RecruitingPhase 1ACTRN12624001111561

A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple- Ascending Dose Study to Evaluate the Safety and Tolerability of OLX75016 in Healthy Volunteers and Patients with Non-Alcoholic Fatty Liver Disease.

Sponsor

OliX AU Pty Ltd

Enrollment

40 participants

Start Date

Jul 3, 2024

Study Type

Interventional

Conditions

Cirrhosis Fibrosis

Summary

OLX75016 is being developed by OliX Pharmaceuticals as a treatment for patients with treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis. This study will evaluate the safety and tolerability of single and multiple ascending doses of OLX75016 in patients with non-alcoholicfatty liver disease (NAFLD). This study will be conducted in 2 parts : Part A (Single ascending dose) and PartB (Multiple ascending dose). Up 20 patients with NAFLD are expected to be engaged with the study for up to 87 days in Part A or up to 172 days in Part B of the study. OLX75016 and matching placebo will be administered as SC injections in the abdominal region in this study. Part A- Following confirmation of eligibility, patients with NAFLD will be randomized to receive OLX75016 or placebo prior to dose administration on Day 1. All patients with NAFLD will be confined to the clinic until the completion of all safety/tolerability and PK assessmentson Day 3. Participants will be required to return to the clinic for additional outpatient safety/tolerability assessments on Day 4, 7, 14, 28, 42, 84, 112, 140, 168, 196 and 224. Participants will be discharged from each visit following completion of all safety and PK assessments, the end of study (EoS) visit will be on Day 224. Part B - Following confirmation of eligibility, patients with NAFLD will be randomized to receive OLX75016 or placebo prior to dose administration on Day 1 and Day85. All patients with NAFLD will be confined to the clinic from day prior to dosing until the completion of all safety/tolerability and PK assessments 3 days post-dose and will be discharged following completion of all safety and PK assessments on Day 3. Patients with NAFLD will be required to attend the clinic on Days 4, 7, 14, 28 and 56 for safety and tolerability assessments. Patients with NAFLD will return to the clinic for a second confinement period from Day 84 to Day 87, with the second dose of OLX75016 or placebo administered on Day 85. NAFLD patients will be required to attend the clinic on Days 88, 91, 98, 112, 140, 169 for safety and tolerability assessments before the EoS visit on Day 253. It is hoped that the information learned from this study will help the sponsor learn more about how best to treat patients suffering from NASH and liver fibrosis in future. This research may also give rise to new or improved improvements.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 65 Yearss

Inclusion Criteria23

Must have given written informed consent, before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
Willing, committed, and able to return for all clinic visits and complete all protocol specified procedures.
Male or female, aged between 18 and 65 years, inclusive at screening.
Body mass index (BMI) of greater than or equal to 27 kg/m2 and less than or equal to 40 kg/m2 at Screening.
Liver fat content greater than or equal to 6% and less than 33% as determined by MRI-PDFF.
Negative for Human immunodeficiency virus, viral hepatitis B and C serology, autoimmune hepatitis (Liver KidneyMicrosomal [LKM] Antibody), transferrin saturation less than 45%, at Screening.
On a stable diet for at least 4 weeks prior to Day -1, with no plans to significantly alter lifestyle for the duration of the study.
Patient has well controlled systolic blood pressure with or without stable medication in the range 90 to 160 and diastolic blood pressure in the range of 40 to 90 mmHg after 5 minutes in supine or semi-supine position.
Body temperature (tympanic), between 35.5°C and 37.5°C (inclusive).
Electrocardiogram (ECG) without clinically significant abnormal findings and average QT interval (QTc),QT interval corrected for Fredericia (QTcF) less than 450 msec for male participants and less than 470 msec for female participants. Note: The above assessments may be repeated, if abnormal values were recorded in the first instance, at the discretion of the Investigator (or delegate).
Patient is willing to refrain from consuming caffeine and/or xanthene products (e.g., coffee, tea, chocolate, and caffeine-containing sodas, colas), for:
a. At least 24 hours prior to Day -1 and while confined to the clinical facility and prior to each clinic visit from screening through to EoS (Part A, SAD).
b. At least 24 hours prior to each admission and while confined to the clinical facility and prior to each clinic visit from screening through to EoS (Part B, MAD).
Female patients must be of non-childbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or post-menopausal(where post-menopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with post-menopausal status, per local laboratory guidelines), or, if of child-bearing potential:
a. Must have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test on Day -1.
b. Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 30 days (or 5 half-lives of OLX75016, whichever is longer) after the last dose of study drug.
c. If not exclusively in a same-sex relationship, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception) from one month prior to screening until at least 30 days (or 5 half-lives of OLX75016, whichever is longer) after the last dose of study drug.
d. If in a same-sex relationship or being completely abstinent as a life-style choice, no form of contraception is required.
Male patients must:
a. Agree not to donate sperm from the time of signing consent until at least 90 days after the last dose of study drug.
b. If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception (defined as use of a condom plus a highly effective method of contraception) from the time of signing consent until at least 90 days (or 5 half-lives of OLX75016, whichever is longer) after the last dose of study drug.
c. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, must agree to use a condom from the time of signing consent until at least 5 half-lives of OLX75016 after the last dose of study drug. If being completely abstinent as a life-style choice, no form of contraception is required.
Must have received at least 1 dose of a Therapeutic Goods Association approved COVID-19 vaccine, with the most recent dose administered greater than 1 week prior to administration of study drug.

