Oral Testosterone (T) Non Alcoholic Steatohepatitis (NASH)

Transcription

1 Oral Testosterone (T) Non Alcoholic Steatohepatitis (NASH) 1

2 LPCN 1144: Well Positioned for Success Unique Mechanism of Action with Compelling Clinical Signal Targeting Full Spectrum of NASH Pathogenesis + Additional Health Benefits - Testosterone deficiency in men is prevalent across the full spectrum of NAFLD - LPCN 1144 results suggest therapy has potential for collateral health benefits Well Tolerated Oral Candidate - Prodrug of a bio-identical hormone - Good gastrointestinal tolerability with no signs of skeletal fragility or nephrotoxicity - Demonstrated with multiple studies with up to 52 week exposure Compelling Clinical Data - Absolute mean reduction of 7.6% liver fat in subjects with baseline liver fat 1% - 38% relative mean liver fat reduction in subjects with baseline liver fat 1% - Significant reductions in both the key ALT and TG serum NASH biomarkers - Good potential of histological improvement in NASH and fibrosis 2

3 Non-Alcoholic Fatty Liver Disease (NAFLD) Clinical Progression Fatty liver is a reversible condition wherein large vacuoles of triglyceride (TG) fat accumulate in liver cells via the process of steatosis Healthy Liver 2 3% US Adults 15 2% NAFLDs Fatty Liver TGs LFTs Liver fat 1 2% NASH NASH Liver Steatosis Ballooning Inflammation Fibrosis Cirrhotic Liver Late stage of fibrosis Hepatocellular Carcinoma No Approved Product Eligible for Liver Transplantation 3 LFTs: Liver function test, especially Alaninine amino transferase (ALT) and Aspartame amino transferase (AST) NASH: Non-alcoholic Steatohepatitis, TG: Triglyceride

4 Prevalence of nonalcoholic fatty liver disease (%) T = ng/dl T = ng/dl Clinical Relationship Between Testosterone and NAFLD Association of Total T with NAFLD and Cirrhosis Increased prevalence of hepatic steatosis is associated with low serum testosterone in men* 1 NAFLD and Low T 1 Cirrhosis survival and Low T Testosterone quintile After adjusting for age, smoking, diabetes, exercise, BMI, TG and HDL, the lowest T quintile ( ng/dl) have OR of 5.12 ( ) for NAFLD Low T (<8.3 nmol/l; 239 ng/dl) remained a significant predictor of reduced survival in cirrhotic patients 4 1. Kim et al, Gastroenterol Sinclair et al, Liver Trans 216 * Volzke et al, Int J Androl 21 OR: Odds Ratio

5 Free T Free T Clinical Relationship Between Testosterone and NAFLD Association of Free T with NASH/Fibrosis Progression Patients with NASH show significantly lower free T than those with nonalcoholic fatty liver (NAFLD)* Free T and NAFL/NASH Free T and Stages of NASH Fibrosis 5 * Sumida et al, Gastroenterol Hepatol 215

6 Proposed Mechanism of Action Androgen Action via Androgen Receptor ( AR ) in Males* Normal level and signaling of androgens prevent hepatic fat accumulation in males** Testosterone increases muscle protein synthesis*** 6 * Navarro et al., Obesity 215 ** Shen and Shi, Int J Endocrinol 215 ***Brodsky et al., J Clin Endo Met 1996

7 LPCN 1144: Targeting Full Spectrum of NASH Pathogenesis Plus Collateral Health Benefits Well Evidenced Mechanistic Roles of Testosterone Homeostasis Modifier Anti-Inflammatory Fibrosis Mediator / Regeneration Haemopoietic / Anabolic / Immune Modulator Accumulation of Fat in Liver Cell Damage/ Steatosis Inflammation/ Steatohepatitis Fibrosis Cirrhosis NASH Pathogenesis Reduction of elevated ALT levels generally predicts liver histological improvement in NASH 1 A 29% reduction in liver fat as measured by MRI-PDFF was associated with a histologic response in non-alcoholic steatohepatitis, Histologic responders had a statistically significant reduction in MRI-PDFF of 4.1% ± Hoffnagle et al., APT Patel et al., Therap Adv Gastroenterol 216

