AASLD24 Poster Presentation: PHIN-214: Phase 1 Study in Compensated and Decompensated Cirrhotic Patients – A Novel Treatment to Manage Complications of Portal Hypertension with Subcutaneous, Once-daily Self-administration

Portal hypertension drives disease progression and decompensation in liver cirrhosis. Treatment of decompensated cirrhosis is largely palliative and there are no approved directed pharmacologic therapies for long-term management of portal hypertension. Terlipressin, a vasopressin-analog recently approved by FDA, reduces portal pressure, however, its potential to elicit ischemia mandates inpatient venous infusion and stringent safety monitoring. PHIN-214 is a proprietary, structurally optimized derivative of terlipressin designed to exhibit partial V1a receptor agonism with a reduced V2 receptor affinity, and a 10-fold broader therapeutic index than terlipressin. PHIN-214 was engineered to manage portal hypertension and associated complications, as a self- administered, subcutaneous (SC), once-daily (QD) injection in an outpatient setting. PHIN-001 is an on-going Phase 1 dose-optimization study comprising both single and multi-ascending dose assessments of SC PHIN-214 in patients with cirrhosis. The primary objectives of the PHIN-001 study are to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) properties of PHIN- 214, and to establish the recommended Phase 2 dose for further development. D. SIMONETTO 1, N. ALKHOURI2 , E. WEINBERG3, P. SCHWABL4, A. KOHLI2, M. PORAYKO5, E. LAWITZ6 1Mayo Clinic College of Medicine and Science, Rochester, Minnesota, US; 2Arizona Liver Health, Chandler, Arizona, US; 3University of Pennsylvania, Philadelphia, Pennsylvania, US; 4Medical University of Vienna, Vienna, Austria; 5Vanderbilt University Medical Center, Nashville, TN; 6Texas Liver Institute, University of Texas Health, San Antonio, San Antonio, Texas, US *PHIN-001 is sponsored by PharmaIN Corporation: 11812 N. Creek Parkway North, Suite 101, Bothell, WA 98011. http://www.pharmain.com/ *PHIN-214: Phase 1 Study in Compensated and Decompensated Cirrhotic Patients - A Novel Treatment to Manage Complications of Portal Hypertension with Subcutaneous, Once-daily Self-administration PHIN-214 is a small peptide prodrug that is metabolized rapidly post- administration into the pharmacologically active metabolite PHIN-156 (Fig 1). PHIN-156 activates V1a receptors on arterial smooth muscle causing mesenteric arterial vasoconstriction, reducing splanchnic blood flow and reducing portal pressure. Vasoconstriction also increases systemic arterial pressure preventing activation of the renin-angiotensin-aldosterone system (RAAS) and sodium retention. Moreover, increased systemic and renal arterial pressure improves kidney perfusion, glomerular filtration rate (GFR) and creatinine clearance. Figure 1: Amino acid sequence of PHIN-214 and its active metabolite, PHIN-156 (right) compared to terlipressin and its active metabolite, lysine vasopressin (LVP, left). PHIN-001: Phase 1 open label, single-arm, dose optimization study Part 1 – Single-Ascending Dose (SAD) • Single dose • 24-hour observation period, PK/PD assessments Part 2 – Multiple-Ascending Dose (MAD) • 28-days of single, daily administration ▪ Days 1-4, 7, 14, 21 & 28 clinic visits for observation, PK/PD assessments ▪ Days 4-28 daily self-administration at home​ Option for SAD patients to roll into MAD study​ To date, a total of 6 single ascending dose levels of PHIN-214 have been administered in a total of n=13 subjects INTRODUCTION Demographic/Baseline Characteristic (n=13) Value Average age 55.5 (range: 43-72) Average BMI 33.1 (range: 26-38) Female (n) 8 Ascites (n) 4 NSBB (n) 8 Diuretic use (n) 7 Disease etiology Alcohol (n) 6 NASH (n) 3 HCV (n) 2 Alcohol & HCV (n) 2 Prodrugs Active