Download Effect of Human pro-Islet PepMde 2B on β

EffectofHumanpro-IsletPep6de2Bonβ-cellFunc6oninMeVormin-TreatedType2Diabetes:
ARandomized,Double-Blind,Placebo-ControlledStudy
WatkinsE1,MorrowL1,KrentzAJ1,FeigPU1,UphamL2,ReiserHJ2,HompeschM1
1.ProfilIns1tuteforClinicalResearch,ChulaVista,CA,USA;2.CureDM,Inc.Wilmington,DE,USA
ABSTRACT
Humanpro-IsletPep1de(HIP2B)s1mulatesdifferen1a1onofpancrea1c
progenitor cells into new islet structures. In a single center, phase 1b
randomized, double-blind, parallel group, placebo-controlled study the
effects of 49 days of treatment with HIP2B were examined in adults
withmeXormin-treatedtype2diabetes.SubjectsreceivedHIP2B400mg
(n=14mean[+SD]age53+6y;BMI32.8+5.1kg/m2)or600mg(n=14
age52+8y;BMI32.4+5.2kg/m2)orplacebo(n=10;age56+7y;BMI
31.8 + 5.3 kg/m2) in a ra1o of 3:3:2 respec1vely as twice-daily (BID,
every 12 h ±1 h) subcutaneous injec1ons. Metabolic evalua1ons were
performed during seven in-house periods. Of 38 subjects who were
enrolled30completedthestudy.PK:dose-relatedincreasesinCmaxand
AUC were observed for HIP2B with no significant difference between
thetwodoses.Changesinprehepa1cinsulinsecre1onrates(pmol/kg/
min) Placebo: -60.5 +/- 61.25; HIP2B 400 mg: 60.63 +/- 37.17; 600mg:
55.13 +/- 24.31; pooled HIP2B: 58 +/- 22.13 (p=0.031) were observed.
Injec1on site reac1ons being the most common AE, were of mild to
moderateintensity.Noclinicallysignificantchangesinclinicallaboratory
values, vital signs or ECGs were observed thus achieving the primary
endpoint. In conclusion, treatment with HIP2B was associated with
trendstowardsincreasedinsulinsecre1onwithasta1s1callysignificant
increaseinpre-hepa1cinsulinsecre1onratesfrombaselinetoDay46in
the pooled HIP2B treatment groups. The results support addi1onal
studiesofHIP2Bintype2diabetes.
METHODS
Methodology:
This was a phase 1b, single center, randomized, double-blind, parallel
group, placebo-controlled study of the effect of 49 days of treatment
withrepeatedsubcutaneous(SC)dosesofHIP2Bonmeasuresofislet
β-cellfunc1oninadultswithT2DM.
•  DoubleBlind,Placebo,ControlledPhase1b
•  Totalof38Subjects
•  3:3:2(600mg:400mg:placebo)
•  BID,every12hours±1hourSC
•  SevenIn-houseVisitsforGGI6,IVGTT7,ISR8,9
BACKGROUND
Human Pro-Islet Pep1de (HIP2B) is a 14 amino acid pep1de derived
fromtheReggenethatisknowntos1mulatethenaturalprocessofislet
neogenesis. HIP2Bisbeingdevelopedforthetreatmentoftype1and
type2diabetesmellitus.
•  HIP2B s1mulates exis1ng progenitor cells in the pancreas to
differen1ateintonewhealthyisletstructuresinorderto:
•  supplement endocrine func1on and alleviate stress on
exis1ngisletsinT2DM,or
•  re-establish func1on in the absence func1onal islets in
T1DM, in combina1on with an immune tolerance or
immunesuppressiontreatment.1
•  HIP2BbindstoEXTL3,thetransmembrane
Receptorfoundonprogenitorcellsandtriggers
upregula1onofknowntranscrip1onfactors
thatleadtoisletneogenesis.2
Bio6nylated-HIP2B=green(FITC)
EXTL3posi6vecells=red(Cy3);
Co-localiza6on=orange
•  Lackoffirst-phaseinsulinsecre1onisusuallyprofoundwhenT2DM
is established and fas1ng hyperglycemia is present as a func1on of
reducedisletnumber3and/orreducedβ-cells.4,5
•  AkeyaspectofHIP2Bisitsabilitytos1mulateisletneogenesisfaster
thantheaUri1onratemakingT2DMisalogicaldiseasetarget.
