NDA 22-231 Terlipressin for the Treatment of HRS Type 1

Cardiovascular and Renal Drugs Advisory Committee July 15, 2020

CC-1 Introduction

Khurram Jamil, MD Khurram Jamil, MD Vice President, Clinical Research in Hepatology Critical Care Division Mallinckrodt

CC-2 Hepatorenal Syndrome Type 1 (HRS-1)

• Rare condition: estimated US incidence ~ 35,000 • Functional renal failure with structurally normal kidney – Portal hypertension leads to splanchnic vasodilation – Compensatory renal vasoconstriction • Occurs in the setting of decompensated cirrhosis – Primary etiologies: NASH, hepatitis C or alcoholic liver disease

NASH=Non-Alcoholic Steato-Hepatitis CC-3 Diagnosis of HRS-1

• Diagnosis of exclusion • Rapid intervention is critical • Requires interdisciplinary approach – Hepatologists – Nephrologists – Intensivists – Transplant surgeons

CC-4 Treatment of HRS-1

• Goals of treatment – Improve renal function – Reverse HRS-1 • Successful treatment – Facilitates medical management of critically ill patient – Allows recovery of patients with reversible component of liver disease – Improves outcomes of patients with liver transplant • No approved treatment for HRS-1 in the US

CC-5 Terlipressin

• A synthetic vasopressin analogue

• V1 receptor selectivity: splanchnic vasculature • Restores effective blood volume and improves renal perfusion • Improves renal function, HRS reversal, clinical outcomes • Approved in EU, Asia, Australia, Africa and Latin America • Recommended for use in combination with albumin1,2

1. Angeli P. et al. J Hepatol. 2015;62(4):968-74. 2. EASL Clinical Practice Guidelines. J Hepatol. 2018;69:406-460 CC-6 Terlipressin Phase 3 Program

OT-0401 Study CONFIRM Study

N=112 N=300

Supportive Additional Data Pivotal

2004 2005 2006 2010 2011 2012 2013 2016 2017 2018 2019

CC-7 Overview of Study Findings

• Demonstrated efficacy – Higher rate of HRS reversal and greater improvement in SCr – Decreased incidence of RRT – Decreased length of ICU stay – Improved outcomes in transplant patients • Manageable safety profile – GI and ischemia events • CONFIRM study: higher rate of respiratory and related sepsis events – Imbalance of deaths on terlipressin driven by these events – Risk management program should reduce events and deaths

SCr=Serum creatinine CC-8 Agenda

Khurram Jamil, MD Introduction Vice President, Clinical Research in Hepatology Critical Care Division, Mallinckrodt Michael P. Curry, MD Pathophysiology of HRS-1 Section Chief of Hepatology and Rationale for Terlipressin Beth Israel Deaconess Medical Center Harvard Medical School Khurram Jamil, MD Efficacy Vice President, Clinical Research in Hepatology Critical Care Division, Mallinckrodt Chris Pappas, MD, JD, FAASLD Safety Clinical Hepatologist Consultant, Mallinckrodt Khurram Jamil, MD Risk Management Vice President, Clinical Research in Hepatology Critical Care Division, Mallinckrodt Arun Sanyal, MD Benefit/Risk and Professor, Department of Internal Medicine Clinical Considerations Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University School of Medicine CC-9 Available for Questions

Professor of Hepatology Kevin Moore, PhD, MBBS Ex Secretary, International Club of Ascites Royal Free Hospital, University College, London Chair Department of Nephrology Juan Carlos Q. Velez, MD Ochsner Clinic Foundation, New Orleans, LA

Shannon Escalante Biostatistics, Mallinckrodt

Rick Fitch, PhD Nonclinical, Mallinckrodt

CC-10 Pathophysiology of HRS-1 and Rationale for Terlipressin

Michael P. Curry, MD Michael P. Curry, MD Section Chief of Hepatology Beth Israel Deaconess Medical Center Harvard Medical School

CC-11 Progression of Liver Disease and Decompensation

Decompensation Ascites Variceal bleed Onset of Encephalopathy Liver chronic liver Diagnosis of Jaundice Transplant disease cirrhosis HRS or Death

Years to decades 5-7% per annum Weeks-months

Compensated Decompensated

CC-12 Common Precipitating Factors of HRS

Bacterial infection

Alcoholic hepatitis Diarrhea HRS

GI blood Over- loss diuresis

CC-13 Renal Failure in Cirrhosis

1.0

0.8 Parenchymal nephropathy

0.6

Hypovolemia

0.4 Infection Probability of Survival of Probability 0.2 HRS

0.0 0 306 09 0 Days

Martín-Llahí et al, Gastroenterology 2010. CC-14 Hepatorenal Syndrome Type 1 (HRS-1)

• Serious acute complication of decompensated cirrhosis • Incidence in the US is 35,000 patients per annum • Potentially reversible functional renal failure – Renal hypoperfusion due to hemodynamic changes • One aspect of complex multi-organ dysfunction

Pant C, et al. J Invest Med. 2016;64(1):33-8. Wong F. Nat Rev Gastroenterol Hepatol. 2012;9:382-91. CC-15 Burden of HRS-1

• Patient – Acute complication of a critical illness – Risk of transplant delisting – Prolonged hospitalization and increased ICU days • Family and caregivers • Healthcare system • Physicians and healthcare team

CC-16 Onset of HRS-1

Advanced Cirrhosis DECREASED

Portal Splanchnic Effective Hypertension Arterial Arterial Blood Vasodilation Volume

Renal Artery

Based on Wong F. Nat Rev Gastroenterol Hepatol. 2012;9:382-91. CC-17 Increased Renal Vasoconstriction

Advanced Cirrhosis DECREASED

Portal Splanchnic Effective Activation of Renal Decreased Hypertension Arterial Arterial Blood Vaso- Vaso- GFR Vasodilation Volume constrictor constriction Factors

Renal Artery

Based on Wong F. Nat Rev Gastroenterol Hepatol. 2012;9:382-91. CC-18 Increased Renal Vasoconstriction: HRS-1

Advanced Cirrhosis DECREASED

Portal Splanchnic Effective Activation of Renal Decreased Hypertension Arterial Arterial Blood Vaso Vaso GFR Vasodilation Volume constrictor constriction Factors

Renal Artery

HRS-1

Based on Wong F. Nat Rev Gastroenterol Hepatol. 2012;9:382-91. CC-19 HRS-1 Treatment Desired Outcomes

Improve renal function Improve clinical outcomes Reverse HRS-1

CC-20 HRS-1 Treatment Desired Outcomes

Less RRT – Improve RRT-free survival Facilitate medical Improve renal function management Improve Potential to return to clinical outcomes compensated state Reverse HRS-1 Shorter ICU stays Liver transplanted patients – Less RRT – Improved survival

CC-21 Liver Transplantation

• Definitive treatment for advanced decompensated cirrhosis • Not available to all patients – Over 12,000 candidates are waiting for liver transplant – Only 8,767 liver transplants were performed in 2019 – Over 1,000 patients died on the waiting list – Over 1,000 were removed from waiting list as “too sick” to transplant

European Association for the Study of the Liver (EASL). J Hepatol. 2018;69(2):406-60. Organ Procurement and Transplantation Network. OPTN Policies updated 03 April 2020. Runyon BA. AASLD. Hepatology. 2013;57(4):1651-3. CC-22 Ways to Treat HRS-1

• Renal replacement therapy (RRT) – Does not restore renal function – Does not improve prognosis – High risk in cirrhotic patients • Albumin – Volume expansion – Anti-inflammatory • Vasoconstrictors – Reduce vasodilation of advanced cirrhosis

Bernardi M, et al. Critical Care. 2012;16:211. Garcia-Martinez R, et al. Hepatology. 2013 Nov;58(5):1836-46. European Association for the Study of the Liver (EASL). J Hepatol. 2018;69(2):406-60. Runyon BA. AASLD. Hepatology. 2013;57(4):1651-3. CC-23 Outcomes of RRT in Patients with Cirrhosis

• Study of cirrhotics admitted to ICU – ~50% of patients required mechanical ventilation and vasopressors – ~40% of patients required RRT • 28 day mortality of 83% • Only 13% had spontaneous renal recovery after ICU discharge • RRT in cirrhotics is associated with greater morbidity and worse outcomes

Staufer K, et al. Liver Int. 2017;37:843-850. CC-24 Vasoconstrictors Used for HRS-1

• Terlipressin – Most clinical trial evidence; not available in US • Midodrine and octreotide – Used despite limited evidence • Norepinephrine – Used despite limited evidence; administered in ICU setting

CC-25 Vasoconstrictors Available in US vs. Terlipressin

Midodrine and Octreotide (n=49) Norepinephrine (n=120)

Terlipressin Midodrine and Octreotide Terlipressin Norepinephrine

p<0.001 p=0.004

60 55.5% 60

50 50

40.0% 40 40

30 30

HRS Reversal HRS Reversal (%) 20 HRS Reversal (%) 20 16.7%

10 10 4.8% N=27 0 0

Cavallin M, et al. Hepatology 2015;62:567–574 Arora V, et al. Hepatology 2020;71:600-610 CC-26 Guidelines Referencing Terlipressin as Preferred Therapy

