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0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) HC subjects: SUV and SUVr HC 05 51 yrs, MMSE 29 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) 0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) HC 08 53 yrs, MMSE 29 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) Olivier Barret 1 , John Seibyl 1 , Andrew Stephens 2 , Jennifer Madonia 1 , David Alagille 1 , Andre Mueller 2 , Mathias Berndt 2 , Heiko Kroth 3 , Andreas Muhs 3 , Andrea Pfeifer 3 , Gilles Tamagnan 1 , Ludger Dinkelborg 2 , Kenneth Marek 1 , 1 Molecular Neuroimaging, New Haven, USA, 2 Piramal Imaging, Berlin, Germany, 3 AC Immune, SA, Lausanne, Switzerland STUDY DESIGN RESULTS CONCLUSIONS BACKGROUND / RATIONALE RESULTS • Positron emission tomography may prove a useful tool for detecting the presence and spatial extent of brain tau accumulation, a key pathologic feature of Alzheimer’s disease (AD) and other non-AD tauopathies. Current tau tracers suffer from sub-optimal kinetics and high off-target binding, confounding quantification, as well as variable affinity for tau isoforms, diminishing utility for evaluating non-AD tauopathies like progressive supranuclear palsy (PSP). • The novel PET tau tracer PI-2620 has an IC50 of 1.8 nM for tau in AD brain homogenate competition- assays and binds specifically to tau deposits on AD brain sections (Braak I-VI), Pick’s and PSP pathology. • PI-2620 binds to both Tau isoforms 3R and 4R and demonstrates high selectivity over beta-amyloid, MAO A and MAO B, with very low off-target binding. • In vivo preclinical studies show high brain uptake and fast wash-out in mice and non-human primate. Objective: To extend these studies to first in human evaluation of the tau PET tracer PI-2620 (MNI-960) in research participants with and without suspected tau pathology. • In an ongoing clinical study, participants diagnosed with mild Alzheimer’s (AD), non-AD tauopathies, and healthy controls (HC) underwent dynamic PET imaging for approximately 3 h following 350 MBq bolus injection of 18F-PI-2620. AD subjects and controls had screening florbetaben PET screening scans to confirm cohort- appropriate amyloid status • Venous blood was obtained to characterize the metabolism of parent compound. • SUV and SUVrs were calculated for brain regions derived from the Hammers template placed on each spatially normalized, grey matter segmented PET image volume. • In addition, a single human biodistribution/dosimetry study was performed in a male control with preliminary estimates of target organ radiation absorbed dose and Effective Dose (ED). Table 1. Baseline Characteristics Fig. 2a PET in two healthy controls acquired 60-90 min post injection of 350 MBq of 18F-PI-2620. Note lack of non-specific, off-target uptake. SUV time-activity curves show high brain penetrance and fast wash-out with secular equilibrium achieved at 50 min and persisting for the next 1.5 h in AD, PSP, and controls (Fig. 2b,c). • Initial clinical data in AD subjects shows robust brain uptake and fast wash-out in non- target regions. • No increased uptake