ANAGRELIDE CONTROLLED RELEASE (GALE-401) SAFETY PROFILE CONSISTENTLY WELL TOLERATED IN MYELOPROLIFERATIVE NEOPLASMS PATIENTS AND HEALTHY VOLUNTEERS

BackgroundSTUDYGALE-401-201

Results

GALE-401-201 study is sponsored by Galena Biopharma, Inc. Contact Remy Bernarda at ClinicalTrials@galenabiopharma.com for permission to reprint and/or distribute. Conflict of interest disclosures: Research funding from Galena – Verstovsek S1, Saltzman M2, Dakhil S3; employees of Galena – Lee J4, Chance L4, Flores S4, Fernandez V4, Dinh P4, Choy GS4, Nejadnik B4; Galena consultancy, stock options, ownership interest and royalties as former owner of compound – Glidden P; Pilgrim A – employee of Biovascular.

Anagrelidehydrochloride (HCL)wasdevelopedasan inhibitorofplateletaggrega;onbutwaslater found to reduce platelet counts at doses lower than the amount needed for plateletaggrega;on.Anagrelide(Agrylin®(UnitedStates)andXagrid®(EuropeanUnion)isanimmediaterelease (IR)agent thatblocksmegakaryocytedifferen;a;onandprolifera;onand inhibits theac;onofcyclicAMPphosphodiesterase.AnagrelideHCLisextensivelymetabolizedto2majormetabolites:3-hydroxy-anagrelide(3-OH)andasubsequentbiotransforma;onproduct,RL603.Themetabolite3-hydroxy-anagrelideisequipotentwiththeparentdruginitsinvitroeffectsonmegakaryocytopoesisandisthereforepoten;allyplatelet‑lowering,andpublishedstudieshaveiden;fied 3-hydroxy-anagrelide as ac;ve (AhluwaliaM et al. 2010). An alternate formula;onthatmodifiesthispharmacokine;c(PK)profilemayimprovepa;enttolerabilityandtreatmentoutcomes.This led to thedevelopmentofacontrolled-release (CR) formula;onofanagrelide(GALE-401).Todate,98healthyvolunteer (HV) subjectsand18myeloprolifera;veneoplasms(MPN)subjectshavebeenenrolledamongfivePhase1clinicaltrialsofGALE-401(BIO-ANA101,102,103,104,105)(LaliberteRJetal.2014),andaPhase2singlearm,openlabelpilotstudy,(GALE-401-201) study in subjectswithMPN-related thrombocytosis (VerstovsekSetal. 2015;TruongPetal.2015).

Phase2,pilot, singlearm,open label,mul;-center studyevalua;ng theefficacyandsafetyofanagrelidecontrolled release (CR) in subjectswith thrombocytosissecondary to essen;al thrombocythemia (ET) and other myeloprolifera;veneoplasms.

u ObjecBves:•  Primaryobjec;ve:Es;matetheoverallplateletresponserate(ORR).•  Secondaryobjec;ves:Safety,tolerabilityandpharmacokine;cs(PK).

u MajorEligibility:•  Providewrideninformedconsent.•  Diagnosedwith aMPN related elevated platelet count to include chronic

myelogenous leukemia [CML], polycythemia vera [PV], primarymyelofibrosis [PMF], or ET, based on the 2008 WHO classifica;on ofmyeloidmalignancies.

•  Plateletcount≥600x109/Lontwooccasionsatleast14daysapartpriortofirstdoseofstudydrug.

•  MPNdiagnosisotherthanET,concurrentan;-MPNtreatmentispermided,provided that the doses are stable at least 4weeks prior to first dose ofstudydrug.

u Methods:•  AnagrelideCRisadministeredatastar;ngdoseof0.5mgtwicedaily(1.0

mg/day).Thedosewas;tratedatweekly intervals,onan individualbasis,to determine the lowest dose required to achieve andmaintain a targetplateletcountof150–400x109/L.

•  Platelet response is defined as complete response (CR, ≤ 400 x 109/L) orpar;al response (PR, ≤ 600 x 109/L or ≥ 50% reduc;on from baseline)maintainedforatleast4weeks.