Consensus Recommendations European Association for the of the International Study of the Liver (EASL) Club of Ascites Clinical Practice Guidelines

• Terlipressin and albumin are • Terlipressin plus albumin as the most investigated and effective first-line therapy for treatment treatment for HRS-1 of HRS-AKI • Terlipressin dose: IV boluses of 1 mg every 4-6 hours

Angeli P, et al. J Hepatol 2015;62:968-74. European Association for the Study of the Liver (EASL). J Hepatol. 2018;69(2):406-60. CC-27 Terlipressin

• Synthetic vasopressin analogue

– Prodrug for lysine-vasopressin (LVP); 1% of its V1 activity – LVP slowly released via tissue peptidase metabolism – Slow release is advantage over vasopressin

–T½ ≈ 50 minutes (LVP T½ ≈ 3 hrs) • Administered IV – Typical treatment period is 6 days (up to 14 days)

CC-28 Terlipressin – V1 Dominant Effects in HRS-1

• V1 receptor (vascular smooth muscle) – Vasoconstriction – Increases mean arterial pressure – Reduces portal inflow and portal pressure

• V2 receptor (renal tubules) – Antidiuretic effect

CC-29 MOA of Terlipressin: Splanchnic Vasoconstriction

Terlipressin

Advanced Cirrhosis DECREASED DECREASED INCREASED X X Portal Splanchnic Effective Activation of Renal Decreased Hypertension Arterial Arterial Blood Vaso- Vaso- GFR Vasodilation Volume constrictor constriction Factors

HRS-1

Based on Wong F. Nat Rev Gastroenterol Hepatol. 2012;9:382-91. CC-30 MOA of Terlipressin: Improve Renal Perfusion

Terlipressin

Advanced Cirrhosis DECREASED DECREASED INCREASED DECREASED DECREASED X X X X X Portal Splanchnic Effective Activation of Renal Decreased Hypertension Arterial Arterial Blood Vaso Vaso GFR Vasodilation Volume constrictor constriction Factors

HRS Reversal HRS-1

Based on Wong F. Nat Rev Gastroenterol Hepatol. 2012;9:382-91. CC-31 CONFIRM Study Case: 48-Year-Old Male With Cirrhosis

48-year-old male with alcoholic cirrhosis, alcoholic hepatitis, 5.0 ascites, pneumonia and acute kidney injury

4.0

CONFIRM site admission 3.0

1st Hospital 2.0 Admission

Midodrine 1.0 Serum Creatinine Creatinine Serum (mg/dL) Administered

0.0 -12-11 -10 -9 -8-7-6-5-4-3 -2-1 0 Day

Daily Albumin (gm): 50 75 25 100 CC-32 CONFIRM Study Case: 48-Year-Old Male With Cirrhosis

48-year-old male with alcoholic cirrhosis, alcoholic hepatitis, 5.0 ascites, pneumonia and acute kidney injury

Terlipressin 4.0 1 mg q 6h START

CONFIRM site admission 3.0

SCr at Day 1st Hospital Verified HRS Reversal 2.0 with SCr of 1.1 mg/dL 30 follow-up Admission of 0.8 mg/dL

Midodrine 1.0 Serum Creatinine Creatinine Serum (mg/dL) Administered Terlipressin 1 mg q 6h END 0.0 -12-11 -10 -9 -8-7-6-5-4-3 -2-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 30 Day

Daily Albumin (gm): 50 75 25 100 50 50 50 50 50 50 50 50 50 50 CC-33 Conclusions

• HRS-1 is a rare life-threatening complication of decompensated cirrhosis • No approved treatment for HRS-1 in US – Physicians unable to treat a potentially reversible condition • Unmet need to improve kidney function and reverse HRS-1 – Facilitate medical management – Improve renal function and transplant outcomes

CC-34 Efficacy

Khurram Jamil, MD Khurram Jamil, MD Vice President, Clinical Research in Hepatology Critical Care Division Mallinckrodt

CC-35 Terlipressin Phase 3 Program

OT-0401 Study1 3 CONFIRM Study2

N=112 N=300

Supportive Additional Data Pivotal

2004 2005 2006 2010 2011 2012 2013 2016 2017 2018 2019

CC-36 Three Randomized Controlled Trials

• Similar designs – Small differences from evolving knowledge • Similar populations – Subjects with cirrhosis, ascites and HRS-1 • Similar treatment regimens – 1-2 mg IV every 6 hours – Albumin was strongly recommended per treatment guidelines

CC-37 CONFIRM Study Design

Active Study Follow-up Period Period Pre-study Period Terlipressin (N=199)

R 2:1 Placebo (N=101) Albumin Fluid Challenge ≥2 Days

Day 4 Day Day Day Day Dose Decision ≤14 30 60 90

CC-38 Primary Efficacy Endpoints Phase 3 Studies of Terlipressin

OT-0401 Study Sep 2004 – Aug 2006 Treatment Success at Day 14 Endpoint Alive with HRS reversal

SCr SCr ≤1.5 mg/dL Requirements ≥2 values

SCr 48 ± 8 hours apart Timing

Clinical Without dialysis or HRS recurrence Requirements (SCr value at Day 14 <2.5 mg/dL)

Note: Up to Day 14 or discharge CC-39 Primary Efficacy Endpoints Phase 3 Studies of Terlipressin

OT-0401 Study • Original analysis Sep 2004 – Aug 2006 – Double rate of success but not statistically significant Treatment Success at Day 14 – Logistical issues collecting data required for primary endpoint Endpoint Alive with HRS reversal • E.g. required Day 14 SCr difficult to collect in subjects discharged prior to Day 14 SCr SCr ≤1.5 mg/dL • FDA agreed to collection of additional post treatment SCr data Requirements ≥2 values – From existing medical records for all subjects – Predefined threshold of SCr improvement SCr 48 ± 8 hours apart Timing • Reanalysis – Two additional terlipressin subjects with treatment success Clinical Without dialysis or HRS recurrence – No additional on placebo Requirements (SCr value at Day 14 <2.5 mg/dL) • Agency accepted as confirmatory evidence of efficacy – Complete response letter required one more study at p<0.05 – Pivotal CONFIRM study meets this requirement

Note: Up to Day 14 or discharge CC-40 Primary Efficacy Endpoints Phase 3 Studies of Terlipressin

OT-0401 Study REVERSE Study Sep 2004 – Aug 2006 Oct 2010 – May 2013 Treatment Success at Day 14 Confirmed Endpoint Alive with HRS reversal HRS reversal

SCr SCr ≤1.5 mg/dL SCr of ≤1.5 mg/dL Requirements ≥2 values 2 values

SCr 48 ± 8 hours apart At least 48 hours apart1 Timing

Clinical Without dialysis or HRS recurrence N/A Requirements (SCr value at Day 14 <2.5 mg/dL)

1. 22 hours apart if subject has transplant or discharge

Note: Up to Day 14 or discharge CC-41 Primary Efficacy Endpoints Phase 3 Studies of Terlipressin

OT-0401 Study REVERSE Study CONFIRM Study Sep 2004 – Aug 2006 Oct 2010 – May 2013 Jul 2016 – Jul 2019 Treatment Success at Day 14 Confirmed Verified Endpoint Alive with HRS reversal HRS reversal HRS reversal

SCr SCr ≤1.5 mg/dL SCr of ≤1.5 mg/dL SCr ≤1.5 mg/dL Requirements ≥2 values 2 values 2 consecutive values

SCr At least 2 hours apart, on 48 ± 8 hours apart At least 48 hours apart1 Timing treatment2

Clinical Without dialysis or HRS recurrence N/A Alive without RRT ≥10 days Requirements (SCr value at Day 14 <2.5 mg/dL)

1. 22 hours apart if subject has transplant or discharge 2. On treatment defined as up to 24 hours after the final dose of study drug; SCr values after RRT, TIPS, liver transplant, or open-label vasopressor use were excluded from primary endpoint analysis Note: Up to Day 14 or discharge CC-42 Demographics and Baseline Characteristics CONFIRM Study

Terlipressin Placebo Parameter N=199 N=101 Age, mean (SD), years 54.0 (11.3) 53.6 (11.8) Sex, % Male 60.3 58.4 Alcoholic hepatitis present, % 40.7 38.6 Serum creatinine, mg/dL Mean (SD) 3.5 (1.0) 3.5 (1.1) Minimum, maximum 2.3, 6.9 2.1, 6.2 SIRS, % 42.2 47.5 MELD score, mean (SD) 32.7 (6.6)1 33.1 (6.2)2 Baseline ACLF Grade 3, % 20.1 17.8 Bilirubin, mean (SD), mg/dL 13.0 (13.4)3 15.2 (15.8)4 CLIF-SOFA score, mean (SD) 10.4 (2.4)5 10.8 (2.5)6

1. n=177; 2. n=88; 3 n=188; 4 n=99; 5. n=107; 6. n=58 CLIF-SOFA, chronic liver failure-sequential organ failure assessment; MELD, model for end-stage liver disease; SIRS, systemic inflammatory response syndrome; ACLF, Acute on Chronic Liver Failure CC-43 Primary Endpoint: Verified HRS Reversal CONFIRM Study