was noted in choroid plexus, striatum, amygdala, or other regions seen in first generation tau agents. • SUVr time curves suggest a plateau occurs 60-90 min post injection with resultant SUVrs in abnormal regions up to 2.5-2.8. • Blood data confirmed fast kinetics with 20% of parent compound present at 60 min. • No lipophilic metabolites were observed. • AD and PSP subjects show expected patterns of tau uptake. • Non-invasive pk modeling indicates SUVr (60-90 min) could be a good proxy for BPnd pending full validation of quantitative outcome measures using metabolite corrected arterial input functions. 0.0 SUVr 6.0 Substantia nigra 60-90 min 75 yrs, MMSE 19, PSP scale 54 Pallidum 0.0 SUVr 5.0 HC 05 HC 08 60-90 min p.i. SUVR-1 and BP ND Correlation in AD Subjects 0.0 SUV (g/ml) Subject 03-01-02 (male) 10.0 0-10 66-87 164-210 276-322 min 12 mm smoothing applied R L 22-43 Fig. 1. Healthy control biodistribution and dosimetry 1. Elimination is via both hepatobiliary (main route) and urinary pathways. 2. Target organs with highest exposure are gallbladder wall and upper large intestine. 3. The Effective Dose per 185 MBq(5 mCi) injection is 4.1 mSv with no UB voiding, and 4.0 mSv with 2 hour UB voiding interval for adult male , which compares favorably to other 18 F radiopharmaceuticals. Fig. 2 b,c PET in four AD (above) and two PSP (below) participants acquired 60-90 min post injection of 350 MBq of 18F-PI-2620. Three of the AD patients show typical asymmetric patterns of tracer uptake involving temporal lobes, precuneus, and post cingulate. The third AD subject, very mild clinically, shows no uptake, a phenomena noted with AV1451 (Pontecorvo, et al, Brain, Jan 11, 2017). The PSP subjects (below) show focally discrete uptake in substantia nigra and pallidum, consistent with pathological reports in the literature. Fig. 3 PET SUVr for left cortical and subcortical brain regions show good separation between visually detected areas of higher uptake described above (Fig 2) and elevated SUVrs. Fig. 4 Correlation of SUVrs and BPnd determined by non-invasive PK modeling suggests 60-90 mins may best align with BPnd. Fig. 5 Metabolism of PI- 2620 shows, similarly across subjects, rapid kinetics with 20% of parent present at 60 minute (top) and production of hydrophilic metabolites (bottom). The latter are unlikely to cross the blood-brain barrier. #224 Table 2. SUVr Measures AD subjects: SUV and SUVr 0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) PSP subjects: SUV and SUVr PSP 03 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) 0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) PSP 07 FL_OFC_L FL_OFC_R TL_SupLat_L TL_SupLat_R TL_InfLat_L TL_InfLat_R TL_Mesial_L TL_Mesial_R PL_L PL_R OL_L OL_R Cing_Ant_L Cing_Ant_R Cing_Post_L Cing_Post_R CaudateNucl_L CaudateNucl_R Putamen_L Putamen_R Cerebellum Pallidum_L Pallidum_R S_nigra_L S_nigra_R 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) 0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) 0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) 0 50 100 150 200 0 2 4 6 Time (min) SUV (g/mL) 