TherapeuticStrategyAgainstTumorAcidityInducedImmune-Suppression:L-DOS47aClinicalCandidateforLungCancer

Precision Lung Cancer SummitBoston USASept 2016

Forward-lookingStatementsThis presentation document contains certain forward-looking statements and information (collectively, “forward-

looking statements”) within the meaning of applicable securities laws. Forward-looking statements are statements and informationthat are not historical facts but instead include financial projections and estimates; statements regarding plans, goals, objectives,intentions and expectations with respect to Helix’s future business, operations, research and development, including the focus of Helixon its DOS drug candidate generally and L-DOS47 in particular, the anticipated timelines for the commencement or completion ofcertain activities, including enrolment of patients in Helix’s Phase I/II clinical trial for L-DOS47 in Poland, the expansion of the DOS47platform into other compounds and indications and other information in future periods. Forward-looking statements, which may beidentified by words including, without limitation, “expects”, “plans”, “will”, “intends”, “may”, “pending”, “objective”, “exploring”,“potential”, “projected”, “possible” and other similar expressions, are intended to provide information about management’s currentplans and expectations regarding future operations.

Although Helix believes that the expectations reflected in such forward-looking statements are reasonable, suchstatements involve risks and uncertainties that may cause actual results or events to differ materially from those anticipated and noassurance can be given that these expectations will be realized, and undue reliance should not be placed on such statements. Riskfactors that could cause actual results or events to differ materially from the forward-looking statements include, without limitation: (i)the inherent uncertainty involved in scientific research and drug development, including with respect to costs and difficulties inpredicting accurate timelines for the commencement or completion of certain activities; (ii) the risks associated with delay or inabilityto complete clinical trials successfully and the long lead-times and high costs associated with obtaining regulatory approval to marketany product which may result from successful completion of such trials; (iii) need to secure additional financing on terms satisfactory toHelix or at all, including that the additional funding required in order to complete the proposed U.S. Phase I clinical trial will be obtainedon terms satisfactory to Helix or at all; (iv) clinical trials that yield negative results, or results that do not justify future clinicaldevelopment, including that Helix’s ongoing Polish Phase I/II clinical trial for L-DOS47 and/or that Helix’s proposed U.S. Phase I clinicaltrial will yield negative results; (v) Helix’s clinical development plan for the proposed US Phase I clinical trial does not proceed in themanner or on the timelines anticipated by Helix or at all; and (vi) those risks and uncertainties affecting Helix as more fully described inHelix’s most recent Annual Information Form, including under the headings “Forward-Looking Statements” and “Risk Factors”, filedunder Helix’s profile on SEDAR at www.sedar.com (together, the “Helix Risk Factors”). Certain material factors and assumptions areapplied in making the forward-looking statements, including, without limitation, that the Helix Risk Factors will not cause Helix’s actualresults or events to differ materially from the forward-looking statements. Helix.

Forward-looking statements and information are based on the beliefs, assumptions and expectations of Helix’smanagement on the date of this presentation, and are presented solely to acquire a better understanding of Helix and may not beappropriate for other purposes nor should this presentation be redistributed to other parties. Helix does not assume any obligation toupdate any forward-looking statement or information should those beliefs, assumptions or expectations, or other circumstanceschange, except as required by law. 2

TheHallmarksofCancer

Cell 2011 144, 646-674 3

MetabolicReprogramming

Cancer Cell 2008, 13 472-482 4

CancerHallmarksLinktoMetabolism

Cancer Cell 2008, 13 472-482 5

DysregulatedpHisEmergingasaHallmarkofCancer

6NatureReviewsCancer11,671-677(September2011)

CancercellpHisregulatedbyanumberofmechanisms

• CancercellsupregulateGlut1andGlut2toimportglucoseforglycolysis

• Excessprotonandlactateareexcretedbymonocarboxylate transpoters(MCTs);Na/Protonexchangers(NHEs);andprotonpumpvacuolarATPase(V-ATPase)