metabolites Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-Lys-Gly Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-Lys-Gly Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly (Gly)6 Baseline Dose Level 1 1 2 2 3 4 4 4 5 5 5 6 6 CTP class A A A B A A A B A B B A A MELD-Na 7 6 6 12 14 14 14 9 11 9 11 7 8 Albumin (g/dL) 4.4 3.8 4.1 4.1 3.6 3.3 4.0 3.5 3.4 3.6 2.7 3.7 4.6 Creatinine (mg/dL) 0.7 0.6 0.7 0.6 1.4 0.6 1.1 1.1 0.5 0.7 0.6 0.6 0.9 eGFR-Cr (mL/min) 100 98 89 109 49 118 76 72 113 103 111 102 103 Total Bilirubin (mg/dL) 0.7 0.4 0.4 2.0 0.6 2.7 2.2 1.2 1.4 0.5 0.8 0.7 0.7 Sodium (mmol/L) 143 140 142 142 137 136 137 138 139 136 140 140 138 Hemoglobin (g/dL) 14 13 13 13 12 13 13 13 14 12 12 10 18 Platelets (x109/L) 124 137 156 128 56 79 61 110 144 82 56 227 135 INR 1.1 1.0 1.0 1.3 1.4 1.3 1.4 1.1 1.5 1.2 1.5 1.1 1.2 Metabolism of PHIN-214 and PHIN-156 are thought to be mediated by peripheral peptidases, and exposure is not anticipated to increase as a function of hepatic impairment. However, in this first-in-human study, Child-Pugh grade A (CP-A) subjects with less advanced cirrhosis were enrolled before Child-Pugh grade B (CP-B) subjects, to explore any association between disease severity and drug metabolism. Table 1: Summary of study population demographics and baseline characteristics (n=13) eGFR (n=13) Change from baseline (calculated with cystatin C) 8 hr 24 hr Delta % 28.5 CI 95% [18.7, 38.3] 14.8 CI 95% [6.4, 23.3] Figure 2: Pharmacokinetic plots of PHIN-214 (A) and PHIN-156 (B); serum creatinine (C); serum cystatin C (D); serum sodium for the whole population (E); and for subjects taking concomitant diuretics (F); eGFR calculated based on cystatin C (F); with % chan ge from baseline at 8 and 24 hours (H); * indicates a CP-B subject INTRODUCTION Pseudo-hyponatremia was evident in some patients with elevated baseline hyperglycemia. Of note, an improvement in eGFR was observed in the majority of subjects (Fig. 2G, H), with a median 28.5% improvement at 8 hours being sustained at 14.8% by 24 hours following a single dose of PHIN-214. The emerging PK profile of PHIN-156 supports QD dosing with little predicted accumulation. 1DS: Consultant: PharmaIN, Mallinckrodt, Evive, Resolution Therapeutics, AstraZeneca, Iota and BioVie. 2NA: Received grant/research support from 89bio, Akero Therapeutics, Arbutus Biopharma, AstraZeneca, BioAge, Boehringer Ingelheim, Bristol Myers Squibb, Corcept Therapeutics, CymaBay Therapeutics, DSM, Galectin Therapeutics, Genentech, Genfit, Gilead Sciences, Healio, Hepagene Therapeutics, Intercept Pharmaceuticals, Inventiva Pharma, Ionis Pharmaceuticals, Ipsen, Lilly, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Noom, NorthSea Therapeutics, Novo Nordisk, Perspectum, Pfizer, PharmaIN, Poxel, Viking Therapeutics, and Zydus Pharmaceuticals; reports speaker’s fees from AbbVie, AstraZeneca, Echosens, Gilead Sciences, Intercept Pharmaceuticals, Ipsen, Madrigal Pharmaceuticals, and Perspectum; and reports consulting for 89bio, Akero, Boehringer Ingelheim, Echosens, Fibronostics, Gilead Sciences, Intercept Pharmaceuticals, Ipsen, Madrigal Pharmaceuticals, NorthSea Therapeutics, Novo Nordisk, Perspectum, Pfizer, and Zydus Pharmaceuticals 3EW: Consultant: PharmaIN, Biovie, Novo Nordisk, Sequana, Astra Zeneca, Kezar 4PS: Consultant: PharmaIN. Travel support: Falk Pharma 2AK: Madrigal, Gilead 5MP: Consultant: PharmaIN, BioVie and River2Renal. 