Terlipressin (N=199) Placebo (N=101)

p=0.012 50

29.1% 30

20 15.8%

10 n=44 Verified HRS Reversal (%) (%) Reversal HRS Verified

n=58 n=16 0

Z score=2.52618 CC-44 Secondary Endpoints CONFIRM Study

Endpoint Definition

Subjects with a SCr value ≤1.5 mg/dL while HRS Reversal receiving treatment by Day 14 or discharge

Percentage of subjects with HRS reversal Durability of HRS Reversal without RRT to Day 30

Incidence of HRS Reversal in the Systemic Percentage of SIRS subjects Inflammatory Response Syndrome (SIRS) Subgroup with HRS reversal

Incidence of Verified HRS Reversal Without Recurrence No recurrence of HRS by Day 30

CC-45 Secondary Endpoint Results CONFIRM Study (ITT Population)

Terlipressin Placebo n=199 N=101 % % P-value1

HRS Reversal (SCr ≤1.5) 36.2 16.8 <0.001

Durability of HRS Reversal (No RRT for 30 days) 31.7 15.8 0.003

HRS Reversal in the SIRS Subgroup 33.3 6.3 <0.001

Verified HRS Reversal With No Recurrence of HRS by Day 30 24.1 15.8 0.092

1. From a CMH Test stratified by qualifying SCr (<3.4 vs ≥3.4 mg/dL) and prior LVP within 14 days of randomization (at least one single event of ≥4 vs <4 L). CC-46 Pre-specified Renal Function Endpoints

• Change in renal function (SCr) from baseline through end of treatment as repeated measure analysis

• Incidence of greater than 30% improvement in SCr • Change from baseline through the end of treatment in creatinine clearance (CrCl)

• Full response and partial response as per ICA Guidelines

ICA, International Club of Ascites CC-47 Change in Serum Creatinine, Baseline Through Day 14 CONFIRM Study – Repeated Measures Analysis (ITT Population)

1.0 Terlipressin Placebo

0.5

0.0

-0.5

-1.0 p<0.001

-1.5

-2.0

-2.5

LS Mean Change from Baseline (±SE) from Baseline Mean Change LS -3.0 12 3 45 67 8 91011 12 13 14 Day

p-value is nominal CC-48 Incidence of RRT in Subjects Alive Through Day 90 CONFIRM Study (ITT Population)

Terlipressin Placebo 100 p=0.006 p=0.027 p=0.027 p=0.051 90 80 70 60 50 46.7% 46.4% 43.1% 39.0% 40 28.6% 30.3% 30 26.4% 21.9%

% Subjects with RRT Visit Visit RRT with Subjects % 20 10 n=32 n=30 n=32 n=28 n=30 n=28 n=30 n=26 0 Through Day 14 Through Day 30 Through Day 60 Through Day 90

p-values are nominal p-values from a Cochran-Mantel-Haenszel (CMH) Test stratified by qualifying serum creatinine (<3.4 vs ≥3.4 mg/dL) and prior large volume paracentesis (LVP) within 14 days of randomization (at least one single event of ≥4 vs <4 L). CC-49 RRT-free Survival up to Day 90 CONFIRM Study (ITT Population)

Terlipressin Placebo

1.0 0.9 0.8 0.7 0.6 0.5 0.4 p=0.084 0.3 0.2

Survival Distribution Survival Distribution Function 0.1 0.0 0 14 306 09 0 Survival (Days)

Nominal p-value based on two-sample log rank test stratified by qualifying SCr (< 3.4 vs ≥ 3.4 mg/dL) and prior large volume paracentesis (LVP) within 14 days of randomization (at least one single event of ≥ 4vs <4 L). CC-50 Incidence of RRT Post Liver Transplant CONFIRM Study (ITT Population)

Terlipressin (N=46) Placebo (N=29)

50 44.8%

19.6% 20

10 n=44

n=9 n=13 0 Subjects with RRT After Transplant (%) (%) After Transplant withSubjects RRT

CC-51 Intensive Care Unit Length of Stay CONFIRM Study (ITT Population)

14 13.2

8 6.4 6 Mean, days 4

2 n=44 n=31 n=14 0 Terlipressin (N=199) Placebo (N=101)

ICU admission, % 15.6 13.9 Time from ICU admission to death 12.2 13.0 (days), mean

CC-52 Outcomes for Subjects Admitted to ICU CONFIRM Study (ITT Population)

Subjects with ICU Admission Terlipressin Placebo N=31 N=14 % %

Alive without RRT or Transplant at Day 14 29.0 7.1

Alive without RRT or Transplant at Day 30 12.9 0.0

Weil et al. Ann. Intensive Care (2017) 7:33 CC-53 Primary Endpoint Results OT-0401 and REVERSE Studies

OT-0401 Study REVERSE Study Treatment Success at Day 14 Confirmed HRS Reversal

Terlipressin (N=56) Placebo (N=56) Terlipressin (N=97) Placebo (N=99)

50 50 p=0.037 p=0.2214

40 40

30 28.6% 30

19.6% 20 20 12.5% 13.1% 10 10

n=13n=16 n=7 n=19 n=15n=13

Treatment Success at Day 14 (%) at Day Success 14 (%) Treatment 0 Confirmed HRS Reversal (%) 0

CC-54 Outcomes In Pooled Analyses

CC-55 Durability of HRS Reversal CONFIRM, OT-0401, REVERSE Studies, and Pooled Population (ITT Population)

Terlipressin Placebo

33.2 32.1 30.1 30 22.7 20 17.8 15.2 14.3 13.1

10 Durability of HRS Reversal (%) (%) Reversal HRS of Durability 66/199 18/101 18/56 8/56 22/97 13/99 106/352 39/256 0 CONFIRM OT-0401 REVERSE Pooled

CC-56 Incidence of RRT in Subjects Alive Through Day 90 Pooled ITT Population

Terlipressin Placebo

100

44.8% 45.1% 42.2% 40 28.6% 25.7% 26.9%

Subjects with RRT (%) RRT (%) withSubjects 20

n=56 n=70 n=52 n=64 n=52 n=60 0 Through Day 30 Through Day 60 Through Day 90

Note: REVERSE only captures yes/no if there was an RRT by these follow up days. This information is used instead of the study day. CC-57 Incidence of RRT Through Day 90 for Transplanted Subjects Pooled ITT Population

Terlipressin (N=94) Placebo (N=78)

100

60.3% 61.5% 60 55.1%

40.4% 42.6% 40 36.2%

Subjects with RRT (%) RRT (%) withSubjects 20

n=34 n=43 n=38 n=47 n=40 n=48 0 Through Day 30 Through Day 60 Through Day 90

Note: For OT-0401 and CONFIRM, dates/times were used to determine 30, 60, and 90 days. For REVERSE, RRT was recorded at the visits for days 30, 60, and 90 without an RRT date CC-58 Survival of Transplanted Subjects Through Day 90 Pooled ITT Population

Terlipressin Placebo

1.0

0.9 p=0.0141 0.8

0.7

0.6

0.5

0.4

0.3 Terlipressin Placebo N=94 N=78 0.2 Alive at Day 90, % 98.9 91.0 Survival Distribution Survival Distribution Function 0.1

0.0 0 14 306 09 0 Survival (Days)

1. The p-value comparing the survival estimates is from a two-sample log-rank test. Lee et al., US trends for transplant outcomes. JAMA internal medicine 2019 CC-59 Terlipressin Efficacy Conclusions

• Positive pivotal and supportive Phase 3 study results – Higher rate of HRS Reversal and greater reduction in SCr • Improved clinical outcomes – Decreased incidence of RRT – Improved RRT-free survival – Shorter ICU stays • Clinical benefit in transplant subjects – Decreased incidence of RRT post transplant – Improved survival in transplant recipients

CC-60 Safety

Chris Pappas, MD Chris Pappas, MD Clinical Hepatologist Consultant, Mallinckrodt

CC-61 Subject Distribution Across Studies

Terlipressin Placebo N N

Overall number of subjects (pooled) 349 249

CONFIRM study 200 99

OT-0401 study 56 55

REVERSE study 93 95

CC-62 Summary of Exposure to Treatment Integrated Studies (Safety Population)

Terlipressin Placebo Parameter N=349 N=249 Daily exposure (mg/day)

Mean (SD) 3.6 (1.39) 3.8 (1.46)

Duration1,2 (days)

Mean (SD) 6.2 (4.39) 6.0 (3.86)

Min, max 1.0, 25.0 1.0, 19.0

1. For retreated subjects, data are combined from initial and retreatment periods. 2. Includes number of days the subject received ≥1 dose of study drug. CC-63 Overview of Adverse Event Profile Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 Safety Parameter1 % % AEs up to 7 days post-treatment 91.1 90.4

SAEs up to 30 days post-treatment 65.0 59.8

Permanent withdrawals due to adverse events 13.5 5.2

Gastrointestinal disorders 4.6 1.2

Ischemia-related AEs 3.7 0.4

Respiratory disorders 3.4 0.8

Other 1.8 2.8

1. Subjects with multiple AEs of one preferred term are counted once. CC-64 Deaths Due to Adverse Events Integrated and Individual Studies (Safety Population)