• OtherproteinsthatregulatepHinclude:anionexchangers(AEs);Bicarbonatetransporters(BTs);Cl-/HCO3- exchangers(CBEs);Na+/HCO3-contransporter (NBC);NA+dependentCl-/HCO3- exchangers(NDCBE)

• CO2regulationbycarbonicanhydrasesCAII,CAIX,CAXIIalsoaffectpH

7PigmentCellMelanomaRes.2016May27

AcidosisandTumorProgression

8NatureCommunications6:87522015

LowpHandTumorInvasion

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(A)TheTumoredgehasanincreasedexpressionofNHE-1(smallthinarrows)andGLUT1(largearrows),whichisindicativeofacidificationcausedbyanincreaseinglycolysis.Thisisconsistentwithmicroenvironmental acidosisobservedinvivoleadingtosubsequentinvasion.(B)ExpressionofGLUT-1andNHE-1asafunctionofdistancefromtheTumoredge.(C)and(D)ExpressiontrendsofGLUT-1andNHE-1asafunctionofdistancefromTumoredgeinN=4Tumors.

CancerRes.2013Mar1;73(5):1524–1535

LactateLowersTumorpHandPolarizesMacrophages

Macrophages integrate metabolic andenvironmental signals to promoteTumor growth. Tumor lactate whichlower pH polarizes macrophage andup-regulate Arg1. Area within dottedrectangle indicates proposedmechanisms of action. ARG, arginase;HIF, hypoxia-inducible factor; MCT,monocarboxylate transporter; NADH,reduced nicotinamide adeninedinucleotide; PKM2, M2 isoform ofpyruvate kinase; VEGF, vascularendothelial growth factor.

10Nature 513:559-563 (2014)

TCellLossofFunctionfromLowpHandElevatedLactateLevel

Severalfactorsintheinflammatorymicroenvironment(e.g.,oxygenconcentration,pH,lactate,fattyacidsandROS)caninfluencethefunctionofTcellsandotherimmunecellsonanumberoflevelsanddeterminetheoutcomesoftheinflammatoryprocess.

ThemotilityofCD4+andCD8+Tcellsisblockedoncetheygetexposedtoelevatedlevelsoflactateintheinflammatorysite.Lacticacidalsocauseslossofcytolytic activitybyCD8+Tcells,andsodiumlactatepromotestheproductionofIL-17byCD4+Tcells.

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AmJ.Clinic.Immunol.2(2):146-155(2013

PLoSBiol.13(7)(2015)

TCellLossofFunctionfromLowpH

CD8+TcellsisolatedfrompmelmicetransgenicallyexpressaTCRspecificforthemelanocyte-associatedpeptide,Gp100(25-33)whileremainviableinlowpH,haslowerIFNg secretionuponstimulation(A,B).Theeffectcanbereversedbyre-stimulationinhigherpH(D).

Cancer Res; 76(6) March 15, 2016 12

AcidityAffectsAdoptiveTcellTherapy

Cancer Res; 76(6) March 15, 2016

EffectofbicarbonateonadoptiveT-celltransfer.A,TumorgrowthafteradoptivetransferofTcellsorcontrolsincombinationwithorwithoutbuffertherapy.GroupmeandifferencesbetweenTcellsvs.Tcellsvsbicarbonatewerenotsignificant.However,therewasasurvivaladvantage,asshowninthesurvivalcurveinB

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TumorpHandCheck-PointInhibitors

14

Buffertherapyenhancesefficacyofanti-immunotherapyinB16melanoma.C57BL/6

CancerRes;76(6)March15,2016

TherapeuticStrategyAgainstAcidosis

• Inhibitors(smallmoleculesorantibodies)totarget:

– Carbonicanhydraseisoforms– V-ATPaseinhibitorsandprotonpump

inhibitors– Na+/HCO3−co-transporters,anion

exchangersandNa+/H+exchanger1– Monocarboxylate transporterinhibitors

• TargetingaspecificproteintocombatTumoracidityisnoteasilyachieved;manyoftheseregulatorshavemultipleisoformsandsomehavecriticalfunctionincellularhomeostasis

