Emerging Therapies in NASH

Stephen A Harrison, MD, FACP, FAASLD COL (ret.), USA, MC Visiting Professor of Hepatology Radcliffe Department of Medicine, University of Oxford Medical Director, Pinnacle Clinical Research President, Summit Clinical Research San Antonio, TX Disclosures

• Scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Canfite, Cirius, CiVi Biopharma, Cymabay, Echosens, Fibronostics, Forest Labs, Galectin, Genfit, Gilead, Hepion, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, Ridgeline, Sagimet, Terns, Viking, 89 Bio. • Stock options: Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northsea. • Grant/Research support: Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer,Sagimet, Viking. Goals of NASH Treatment

• Improve metabolic abnormalities • Decrease inflammation • Prevent/arrest/reverse liver fibrosis – AASLD recommends pharmacological treatments aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis • Prevent advanced liver disease, liver failure, liver cancer and related outcomes • Systemic outcomes (eventually)

Chalasani N et al. Hepatology. 2018;67:328-35. Lifestyle Recommendations for Treating NASH

Caloric intake Weight loss Exercise No heavy alcohol reduction of 3% to 5% can improve alone may reduce steatosis, consumption steatosis, but 6% to 10% is ≥30% or but effect on other histologic Insufficient data to guide needed to improve NASH/fibrosis ~750-1,000 kcal/day features unknown recommendations regarding improved insulin resistance nonheavy alcohol consumption and hepatic steatosis **Drink ≥ 2 cups of caffeinated *Limit consumption of coffee daily fructose-enriched beverages

*Fructose increases the odds of the development of nonalcoholic fatty liver in high-risk patients and of nonalcoholic steatohepatitis and more advanced liver fibrosis in patients who already have nonalcoholic fatty liver disease. **Caffeinated coffee reduces the risk of liver fibrosis in several liver diseases, including nonalcoholic fatty liver disease.

Chalasani N et al. Hepatology. 2018;67(1):328-357; Diehl AM, Day C. New Engl J Med. 2017; 377:2063-72. Sources of Excess Clinical Outcomes in NAFLD and Where Interventions Will Have Greatest Impact

Closest to cirrhosis and most likely to benefit Most closely tied to from prevention liver-related mortality of progression

NAFL NASH NASH with fibrosis NASH Cirrhosis

Cardiovascular, CKD and all-cause cancer outcomes

Liver decompensation Pathogenesis of NASH and Related Fibrosis

ANTI-INFLAMMATORY

Insulin resistance METABOLIC SGLT Regulatory T cells  Insulin/glucose FGF21

 Adiponectin ACC  TNF-α TR Immune cell  FFA trafficking  VLDL Mitochondrial  Lipogenesis dysfunction Apoptosis NLRP3  SHP  SREPB-1  DNL inflammasom  FFA ROS e ER Stress FGF19  FXR/TGR5 Collagen  JNK deposition  UPR

Bile acids Hepatic stellate Kupffer cell activation cell ANTI-FIBROTIC LPS

ACC, acetyl-CoA carboxylase; AOC, amine oxidase, copper containing; ASK, apoptosis signal-regulating kinase; CCR, CC chemokine receptor; DNL, de novo lipogenesis; ER, endoplasmic reticulum; FFA, free fatty acids; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IL, interleukin; JNK, Jun N-terminal kinases; LPS, lipopolysaccharide; NLRP3, nucleotide-binding oligomerization domain and leucine rich repeat and pyrin domain containing protein 3; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species; SCD, stearoyl CoA desaturase; SGLT, sodium-glucose linked transporter; SHP, small heterodimer partner; SREBP, sterol regulatory element binding proteins; TGF, transforming growth factor; TGR5, G protein-coupled bile acid receptor 1; TLR, toll like receptor; TNF, tumor necrosis factor; TR, thyroid receptor; UPR, unfolded protein response VLDL, very low density lipoprotein. Adapted from Konerman MA et al. J Hepatol. 2018;68:362–375. NASH: Potential Therapeutic Targets