•  Toxici;esbasedonNCICTCAEv4.03.

European Hematology Association Annual Meeting and Exposition, Copenhagen, Denmark, June 9–12, 2016

Verstovsek S1, Saltzman M2, Dakhil S3, Lee J4, Chance L4, Glidden PF4, Pilgrim A5, Flores S4, Fernandez V4, Dinh P4, Choy GS4, Nejadnik B4

u  GALE-401iswelltoleratedinthenumberofMPNsubjectsaswellashealthyvolunteers.Thefavorablesafetyprofilemayberelatedtotheimproved PK as published previously by Truong et al. (ASH, 2015).Poten;ally,oncedailydose,;tratedevery2weekscanbeexploredtofurtherreducetheincidenceofadverseevents.

u  Basedon theAgrylin® intolerant subjects enrolled in theMPNpilotstudy, GALE-401 appears to offer a longer dura;on on therapycomparedtopreviouslyadministra;onofanagrelideIR.

u  GALE-401 remains a viable poten;al treatment op;on for MPNsubjects,par;cularlyET. ArandomizedtrialcomparingGALE-401vs.anagrelide IR in anagrelide naïve subjects, alterna;vely or togetherwithatrialevalua;ngAgrylin®intolerantsubjectsiswarranted.

SubjectswithRelatedTreatmentEmergentAdverseEventsinGALE-401-201andHVStudies

u  AhluwaliaM,etal.JThrombHaemost.2010;8(10):2252-61.u  LaliberteRJ,etal.Abstract3178.ASH,2014.u  VerstovsekS,etal.AbstractP671.EHA,2015.u  TruongP,etal.Abstract4074.ASH,2015.

1University of Texas, MD Anderson Cancer Center, Houston, TX, USA, 2Innovative Medical Research of South Florida, FL, USA, 3Cancer Center of Kansas, Wichita KS, USA 4Galena Biopharma, Inc., San Ramon, CA, USA 5Biovascular, Inc., San Diego, CA, USA.

HealthyVolunteerStudies1

Study No. Phase Description

No. of Subjects

(M/F) Mean Age

(SD)

Product (Treatment Arms)

Dose Duration

BIO-ANA101 Phase 1

Randomized, Open-label, 3-way Cross-over Study to Compare the Pharmacokinetics of Two New Formulations of Anagrelide With Xagrid® in Healthy Subjects

N = 12 (12 M)

36.0 (± 9.2)

A. Anagrelide IR/CR: 5 × 0.1 mg B. Anagrelide CR: 5 × 0.1 mg C. Xagrid® capsules 0.5 mg

Single-dose

BIO-ANA102 Phase 1

Placebo-Controlled, Double-Blind Repeat-Dose, Dose-Escalation, Sequential Cohort Study to Evaluate the PK and PD in Healthy Subjects

N = 32 (12 M / 20 F) 40.3 (± 7.3)

Anagrelide CR capsules 0.2 mg (2 × 0.1 mg) b.i.d. 0.3 mg (1 × 0.3 mg) b.i.d. 0.4 mg (0.3 + 0.1 mg) b.i.d. 0.6 mg (2 × 0.3 mg) b.i.d.

Placebo b.i.d.

Up to 21 days of repeated dosing

BIO-ANA103 Phase 1

Placebo-Controlled, Double-Blind, Repeat-Dose Study to Evaluate the PK and PD of Two Dose Levels of Anagrelide CR in Healthy Subjects

N = 16 (6 M / 10 F) 33.8 (± 6.9)

Anagrelide CR capsules 0.2 mg (2 × 0.1 mg) b.i.d. 0.2 mg titrated to 0.4 mg b.i.d

Placebo b.i.d.