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) 0 50 100 150 200 0 1 2 3 Time (min) SUVr (cerebellar cortex) AD subject 01 MMSE 7 AD subject 02 MMSE 22 AD subject 04 MMSE 26 Cing_Ant_L Cing_Ant_R CaudateNucl_L CaudateNucl_R Putamen_L Putamen_R Pallidum_L Pallidum_R S_nigra_L S_nigra_R FL_OFC_L FL_OFC_R TL_SupLat_L TL_SupLat_R TL_InfLat_L TL_InfLat_R TL_Mesial_L TL_Mesial_R PL_L PL_R OL_L OL_R Cing_Post_L Cing_Post_R Cerebellum 0 50 100 150 0 1 2 3 Time (min) SUVr (cerebellar cortex) 0 50 100 150 0 2 4 6 Time (min) SUV (g/mL) AD subject 09 MMSE 17 0.0 SUVr 5.0 AD 01 MMSE 7 AD 02 MMSE 22 AD 04 MMSE 26 60-90 min p.i. AD 09 MMSE 17 HC 05 HC 08 PSP 03 PSP 07 AD 01 AD 04 AD 02 AD 09 FL_OFC_L 1.21 1.30 1.27 1.32 1.60 1.03 1.40 1.50 FL_OFC_R 1.19 1.30 1.30 1.37 1.31 1.05 1.33 1.49 TL_SupLat_L 1.07 1.03 1.15 1.30 2.01 1.06 2.00 1.36 TL_SupLat_R 1.17 1.01 1.17 1.27 1.61 1.08 1.46 1.81 TL_InfLat_L 1.06 1.09 1.27 1.23 2.27 1.15 2.27 1.77 TL_InfLat_R 1.12 1.07 1.17 1.19 1.70 1.15 1.57 2.10 TL_Mesial_L 1.07 1.04 1.27 1.25 1.70 1.15 1.85 1.71 TL_Mesial_R 1.20 1.15 1.22 1.34 1.40 1.27 1.23 2.16 PL_L 1.07 1.03 1.04 1.25 1.69 0.95 1.53 1.06 PL_R 1.11 0.98 1.04 1.20 1.55 0.94 1.21 1.13 OL_L 1.17 1.12 1.19 1.38 2.04 1.04 1.36 1.23 OL_R 1.22 1.11 1.22 1.41 1.65 1.10 1.29 1.50 Cing_Ant_L 0.96 0.88 0.97 1.08 1.05 0.75 1.17 0.89 Cing_Ant_R 1.00 0.84 0.85 1.05 0.91 0.88 1.04 0.90 Cing_Post_L 0.99 0.88 1.05 1.15 1.64 0.86 1.39 1.07 Cing_Post_R 0.95 0.86 0.99 1.17 1.63 0.86 1.26 1.14 CaudateNucl_L 0.85 0.64 0.89 0.96 0.88 0.66 0.85 0.67 CaudateNucl_R 0.88 0.67 0.85 1.05 0.93 0.54 0.97 0.64 Putamen_L 0.93 0.84 1.42 1.19 1.11 0.88 1.32 1.01 Putamen_R 1.07 0.73 1.26 1.37 0.92 0.87 1.12 1.03 Pallidum_L 1.09 0.83 2.11 1.59 1.12 0.97 1.19 0.96 Pallidum_R 1.07 0.74 1.99 1.85 0.94 0.84 1.26 1.00 S_nigra_L 1.68 1.15 2.58 2.03 1.16 1.21 1.57 1.54 S_nigra_R 1.54 1.05 2.41 1.70 1.04 1.39 1.60 1.08 FL_OFC TL_SupLat TL_InfLat TL_Mesial PL OL Cing_Ant Cing_Post 0 1 2 3 Left Cortical VOIs SUVr (cerebellar cortex) AD Subject 1 PSP Subject 3 HC Subject 5 AD Subject 4 AD Subject 2 PSP Subject 7 HC Subject 8 AD Subject 9 CaudateNucl Putamen Pallidum S_nigra 0 1 2 3 Left Subcortical VOIs SUVr (cerebellar cortex) 0 20 40 60 80 0 20 40 60 80 100 Percent Unchanged Parent Time (min) % Parent fraction AD Subject 1 PSP Subject 3 HC Subject 5 AD Subject 4 AD Subject 2 HC Subject 8 PSP Subject 7 AD Subject 9 0 20 40 60 80 0.0 0.5 1.0 1.5 Total Plasma Time (min) SUV (g/mL) AD Subject 1 PSP Subject 3 HC Subject 5 AD Subject 4 AD Subject 2 HC Subject 8 PSP Subject 7 AD Subject 9 FIRST IN HUMAN CHARACTERIZATION OF PI-2620, A NEXT GENERATION PET TRACER FOR ASSESSING TAU IN ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES Subject number Cohort Age MMSE CDR ADAS-Cog PSP Scale Injected dose (MBq) MNI-960-01-01-01 AD 01 63 7 2 53 N/A 340.4 MNI-960-01-01-02 AD 02 70 22 0.5 21 N/A 351.5 MNI-960-01-01-03 PSP 03 75 19 N/A N/A 54 358.9 MNI-960-01-01-04 AD 04 65 26 0.5 11 N/A 340.4 MNI-960-01-01-05 HC 05 51 29 0 6 N/A 347.8 MNI-960-01-01-07 PSP 07 66 26 N/A N/A 38 351.5 MNI-960-01-01-08 HC 08 53 29 0 5 N/A 355.2 MNI-960-01-01-09 AD 09 80 17 0.5 14 N/A 351.5

