AnOrallyAdministeredSmallMoleculeFactorDInhibitor(ACH-4471)
ForTreatmentofPNH,C3GandComplement– MediatedDiseases:
InterimPhase1ResultsInHealthyVolunteers
Authors,R.Ellis-Pegler1,C.Schwabe1,I.Ajari2,H.Robison2,R.Sorensen2,J.Lahey2,W.Yang2,M.Huang2,J.Hui2,H.Kocinsky2,M.Geffner2,D.Apelian2
1AucklandClinicalStudiesLtd,Auckland,NewZealand, 2AchillionPharmaceuticals,Inc.,NewHaven,UnitedStates
Contactinformation,M. Geffner2, [email protected]
Demographics
o
o
OBJECTIVES
• Assesssafetyandtolerabilityofsingleascendingoraldosesinhealthyvolunteers
• Evaluatepharmacokinetic(PK)andpharmacodynamic(PD)profilesandPK/PD
relationshipasmeasuredbyserumAPactivityexvivo
METHODS
Phase1aHealthyVolunteerStudy(evaluatedfor28daysafterdosing)
•
•
•
•
•
Group1:200mg,singledose(6active+6placebosubjects)
Group2:600mg,singledose(6active+2placebosubjects)
Group3:1200mg,singledose(6active+2placebosubjects)
Group4:1200mgx2doses(Q12H) (6active+2placebosubjects)
AllGroups:
o InhibitionofserumAPactivityevaluatedbyAPWieslab*andhemolysis*assays
o 36subjectsdosedandevaluated(35males+1female)
o Medianageof24.2years(range21.0- 54.2)
o FollowedforAEs/SAEsthroughthelastscheduledvisitatDay28
o BloodsamplescollectedatpredefinedtimepointsfromDay1toDay7 to
determineplasmaconcentrations
*Testsinthepresenceofpotentactivator:LPS,abacterialendotoxin(Wieslab®)orrabbiterythrocytes(hemolysis)
Abstract ID:EHA-4145
Group 3
Group 4
Placebo
200mg QD(N=6)
600mgQD (N=6)
1200mgQD (N=6)
1200mgx2doses(Q12H) (N=6)
0mg (N=12)
100
26.4
22.3
26.2
24.9
30.3
90
6(100)
Male,n(%)
0
Female,n(%)
6(100)
6(100)
6(100)
11(91.7)
0
0
0
1(8.3)
White,n(%)
5(83.3)
5(83.3)
2(33.3)
2(33.3)
10(83.3)
Asian,n(%)
0
1(16.7)
4(66.7)
3(50.0)
0
Other, n(%)
1(16.7)a
0
0
1(16.7)b
2(16.7)c
24.7
24.7
23.5
23.2
24.4
MeanBMI(kg/m2)
1000.0
10.0
•
•
1.0
12
24
36
48
60
by1to2.5hoursforalldosegroups
Majorityofexposure(measuredasAUC)
occurredoverfirst24 hours
Terminalphasebegins16 hourspostdose
Meanterminalhalf-life~9 hours
72
Time(hr)
Pharmacodynamics
Fig2:APWieslabActivityvsAPHemolysisActivity
Fig3:ComplementBbPlasmaConcentrations
160
1.2
140
1.1
120
100
80
60
40
R²=0.86
20
Placebo(N=12)
Group3(1200mgQDN=6)
Group4(1200mgx2doses (Q12H)N=6)
1.0
0.9
0.8
0.7
0.6
0.5
LLOQrange
0.4
0.3
0
0
20
40
60
80
100
120
APActivitybyHemolysisRelativetoBaseline(%)
140
0
2
4
6
8
10
12
14
16
18
20
2
4
6
8
10
12
14
16
18
20
22
24
48
• MedianInhibitionofAPhemolysisat24hourtimepointinGroup4is99.5%
0.1
0
30
Time(hr)
• Peakplasmaconcentrations(Cmax)achieved
•
40
0
Pharmacokinetics
100.0
50
0
• Notreatmentemergentadverseevents(TEAEs)leadingtodiscontinuation
• Nodrug-relatedseriousadverseeventsordrug-related Grade3/4TEAEs
Group1(200mgQDN=6)
Group2(600mgQDN=6)
Group3(1200mgQDN=6)
Group4(1200mgx2doses (Q12H)N=6)
60
10
Safety
10000.0
70
20
a. Mixed;WhiteandPacificIslander, b Maori/Tongan, cOnesubjectidentifies asMaori.Onesubject identifies asNewZealandMaori.
