Inclusion Criteria:

• Participants must be willing and able to participate in the study, comprehend and sign the informed consent form (ICF).
• Participants must be willing and able to complete all study-specific procedures and visits.
• Age 18-70 years.
• Patients with liver cirrhosis confirmed by reliable biopsy (within 12 months) or reliable Fibroscan > 15 kPa at screening.
• Cause of liver disease must be unequivocally identified by a hepatologist PI or Sub-I. Only patients with the following etiologies of cirrhosis can be included: alcohol, hepatitis B, hepatitis C, NASH, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC).
• EGD.
• Endoscopy is not necessary in patients with liver stiffness < 20 kPa and platelets >150,000/μL (equal to > 150 x 10^9/L).
• In patients without known varices and liver stiffness ≥ 20 kPa and platelets ≤150 x 10^9/L, a EGD is required prior to enrollment if not performed in the previous 24 months.
• In patients with varices that never had a bleeding episode, endoscopy is required within 12 months if no primary prophylaxis for variceal bleeding has been established. If a primary bleeding prophylaxis has successfully been established, the EGD interval can be expanded to 24 months for this study.
• In patients with varices that had a previous bleeding episode, an EGD <12 months is mandatory.
• Compensated cirrhosis - defined as being classified as Child-Pugh A5 or A6 during screening.
• Recompensated patients may be included if their decompensating event resolved > 6 months prior to screening and the patient did not experience > 1 decompensating events in the past 12 months.
• Negative urine drug test on Screening.
• Investigators shall counsel women of childbearing potential (WOCBP) and male participants who are sexually active with WOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy and the potential of fetal toxicity occurring due to transmission of study drug, present in seminal fluid, to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
• The investigator shall evaluate the effectiveness of the contraceptive method in relation to the first dose of study intervention. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Women who are not of childbearing potential are exempt from contraceptive requirements. Women participants must have documented proof that they are not of childbearing potential.
• WOCBP must have a negative urine or serum pregnancy test within 24 hours before the first dose of study treatment. If a urine test cannot be confirmed as negative (e.g., ambiguous result), a serum pregnancy test is required. In such cases, the participant is excluded from participation in the study if the result is positive.
• Additional requirements for pregnancy testing during and after study intervention are in the Schedule of Assessments.
• A woman of childbearing potential is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), nonhormonal method of contraception with low user dependency, as described in Appendix 2, during the intervention period and for at least five half-lives of the study intervention (7 days) plus 30 days, and agrees not to donate oocytes for the purpose of reproduction for the same time period.
• WOCBP who are not sexually active with men are exempt from the contraception requirements but must still have pregnancy tests as scheduled.
• Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception as defined in Appendix 2 and as described below.
• Male participants will be required to always use a latex or other synthetic condom during any sexual activity (e.g., vaginal, anal, oral) with WOCBP; even if the participants have undergone a successful vasectomy or if their partner is already pregnant or breastfeeding. Males should continue to use a condom during the intervention period and for at least five half-lives of the study intervention (7 days) after the last dose of the male participant’s study intervention.
• Azoospermic men are not exempt from contraceptive requirements and are required to always use a latex or other synthetic condom during any sexual activity (e.g., vaginal, anal, oral) with WOCBP, even if the participant has undergone a vasectomy or if the partner is pregnant.
• Female partners of males participating in the study should be advised to use a highly effective method of contraception during the intervention period and for at least 32 days after the last dose of the male participant’s study intervention.
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal intercourse or use a male condom during each episode of penile penetration during the intervention period and for at least 32 days after the last dose of study intervention.
• Male participants must refrain from donating sperm during the intervention period and for at least 90 days (approximate sperm lifetime) after the last dose of study intervention.

Exclusion Criteria:

• Women who are breastfeeding.
• Inability to tolerate the testing conditions.
• Inability to tolerate venipuncture and/or inadequate venous access.
• History of allergic reactions as well as known or suspected allergy or intolerance to any agent given in the trial or terlipressin.