8 LPCN 1144: Oral T Proposed Multidimensional Mechanism of Actions Homeostasis Modifier 1, 2 Alter lipid, cholesterol, and glucose metabolism Reduce visceral abdominal fat Modify activity of hepatic lipase, and skeletal muscle/ adipose lipoprotein lipase Anti-inflammatory 2 / Immuno-modulator 3 Low T results in compromised immune system Inflammatory Cytokines, IL-6, TNF-α and IL-1β, inhibit testosterone secretion by their influence on the central (hypothalamic-pituitary) and peripheral (testicular) components of the gonadal axis. Regenerative Stimulate satellite cells and myocyte precursor resulting in cell differentiation and myocyte proliferation Clinical data demonstrate that adult males who undergo a 4 6% partial hepatectomy experience T levels decline similar to those observed in male rats following a 7% hepatectomy. 4,5 Anabolic effects on muscle, bone and hematopoiesis Low T is a predictor of mortality in men with advanced liver disease Shen and Shi, Int J Endocrinol Kelly and Jones, J Endocrinol Sinclair et al., J Gastroenterol Hepatol Francavilla et al., Digest Dis Sci Vic et al., Hepatol Sinclair et al., J Gastroenterol Hepatol 216

9 Testosterone Deficiency Induces NAFLD/NASH Testosterone Treatment Improves Liver Functions 1 Groups Intact + Normal Diet I + RCD (Control) Intact + High Fat Diet I + HFD Castrated + High Fat Diet C + HFD Castrated + High Fat Diet + Testosterone C + HFD + T Histology Histopathology lipid deposits: Normal Similar to control Increase in score Similar to control Hepatocyte Apoptosis: Rare occurrence Higher than control Significantly higher than control Similar to I + HFD ALT: 4.7 ± 4.4 IU/L 47.4 ± 3.8 IU/L 6.6 ± 6.4 IU/L 44.4 ± 4.5 IU/L Macrovascular Inflammation: Normal No Yes No 9 1 Nikolaenko et al., Endocrinol 214

10 T Therapy Effects in Liver Regeneration Liver Mass Restoration in T Treated Hepatectomized Rat Model* 9% Hepatectomized rat groups Group 1 (n=5) No Treatment Group 2 (n=5) T Treatment Group1 Steatosis occurs with cell damage 1% died within 4 hrs. Group2 Cell activity 8% survived beyond 4 hrs. (5% had a normal life span) Fig 1. Group 1: 24 hr post hepatectomy. (I) massive steatosis, (ch) rare chromatin, organelle depletion = cell damage Pretreatment 4% 6% Total liver mass recovery completed Day-3 1 TE Day Hepatectomy * Vic et al., Hepatol 1982 Day3 Day4 Day15 TE: Testosterone Enanthate Fig 2. Group 2: 24 hr post hepatectomy. (dch) dispersed rare chromatin, numerous cytoplasmic organelles = cell activity

11 Estimated NASH Prevalence in US Hypogonadal Males NAFLD is Over-Represented in Hypogonadal Males 92M Males ages 3 yrs 1 22M Hypogonadal M NAFLD 3 5.5M Male Hypogonadal NASH Patients US Census (216) 2 Araujo AB et al., JCEM 27 3 NAFLD prevalence of 58% estimated from Lipocine LFS study based on liver fat% 5% 4 NASH prevalence of 25% estimated from Lipocine LFS study based on liver fat% 1%

12 % Subjects LPCN 1144: General Safety LPCN 1144 is a prodrug of bioidentical sex hormone Extensive clinical safety database with LPCN subjects in 12 studies with up to 52 week exposure Safety profile well-characterized and demonstrated no unexpected risks Well tolerated with no adverse liver enzyme signals, no deaths or MACE events Good gastrointestinal tolerability with no signs of skeletal fragility or nephrotoxicity No drug related SAEs