Up to 43 days

repeated-dose

BIO-ANA104 Phase 1

Randomized Open-label, Three-Way Cross-over Study to Compare the PK of Anagrelide CR under Fed and Fasted Conditions with Agrylin® under Fasted Conditions in Healthy Subjects

N=18

0.5mg single oral doses of: Anagrelide CR (fed) Anagrelide CR (fasted) Agrylin® (fasted)

Single-dose

BIO-ANA105 Phase 1

Randomized, Open-label, Two-Period, Cross-Over Study to Compare Single and Repeat Dose PK of a Anagrelide CR with Agrylin under Fasted Conditions in Healthy Subjects

N=20

0.5mg single oral dose followed by 0.5mg orally twice a day for 5 days of:

Anagrelide CR Agrylin®

6 days

1Twelve subjects received placebo, 86 subjects received GALE-401

Phase2MPN(N=18)* Phase1HV(N=86)SystemOrganClass/PreferredTerm G1/2 G3 G4 Any G1/2^ G3 G4 AnyBLOODANDLYMPHATICSYSTEMDISORDERS 1 1 1 ANAEMIA 1 1 THROMBOCYTOPENIA 1 1 CARDIACDISORDERS 6 6 1 1PALPITATIONS 5 5 1 1TACHYCARDIA 1 1 GASTROINTESTINALDISORDERS 8 1 9 5 5ABDOMINALDISCOMFORT 1 1 ABDOMINALDISTENSION 2 2 ABDOMINALPAIN 3 3 DIARRHOEA 4 4 2 2NAUSEA 3 3 3 3PANCREATITISACUTE 1 1 VOMITING 1 1 1 1GENERALDISORDERSANDADMINISTRATIONSITECONDITIONS 5 5 6 6CHILLS 1 1FATIGUE 3 3 4 4MALAISE 1 1 OEDEMAPERIPHERAL 2 2 VESSELPUNCTURESITEHAEMATOMA 1 1HEPATOBILIARYDISORDERS 1 1 2 DRUG-INDUCEDLIVERINJURY 1 1 JAUNDICECHOLESTATIC 1 1 INFECTIONSANDINFESTATIONS 1 1NASOPHARYNGITIS 1 1ORALHERPES 1 1INVESTIGATIONS 2 1 3 2 2ALANINEAMINOTRANSFERASEINCREASED 1 1 ASPARTATEAMINOTRANSFERASEINCREASED 1 1 BLOODALKALINEPHOSPHATASEINCREASED 1 1 BLOODCREATININEINCREASED 1 1 HEARTRATEINCREASED 1 1 PLATELETCOUNTDECREASED 7 7METABOLISMANDNUTRITIONDISORDERS 1 1DECREASEDAPPETITE 1 1MUSCULOSKELETALANDCONNECTIVETISSUEDISORDERS 1 1 3 3BACKPAIN 3 3BONEPAIN 1 1 MUSCULOSKELETALCHESTPAIN 1 1PAININEXTREMITY 1 1NERVOUSSYSTEMDISORDERS 7 2 9 12 12DIZZINESS 2 2 DYSGEUSIA 1 1 HEADACHE 6 2 8 21 21REPRODUCTIVESYSTEMANDBREASTDISORDERS 1 1DYSMENORRHOEA 1 1RESPIRATORY,THORACICANDMEDIASTINALDISORDERS 2 2 1 1DYSPNOEA 2 2 PHARYNGOLARYNGEALPAIN 1 1SKINANDSUBCUTANEOUSTISSUEDISORDERS 2 2 2 2HYPERHIDROSIS 1 1NIGHTSWEATS 1 1 PRURITUS 1 1 1 1PRURITUSGENERALISED 1 1VASCULARDISORDERS 2 1 3 HYPERTENSION 1 1 2 HYPOTENSION 1 1

Summary/Conclusions References*Data as of 25 May 2016; ^Grade 1/2 denoted mild to moderate severity in healthy volunteer studies