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Page 1: FIRST IN HUMAN CHARACTERIZATION OF PI-2620, A ... 2017 _PI2620_Seibyl...•PI-2620 binds to both Tau isoforms 3R and 4R and demonstrates high selectivity over beta-amyloid, MAO A and

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HCsubjects:SUVand SUVrHC0551yrs,MMSE29

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OlivierBarret1,JohnSeibyl1,AndrewStephens2,JenniferMadonia1,DavidAlagille1,AndreMueller2,MathiasBerndt2,HeikoKroth3,AndreasMuhs3,AndreaPfeifer3,GillesTamagnan1,Ludger Dinkelborg2,KennethMarek1,1Molecular

Neuroimaging,NewHaven,USA, 2Piramal Imaging,Berlin,Germany, 3 ACImmune,SA,Lausanne,Switzerland

STUDY DESIGN

RESULTS

CONCLUSIONS

BACKGROUND / RATIONALE RESULTS

• Positronemissiontomographymayproveausefultoolfordetectingthepresenceandspatialextentofbraintauaccumulation,akeypathologicfeatureofAlzheimer’sdisease(AD)andothernon-ADtauopathies.Currenttautracerssufferfromsub-optimalkineticsandhighoff-targetbinding,confoundingquantification,aswellasvariableaffinityfortauisoforms,diminishingutilityforevaluatingnon-ADtauopathies likeprogressivesupranuclear palsy(PSP).

• ThenovelPETtautracerPI-2620hasanIC50of1.8nM fortauinADbrainhomogenatecompetition-assaysandbindsspecificallytotaudepositsonADbrainsections(Braak I-VI),Pick’sandPSPpathology.

• PI-2620bindstobothTauisoforms3Rand4Randdemonstrateshighselectivityoverbeta-amyloid,MAOAandMAOB,withverylowoff-targetbinding.

• Invivopreclinicalstudiesshowhighbrainuptakeandfastwash-outinmiceandnon-humanprimate.

Objective:ToextendthesestudiestofirstinhumanevaluationofthetauPETtracerPI-2620(MNI-960)inresearchparticipantswithandwithoutsuspectedtaupathology.

• Inanongoingclinicalstudy,participantsdiagnosedwithmildAlzheimer’s(AD),non-ADtauopathies,andhealthycontrols(HC)underwentdynamicPETimagingforapproximately3hfollowing350MBq bolusinjectionof18F-PI-2620.ADsubjectsandcontrolshadscreeningflorbetaben PETscreeningscanstoconfirmcohort- appropriateamyloidstatus

• Venousbloodwasobtainedtocharacterizethemetabolismofparentcompound.• SUVandSUVrs werecalculatedforbrainregionsderivedfromtheHammerstemplateplacedon

eachspatiallynormalized,greymattersegmentedPETimagevolume.• Inaddition,asinglehumanbiodistribution/dosimetrystudywasperformedinamalecontrolwith

preliminaryestimatesoftargetorganradiationabsorbeddoseandEffectiveDose(ED).

Table1.BaselineCharacteristics

Fig.2aPETintwohealthycontrolsacquired60-90minpostinjectionof350MBq of18F-PI-2620.Notelackofnon-specific,off-targetuptake.SUVtime-activitycurvesshowhighbrainpenetranceandfastwash-outwithsecularequilibriumachievedat50minandpersistingforthenext1.5hinAD,PSP,andcontrols(Fig.2b,c).

• InitialclinicaldatainADsubjectsshowsrobustbrainuptakeandfastwash-outinnon-targetregions.

• Noincreaseduptakewasnotedinchoroidplexus,striatum,amygdala,orotherregionsseeninfirstgenerationtauagents.

• SUVr timecurvessuggestaplateauoccurs60-90minpostinjectionwithresultantSUVrsinabnormalregionsupto2.5-2.8.

• Blooddataconfirmedfastkineticswith20%ofparentcompoundpresentat60min.• Nolipophilicmetaboliteswereobserved.• ADandPSPsubjectsshowexpectedpatternsoftauuptake.• Non-invasivepk modelingindicatesSUVr (60-90min)couldbeagoodproxyforBPnd

pendingfullvalidationofquantitativeoutcomemeasuresusingmetabolitecorrectedarterialinputfunctions.

