mri-pdff response (mgl-3196 and placebo treated) predicts ... · in pbo patients with

MRI-PDFFResponse(MGL-3196andPlacebotreated)PredictsReductionsinBallooningandInflammationComponentsofNASandNASHResolutionina36-WeekPhase2SerialLiverBiopsyStudyStephenA.Harrison,OxfordUniversity;MustafaR.Bashir,CenterforAdvancedMagneticResonanceDevelopment,Departmentsof RadiologyandMedicine(Gastroenterology),DukeUniversity;CynthiaGuy,DukeUniversity;RebeccaTaub,MadrigalPharmaceuticals

INTRODUCTION RESULTSMGL-3196 is a liver-directed,orally active, highly selective THR-β agonist which may reduce NASHby increasing hepatic fatmetabolism and normalizing liverfunction (Fig 1). In a 12-wk interimand 36-wk final analysis of theserial liver biopsy study, MGL-3196 treated patients hadreduced liver fat on MRI-PDFFcompared with Placebo (pbo)patients and more MGL-3196(60%) treated than pbo (18%)patients showed at least 30%reduction in hepatic fat (PDFFresponse) (p<0.0001). NASHresolution on liver biopsy at 36Weeks was observed in 39% ofMGL-3196 patients who wereMRI-PDFF responders at Wk 12(P<0.001)1. We assessed whetherresponse and magnitude ofresponse PDFF at Week 12 in pboor MGL-3196 patients predictedALT improvement and histologicresponse on liver biopsy atWeek 36

• InbothMGL-3196andplacebotreatedpatients,MRI-PDFFresponsecorrelatedwithreductioninballooningandinflammationscoresonliverbiopsyandwasstronglyassociatedwithNASHresolution.

• Inpbo,butnotMGL-3196patients,mostoftheresponsewasdrivenbyweightloss.

• ThesedatasupportthecontentionthatreductionofhepaticfatisacriticalcomponentofNASHimprovementandresolution

MGL-3196-05 (NCT02912260) wasa 36-wk multicenter, randomized,double-blind, pbo-controlled serialMRI-PDFF, paired liver biopsy studyin adults with biopsy-confirmedNASH (NAS≥4, F1-F3) and hepaticfat fraction ≥10%, assessed by MRI-PDFF (Fig 2, Table 1). At 36 weeks107 paired liver biopsies, 73 drug-treated, 34 pbo were assessed(Fig 3). NAS component, correlationand responder analyses wereconducted to examine thepredictive power of MRI-PDFFresponse on histologic response ofNAS components and ALT reductionin pbo and MGL-3196 patients.

In MGL-3196 patients, week 12 MRI-PDFF response (>=30% fat reduction) versus non-response predicted NASH resolution at Week 36 (p=0.001. Fig 4-5A, B). MGL-3196 PDFF and/or steatosis responders compared with MGL-3196 non-responders weremore likely to show a reduction in other components of NAS (ballooning, inflammation) (OR 8.86, p=0.0036). In MGL-3196 patients, Week 12 PDFF response correlated with improvement in inflammation and ballooning components of NAS (0.42, Fig6A), and reduction in ALT (0.34). Steatosis grade change underpredicted the MRI-PDFF response (Fig. 6B), particularly in patients with Grade 1 steatosis at baseline. Pbo patients with ≥5% weight loss were likely PDFF responders (71%, p=0.007). In pbopatients PDFF response correlated with weight loss (0.58), which predicted inflammation and ballooning responses (Fig. 7. 0.58). In pbo patients with <3% weight loss, a 1 pt. ballooning reduction was unrelated to any benefit, and not associated withimprovement in steatosis, inflammation, fibrosis or ALT (Fig 8). Steatosis was further assessed by Second Harmonic Generation (qSteatosis), which provides a continuous variable steatosis score, correlated well with pathologist steatosis score (Fig 9A)and MRI-PDFF (Fig 9B), and in the absence of MRI-PDFF assessment, provides a potential opportunity to provide a more accurate assessment of hepatic steatosis and change in steatosis than the pathology steatosis score.

1Hepatology Nov 2018. AASLDLiver Meeting 2018. In a PlaceboControlled 36 Week Phase 2 Trial,Treatment with MGL-3196Compared to Placebo Results inSignificant Reductions in HepaticFat (MRI-PDFF), Liver Enzymes,Fibrosis Biomarkers, AtherogenicLipids, and Improvement in NASHon Serial Liver Biopsy.