SGLT2 inhibitor ANTI-INFLAMMATORY METABOLIC GLP1 ag Insulin sensitizer MPC inh Insulin resistance Regulatory FGF21 analog/agonist SGLT ACC inhibitor T cells  Insulin/glucose FGF21 PPAR agonists FASN inh

 Adiponectin ACC  TNF-α THRᵦ ag Immune cell  FFA trafficking  VLDL Mitochondrial Apoptosis SCD1 inh  Lipogenesis dysfunction NLRP3  SHP  SREPB-1  DNL inflammasome  FFA ROS ER Stress FGF19  FXR/TGR5 Collagen  JNK FGF19 analog deposition  UPR Bile acids Hepatic stellate Kupffer FXR ag cell activation cell

LPS ANTI-FIBROTIC

NORMAL LIVER STEATOSIS STEATOHEPATITIS CIRRHOSIS

Targets related to Targets related to Targets related to Targets related to Targets related to insulin resistance cell death lipotoxicity & inflammation and fibrogenesis & and/or lipid (apoptosis and oxidative stress immune activation collagen turnover metabolism necrosis)

PPARγ: Pioglitazone PPARα/∂: Elafibranor CCR2/5: Cenicriviroc ASK1 Selonsertib LOXL2: Simtuzumab Liraglutide, PPARα/∂/γ: Lanifibranor GLP-1: AOC3: BI 1467335 Galectin GR-MD-02 Semaglutide PPARα/γ: Saroglitazar Caspase Emricasan GLP-1/GR: MEDI0382 MPC MSDC-0602K, PXL065 TLR4: JKB-121 CRV431 GS-0976, PF- CRV431 ACC: OCA, GS-9674, Anti-LPS: IMM-124E 05221304 FXR: tropifexor, LMB-763, CRV431 SCD1: Aramchol EYP001, MET409 SGLT1/2: LIK066 TGR5: INT-767, INT-777 BMS-986036, AKR- FGF21: 001,BIO89-100 ASBT: Volixibat THR-β: MGL-3196, VK2809 FGF19: NGM282 FGFR1/KLB BFKB8488A Vitamin E Some drugs have pleiotropic effects MPC MSDC-0602K, PXL065 Mixed ag- antagonist GR and Miricorilant antagonist MR Making Sense of NASH Clinical Development

Clinical trial endpoints • Phase 2 • Phase 3 registration trials Clinical Trial Landscape – Ongoing NASH Trials • Phase 2 • Phase 3 • Combination trials Clinical Trials- Comparison of endpoints Making Sense of NASH Clinical Development

Clinical trial endpoints • Phase 2 • Phase 3 registration trials Clinical Trial Landscape – Ongoing NASH Trials • Phase 2 • Phase 3 • Combination trials Clinical Trials – Comparison of endpoints Endpoints for Outcome Measures in NASH

Surrogate Endpoints Outcomes Hard Endpoints in Early-Phase Studies

• Progression to cirrhosis VCTE and MRE, wet biomarkers* Clinical • All-cause mortality • Liver-related mortality, hepatic CTP and MELD scores, HVPG decompensation

• Reduction in liver fat content MRI-PDFF, multiparametric MRI, CAP • Improvement in IR A1C, fasting glucose, HOMA-IR Metabolic • Impact on lipids • Change in weight/BMI

• Change in necroinflammation Multiparametric MRI, liver enzymes Inflammatory • Change in ballooning Fibrosis • Change in fibrosis stage VCTE and MRE, wet biomarkers*

*eg, pro-C3, FIB-4, NFS, ELF. Konerman. J Hepatol. 2018;68:362. Clinical Trial Endpoints in Early Phase 2 Development

ALT Liver fat fraction (MRI-PDFF)

• 10 Units/L reduction associated with • ≥ 5% absolute reduction associated histologic improvement or resolution of with improvement NASH in steatosis • ≥ 17 Units/L reduction predicted • ≥ 30% relative reduction associated histologic with improvement in NAFLD activity response score without fibrosis worsening

In large clinical trials that include paired biopsies, surrogate endpoints can be validated against histologic endpoints MRI-PDFF has shown to be correlated to histological response