0.0

SUVr

6.0

Substantianigra

60-90min75yrs,MMSE19,PSPscale 54

Pallidum

0.0

SUVr

5.0

HC05

HC08

60-90minp.i.

SUVR-1andBPND CorrelationinADSubjects

0.0

SUV(g/m

l)

Subject03-01-02(male)

10.0

0-10 66-87 164-210 276-322

min

12mmsmoothingapplied

R L

22-43

Fig.1.Healthycontrolbiodistribution anddosimetry

1. Eliminationisviabothhepatobiliary(mainroute)andurinarypathways.

2. Targetorganswithhighestexposurearegallbladderwallandupperlargeintestine.

3. TheEffectiveDoseper185MBq(5mCi)injectionis4.1mSvwithnoUBvoiding,and4.0mSvwith2hourUBvoidingintervalforadultmale,whichcomparesfavorablytoother18Fradiopharmaceuticals.

Fig.2b,c PETinfourAD(above)andtwoPSP(below)participantsacquired60-90minpostinjectionof350MBq of18F-PI-2620.ThreeoftheADpatientsshowtypicalasymmetricpatternsoftraceruptakeinvolvingtemporallobes,precuneus,andpostcingulate.ThethirdADsubject,verymildclinically,showsnouptake,aphenomenanotedwithAV1451(Pontecorvo,etal,Brain,Jan11,2017).ThePSPsubjects(below)showfocallydiscreteuptakeinsubstantia nigra andpallidum,consistentwithpathologicalreportsintheliterature.

Fig.3PETSUVr forleftcorticalandsubcorticalbrainregionsshowgoodseparationbetweenvisuallydetectedareasofhigheruptakedescribedabove(Fig2)andelevatedSUVrs.

Fig.4CorrelationofSUVrs andBPnddeterminedbynon-invasivePKmodelingsuggests60-90minsmaybestalignwithBPnd.

Fig.5MetabolismofPI-2620shows,similarlyacrosssubjects,rapidkineticswith20%ofparentpresentat60minute(top)andproductionofhydrophilicmetabolites(bottom).Thelatterareunlikelytocrosstheblood-brainbarrier.

#224

Table2.SUVr Measures

ADsubjects:SUVand SUVr

0 50 100 150 2000

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6

Time (min)

SUV

(g/m

L)

PSPsubjects:SUVand SUVr

PSP03

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SU

Vr (c

ereb

ella

r co

rtex

)

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Time (min)

SUV

(g/m

L)

PSP07

FL_OFC_L

FL_OFC_RTL_SupLat_L

TL_SupLat_R

TL_InfLat_L

TL_InfLat_R

TL_Mesial_L

TL_Mesial_R

PL_L

PL_R

OL_L

OL_R

Cing_Ant_L

Cing_Ant_R

Cing_Post_L

Cing_Post_R

CaudateNucl_LCaudateNucl_RPutamen_LPutamen_RCerebellumPallidum_LPallidum_RS_nigra_LS_nigra_R

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)

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rtex)

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SU

Vr

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rtex)

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ADsubject01

MMSE7

ADsubject02

MMSE22

ADsubject04

MMSE26

Cing_Ant_L

Cing_Ant_R

CaudateNucl_L

CaudateNucl_R

Putamen_L

Putamen_R

Pallidum_L

Pallidum_R

S_nigra_L

S_nigra_R

FL_OFC_L

FL_OFC_R

TL_SupLat_L

TL_SupLat_R

TL_InfLat_L

TL_InfLat_R

TL_Mesial_LTL_Mesial_R

PL_LPL_R

OL_LOL_R

Cing_Post_L

Cing_Post_R

Cerebellum

0 50 100 1500

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rtex)

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V (

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L)

ADsubject09

MMSE17

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AD02MMSE22

AD04MMSE26

60-90minp.i.

