimbursement is available, what the level of reimbursement will be.

There has been heightened governmental scrutiny recently over the manner in which drug manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to prescription drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products. For example, under the American Rescue Plan Act of 2021, effective January 1, 2024 (the “American Rescue Plan”), the statutory cap on Medicaid Drug Rebate Program rebates that manufacturers pay to state Medicaid programs will be eliminated. Elimination of this cap may require pharmaceutical manufacturers to pay more in rebates than it receives on the sale of products, which could have a material impact on our business. In July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at increasing competition for prescription drugs. In response to this executive order, the HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and potential legislative policies that Congress could pursue to advance these principles. In addition, Congress is considering legislation that, if passed, could have significant impact on prices of prescription drugs covered by Medicare, including limitations on drug price increases. A number of states are considering or have recently enacted state drug price transparency and reporting laws that could substantially increase our compliance burdens and expose us to greater liability under such laws once we begin commercialization for FYARRO or, after obtaining regulatory approval, any of our other product candidates that we may develop in the future. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize FYARRO or any other product candidates that we may develop in the future if approved. Complying with any new legislation and regulatory changes could be time-intensive and expensive, resulting in a material adverse effect on our business.

OutsidetheUnitedStates,thecommercializationof therapeuticsisgenerallysubjectto extensive governmentalpricecontrolsand othermarketregulations,and we believetheincreasingemphasison cost containmentinitiativesin Europe, Canada and othercountrieshas and willcontinueto put pressureon thepricing and usageof therapeuticssuch as FYARRO or any other productcandidates that we may develop in the future if approved.In manycountries,particularlythecountriesof the EuropeanUnion, medicalproductpricesaresubjectto varyingpricecontrolmechanismsas partof national healthsystems.In thesecountries,pricingnegotiationswith governmentalauthoritiescan takeconsiderabletime aftera productreceivesregulatoryapproval.To obtainfavorablereimbursementor pricingapprovalin some countries,we maybe requiredto conducta clinicaltrialthatcomparesthecost-effectivenessof FYARRO or any other product candidate that we may develop in the future if approved to otheravailabletherapies.In general,productpricesundersuch systemsaresubstantiallylowerthan in theUnitedStates.Othercountriesallowcompaniesto fixtheirown pricesforproductsbut monitorand control companyprofits.Additionalforeignpricecontrolsor otherchangesin pricingregulationcouldrestrictthe amountthatwe areableto chargefor FYARRO or any other productcandidates that we may develop in the future if approved.Accordingly,in marketsoutsidetheUnitedStates, thereimbursementfor FYARRO or any other products that we may develop in the future and receive regulatory approval formaybe unavailableor reducedcomparedwith theUnitedStatesand maybe insufficientto generatecommerciallyreasonablerevenueand profits.Ifreimbursementisconditionedupon ourcompletionof additionalclinicaltrials,or ifpricingissetatunsatisfactorylevels,ouroperatingresults couldbe materiallyadverselyaffected.

Ifwe areunableto establishor sustaincoverageand adequatereimbursementfor FYARRO orany other productcandidates that we may develop in the future if approved fromthird-partypayors,theadoptionof FYARRO or those otherproducts if approved,thepricesof FYARRO or those otherproducts if approvedand salesrevenue from FYARRO or those other products if approved willbe adverselyaffected,which, in turn,couldadverselyaffecttheabilityto marketor sellFYARRO or any otherproductcandidates that we may develop in the future,if approved.Coveragepoliciesand third-partypayorreimbursementratesmaychangeatany time.Further,due to theCOVID-19pandemic,millionsof individualshave lost/willbe losingemployer-basedinsurancecoverage, which mayadverselyaffectour abilityto commercialize FYARRO or any other products candidates that we may develop in the future if approved.Itisunclearwhat effect,ifany, the AmericanRescue Plan willhave on thenumberof coveredindividuals.Even iffavorablecoverageand reimbursementstatusisattainedfor FYARRO or one or moreproduct candidates that we may develop in the futureforwhich we receiveregulatoryapproval,less favorablecoveragepoliciesand reimbursementratesmaybe implementedin thefuture.

We may not be able to obtain FDA approval of any future NDA for FYARRO or any other product candidates we may develop in the future.

The clinical development, manufacturing, labeling, packaging, storage, recordkeeping, advertising, promotion, export, import, marketing and distribution and other possible activities relating to FYARRO and any other product candidate that we may develop in the future are subject to extensive regulation in the United States. Prior to the recent approval of our NDA for FYARRO for advanced malignant PEComa, we had not submitted an application for approval or obtained FDA approval for any product.

Approval of an NDA is not guaranteed, and the approval process is an expensive and uncertain process that may take several years. The FDA and foreign regulatory entities also have substantial discretion in the approval process. The number and types of preclinical studies and clinical trials that will be required for approval varies depending on the product candidate, the disease or the condition that the product candidate is designed to target and the regulations applicable to any particular product candidate. Data are subject to varying interpretation and the FDA may not agree that our clinical data support that any of our product candidates are safe and effective for the proposed therapeutic use. Despite the time and expense associated with preclinical studies and clinical trials, failure can occur at any stage, and we could encounter problems that require us to repeat or perform additional preclinical studies or clinical trials or generate additional chemistry, manufacturing and controls data, including drug product stability data. The FDA and similar foreign authorities could delay, limit or deny approval of a product candidate, and may ultimately approve the product for narrower indications or with unfavorable labeling that would impede our commercialization of the drug.

Approval procedures vary among countries and can involve additional product testing and additional administrative review periods, including obtaining reimbursement and pricing approval in select markets. The time required to obtain approval in other countries might differ from that required to obtain FDA approval. The regulatory approval process in other countries may include all of the risks associated with FDA approval as well as additional, presently unanticipated, risks. Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country may negatively impact the regulatory process in others, including the risk that our product candidates may not be approved for all indications requested and that such approval may be subject to limitations on the indicated uses for which the product may be marketed.

Failure to obtain marketing approval in international jurisdictions would prevent FYARRO and any other product candidates we may develop in the future from being marketed abroad.

In order to market and sell our products in the European Union and any other jurisdictions, we must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA approval. The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside the United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country. We may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. However, failure to obtain approval in one jurisdiction may impact our ability to obtain approval elsewhere. We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any market.

A variety of risks associated with marketing FYARRO and any other product candidates we may develop in the future internationally could affect our business.

We may seek regulatory approval for FYARRO and our product candidates outside of the United States and, accordingly, we expect that we will be subject to additional risks related to operating in foreign countries if we obtain the necessary approvals, including:

• differing regulatory requirements in foreign countries;

• foreign taxes, including withholding of payroll taxes;

• difficulties staffing and managing foreign operations;

• potential liability under the FCPA or comparable foreign regulations;

In addition, the conflict between Russia and Ukraine could lead to disruption, instability and volatility in global markets and industries that could negatively impact our operations. The U.S. government and other governments in jurisdictions in which we may operate in the future have imposed severe sanctions and export controls against Russia and Russian interests and threatened additional sanctions and controls. The impact of these measures, as well as potential responses to them by Russia, is currently unknown and they could adversely affect our business, supply chain, business partners or customers.

These and other risks associated with our international operations may compromise our ability to achieve or maintain profitability

The preclinicalstudiesand clinicaltrialsfor FYARRO or any other of ourproductcandidates that we may develop in the future maynot demonstratesafetyand efficacyto the satisfactionof the FDA,EMAor othercomparableforeignregulatoryauthoritiesor otherwise produce positiveresults,which would prevent,delay,or limitthe scopeof development,regulatoryapproval and commercialization.

Beforeobtainingregulatoryapprovalfrom theEMA or otherforeignregulatory authoritiesforthesaleof FYARRO for malignant PEComa or any additional indications that we may seek approval for, or other product candidates when approved,we, amongotherrequirements,mustcompletepreclinical developmentand extensiveclinicaltrialsto demonstratewith substantialevidencethesafetyand efficacyof such product or other productcandidates.Each product or productcandidatemustdemonstratean adequateriskversusbenefitprofilein our intendedpatientpopulationand forourintendeduse. Drug product must also be manufactured and tested in accordance with regional regulatory requirements which may differ from region to region. Clinicaltestingisexpensive,difficultto designand implement,can takemanyyearsto completeand itsultimateoutcomeisinherentlyuncertain.A failureof one or morepreclinicalstudiesor clinicaltrialscan occuratany stageof theprocess.The outcomeof preclinicalstudies and early-stageclinicaltrialsmaynot be predictiveof thesuccessof laterclinicaltrials.In addition,initial successin clinicaltrialsmaynot be indicativeof resultsobtainedwhen such trialsarecompleted.Moreover, preclinicaland clinicaldataareoftensusceptibleto varyinginterpretationsand analyses,and manycompaniesin thebiopharmaceuticalindustrythathave believedtheirproductcandidatesperformedsatisfactorilyin preclinical

studiesand clinicaltrialshave nonethelessfailedto obtainregulatoryapprovalof theirproducts.Ourcurrentor futureclinicaltrialsmaynot ultimatelybe successfulor supportfurtherclinicaldevelopmentof FYARRO or any other productcandidates we may develop in the future.

We mayexperiencenumerousunforeseeneventsduring,or as a resultof, clinicaltrialsthatcoulddelayor preventourabilityto receiveregulatoryapprovalor ourabilityto commercialize FYARRO for additional indications or for any other productcandidates we may develop in the future,including:

For instance, we do not know whetherFYARRO willperformin currentor futureclinicaltrials for additional indicationsas ithas performedin preclinicalstudiesor priorclinicaltrials.Productcandidatesin later-stageclinicaltrialsmayfailto demonstratesufficientsafetyand efficacyto thesatisfactionof theFDA,EMA, and othercomparableforeign regulatoryauthoritiesdespitehavingprogressedthroughpreclinicalstudiesand early-stageclinicaltrials. Additionally,whilewe areawareof severalotherapprovedand clinical-stagemTORinhibitorsbeingdeveloped by multipleothercompanies,to ourknowledge, thereareno mTORinhibitorsapprovedspecificallyforthe treatmentof advancedmalignantPEComa other than FYARRO. As such, thedevelopmentof FYARRO and ourstockpricemaybe impactedby inferences,whethercorrector not, thataredrawn betweenthesuccessof ourproductand thoseof othercompanies’mTORinhibitors.Regulatoryauthoritiesmayalsolimitthescopeof later-stagetrials untilwe have demonstratedsatisfactorysafety and efficacy results,which coulddelayregulatoryapproval,limitthesizeof the patientpopulationto which wemaymarketourproductcandidates,or preventregulatoryapproval.

In someinstances,therecan be significantvariabilityin safetyand efficacyresultsbetweendifferentclinical trialsof thesameproductcandidatedue to numerousfactors,includingchangesin trialprotocols,differencesin sizeand typeof thepatientpopulations,differencesin and adherenceto thedose and dosingregimenand other trialprotocolsand therateof dropoutamongclinicaltrialparticipants.Patientstreatedwith ourproductsmayalsobe undergoingsurgical,radiationand chemotherapytreatmentsand maybe usingother approvedproductsor investigationalnew drugs,which can causesideeffectsor adverseeventsthatareunrelated to ourproducts.As a result,assessmentsof efficacycan varywidelyfora particularpatient,and from patientto patientand siteto sitewithina clinicaltrial.This subjectivitycan increasetheuncertaintyof, and adverselyimpact,ourclinicaltrialoutcomes.

We do not know whetherany clinicaltrialswemayconductwilldemonstrateconsistentor adequate efficacyand safetysufficientto obtainapprovalto market FYARRO for additional indications or forany other productcandidates we may develop in the future.Ifwe arerequiredto conductadditionalclinicaltrialsor othertestingof ourproductbeyond thosethatwecurrently contemplate,ifwe areunableto successfullycompleteclinicaltrialsof ourproductor othertestingin a timelymanner,iftheresultsof thesetrialsor testsarenot positiveor areonly modestlypositiveor ifthereare safetyconcerns, we may(i)incurunplannedcosts,(ii)be delayedin seekingand obtainingregulatoryapproval for respective indications,if wereceivesuch approvalatall,(iii)receivemorelimitedor restrictiveregulatoryapproval for respective indications,(iv)be subjectto additionalpost-marketingtestingrequirementsor (v)have thedrug removedfromthemarketafterobtaining regulatoryapproval.Even if

regulatoryapprovalissecuredforany of ourproductcandidates,thetermsof such approvalmaylimitthescopeand use of ourproductcandidates,which mayalsolimittheircommercialpotential.

Ourproductcandidatesmaycause significantadverseevents,toxicitiesor otherundesirablesideeffects whenused alone or in combinationwith otherapprovedproductsor investigationalnew drugs thatcould delayor preventregulatoryapproval,preventmarketacceptance,limittheircommercialpotentialor resultin significantnegativeconsequences.