13 LPCN 1144 Liver Fat Study On-going 13

14 LPCN 1144: Liver Fat Imaging Study ( LFS ) Study Design and Liver Fat Baselines LFS is an open-label, multi-center single-arm 16-week study (N=36) with LPCN 1144 in hypogonadal males 14 LF = liver fat

15 % of Population LPCN 1144: Liver Fat Imaging Study ( LFS ) Comorbidity Demographics 9% 8% 81% 7% 6% 58% 5% 4% 3% 2% 33% 19% 28% 1% % OBS HTG HTN T2D MetS 15 OBS: Obesity, HTG: Hypertriglyceridemia, HTN: Hypertension, T2D: Type2 Diabetes, MetS: Metabolic Syndrome (at least three of OBS, HTG, HTN, and T2D)

16 % of NAFLD Patients LPCN 1144: Liver Fat Imaging Study ( LFS ) NAFLD Prevalence in Hypogonadal Males vs. General Male Population Prevalence of NAFLD in LFS Population vs. General Population 7% 58% 6% 5% 4% 3% 28% 2% 1% % LFS Population General Population 16 NAFLD identified by MRI-PDFF 5% in LPCN 1144 Liver Fat Study 28% was estimated from 25% of general population diagnosed as NAFLD by imaging hepatosteatosis 5% liver fat (Younossi et al, ) by male ratio to female in NAFLD = ~1.1

17 Absolute Liver Fat % CBL LPCN 1144: Absolute Liver Fat % Reduction Comparable/Better Liver Fat Reductions Absolute Change of MRI-PDFF % PLC Dose1 Dose Wk 12Wk 12Wk 36Wk 16Wk 36D 12Wk 72Wk LPCN 1144 NGM282 VK-289 MGL-3196 BMS98636 NGM313 GS 976 OCA BL PDFF % Criteria > 1% > 8% > 1% > 1% > 1% > 8% > 1% Mean 18.6% 17 LPCN 1144 (LFS Study Interim Results); NGM282 (Harrison et al., NASH-TAG 218); VK-289 (Press Release, Nov 218); MGL-3196 (Corp ppt, Evercore ISI, Nov 218); BMS98636 (Sanyal et al., NASH-TAG 218); NGM313 (Shankar et al., AASLD 218); GS 976 (Press Release, Oct 218); OCA (Middleton et al., Gastroenterol 217)

18 Relative Liver Fat % CBL LPCN 1144: Relative Liver Fat % Reduction Comparable/Better Liver Fat Reductions Relative Change of MRI-PDFF % PLC Dose1 Dose Wk 12Wk 12Wk 36Wk 16Wk 36D 12Wk 72Wk LPCN 1144 NGM282 VK-289 MGL-3196 BMS98636 NGM313 GS 976 OCA BL PDFF % Criteria > 1% > 8% > 1% > 1% > 1% > 8% > 1% Mean 18.6% 18 LPCN 1144 (LFS Study Interim Results); NGM282 (Harrison et al., NASH-TAG 218); VK-289 (Press Release, Nov 218); MGL-3196 (Corp ppt, Evercore ISI, Nov 218); BMS98636 (Sanyal et al., NASH-TAG 218); NGM313 (Shankar et al., AASLD 218); GS 976 (Press Release, Oct 218); OCA (Middleton et al., Gastroenterol 217)

19 LPCN 1144 Post-hoc Analyses M Study (N=24) SOAR Study (N=21) 16-2 Study (N=94) 19

20 LPCN 1144: Post-hoc Analysis Methods Analyses of LPCN 1144 therapy results were performed with multiple clinical studies involving hypogonadal male cohorts with baseline liver enzymes* and lipids** Placebo-controlled, randomized, double blind study (M12-778) with four week treatment Analysis of 225mg BID, 3mg BID and Placebo (N=24) Active-controlled, randomized, open label study (SOAR, N=21) with 52 week treatment - 225mg ± 75mg BID Single-arm open label study (16-2, N=94) with three week treatment 225mg BID 2 * ALT, AST, ALP, GGT; Persistent elevated ALT is a biomarker often used in clinical diagnosis of NAFLD/NASH ** Triglyceride is strongly associated with non-alcoholic fatty liver disease