RESULTS:SafetyEvalua6on
Twice-daily subcutaneous administra1on of HIP2B at 200 mg BID (400
mg daily) and 300 mg BID (600 mg daily) for 49 days is generally safe
andwelltolerated.
•  The types of reported AEs were generally similar between both
dosesofHIP2Bandplaceboanddidnotresultinpa1entdropouts.
•  noclinicallysignificantchangesintheclinicallaboratoryparameters
(chemistry,hematology,urinalysis)duringthestudy.
•  noclinicallysignificantchangesinECGsorvitalsigns.
RESULTS:PharmacodynamicEffects
ChangefromBaselinetoDay46inIncrementalAUCInsulin-GGI(±SE)
Figure 1: Change from Baseline to Day 46 in Incremental AUC InsulinGGI (±SE) Total HIP2B = combined HIP2B treatment groups (i.e., HIP2B
400 mg + 600 mg) 400mg group p=0.056, 600mg group p=0.146, Total
HIP2Bp=0.058.
ChangefromBaselinetoDay46in
Pre-Hepa6cInsulinSecre6onRate-GGI(±SE)
Figure 2: Change from Baseline to Day 46 in Pre-Hepa1c Insulin
Secre1on Rate-GGI (±SE) ISR = insulin secre1on rate, Total TX =
combined HIP2B treatment groups (i.e., HIP2B 400 mg + 600 mg);
400mggroupp=0.048,600mggroupp=0.061,TotalHIP2Bp=0.031.
ChangeinSlopeofInsulinSecre1onduringGGI
Figure 3: Improvements in insulin secre1on in HIP2B group during
Graded Glucose Infusion compared to placebo from start to end of
study.
ChangeinInsulinSecre6onRateinresponsetoIVGTT.
Figure4:ChangeinInsulinSecre1onRateinresponsetoIVGTT.
ChangesinHemoglobinA1c
ChangeinHbA1cfromBaselinetoDay49
Figure5:LeastsquaresmeanchangeinHbA1cfrombaselinetoday49
treatmentwithPlacebo,HIP2Bdosesof400mg,andHIP2B600mg.p=NS.
CONCLUSIONANDDISCUSSION
Astheprimaryobjec1ve,resultsindicatedthattwicedailysubcutaneous
injec1onsofHIP2Bat400mgand600mgfor49dayswere:
•  welltoleratedinsubjectswithT2DMonmeXormin,with
•  no clinically significant changes in clinical laboratory values, ECGs or
vitalsignsduringthestudy,and
•  nodeathsorwithdrawalsduetoAEs.
Despite the small sample size, compared to treatment with placebo,
treatmentwithHIP2Bresultedin:
•  improvementsinmeaninsulinconcentra1onsmeasuredbyGGIfrom
baselinetoDay46thattrendedtowardsignificance,
•  mean change in pre-hepa1c insulin secre1on rate from baseline to
Day46wassta6s6callysignificantinthecombinedHIP2Btreatment
groupscomparedtoplacebo,
•  improvements in mean insulin concentra1ons as measured by GGI
and IVGTT, including some that seemed to persist during the post-
treatmentperiod.
Improvementsininsulinsecre1onlevels,andimprovementsincontrolof
insulin secre1on under glucose challenge, is the benefit of islet
neogenesisasamechanism,whichleadtoimprovementinHbA1c.
We propose that a longer, larger defini1ve Phase II study will elucidate
theseeffectsofHIP2Basanimportantnewtreatmentop1onforType2
Diabetes.
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diabetesandhealthysubjects.DiabetesObesMetab.2014;16:793-800Appendices
CONTACT
ElaineWatkins,DO,MSPH
Profil™Ins1tuteforClinicalResearch
8553rdAvenue,Suite4400
ChulaVista,CA91911U.S.A.
(p):(619)409-1264
elaine.watkins@profilins1tute.com
LoraineV.Upham
CureDM,Inc.
1201MarketSt.Suite701
Wilmington,DE19801
(p):505-515-1947
[email protected]