If our product candidates are associated with serious adverse events or other undesirable side effects or have unexpected characteristics in preclinical studies or clinical trials when used alone or in combination with other approved products or investigational new drugs, we may need to conduct additional studies to further evaluate the product candidates’ safety, interrupt, delay or abandon their development or halt clinical trials or limit development to more narrow uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective. Treatment- related side effects could also affect patient recruitment or the ability of enrolled subjects to complete the trial or result in a more restrictive label, delay or denial of regulatory approval or potential product liability claims. Any of these occurrences may prevent us from achieving or maintaining market acceptance of the affected product candidate, could substantially increase the costs of commercializing our product candidates and significantly impact our ability to successfully commercialize our product candidates and generate revenues, and may harm our business, financial condition and prospects significantly. For example, in our AMPECT trial of FYARRO, most treatment-related adverse events were mild or moderate, with the most commonly reported adverse events being anemia, edema, infections, mucositis, pain, nail changes, vomiting, thrombocytopenia, hypertension and nausea. Treatment-related adverse events in our other oncology and PAH trials of FYARRO included thrombocytopenia, diarrhea, fatigue, mucosal inflammation, nausea, anemia, and rash. Additionally, in our first- in-human study of FYARRO in solid tumors, one patient died of dyspnea which was deemed possibly related to FYARRO.

Patientsin ourcompletedand plannedclinicaltrialsmayin thefuturesufferothersignificantadverse eventsor othersideeffectsnot observedor anticipatedbasedon ourpreclinicalstudiesor previousclinicaltrials. FYARRO or otherproductcandidatesmaybe used in populationsforwhich safetyconcernsmaybe particularly scrutinizedby regulatoryagencies.In addition,FYARRO isbeingstudiedin combinationwith othertherapies, which mayexacerbateadverseeventsassociatedwith thetherapy.Patientstreatedwith FYARRO or ourother productcandidates that we may develop in the futuremayalsobe undergoingsurgical,radiationand/orchemotherapytreatments,which can cause sideeffectsor adverseeventsthatareunrelatedto ourproductcandidatebut maystillimpactthesuccessof our clinicaltrials.The inclusionof criticallyillpatientsin ourclinicaltrialsmayresultin deathsor otheradverse medicaleventsdue to othertherapiesor medicationsthatsuch patientsmaybe usingor due to thegravityof such patients’illnesses.For example,itisexpectedthatsomeof thepatientsenrolledin ourFYARRO clinicaltrialswill dieor experiencemajoradverseclinicaleventseitherduringthecourseof ourclinicaltrialsor aftersuch trials,which has occurredin thepast.

Iffurthersignificantadverseeventsor othersideeffectsareobservedin any of ourcurrentor future clinicaltrials,we mayhave difficultyrecruitingpatientsto theclinicaltrials,patientsmaydrop out of ourtrials, or wemaybe requiredto abandon thetrialsor ourdevelopmenteffortsof thatproductcandidatealtogether. We, theFDA,EMA, othercomparableregulatoryauthoritiesor an institutionalreviewboardmaysuspendor terminateclinicalresearchatany timeforvariousreasons,includingnoncompliancewith regulatory requirementsor a findingthattheparticipantsarebeingexposedto unacceptablehealthrisksor adverseside effects.Some potentialtherapeuticsdevelopedin thebiotechnologyindustrythatinitiallyshowed therapeutic promisein early-stagetrialshave laterbeen found to causesideeffectsthatpreventedtheirfurtherdevelopment.

Even ifthesideeffectsdo not precludetheproductcandidatefromobtainingor maintainingregulatoryapproval, undesirablesideeffectsmayinhibitmarketacceptancedue to itstolerabilityversusothertherapies.Any of these developmentscouldmateriallyharmourbusiness,financialconditionand prospects.

Further, for FYARRO for advanced malignant PEComa, or if FYARRO receives regulatory approval for any other indication, or if any other product candidate that we may develop in the futureifany of ourproductcandidatesobtainsregulatoryapproval,toxicitiesassociatedwith such productcandidatesand not seenduringclinicaltestingmayalsodevelopaftersuch approvaland leadto a requirementto (i)conductadditionalclinicalsafetytrials,(ii)add additionalcontraindications,warningsand precautionsto thedrug label,(iii)significantlyrestricttheuse of theproduct, (iv)changetheway theproductis distributedor administered, (v)implementa riskevaluationand mitigationstrategy,or createa medicationguide outliningtherisksof such sideeffectsfordistributionto patients,

or (vi)suspendor withdrawtheproductfrom themarket.We cannotpredictwhetherourproductcandidateswillcausetoxicitiesin humansthatwould precludeor leadto therevocationof regulatoryapprovalbasedon preclinicalstudiesor early-stageclinicaltrials.

Resultsfromearlypreclinicalstudiesand clinicaltrialsof ourproductcandidatesare not necessarily predictiveof the resultsof laterpreclinicalstudiesand clinicaltrialsof ourproductcandidates.Ifwe cannot replicatethe resultsfromourearlierpreclinicalstudiesand clinicaltrialsof ourproductcandidatesin ourlater preclinicalstudiesand clinicaltrials,we maybe unable to successfullydevelop,obtainregulatoryapproval forand commercializeourproductcandidates.

Any resultsfromearlypreclinicalstudiesand clinicaltrialsof ourproductcandidatesmaynot necessarilybe predictiveof theresultsfromlaterpreclinicalstudiesand clinicaltrials.Similarly,even ifwe are ableto completeourplannedpreclinicalstudiesand clinicaltrialsof ourproductcandidatesaccordingto ourcurrent developmenttimeline,theresultsfromsuch preclinicalstudiesand clinicaltrialsof ourproductcandidatesmay not be replicatedin subsequentpreclinicalstudiesor clinicaltrialresults.

Many companiesin thepharmaceuticaland biotechnologyindustrieshave sufferedsignificantsetbacksin late-stageclinicaltrialsafterachievingpositiveresultsin early-stagedevelopmentand we cannotbe certain that we willnot facesimilarsetbacks.These setbackshave been causedby, amongotherthings,preclinicaland othernonclinicalfindingsmadewhileclinicaltrialswere underway, or safetyor efficacyobservationsmadein preclinicalstudiesand clinicaltrials,includingpreviouslyunreportedadverseevents.Moreover,preclinical, nonclinicaland clinicaldataareoftensusceptibleto varyinginterpretationsand analysesand manycompanies thatbelievedtheirproductcandidatesperformedsatisfactorilyin preclinicalstudiesand clinicaltrialsnonetheless failedto obtainFDAor EMA approval.

Additionally,someof ourongoing, plannedand futureclinicaltrials may utilizean open-labelstudydesign and maybe conductedata limitednumberof clinicalsiteson a limitednumberof patients.An “open-label” clinicaltrialisone where both thepatientand investigatorknow whetherthepatientisreceivingthe investigationalproductcandidateor eitheran existingapproveddrug or placebo.Mosttypically,open-label clinicaltrialstestonly theinvestigationalproductcandidateand sometimesmaydo so atdifferentdose levels. Open-labelclinicaltrialsaresubjectto variouslimitationsthatmayexaggerateany therapeuticeffectas patients in open-labelclinicaltrialsareawarewhen theyarereceivingtreatment.Open-labelclinicaltrialsmaybe subject to a “patientbias”where patientsperceivetheirsymptomsto have improvedmerelydue to theirawarenessof receivingan experimentaltreatment.Moreover,patientsselectedforearlyclinicalstudiesoftenincludethemost severesufferersand theirsymptomsmayhave been bound to improvenotwithstandingthenew treatment.In addition,open-labelclinicaltrialsmaybe subjectto an “investigatorbias”where thoseassessingand reviewing thephysiologicaloutcomesof theclinicaltrialsareawareof which patientshave receivedtreatmentand may interprettheinformationof thetreatedgroup morefavorablygiventhisknowledge. The resultsfroman open- labeltrialmaynot be predictiveof futureclinicaltrialresultswith any of ourproductcandidateswhen studiedin a controlledenvironmentwith a placeboor activecontrol.

Interim,toplineand preliminarydata fromourclinicaltrialsthatweannounce or publishfromtimeto timemaychange as morepatientdata becomeavailableor as additionalanalysesare conducted and are subjectto auditand verificationproceduresthatcould resultin materialchanges in the finaldata.

From time to time, we may publicly disclose preliminary, interim or topline data from our clinical trials, such as the preliminary data from our completed AMPECT trial of FYARRO in patients with malignant PEComas. The preliminary data is based on a preliminary analysis of then available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the data related to the particular study or trial. For example, we may report tumor responses in certain patients that are unconfirmed at the time and which do not ultimately result in confirmed responses to treatment after follow-up evaluations. We also make assumptions, estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data. As a result, the topline results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated. Topline data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, topline data should be viewed with caution until the final data are available. In addition, we may report interim analyses of only certain endpoints rather than all endpoints. Interim data from clinical trials that we may complete are subject to the risk that one or more of the clinical outcomes may materially

change as patient enrollment continues and more patient data become available. Adverse changes between interim data and final data could significantly harm our business and prospects. Further, additional disclosure of interim data by us or by our competitors in the future could result in volatility in the price of our common stock.

In addition,theinformationwe chooseto publiclydiscloseregardinga particularclinicaltrialistypically selectedfroma moreextensiveamountof availableinformation.You or othersmaynot agreewith what we determineisthematerialor otherwiseappropriateinformationto includein ourdisclosure,and any informationwe determinenot to disclosemayultimatelybe deemedsignificantwith respectto futuredecisions,conclusions, views, activitiesor otherwiseregardinga particularproductcandidateor ourbusiness.Ifthepreliminaryor topline datathatwe reportdifferfromlate,finalor actualresults,or ifothers,includingregulatoryauthorities, disagreewith theconclusionsreached,ourabilityto obtainapprovalfor,and commercialize,FYARRO in other indications or any otherproductcandidates that we may develop in the futuremaybe harmed,which couldharmourbusiness,financialcondition,resultsof operations and prospects.

Adverseresultsof clinicaltrialsconductedby thirdpartiesinvestigatingthe sameproductcandidatesas us in differentterritoriescould adverselyaffectourdevelopmentof such productcandidate.

Lack of efficacy,adverseevents,undesirablesideeffectsor otheradverseresultsmayemergein clinical trialsconductedby thirdpartiesinvestigating our approved product or thesameproductcandidatesas us in differentterritoriesforthe sameor differentindications.For example,pursuantto theexclusivelicenseagreement(the“EOC LicenseAgreement”)with EOCPharma(Hong Kong) Limited(“EOC”)forthedevelopmentand commercializationof FYARRO in GreaterChina, includingtheRepublicof China, Hong Kong, Macauand Taiwan (collectively, the“EOC Territory”),EOChas been grantedtherightto developand commercializethesamecompoundslicensedto us, as specifiedin theEOCLicenseAgreement,including FYARRO, in theEOCTerritoryand, subjectto certainrestrictions,to collaboratewith othersforsuch developmentand commercialization.We do not have controloverEOC’s clinicaltrialsor development program,and adversefindingsfromor EOC’s conductof clinicaltrialscouldadverselyaffectour development and commercializationof FYARRO or theviabilityof FYARRO as a productcandidate.We maybe requiredto report EOC’s adverseeventsor unexpectedsideeffectsto theFDAor comparableforeignregulatoryauthorities,which could,amongotherthings,orderus to ceasefurtherdevelopmentof FYARRO.

Ifwe experiencedelaysor difficultiesin the enrollmentand/or maintenanceof patientsin clinicaltrials,our regulatorysubmissionsor receiptof necessaryregulatoryapprovalscould be delayedor prevented.

We may not be able to initiate or continue clinical trials for our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials to such trial’s conclusion as required by the FDA, EMA or other comparable foreign regulatory authorities. Orphan indications, in particular, have small populations, and it may be difficult for us to locate and enroll sufficient patients in trials for orphan-designated indications. Patient enrollment is a significant factor in the timing of clinical trials. Our ability to identify and enroll eligible patients for clinical trials may be limited or may result in slower enrollment than we anticipate. For instance, patients for our trials for the TSC1 & TSC2 study are screened using genomic information to identify alterations in the TSC1 & TSC2 genes and utilizing such criteria and/or certain highly specific criteria related to the cancer sub-types may limit patient populations eligible for our clinical trials. In particular, because we are focused on patients with specific genetic mutations for certain of our development programs, our ability to enroll eligible patients may be limited or may result in slower enrollment than anticipated. For example, with respect to FYARRO, we cannot be certain how many patients will harbor the TSC1 & TSC2 mutations that FYARRO is designed to target or that the number of patients enrolled for each mutation will suffice for regulatory approval and inclusion of each such mutation in the approved label. We may also engage third parties to develop companion diagnostics for use in our clinical trials, but such third parties may not be successful in developing such companion diagnostics, furthering the difficulty in identifying patients with the targeted genetic mutations for our clinical trials. If our strategies for patient identification prove unsuccessful, we may have difficulty enrolling or maintaining patients appropriate for FYARRO.