21 Placebo-adjusted Mean Change (±SEM) LPCN 1144: Significant Reduction in Liver Enzyme Levels Placebo Controlled 4 Week Study (M12-778) ALT AST ALP GGT % -1% -2% -11.5% -11.% -21.% -6.6% -15.8% -16.7% -3% -4% -47.4% -47.3% -5% -6% LPCN mg BID LPCN mg BID 21

22 ALT Mean Change from BL (±SEM), U/L LPCN 1144: Significant Reduction in ALT Levels Placebo Controlled 4 Week Study (M12-778) p =.2 5 p = N = Placebo LPCN mg BID LPCN mg BID 22

23 % of Patients in SOAR Trial LPCN 1144: SOAR Trial Comorbidity Distribution Active Controlled 52 Week Study (SOAR) 6% 56% 5% 48% 4% 3% 2% 22% 1% 9% % Obesity (OBS) Hypertension (HTN) T2 Diabetes (T2D) MetS* (OBS + T2D + HTN) 23

24 ALT Mean Change from BL (±SEM), U/L Mean Change from BL (±SEM), U/L LPCN 1144: Reductions of Elevated ALT in Patients at Risk of NAFLD Active Controlled 52 Week Study (SOAR) In Patients with NAFLD Comorbidity Sustained Reduction of Elevated ALT** Mean BL (U/L) OBS T2D HTN OBS & T2D MetS* Study Period (Week) ** Patients + with ALT > 4 U/L at BL (N=42); ALT mean BL = 53.6 U/L Patients with ALT > 4 U/L at BL in SOAR Trial * Metabolic syndrome: obesity + diabetes + hypertension 24

25 TG Mean Change from BL (±SEM), mg/dl TG Mean Change from BL (±SEM), mg/dl LPCN 1144: Reductions of Elevated TG in Patients at Risk of NAFLD Active Controlled 52 Week Study (SOAR) In Patients with NAFLD Comorbidity Sustained Reduction of Elevated TG** OBS T2D HTN OBS & T2D MetS* Study Period (Week) Mean BL (UL) 1.5xUL 2.xUL 1.6xUL 1.9xUL 2.1xUL ** Patients + for TG > 2 mg/dl at BL (N=73); TG mean BL = 32 mg/dl Patients with TG > 2 mg/dl at BL in SOAR Trial * Metabolic syndrome: obesity + diabetes + hypertension 25

26 LPCN 1144: Consistent Liver Function Improvement Across Studies* Effect Observed as Early as 3 Weeks Mean Change from BL (±SEM) % SOAR (52 Week) 16-2 (3 Week) -5% -5.1% -1% -1.3% -13.2% -1.1% -9.6% -15% -17.4% -18.8% -18.5% -2% -25% -3% ALT AST ALP GGT Mean BL (U/L) * LPCN 1144 Patients for ALT > 4 U/L at BL; SOAR (N=42), 16-2 (N=13) 26

27 LPCN 1144: Elevated Biomarker Normalization Appreciable % of Patients Experienced Normalization of Lipids and Liver Biomarkers % of Normalized Patients from Abovenormal at Baseline Normlization of Serum Biomarkers with LPCN % 56% 52% 5% 4% 3% 34% 31% 28% 2% 1% % ALT* TG* LDL-C* GGT* Liver Fat %** 27 * Data obtained from SOAR Trial; ALT, TG, LDL-C, and GGT normal range upper limit is 4 U/L, 2 mg/dl, 16 mg/dl, and 49 U/L, respectively ** Data obtained from LFS; Liver fat % 5% at baseline to < 5% at interim visit (8 weeks)

