AASLD25 Poster Presentation: Phase 1, Single-Ascending Dose Results from the PHIN-001® Study of PHIN-214 in Compensated and Decompensated Patients with Cirrhosis.

NON-USABLE AREA NON-USABLE AREA NON-USABLE AREA NON-USABLE AREA 0 5 10 80 85 90 95 100 Time, hrs Median MAP, mmHg Error bars: SEM Portal hypertension is a major driver of decompensation in patients with cirrhosis, yet effective long-term pharmacologic options remain limited. PHIN-214 is a novel vasopressin analogue with partial V1a receptor agonism, reduced V2 activity, and a wide therapeutic index. It is being developed as a once-daily, subcutaneous self-injection for outpatient management of portal hypertension and its complications. PHIN-001 (NCT05490888) is an ongoing phase 1 dose-optimization study evaluating single and multiple doses of PHIN-214 in adults with Child-Pugh class A and B cirrhosis. The objectives are to assess safety, tolerability, pharmacokinetics, and pharmacodynamics. Douglas A. SIMONETTO 1, Naim ALKHOURI2 , Ethan WEINBERG3, Christina C. LINDENMEYER4, Gary REISS5, Eric. LAWITZ6 1Mayo Clinic College of Medicine and Science, Rochester, Minnesota, US; 2Arizona Liver Health, Chandler, Arizona, US; 3University of Pennsylvania, Philadelphia, Pennsylvania, US; 4Cleveland Clinic Foundation, Cleveland, Ohio, US; 5Tandem Clinical Research, Louisianna, US; 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/ Phase 1, Single-Ascending Dose Results from the PHIN-001* Study of PHIN-214 in Compensated and Decompensated Patients with Cirrhosis. 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​ Demographic/Baseline Characteristic n=15 subjects Age in years, mean (range) 56 (42 - 72) Body Mass Index in Kg/m2, mean (range) 31.6 (24.1 - 39.7) Sex, number (%) Male Female 8 (53) 7 (47) Race, number (%) White Black or African American American Indian or Alaskan Native 13 (87) 1 (7) 1 (7) Ethnicity, number (%) Hispanic or Latino Not Hispanic or Latino 2 (13) 13 (87) Child-Pugh (CP) class, number (%) A B 11 (73) 4 (27) MELD-Na score, mean (range) 10 (6 - 14) Table 2: Relevant Concomitant Medications – Part 1 (SAD) (n=15) BACKGROUND STUDY OVERVIEW EVIDENCE OF CLINICAL ACTIVITY SAFETY Medication Class Number (%) Any diuretics Furosemide Spironolactone Eplerenone 9 (60) 9 (60) 8 (53) 1 (7) Beta Blockers 8 (53) Lactulose 1 (7) Rifaximin 1 (7) Table 1: Baseline demographics and subject characteristics – Part 1 (SAD) (n=15) PHIN-214 was generally well tolerated with a safety profile consistent with on-target V1a engagement. 4 of the 15 total subjects treated experienced AEs considered possibly or likely drug- related adverse events. No AEs were reported in subjects treated at dose levels 1-3. A dose limiting toxicity (DLT) (hypertension) occurred at dose level 8, at which point enrollment into SAD ceased and the study transitioned to part 2 (MAD), per protocol. Dose Level Subject AE (verbatim term) CTCAE Grade DLT 4 106-028 Injection Site Reaction-Blanching 1 No 5 107-032 Acid Reflux 2 No Abdominal pain 1 No Diarrhea 1 No 6 100-027 Diarrhea 2 No 8 105-037 Increased systolic blood pressure 3 YES Blood in stool 2 No Abdominal cramping 2 No Weight loss 1 No Nausea 1 No Headache 1 No Abdominal distension 1 No Irregular, frequent bowel movements 1 No Table 3: Reported AEs possibly/probably/definitely related to PHIN-214 administration An asymptomatic decrease in serum sodium was observed in all cases with a mean decrease of 6.2 mmol/L (95% CI: 4.6-7.8) and mean minimum of 133 mmol/L (95% CI: 131.6-134.4). At 24 hrs. serum sodium recovered to a mean of 135.5 mmol/L (95% CI: 133.8-137.2). Serum sodium changes did not differ between Child Pugh A and B subjects nor between subjects with and without diuretics. PHIN-001: Phase 1 open label, single-arm, dose optimization study PATIENT CHARACTERISTICS The single ascending dose phase of the study is complete. 15 subjects were treated across 8 single-ascending dose levels. 