Patientenrollmentmaybe affectedifourcompetitorshave ongoing clinicaltrialsforproductcandidates thatareunderdevelopmentforthesameindicationsas ourproductcandidates,and patientswho would otherwisebe eligibleforourclinicaltrialsinsteadenrollin clinicaltrialsof ourcompetitors’product candidates.

Also, marketingauthorizationof competitorsin thissameclassof drugsmayimpairourabilityto enrollpatientsintoourclinicaltrials,delayingor potentiallypreventingus fromcompletingrecruitmentforone or moreof our

trials.Patientenrollmentand retentionforourcurrentor any futureclinicaltrialsmaybe affectedby otherfactors,including:

• size and nature of the patient population;

• severity of the disease under investigation;

• perceived risks and benefits of the product candidate under study;

• patient referral practices of physicians;

• the ability to obtain and maintain patient consents;

• the ability to monitor patients adequately during and after treatment;

Ourinabilityto enrolla sufficientnumberof patientsforourclinicaltrialscouldresultin significant delaysor mayrequireusto abandon one or moreclinicaltrialsaltogether.Furthermore,any negativeresults we mayreportin clinicaltrialsof ourproductcandidatesmaymakeitdifficultor impossibleto recruitand retain patientsin otherclinicaltrialswe areconducting.Similarly,negativeresultsreportedby ourcompetitorsabout theirdrug candidatesmaynegativelyaffectpatientrecruitmentin ourclinicaltrials.Enrollmentdelaysin ourclinicaltrialsmayresultin increaseddevelopmentcostsforourproductcandidatesand jeopardizeour abilityto obtainregulatoryapprovalforthesaleof ourproductcandidates.Furthermore,even ifwe areableto enrolla sufficientnumberof patientsforourclinicaltrials,thereisa riskthatpatientsenrolledin clinicaltrials willdrop out of thetrialsbeforecompletionor, becausetheymaybe late-stagecancerpatients,willnot survive thefulltermsof theclinicaltrials.As a result,we mayhave difficultymaintainingparticipationin ourclinical trialsthroughthetreatmentand any follow-upperiods.In addition,we relyon clinicaltrialsitesto ensure timelyconductof ourclinicaltrialsand, whilewe have enteredintoagreementsgoverningtheirservices,we are limitedin ourabilityto compeltheiractualperformance.

We expectto developFYARRO and potentiallyotherproductcandidatesin combinationwith othertherapies, which exposes us to additionalrisks.

We intendto developFYARRO and potentiallyotherproductcandidates,in combinationwith one or more currentlyapprovedor unapprovedtherapiesto treatcanceror otherdiseases.Patientsmaynot be ableto tolerate FYARRO or any of ourotherproductcandidatesin combinationwith othertherapiesor dosingof FYARRO in combinationwith othertherapiesmayhave unexpectedconsequences.Even though FYARRO has received FDA approval for advanced malignant PEComa, and even if FYARRO receives regulatory approval for additional indications, ifany of ourproductcandidates were to receiveregulatoryapprovalor be commercializedforuse in combinationwith otherexistingtherapies, we would continueto be subjectto therisksthattheFDA,EMA or othercomparableforeignregulatory authoritiescouldrevokeapprovalof thetherapyused in combinationwith any of ourproductcandidates,or safety,efficacy,manufacturingor supplyissuescouldarisewith theseexistingtherapies.In addition,itis possiblethatexistingtherapieswith which ourproductcandidatesareapprovedforuse couldthemselvesfall out of favoror be relegatedto laterlinesof treatment.This couldresultin theneed to identifyothercombination therapiesforourproductcandidates,theFDA,EMA or comparableforeignregulatoryauthoritiesin other jurisdictionsrequiringadditionalclinicaltrials,or ourown productsbeingremovedfromthemarketor being lesssuccessfulcommercially.

We mayalsoevaluateourproductcandidatesin combinationwith one or moreothercancertherapiesthat have not yetbeen approvedformarketingby theFDA,EMA or comparableforeignregulatoryauthorities.We willnot be ableto marketand sellany productcandidatein combinationwith any such unapprovedcancer therapiesthatdo not ultimatelyobtainregulatoryapproval.

IftheFDA,EMA or othercomparableforeignregulatoryauthoritiesdo not approveor revoketheirapproval of theseothertherapies,or ifsafety,efficacy,commercialadoption,manufacturingor supplyissuesarisewith the therapieswe chooseto evaluatein combinationwith FYARRO or any otherproductcandidate,we maybe unableto obtainapprovalof or successfullymarketany one or allof theproductcandidateswedevelop.These unapprovedtherapiesfacethesamerisksdescribedwith respectto ourproductcandidatescurrentlyin development,includingseriousadverseeffectsand delaysin theirclinicaltrials.In addition,othercompanies mayalsodeveloptheirproductsor productcandidatesin combinationwith theunapprovedtherapieswith which we aredevelopingourproductcandidatesforuse in combination.Any setbacksin thesecompanies’clinical trials,includingtheemergenceof seriousadverseeffects,maydelayor preventthedevelopmentand approvalof ourproductcandidates.

Additionally,ifthethird-partyprovidersof therapiesor therapiesin developmentused in combinationwith ourproductcandidatesareunableto producesufficientquantitiesforclinicaltrialsor forcommercialization of ourproductcandidates,or ifthecostof combinationtherapiesareprohibitive,ourdevelopmentand commercializationeffortswould be impaired,which would have an adverseeffecton ourbusiness,financial condition,resultsof operationsand growth prospects.

We have limitedresourcesand arecurrentlyfocusingoureffortson developing and commercializingFYARRO forparticular indications.As a result,we mayfailto capitalizeon otherindicationsor productcandidatesthatmay ultimatelyproveto be moreprofitableor to have a greaterlikelihoodof success.

We are currently focusing our resources and efforts on developing and commercializing FYARRO for particular indications and advancing our preclinical programs for certain other product candidates. As a result, because we have limited financial and managerial resources, we may forgo or delay pursuit of opportunities for other indications or with other product candidates that may later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial drugs or profitable market opportunities. Failure to properly assess potential product candidates could result in our focus on product candidates with low market potential, which would harm our business, financial condition, results of operations and prospects. Our spending on current and future research and development activities for FYARRO and other programs may not yield any commercially viable drugs. If we do not accurately evaluate the completed clinical trial data, likelihood of future clinical trial success, commercial potential or target markets for FYARRO or any of our other product candidates that we may develop in the future, we may relinquish valuable rights to that product candidate or program through collaboration, licensing or other strategic or royalty arrangements in cases in which we would have been more advantageous for us to retain sole development and commercialization rights to such product candidate or program.

We facesignificantcompetition,and ifourcompetitorsdevelopand markettechnologiesor productsmore rapidlythan wedo or achieveregulatoryapprovalbeforewedo or thatare moreeffective,saferor less expensivethan the productswedevelop,ourcommercialopportunitieswillbe negativelyimpacted.

The biotechnologyand pharmaceuticalindustriesarecharacterizedby rapidlyadvancingtechnologies, intensecompetitionand a strongemphasison proprietaryand novelproductsand productcandidates.Our competitorshave developed,aredevelopingor maydevelopproducts,productcandidatesand processes competitivewith FYARRO for advanced malignant PEComa or for any additional indications we may seek approval for, and for any other productcandidatesthat we may develop in the future,ifapproved.Any productcandidatesthatwe successfullydevelopand commercializewillcompetewith existingtherapiesand new therapiesthatmay becomeavailablein thefuture.We believethata significantnumberof productsarecurrentlyunder development,and maybecomecommerciallyavailablein thefuture,forthetreatmentof conditionsforwhich we mayattemptto developproductcandidates.In addition,ourproductsmayneed to competewith drugs thatphysicianscurrentlyuse to treattheindicationsforwhich we seekapproval.This maymakeitdifficultfor us to replaceexistingtherapieswith ourproducts.

In particular,thereisintensecompetitionin thefieldof oncology.We have competitorsboth in theUnited Statesand internationally,includingmajormultinationalpharmaceuticalcompanies,establishedbiotechnology

companies,specialtypharmaceuticalcompanies,emergingand start-upcompanies,governmentagencies, universitiesand otherresearchinstitutions.We alsocompetewith theseorganizationsto recruitand retain management,scientistsand clinicaldevelopmentpersonnel,which couldnegativelyaffectourlevelof expertise and ourabilityto executeourbusinessplan.We willalsofacecompetitionin establishingclinicaltrialsites, enrollingsubjectsforclinicaltrialsand in identifyingand in-licensingnew productcandidates.

Other than FYARRO, we are not aware of any FDA or EMA approved products indicated specifically for the treatment of advanced malignant PEComa. Patients with malignant PEComa commonly receive chemotherapy regimens and currently mTOR inhibitors including sirolimus, everolimus, and temsirolimus are recommended in the National Comprehensive Cancer Network (the “NCCN”) guidelines for treatment of advanced malignant PEComa based on published retrospective data. Following FDA approval, FYARRO was added to the NCCN guidelines as the only preferred regimen for treatment of malignant PEComa. For tumor agnostic TSC1 & TSC2 inactivating alterations, there are no existing FDA or EMA approved products indicated for such use. If FYARRO receives additional regulatory approval for these TSC1 & TSC2 indications, it may face competition from other drug candidates in clinical trials that target the mTOR pathway. These may include dual mTORC1/2 inhibitors in clinical trials or next generation mTOR inhibitors in development. Any potential competitors may have significantly greater financial, manufacturing, marketing, drug development, technical and human resources, and commercial expertise than us. Large pharmaceutical and biotechnology companies, in particular, have extensive experience in clinical testing, obtaining regulatory approvals, recruiting patients and manufacturing biotechnology products. These companies also have significantly greater research and marketing capabilities than we do and may also have products that have been approved or are in late stages of development, and collaborative arrangements in our target markets with leading companies and research institutions. Established pharmaceutical and biotechnology companies may also invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make the product candidates that we develop obsolete. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies, as well as in acquiring technologies complementary to, or necessary for, our programs. As a result of all of these factors, our competitors may succeed in obtaining approval from the FDA, EMA or other comparable foreign regulatory authorities or in discovering, developing and commercializing products in the field before us.

Ourcommercialopportunitycouldbe reducedor eliminatedifourcompetitorsdevelopand commercialize productsthataresafer,moreeffective,have feweror lessseveresideeffects,aremoreconvenient,have a broaderlabel,aremarketedmoreeffectively,aremorewidelyreimbursedor arelessexpensivethanany products thatwe maydevelop and commercialize.OurcompetitorsalsomayobtainregulatoryapprovalfromtheFDA,EMA or other comparableforeignregulatoryauthoritiesfortheirproductsmorerapidlythanwe mayobtainapprovalforour products,which couldresultin ourcompetitorsestablishinga strongmarketpositionbeforewe areableto enter themarket.Our approved product, or productcandidateswe may develop in the future which achieveregulatoryapproval,maybe pricedata significantpremiumovercompetitiveproductsifany have been approvedby then,resultingin reduced competitiveness.Technologicaladvancesor productsdevelopedby ourcompetitorsmayrenderour technologiesor productcandidatesobsolete,lesscompetitiveor not economical.Ifwe areunableto compete effectively,ouropportunityto generaterevenuefromthesaleof FYARRO or any other productswemaydevelop in the future,ifapproved,could be adverselyaffected.

Changes in methodsof productcandidatemanufacturingor formulationmayresultin additionalcostsor delay.

As productcandidatesprogressthroughpreclinicalstudiesand clinicaltrialsto regulatoryapprovaland commercialization,itiscommonthatvariousaspectsof thedevelopmentprogram,such as manufacturing methodsand formulation,arealteredalongtheway in an effortto optimizeyieldand manufacturingbatchsize, minimizecostsand achieveconsistentqualityand results.For example,we mayintroducealternative formulationsor dosageformsof FYARRO in additional clinical trials for other indications.Such materialchangeswill requireregulatoryapprovalbeforeimplementationand carrytheriskthattheywillnot achievetheseintended objectives.Any of thesechangescouldcause FYARRO and any other productcandidate that we may develop in the futureto performdifferentlyand affectthe resultsof plannedclinicaltrialsor otherfutureclinicaltrialsconductedwith thealteredmaterials.This could delaycompletionof clinicaltrials,requiretheconductof bridgingclinicaltrialsor therepetitionof one or more clinicaltrials,increaseclinicaltrialcosts,delayapproval

of ourproductcandidatesand jeopardizeour abilityto commercializeFYARRO or any other productcandidates that we may develop in the future,ifapproved,and generaterevenue.

We maynot be successfulin growing ourproductpipelinethrough acquisitionsand in-licenses.