ALT, alanine aminotransferase; MRI, magnetic resonance imaging; PDFF, proton density fat fraction, U/L, units per liter. Vuppalanchi R et al. Clin Gastroenterol Hepatol. 2014;12:2121; Loomba R et al. Gastroenterology. 2019;156:88–95; Middleton MS et al. Gastroenterology. 2017;153:753–761; Patel J et al. Therap Adv Gastro. 2016;9:692–701. Regulatory Endpoints for Registration Trials – Phase 2B/3

FDA: Sub-part H conditional approval Endpoints NASH Resolution Fibrosis Improvement

Resolution of steatohepatitis Improvement ≥ 1 fibrosis stage (Ballooning = 0, Inflammation = 0/1) AND AND No worsening of steatohepatitis No worsening of liver fibrosis

Full approval • Progression to cirrhosis: – Number of individuals who progressed to cirrhosis in the treatment-arm versus placebo • Clinical endpoints – Hepatic decompensation (clinical ascites, SBP, HE, Variceal bleeding or HRS [HCC] • MELD ≥15 US FDA. Draft Guidance. Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment Guidance for Industry. December 2018. ALT (Marker of Liver Injury) Reduction Among Top in NASH

Leading Mechanisms FGFs FGFs (NASH) (NASH) (NAFLD) FXR GLP-1 PPAR TR-β Fc-FGF21 Peg-FGF21 FGF19 Peg-FGF21 FGFR1c

OCA Semaglutide Lanifibranor Resmetirom Efruxifermin Pegbelfermin Aldafermin BIO89-100 BFK8488A 78 Wks 72 Wks 24 Wks 36 Wks 16 Wks 16 Wks 24 Wks 12 Wks 12 Wks Ph3 Ph2b Ph2b Ph2a Ph2a Ph2a Ph2a Ph1b/2a Ph1b +18

0 7 -6 -5 -6 -4 -5

-19 -22 -26 -31 -30 -33 -33 -42 -41 -41 -40 -44 -44 -49 -51 Association of PDFF Response With NASH Resolution and Fibrosis Reduction – Resmetirom

• Percentages of patients with NASH 70 Resmetirom Treated resolution increased with greater PDFF reduction (both Pathologists) 60

50 • In resmetirom-treated patients with ≥50% fat reduction at Week 12, 64% 40 had NASH resolution (primarily by 30 ballooning and inflammation)

20 • PDFF reduction ≥ 30 and ≥ 50% at Week 12 was associated with fibrosis 10 reduction on subsequent liver biopsy 0 NASH Resolution Fibrosis Reduction Both NR and fibrosis • ≥ 30% and ≥ 50% fat reduction were (NR) reduction1 associated with ~60% achievement of >50% PDFF >=30% PDFF MRI-PDFF Non-Responder both endpoints: NASH resolution and ≥ 1 point fibrosis reduction Non Responder: <30% fat reduction on Week 12 MRI-PDFF. 1%fibrosis reduction in biopsies with NR. Association of PDFF Response With Fibrosis Reduction – Aldafermin

Fibrosis Improvement ≥ 1 Stage with No Worsening of NASH1 at Week 24

F3 Patients F3 Patients with ≥ 30% LFC Reduction 46%

30%

Patients (%) Patients (%) Patients 0% 0% Placebo Aldafermin 1mg Placebo Aldafermin 1mg (n=9) (n=23) (n=1) (n=13)

1 Defined as patients who have an improvement in liver fibrosis by ≥1 stage with no worsening of NASH (no worsening of steatosis, lobular inflammation or hepatocyte ballooning grade) from baseline to W24 (not powered for statistical significance); LFC, liver fat content. Making Sense of NASH Clinical Development

243 NASH studies on Clinicaltrials.gov • 1 Triple glucagon/GIP/GLP-1 agonist • 1 glucagon/GLP-1 agonist 34 actively recruiting studies • 1 GIP/GLP-1 agonist • 1 oral prodrug of bioidentical testosterone • 3 THR-beta agonist • 3 FXR • 3 FGF-21 • 1 FGF-19 • 1 JNK inhibitor • 1 SCD inhibitor • 1 Structurally engineered fatty acid • 1 CCR 2/5 antagonist • 1 Ketohexokinase inhibitor • 1 Pancyclophylin inhibitor • 1 Galectin-3 inhibitor • 6 combination trials Clinicaltrials.gov. NASH Clinical Trials – Patient Enrollment