28 % of ALT Responders at EOS LPCN 1144: Robust ALT Response Good Potential for Histological Improvement in NASH and Fibrosis 1 Comparable LPCN1144 ALT response to Vitamin E in PIVENS Trial 2 6% 5% 4% 3% 2% 1% 43% 48% * ALT Responders: Patients with ALT > 4 U/L at baseline, ending with 4 U/L and more than 3% reduction at end of study post therapy Total non-alcoholic fatty liver activity score (NAS), comprising the sum of scores for steatosis, inflammation, and ballooning cell injury Resolution of histological features that fulfil the criteria for diagnosis of NASH % N = 42* N = 71* LPCN 1144 (Wk 52) Vitamin E (Wk 12) Total N is for patients with ALT > 4 U/L at baseline (ALT normal range is 4 U/L) 28 1 Hoffnagle et al. APT Sanyal et al, New Eng J Med, 21

29 PDQ SF-36 LPCN 1144: Additional Health Benefits Observed in Hypogonadal Subjects with Elevated ALT* Active Controlled 52 Week Study (SOAR) Mental Component Summary Mental Health Role Emotional Maintained Erection Sexual Activity Negative Mood Positive Mood Overall Sexual Desire Mean Change (±95% CI) from Baseline 29 SF-36, Short Form-36 (-1); PDQ, Psychosexual Daily Questionnaire (-7); * ALT > 4 U/L at Baseline in 52 week SOAR Trial (N=33)

30 LPCN 1144 Comparison with Topical Testosterone 3

31 Mean Change from Baseline (mg/dl) Mean Value for Patients with Above-normal at BL (mg/dl) LPCN 1144: Unique TG Reduction 52 Week SOAR Trial TG mean change post therapy in patients on oral T vs non-oral T therapy TG Mean Change after 52 Week for Patients with Above-normal TG* at BL TG Mean Value for Patients with Abovenormal TG* at BL during 52 Week Therapy 6 LPCN 1144 Topical T Mean BL = 32 mg/dl 323 mg/dl 25 N = 73/21 34/14 LPCN 1144 Topical T Therapy Duration (Week) 31 * TG normal range in SOAR Trial: 45 2 mg/dl

32 TG Mean Change from BL (mg/dl) LPCN 1144: Oral T TG Reduction Comparison with Topical T Across Various Comorbidities 52 Week SOAR Trial Unique Oral T Therapy in TG Reduction Post 52 Week Therapy in Patients with Comorbidities Oral T Topical T Overall Obesity Diabetes Hypertension OBS & Diab MeS* N Overall Obesity Diabetes Hypertension OBS & Diab MeS Oral T Topical T * MeS: Metabolic syndrome (Obesity + Diabetes + Hypertension)

33 LPCN 1144 Biomarker Change Comparison (Separate Studies/Not Head to Head) 33

34 TG Mean Change from BL (mg/dl) LPCN 1144: Comparison of TG Mean Change from BL with Phase 3 Drug Candidates 2 TG Mean Change from Baseline Mean BL=1.6xULN* 1.2xULN* 1.3xULN**** 1.2xULN**** 1.2xULN**** 1.2xULN**** N = 73** 141*** LPCN 1144 (Wk 52) Obeticholic acid (Wk 72) - 25mg Cenicriviroc (Wk 52) - 15mg Selon/Simtu (Wk 24) - 18mg/125mg Selon/Simtu (Wk 24) - 6mg/125mg * Upper limit of normal range (ULN) is 2 mg/dl **, *** SOAR Trial patients with TG > 2 mg/dl and >12 mg/dl at baseline, respectively **** ULN is not reported; typical ULN is 15 mg/dl Mean change values for Selonsertib/Simtuzumab are median in interquartile range 34 Obeticholic acid: Neuschwander-Tetri et al, Lancet 215 Cenicriviroc: Friedman et al, Hepatology 218, Suppl. Table 5 Selonsertib/Simtuzumab: Loomba et al, Hepatology 218