We believethataccessingexternalinnovationand expertiseisimportantto oursuccess;and whilewe planto leverageourleadershipteam’spriorbusinessdevelopmentexperienceas weevaluatepotentialin-licensingand acquisitionopportunitiesto furtherexpand ourportfolio,wemaynot be ableto identifysuitable licensingor acquisitionopportunities,and even ifwedo, wemaynot be ableto successfullysecuresuch licensing and acquisitionopportunities.The licensingor acquisitionof third-partyintellectualpropertyrightsisa competitivearea,and severalmoreestablishedcompaniesmaypursuestrategiesto licenseor acquirethird-party intellectualpropertyrightsthatwe mayconsiderattractiveor necessary.These companiesmayhave a competitiveadvantageoverus due to theirsize,capitalresourcesand greaterclinicaldevelopmentand commercializationcapabilities.In addition,companiesthatperceiveus to be a competitormaybe unwillingto assignor licenserightsto us. We mayalsobe unableto licenseor acquirethird-partyintellectualproperty rightson termsthatwould allowusto makean appropriatereturnon ourinvestment,or atall.Ifwe areunableto successfullylicenseor acquireadditionalproductcandidatesto expand ourportfolio,ourpipeline,competitive position,business,financialcondition,resultsof operations,and prospectsmaybe materiallyharmed.

Ourbusinessentailsa significantriskof productliabilityand ifweareunable to obtainsufficientinsurance coveragesuch inabilitycould have a materialadverseeffecton ourbusinessand financialcondition.

Ourbusinessexposesusto significantproductliabilityrisksinherentin thedevelopment,testing, manufacturingand marketingof therapeutictreatments.Productliabilityclaimsmightbe broughtagainstus by patients,healthcareproviders,or otherssellingor otherwisecomingintocontactwith FYARRO or any other productcandidates that we may develop in the future. For example,we maybe sued if FYARRO or any other productwe developallegedlycausesinjuryor isfound to be otherwise unsuitableduringproducttesting,manufacturing,marketingor sale.Any such productliabilityclaimsmay includeallegationsof defectsin manufacturing,defectsin design,a failureto warn of dangersinherentin the product,negligence,strictliability,and a breachof warranties.Claimscouldalsobe assertedunderstate consumerprotectionacts.Ifwe becomesubjectto productliabilityclaimsand cannotsuccessfullydefend againstthem,we couldincursubstantialliabilities.Productliabilityclaimscoulddelayor prevent completionof ourdevelopmentprograms.Ifwe succeedin marketingproducts,such claimscouldresultin an FDA,EMA or otherregulatoryauthorityinvestigationof thesafetyand effectivenessof ourproducts,our(or third-party)manufacturingprocessesand facilitiesor ourmarketingprograms.FDA,EMA or otherregulatory authorityinvestigationscouldpotentiallyleadto a recallof ourproductsor moreseriousenforcementaction, limitationson theapprovedindicationsforwhich theymaybe used or suspensionor withdrawalof approvals. Regardlessof themeritsor eventualoutcome,liabilityclaimsmayalsoresultin decreaseddemandforour products,injuryto ourreputation,coststo defendtherelatedlitigation,a diversionof management’stimeand our resourcesand substantialmonetaryawardsto trialparticipantsor patients.Although we have obtained product liability insurance coverage, our insurance coverage maynot provide sufficientcoverageagainstpotentialliabilities.Furthermore,clinicaltrialand productliabilityinsuranceis becomingincreasinglyexpensive.As a result, we maybe unableto obtainor maintainsufficientinsuranceata reasonablecostto protectusagainstlossescausedby productliabilityclaimsthatcouldhave an adverseeffecton ourbusinessand financialcondition.Largejudgmentshave been awardedin classactionlawsuitsbasedon drugs thathad unanticipatedsideeffects.The costof any productliabilitylitigationor otherproceedings,even if resolvedin ourfavor,couldbe substantial,particularlyin lightof thesizeof ourbusinessand financialresources. A productliabilityclaimor seriesof claimsbroughtagainstus could alsocauseourstockpriceto decline.

The recentglobalCOVID-19outbreakhas affectedand isexpectedto continueto affectourbusinessand operations.

Broad-basedbusinessor economicdisruptionscouldadverselyaffectourongoing or plannedresearch and developmentactivities.To date,theCOVID-19pandemichas causedsignificantdisruptionsto theUnited Statesand globaleconomy.Further,infectionsand deathsrelatedto COVID-19aredisruptingcertainhealthcare and healthcareregulatorysystemsglobally.Such disruptionscoulddiverthealthcareresourcesaway from,or materiallydelayreviewby, theFDAand comparableforeignregulatoryagencies.Itisunknown how long these disruptionscouldcontinue,were theyto occur.Any elongationor de-prioritizationof ourclinicaltrialsor delayin regulatoryreviewresultingfromsuch disruptionscouldmateriallyadverselyaffectthedevelopmentand studyof ourproductcandidates.The COVID-19pandemiccausedus to modifybusinesspractices(including but not

limitedto curtailingor modifyingemployeetravel,curtailingor modifyingourclinicaltrials,moving to fullremotework, and cancellingphysicalparticipationin meetings,events,and conferences).For example, we have experienced, and continue to experience,someclinicaldevelopmentdisruptionsdue to thepandemic,includingclosuresatcertain labfacilities,which have led, and continue to lead,to longerthananticipatedclinicaldevelopmenttimes.In addition, our clinical trials have been, and may continue to be, affected by the closure of offices, or country borders, among other measures being put in place around the world. The inability to travel and conduct face-to-face meetings can also make it more difficult to enroll new patients in ongoing or planned clinical trials.

As a resultof theevolvingCOVID-19pandemic,we have experiencedand expectto continueto experiencedisruptionsthatcouldseverelyimpactourbusiness,preclinicalstudiesand clinicaltrials,including:

• interruption or delays to our sourced discovery and clinical activities; and

The extentof theimpactof theCOVID-19pandemicon ourfutureliquidityand operationalperformance willdepend on certaindevelopments,includingthedurationand spreadof theoutbreak,theavailabilityand effectivenessof vaccines,theimpacton ourclinicaltrials,patients,and collaborationpartners,and theeffectonoursuppliers.

Risks Relatedto RegulatoryApproval and OtherLegal ComplianceMatters

If the FDA does not conclude that our product candidates and/or new indications satisfy the requirements under the 505(b)(2)regulatorypathway, or if the requirements for such product candidates and/or new indications under Section 505(b)(2) are not as we expect, the approval pathway for our product candidates and/or new indications may take longer, cost more or entail greater complications and risks than anticipated, which maydelayor preventthe approvalof our product candidates and/or new indications forcommercialuse.

We submitteda Section505(b)(2)NDAto theFDAin May 2021 forFYARROforthetreatmentof advancedmalignantPEComa, and the FDA approved the NDA in November 2021. We may not be successful in obtaining FDA approval under 505(b)(2) regulatory pathway for other indications or product candidates that we develop.

Section505(b)(2)of theFederalFood, Drug, and CosmeticAct (the “FDCA”)was enactedas partof theDrug PriceCompetitionand PatentTermRestorationAct of 1984 (the“Hatch-WaxmanAmendments”)and permitsthesubmissionof an NDAwhere atleastsomeof the informationrequiredforapprovalcomesfrompreclinicalstudiesor clinicaltrialsnot conductedby or forthe applicantand forwhich theapplicanthas not obtaineda rightof reference.The FDAinterpretsSection505(b)(2) of theFDCAto permittheapplicantto relyupon theFDA’s previousfindingsof safetyand efficacyforan approvedproduct.The FDArequiressubmissionof informationneededto supportany changesto a previously approveddrug, such as publisheddataor new studiesconductedby theapplicantor clinicaltrialsdemonstrating safetyand efficacy.The FDA is not required to meet the PDUFA goal date, and the FDAcouldrequireadditionalinformationto sufficientlydemonstratesafetyand efficacy to supportapproval.Moreover,even ifany new indication or product candidate isapprovedundertheSection505(b)(2) regulatorypathway, theapprovalmaybe subjectto limitationson theindicatedusesforwhich wemaybe marketedor to otherconditionsof approval,or maycontainrequirementsforcostlypost-marketingtestingand surveillanceto monitorthesafetyor efficacyof theproduct.

We maybe unable to obtainUnited States approval for FYARRO for additional indications or our other product candidates that we may develop in the futureor foreignregulatoryapprovalforFYARRO or ourotherproduct candidates that we may develop in the future and, as a result,maybe unable to commercializeFYARRO or ourproductcandidatesand our businesswillbe substantiallyharmed.

Ourproductcandidatesareandwillcontinuetobesubjecttoextensivegovernmentalregulationsrelatingto, amongotherthings,research,testing,development,manufacturing,safety,efficacy,approval,recordkeeping, reporting,labeling,storage,packaging,advertisingandpromotion,pricing,marketinganddistributionofdrugs. Rigorouspreclinicaltestingandclinicaltrialsandanextensiveregulatoryapprovalprocessmustbesuccessfully completedintheUnitedStatesandinmanyforeignjurisdictionsbeforeanewdrugcanbeapprovedformarketing. Satisfactionoftheseandotherregulatoryrequirementsiscostly,timeconsuming,uncertainandsubjectto unanticipateddelays.wecannotprovideanyassurancethatanyproductcandidatewemaydevelopwillprogress throughrequiredclinicaltestingandobtaintheregulatoryapprovalsnecessaryforustobeginsellingthem.

We submittedan NDAunderSection505(b)(2)to theFDAin May 2021 forFYARROforthetreatmentof advancedmalignantPEComa, and the FDA approved the NDA in November 2021.The timerequiredto obtainapprovalsfromtheFDAand otherregulatoryauthoritiesis unpredictableand requiressuccessfulcompletionof extensiveclinicaltrialswhich typicallytakesmanyyears, dependingupon numerousfactors,includingthetype,complexityand noveltyof theproductcandidate.The standardsthattheFDAand ourforeigncounterpartsuse when evaluatingclinicaltrialdatacan, and oftendoes, changeduringdrug development,which makesitdifficultto predictwith any certaintyhow theywillbe applied. We mayalsoencounterunexpecteddelaysor increasedcostsdue to new governmentregulations,including futurelegislationor administrativeaction,or changesin FDApolicyduringtheperiodof drug development, clinicaltrialsand FDAregulatoryreview.Regulatoryauthoritieshave substantialdiscretionin theapproval processand mayrefuseto acceptany applicationor maydecidethatourdataareinsufficientforapprovaland requireadditionalpreclinical,clinicalor otherstudies.Itispossiblethatnone of ourexistingproduct candidatesor any productcandidateswe mayseekto developin thefuturewilleverobtainregulatoryapproval.

Additionally,as of March18, 2021, theFDAnoteditiscontinuingto ensuretimelyreviewsof applications formedicalproductsduringtheCOVID-19pandemicin linewith itsuserfeeperformancegoalsand conducting missioncriticaldomesticand foreigninspectionsto ensurecomplianceof manufacturingfacilitieswith FDA qualitystandards.However, theFDAmaynot be ableto continueitscurrentpaceand approvaltimelinescould be extended,includingwhere a pre-approvalinspectionor an inspectionof clinicalsitesisrequiredand due to theCOVID-19pandemicand travelrestrictionstheFDAisunableto completesuch requiredinspectionsduring thereviewperiod.In 2020 and 2021, a numberof companiesannouncedreceiptof completeresponselettersdue to theFDA’s inabilityto completerequiredinspectionsfortheirapplications.

Any delayor failurein seekingor obtainingrequiredapprovalswould have a materialand adverseeffecton ourabilityto generaterevenuefromany particularproductcandidateswe aredevelopingand forwhich we are seekingapproval.Furthermore,any regulatoryapprovalto marketa drug maybe subjectto significantlimitations on the

approvedusesor indicationsforwhich we maymarket,promoteand advertisethedrug or thelabelingor otherrestrictions.In addition,theFDAhas theauthorityto requirea Risk Evaluationand MitigationStrategy (“REMS”)planas partof approvingan NDA,or afterapproval,which mayimposefurther requirementsor restrictionson thedistributionor use of an approveddrug. These requirementsor restrictions mightincludelimitingprescribingto certainphysiciansor medicalcentersthathave undergonespecialized training,limitingtreatmentto patientswho meetcertainsafe-usecriteriaand requiringtreatedpatientsto enrollin a registry.These limitationsand restrictionsmaysignificantlylimitthesizeof themarketforthedrug and affectreimbursementby third-partypayors.

We are also subject to numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement. The foreign regulatory approval process varies among countries, and generally includes all of the risks associated with FDA approval described above as well as risks attributable to the satisfaction of local regulations in foreign jurisdictions. Moreover, the time required to obtain approval may differ from that required to obtain FDA approval.

The regulatoryapprovalprocessesof the FDA,EMAand othercomparableforeignregulatoryauthoritiesare lengthy,timeconsumingand inherentlyunpredictable.If we areultimatelyunable to obtainregulatory approvalforourproductcandidates,we willbe unable to generateproductrevenue,and ourbusinesswillbe substantiallyharmed.