• Otherstrategyattemptedincludessystemicalkalizationusingsodiumbicarbonatesolution

• Helix’sapproach:targeteddeliveryofalkalizingenzyme

15NatureReviewsDrugDiscovery10,767-777

DOS47TargetingtheTumorAcidicBarrier

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DOS47

• DOS47isatechnologythatchangestheTumormicroenvironmentfromacidictoalkalineusingtheenzyme‘urease’

• AlkalinizingtheTumorhasthepotentialto– ToexertdirectcytotoxiceffectonTumors– toincreasetheactionofcertainchemo-therapies– tocorrectanimpairedimmunemicroenvironment

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L-DOS47HelixFirstClinicalDrugCandidate

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L-DOS47

• L-DOS47isaconjugateofureasewithaproprietarycamelidsingledomainantibodyspecificforCEACAM6

• CEACAM6isacellsurfaceTumorantigenhighlyexpressedonlung,colon,pancreaticandothercancercells

• L-DOS47isinclinicalstudiesforthetreatmentofnon-squamous,non-smallcelllungcancer(NSCLC)

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L-DOS47– DualFunctionAntigen:CEACAM6

• Glycosylated90kDa(286aa)GPI-linkedmembraneprotein

• IntercellularadhesionmoleculeforminghomotypicandheterotypicbondswithCEACAM-1,5and-8

• Importantforcellattachmentandproliferation

• MayactasacheckpointinhibitorinMultipleMyeloma

Enzymesubstrate:urea• Ureaisanaturalmetabolite• Ammonia/Ammonium

producedfromureahydrolysisistoxictocells

• Apoptoticenzymescaspase2and3(A549lungcell)andcaspase8and9(BxPC3pancreaticcells)areinduced

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SpecificDeliverytoTumors

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Full Body ScanA549 Tumor (8 x 7 mm)L-DOS47-Cy5.5

Filtered ScanL-DOS47-Cy5.5

Cy5.5 emission max @710nm

Tumor specific localization

L-DOS47AffectsMetabolism1H-NMR anatomical imaging

control

Treatment

32P-NMR microenvironment

NMR imaging on A549 xenograft mice showing a change in energy metabolism (Pi/Pcr) as a result of L-DOS47 treatment

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L-DOS47CytotoxictoCEACAM6-PositiveTumorCells

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Celllines Bindingassay Cytotoxicityassay

A549 Lungcarcinoma ++ +

H460 Lungcarcinoma - ND

H647 Lungcarcinoma + ND

H23 Lungadenocarcinoma - +

BxPC-3 Pancreaticadenocarcinoma +++ +++

Capan-1 Pancreaticadenocarcinoma +++ ++

MIAPaCa-2 Pancreaticcarcinoma + +

MDA-MB231 Breastadenocarcinoma - -

JIMT-1 Breastcarcinoma - ND

MCF-7 Breastcarcinoma - -

BT-474 Breastductalcarcinoma + -

HCC-1954 Breastductalcarcinoma +++ +++

ZR-75-30 Breastductalcarcinoma +++ +++

HCC-1806 Breastsquamouscellcarcinoma - ND

LS174T Colonadenocarcinoma ++ ++

SW620 Colorectaladenocarcinoma - ND

HL-60 Promyelocyticleukemia - ND

CertainLung,pancreas,breastandcoloncelllinesaregoodmodels

L-DOS47InhibitsTumorGrowthinLungandPancreaticModels

0 5 10 15 200

50100150200250300350

Days

%C

hang

e in

Tum

orVo

lum

e

A549 (lung)L-DOS47 (10,20,35U/kg)Cisplatin control

BxPC3 (Pancreatic)L-DOS47 (7,35,175ug/kg)Paclitaxel control

Tianet.al.Bioconjug Chem.2015Jun17;26(6):1144-55

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L-DOS47BindstoCEACAM6PositiveCancerPatientTissues

Positive Negative NegativeKidney carcinoma 12/12 12/12Parathyroid adenoma 1/1 n/a