AD09MMSE17

HC05

HC08

PSP03

PSP07

AD01

AD04

AD02

AD09

FL_OFC_L 1.21 1.30 1.27 1.32 1.60 1.03 1.40 1.50FL_OFC_R 1.19 1.30 1.30 1.37 1.31 1.05 1.33 1.49TL_SupLat_L 1.07 1.03 1.15 1.30 2.01 1.06 2.00 1.36TL_SupLat_R 1.17 1.01 1.17 1.27 1.61 1.08 1.46 1.81TL_InfLat_L 1.06 1.09 1.27 1.23 2.27 1.15 2.27 1.77TL_InfLat_R 1.12 1.07 1.17 1.19 1.70 1.15 1.57 2.10TL_Mesial_L 1.07 1.04 1.27 1.25 1.70 1.15 1.85 1.71TL_Mesial_R 1.20 1.15 1.22 1.34 1.40 1.27 1.23 2.16PL_L 1.07 1.03 1.04 1.25 1.69 0.95 1.53 1.06PL_R 1.11 0.98 1.04 1.20 1.55 0.94 1.21 1.13OL_L 1.17 1.12 1.19 1.38 2.04 1.04 1.36 1.23OL_R 1.22 1.11 1.22 1.41 1.65 1.10 1.29 1.50Cing_Ant_L 0.96 0.88 0.97 1.08 1.05 0.75 1.17 0.89Cing_Ant_R 1.00 0.84 0.85 1.05 0.91 0.88 1.04 0.90Cing_Post_L 0.99 0.88 1.05 1.15 1.64 0.86 1.39 1.07Cing_Post_R 0.95 0.86 0.99 1.17 1.63 0.86 1.26 1.14CaudateNucl_L 0.85 0.64 0.89 0.96 0.88 0.66 0.85 0.67CaudateNucl_R 0.88 0.67 0.85 1.05 0.93 0.54 0.97 0.64Putamen_L 0.93 0.84 1.42 1.19 1.11 0.88 1.32 1.01Putamen_R 1.07 0.73 1.26 1.37 0.92 0.87 1.12 1.03Pallidum_L 1.09 0.83 2.11 1.59 1.12 0.97 1.19 0.96Pallidum_R 1.07 0.74 1.99 1.85 0.94 0.84 1.26 1.00S_nigra_L 1.68 1.15 2.58 2.03 1.16 1.21 1.57 1.54S_nigra_R 1.54 1.05 2.41 1.70 1.04 1.39 1.60 1.08

FL_OFC

TL_SupLat

TL_InfLat

TL_Mes

ial PL OL

Cing_Ant

Cing_Post

0

1

2

3

Left Cortical VOIs

SUVr

(cer

ebel

lar c

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x)

AD Subject 1

PSP Subject 3

HC Subject 5

AD Subject 4

AD Subject 2

PSP Subject 7

HC Subject 8

AD Subject 9

Caudate

Nucl

Putamen

Pallidum

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0 20 40 60 800

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Time (min)

% P

aren

t fra

ctio

n

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PSP Subject 3

HC Subject 5

AD Subject 4

AD Subject 2

HC Subject 8

PSP Subject 7

AD Subject 9

0 20 40 60 800.0

0.5

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PSP Subject 3

HC Subject 5

AD Subject 4

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HC Subject 8

PSP Subject 7

AD Subject 9

FIRSTINHUMANCHARACTERIZATIONOFPI-2620,ANEXTGENERATIONPETTRACERFORASSESSINGTAUINALZHEIMER’SDISEASEANDOTHERTAUOPATHIES

Subject number Cohort Age MMSE CDR ADAS-Cog PSPScale Injecteddose(MBq)

MNI-960-01-01-01 AD01 63 7 2 53 N/A 340.4

MNI-960-01-01-02 AD02 70 22 0.5 21 N/A 351.5

MNI-960-01-01-03 PSP03 75 19 N/A N/A 54 358.9

MNI-960-01-01-04 AD04 65 26 0.5 11 N/A 340.4

MNI-960-01-01-05 HC05 51 29 0 6 N/A 347.8

MNI-960-01-01-07 PSP07 66 26 N/A N/A 38 351.5

MNI-960-01-01-08 HC08 53 29 0 5 N/A 355.2

MNI-960-01-01-09 AD09 80 17 0.5 14 N/A 351.5

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