• History of any malignancy except basal cell carcinoma that has been resected.
• Patients with rare liver diseases not specifically mentioned in the inclusion criteria.
• Significant abnormalities in medical history or on physical examination, including, but not limited to:
  • Respiratory disease requiring therapy (example asthma, COPD requiring chronic therapy) or oxygen supplementation;
  • History of respiratory failure;
  • Significant cardiovascular disease such as heart failure, ischemic and nonischemic cardiomyopathy, coronary heart disease, conduction system disease (such as: significant 1-degree atrioventricular block > 240 msec, left bundle branch block, bifascicular block), patients with reported supraventricular tachycardia or ventricular tachycardia of any sort, pulmonary hypertension, uncontrolled hypertension, stroke, myocarditis, abnormal cardiac anatomy/structural heart disease, or pericarditis;
  • Patients presenting with dizziness, palpitation, syncope, shortness of breath or chest pain;
  • Patients with arterial hypertension requiring current treatment; beta blockers are allowed if the hypertension is controlled;
  • Personal or immediate family (genetically related mother, father or children who were diagnosed before the age of 55) history of vascular disorders, including but not limited to: aneurysms, cerebrovascular accidents, stroke, peripheral artery disease, peripheral vascular disease (including regional pain syndrome or reflex sympathetic dystrophy), Raynaud’s syndrome;
  • History of vaso-occlusive disorders or acute angle glaucoma;
  • Hyperthyroidism;
  • Organ transplant;
  • Active gallbladder disease: cholecystectomized patients are not excluded.
• Left ventricular ejection fraction <60% using Simpson’s criteria. Signs of pulmonary hypertension with either TRV (tricuspid regurgitation velocity) > 2.8 m/s based on transthoracic echocardiogram during Screening or echocardiographic signs from at least two different categories (A/B/C) as outlined in the table below.
• Resting heart rate ≤ 60 or ≥ 100 bpm, SBP ≤ 90 or ≥ 140 mmHg, DBP ≤ 60 or ≥ 90 mmHg at Screening
• At screening, electrocardiogram abnormalities (PR>200msec; QRS complex >120 msec; signs of a bifascicular block, QTcF interval > 450 msec (male) or > 470 msec (female), or history of significant EKG abnormalities (such as cardiac arrythmia, familial long QT syndrome, previous torsade de pointes, supraventricular tachycardia or ventricular tachycardia of any sort).
• History of diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, or any other disorder associated with fluid or sodium imbalance.
• Significant kidney disease as evaluated by the investigator.
• Type 1 hepatorenal syndrome.
• Estimated glomerular filtration rate (eGFR by CKD-Epi) < 90 ml/min/1.73 m^2 or Cr > 1.2 mg/dL.
• BMI <18 or >40 kg/m^2.
• The following abnormal screening laboratory values:
  • Serum sodium concentration < 125 mmol/L;
  • Hemoglobin < 10g/dL;
  • ALT, AST, total bilirubin, or alkaline phosphatase >3 x ULN;
  • Platelet count < 100x10^9/L;
  • Blood magnesium < 1.3 mEq/L;
  • Clinical laboratory results outside of laboratory normal range that are determined by the Investigator to be clinically significant;
  • Model for end-stage liver disease (MELD-Na) score ≥ 18 at Screening;
  • Positive for anti-HIV-1 or -2 antibodies;
  • Positive SARS-COV-2 PCR within 7 days prior to Day 1;
  • Positive Fecal occult blood test.
• Hepatic encephalopathy ≥ grade 1 or drug treatment for hepatic encephalopathy.
• Gastrointestinal bleeding within 8 weeks prior to dosing.
• Patients with Grade ≥ 3 or larger esophageal varices (per Conn’s classification of esophageal varicies) or red spots on most recent eligibility EGD.
• Patients who underwent variceal banding procedures that have been completed < 8 weeks prior to Screening.