Obtainingapprovalby theFDA,EMA and othercomparableforeignregulatoryauthoritiesisunpredictable, typicallytakesmanyyearsfollowingthecommencementof clinicaltrialsand dependsupon numerousfactors, includingthetype,complexityand noveltyof theproductcandidatesinvolved.In addition,approvalpolicies, regulationsor thetypeand amountof clinicaldatanecessaryto gainapprovalmaychangeduringthecourseof a productcandidate’sclinicaldevelopmentand mayvaryamongjurisdictions,which maycausedelaysin the approvalor thedecisionnot to approvean application.Regulatoryauthoritieshave substantialdiscretionin the approvalprocessand mayrefuseto acceptany applicationor maydecidethatourdataareinsufficientfor approvaland requireadditionalpreclinical,clinicalor otherstudies.Even though FYARRO has been approved by the FDA, and even ifwe eventuallycompleteclinical testingand receiveapprovalfor FYARRO in additional indications or for any other productcandidates that we may develop in the future,theFDA,EMA and othercomparableforeignregulatory authoritiesmayapproveourproductcandidatesfora morelimitedindicationor a narrowerpatientpopulationthan weoriginallyrequestedor mayimposeotherprescribinglimitationsor warningsthatlimittheproduct’s commercialpotential.We have not obtainedregulatoryapprovalforany productcandidate,and itispossiblethat none of ourproductcandidateswilleverobtainregulatoryapproval.

Further,regulatoryapprovalmaybedelayedforreasonsbeyondourcontrol.Forexample,aUnitedStates federalgovernmentshutdownorbudgetsequestration,suchasonesthatoccurredduring2013,2018and2019,or thecurrentdiversionofresourcestohandletheCOVID-19publichealthemergencyandpandemicmayresultin significantreductionstotheFDA’sbudget,employeesandoperations,whichmayleadtoslowerresponsetimesand longerreviewperiods,potentiallyaffectingourabilitytoobtainregulatoryapprovalforourproductcandidates.In addition,theimpactofCOVID-19maycausetheFDAtoallocateadditionalresourcestoproductcandidates focusedontreatingrelatedillnesses,whichcouldleadtolongerapprovalprocessesforourproductcandidates. Finally,ourcompetitorsmayfilecitizens’petitionswiththeFDAinanattempttopersuadetheFDAthatour productcandidates,ortheclinicaltrialsthatsupporttheirapproval,containdeficiencies.Suchactionsbyour competitorscoulddelayorevenpreventtheFDAfromapprovinganyofourNDAs.

Applicationsforourproductcandidatescouldfailto receiveregulatoryapprovalformanyreasons, includingthefollowing:

This lengthyapprovalprocess,as wellas theunpredictabilityof theresultsof clinicaltrials,mayresultin us failingto obtainregulatoryapprovalto marketany of ourproductcandidates,which would significantly harmourbusiness,resultsof operationsand prospects.

The FDA,EMAand othercomparableforeignregulatoryauthoritiesmaynot acceptdata fromtrials conductedin locationsoutsideof theirjurisdiction.

Ourclinicaltrialshave been and mayin thefuturebe undertakenin theUnitedStates.We maychoose to conductadditionalclinicaltrialsinternationallyas well.For example,we mayconductourPRECISION1 trialof FYARRO in theUnitedStates,Europe and othercountries.The acceptanceof studydataby theFDA, EMA or othercomparableforeignregulatoryauthorityfromclinicaltrialsconductedoutsideof theirrespective jurisdictionsmaybe subjectto certainconditions.In caseswhere datafromUnitedStatesclinicaltrialsare intendedto serveas thebasisforregulatoryapprovalin foreigncountriesoutsidetheUnitedStates,thestandards forclinicaltrialsand approvalmaybe different.Therecan be no assurancethatany UnitedStatesor foreign regulatoryauthoritywould acceptdatafromtrialsconductedoutsideof itsapplicablejurisdiction.IftheFDA, EMA or any applicableforeignregulatoryauthoritydoes not acceptsuch data,itwould resultin theneed for additionaltrials,which would be costlyand time-consumingand delayaspectsof ourbusinessplan,and which mayresultin ourproductcandidatesnot receivingapprovalor clearanceforcommercializationin the applicablejurisdiction.

Brexitand uncertaintyin theregulatoryframeworkas wellas futurelegislationin theUnitedKingdom (the“UK”),EuropeanUnion, and otherjurisdictionscan leadto disruptionin theexecutionof internationalmulti-centerclinicaltrials,themonitoringof adverseeventsthroughpharmacovigilanceprograms, theevaluationof thebenefit-riskprofilesof new medicinalproducts,and determinationof marketing authorizationacrossdifferentjurisdictions.Uncertaintyin theregulatoryframeworkcouldalsoresultin disruptionto thesupplyand distributionas wellas theimport/exportboth of activepharmaceuticalingredients and finishedproduct.Such a disruptioncouldcreatesupplydifficultiesforongoing clinicaltrials.The cumulative effectsof thedisruptionto theregulatoryframework,uncertaintyin futureregulation,and changesto existing regulationsmayincreaseourdevelopmentleadtimeto marketingauthorizationand commercializationof productsin theEuropeanUnion and/ortheUKand increaseourcosts.We cannotpredicttheimpactof such changesand futureregulationon ourbusinessor theresultsof ouroperations.

Obtaining and maintainingregulatoryapprovalof ourproductcandidatesin one jurisdictiondoes not mean thatwe willbe successfulin obtainingregulatoryapprovalof ourproductcandidatesin other jurisdictions.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other jurisdiction. For example, even if the FDA or EMA grants regulatory approval of a product candidate, comparable regulatory authorities in foreign jurisdictions must also approve the manufacturing, marketing and promotion and reimbursement of the product candidate in those countries. However, a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory approval process in others. Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from those in the United States, including additional preclinical studies or clinical trials as clinical trials conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions. The regulatory approval processes in other countries may implicate all of the risks detailed above regarding FDA approval in the United States, as well as other risks. In many jurisdictions outside the United States, a product candidate must be approved for reimbursement before it

can be approved for sale in that jurisdiction. In some cases, the price that we intend to charge for our products is also subject to approval.

Obtainingforeignregulatoryapprovalsand establishingand maintainingcompliancewith foreignregulatory requirementscouldresultin significantdelays,difficultiesand costsforus and coulddelayor preventthe introductionof ourproductsin certaincountries.Ifwe or any futurecollaboratorfailto complywith the regulatoryrequirementsin internationalmarketsor failto receiveapplicableregulatoryapprovals,ourtarget marketwillbe reducedand ourabilityto realizethefullmarketpotentialof ourproductcandidateswillbe harmed.

FollowingBrexit,to theextentwe conductany operationsin theUK,we willbe subjectto applicable regulatoryrequirementsin theUK.Although theUKisno longera memberof theEuropeanUnion, European Union law remainsapplicablein NorthernIreland.Therearea numberof new marketingauthorizationroutes availablein theUK,GreatBritain(England,Scotlandand Wales)or NorthernIreland,in additionto thenational procedure.As with theEuropeanUnion position,a companycan only startto marketa medicinein theUKonce ithas receiveda marketingauthorization.The mainlegislationthatappliesto clinicaltrialsin theUKistheUK MedicinesforHuman Use (ClinicalTrials)Regulations2004, which transposestheClinicalTrialsDirectiveinto domesticlaw. Consequently,therequirementsand obligationsthatrelateto theconductof clinicaltrialsin the UKcurrentlyremainlargelyalignedwith theEuropeanUnion position.Itisunclearhow futureregulatory regimein theUKwillimpactregulationsof products,manufacturers,and approvalof productcandidatesin the UK.In theimmediatelyforeseeablefuture,theUKregulatoryapprovalprocessislikelyto remainsimilarto thatapplicablein theEuropeanUnion, albeitthattheprocessesforapplicationswillbe separate.Longer term,theUK islikelyto developitsown legislationthatdivergesfromthatin theEuropeanUnion.

FYARRO is, and any other product candidate we may develop in the future for which we obtain marketing approval for could be, subject to post-marketing restrictions or recall or withdrawal from the market, and we may be subject to penalties if we or our collaborators fail to comply with regulatory requirements or if we or our collaborators experience unanticipated problems with FYARRO, or any other product candidate we may develop in the future when and if any of them are approved.

FYARRO is, and any other product candidate we may develop in the future for which we obtain marketing approval could be, subject to a comprehensive regulatory scheme, which includes the regulation of manufacturing processes, post-approval clinical data, labeling, advertising, marketing, distribution and promotional activities for such product, by the FDA and other regulatory authorities. The FDA has significant post-marketing authority, including, for example, the authority to require labeling changes based on new safety information and to require post-marketing studies or clinical trials to evaluate serious safety risks related to the use of a drug. For example, the FDA may require the submission of a REMS in order to approve our product candidates,which couldentailrequirementsfora medicationguide,physiciantrainingand communicationplansor additional elementsto ensuresafeuse, such as restricteddistributionmethods,patientregistriesand otherriskminimization tools.Any REMSrequiredby theFDAmayleadto increasedcoststo assurecompliancewith new post-approval regulatoryrequirementsand potentialrequirementsor restrictionson thesaleof approvedproducts,allof which couldleadto lowersalesvolumeand revenue.In addition,iftheFDAor foreignregulatoryauthoritiesapprove ourproductcandidates,themanufacturingprocesses,labeling,packaging,distribution,adverseevent reporting,storage,advertising,promotion,import,exportand recordkeepingforourproductcandidateswillbe subjectto extensiveand ongoing regulatoryrequirements.These requirementsincludesubmissionsof safetyand otherpost-marketinginformationand reports,registration,as wellas on-goingcompliancewith currentgood manufacturingpractices(“cGMPs”), good laboratorypractices(“GLPs”)and good clinicalpractices(“GCPs”)forany clinicaltrialsthatwe conductpost-approval.In addition, manufacturersof drug productsand theirfacilitiesaresubjectto continualreviewand periodic,unannounced inspectionsby theFDAand otherregulatoryauthoritiesforcompliancewith cGMP regulationsand standards. Accordingly,we and otherswith whom we work mustcontinueto expend time,money,and effortin all areasof regulatorycompliance,includingmanufacturing,production,and qualitycontrol.

FYARRO is, and if marketing approval of any other product candidate we may develop in the future is granted may be, subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, including the requirement to implement a REMS, which could involve requirements for, among other things, a medication guide, special training for prescribers and dispensers, and patient registries. As a condition of the approval of the NDA for FYARRO, we are required to conduct certain post-marketing requirements (“PMR”) and/or post-marketing commitments (“PMC”). If we fail to comply with the PMR and/or PMC, the FDA may take

enforcement actions, which may include, among other things, the issuance of a Warning Letter and assessing civil monetary penalties. The product may also be deemed misbranded.

FYARRO does, and if any other product candidate that we may develop in the future receives marketing approval they may, have a label that limits their approved uses, including more limited subject populations, than we request, and regulatory authorities may require that contraindications, warnings or precautions be included in the product labeling, including a boxed warning, or may approve a product candidate with a label that does not include the labeling claims necessary or desirable for the successful commercialization of that product candidate, which could limit sales of the product.

The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of the product. The FDA closely regulates the post-approval marketing and promotion of products to ensure products are marketed only for the approved indications and in accordance with the provisions of the approved labeling. The FDA imposes stringent restrictions on manufacturers’ communications regarding off-label use and if we do not market our prodrug products, if any, for their approved indications, we may be subject to enforcement action for off-label marketing. Violations of the Federal Food, Drug and Cosmetic Act relating to the promotion of prescription drugs may lead to a number of actions and penalties, including warning letters, cyber letters, or untitled letters, adverse publicity, the requirement for dear-health-care-provider letters or other corrective information, fines and other monetary penalties, civil or criminal prosecution, including False Claims Act liability, restrictions on our operations and other operating requirements through consent decrees or corporate integrity agreements, debarment, exclusion from participation in federal health care programs and refusal of government contracts or future orders under existing contracts, among other consequences.

We willbe requiredto reportcertainadversereactionsand productionproblems,ifany, to theFDAand comparableforeignregulatoryauthorities.Ifwe or a regulatoryagencydiscoverpreviouslyunknown problems with a product,such as adverseeventsof unanticipatedseverityor frequency,or problemswith thefacilities where theproductismanufactured,a regulatoryagencymayimposerestrictionson thatproduct,the manufacturingfacilityor us, includingrequiringrecallor withdrawalof theproductfromthemarketor suspensionof manufacturing.Any new legislationaddressingdrug safetyissuescouldresultin delaysin product developmentor commercialization,or increasedcoststo assurecompliance.In addition,failureto complywith FDA,EMA and othercomparableforeignregulatoryrequirementsmayhave negative consequences,including:

• adverse inspection findings;

• product seizures, detentions or import bans;

• total or partial suspension of production;

• requirement to establish or modify a REMS;

• requirement to conduct post-marketing studies or surveillance;

• restrictions on drug distribution or use;

• requirements to conduct post-marketing studies or clinical trials;

• delays in or the rejection of approvals of additional indications for FYARRO;

• fines, restitution or disgorgement of profits or revenue;

• reputational harm;

The holderof an approvedNDAor comparableregulatoryapprovalmustsubmitnew or supplemental applicationsand obtainapprovalforcertainchangesto theapprovedproduct,productlabeling,or manufacturing processand theFDAor comparableforeignregulatoryauthoritymayrefuseto approvependingapplicationsor supplementsto approvedapplicationsfiledby us.