CONFIRM OT-0401 REVERSE Integrated Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo N=200 N=99 N=56 N=55 N=93 N=95 N=349 N=249 % % % % % % % %

Deaths up to 30 days 41.5 40.4 48.2 49.1 37.6 35.8 41.5 40.6 post-treatment

AEs leading to death up to 90 days from the 51.0 44.4 48.2 50.9 43.0 45.3 48.4 46.2 start of study treatment

CC-65 Adverse Events (≥5%) Leading to Death up to 30 Days Post-treatment Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 % % Total with AE leading to death 41.5 40.6

Chronic hepatic failure + hepatic failure 11.7 14.9

Respiratory failure + acute respiratory failure 7.7 2.0

Multiple organ dysfunction syndrome 6.3 3.2

Sepsis + septic shock + urosepsis 5.7 1.6

CC-66 Most Common Adverse Events (≥10%) Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 Preferred Term1,2 % % Abdominal pain 21.5 12.4

Nausea 15.2 12.0

Diarrhea 14.9 5.6

Dyspnea 12.0 6.0

Hypotension 11.7 7.6

Vomiting 10.3 6.4

Hepatic encephalopathy 8.6 11.2

1. Up to 7 days after the end of treatment 2. Subjects with multiple AEs of one preferred term are counted once CC-67 Adverse Events Occurring at ≥5% Higher Incidence Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 Preferred Term1,2 % % Abdominal pain 21.5 12.4

Diarrhea 14.9 5.6

Dyspnea 12.0 6.0

Bradycardia 6.3 0.8

1. Up to 7 days after the end of treatment 2. Subjects with multiple AEs of one preferred term are counted once CC-68 Most Common Serious Adverse Events (≥5%) Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 Preferred Term1,2 % % Total with any SAEs 65.0 59.8

Respiratory failure 8.3 2.4

Multiple organ dysfunction syndrome 7.4 3.2

Chronic hepatic failure 6.0 6.0

Hepatic failure 6.0 9.2

Sepsis 5.2 1.6

1. Up to 30 days posttreatment. 2. Subjects with multiple AEs of one preferred term are counted once. CC-69 Most Common Serious Adverse Events (≥5%) Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 Preferred Term1,2 % % Total with any SAEs 65.0 59.8

Respiratory failure 8.3 2.4

Multiple organ dysfunction syndrome 7.4 3.2

Chronic hepatic failure 6.0 6.0

Hepatic failure 6.0 9.2

Sepsis 5.2 1.6

1. Up to 30 days posttreatment. 2. Subjects with multiple AEs of one preferred term are counted once. CC-70 Cardiopulmonary Complications of Decompensated Cirrhosis

• Fluid overload • Cirrhotic cardiomyopathy • Intrapulmonary shunting • Porto-pulmonary hypertension • Ascites leading to pleural effusions • Increased aspiration risk

CC-71 Respiratory Failure SAEs and Deaths Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 % % Serious adverse events

Respiratory failure 11.2 4.4

Respiratory failure 8.3 2.4

Acute respiratory failure 3.2 2.0

AEs leading to death

Respiratory failure 7.7 2.0

Respiratory failure 5.4 1.2

Acute respiratory failure 2.3 0.8

CC-72 Respiratory Failure and Acute Respiratory Failure AEs and Deaths CONFIRM, OT-0401, REVERSE, and Integrated Studies (Safety Population)

OT-0401 (2004 – 2006) REVERSE (2010 – 2013) CONFIRM (2016 – 2019) Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo N=56 N=55 N=93 N=95 N=200 N=99 Preferred Term1,2 % % % % % % SAE

Respiratory failure 5.4 3.6 6.5 1.1 10.0 3.0

Acute respiratory failure 0 0 3.2 3.2 4.0 2.0

AE leading to death

Respiratory failure 3.6 3.6 5.4 1.1 6.0 0

Acute respiratory failure 0 0 2.2 1.1 3.0 1.0

1. Up to 30 days posttreatment 2. Subjects with multiple AEs of one preferred term are counted onc. CC-73 Albumin Use in Clinical Practice

• Increased use in clinical practice during development program – CONFIRM > REVERSE > OT-0401 • Changes in guidelines before REVERSE study – ICA 2007 • Increased use prior to CONFIRM study – Literature supported higher use • Bernardi et al, 2012; Garcia-Martinez et al, 2013; Chasou et al, 2016

CC-74 Prior Albumin Exposure CONFIRM, OT-0401, and REVERSE Studies

OT-0401Study REVERSE Study CONFIRM Study Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo N=56 N=56 N=97 N=99 N=199 N=101

Overall subjects exposed 64.3% 80.0% 100.0% 100.0% 99.0% 99.0% to prior albumin (%)

Mean total prior - - 243.2 218.1 335.0 370.7 albumin exposure (g)

CC-75 Fluid Management Pre/Post DSMB Meeting CONFIRM Study

Before DSMB Meeting After DSMB Meeting Terlipressin Placebo Terlipressin Placebo N=87 N=44 N=112 N=57 % % % %

Concomitant diuretics 23.0 15.9 27.7 10.5

Subjects receiving concomitant albumin 83.9 95.5 82.1 87.7

Subjects receiving >662.5 g 26.4 31.8 18.8 24.6 of cumulative albumin

CC-76 Respiratory Failure Deaths Pre/Post DSMB Meeting CONFIRM Study

Before DSMB Meeting After DSMB Meeting Terlipressin Placebo Terlipressin Placebo N=87 N=43 N=113 N=56 % % % %

Acute respiratory failure 11.5 0 7.1 1.8 or respiratory failure AE

Acute respiratory failure AE 4.6 0 1.8 1.8

Respiratory failure AE 6.9 0 5.3 0

Note: Subjects experiencing multiple episodes of a given adverse event are counted once within each preferred term and within each system organ class. CC-77 Incidence of Respiratory Failure SAEs by Total Prior Albumin Exposure Safety Population

Terlipressin Placebo Total Prior Albumin Exposure N % N % RD (95% CI)

Overall respiratory failures SAEs 349 12.6 249 7.6 5.0 (0.2, 9.8)

Albumin <175 g 55 10.9 58 10.3 0.6 (-11.0, 11.9)

Albumin 175 g to <300 g 90 12.2 51 7.8 4.4 (-5.6, 14.4)

Albumin 300 g to <423 g 85 12.9 53 5.7 7.3 (-2.2, 16.7)

Albumin ≥423 g 79 16.5 52 7.7 8.8 (-2.2, 19.7)

CC-78 Respiratory Effects with Terlipressin Treatment

• Increases cardiac afterload, effective circulating volume, preload • Perturbs the perfusion/ventilation relationships in lung • Increased risk of respiratory events in subjects with – Advanced liver disease, particularly ACLF grade 3 – Cardiorespiratory events – Upper GI hemorrhage – Increased hepatic encephalopathy

CC-79 Selected SAEs by ACLF Grade (≥5% Incidence in Terlipressin ACLF3 Group) CONFIRM Study (Safety Population)

Baseline ACLF Grade 0-2 Baseline ACLF Grade 3 Terlipressin Placebo Terlipressin Placebo N=160 N=81 N=40 N=18 % % % % Overall 61.3 59.3 80.0 66.7 Respiratory failure 6.3 3.7 25.0 0 Multiple organ dysfunction syndrome 3.1 2.5 10.0 5.6 Abdominal pain 4.4 1.2 7.5 0 Hepatic failure 3.8 6.2 7.5 27.8 Sepsis 3.8 0 7.5 0 Gastrointestinal hemorrhage 3.1 0 7.5 0 Hepatic cirrhosis 1.9 2.5 7.5 0 Chronic hepatic failure 4.4 8.6 5.0 5.6 Acute respiratory failure 3.8 2.5 5.0 0 Shock 1.9 2.5 5.0 5.6 Cirrhosis alcoholic 1.3 1.2 5.0 11.1

CC-80 Selected AEs Leading to Death by ACLF Grade (≥5% Incidence in Terlipressin ACLF3 Group) CONFIRM Study (Safety Population)

Baseline ACLF Grade 0-2 Baseline ACLF Grade 3 Terlipressin Placebo Terlipressin Placebo N=160 N=81 N=40 N=18 % % % % Overall 45.6 43.2 72.5 50.0 Respiratory failure 3.1 0 17.5 0 Multiple organ dysfunction syndrome 4.4 4.9 10.0 5.6 Chronic hepatic failure 6.9 8.6 7.5 5.6 Hepatic failure 5.0 6.2 7.5 22.2 Hepatic cirrhosis 3.1 2.5 7.5 0 Sepsis 1.3 0 7.5 0 Acute respiratory failure 2.5 1.2 5.0 0 Cirrhosis alcoholic 1.9 1.2 5.0 11.1

CC-81 Infections and Infestations SOC Adverse Events Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 % %

Infections and infestations 26.1 21.3

CC-82 Sepsis Adverse Events and Deaths Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 % % AEs1 Combined sepsis 9.7 4.0 Sepsis 6.3 3.2 Septic shock 2.9 1.2 Urosepsis 0.6 0.0 AEs leading to death1 Combined sepsis 5.7 1.6 Sepsis 3.4 1.2 Septic shock 2.3 0.4 Urosepsis 0.0 0.0