6EL: Research: 89Bio Inc., Akero Therapeutics, Alnylam Pharmaceuticals Inc., Amgen, Astrazeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cour Pharmaceuticals, Cymabay Therapeutics, Eli Lilly and Company, Enanta Pharmaceuticals, Enyo Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead Sciences, GlaxoSmithKline, Hanmi Pharmaceuticals, Hightide Biopharma, Intercept Pharmaceuticals, Inventiva, Ipsen, Janssen Pharmaceuticals, Madrigal Pharmaceuticals, Merck & Co., NGM Biopharmaceuticals Inc., Northsea Therapeutics, Novartis, Novo Nordisk Inc., Organovo, Poxel Co., Regeneron, Sagimet Biosciences, Takeda, Terns Pharmaceuticals, Viking Therapeutics, Zydus Pharmaceuticals. Speaker: Abbvie, Gilead Sciences, Intercept, Madrigal. Consultant: 89Bio Inc, Astrazeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck & Co, Novo Nordisk Inc, Organovo, Regeneron, Sagimet Biosciences No treatment-emergent dose-limiting toxicities, serious adverse events (SAEs) or incidents of peripheral or central ischemia have occurred to date. Adverse events (AEs) reported as related to PHIN-214 include: • One CP-B subject (DL4) experienced a Grade 1 transient injection site reaction (blanching of skin) • One CP-B subject (DL5) experienced acid reflux (Grade 2); abdominal pain & diarrhea (Grade1). • One CP-A subject (DL6) experienced Grade 2 diarrhea with onset at 5 hours post dose which resolved by 21 hours post dose. • Additional adverse events include transient Grade 2 asymptomatic hypo- natremia (3 subjects), which were coincident with concomitant diuretic therapy. AEs reported as unrelated to PHIN-214 include: • One incidence of hypotension (Grade 1) Single, SC injection of PHIN-214 is well tolerated in compensated and decompensated cirrhosis, and yielded preliminary evidence of clinical activity at all dose levels administered These emerging data support further development of PHIN-214 as a self- administered, SC, QD injection for treatment of complications of portal hypertension in patients with decompensated cirrhosis. PharmaIN Corporation would like to acknowledge the patients, patient caregivers, investigators and their staff participating in the clinical trial, & partial financial funding provided by NIH grant DK103553 The clinical PK profile of both PHIN-214 and PHIN-156 are consistent with preclinical observations1 (Fig 2A, B), with overall exposure being more comparable to dogs than rats. PHIN-214 is absorbed and metabolized rapidly (median Tmax = 0.5 hrs; median half life = 0.9 hrs) to the active metabolite PHIN-156 which persists longer (median Tmax = 8 hrs; median half life = 5.2 hrs). Overall, exposure to PHIN-214 and PHIN-156 appears dose-proportional. All subjects dosed to date demonstrate a drop in serum concentrations of sodium (Fig. 2E, F), creatinine (Fig. 2C) and cystatin C (Fig. 2D) with creatinine and cystatin C appearing concentration-dependent. Subjects on concomitant diuretic therapy tend to exhibit more pronounced hyponatremia (Fig. 2F). Reference: 1Biomedicine & Pharmacotherapy 2024 (171) 116068. (https://doi.org/10.1016/j.biopha.2023.116068) Terlipressin LVP PHIN-214 PHIN-156 0 5 10 15 20 25 30 0 500 1000 1500 2000 2500 Pharmacokinetics: PHIN-156 Hours post dose Concentration 0 5 10 15 20 25 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Serum Creatinine Hours post dose Serum Creatinine (mg/dL) 0 5 10 15 20 25 0.5 1.0 1.5 2.0 Serum Cystatin C Hours post dose Serum Cystatin C (mg/L) 0 5 10 15 20 25 125 130 135 140 145 Serum Sodium Hours post dose Serum Sodium (mmol/L) 0 1 2 3 4 5 0 2000 4000 6000 Pharmacokinetics: PHIN-214 Hours post dose Concentration ** * * Table 2: Summary of individual subject characteristics (n=13) INTRODUCTION BACKGROUND STUDY OVERVIEW SAFETY OBSERVATIONS CONCLUSIONS ACKNOWLEDGEMENTS AUTHOR DISCLOSURES PK & PD OBSERVATIONS Pharmacokinetics: PHIN-214 Pharmacokinetics: PHIN-156 Serum Sodium Serum Cystatin CSerum Creatinine A G H FE DC B DL1 DL1 DL2 DL2* DL3 DL4 DL4 DL4* DL5* DL5* DL6 DL6 -20 0 20 40 60 eGFR by Cystatin C % change % Change from 0hr 8h 24h eGFR by Cystatin C % change 0 5 10 15 20 25 125 130 135 140 145 Serum Sodium, subjects with Hours post dose Serum Sodium (mmol/L) Serum Sodium, subjects with diuretics

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