Background: Themost frequently reportedAEs leading to treatmentdiscon;nua;onwithanagrelide(Agrylin®, Shire) were headache, diarrhea, edema, palpita;ons, and abdominal pain. Of the 942subjects treated with anagrelide for a mean dura;on of approximately 65 weeks, 161 (17%) werediscon;nued due to AEs or abnormal laboratory test results (PI, Agrylin®). These effects may beadributable to anagrelide’s inhibitory effects on human PDE3. Modifica;on of the PK profile ofanagrelidetoreducepeakplasmalevelswhilemaintainingtherapeu;cbloodlevelsmayofferameanstoretainplateletloweringac;vitywhilereducingpoten;alside-effects.InthePhase1HVstudy,BIO-ANA101, 2 such novel controlled release formula;ons of anagrelide (CR and IR/CR)were comparedwiththeEUmarketedformula;on(Xagrid®,Shire)inasingledosecross-overstudyatadoseof0.5mg.The CR formula;on demonstrated Cmax/AUC0-inf values that were 23%/72% of Xagrid’s, respec;velyleadingtothedevelopmentprogramofanagrelideCR(GALE-401).Aim:CharacterizethesafetyprofileofGALE-401inHVandMPNsubjects.Methods:Todate,98HVand18MPNsubjectshavebeenenrolledamong5Phase1clinicaltrials(BIO-ANA101, 102, 103, 104, 105) and a Phase 2 single arm, open label pilot study (NCT02125318) ofGALE-401, respec;vely. All studies were conducted in accordance with ICH Guidelines and GCPprinciples.SafetyeventswerecomparedacrossHVvs.MPNsubjectstreatedwithGALE-401.Results: In theHV studies, single andmul;ple doses of GALE-401were safe andwell tolerated andtherewerenoclinically relevantchanges invitalsigns,ECGs,andsafety laboratoryparametersotherthan a reduc;on in platelet counts. The most frequent TEAEs reported included headache, pain inextremi;esorback,palpita;onsandgastrointes;naldisturbances. Inpar;cular, inBIO-ANA105,with20subjectsrandomizedtoreceiveeitherGALE-401orAgrylin®(0.5mgBIDfor7days)aterwhichtheywerewashedout for aminimumof 21days and received the alterna;vedrugproduct for an equalperiod, the overall AEs considered by the Inves;gator to be related to treatment were observed[GALE-401(7events/6subjects)vs.Agrylin®(12events/8subjects)].Withtheexcep;onofGIdisorders(15%,GALE-401 vs. 10.5%,Agrylin®), the incidenceof TEAEs across SOCswas higher duringAgrylin®treatment compared to GALE-401 treatment. In the Phase 2 MPN study, subjects treated withGALE-401 exhibited fewer of the more common AEs associated with Agrylin® (cardiac; general;gastrointes;nal;respiratory,thoracic,andmedias;nal;skinandsubcutaneous;ssue;nervoussystem)orequivalent (musculoskeletal andconnec;ve;ssue)AEsassociatedwithAgrylin®. Someof the lesscommon AEs of Agrylin® were compara;vely more frequent for GALE-401 (vascular; hepatobiliary;blood and lympha;c). Addi;onally, fewer moderate to severe (Grade 3/4) AEs and fewer AEs perpa;ent (2.3 vs. 3.3) were observed with GALE-401 vs. Agrylin®, respec;vely. Further, based ontreatmentdiscon;nua;onduetoanAE,5subjectswhowerepreviouslyintoleranttoAgrylin®(becauseofAEs)havecon;nuedtheirtreatmentwithGALE-401.Overall,3ofthese5subjectswereonstudyfora longerdura;on [mean;meonstudy,106days, (47–196days)] compared to theirexperiencewithAgrylin®priortoenrollmentintothePhase2study(~7days).Twosubjects(40%)haveremainedinthestudy and have been able to con;nue their treatment with GALE-401 for 15 and 22 months,respec;vely.Giventhisinforma;on,GALE-401seemstoconferanimprovedoverallsafetyprofileandpoten;allyofferspa;entsimprovedtolerabilitycomparedtothelicensedproduct.Conclusion:AcrossHVandMPNsubjects,GALE-401consistentlydemonstratedawell-toleratedsafetyprofile. Moreover, in a small subset of subjects enrolled in the Phase 2 MPN pilot study, somepreviously treated Agrylin® intolerant subjects, demonstrated a con;nued prolonged clinical benefitwithGALE-401.ArandomizedtrialcomparingAgrylin®vs.GALE-401isneeded,alterna;velyortogetherwithatrialevalua;ngAgrylin®intolerantsubjectsiswarranted.

Abstract

IntroducBon