• Patients with current ascites or current use of treatment for ascites.
• Recipient of a transjugular intrahepatic portosystemic shunt (TIPS).
• Use of certain pharmacologic agents will be prohbited or will require washout period including those with vasoconstrictive or hypertensive potential, including but not limited to (any other agents not listed below with this potential, should be reviewed with PI and medical monitor):
  • Caffeine and caffeine containing products and alcohol 12 hours prior to injection;
  • Amphetamines within 48 hours of injection with negative urine drug screen to support no use. Use of ephedra is prohibited;
  • Angiogenesis inhibitors will be prohibited;
  • Tricyclic antidepressants will be prohibited and require two week wash-out if previous consumption. All other classes of anti-depressants will require a one week washout prior to injection;
  • Topical corticosteroids will be allowed. Oral corticosteroids will be prohibited. If taken prior to study for acute indication will require a two-week washout prior to injection. Other systemic immunosuppressants will be prohibited;
  • Erythropoietin agents will be prohibited;
  • Estrogen will be allowed per investigator discretion at low doses similar to those used for hormone replacement therapy;
  • Testosterone and anabolic steroids will require one week washout prior to injection;
  • Use of agents to treat migraine will require a one week washout prior to injection;
  • NSAIDS will not be allowed with 48 hours of injection;
  • Yohimbe is prohibited.
• Current use of angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), alpha-blockers, calcium channel blockers, renin antagonists, or midodrine or history of use within 2 weeks prior to screening.
• Treatment with dobutamine, levosimendan, milrinone and any phosphodiesterase inhibitor, octreotide, midodrine, vasopressin, dopamine, soluble guanylate cyclase agonists or other vasopressors within 2 weeks prior to screening.
• Use of tobacco or nicotine containing products in the 6 months prior to Screening or intent to smoke during the study.
• Use of cannabinoids or cannabis containing products in the week prior to Screening or intent to use cannabis during the study.
• Ongoing significant medical condition that is uncontrolled, untreated, or could interfere with the study objectives.
• Spontaneous bacterial peritonitis within 6 months of Screening.
• Clinically significant active bacterial, viral, or fungal infection requiring systemic (parenteral or oral) anti-infective agent within 2 weeks of Screening.
• Use of treatments for Hepatitis C virus within 6 months of Screening or anticipated use during the trial.
• Known positive HIV serology confirmed by HIV viral load.
• Patients with known chronic hepatitis B are eligible if treatment regimen is not changed in the 4 weeks prior to study inclusion:
  • Patients with acute hepatitis B are to be excluded.
• Positive HCV antibody serology with detectable HCV ribonucleic acid (RNA).
• History of positive testing for SARS-CoV-2 or diagnosis of COVID-19 within 4 weeks of Screening.
• Substance or alcohol abuse within 6 months of consent, or medical, psychological, or social conditions that may interfere with the patient’s participation in the trial or evaluation of trial results in the opinion of the Investigator.
• Current Alcohol Use Disorders Identification Test (AUDIT) score ≥ 9.
• Presence of rash, abnormal skin state, dermatological conditions requiring systemic therapy, tattoos, or other skin abnormalities at the site of administration.
• Any planned surgery or procedures that could interfere with trial completion (check with Medical Monitor).
• Any major surgery involving risk to the life of the participant (specifically, surgery on an organ in the cranium, chest, abdomen, or pelvic cavity) within 12 weeks before screening (sites should discuss cases with Medical Monitor as needed).
• Hospitalization for a major infection within 4 weeks before screening.
• Participants who received a non-biologic investigational study medication must wait over 4 weeks before screening for this trial. Participants who received a biologic investigational study agent must wait over 12 weeks or 5 half-lives for this trial.
• Capillary refill time of > 2 sec at screening.
• At screening, SpO2 < 97%.
• Participants who have been diagnosed with sleep apnea.

Eligibility last updated 2/28/22. Questions regarding updates should be directed to the study team contact.