1. Subjects reporting >1 AE are counted only once by the first AE reported. CC-83 Terlipressin Subjects with Sepsis AE Integrated Studies (Safety Population) Subjects

0 4 8 12 16 20 24 28 32 36 40 44 48 Days on Study Drug

Sepsis AE includes abdominal sepsis, enterococcal sepsis, klebsiella sepsis, septic shock, sepsis syndrome, sepsis, and urosepsis CC-84 Terlipressin Subjects with Sepsis AE Integrated Studies (Safety Population)

Day of death Subjects

0 4 8 12 16 20 24 28 32 36 40 44 48 55 65 75 Days on Study Drug

Sepsis AE includes abdominal sepsis, enterococcal sepsis, klebsiella sepsis, septic shock, sepsis syndrome, sepsis, and urosepsis CC-85 Terlipressin Subjects with Sepsis AE Integrated Studies (Safety Population)

Day of death Event during/within 7 days of the end of treatment Subjects

0 4 8 12 16 20 24 28 32 36 40 44 48 55 65 75 Days on Study Drug

Sepsis AE includes abdominal sepsis, enterococcal sepsis, klebsiella sepsis, septic shock, sepsis syndrome, sepsis, and urosepsis CC-86 Terlipressin Subjects with Sepsis AE Integrated Studies (Safety Population)

Day of death Event during/within 7 days of the end of treatment Event >7 days after of the end of treatment Subjects

0 4 8 12 16 20 24 28 32 36 40 44 48 55 65 75 Days on Study Drug

Sepsis AE includes abdominal sepsis, enterococcal sepsis, klebsiella sepsis, septic shock, sepsis syndrome, sepsis, and urosepsis CC-87 Early Sepsis AEs in Terlipressin Subjects and Associated Respiratory AEs Integrated Studies (Safety Population)

Respiratory Event Sepsis Event Subjects

04 81 216 Days on Study Drug

CC-88 Summary of Multi-organ Dysfunction Syndrome Events Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 % %

AEs up to 7 days post-treatment 5.4 3.2

Deaths up to 30 days post-treatment 6.3 3.2

CC-89 Multiple-organ Dysfunction Syndrome Definition

• Over 50% of subjects with MODS had MODS at Baseline – Did not appear to worsen • Evaluation of REVERSE study data – Objective definition for an AE of MODS in this subject population • Investigators used CLIF-SOFA scores and ACLF grades – Well-validated scoring systems – Used to capture MODS AEs in CONFIRM

CC-90 Multiple-organ Dysfunction Syndrome CONFIRM, OT-0401, and REVERSE Studies

CONFIRM Study OT-0401 Study REVERSE Study

Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo N=200 N=99 N=56 N=55 N=93 N=95 % % % % % %

AEs 2.5 3.0 7.1 0.0 10.8 5.3

SAEs 4.5 3.0 8.9 0.0 12.9 5.3

Deaths up to 30 days post-treatment 4.5 3.0 8.9 0.0 8.6 5.3

CC-91 Most Common Ischemic AEs with Onset ≤24 Hours After Last Dose Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 Preferred Term1,2 % % Ischemic AEs up to 24 hours after dose 7.2 0.4

Skin discoloration 1.7 0.0

Cyanosis 1.4 0.0

Intestinal ischemia 1.1 0.0

Withdrawals due to ischemia-related AEs 3.7 0.4

Deaths due to ischemia-related AEs 0.0 0.0

Events of skin necrosis 0.0 0.0

1. Subjects were counted only if study drug was received that day. 2. Subjects with multiple AEs of one preferred term are counted once. CC-92 Serious Ischemic-related Adverse Events Integrated Studies (Safety Population)

Terlipressin Placebo N=349 N=249 % % Total subjects with SAEs1,2 2.9 0.4 Intestinal ischemia 1.1 0.0 Vascular skin disorder 0.6 0.0 Cyanosis 0.3 0.0 Livedo reticularis 0.3 0.0 Myocardial infarction 0.3 0.0 Poor peripheral circulation 0.3 0.0 Myocardial ischemia 0.0 0.4 Deaths 0.0 0.0

1. Up to 30 days posttreatment 2. Subjects with multiple AEs of one preferred term are counted once. CC-93 Ischemic Events

• Incidence of ischemic events on terlipressin – Integrated Phase 3 studies: 7.2% – Literature: 4-13% • Manageable with dose interruption – Followed by dose reduction or permanent discontinuation

CC-94 Gastrointestinal Bleeding Events CONFIRM (Safety Population)

Terlipressin Placebo N=200 N=99 % %

Gastrointestinal disorders 15.0 6.1

Gastrointestinal hemorrhage 4.0 0

Esophageal varices hemorrhage 1.5 2.0

Upper gastrointestinal hemorrhage 1.5 2.0

CC-95 Safety Conclusions

• AEs are generally predictable, recognizable, and manageable • Rates of AEs were high in both treatment groups • Type and severity were consistent with terlipressin and with decompensated cirrhosis • Respiratory failure was more common in subjects with ACLF Grade 3 and respiratory compromise • Detect and treat infection early • Ischemia manageable with prompt treatment interruption • Supports use in HRS-1

CC-96 Risk Management

Khurram Jamil, MD Khurram Jamil, MD Vice President, Clinical Research in Hepatology Critical Care Division Mallinckrodt

CC-97 Risk Management Overview

• Selection of appropriate patients • Respiratory failure minimization • Expected impact • Risk management tools

CC-98 Selection of Appropriate Patients

• Use in patients with SCr <5 and ACLF 0-2 • Patients with SCr ≥51 or ACLF 3 – Lower rate of HRS Reversal – Higher rate of serious adverse events – Higher mortality

1. Highest grade of kidney failure within the Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) score CC-99 Mortality With Baseline ACLF 0-2 and 3 Integrated Studies (ITT Population)

Baseline ACLF 3 Baseline ACLF 0-2 Terlipressin Placebo Terlipressin Placebo N=72 N=49 N=280 N=206 % % % %

Death by Day 14 47.2 38.8 19.3 20.4

Death by Day 90 66.7 53.1 43.6 46.6

CC-100 Mortality With Baseline ACLF 0-2 and 3 Integrated Studies (ITT Population)

Baseline ACLF 3 Baseline ACLF 0-2 Terlipressin Placebo Terlipressin Placebo N=72 N=49 N=280 N=206 % % % %

Death by Day 14 47.2 38.8 19.3 20.4

Death by Day 90 66.7 53.1 43.6 46.6

CC-101 Mortality With Baseline SCr ≥5 and <5 Integrated Studies (ITT Population)

Baseline SCr ≥5 mg/dL Baseline SCr <5 mg/dL Terlipressin Placebo Terlipressin Placebo N=44 N=33 N=308 N=223 % % % %

Death by Day 14 54.5 27.3 20.8 23.3

Death by Day 90 70.5 51.5 45.1 47.5

CC-102 Mortality With Baseline SCr ≥5 and <5 Integrated Studies (ITT Population)

Baseline SCr ≥5 mg/dL Baseline SCr <5 mg/dL Terlipressin Placebo Terlipressin Placebo N=44 N=33 N=308 N=223 % % % %

Death by Day 14 54.5 27.3 20.8 23.3

Death by Day 90 70.5 51.5 45.1 47.5

CC-103 Risk Identification: Respiratory Events

• Increased rate of respiratory events – Respiratory failure – Deaths in respiratory failure patients • Events of sepsis related to respiratory events – Deaths in respiratory-related sepsis patients

CC-104 Patients at Increased Risk for Respiratory Events

• Decompensated cirrhosis and ≥3 failing organs at Baseline – ACLF Grade 3 • Recent history, ongoing, or emergent events – Primarily: dyspnea, pleural effusion, pneumonia, atelectasis, hematemesis and upper GI hemorrhage

CC-105 Clinical Measures to Mitigate Risk for Respiratory Events Prior to Terlipressin Treatment

• Hepatic encephalopathy (Grade ≥3) should be treated and the airway should be protected as clinically indicated prior to initiating terlipressin

• Do not treat with terlipressin until any pulmonary edema, pneumonia, tachypnea, or dyspnea have been adequately addressed or resolved

CC-106 Patient Management to Mitigate Risk for Respiratory Events During Terlipressin Treatment

• Do not increase dose with cardiorespiratory AEs • Close observation of respiratory status • Patients with fluid overload or respiratory symptoms: – Evaluate for pulmonary edema – Consider reduction or discontinuation of albumin and fluids – Consider short term diuretic therapy – If symptoms persist: reduce, interrupt, or discontinue terlipressin • If pneumonia occurs or progresses, or pulmonary edema is severe, or there is new onset or worsening HE ≥3 with risk of aspiration: interrupt or discontinue terlipressin CC-107 CONFIRM Study Protocol Reinforcement Training