• Phase 3 trial enrollment needed: 6000 non-cirrhotic subjects

• Phase 2 trial enrollment needed: ~4300 non-cirrhotic subjects

• Cirrhotic patients needed for phase 2/3 trials: ~600 subjects

• Anticipated or enrolling trials in 2020/2021 not listed in Clinicaltrials.gov: 5 (representing another 500-1000 subjects)

• Current screen fail rate for histology-based endpoints: ~60-75% NASH: Metabolic Agents in Phase 2 Clinical Development – Trials Without Biopsy

EYP0014 PXL7706 FXFR agonist AMPK activator N=160*, Q1 2020 N=120*, Q2 2020

LCPN 11445 TVB-26407 Testosterone analog FASN inhibitor N=75 ,Q1 2020 N=117*, Q2 2020 MT39951 Aldosterone receptor AXA1125 & AXA1957 (Axcella) Elobixibat8 antagonist multifactorial protein IBAT inhibitor N=48*, Q3 2019 supplements N=105*, Q1 2020 N=46*, Q2 2020

EDP-3053 HTD18012 BIO89-1009 FXFR agonist Multifactorial lipid modulator FGF21R agonist N=125*, Q3 2019 N=117*, Q4 2019 N=83*, Q2 2020 ESTIMATED READOUT

*Planned. FASN, Fatty acid synthase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; IBAT, ileal bile acid transporter. ClinicalTrials.gov.: 1. NCT02923154; 2. NCT03656744; 3. NCT03421431; 4. NCT03812029; 5. https://www.pharmiweb.com/press-release/2019-02- 14/lipocine-inc-announces-fda-clearance-of-ind-to-commence-phase-2-study-of-lpcn-1144-in-biopsy-confir; 6. NCT03763877; 7. NCT03938246; 8. NCT04006145; 9. NCT04048135. NASH: Metabolic Agents in Phase 2 Clinical Development – Trials With Biopsy

Tropifexor3 NGM28211 METABOLIC AGENTS FXR agonist FGF 19 analog N=345*, Q1 2020 N=152*, Q1 2021

Pegbelfermin12 Lanifibranor4 Peg FGF21 recomb PPARα, γ & δ agonist N=100*, Q2 2021 N=225*, Q1 2020 1 VK2809 13 liver thyroid receptor Pegbelfermin Peg FGF21 recomb β-agonist 5 8 MSDC-0602K Semaglutide OW N=160*, Q3 2021 N=59*, Q2 2019 MPC modulator GLP-1R agonist N=402, Q4 2019 N=320*, Q3 2020 VK280915 Gemcabene2 THRβ-agonist N=337*, Q2 2021 Lipid metabolism NGM2826 AKR 1019 N=40*, Q3 2019 FGF 21 agonist FGF 19 analog Icosabutate14 N=250*, Q4 2019 N=80*, Q3 2020 Structurally engineered fatty acid N=264*, Q3 2021

Saroglitazar7 Seladelpar10 16 PXL065 BFKB8488A PPARα & γ agonist PPARδ agonist ESTIMATED MPC Inhibitor FGFR1/KLB READOUT N=104*, Q4 2019 N=181*, Q4 2020 N=120*, Q4 2021 N=260*, Q3 2022

*Estimated. FGF, fibroblast growth factor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; MCP, mitochondrial pyruvate carrier; PPAR, peroxisome proliferator-activated receptor. ClinicalTrials.gov: 1. NCT02927184; 2. NCT03436420; 3. NCT02855164; 4. NCT03008070; 5. NCT02784444; 6. NCT02443116; 7. NCT03061721; 8. NCT02970942; 9. NCT03976401; 10. NCT03551522; 11. NCT03912532; 12. NCT03486912; 13. NCT03486899; 14. NCT04052516. 15.NCT04173065. 16. NCT04171765 NASH: Anti-Inflammatory and Anti-Fibrotic Agents in Phase 2 Clinical Development – Trials Without Biopsy

