Oral Small Molecule GLP-1 Receptor (GLP-1R) Agonists for Type 2 Diabetes

(T2DM) with Negligible Nausea and Vomiting

vTv Identified the First Oral Small Molecule (allosteric) Agonists of the GLP-1 Receptor in 2004

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2004 Start of vTv’s Oral GLP-1R Agonist Research Program

2005 Byetta Approved in the US

2008 vTv’s First Generation,

TTP054, FIM Study

2012 vTv’s Second Generation,

TTP273, FIM Study

vTv’s GLP-1R Agonists Program Genesis

q Coordinatedu1liza1onofdatafromcellEC50assays,livermicrosomestability,andpharmacokine1csledtopotentleadserieswhichresultedin2clinicalcandidates

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TTP-595(TTProbe™)EC5045µM

TTP054EC5040nM

(ClinicalPOC)

TTP273EC505nM

(ClinicalPOM)Phase2ongoing

FirstGenera1onSeries

SecondGenera1onSeries

vTv's Oral GLP-1R Agonists q Novel,small,orallybioavailablemoleculesthatac1vatethehumanGLP-1R

q Stand-aloneallostericGLP-1receptoragonists

q SpecificfortheGLP-1receptorØ Func1onalbiasforG-proteinsignaling

q TypicalGLP1PharmacologyinanimalsandhumansØ Enhancesinsulinsecre1oninresponsetoglucoseØ DecreasesglucoseØ Decreasesfoodintakeandbodyweight

April2016 vTvTherapeu1cs,LLC 4(Rodent:EC5034nM;34%ac1va1on)

Oral Small Molecule GLP-1 Receptor (GLP-1R) Agonists with Negligible Nausea and Vomiting

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Nausea Vomi:ngPlacebo(n=21) 0 1200QD(n=11) 1 1400QD(n=9) 1 1200BID(n=10) 0 0400BID(n=4) 0 0

TTP054-108Phase1bT2DonMeBormin4w

Nausea Vomi:ng

Placebo(n=50) 3 2200QD(n=27) 1 0400QD(n=51) 0 0800QD(n=56) 4 3

TTP054-201Phase2T2DonMeBormin12w

TTP273-102Phase1bT2DonMeBormin2w

q  TTP054andTTP273aresafeandwelltoleratedatalldosestestedØ  NegligibleNauseaandVomi1ngØ  NoevidenceofHypoglycemia

Nausea Vomi:ngPlacebo(n=29) 0 025QD(n=9) 1 050QD(n=9) 0 025BID(n=9) 0 075QD(n=8) 1 075QPM(n=7) 0 0100QD(n=9) 0 1*150QD(n=9) 0 075BID(n=8) 1 0150BID(n=8) 1 0450QD(n=7) 0 0

*unrelatedtostudydrug

TTP273 Shows Greater Improvement in Glycemic Control than TTP054 in a Phase 1b Trial

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q TTP273ismoreefficaciousthanTTP054inphase1batthesamedosesdespiteshorterstudydura1on

TTP273 Seems to Have a Better Effect on Body Weight Loss than TTP054 in a Phase 1b Trial

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q Noweightlosswasseeninphase1bTTP054trialcomparedtoplaceboq TTP273phase1btrialshowedatrendinweightlosswiththeBIDdoseregimentsdespiteshorterstudydura1onandisocaloricdiet

q Ina3monthphase2studywithTTP054,significantbodyweightloss(1Kg)observedinthetargetpopula1on(A1c8-11%)atthehighdosegroup(800mgQD)

Proof of Concept

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Phase2:TTP054-201

Ina3monthphase2study,TTP054showedsignificantreduc:oninA1c

•  3month,randomized,double-blind,placebo-controlled,parallelgrouptrialin184type2diabe1csonstabledosesofmecormin

•  7-11.5%baselineHbA1c•  Arms:Placebo;TTP054200mg,400mgand800mgQD•  Primaryendpoint:ChangefrombaselineinHbA1cat3

months

vTv Oral GLP1r Agonists: a Better Alternative to the GLP-1 Analogue therapy

EffectsObservedinPa:ents vTvGLP1rAgonists GLP-1

Analogues

SafetyNosignificantgastrointes1nalsideeffects

ü  X

Convenience

Oral ü  XIdealforco-formula1onwithexis1ngOADs ü  XNoneedformedicaldevice ü  X

Efficacy

Lowersbloodglucose ü  ü  DecreasesHbA1clevels ü  ü  Weightloss ü  ü 

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q With a superior safety and convenience profile, TTP273 could provide an alternative to current GLP-1r therapies and expand the use of this therapeutic class

Acknowledgements

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q vTvDiscoveryanddevelopmentteams

q PatriciaMcDonald’slabatTheScrippsResearchIns1tute,Florida