CONCLUSIONS

METHODS

DISCLOSURESStephenA.Harrison,OxfordUniversity.ReceivedremunerationfromMadrigalforconsultingservices

MustafaR.Bashir,CenterforAdvancedMagneticResonanceDevelopment,DepartmentsofRadiologyandMedicine(Gastroenterology),DukeUniversity

CynthiaGuy,DukeUniversity

RebeccaTaub,ManagementPosition:MadrigalPharmaceuticals

REFERENCES

Figure 3. Patient Disposition

Figure 7. Effect of >3% Weight Loss on Bx in Placebo PatientsFigure 1. MechanismofAction:TheImportanceofLiverTHR-βinNASH

Figure 2. Phase 2 Study Design

ê LowersLDL-cholesterolê Lowerstriglyceridesê Lowersliverfat,potentially

reducinglipotoxicity,NASH

Nothyrotoxicosis(THR-αeffect)

Inhumans,thyroidhormonereceptor-β(THR-β)agonism:

ExtensionStudy

Screening

MRI-PDFFLiverBiopsy

MRI-PDFFLiverBiopsyMRI-PDFF MRI-PDFFPK

D1 W2 W4 W12 W36 W12 W36ExD136WeekMainStudy

Table 1. Study Patient Baseline Characteristics

Figure 4. MRI-PDFF Responder, MGL-3196 Treated

Patient

Figure 5. Week 36 NASH Resolution Assessed byWeek 12 MRI-PDFF Response

Figure 8. Placebo Patients With <3%Weight Loss

Comparator/Arms

n 2:1MGL-3196toplacebo

n 125patientsenrolledinUSA,18sites

n MGL-3196orplacebo,oral,QD;dose80mg(+/-20mgdoseadjustmentpossibleatWk 4)

Inclusion/Exclusion

n NASHonliverbiopsy:NAS≥4withfibrosisstage1-3

n ≥10%liverfatonMRI-PDFF

n Includesdiabetics,statintherapy,representativeNASHpopulation

Contactinformation Rebecca Taub, M.D., Chief Medical Officer, Executive Vice President R&D. Madrigal Pharmaceuticals. becky@madrigalpharma.com

Baseline Week 12

“MRI-PDFFResponder”=atleast30%reductioninhepaticfat

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Figure 6. MRI-PDFF Week 12 and 36 Relative Change:Correlation with Components of NAS

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BiopsySteatosisScoredoesnotaccuratelyreflectsteatosisimprovementespeciallywhenbaselinesteatosisscore=1

Figure 9. SHG qSteatosis Scoring Correlation to PathologistScoring and Baseline and Week 36 MRI-PDFF

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Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement

in Ballooning and Inflammation on Liver Biopsy

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n Patients who were not MRI-PDFF Responders (≥30% fat reduction) had a low rate of NASH resolution (left panel)

n In both MGL-3196 (correlation coefficient 0.42) (right panel) and placebo (correlation coefficient 0.58) % relative change in MRI-PDFF was correlated with reduction in ballooning plus inflammation scores on liver biopsy (steatosis score removed)

NASH Resolution (%)

MGL-3196-treated

MRI-PDFF Week 12, % Relative Change: Correlation with Change in

Ballooning Plus Inflammation Scores

26.7% 7.4% 4.0%

26.7% 7.4% 4.0%

Placebo(41) MGL-3196(84)Meanage,years(SD) 47.3(11.7) 51.8(10.4)

Male,n(%) 24(58.5) 38(45.2)

White 37(90.2) 79(94.0)

Hispanic/Latino 22(53.7) 37(44.0)

Diabetic,n(%) 13(31.7) 36(42.4)

MeanBMI(SD) 33.6(5.8) 35.8(6.2)

MeanALT 60.1(32.8) 50.0(29.2)

PRO-C3 16.2(8.3) 17.8(10.3)

ELF 9.2(1.0) 9.2(0.88)

MeanLDL-C 116.9(30.0) 111.3(30.4)

MeanTriglycerides(TG) 161.1(75.2) 178.5(82.4)

MeanMRI-PDFF* 19.8(6.7) 20.7(7.0)

MeanNAS 4.8(1.1) 4.9(1.0)

Fibrosisstage**1,n(%) 19(46.3) 47(55.9)

2-3,n(%) 20(48.8) 36(42.8)

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*Patientswithbothbaselineandweek12assessments;**F0placebo=2(4.9);MGL-3196=1(1.2)wereincludedinallanalyses

84assignedtoMGL-3196

41assignedtoplacebo

78withWeek12MRI-PDFF

38withWeek12MRI-PDFF

348screened

125randomized

74withWeek36liverbiopsy

(1inadequate,muscle)

34withWeek36liverbiopsy