ANTI-INFLAMMATORY AGENTS

ANTI-FIBROTIC AGENTS CRV431 Cyclophilin inhibitor Q2 2020

BI 14673351 HepaStem3 SSAO inhibitor (apoptosis) Liver-derived mesenchymal cells N=114, Q3 2019 N=24, Q2 2020

Namodenoson2 GRI06214 A3AR agonist (energy homeostasis) NK cell R antagonist N=60, Q4 2019 N=60, Q3 2021

ESTIMATED READOUT

*Planned. A3AR, A3 adenosin receptor; NK, natural killer; R, receptor; SSAO, semicarbazide-sensitive amine oxidase. 1. ClinicalTrials.gov. NCT03166735; 2. https://www.biospace.com/article/releases/the-anti-nash-effect-of-namodenoson-will-be-presented-at-the- international-conference-on-fatty-liver-in-berlin/ (accessed Sept 2019); 3. ClinicalTrials.gov. NCT03963921; 4. https://www.gribio.com/clinical.html# (accessed Sept 2019). NASH: Anti-Inflammatory and Anti-Fibrotic Agents in Phase 2 Clinical Development – Trials With Biopsy

ANTI-INFLAMMATORY AGENTS

ANTI-FIBROTIC AGENTS

Emricasan (ENCORE-LF)1 Tropifexor/Cenicriviroc4 caspase inhibitor (apoptosis) FXR agonist / CCR2/5 inhibitor N=210, Q4 2019 N=200, Q4 2020

Cilofexor/Firsocostat/Selonserib2 FXR agonist/ACC inh/ ASK1 inh N=154, Q4 2019

Cilofexor/Firsocostat/Selonserib3 FXR agonist/ACC inh/ ASK1 inh ESTIMATED N=395, Q4 2019 READOUT

*Planned. ACC, acetyl-CoA carboxylase; ASK, apoptosis signal-regulating kinase; FXR, farnesoid X receptor. ClinicalTrials.gov: 1. NCT03205345; 2. NCT02781584; 3. NCT03449446; 4. NCT03517540. NASH: Metabolic Agents in Phase 3 Clinical Development

METABOLIC AGENTS AGENT MoA (TARGET) TRIAL, PATIENTS AND ENDPOINT(S)

RESOLVE-IT (n=2000*, fibrosis stage 1–3) – PRO: JAN 2020 – FRO: DEC 20211 1 1 Lipotoxicity/oxidative stress • NASH resolution without worsening of fibrosis Elafibranor (PPARα/δ agonist) • Long-term composite of all-cause mortality, cirrhosis and liver-related events

REGENERATE (n=2065*, fibrosis stage 1–3) – PRO: FEB 2019 REVERSE (n=540*, compensated Obeticholic 2 - Final Completion: OCT 20223 3 3 Lipotoxicity/oxidative stress cirrhosis) – Q3 20202 • Fibrosis improvement ≥1 NDAstage without NASH worsening Acid (FXR agonist) • Fibrosis improvement ≥1 stage without • NASH resolution without fibrosis worsening / All-cause (Ocaliva) NASH worsening mortality and liver-related events

MAESTRO-NASH (n=2000*, fibrosis stage 2–3) – PRO: JUN 2021 – Final Completion: MAR 20244 4 4 Resmetirom Lipotoxicity • NASH resolution without worsening of fibrosis (THR-ß agonist) (MGL-3196) MAESTRO-NAFLD1 (n=700) Completion DEC 2021 4B

ARMOR (NASH and fibrosis, N=2000) – PRO: JUN 2022 – Final Completion: DEC 20245 5 5 Fatty acid synthesis • Histological endpoint at 52 weeks Aramchol (SCD1 inhibitor) • Composite of progression to cirrhosis, liver-related clinical outcomes and all-cause mortality 1 3 1 2 4 5 3 4 5 4B PRIMARY and FINAL READOUT