The occurrenceof any eventor penaltydescribedabove mayinhibitourabilityto commercialize FYARRO and any other productcandidates that we may develop in the future,ifapproved,and generaterevenue.Ifregulatorysanctionsareappliedor ifregulatory approvaliswithdrawn,thevalueof thecompanyand ouroperatingresultswillbe adverselyaffected.

The FDAand otherregulatoryagenciesactivelyenforcethe laws and regulationsprohibitingthe promotionof off-labeluses.

If any of our product candidates are approved and we are found to have improperly promoted off-label uses of those products, we may become subject to significant liability. The FDA and other regulatory agencies, including the U.S. Department of Justice, strictly regulate the post-approval marketing and promotional claims that may be made about prescription products, such as for FYARRO. In particular, a product may not be promoted for uses that are not approved by the FDA or such other regulatory agencies as reflected in the product’s approved labeling. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant civil, criminal and administrative penalties. As such, we may not promote our products for indications or uses for which they do not have approval. For example, physicians may, in their practice of medicine, use drug products for their patients in a manner that is inconsistent with the approved label. If we, or any of our contractors or agents acting on behalf of us, are found to have promoted such off-label uses, we may become subject to significant liability. The United States federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined several companies from engaging in off-label promotion. The FDA has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed. If we cannot successfully manage the promotion of FYARRO and any other product candidate that we may develop in the future, if approved, we could become subject to significant liability, which would materially adversely affect our business and financialcondition.

Ifwe arerequiredby the FDAto obtainapprovalof a companiondiagnosticproductin connectionwith approvalof any futureproductin candidatesor new indicationthat wemaydevelop,and ifwe failto obtain or facedelaysin obtainingFDAapprovalof such companiondiagnosticproduct,we willnot be ableto commercializesuch productcandidateintendedforuse with such companiondiagnosticproductand ourability to generaterevenueformsuch productcandidatewillbe materiallyimpaired.

In connectionwith thedevelopmentof any futureproductcandidatesor new indicationwe maydevelopor work with collaboratorsto developor obtainaccessto companiondiagnosticteststo identifypatientsubsets withina diseasecategorywho mayderiveselectiveand meaningfulbenefitfromourprograms.Such companiondiagnosticswould be used duringourclinicaltrialsas wellas in connectionwith the commercializationof any futureproductcandidates or new indicationwemaydevelop. To be successfulin developingand commercializingsuch productcandidatein combinationwith thesecompaniondiagnostics,we or our collaboratorswillneed to addressa numberof scientific,technical,regulatoryand logisticalchallenges. Accordingto FDAguidance,iftheFDAdeterminesthata companiondiagnosticdeviceisessentialto thesafe and effectiveuse of a noveltherapeuticproductor indication,theFDAgenerallywillnot approvethetherapeutic productor new therapeuticproductindicationifthecompaniondiagnosticisnot alsoapprovedor clearedatthe sametimetheproductcandidateisapproved.To date,theFDAhas requiredmarketingapprovalof all companiondiagnostictestsforcancertherapies.Variousforeignregulatoryauthoritiesalsoregulatein vitro companiondiagnosticsas medicaldevicesand, underthoseregulatoryframeworks,willlikelyrequirethe conductof clinicaltrialsto demonstratethesafetyand effectivenessof ourcurrentdiagnosticsand any future diagnosticswe maydevelop,which weexpectwillrequireseparateregulatoryclearanceor approvalpriorto commercialization.

The approval of a companion diagnostic as part of the therapeutic product’s labeling limits the use of the therapeutic product to only those patients who express certain biomarkers or the specific genetic alteration that the

companion diagnostic was developed to detect. If the FDA, EMA or a comparable regulatory authority requires approval of a companion diagnostic for any future product candidate or new indication that we may develop, whether before or concurrently with approval of such product candidate, we, and/or future collaborators, may encounter difficulties in developing and obtaining approval for these companion diagnostics. Any delay or failure by us or third-party collaborators to develop or obtain regulatory approval of a companion diagnostic could delay or prevent approval or continued marketing of such product candidate. Further, in April 2020, the FDA issued new guidance on developing and labeling companion diagnostics for a specific group of oncology therapeutic products, including recommendations to support a broader labeling claim rather than individual therapeutic products. We will continue to evaluate the impact of this guidance on our companion diagnostic development and strategy. This guidance and future issuances from the FDA and other regulatory authorities may impact our development of a companion diagnostic for our product candidates and result in delays in regulatory approval. We may be required to conduct additional studies to support a broader claim. Also, to the extent other approved diagnostics are able to broaden their labeling claims to include our approved drug products, we may be forced to abandon our companion diagnostic development plans or we may not be able to compete effectively upon approval, which could adversely impact our ability to generate revenue from the sale of our approved products and our business operations.

Additionally,wemayrelyonthirdpartiesforthedesign,developmentandmanufactureofcompanion diagnostictestsforourproductcandidatesthatmayrequiresuchtests.Ifweenterintosuchcollaborative agreements,wewillbedependentonthesustainedcooperationandeffortofourfuturecollaboratorsindevelopingand obtainingapprovalforthesecompaniondiagnostics.Itmaybenecessarytoresolveissuessuchasselectivity/specificity,analyticalvalidation,reproducibility,orclinicalvalidationofcompaniondiagnosticsduringthe developmentandregulatoryapprovalprocesses.Moreover,evenifdatafrompreclinicalstudiesandearlyclinical trialsappeartosupportdevelopmentofacompaniondiagnosticforaproductcandidate,datageneratedinlater clinicaltrialsmayfailtosupporttheanalyticalandclinicalvalidationofthecompaniondiagnostic. We andour futurecollaboratorsmayencounterdifficultiesindeveloping,obtainingregulatoryapprovalfor,manufacturingand commercializingcompaniondiagnosticssimilartothosewefacewithrespectto our productcandidates,including issueswithachievingregulatoryclearanceorapproval,productionofsufficientquantitiesatcommercialscaleand withappropriatequalitystandards,andingainingmarketacceptance.Ifwe areunabletosuccessfullydevelop companiondiagnosticsforanyfutureproductcandidateornewindication,orexperiencedelaysindoingso,the developmentofsuchproductcandidatemaybeadverselyaffected,theproductcandidatemaynotobtainmarketing approval,andwemaynotrealizethefullcommercialpotentialofsuchproductcandidateafterobtaining marketingapproval.Asaresult,ourbusiness,resultsofoperationsandfinancialconditioncouldbematerially harmed.Inaddition,adiagnosticcompanywithwhomwecontractmaydecidetodiscontinuesellingor manufacturingthecompaniondiagnostictestthatweanticipateusinginconnectionwithdevelopmentand commercializationofanysuchfutureproductcandidateorourrelationshipwithsuchdiagnosticcompanymay otherwiseterminate.Wemaynotbeabletoenterintoarrangementswithanotherdiagnosticcompanytoobtain suppliesofanalternativediagnostictestforuseinconnectionwiththedevelopmentandcommercializationofany suchfutureproductornewindication.ordosooncommerciallyreasonableterms,whichcouldadverselyaffect and/ordelaythedevelopmentorcommercializationofanysuchfutureproductcandidatewemaydevelop.

A Fast Track or Breakthrough Therapy designationforFYARRO maynot leadto a fasterdevelopmentor reviewprocess,or we maybe unable to maintainor effectivelyutilizesuch a designation.We mayalsoseek additionalFast Track designationsfromthe FDAforFYARRO or any of ourotherproductcandidates.Even if one or moreof ourproductcandidatesreceiveFast Track designation,we maybe unable to obtainor maintainthe benefitsassociatedwith the Fast Track designation.

In October2018, we announcedthattheFDAgrantedFastTrackdesignationforFYARRO forthe investigationof thetreatmentof patientswith advancedmalignantPEComa. This FastTrackdesignationdoes not guaranteethatwe willqualifyforor be ableto takeadvantageof theexpeditedreviewproceduresor thatwe willultimatelyobtainregulatoryapprovalof FYARRO in other indications. Even though we receivedthisFastTrackdesignation in the past,we maynot experiencea fasterdevelopmentprocess,reviewor approvalcomparedto conventionalFDAprocedures for other indications for FYARRO. We mayalsoseekFastTrackdesignationfor additionalcancerindicationsor otherdiseases,and wemaynot be successfulin securingsuch additional designationor in expeditingdevelopmentifsuch designationswere received. Even if we receive Fast Track designation for additional cancer indications, the FDA may withdraw such Fast Track designation if it believes that the Fast Track designation is no longer supported by data from our clinical development program.

Fast Track designation is designed to facilitate the development and expedite the review of therapies intended for the treatment of a serious or life-threatening condition which demonstrate the potential to address unmet medical

needs for the condition. Programs with Fast Track designation may benefit from early and frequent communications with the FDA, potential priority review and the ability to submit a rolling application for regulatory review. Fast Track designation applies to both the product candidate and the specific indication for which it is being studied. If FYARRO for any other indication or any other product candidates that we may develop in the future receive Fast Track designation but do not continue to meet the criteria for Fast Track designation, or if our clinical trials are delayed, suspended or terminated, or put on clinical hold due to unexpected adverse events or issues with clinical supply, we will not receive the benefits associated with the Fast Track program. The FDA may withdraw any Fast Track Designation at any time. Furthermore, Fast Track designation does not change the standards for approval. Fast Track designation alone does not guarantee qualification for the FDA’s priority review procedures and we may not experience a faster development process, review or approval compared to conventional FDA procedures.

In December2018, we announcedthattheFDAgrantedBreakthroughTherapydesignationforFYARRO forthetreatmentof patientswith advancedmalignantPEComa. We mayalsoseeka BreakthroughTherapy designationforFYARRO forvariouscancerindicationsor otherdiseases.BreakthroughTherapydesignationis fora productcandidatethatisintended,aloneor in combinationwith one or moreotherdrugsor biologics,to treata seriousor life-threateningdiseaseor conditionand preliminaryclinicalevidenceindicatesthattheproduct candidatemaydemonstratesubstantialimprovementoverexistingtherapieson one or moreclinicallysignificant endpoints,such as substantialtreatmenteffectsobservedearlyin clinicaldevelopment.A sponsormayrequest theFDAto designateourproductcandidateas a BreakthroughTherapyatthetimeof, or any timeafter,the submissionof an IND fortheproductcandidate.For productcandidatesthathave been designatedas a BreakthroughTherapy,theFDAmaytakeactionsappropriateto expeditethedevelopmentand reviewof the application,which mayincludeholdingmeetingswith thesponsorand thereviewteamthroughoutthe developmentof theproductcandidate;providingtimelyadviceto, and interactivecommunicationwith, the sponsorregardingthedevelopmentof theproductcandidateto ensurethatthedevelopmentprogramto gatherthe nonclinicaland clinicaldatanecessaryforapprovalisas efficientas practicable;involvingseniormanagersand experiencedreviewstaff,as appropriate,in a collaborative,cross-disciplinaryreview;assigninga cross-disciplinaryprojectleadfortheFDAreviewteamto facilitatean efficientreviewof thedevelopmentprogram and to serveas a scientificliaisonbetweenthereviewteamand thesponsor;and takingstepsto ensurethatthe designof theclinicaltrialsisas efficientas practicable,when scientificallyappropriate,such as by minimizing thenumberof patientsexposedto a potentiallylessefficacioustreatment.

The FDAhas broaddiscretionin determiningwhetherto granta FastTrackor BreakthroughTherapy designationfora drug. Obtaininga FastTrackor BreakthroughTherapydesignationdoes not changethe standardsforproductapproval but mayexpeditethedevelopmentor approvalprocess.Thereisno assurancethat theFDAwillgranteithersuch designationforany otherindicationor productcandidatethatwe maypursue. Even iftheFDAdoes granteithersuch designation,itmaynot actuallyresultin fasterclinicaldevelopmentor regulatoryreviewor approval.Furthermore,such a designationdoes not increasethelikelihoodthatFYARRO willreceiveregulatoryapprovalin theUnitedStates in other indications.

We maynot be ableto obtainor maintainorphan drug designationor obtainor maintainorphan drug exclusivityforourproductcandidatesand, even ifwedo, such exclusivitymaynot preventthe FDA,EMAor othercomparableforeignregulatoryauthorities,fromapprovingcompetingproducts.