35 TG Mean Change from BL (mg/dl) LPCN 1144: Comparison of TG Mean Change from BL with Phase 2 Drug Candidates 6 TG Mean Change from Baseline Mean BL=1.6xULN* 1.2xULN* 1.2xULN**** 1.3xULN**** 1.1xULN**** 1.4xULN**** 1.2xULN**** 1.1xULN**** N = 73** 141*** LPCN 1144 (Wk 52) MGL 3196 (Wk 12) - 8±2mg NGM282 (Wk 12) - 3mg NGM282 (Wk 12) BMS98636 (Wk BMS98636 (Wk GS-976 (Wk 12) - 6 mg 16) - 1mg 16) - 2mg - 2mg * Upper limit of normal range (ULN) is 2 mg/dl. **, *** SOAR Trial patients with TG > 2 mg/dl and 12 mg/dl at baseline, respectively. **** ULN is not reported; typical ULN is 15 mg/dl. Mean change for GS 976 is recalculated from mean values at BL and EOS. 35 MGL 3196: EASL International Liver Congress 218, April 218 NGM282: Harrison et al, The Lancet 218 BMS98636: Sanyal et al, AASLD, Oct 217 GS976: Lawitz et al, Clin Gasteroenterol Hepatol 218

36 ALT Mean Change from BL (U/L) LPCN 1144: Comparison of ALT Mean Change from BL with Phase 3 Drug Candidates 2 ALT Mean Change from Baseline Mean BL=82.7 U/L 57.2 U/L 83 U/L 6.4 U/L 69 U/L 56 U/L N=3* 32** LPCN 1144 (Wk 52) Obeticholic acid (Wk 72) - 25mg Cenicriviroc (Wk 52) - 15mg Selon/Simtu (Wk Selon/Simtu (Wk 24) - 18mg/125mg 24) - 6mg/125mg * SOAR Trial Patients with ALT > 75 U/L at baseline ** SOAR Trial Patients with ALT 45 U/L at baseline Mean change values for Selonsertib/Simtuzumab are median in interquartile range 36 Obeticholic acid: Neuschwander-Tetri et al, Lancet 215 Cenicriviroc: Friedman et al, Hepatology 218, Suppl. Table 5 Selonsertib/Simtuzumab: Loomba et al, Hepatology 218

37 Mean Change from BL (U/L) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with Obeticholic Acid Obeticholic Acid (FXR agonist) FLINT Study, P2, 72 weeks, 25mg dose Comparison of ALT Mean Change Comparison of TG Mean Change LPCN 1144 (Wk 52) Obeticholic acid (Wk 72) LPCN 1144 (Wk 52) Obeticholic acid (Wk 72) ALT TG -19 Mean BL 82.7 U/L 83 U/L** N 3* 126 * SOAR Trial patients with ALT > 75 U/L at baseline ** Reported mean baseline level for Obeticholic Acid (N=141) Reported placebo mean change for Obeticholic Acid is -18 U/L Mean BL 1.3xULN* 1.3xULN*** N 19** 126 * Upper limit of normal range (ULN) is 2 mg/dl ** SOAR Trial patients with TG > 15 mg/dl at baseline *** ULN is not reported; typical ULN is 15 mg/dl Reported placebo mean change for Obeticholic Acid is -7 mg/dl Neuschwander-Tetri et al, Lancet

38 LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with Elafibranor Elafibranor (PPAR-a, d agonist) P2, 52 weeks, 12mg dose LPCN 1144 ALT Elafibranor Elafibranor ALT Mean BL 62.2 U/L Mean BL 63.8 U/L N 22* N 78 Mean Change from BL, (SE) -2 (±3.1) U/L Mean Change from BL, (SE) -12 U/L * SOAR Trial patients with ALT > 5 U/L Mean BL LPCN 1144 TG 1.2xULN** Possible Unit typo mmol/l Elafibranor Mean BL Elafibranor TG 1.2xULN N 141*** N 78 Mean Change from BL, (SE) -.4 (±.1) mmol/l Mean Change from BL, (SE) -.5 mmol/l ** Upper limit of normal range (ULN) is 2 mg/dl *** SOAR Trial patients with TG > 12 mg/dl at baseline ULN is not reported; typical ULN for TG is 15 mg/dl. Ratziu et al, Gastroenterol,