1 subject was treated twice, at dose level 1 and dose level 2. Evidence of improved renal function was observed with improved eGFR (CKD-EPI Cystatin C) in all subjects, irrespective of Child-Pugh classification or baseline eGFR. Improvements in eGFR persisted until at least 24 hours following PHIN-214 dosing in most subjects. Note: Due to missing data in 1 subject at DL5 only 15 data points are included. Figure 3: Changes in eGFR (CKD-EPI Cystatin C); Maximum change and change at 8 hrs. and 24 hrs. post PHIN-214 administration Improvements in eGFR were correlated with PHIN-156 exposure (active metabolite), particularly at higher dose levels. A statistically significant & strong positive correlation was observed in all patients for which sufficient data points were available (Figure 4). Moreover, PHIN-214 treatment resulted in greater decrease in cystatin C than albumin in all subjects (Table 4) and there was no statistically significant correlation between serum albumin and PHIN-156 PK in any subject supporting a true improvement in eGFR mediated by PHIN-214. Pearson r 0.8303 0.9885 0.8592 0.8983 0.8676 P value 0.0056 <0.0001 0.0014 0.001 0.0024 *eGFR based on cystatin C, ML/min *PHIN-156 concentration, pg/ML DL5 DL6 DL6 DL7 DL8 Table 4: Comparison of changes in cystatin C vs Albumin at 8hrs post PHIN-214 administration Figure 4: Correlation between PHIN-214 PK and eGFR (CKD-EPI Cystatin C) % change at 8 hrs. Dose Level Average [95% CI]1 2 3 4 5 6 7 8 Cystatin C -21.6 -3.2 -19.2 -26.7 -14.5 -12.2 -23.0 -9.9 -29.9 -14.9 -28.3 -23.9 -25.3 -29.6 -15.6 -19.8 [-23.9, -15.8]​ Albumin -13.6 +2.6 -7.3 -9.8 -5.6 -6.1 -5.0 -5.7 0 -7.4 +2.7 -4.3 -7.9 -9.3 0 -5.1 [-7.5, -2.7]​ Dose Level 1 2 3 4 5 6 7 8 Child Pugh Class A A A B A A A A A A B A A B A B Dose Level 1 2 3 4 5 6 7 8 CP class A A A B A A A A A B A A B A B Baseline eGFR 57 78 74 90 33 107 45 46 78 60 63 67 87 65 67 Maximum eGFR 85 96 100 116 43 119 95 54 110 78 100 99 116 104 85 eGFR at 24hrs 75 74 76 95 39 106 63 49 95 75 74 80 110 83 69 PHIN-214 treatment resulted in a median Mean Arterial Pressure (MAP) increase of 3.24mmHg over the first 12 hours following PHIN-214 treatment and the median MAP was significantly increased at 7hrs following PHIN-214 administration. Figure 5: Median Mean Arterial Pressure (MAP) post PHIN-214 administration Median at 7 hrs. 96.5 vs baseline 87.2 p=0.0207 * PHARMACOKINETICS 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). PHIN-214 and its active metabolite PHIN-156 demonstrate dose-proportional pharmacokinetics consistent with preclinical observations. 0 1 2 3 4 5 0.0 2.0 4.0 6.0 8.0 10.0 Hours post dose PHIN-214 Concentration, ng/mL DL1 DL1 DL2 DL2 DL3 DL4 DL4 DL5 DL5 DL6 DL6 DL4 DL5 DL6 DL7 DL8 Figure 2: PHIN-214 (parent) and PHIN-156 (active metabolite) pharmacokinetics Baseline Nadir 24 hrs 1DS: Consultant/Advisor: Mallinckrodt, BioVie, Resolution Therapeutics, Evive and Iota. 2NA: Speaking and Teaching: Echosens, Intercept, Ipsen, Gilead, Madrigal; Consultant/Advisor: 89Bio, Boehringer Ingelheim, Cima, Fibronostics, Gilead, Ipsen, Madrigal, Novo Nordisk, Perspectum; Grants/Research Support: 89Bio, Akero, Arbutus, AstraZeneca, Boehringer Ingelheim, Boston Pharma, Corcept, Eli Lilly, Galectin, Gilead, GSK, Inventiva, Ipsen, Madrigal, Merck, Novo Nordisk, Perspectum, Pfizer, Regeneron. 3EW: Consultant/Advisor: Biovie, Amgen, Astra Zeneca, Kezar, Mallinkcrodt, Novo Nordisk, PharmaIN, Sequana. 4CL: Nothing to disclose 5GR: Nothing to disclose 6EL: Speaking and Teaching: AbbVie, Gilead Sciences, Intercept, Madrigal Pharmaceuticals; Grants/Research Support: 89Bio, Akero Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept Therapeutics, Cour Pharmaceuticals, Cymabay Therapeutics, Eli Lilly and Company, Galectin Therapeutics, Gilead Sciences, GlaxoSmithKline, Hanmi Pharmaceuticals, Hightide Biopharma, Intercept Pharmaceuticals, Inventiva, Ipsen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Regeneron, Sagimet Biosciences, Takeda, Terns Pharmaceuticals, Viking Therapeutics, Zydus Pharmaceuticals; Consultant/Advisor: 89Bio, AstraZeneca, Boehringer Ingelheim, Corcept Therapeutics, Inventiva, Merck, Novo Nordisk, Organovo, Sagimet. Figure 1: Hyponatremia by dose level showing baseline, nadir and serum sodium recovery at 24 hrs. post PHIN-214 administration Serum Sodium, mmol/L 150 140 130 120 110 % change from baseline 100 50 24hrs Mean: 16% 95% CI [9.2, 22.7] 8hrs Mean: 30.9% 95% CI [22.8, 39.1] Maximum Mean: 40.3% 95% CI [28.1, 52.5] CONCLUSIONS Single, SC injection of PHIN-214 is well tolerated and 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 injection for treatment of complications of portal hypertension in patients with decompensated cirrhosis. Enrollment into part 2 - multiple ascending dose - is ongoing. AUTHOR DISCLOSURES ACKNOWLEDGEMENTS 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.

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