Exclusion Criteria32

Has any clinical safety laboratory result considered clinically significant by the Investigator (or designee)and that could compromise the interpretation of the study objectives.
Use of an investigational agent (including previous exposure to siRNAs) or device within 30 days or 5 half-lives of Day 1 drug administration in this trial, whichever is longer prior to dosing or current participation in an investigational study. History of having received long-duration RNA-based therapies.
In the opinion of the PI (or designee), has any uncontrolled or serious disease, medical or surgical condition that may interfere with participation or data interpretation.
Participant smokes greater than or equal to 5 cigarettes per week and/or is unwilling to refrain from smoking (and use of any tobacco products or nicotine-containing products) whilst confined to the clinical unit.
History of substance dependence (within the last 12 months) or positive urine drug screen at screening(Part A [SAD] and Part B [MAD]), Day -1 (Part A and Part B), Day 28 (Part B, only) and Day 84 (Part B) or excessive alcohol consumption (defined as more than 14 standard drinks per week or regularly consuming more than 4 standard drinks on any one day; where one standard drink is 10g of pure alcohol and is equivalent to 285mL beer [4.9% Alc./Vol], 100 mL wine [12% Alc./Vol], 30 mL spirit [40% Alc./Vol]) during less than or equal to1 year prior to Screening.
Use of any vaccinations within 14 days prior to the first study drug administration (vaccination for COVID-19 is permitted with the most recent dose administered greater than 1 week prior to first study drug administration).
In the opinion of the PI (or designee), has an aversion to, or has history of site reactions to SC administrations that would make them unsuitable for inclusion in this trial.
Has contraindications to MRI (e.g., metal implants [excluding Titanium]; severe claustrophobia and inability to lie flat for 1 hour).
Has HbA1c greater than or equal to 8.5% (or serum fructosamine greater than or equal to 381 µmol if HbA1c measurement is not available). Patients are permitted to be on a stable dose of Metformin for 3months prior to Screening.
Has hemoglobin less than or equal to 110 g/L
Has International normalized ratio (INR) greater than or equal to 1.3
Use of anticoagulant medication within 6 months prior to first dose of study drug.
Has direct bilirubin greater than or equal to 6.7 µmol/L
Has total bilirubin greater than or equal to 1.5 x upper limit of normalization (ULN), unless due to an alternate etiology such as Gilbert’s syndrome or hemolytic anemia
Has platelet count less than or equal to 150,000/µL
Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
Participants with history or pre-existing renal disease, as defined below:
c. estimated glomerular filtration rate (eGFR) less than or equal to 60 mL/min (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula); slight changes permitted as deemed appropriate by the PI/delegate or
d. urinary albumin-to-creatinine ratio greater than 3.5 mg/mmol (females) and greater than 2.5 mg/mmol (males).
Relevant history (in the opinion of the PI or designee) of cardiac arrythmias including long QT syndrome, sudden cardiac death, or Torsades de Pointes and/or syncope and/or clinically significant cardiovascular event within the last 6 months prior to the Screening Visit.
Participants with a positive SARS-CoV-2 infection (polymerase chain reaction [PCR] or rapid antigen test[RAT] as deemed appropriate by the site’s SOPs or PI discretion) at Screening or Day -1 Visit.
Participants with a significant Coronavirus disease 2019 (COVID-19) illness within 6 months of enrolment, defined by one of the following:
d. Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment.
e. Participants with diagnosis of COVID-19 with significant findings from pulmonary imaging tests.
f. Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementation therapy.
Weight loss of more than 10% within the last 3 months prior to screening.
Has donated blood or blood products within 3 months prior to first dose administration.
Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).
History of major bleed or high-risk of bleeding diathesis.
Use of anabolic steroids and systemic treatment with glucocorticosteroids within 3 months prior to the Screening Visit.
Presence or evidence of recent sun burn, scar tissue, tattoo, open sore or branding that, in the opinion of the PI or medically qualified designee, would interfere with the interpretation of skin adverse reactions at the injection site.
Any other condition or prior therapy that in the opinion of the PI (or designee) would make the participant unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of non compliance with any study requirements.