*Planned. PRO, Primary Readout; FRO, Final Readout; FXR, farnesoid X receptor; PPAR, peroxisome proliferator-activated receptor; SCD, stearoyl CoA desaturase; THR, thyroid hormone receptor. 1. ClinicalTrials.gov. NCT02704403; 2. ClinicalTrials.gov. NCT03439254; 3. ClinicalTrials.gov. NCT02548351;. 4. NCT03900429; 5. https://www.prnewswire.com/il/news-releases/galmed-pharmaceuticals-announces-successful-completion-of-end-of- phase-2-meeting-with-fda-and-plan-for-start-of-phase-3-300827912.html (accessed Sept 2019). NASH: Anti-Inflammatory and Anti-Fibrotic Agents in Phase 3 Clinical Development

ANTI-INFLAMMATORY AGENTS

ANTI-FIBROTIC AGENTS AGENT MoA (TARGET) TRIAL, PATIENTS AND ENDPOINT(S)

1 STELLAR-3 (n=808, fibrosis stage 3) – Q2 20192 2 STELLAR-4 (n=883, compensated cirrhosis) – Q1 20191 Apoptosis/necrosis • Fibrosis improvement ≥1 stage without Selonsertib • Fibrosis improvement ≥1 stage without NASH worsening (ASK1 inhibitor) NASH worsening • Event-free survival • Event-free survival

3 Belapectin Fibrosis NASH-RX (n=500*, compensated NASH cirrhosis) – Q4 20223 (GR-MD-02) (Galectin-3 inhibitor) • NASH resolution without worsening of fibrosis

4 4 AURORA (n=2000*, fibrosis stage 2–3) – PRO: OCT 2021 – Final Completion: 20284 Inflammation/fibrosis Cenicriviroc • Fibrosis improvement ≥1 stage without NASH worsening (CCR2/5 antagonist) • Composite of progression to cirrhosis, liver-related clinical outcomes and all-cause mortality

1 2 4 3 4 PRIMARY and FINAL READOUT

*Planned. PRO, Primary Readout; FRO, Final Readout; ASK, apoptosis signal-regulating kinase; CCR, CC chemokine receptor; PPAR, peroxisome proliferator-activated receptor; FXR, farnesoid X receptor; THR, thyroid hormone receptor. 1. ClinicalTrials.gov. NCT03053063; 2. ClinicalTrials.gov. NCT03053050; 4. ClinicalTrials.gov. NCT02704403; Phase 2 Combination Therapy Trials

Agent Target Trial, patients and primary endpoint(s) (mechanism)

Semaglutide GLP1 agonist Proof of concept study (n=109, biopsy-proven NASH and fibrosis stage 2–3) Firsocostat ACC inhibitor • Safety and tolerability Cilofexor FXR agonist • 24 weeks treatment

TANDEM (n=200, NASH and fibrosis stage 2–3) Tropifexor FXR agonist • Safety and tolerability Cenicriviroc CCR2/5 antagonist • Fibrosis improvement ≥1 stage without NASH worsening or NASH resolution without fibrosis worsening • 48 weeks treatment

ELIVATE (n=210, NASH and fibrosis stage 2–3) Tropifexor FXR agonist • Fibrosis improvement ≥1 stage without NASH worsening or NASH resolution without fibrosis worsening Licogliflozin SGLT1 and 2 inhibitor • 48 weeks treatment

NEXSCOT (n=250, phenotypic NASH, ELF ≥8.5 and PDFF≥8%) LYS006 LTA4 hydrolase inhibitor • Safety and tolerability Tropifexor FXR agonist • ELF, MRI-PDFF, lipids • 12 weeks treatment

Selonsetrtib ASK1 inhibitor ATLAS (n=395, NASH and fibrosis stage 3-4) Firsocostat ACC inhibitor • Safety and tolerability Cilofexor FXR agonist • Fibrosis improvement ≥1 stage without NASH worsening • 48 weeks treatment Making Sense of NASH Clinical Development

Clinical trial endpoints • Phase 2 • Phase 3 registration trials Clinical trial Landscape – Ongoing NASH Trials • Phase 2 • Phase 3 • Combination trials Clinical Trials – Comparison of endpoints NASH Development Landscape: Fibrosis Improvement Proportion of Subjects With ≥1 Stage Improvement in Fibrosis and No Worsening of NAS1