Plaenta, umbilical cord, allantois 1/1Myofibroblastic Tumor 1/1 n/a

Prostate carcinoma 4/4 4/4Thyroid carcinoma 2/2 2/2

7/57 weak8/57 v. weak

Neuroendocrine Tumors 9/9 n/a

Brain, heart muscle, testis, spleen 30/30Testis - teratoma and seminoma 3/3 3/3Parotis Tumor 1/1 1/1Cervix squamous carcinoma 2/2 n/a

Thymoma 2/2 n/a

Colon adenocarcinoma 14/24 weak 10/24- lymph node metastasis 3/3

Breast adenocarcinoma 13/13- lymph node metastasis 2/2

Leiomoma - lung metastasis 1/1 n/a

Ovary carcinoma 4/4 n/a

Bladder carcinoma 42/42- lymph node metastasis 1/1 strong- squamous carcinoma metastasis 2/2

Lung - small cell carcinoma 1/1- adenocarcinoma 5/5 strong

Stomach adenocarcinoma 3/3 3/3Liver carcinoma 4/4 4/4Soft tissue Tumors 3/3 n/a

Melanoma 48/48- metastasis 18/18 18/18

36/36

24/24

13/13

n/a

5/5

Samples

Pancreas adenocarcinoma 42/57

Age-matched Normal TissueTumor Tissue

n/a

25/25

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TumorFormationInhibition

26

EnhancesOtherChemotherapeutics

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The cytotoxic effect of weakly basic drugs is directly related to the solution pH (left panel). At anacidic Tumor pH (<6.8), the effectiveness of these drugs is significantly reduced. L-DOS47 candramatically raise the effectiveness of these drugs (e.g. navelbine, right panel). This synergisticeffect is directly related to its enzymatic properties of generating ammonia from urea and raisingsolution pH. Depending on the dosages and available urea, a 2–10 fold drug effect enhancementcan be observed.

ØL-DOS47 enhances chemo drugs

L-DOS47EnhancesPemetrexed andCarboplatin

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A549 (No Pemetrexed)

0 25 50 100 2000

20

40

60

80

100

Carboplatin ( M)

%S

urv

ival

(2.5 M Pemetrexed)

0 25 50 100 200Carboplatin ( M)

(12.5 M Pemetrexed)

0 25 50 100 200

No L-DOS471 g/mL L-DOS47/4mM urea

Carboplatin ( M)

A549 cells were treated with various concentrations of pemetrexed and/or carboplatin with or without 1 µg/mL L-DOS47 and 4mM urea. The results showed that L-DOS47/ urea treatment significantly enhanced the cytotoxicity of carboplatin alone (25-100µM), pemetrexed alone (2.5µM), or in combination. Further increase the concentration of pemetrexed to 12.5µM did not increase the cytotoxic effects.

L-DOS47ClinicalUpdate• L-DOS47PhaseI/IITrial(LDOS002)

– MonotherapyinadvancedNSCLCpatients– CurrentlyenrollingPhaseIIpatients

• L-DOS47PhaseIwithExpansionTrial(LDOS001)– Combinationwithpemetrexed andcarboplatin– Currentlyenrollingincohort2

• L-DOS47PhaseII(LDOS003)– Combinationwithvinorelbine andcisplatin– Intheplanningphase

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L-DOS47PhaseI/IITrial(LDOS002)• MonotherapytreatmentprotocolinNSCLCpatientsthathavenot

respondedtoothertreatments;• StageIIIb /IV,metastatic,andprogressionafterseverallinesofchemo,

rad,surgeryorchemo-naïvepatientsthathaverefusedotherlinesoftherapy;

• Dosedonceaweekfor2weeks,1weekrest(3-weekcycle);• Conductedin5CentersinPolandtoassesssafety(phaseI)andthen

preliminaryefficacy(phaseII);• CentersincludeTheMariaSklodowska-CurieInstituteofOncology,

MilitaryInstituteofHealthInstitute,MazovianCentreofPulmonaryDiseasesandTuberculosisinOtwock,DepartmentofOncology,PoznanUniversityofMedicalSciences,NationalTuberculosisandLungDiseasesResearchInstitute