39 Mean Change from BL (U/L) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with Cenicriviroc Cenicriviroc (CCR2/CCR5 inhibitor) P2, 52 weeks, 15mg dose Comparison of ALT Mean Change LPCN 1144 (Wk 52) Cenicriviroc (Wk 52) Comparison of TG Mean Change LPCN 1144 (Wk 52) Cenicriviroc (Wk 52) ALT -5 TG Mean BL 57.2 U/L 6.4 U/L N 32* 123 * SOAR Trial patients with ALT 45 U/L. Mean BL 1.2xULN* 1.2xULN*** N 141** 123 * Upper limit of normal range (ULN) is 2 mg/dl. ** SOAR Trial patients with TG > 12 mg/dl at baseline. *** ULN is not reported; typical ULN is 15 mg/dl. Friedman et al, Hepatology 218, Suppl. Table 5 39

40 Mean Change from BL (U/L) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with Selonsertib/Simtuzumab Selonsertib/Simtuzumab (ASK1 inhibitor) P2, 24 weeks, 18mg or 6mg Selonsertib with fixed Simtuzumab dose Comparison of ALT Mean Change Comparison of TG Mean Change LPCN 1144 (Wk 52) Selon/Simtu (Wk 24) - 6mg* Selon/Simtu (Wk 24) - 18mg* LPCN 1144 (Wk 52) Selon/Simtu (Wk 24) - 6mg Selon/Simtu (Wk 24) - 18mg ALT TG 12 Mean BL 57.2 U/L 69 U/L 56 U/L N SOAR Trial patients with ALT 45 U/L * Mean change values for Selonsertib/Simtuzumab are median in interquartile range Mean BL 1.2xULN* 1.2xULN*** 1.2xULN*** N 141** 32 3 * Upper limit of normal range (ULN) is 2 mg/dl ** SOAR Trial patients with TG > 12 mg/dl at baseline *** ULN is not reported; typical ULN is 15 mg/dl Mean change values for Selonsertib/Simtuzumab are median in interquartile range Loomba et al, Hepatology 218 4

41 Mean Change from BL (U/L) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with MGL 3196 MGL 3196 (THR-b agonist) P2, 12 weeks, 8mg ± 2mg dose Comparison of ALT Mean Change Comparison of TG Mean Change LPCN 1144 (Wk 52) MGL 3196 LPCN 1144 (Wk 52) MGL ALT -5 TG N 32* 47** * SOAR Trial Patients with ALT 45 U/L for males ** Patients of MGL 3196 are with ALT 45 U/L for males and > 3 for females; mean BL for these patients of MGL 3196 is not reported Reported placebo ALT mean change is -7.7 U/L. * Upper limit of normal range (ULN) is 2 mg/dl ** SOAR Trial patients with TG > 12 mg/dl at baseline *** ULN is not reported; typical ULN is 15 mg/dl Mean BL 1.2xULN* 1.2xULN*** N 141** 79 * Upper limit of normal range (ULN) is 2 mg/dl ** SOAR Trial patients with TG > 12 mg/dl at baseline *** ULN is not reported; typical ULN is 15 mg/dl EASL International Liver Congress 218. Paris, France April 11-15,

42 Mean Change from BL (U/L) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with Injectable NGM282 NGM282 (FGF19 analog) P2, 12 weeks, 3mg and 6mg dose Comparison of ALT Mean Change Comparison of TG Mean Change LPCN 1144 (Wk 52) NGM282 (Wk 12) - 3mg LPCN 1144 (Wk 52) NGM282 (Wk 12) - 3mg NGM282 (Wk 12) - 6 mg NGM282 (Wk 12) - 6 mg ALT -6 TG Mean BL 62.2 U/L 67.4 U/L 61.8 U/L N 22* * SOAR Trial Patients with ALT > 5 U/L at baseline. Mean BL 1.2xULN* 1.3xULN*** 1.1xULN*** N 141** * Upper limit of normal range (ULN) is 2 mg/dl. ** Patients are with TG > 12 mg/dl at baseline. *** ULN is not reported; typical ULN is 15 mg/dl. Harrison et al, The Lancet