Regulatoryauthoritiesin somejurisdictions,includingtheUnitedStatesand theEuropeanUnion, may designatedrugsforrelativelysmallpatientpopulationsas orphandrugs.Under theOrphan Drug Act, theFDA maydesignatea productcandidateas an orphandrug ifitisintendedto treata rarediseaseor condition,which is generallydefinedas a patientpopulationof fewerthan200,000 individualsannuallyin theUnitedStates,or a patientpopulationgreaterthan200,000 in theUnitedStateswhere thereisno reasonableexpectationthatthecost of developingthedrug willbe recoveredfromsalesin theUnitedStates.Ourtargetindicationsmayinclude diseaseswith largepatientpopulationsor mayincludeorphanindications.However, therecan be no assurances thatwe willbe ableto obtainorphandesignationsforourproductcandidates.

IntheUnitedStates,orphandrugdesignationentitlesapartytofinancialincentivessuchasopportunitiesfor grantfundingtowardsclinicaltrialcosts,taxadvantagesanduser-feewaivers.Inaddition,ifaproductthathas orphandrugdesignationsubsequentlyreceivesthefirstFDAapprovalforthediseaseforwhichithassuch designation,theproductisentitledtoorphandrugexclusivity.OrphandrugexclusivityintheUnitedStatesprovides thattheFDAmaynotapproveanyotherapplications,includingafullNDA,tomarketthesamedrugforthesame indicationforsevenyears,

exceptinlimitedcircumstances.TheapplicableexclusivityperiodistenyearsinEurope. TheEuropeanexclusivityperiodcanbereducedtosixyearsifadrugnolongermeetsthecriteriafororphandrug designationorifthedrugissufficientlyprofitablesothatmarketexclusivityisnolongerjustified.

Even iforphandrug designationisgrantedfora productcandidate,we maynot be ableto obtainor maintainorphandrug exclusivityforthatproductcandidate.We maynot be thefirstto obtainregulatory approvalof any productcandidateforwhich wehave obtainedorphandrug designationfortheorphan-designated indicationdue to theuncertaintiesassociatedwith developingpharmaceuticalproducts.In addition,exclusive marketingrightsin theUnitedStatesmaybe limitedifwe seekapprovalforan indicationbroaderthanthe orphan-designatedindicationor maybe lostiftheFDAlaterdeterminesthattherequestfordesignationwas materiallydefectiveor ifwe areunableto ensurethatwewillbe ableto manufacturesufficientquantitiesof the productto meettheneedsof patientswith therarediseaseor condition.Further,thattheorphandrug exclusivity maynot effectivelyprotectan approvedproductfromcompetitionbecausedifferentdrugswith differentactive moietiesmaybe approvedforthesamecondition.Even afteran orphandrug isapproved,theFDAcan subsequentlyapprovethesamedrug with thesameactivemoietyforthesameconditioniftheFDAconcludes thatthelaterdrug isclinicallysuperiorin thatitisshown to be safer,moreeffectiveor makesa major contributionto patientcareor themanufacturerof theproductwith orphanexclusivityisunableto maintain sufficientproductquantity.Orphan drug designationneithershortensthedevelopmenttimeor regulatoryreview timeof a drug nor givestheproductcandidateany advantagein theregulatoryreviewor approvalprocessor entitlestheproductcandidateto priorityreview.

We receivedorphandrug designationfromtheFDAforFYARRO forthetreatmentof advancedmalignant PEComa. We maybe unableto obtain orphan drug designation for any other indication or regulatoryapprovalforFYARRO forany other orphanpopulation,or we maybe unableto successfullycommercializeFYARRO forsuch orphanpopulation due to risksthatinclude:

• the orphan patient populations may change in size;

• there may be difficulties in enrolling patients for clinical trials;

Ifwe areunableto obtainregulatoryapprovalforFYARRO in any other orphan populationforwhich weobtainorphandrug designationor we areunableto successfullycommercializeFYARRO for such orphanpopulation,itcouldharm ourbusinessprospects,financialconditionand resultsof operations.

We maynot be ableto obtainorphan drug exclusivityforFYARRO in additional indications or forone or moreof ourproduct candidatesthatwemaydevelopin the future,and even ifwe do, thatexclusivitymaynot preventthe FDA fromapprovingothercompetingproducts.

Under the Orphan Drug Act, the FDA may designate a product candidate as an orphan drug if it is a drug or biologic intended to treat a rare disease or condition. A similar regulatory scheme governs approval of orphan product candidates by the EMA in the European Union. Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the FDA or the EMA from approving another marketing application for another similar product candidate for the same orphan therapeutic indication for that time period. The applicable period is seven years in the United States and ten years in the European Union. The exclusivity period in the European Union can be reduced to six years if a product no longer meets the criteria for orphan drug designation, in particular if the product is sufficiently profitable so that market exclusivity is no longer justified.

In orderfortheFDAto grantorphandrug exclusivityto one of our productcandidates,theagencymustfind thattheproductcandidateisindicatedforthetreatmentof a conditionor diseasethataffectsfewerthan200,000 individualsin theUnitedStatesor thataffects200,000 or moreindividualsin theUnitedStatesand forwhich thereisno reasonableexpectationthatthecostof developingand makingtheproductcandidateavailableforthe diseaseor conditionwillbe recoveredfromsalesof theproductin theUnitedStates.The FDAmayconcludethat theconditionor diseaseforwhich we seekorphandrug exclusivitydoes not meetthisstandard.Even ifwe obtainorphandrug exclusivityfora productcandidate,thatexclusivitymaynot effectivelyprotecttheproduct candidatefromcompetitionbecausedifferentproductcandidatescan be approvedforthesamecondition.In addition,even afteran orphandrug isapproved,theFDAcan subsequentlyapprovethesameproductcandidate forthesameconditioniftheFDAconcludesthatthelaterproductcandidateisclinicallysuperiorin thatitis shown to be safer,moreeffectiveor makesa majorcontributionto patientcarecomparedwith theproductthat has orphanexclusivity.Orphan drug exclusivitymayalsobe lostiftheFDAor EMA determinesthattherequest fordesignationwas materiallydefectiveor ifthemanufacturerisunableto assuresufficientquantityof the productto meettheneedsof thepatientswith therarediseaseor condition.

Whereappropriate,we plan to secureapprovalfromthe FDAor comparableforeignregulatoryauthorities through the use of acceleratedregistrationpathways. Ifwe areunable to obtainsuch approval,wemaybe requiredto conduct additionalpreclinicalstudiesor clinicaltrialsbeyond thosethatwecontemplate,which could increasethe expenseof obtaining,and delaythe receiptof, necessaryregulatoryapprovals.Even ifwe receiveacceleratedapprovalfromthe FDA,ifourconfirmatorytrialsdo not verifyclinicalbenefit,or ifwedo not complywith rigorousPMRs,the FDAmayseekto withdraw acceleratedapproval.

Where possible, we plan to pursue accelerated development strategies in areas of high unmet need. We may seek an accelerated approval pathway for one or more of our product candidates. Under the accelerated approval provisions in the FDA, and the FDA’s implementing regulations, the FDA may grant accelerated approval to a product candidate designed to treat a serious or life-threatening condition that generally provides a meaningful therapeutic benefit over available therapies upon a determination that the product candidate has an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit. The FDA considers a clinical benefit to be a positive therapeutic effect that is clinically meaningful in the context of a given disease, such as irreversible morbidity or mortality. For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. An intermediate clinical endpoint is a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. The accelerated approval pathway may be used in cases in which the advantage of a new drug over available therapy may not be a direct therapeutic advantage but is a clinically important improvement from a patient and public health perspective. If granted, accelerated approval is usually contingent on the sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the drug’s clinical benefit. If such post-approval studies fail to confirm the drug’s clinical benefit, the FDA may withdraw its approval of the drug. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Prior to seeking such accelerated approval, we will seek feedback from the FDA and will otherwise evaluate our ability to seek and receive such accelerated approval. There can be no assurance that after our evaluation of the feedback and other factors we will decide to pursue or submit an NDA for accelerated approval or any other form of expedited development, review or approval. Similarly, there can be no assurance that after subsequent FDA feedback we will continue to pursue or apply for accelerated approval or any other form of expedited development, review or approval, even if we initially decide to do so. Furthermore, if we decide to submit an application for accelerated approval or under another expedited regulatory designation (e.g., breakthrough therapy designation), there can be no assurance that such submission or application will be accepted or that any expedited development, review or approval will be granted on a timely basis, or at all. The FDA or other comparable foreign regulatory authorities could also require us to conduct further studies prior to considering our application or granting approval of any type. A failure to obtain accelerated approval or any other form of expedited development, review or approval for our product candidate would result in a longer time period to commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.

We mayfacedifficultiesfromchanges to currentregulationsand futurelegislation.

Existingregulatorypoliciesmaychange,and additionalgovernmentregulationsmaybe enactedthatcould prevent,limitor delayregulatoryapprovalof ourproductcandidates.We cannotpredictthelikelihood, natureor extentof governmentregulationthatmayarisefromfuturelegislationor administrativeaction,eitherin theUnitedStatesor abroad.If we are slow or unableto adaptto changesin existingrequirementsor theadoption of new requirementsor policies,or ifwearenot ableto maintainregulatorycompliance,wemayloseany regulatory approvalthatwemayhave obtained,and wemaynot achieveor sustainprofitability.

For example,in March2010, thePatientProtectionand AffordableCare Act of 2010, as amendedby the HealthCare and EducationReconciliationAct of 2010 (the“ACA”),was passed,which substantiallychangestheway healthcareisfinancedby both thegovernmentand privateinsurers,and significantlyimpactstheUnitedStatespharmaceuticalindustry.In December2018, CMS publisheda finalrule permittingfurthercollectionsand paymentsto and fromcertainACAqualifiedhealthplansand healthinsurance issuersundertheACAriskadjustmentprogramin responseto theoutcomeof thefederaldistrictcourtlitigation regardingthemethodCMS usesto determinethisriskadjustment.Sincethen,theACAriskadjustmentprogram paymentparametershave been updatedannually.Some of theprovisionsof theACAhave yetto be implemented,and therehave been judicialand Congressionalchallengesto certainaspectsof theACA,as wellas recenteffortsby theformerTrumpadministrationto repealor replacecertainaspectsof theACA.In June 2021, theSupremeCourt heldthatTexas and otherchallengershad no legalstandingto challengetheACA, dismissing the case without specifically ruling on the constitutionality of the ACA. Accordingly, the ACA remains in effect in its current form.Itisunclearhow thisdecisionand otherhealthcarereformswillimpactourbusiness.

In addition,otherlegislativechangeshave been proposedand adoptedin theUnitedStatessincetheACA was enacted.These changesincludedaggregatereductionsto Medicarepaymentsto providersof up to 2% per fiscalyear,effectiveApril1, 2013, which, due to subsequentlegislativeamendments,willstayin effectthrough 2030, with theexceptionof a temporarysuspensionimplementedundervariousCOVID-19relieflegislation fromMay 1, 2020 throughMarch 31, 2022, unlessadditionalcongressionalactionistaken. Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 3% in the final fiscal year of this sequester. In January2013, formerPresidentObama signedintolaw theAmericanTaxpayerReliefAct of 2012, which, amongotherthings, reducedMedicarepaymentsto severalproviders,and increasedthestatuteof limitationsperiodforthe governmentto recoveroverpaymentsto providersfromthreeto fiveyears.These new laws mayresultin additionalreductionsin Medicareand otherhealthcarefunding,which couldhave a materialadverseeffecton customersfor FYARRO or any other productcandidates that we may develop if the future,ifapproved,and accordingly,ourfinancialoperations.

Moreover,therehas been heightenedgovernmentalscrutinyrecentlyoverthemannerin which drug manufacturerssetpricesfortheirmarketedproducts,which has resultedin severalCongressionalinquiriesand proposedand enactedfederaland statelegislationdesignedto, amongotherthings,bringmoretransparencyto productpricing,reviewtherelationshipbetweenpricingand manufacturerpatientprograms,and reform governmentprogramreimbursementmethodologiesfordrug products.For example,atthefederallevel,in September2018, CMS announcedthatitwillallowMedicareAdvantagePlanstheoptionto use steptherapyfor PartB drugsbeginningJanuary1, 2019. Additionally,CMS issueda finalrule,effectiveon July9, 2019, that requiresdirect-to-consumertelevisionadvertisementsof prescriptiondrugsand biologicalproducts,forwhich paymentisavailablethroughor underMedicareor Medicaid,to includein theadvertisementtheWholesale AcquisitionCost, or listprice,of thatdrug or biologicalproductifitisequalto or greaterthan$35 fora monthly supplyor usualcourseof treatment.Prescriptiondrugsand biologicalproductsthatarein violationof these requirementswillbe includedon a publiclist.In 2020, atthefederallevel,undertheformerTrump administration,HHSand CMS issuedvariousrulesthatareexpectedto impact,amongothers,pricereductions frompharmaceuticalmanufacturersto plansponsorsunderPartD, feearrangementsbetweenpharmacybenefit managersand manufacturers,importationof prescriptiondrugsfromCanada and othercountries,manufacturer pricereportingrequirementsundertheMedicaidDrug RebateProgram,includingregulationsthataffect manufacturer-sponsoredpatientassistanceprogramssubjectto pharmacybenefitmanageraccumulatorprograms and Best Pricereportingrelatedto certainvalue-basedpurchasingarrangements.Multiplelawsuitshave been broughtagainsttheHHSchallengingvariousaspectsof thesenew rules. As a result, the Biden administration and HHS have delayed the implementation or published rules rescinding some of these Trump-era policies.