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Interventions

OLX75016 is a chemically synthesized double stranded siRNA targeting expression of the Mitochondrial Amidoxime Reducing Component 1 (MARC1) enzyme for the treatment of nonalcoholic fatty liver disease(NAFLD) with liver fibrosis. OLX75016, which is administered by subcutaneous (SC) injection, OLX75016 and a matching placebo will be administered as SC injections in the abdominal region. This study will be conducted in two parts: Part A (SAD) and Part B (MAD). Each study part will enrol patients with Non-Alcoholic Fatty Liver Disease (NAFLD). - Part A (SAD) NAFLD Patients: Up to 20 patients over 3 cohorts - Part B (MAD) NAFLD Patients: Up to 12 patients over 2 dose escalation cohorts and an optional Cohort 3 - Part A Single Ascending Dose (SAD) NAFLD Patients: NAFLD patients will be enrolled and randomized to 3 cohorts with first cohort having 4 participants, second and third cohorts having 8 participants to receive single doses of OLX75016 or placebo (ratio 3:1 active: placebo). The dose levels will be 90 mg (Cohort 1), 200 mg (Cohort 2) and 45 mg (Cohort 3). At the discretion of the study Sponsor, in consultation with the Safety Review committee (SRC), additional cohorts may be added to evaluate intermediate dose levels. Patients with NAFLD will be screened between Day -28 to Day -2. Eligible participants will be admitted to the clinic on Day -1. Following confirmation of eligibility, participants will be randomized to receive OLX75016 or a placebo before dose administration on Day 1. Doses will be administered in the clinic, under the supervision of site staff . All participants will be confined to the clinic until the completion of all safety/tolerability and PK assessments on Day 3. Sentinels are not required for NAFLD patient cohorts. Participants will be required to return to the clinic for additional outpatient safety/tolerability assessments on Day 4, 7, 14, 28, 42, 84, 112, 140, 168, 196 and 224. Participants will be discharged from each visit following completion of all safety and PK assessments, the end of study (EoS) visit will be on Day 224. Compliance will be monitored by site staff witnessing of dosing and will be documented in participant study files. If participants experience any clinically significant (CS) AEs during the confinement period, they may remain in the clinical facility for further observation at the discretion of the Principal Investigator (PI). - Part B Multiple Ascending Dose (MAD) NAFLD Patients: NAFLD patients will be enrolled and randomized to 2 cohorts (Cohort 1 n=4 and Cohort 2 n=8 per cohort) and if required an optional Cohort 3 (n=8) to receive multiple doses of OLX75016 or placebo (ratio 3:1 active: placebo), with 2 dose levels planned (administered approximately 3 months apart on Day 1 and Day 85). The dose levels will be 30 mg (Cohort 1), 150 mg (Cohort 2) and dose level for Optional Cohort 3 will be based on review of safety data. At the discretion of the study Sponsor, in consultation with the SRC, additional cohort(s) may be added to evaluate (an) additional dose level(s). Dosing in MAD NAFLD Cohort 2 may commence 28 days after the first participant in MAD NAFLD Cohort 1 has completed first dose administration. Sentinel dosing will not be required in Part B (MAD), unless recommended by the SRC following review of data from Part A (SAD). Dosing in each patient cohort will commence only after SRC confirms dosing in SAD NAFLD Cohort 3. Compliance will be monitored by site staff witnessing of dosing and will be documented in participant study files. If patients with NAFLD experience any clinically significant (CS) AEs during the confinement period, they may remain in the clinical facility for further observation at the discretion of the Principal Investigator (PI).