Patients at increased risk for SAEs and death • Not recommended for patients with SCr ≥5 • Patients at increased risk respiratory failure • Grade ≥3 hepatic encephalopathy • Recent history, ongoing, or emergent specific events Prior to initiating or continuing terlipressin • Hepatic encephalopathy (Grade ≥3) should be treated and the airway should be protected as clinically indicated prior to initiating terlipressin • Do not treat with terlipressin if a patient has pulmonary edema, pneumonia, tachypnea, or dyspnea have been adequately addressed or resolved During treatment • Do not increase dose with cardiorespiratory AEs • Patients with fluid overload or respiratory symptoms: • Evaluate for pulmonary edema • Consider temporary dose/volume reduction or discontinuation of albumin and fluids • Consider short term diuretic therapy • If symptoms persist: reduce, interrupt, or discontinue terlipressin • If pneumonia occurs or progresses, or pulmonary edema is severe, or there is new onset or worsening HE ≥3 with risk of aspiration: interrupt or discontinue terlipressin

Fluid Management Training Intervention After Feb 2018 DSMB Meeting CC-108 Current Proposed Risk Management

Patients at increased risk for SAEs and death • Patients with SCr ≥5 or ACLF 3 • Patients at increased risk respiratory failure • Grade ≥3 hepatic encephalopathy • Recent history, ongoing, or emergent specific events Prior to initiating or continuing terlipressin • Hepatic encephalopathy (Grade ≥3) should be treated and the airway should be protected as clinically indicated prior to initiating terlipressin • Do not treat with terlipressin until any pulmonary edema, pneumonia, tachypnea, or dyspnea have been adequately addressed or resolved During treatment • Do not increase dose with cardiorespiratory AEs • Patients with fluid overload or respiratory symptoms: • Evaluate for pulmonary edema • Consider temporary dose/volume reduction or discontinuation of albumin and fluids • Consider short term diuretic therapy • If symptoms persist: reduce, interrupt, or discontinue terlipressin • If pneumonia occurs or progresses, or pulmonary edema is severe, or there is new onset or worsening HE ≥3 with risk of aspiration: interrupt or discontinue terlipressin

CC-109 Expected Impact of Proposed Respiratory Risk Mitigation and Use in Appropriate Patients

CC-110 Respiratory Failure and Sepsis SAEs and Deaths with and without Mitigation CONFIRM Study (ITT Population)

Without With Mitigation for Respiratory Failure and Mitigation for Respiratory Failure and Appropriate Patients (ACLF 0-2, SCr <5) Appropriate Patients (ACLF 0-2, SCr <5) Terlipressin Placebo Terlipressin Placebo N=200 N=99 N=131 N=74 % % % % Respiratory Failure

SAEs 14.0 5.1 4.6 6.8

Deaths 12.0 4.0 3.1 5.4

Sepsis

SAEs 9.0 0.0 6.1 0.0

Deaths 7.5 0.0 4.6 0.0

CC-111 Respiratory Failure and Sepsis SAEs and Deaths with and without Mitigation CONFIRM Study (ITT Population)

SAEs 14.0 5.1 4.6 6.8

Deaths 12.0 4.0 3.1 5.4

Sepsis

SAEs 9.0 0.0 6.1 0.0

Deaths 7.5 0.0 4.6 0.0

CC-112 Respiratory Failure and Sepsis SAEs and Deaths with and without Mitigation CONFIRM Study (ITT Population)

SAEs 14.0 5.1 4.6 6.8

Deaths 12.0 4.0 3.1 5.4

Sepsis

SAEs 9.0 0.0 6.1 0.0

Deaths 7.5 0.0 4.6 0.0

CC-113 Mortality With and Without Mitigation CONFIRM and Integrated Studies (Safety Population)

CONFIRM Study N=199 N=101 N=130 N=75

Death by Day 14 26.6 23.8 14.6 21.3

Death by Day 90 50.3 44.6 39.2 42.7

Integrated Studies N=349 N=249 N=278 N=218

Death by Day 14 24.9 24.1 13.0 20.7

Death by Day 90 48.1 48.2 37.4 46.4

CC-114 Mortality With and Without Mitigation CONFIRM and Integrated Studies (Safety Population)

CONFIRM Study N=199 N=101 N=130 N=75

Death by Day 14 26.6 23.8 14.6 21.3

Death by Day 90 50.3 44.6 39.2 42.7

Integrated Studies N=349 N=249 N=278 N=218

Death by Day 14 24.9 24.1 13.0 20.7

Death by Day 90 48.1 48.2 37.4 46.4

CC-115 Risk Management Tools

• Label • Education plan • Limited distribution • Enhanced pharmacovigilance • Post-approval Prospective Cohort Safety Study

CC-116 Proposed Label: Respiratory Failure, SCr ≥5 and ACLF 3

• Warnings and Precautions • Baseline serum creatinine greater than or equal to 5 and ACLF grade 3 – Patients had higher rates of serious adverse events and all-cause mortality and experienced a lower rate of HRS reversal. Use in patients with SCr ≥5 mg/dL and/or ACLF Grade 3 should be considered only when the anticipated benefit to the patient outweighs the potential risk • Respiratory Failure – Do not administer to patients with new onset or worsening dyspnea, tachypnea, or significant respiratory disease until the patient is stabilized – Due to the risk of aspiration, patients with worsening hepatic encephalopathy (Stage ≥3) should be treated and the airway protected as clinically indicated. – Closely monitor patients for signs of fluid overload. Manage fluid overload by reducing the administration of albumin and other fluids and judicious use of diuretics • Dosage and administration – Do not increase the dose in the presence of ongoing significant adverse reactions – Management of adverse reactions may include temporary dose reduction or interruption. If severe adverse reactions persist following dose adjustment, permanently discontinue

CC-117 Education Plan

• Direct communication to providers and institutions • Medical conference training programs • Field training materials • Speaker programs • Webinars • Digital media • Product website

CC-118 Post-approval Prospective Cohort Safety Study

• Assess terlipressin safety with focus on events of interest – Respiratory failure – Sepsis • Assess effectiveness of risk management – Selection of appropriate patients – Fluid management – Clinical management of respiratory conditions – Appropriate dosing and dose management • Compare to a matched cohort from clinical trial data

CC-119 Risk Management Summary

• Selection of appropriate patients – SCr <5 mg/dL and ACLF <3 • Respiratory failure mitigation – Respiratory events and mortality – Related sepsis events and mortality • Expected impact – Reduced events and mortality – Improved benefit/risk ratio • Risk management tools – Label – Education plan – Limited distribution – Enhanced pharmacovigilance – Post-approval Prospective Cohort Safety Study CC-120 Benefit/Risk and Clinical Considerations

Arun Sanyal, MD Arun Sanyal, MD Professor Department of Internal Medicine Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University School of Medicine

CC-121 HRS-1 Treatment Desired Outcomes

Improve renal function Improve clinical outcomes Reverse HRS-1

CC-122 Demonstrated Benefits of Terlipressin

Less RRT Improved RRT-free survival Facilitate medical Improve renal function management Improve Potential to return to clinical compensated state outcomes Reverse HRS-1 Shorter ICU stays Liver transplanted patients Less RRT Improved survival

CC-123 Demonstrated Risks

• Respiratory disorders

• Sepsis and septic shock

• Ischemic events

• Gastrointestinal events

CC-124 Clinical Perspective on Risk Management

• Evidence-based strategies from clinical trial data • Optimize benefit/risk for each patient • Avoid treating those with most advanced disease –SCr≥ 5 mg/dL or ACLF Grade 3 • Respiratory failure mitigation fits into routine clinical practice – Protect airway and treat hepatic encephalopathy – More aggressive management of fluid balance – More aggressive management of respiratory function – Stop or avoid terlipressin for florid pulmonary edema or pneumonia

CC-125 Incidence of Verified HRS Reversal and RRT by Day 30 in Subjects Alive with Baseline SCr <5 mg/dL and Baseline ACLF Grade 0-2 CONFIRM Study

Incidence of Verified HRS Reversal Terlipressin Placebo 1 50 p=0.012 p=0.007 40 34.8% 29.1% 30 22/115 20/59 22/98 17/49 24/86 17/45 24/80 14/43 20 15.8% 17.3%

10 N=58 N=16 N=49 N=13 0 ITT Population Baseline SCr <5 mg/dL Verified HRS Reversal (%) Verified and Baseline ACLF 0-2 Incidence of RRT by Day 30 in Subjects Alive 50 43.1% 40 34.7% 30 26.4% 22.4% 20

10 N=32 N=28 N=22 N=17 0 Subjects withSubjects RRT (%) ITT Population Baseline SCr <5 mg/dL and Baseline ACLF 0-2 1. Nominal p-value from post-hoc analysis CC-126 Number Needed to Treat/Harm (NNT/NNH) CONFIRM Study (ITT Population)

Without Mitigation for Respiratory Failure and Appropriate Patients (ACLF 0-2, SCr <5)

NNT NNH HRS Reversal 6 -

Alive w/o RRT by Day 90 21 -

No RRT by Day 30 10 -

No RRT Post-Transplant 4 -

Ischemic Event SAEs - 100

Respiratory SAEs - 11

Sepsis SAEs within -25 7 Days Post-Treatment

CC-127 Number Needed to Treat/Harm (NNT/NNH) CONFIRM Study (ITT Population)