Akero Inventiva NGM Bio Madrigal Cymabay Novo Nordisk Intercept Efruxifermin Lanifibranor Aldafermin Resmetirom Seladelpar Semaglutide Ocaliva 16 Wks (Ph2a) 24 Wks (Ph2b) 24 Wks (Ph2a) 36 Wks (Ph2a) 52 Wks (Ph2a) 72 Wks (Ph2b) 78 Wks (Ph3) Weekly Injection Daily Oral Daily Injection Daily Oral Daily Oral Daily Injection Daily Oral

62% 24 Wks Increasing dosing duration 78 Wks

48% 46% 48% 38% 37% 36% 32% 34% 29% 29% 24% 24% 23% 18% 20% 18% 12%

0% Pbo All EFX 50mg Pbo 0.8g 1.2g Pbo 1mg Pbo All Pbo 20mg 50mg Pbo 0.2mg 0.4mg Pbo 10mg 25mg (N=2) (N=40) (N=13) (N=62) (N=63) (N=69) (N=22) (N=50) (N=34) (N=79) (N=25) (N=42) (N=46) (N=80) (N=78) (N=82) (N=311)(N=312)(N=308)

Note: These data are derived from different clinical trials at different points in time, with differences in trial design and patient populations. No head-to-head clinical trials have been conducted. Inventiva (2020) June 16 Corporate Presentation; NGM Bio (2020) June 3 Corporate Presentation; Harrison S et al. Lancet. 2019. 394(10213):2012-24; CymaBay (2020) March 12 Press Release; Novo Nordisk (2020) June 19 R&D Investor Presentation; Younossi Z et al. Lancet. 2019. 394(10215):2184-96. All trademarks are the property of their respective owners. 1 FDA Guidance for Industry: Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment (2018) NASH Development Landscape: Nash Resolution Proportion of Subjects with Resolution of NASH and No Worsening of Fibrosis1

* 54% 50% 48% 24 Wks Increasing dosing duration 78 Wks 49% 47% 40%

26% 23% 24% 25% 23% 19% 15% 11% 12% 9% 8% 8%

Pbo* All EFX 50mg Pbo 0.8g 1.2g Pbo 1mg Pbo All Pbo 20mg 50mg Pbo 0.2mg 0.4mg Pbo 10mg 25mg (N=2) (N=40) (N=13) (N=62) (N=63) (N=69) (N=22) (N=50) (N=34) (N=79) (N=25) (N=42) (N=46) (N=80) (N=78) (N=82) (N=311)(N=312)(N=308)

* A single placebo responder lost 25 pounds over 16 weeks (11% weight reduction). Note: These data are derived from different clinical trials at different points in time, with differences in trial design and patient populations. No head-to-head clinical trials have been conducted. Inventiva (2020) June 16 Corporate Presentation; NGM Bio (2020) June 3 Corporate Presentation; Harrison S et al. Lancet. 2019. 394(10213):2012-24; CymaBay (2020) March 12 Press Release; Novo Nordisk (2020) June 19 R&D Investor Presentation; Younossi Z et al. Lancet. 2019. 394(10215):2184-96. All trademarks are the property of their respective owners. 1 FDA Guidance for Industry: Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment (2018) What’s Left in NASH Development:

Endocrine FGF BOS-580 Anti-Fibrotic ASC42 TERN-101

MET642 NN9500 EYP001 BFKB8488A EDP-297 MET409 MK-3655 aldafermin BIO89-100 ASC41 EDP-305 tropifexor pegbelfermin cilofexor efruxifermin TVB-2640 AZD-2693 VK2809 ARO-HSD Metabolic GB-1211 resmetirom belapectin OCA PF-06865571 ALN-HSD BMS-986263 aramchol NDA/BLA PF-06835919 cenicriviroc ION224 leronlimab icosabutate CM-101 CC-9001 tirzepatide LY3478045 Ph3 efinopegdutide

semaglutide HM15211 JKB-122 danuglipron cotadutide Anti-Inflammatory lanifibranor saroglitazar namodenoson Ph2 ALT-801 TERN-201 Anti-diabetic

Ph1 Stephen Harrison MD, FACP, FAASLD THANK YOU COL (ret.), USA, MC Phone: (210) 982-0320 Email: [email protected]