• PhaseIIdosingregimenchangedtotwiceaweekdosingfor2weeks,1weekrest(3-weekcycle);

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DemographyTotal

(N=40)NSCLC History

Total(N=40)

Age Mean = 61.2Min, Max (34, 83)

Tumor Histology

Adeno = 38 (95%)Large Cell = 1 (2.5%)Unknown = 1 (2.5%)

Weight(kg)

Mean = 69.1Min, Max (48, 95)

Tumor Staging

Stage IIIB = 7 (17.5%)Stage IV = 33 (82.5%)

GenderMale

Female21 (52.5%)19 (47.5%)

Prior Therapy

None = 8 (20%)Chemo/Target = 32 (80%)

Radiation = 21 (52.5%)Surgery = 11 (27.5%)

Race

Caucasian 40 (100%)Prior

Chemo/Target

Therapy

Adjuvant = 2 (5%)Locally Advanced = 3 (7.5%)

Metastatic Disease = 31 (77.5%)

None = 9 (22.5%)

ECOG012

11 (27.5%)27 (67.5%)

2 (5%)

BestResponse

Unknown = 5 (16.1%)CR = 1 (3.2%)PR = 9 (29%)

Stable = 9 (29%)PD = 7 (22.6%)

DemographyandNSCLCBaselineCharacteristics(upto12Cohorts)

31

ClinicalObservationsUptoCohort12

• 21/40patientshadanoverallresponseofSDatcycle2• 10/40patientshadanoverallresponseofSDatcycle4• Patient01-047enrolledincohort9(1.84µg/kg)was

progressionfreefor10cycles(approx.7months)• Noneofthepatientstreatedto-datehavehadapartialor

completeresponseasdefinedbyRECISTv1.1definition• OneDLTreportedincohort13(Grade4BackPain)

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L-DOS002PhaseI

33

• Currentlyhascompleted16cohorts(13.55ug/kg)• OneDoseLimitingToxicity(DLT);• Nosafetyissuesbeyondthoseobservedinpre-clinical

toxicologystudiesorexpectedinthepopulationofpatientsbeingstudied;

• Immunogenicityconsistentwithwhatwasobservedpre-clinically;

• PhaseIIcurrentlyenrolling.

L-DOS47PhaseIwithExpansionTrial(LDOS001)

• Combinationtherapyinfirst-linetreatmentofNSCLC:– StageIIIb /IV,metastatic,andchemo-naïve;– Givenincombinationwithstandardpemetrexed/carboplatin

treatment;– Dosedcontinuouslyeachweek;– Monitorradiologicallyevery6weeks;

• Conductedin3CentersinUStoassesssafety(phaseI)andthenpreliminaryefficacy(expansion);

• ClinicalsitesincludeMDAnderson,HersheyPennState,andCaseWestern;

• secondcohortofpatientsenrolling• Onepartialresponseobservedpreviouslyreported

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DOS47:BreakingDownTumorAcidicBarrier

• L-DOS47istheonlytargetedenzymaticapproachtocombatTumoracidosis

• L-DOS47isbeingstudiedasmonotherapyandchemocombointheclinic

• AsecondDOS47candidatethattargetsVEGFR2isinpreclinicaldevelopment

• ActiveR&DworkareexploringDOS47actionwith check-pointinhibitors,cellbasedtherapiesandchemotherapeutics

35Cancer Cell 2008, 13 472-482

Acknowledgement• HelixPolska Poland• TheMariaSklodowska-CurieInstituteofOncologyPoland• MilitaryInstituteofHealthInstitutePoland• MazovianCentreofPulmonaryDiseasesandTuberculosisinOtwock

Poland• PoznanUniversityofMedicalSciencesPoland• NationalTuberculosisandLungDiseasesResearchInstitutePoland• MDAndersonCancerCenterUSA• PennStateS.HersheyMedicalCenterUSA• UniversityHospitalCaseMedicalCenterUSA• NationalResearchCouncilCanada

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