43 Mean Change from BL (%) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with BMS BMS (Peg-FGF21) P2, 16 weeks, 1mg and 2mg dose Comparison of ALT Mean Change Comparison of TG Mean Change LPCN 1144 (Wk 52) BMS (Wk 16) - 1mg LPCN 1144 (Wk 52) BMS98636 (Wk 16) - 1mg BMS (Wk 16) - 2mg BMS98636 (Wk 16) - 2mg % -1% % -22% -2-3% -31% -34% % ALT -4 TG Mean BL 62.2 U/L 66 U/L 7 U/L N 22* * SOAR Trial Patients with ALT > 5 U/L at baseline. ALT mean change from baseline for BMS was obtained from graph image in reference. Mean BL 1.2xULN* 1.4xULN*** 1.2xULN*** N 141** 2 17 * Upper limit of normal range (ULN) is 2 mg/dl. ** Patients are with TG > 12 mg/dl at baseline. *** ULN is not reported; typical ULN is 15 mg/dl. Sanyal et al, AASLD, Oct

44 Mean Change from BL (U/L) Mean Change from BL (mg/dl) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with GS 976 GS 976 (ACC inhibitor) P2, 12 weeks, 2mg dose Comparison of ALT Mean Change Comparison of TG Mean Change LPCN 1144 (Wk 52) GS-976 (Wk 12) - 2mg LPCN 1144 (Wk 52) GS-976 (Wk 12) - 2mg ALT TG Mean BL 82.7 U/L 11 U/L N 3* 1 * SOAR Trial Patients with ALT > 75 U/L at baseline. Mean Change value is obtained from Mean values at BL and EOS. Mean BL 1.2xULN* 1.1xULN*** N 141** 1 * Upper limit of normal range (ULN) is 2 mg/dl. ** Patients are with TG > 12 mg/dl at baseline. *** ULN is not reported; typical ULN is 15 mg/dl. Mean Change value is obtained from Mean values at BL and EOS. Lawitz et al, Clin Gasteroenterol Hepatol

45 Mean Level (U/L) LPCN 1144: Comparison of Key NASH Biomarker Mean Change from BL with Aramchol LPCN 1144 * 52 weeks, randomized Aramchol P2, 52 weeks, 6mg dose 7 ALT Mean Values over 52 weeks Unadjusted mean change from BL**: ~ -13 U/L 6 5 Mean change from BL to EOS: -2 U/L Visit (Wks) * SOAR Trial patients with ALT > 5 U/L at baseline (Mean BL = 62.2 U/L), N=22 ** Mean BL for 6mg dose: 62.8 U/L, N=98 Galmed Corp PPT, Jun

46 LPCN 1144: LFS Interim Results Summary Strong Liver Fat Reduction Signal in at Risk Hypogonadal Males Higher prevalence of NAFLD was observed in hypogonadal males relative to the general population, even after BMI stratification Substantial reductions of liver fat were achieved with LPCN 1144 therapy as early as 8 weeks Appreciable % of subjects experienced resolution of NAFLD while on LPCN 1144 treatment LPCN 1144 liver fat reductions via MRI-PDFF are comparable or better than other candidates in development Significant reduction of key biomarkers levels in patients with elevated ALT and TG, adjunct markers often used in clinical diagnosis of NASH Significant number of patients for liver enzymes, TG, and LDL-C shifts from abovenormal levels at BL to normal levels at EOS Consistent biomarker reduction independent of therapy duration across multiple studies Significant Biomarker reduction comparable or greater than most drug candidates in advanced drug development with clinical liver biopsy data 46