Under the American Rescue Plan Act of 2021, effective January 1, 2024, the statutory cap on Medicaid Drug Rebate Program rebates that manufacturers pay to state Medicaid programs will be eliminated. Elimination of this cap may require pharmaceutical manufacturers to pay more in rebates than it receives on the sale of

products, which could have a material impact on our business. Further, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at increasing competition for prescription drugs. In response to this executive order, the HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and potential legislative policies that Congress could pursue to advance these principles. In addition, Congress is considering legislation that, if passed, could have significant impact on prices of prescription drugs covered by Medicare, including limitations on drug price increases. The impactof theselegislative,executive,and administrativeactions and any future healthcare measures and agency rules implemented by the Biden administration on us and thepharmaceutical industryas a whole isunclear. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our product candidates if approved. Complying with any new legislation and regulatory changes could be time-intensive and expensive, resulting in a material adverse effect on our business.

At thestatelevel,legislatureshave increasinglypassedlegislation and implementedregulationsdesignedto controlpharmaceuticaland biologicalproductpricing,includingprice or patientreimbursementconstraints,discounts,restrictionson certainproductaccessand marketingcost disclosureand transparencymeasures,and, in somecases,designedto encourageimportationfromother countriesand bulk purchasing. For example, a number of states are considering or have recently enacted state drug price transparency and reporting laws that could substantially increase our compliance burdens and expose us to greater liability under such state laws once we begin commercialization after obtaining regulatory approval for any of our products. Implementationof cost containmentmeasuresor otherhealthcarereformsthataffectthepricingand/oravailabilityof drug productsmay impactourabilityto generaterevenue,attainor maintainprofitability,or commercializeproductsforwhich we mayreceiveregulatoryapprovalin thefuture.

Further,on May 30, 2018, theTrickettWendler,Frank Mongiello,JordanMcLinn,and MatthewBellina Right to Try Act of 2017 (Rightto Try Act),was signedintolaw. The law, amongotherthings,providesa federalframeworkforcertainpatientsto accesscertaininvestigationalnew productcandidatesthathave completeda Phase 1 clinicaltrialand thatareundergoinginvestigationforFDAapproval.Under certain circumstances,eligiblepatientscan seektreatmentwithoutenrollingin clinicaltrialsand withoutobtainingFDA permissionundertheFDAexpandedaccessprogram.Thereisno obligationfora drug manufacturerto makeits productsavailableto eligiblepatientsas a resultof theRight to Try Act.

We expectthattheACA,as wellas otherhealthcarereformmeasuresthatmaybe adoptedin thefuture, mayresultin morerigorouscoveragecriteriaand in additionaldownward pressureon thepricethat we receive forany approvedproduct.Any reductionin reimbursementfromMedicareor othergovernmentprogramsmay resultin a similarreductionin paymentsfromprivatepayors.The implementationof costcontainmentmeasures or otherhealthcarereformsmaypreventus frombeingableto generaterevenue,attainprofitabilityor commercializeourproductcandidates.

Legislativeand regulatoryproposalshave been madeto expand post-approvalrequirementsand restrict salesand promotionalactivitiesforbiotechnologyproducts.We cannotbe surewhetheradditionallegislative changeswillbe enacted,or whetherFDAregulations,guidanceor interpretationswillbe changed,or what the impactof such changeson theregulatoryapprovalsof ourproductcandidates,ifany, maybe. In addition, increasedscrutinyby Congressof theFDA’s approvalprocessmaysignificantlydelayor preventregulatory approval,as wellas subjectus to morestringentproductlabelingand post-marketingtestingand other requirements.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action, either in the U.S. or in other jurisdictions. If we or our collaborators are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we or our collaborators are not able to maintain regulatory compliance, our product candidates may lose any marketing approval that may have been obtained and we may not achieve or sustain profitability, which would adversely affect our business.

Additionally, the collection and use of health data in the European Union is governed by the General Data Protection Regulation (the “GDPR”), which extends the geographical scope of European Union data protection law to non-European Union entities under certain conditions and imposes substantial obligations upon companies and new rights for individuals. Failure to comply with the GDPR and the applicable national data protection laws of the European Union Member States may result in fines up to €20.0 million or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, and other administrative penalties. The

GDPR may increase our responsibility and liability in relation to personal data that we may process, and we may be required to put in place additional mechanisms in an effort to comply with the GDPR. This may be onerous and if our efforts to comply with GDPR or other applicable European Union laws and regulations are not successful, it could adversely affect our business in the European Union.

Finally,stateandforeignlawsmayapplygenerallytotheprivacyandsecurityofinformationwemaintain, andmaydifferfromeachotherinsignificantways,thuscomplicatingcomplianceefforts.Forexample,the CaliforniaConsumerPrivacyActof2018(the“CCPA”),whichtookeffectonJanuary1,2020,gives Californiaresidentsexpandedrightstoaccessandrequiredeletionoftheirpersonalinformation,optoutofcertain personalinformationsharing,andreceivedetailedinformationabouthowtheirpersonalinformationisused.In addition,theCCPA(a)allowsenforcementbytheCaliforniaAttorneyGeneral,withfinessetat$2,500per violation(i.e.,perperson)or$7,500perintentionalviolationand(b)authorizesprivatelawsuitstorecoverstatutory damagesforcertaindatabreaches.WhileitexemptssomedataregulatedbytheHealthInsurancePortabilityand AccountabilityActof1996(“HIPAA”)andcertainclinicaltrialsdata,theCCPA,totheextent applicabletoourbusinessandoperations,mayincreaseourcompliancecostsandpotentialliabilitywith respecttootherpersonalinformationwecollectaboutCaliforniaresidents.SomeobserversnotethattheCCPA couldmarkthebeginningofatrendtowardmorestringentprivacylegislationintheUnitedStates,whichcould increaseourpotentialliabilityandadverselyaffect ourbusiness.

Inadequatefunding forthe FDA,the Securitiesand Exchange Commissionand othergovernmentagencies could hinder theirabilityto hireand retainkey leadershipand otherpersonnel,preventnew productsand servicesfrombeing developedor commercializedin a timelymanner or otherwisepreventthoseagenciesfrom performingnormalbusinessfunctionson which the operationof ourbusinessmayrely,which could negativelyimpactourbusiness.

The abilityof theFDAto reviewand approvenew productscan be affectedby a varietyof factors, includinggovernmentbudgetand fundinglevels,abilityto hireand retainkey personneland acceptthepayment of userfees,and statutory,regulatory,and policychanges.Averagereviewtimesattheagencyhave fluctuatedin recentyearsas a result.In addition,governmentfundingof theSecuritiesand Exchange Commission(the“SEC”)and othergovernmentagencieson which ouroperationsmayrely,includingthosethatfund researchand developmentactivitiesissubjectto thepoliticalprocess,which isinherentlyfluidand unpredictable.

DisruptionsattheFDAand otheragenciesmayalsoslow thetimenecessaryfornew productcandidatesto be reviewedand/orapprovedby necessarygovernmentagencies,which would adverselyaffectourbusiness. For example,in recentyears,includingin 2018 and 2019, theUnitedStatesgovernmentshutdown severaltimes and certainregulatoryagencies,such as theFDAand theSEC,had to furloughcriticalemployeesand stop criticalactivities.Ifa prolongedgovernmentshutdown occurs,itcouldsignificantlyimpacttheabilityof the FDAto timelyreviewand processourregulatorysubmissions,which couldhave a materialadverseeffecton ourbusiness.Separately,in responseto theCOVID-19pandemic,in March2020, theFDAannouncedits intentionto postponemostinspectionsof foreignmanufacturingfacilitiesand productsas wellas routine surveillanceinspectionsof domesticmanufacturingfacilitiesand providedguidanceregardingtheconductof clinicaltrials.In April2021, theFDAissuedguidanceforindustryformallyannouncingplansto employremote interactiveevaluations,usingriskmanagementmethods,to meetuserfeecommitmentsand goaldatesand based on updatedguidanceissuedin May 2021, FDAcontinuesto conductmission-criticalinspectionson a case-by-casebasis,or, where possibleto do so safely,has, sinceJuly2020, resumedprioritizeddomestic inspections,which generallyincludepre-approval,pre-license,surveillance,and for-causeinspections.Should FDAdeterminethatan inspectionisnecessaryforapprovaland an inspectioncannotbe completedduringthe reviewcycledue to restrictionson travel,and theFDAdoes not determinea remoteinteractiveevaluationto be adequate,theagencyhas statedthatitgenerallyintendsto issuea completeresponseletteror deferactionon the applicationuntilan inspectioncan be completed.In 2020 and 2021, a numberof companiesannouncedreceiptof completeresponselettersdue to theFDA’s inabilityto completerequiredinspectionsfortheirapplications.While theFDAindicatedthatitwillconsideralternativemethodsforinspectionsand exercisediscretionon a case-by-casebasisto approveproductsbasedon a desk review,ifa prolongedgovernmentshutdown occurs,or if globalhealthconcernscontinueto preventtheFDAor otherregulatoryauthoritiesfromconductingtheirregular inspections,reviews,or otherregulatoryactivitieson a timelybasis,itcouldsignificantlyimpacttheabilityof theFDAto timelyreviewand processourregulatorysubmissions,which couldhave a materialadverseeffect on ourbusiness.RegulatoryauthoritiesoutsidetheU.S.mayadoptsimilarrestrictionsor otherpolicymeasuresin responseto theCOVID-19pandemicand mayexperiencedelaysin theirregulatoryactivities.Further,in our operationsas a publiccompany,futuregovernmentshutdowns could

impactourabilityto accessthepublic marketsand obtainnecessarycapitalin orderto properlycapitalizeand continueouroperations.

Ifwe failto complywith otherUnited Stateshealthcarelaws and compliancerequirements,we could becomesubjectto finesor penaltiesor incur coststhatcould have a materialadverseeffecton ourbusiness. Further, ourrelationshipswith healthcareprofessionals,clinicalinvestigators,CROsand third-party payorsin connectionwith ourcurrentand futurebusinessactivitiesmaybe subjectto federaland state healthcarefraud and abuse laws, falseclaimslaws, transparencylaws, governmentpricereporting,and healthinformationprivacyand securitylaws, which could exposeus to significantlosses,including,among otherthings,criminalsanctions,civilpenalties,contractualdamages,exclusionfromgovernmental healthcareprograms,reputationalharm, administrativeburdens and diminishedprofitsand futureearnings.

Healthcareprovidersand third-partypayorsplaya primaryrolein therecommendationand prescriptionof any productcandidatesforwhich we obtainregulatoryapproval.Ourcurrentand futurearrangementswith healthcareprofessionals,clinicalinvestigators,CROs,third-partypayorsand customersmayexposeusto broadly applicablefraudand abuseand otherhealthcarelaws and regulationsthatmayconstrainthebusinessor financial arrangementsand relationshipsthroughwhich we market,selland distributeourproductsforwhich weobtain regulatoryapproval.Restrictionsunderapplicablefederaland statehealthcarelaws and regulationsmayinclude thefollowing:

Becauseof thebreadthof theselaws and thenarrownessof availablestatutoryand regulatoryexceptionsor safeharbors,itispossiblethatsomeof ouractivities,includingthoseof ourcontractorsor agentswho conduct businessforor on behalfof us, couldbe subjectto challengeunderone or moreof such laws. Any action broughtagainstus forviolationsof theselaws or regulations,even successfullydefended,couldcauseus to incursignificantlegalexpensesand divertourmanagement’sattentionfromtheoperationof ourbusiness. We maybe subjectto private“quitam”actionsbroughtby individualwhistleblowerson behalfof thefederalor stategovernments.

Ifwe were to grow ourbusinessand expand oursalesorganizationor relyon distributorsoutsideof the UnitedStates,wewould be atincreasedriskof violatingtheselaws or ourinternalpoliciesand procedures.The riskof us beingfound in violationof theseor otherlaws and regulationsisfurtherincreasedby thefactthat manyhave not been fullyinterpretedby theregulatoryauthoritiesor thecourts,and theirprovisionsareopen to a varietyof

interpretations.Any actionbroughtagainstus forviolationof theseor otherlaws or regulations, even ifwesuccessfullydefendagainstit,couldcauseus to incursignificantlegalexpensesand divertour management’sattentionfromtheoperationof ourbusiness.

WHWK US Equity

WHWK · 10-K · period ended 2021-12-31

Item 1A. Risk Factors

WHWK US Equity☆

WHWK · 10-K · period ended 2021-12-31

Item 1A. Risk Factors

WHWK US Equity