Fig1:MeanPlasmaPK
Placebo(N=4)
Group3(1200mgQDN=6)
Group4(1200mgx2doses (Q12H)N=6)
80
Race
APActivitybyWieslab
RelativetoBaseline(%)
o
Group 2
Gender
MeanACH-4471
PlasmaConcentrations(ng/mL)
o
BindingaffinitytohumanfD:KD =0.54nM
InhibitionofcatalyticactivityoffDagainstfactorB:Ki =5.7nM
InhibitionofAPactivityinvitro:
- IC50 =27nMforrabbiterythrocyte hemolysis
- IC50 =14nMforPNHerythrocytehemolysis
- IC50 =26nMbyWieslabassay
Lowpotentialforoff-targetinhibitionofotherserineproteases
Welltoleratedinnon-clinicaltoxicologystudies
Fig4:APActivityasMeasuredbyHemolysis
Group 1
MeanAge(years)
• Preclinical
o
InhibitionofAPHemolysis
MedianAPActivity
RelativetoBaseline(%)
ACH-4471isanovel,highly-potentandspecificorally-administeredsmallmoleculeinhibitor
offactorD(fD),aserineproteasewithinthecomplementalternativepathway(AP)
• Proposedmechanismofaction
o PreventsfactorBcleavageintoBaandBbintheAP,leadingto:
- BlockadeofC3convertaseproductionanditssubsequentamplification
- PreventionofC3fragmentdepositiononparoxysmalnocturnalhemoglobinuria
(PNH)cells1,whichisassociatedwiththedevelopmentofextravascular
hemolysisinthesettingofC5blockade2,3
• Structuralbiology
o Achievedhighresolution(0.8Å),threedimensionalx-raystructure
ofACH-4471complexedwithfD
RESULTS
MedianComplementBbPlasma
Concentrations(ug/mL)
BACKGROUND
INTRODUCTION
22
24
48
(Range96-100%)(Fig4)
• Regimenmodeling:PK/PDmodelingindicatesthata750mg(Q12H)dosing
regimencouldachievegreaterthan90%sustainedinhibitionofAPactivity
CONCLUSIONS
CONCLUSIONS
ACH-4471waswell-toleratedatallevaluateddoselevels,withoutevidencefordrugrelatedsafetyissues,andachievedupto100%inhibitionofAPcomplementactivity.
• PD:1200mgx2doses(Q12H)achievedmedian99.5%inhibitionofAPhemolysisat
24hours
• PK/PDmodeling: Predictsthatadosingregimenof750mgadministeredevery12hours
woulddeliversustainedsuppressionofAPactivity
• BbandBalevels(cleavageproductsoffactorB)arepotentiallyusefulasinvivo
biomarkersoffDinhibition
o Bbdeclinedafterdosing,reachinganadirby16 hoursinGroups3and4
o Bbgraduallyreturnedtobaselineby48 hourspostdose
• Ongoingdevelopmentprogram
o 14-daymultipleascendingdosestudyplannedfor2Q2016
o PlanstoinitiatedosinginPNHandC3Gpatientsbyyearend2016
o ACH-4471maypreventbothintravascularandextravascularhemolysisinPNH
patientsbasedonitsuniquemechanismofaction
o FormulationoptimizationisbeingevaluatedforpotentialQDdosing
Time(hr)
• Upto100%inhibitionofAPcomplementactivitywasachievedinalldosegroups,and
durationofinhibitionwasdose-dependent
• MeanplasmaconcentrationsnecessarytoachieveAPWieslabinhibition:
o >80%~180ng/mLand>90%~230 ng/mL
• APWieslabandAPhemolysisassaysarewellcorrelated(R2=0.86)(Fig2)
(alldataforgroups1-4upto48hours)
• PlasmaBbconcentration decreasedinadose-dependentfashionwithanadirat16 hours
postdoseandgradualrecoverytooriginallevelsby48 hours(Groups3and4)(Fig3)
• NosignificantchangeinserumfDconcentrationaswellascomplementC3,C4,and
classicalpathwayfunctionCH50comparedtobaselineinallGroups(datanotshown)
REFERENCES
1GavriilakiE.,etal.SmallmoleculefactorDinhibitorsblockcomplementactivationinparoxysmal
nocturnalhemoglobinuriaandatypicalhemolyticuremicsyndrome.Blood.2015Dec;126(23):275
2RisitanoAM,etal.Complementfraction3bindingonerythrocytesasadditionalmechanismof
diseaseinparoxysmalnocturnalhemoglobinuriapatientstreatedbyeculizumab.Blood.
2009;113(17):4094-100
3HillA,etal.Eculizumabpreventsintravascularhemolysisinpatientswithparoxysmalnocturnal
hemoglobinuriaandunmaskslow-levelextravascularhemolysisoccurringthroughC3opsonization.
Haematologica.2010Apr;95(4):567-73