Without With Mitigation for Respiratory Failure and Mitigation for Respiratory Failure and Appropriate Patients (ACLF 0-2, SCr <5) Appropriate Patients (ACLF 0-2, SCr <5)

NNT NNH NNT NNH HRS Reversal 6 - 4 -

Alive w/o RRT by Day 90 21 - 12 -

No RRT by Day 30 10 - 11 -

No RRT Post-Transplant 4 - 7 -

Ischemic Event SAEs - 100 - 130

Respiratory SAEs - 11 -N/A1

Sepsis SAEs within -25- 44 7 Days Post-Treatment

1. Placebo has higher incidence than terlipressin with mitigation CC-128 Additional Benefits and Harms of Terlipressin over Albumin: Without Mitigation for Respiratory Failure and Appropriate Patients (ACLF 0-2, SCr <5) CONFIRM Study (Derived from NNT / NNH)

(n=189) HRS Reversal

(n=50) Alive w/o RRT by Day 90

(n=101) No RRT by Day 30

No RRT (n=253) Post-Transplant

Ischemic Events (n=11)

Respiratory (n=92) Failure

Sepsis (n=41)

-150150 -100 100 -5050 0 50 100 150 200 250 300 Of 1000 Patients Treated Patients Harmed Patients Benefitted

AEs of harm: Serious Adverse Events CC-129 Additional Benefits and Harms of Terlipressin over Albumin: With Mitigation for Respiratory Failure and Appropriate Patients (ACLF 0-2, SCr <5) CONFIRM Study (Derived from NNT / NNH)

(n=268) +79 HRS Reversal

(n=85) +35 Alive w/o RRT by Day 90

(n=92) -9 No RRT by Day 30

No RRT (n=164) -89 Post-Transplant

Ischemic Events -3 (n=8)

Respiratory -92 (n=0) Failure

Sepsis -17 (n=24)

-150150 -100 100 -5050 0 50 100 150 200 250 300 Of 1000 Patients Treated Patients Harmed Patients Benefitted

AEs of harm: Serious Adverse Events CC-130 Benefit/Risk Conclusions

• Favorable Benefit/Risk • Benefits clinically meaningful • Risks well characterized and generally manageable • Worldwide standard of care for HRS-1 • Level 1 evidence from 2 positive RCTs supports approval in US • Urgent need to improve care for these patients

CC-131 Sponsor Backup Slides Shown

Cardiovascular and Renal Drugs Advisory Committee July 15, 2020 SAEs Occurring at ≥2% Higher Incidence in High Dose vs. Standard Dose Terlipressin Group and Onset High Dose vs. Standard Dose in Subjects Receiving High Dose Integrated Studies (Safety Population)

Terlipressin Standard2 High2 Dose: High2 Dose: High2 Dose: Dose All Onset Onset Standard Dose Onset High Dose N=254 N=95 N=6 N=57 Preferred Term1 %3 %3 %3 %3 At least one SAE 66.1 62.1 100.0 100.0

Multiple organ dysfunction syndrome 6.3 10.5 0.0 17.5

Abdominal pain 3.5 6.3 0.0 10.5

Hepatic encephalopathy 2.0 5.3 0.0 8.8

Acute kidney injury 1.2 5.3 0.0 8.8

Fluid overload 0.0 2.1 0.0 3.5

1. Up to 30 days post-treatment 2. Subjects in the standard dose level received only 0.5 and 1 mg doses. Subjects in the high dose level received at least one dose ≥2 mg 3. Subjects experiencing multiple episodes of a given adverse event are counted once within each preferred term and within each system organ class. Note: Subjects experiencing multiple episodes of a given adverse event are counted once within each preferred term and within each system organ class BU-180 Demographic and Baseline Characteristics CONFIRM, OT-0401, REVERSE, and Pooled Studies (ITT Populations)

CONFIRM OT-0401 REVERSE Pooled Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo N=199 N=101 N=56 N=56 N=97 N=99 N=352 N=256 Parameter Statistic % % % % % % % %

Hispanic or Latino 16.1 12.9 5.4 17.9 10.3 15.2 12.8 14.8 Ethnicity Not Hispanic or Latino 82.9 87.1 94.6 82.1 88.7 84.8 86.4 85.2

American Indian 1.0 0.0 0.0 5.4 1.0 1.0 0.9 1.6 or Alaskan Native

Asian 2.5 1.0 0.0 0.0 3.1 0.0 2.3 0.4

Race Black or African American 6.0 5.0 8.9 5.4 7.2 6.1 6.8 5.5

Native Hawaiian 0.0 0.0 0.0 1.8 0.0 0.0 0.0 0.4 or Other Pacific Islander

White 88.9 93.1 91.1 87.5 87.6 92.9 88.9 91.8

United States 89.4 88.1 76.8 78.6 94.8 96.0 88.9 89.1 Geographic region Non-United States 10.6 11.9 23.2 21.4 5.2 4.0 11.1 10.9

BU-236 Incidence of Alcoholic Hepatitis CONFIRM (ITT Population)

Terlipressin Placebo N=81 N=39 % %

Alcoholic Hepatitis 40.7 38.6

BU-649 HRS Reversal by Age and Sex Pooled ITT Population

Terlipressin Placebo N % N % p-value1 Age (years) <65 298 33.6 220 16.4 <0.001 ≥65 54 31.5 36 16.7 0.114 Sex Male 213 34.3 165 15.2 <0.001 Female 139 31.7 91 18.7 0.029

BU-785 Incidence of Verified HRS Reversal in Subjects with Alcoholic Hepatitis CONFIRM (ITT Population)

Terlipressin (N=81) Placebo (N=39)

30.9% 30

10 7.7% Verified HRS Reversal (%) (%) Reversal HRS Verified

n=25 n=3 0

BU-650 RRT in Subjects with Alcoholic Hepatitis at Baseline CONFIRM Study (ITT Population)

Terlipressin (N=81) Placebo (N=39)

30 28.2% 28.2% 25.6% 23.1% 23.5% 23.5% 21.0% 20 18.5%

Subjects with RRT (%) withSubjects (%) RRT 10

n=15 n=9 n=17 n=10 n=19 n=11 n=19 n=11 0 By Day 14 By Day 30 By Day 60 By Day 90

BU-651 Time to First Occurrence of RRT in Subjects with Alcoholic Hepatitis at Baseline CONFIRM Study (ITT Population)

Terlipressin Placebo 30

10 Terlipressin Placebo N=81 N=39 Median Days to First Occurrence of RRT 9 6

Subjects with Alcoholic Hepatitis (%) (%) Alcoholic Hepatitis withSubjects 0 0 14 306 09 0 Time to First Occurrence (Days)

BU-652 Figure 12: Cumulative Incidence of RRT Through Day 90 in the CONFIRM Study (ITT Population)

BF-12 Figure 11: Incidence of RRT in Subjects Alive Through Day 90 in the CONFIRM Study (ITT Population)

BF-11 Recognition of Terlipressin-related Sepsis and Respiratory Events in HRS-1

• Sepsis: With respect to sepsis, there is no known association, and mechanistically it is hard to understand how or why • Respiratory: Assumed to be part of multi-organ dysfunction syndrome – Not previously aware but now noted in a few reports – 15% of patients in UK retrospective study had respiratory symptoms or complications on terlipressin – More common in patients with more severe kidney injury – Now that we are aware, we can mitigate the risk by careful fluid management

BU-742 Table 11: Verified HRS Reversal Within Subgroups, ITT Population

FT-11 Figure 22: Incidence of RRT in Transplant Subjects Through Day 90 in the Pooled Studies (Pooled ITT Population)

BF-22 Clinical Significance of Reduction in Need for RRT

• Reduction in serious medical complications of AKI (HRS-1) – Avoidance of serious respiratory (fluid overload), neurological (uremic encephalopathy) and cardiac (hyperkalemia, acidosis) events that lead to RRT initiation • Morbidity associated with RRT – Placement of dialysis catheter in a vein, risk for bleeding and other complications – Risk for catheter-associated bloodstream infections – Intolerance to the dialysis procedure • Necessity of ICU stay for CRRT • Impact of disposition and quality of life / quality of death / organ allocation

BU-921 Time from ICU Admission to Death (Days) CONFIRM Study (ITT Population)

Terlipressin Placebo N=199 N=101 N 259

Mean (SD) 12.2 (12.44) 13.0 (12.86)

Median 9.0 8.0

Minimum, Maximum 1.0, 52.0 2.0, 38.0

BU-363 Change from Baseline Through End of Treatment in Renal Function With and Without Interaction Between Treatment and Day for Subjects Admitted to the ICU CONFIRM Study (ITT Population) – Repeated Measure Analysis

Terlipressin Placebo

1.5 0.9

1.0 0.2 0.5

0.0 -0.7 -0.7 -0.5 LS Mean (SE)

-1.0

-1.5 Difference: -0.9 Difference: -1.7 p=0.001 p<0.001 Without Interaction1 With Interaction2 (N=44) (N=44)

1. From repeated measures analysis of covariance as implemented in Proc Mixed with factors of study, treatment and day. 2. From repeated measures analysis of covariance as implemented in Proc Mixed with factors of study, treatment, day, and the treatment by day interaction. Note: Serum creatinine values after renal replacement therapy (RRT) and liver transplant are excluded. Only SCr collected after treatment start date through 24 hours after treatment end date are included. Model uses compound symmetry covariance matrix, maximum likelihood estimation (ML), and repeated statement with a factor of subject. BU-350 HRS Reversal by Absence of Alcoholic Hepatitis CONFIRM and Pooled Studies (ITT Population)

Terlipressin Placebo % % N % N % p-value CONFIRM study verified HRS reversal 118 28.0 62 21.0 0.302

Pooled studies HRS reversal 231 30.7 172 18.0 0.004

BK-2 Piano, 2018: Side Effects of Treatment with Terlipressin and Albumin

N=2411 % Side effects 45.6 Angina 5.8 Peripheral ischemia 9.3 Circulatory overload 8.3 Diarrhea 26.4 Intestinal ischemia 9.1 Abdominal pain 20.3 Hyponatremia2 7.1 Other 4.6 Withdrawal 19.9 Angina 8.3 Peripheral ischemia 6.3 Circulatory overload 16.7 Diarrhea 10.4 Intestinal ischemia 10.4 Abdominal pain 8.3 Other 2.1 Combination 37.5 1. 57 patients had no information about side effects. 2. Defined as serum sodium <130 mmol/L in patients with baseline sodium ≥130 mmol/l (196 patients) Piano et al, 2018 BK-3 Length of ICU Stay in Subjects Discharged Alive CONFIRM Study (ITT Population)

20 17.9 18

8 Mean, days 5.8 6 n=44 4

2 n=14 n=8 0 Terlipressin (N=199) Placebo (N=101)

BU-261 Selected SAEs by ACLF Grade (≥5% Incidence in Terlipressin ACLF3 Group) CONFIRM Study (Safety Population)

BU-696 Selected AEs Leading to Death by ACLF Grade (≥5% Incidence in Terlipressin ACLF3 Group) CONFIRM Study (Safety Population)

BU-695 Effect of Mitigation Strategy on Respiratory Failure (RF) SAEs CONFIRM Study

Potential Number of SAE Outcomes Mitigated Subjects who had ACLF3 at baseline 12 Subjects with baseline SCr ≥5 mg/dL1 1 Subjects who might have been mitigated 8 • New onset dyspnea, atelectasis, low lung volumes at baseline • Worsening pulmonary edema and hypoxia 1 day before RF onset • Pneumonia and pulmonary edema developed 1 day before RF onset • Worsening tachypnea 2 days before RF onset • Dyspnea and hypoxia developed 2 days and 1 day prior to RF onset • CXR infiltrates, terlipressin dose increased 2 days before RF onset • Grade 3 hepatic encephalopathy developed 2 days prior to RF onset • Grade 3 hepatic encephalopathy developed 3 days prior to RF onset Not-mitigatable (2 on terlipressin, 4 terlipressin discontinued 0 2, 3, 7 and 25 days prior to onset of RF): 6 patients Total Mitigation Impact: 21/27

1. One subject with SCr ≥5 mg/dL included in ACLF3 row BU-909 Proposed Education Plan for In-Hospital Respiratory Mitigation

• Baseline evaluation of CxR; CT Chest; sPO2; BUN; SrCrt • Baseline evaluation of ACLF and during tretament • Start Terlipressin at a very low dose and gradually increase only if there is no respiratory events • Treatment with Albumin infusion - only to be initiated in patients with no respiratory involvement; infusion slowly over time • Oxygenation Index Baseline - monitor every 2 days throughout ICU stay • PaO2/FiO2 Ratio Baseline – monitor every 2 days throughout ICU stay • PEEP with high pressure O2 flow • Mechanical Ventilation to be avoided if pulmonary oedema or CxR shows infiltrates

BU-891 Acute on Chronic Liver Failure: CLIF-SOFA Criteria

Grade Organ Failure This group includes 3 subgroups: (1) No organ failure, (2) patients with a single “non-kidney” organ No ACLF failure with a serum creatinine <1.5 mg/dl and without hepatic encephalopathy, and (3) patients with single cerebral failure with serum creatinine <1.5 mg/dl This group includes 3 subgroups: (1) Single kidney failure, (2) patients with single failure of the liver, coagulation, circulation or respiration who had a serum creatinine between 1.5 and 1.9 mg/dl and/or ACLF Grade 1 hepatic encephalopathy grade I or II, (3) single cerebral failure who had a serum creatinine between 1.5 and 1.9 mg/dl ACLF Grade 2 Two organ failures ACLF Grade 3 Three organ failures or more **Organ failure definitions are according to the CLIF-SOFA Score.

• Liver failure is defined as serum bilirubin ≥12 mg/dL • Kidney failure is defined as serum creatinine ≥2 mg/dL or requirement for renal replacement therapy • Cerebral failure is defined as West Haven score ≥ III or requirement for endotracheal intubation to prevent aspiration pneumonia • Coagulation failure is defined as INR (international normalized ratio) ≥2.5 or platelet count ≤20x109/L • Circulation failure is defined by requirement for vasoactive drugs to maintain hemodynamic stability • Respiratory failure is defined as PaO2/FiO2 ≤200 or SpO2/FiO2 ≤214 BU-854 Competing Risks for RRT-Free Survival Over Time to Day 90 CONFIRM Study (ITT Population)

1.0

0.8

0.6

0.4 RRT, Terlipressin RRT, Placebo 0.2 Survival, Terlipressin Survival, Placebo Survival Distribution Function Function Survival Distribution 0.0 0 14 306 09 0 Survival Days

Terlipressin Placebo N=199 N=101 Event n (%) n (%) P-value RRT-free survival 67 (34) 28 (28) 0.097 1 RRT initiation or death 132 (66) 73 (72) 0.097 1 RRT initiation 58 (29) 39 (39) Death without preceding RRT 74 (37) 34 (34) Death with or without preceding RRT 103 (52) 47 (47)

1. P-value from log rank test BU-658 Outcomes in Patients with Verified HRS Reversal and Recurrence by Day 30

• Four patients died by Day 30 – Hepatic failure (Day 20) – Alcoholic hepatitis (Day 24) – Aspiration pneumonia (Day 30) – Chronic hepatic failure (Day 30) • Six patients were still alive by Day 90 – Three patients received a liver transplant by Day 21, 50, and 66 – Three patients were re-treated with terlipressin, and 2 of them responded again

BU-537 Actions Taken Based on Data and Safety Monitoring Board

• Training initiatives – Site initiation visits – In-service training – Study coordinator calls – Investigator meetings • Education on fluid overload and its management based on CONFIRM Protocol Section 10.3.2.1.1

BU-673 Use of Concomitant Diuretics Before and After the DSMB Meeting CONFIRM Study

Before DSMB Meeting After DSMB Meeting Terlipressin Placebo Terlipressin Placebo N=87 N=44 N=112 N=57 % % % %

Concomitant diuretics 23.0 15.9 27.7 10.5

Data cut-off January 1, 2018 BU-559 Diuretic Use and Fluid Management Pre- and Post-DSMB CONFIRM Study

Before DSMB Meeting After DSMB Meeting Terlipressin Placebo Terlipressin Placebo N=87 N=44 N=112 N=57 % % % %

Concomitant diuretics 23.0 15.9 27.7 10.5

Subject receiving >662.5 g of cumulative albumin 28.2 20.7

BU-516 Change From Baseline to End of Treatment in MELD Score CONFIRM Study (Safety Population)

Terlipressin Placebo N=200 N=99 Baseline Change from Baseline Change from Parameter1 Value Value Baseline Value Value Baseline n 169 169 169 81 81 81

Mean (SD) 29.6 (7.85) 32.6 (6.60) -3.0 (4.88) 31.8 (6.95) 32.7 (6.25) -0.9 (4.06)

1. The end of treatment value is the last value up to 24 hours after the last dose BU-419 Time to Transplant CONFIRM, OT-0401, and REVERSE Studies

CONFIRM OT-0401 REVERSE Terlipressin Placebo Terlipressin Placebo Terlipressin Placebo N=199 N=101 N=56 N=56 N=97 N=99 Time to Transplantation by Day 90, days

Mean (SD) 24.6 (23.47) 21.5 (19.33) 28.3 (29.00) 19.6 (22.90) 16.6 (22.02) 17.6 (20.61)

Median 17.0 13.0 18.5 11.0 5.6 11.2

BU-405 Transplant Rate and Days to Transplant By UNOS Region Pooled Population

Number of Transplanted Subjects Mean Study Day of Transplant UNOS Region Terlipressin Placebo Terlipressin Placebo 1 2 0 48.0 0 2 13 10 10.5 21.6 3 13 5 12.5 7.0 4 8 8 25.0 15.4 5 12 11 24.8 22.5 6 1 1 45.0 22.0 7 12 10 23.8 14.3 8 7 7 10.0 14.0 9 5 6 49.2 9.7 10 7 7 18.0 11.0 11 7 5 38.0 30.4 Ex-US 7 8 44.1 54.0 Total 94 78 - - BU-572