CompletedPhase 1ACTRN12624000023550

A first in human study to Evaluate the Safety and Tolerability of OLX75016 for treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis.

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.

Sponsor

OliX AU Pty Ltd

Enrollment

58 participants

Start Date

Feb 13, 2024

Study Type

Interventional

Conditions

(NAFLD) to steatohepatitis (NASH)Cirrhosis

Summary

OLX75016 is being developed by OliX Pharmaceuticals as a treatment for patients with treatment of non-alcoholic steatohepatitis (NASH) and liver fibrosis. This study will evaluate the safety and tolerability of single and multiple ascending doses of OLX75016 in healthy volunteers. This study will be conducted in 2 parts : Part A (Single ascending dose) and Part B (Multiple ascending dose). Upto 58 Participants are expected to be engaged with the study for upto 56 days in Part A or upto 112 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, participants will be randomized to receive OLX75016 or placebo prior to dose administration on Day 1. All participants will be confined to the clinic until the completion of all safety/tolerability and PK assessments on Day 3. Participants will be required to return to the clinic for additional outpatient safety/tolerability assessments on Day 4, 7, 14, 28 and 42. Participants will be discharged from each visit following completion of all safety assessments, the end of study (EoS) visit will be on Day 56. Part B - Following confirmation of eligibility, participants will be confined to the unit on Day -1 until Day 3. Participants will be randomized to receive OLX75016 or placebo prior to first dose administration (Day 1) and will be discharged following completion of all safety and PK assessments on Day 3. Participants will be required to attend the clinic on Days 4, 7 and 14 for safety and tolerability assessments. Participants will return to the clinic for a second confinement period from Day 28 to Day 31, with the second dose of OLX75016 or placebo administered on Day 29. Participants will be required to attend the clinic on Days 32, 35, 42, 56 and 84 for safety and tolerability assessments before the EoS visit on Day 112. 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 Criteria17

Capable of providing written Informed consent. Willing, committed, and able to return for all clinic visits and complete all protocol specified procedures.
Healthy male or female, aged between 18 and 65 years, inclusive at screening.
Body mass index (BMI) of greater than or equal to 18 kg/m2 and lesser than or equal to 32 kg/m2 at Screening
Liver fat content less than 6% as determined by MRI-PDFF. Negative human immunodeficiency virus, viral hepatitis B and C serology, autoimmune hepatitis (Liver Kidney Microsomal Liver [LKM] Antibody), transferrin saturation < 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.
Stable health status, as established by physical examination and medical history.
Participant is willing to refrain from consuming caffeine and/or xanthene products (e.g., coffee, tea, chocolate, and caffeine-containing sodas, colas), for:
Participants 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.
Female participants must be of non-childbearing potential i.e., surgically sterilised or post-menopausal or, if of childbearing 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 after the last dose of study drug.
c. If not exclusively in a same-sex relationship, must agree to use adequate contraception
d. If in a same-sex relationship, or being completely abstinent as a life-style choice, no form of contraception is required.
Male participants 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
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.

Exclusion Criteria32

Has any clinical safety laboratory result considered clinically significant by the Investigator (or designee).
In the opinion of the PI (or designee), has evidence of other forms of known chronic liver disease that could affect participant’s safety or could limit the interpretability of study objectives.
Use of an investigational agent 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 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 or excessive alcohol consumption during less than or equal to 1 year prior to screening.
Use of any prescription medication or concomitant medications within 14 days prior to the first dose of study drug, or use of over-the-counter medication/vitamins/supplements within 7 days prior to the first dose of study drug. Exceptions include contraception, iron supplements for participants who have ferritin between 15-30 µg/L at screening, occasional paracetamol (up to a maximum of 2 grams per day). Use of St. John’s Wort (hypericin) may not have been taken within 30 days prior to first dose of study drug.
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 Subcutaneous 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 international normalized ratio (INR) greater than 1.3.
Use of anticoagulant medication within 6 months prior to first dose of study drug.
Has platelet count less than 140x10^9/L.
Has transferrin saturation greater than 45%.
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:
a. estimated glomerular filtration rate less than 60 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration formula) or
b. urinary albumin-to-creatinine ratio greater than 3.5 mg/µmol (females) and > 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:
c. Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment.
d. Participants with diagnosis of COVID-19 with significant findings from pulmonary imaging tests.
e. Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen supplementation therapy.
Suspicion of or known Gilbert’s syndrome.
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 sunburn, 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 noncompliance 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, has been designed to specifically target liver hepatocytes and chemically modified to increase stability. 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). Part A- Single Ascending Dose (SAD) Healthy Volunteers (HV): Healthy volunteers will be enrolled and randomized to 6 cohorts with each cohort having 8 participants to receive single ascending doses of OLX75016 or placebo (ratio 3:1 active: placebo). The starting dose will be 10 mg, with 6 dose levels planned 10mg, 30mg, 90 mg, 200mg, 450mg and upto 900mg. At the discretion of the study Sponsor, in consultation with the SRC, additional cohorts may be added to evaluate intermediate dose levels. Healthy volunteers 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. 2 Sentinel participants will be dosed in the SAD Cohorts. 1 Sentinel will be allocated to placebo, and 1 to active treatment via Randomisation list instruction. The Randomisation list will be prepared by the Avance unblinded Biostatistician. Dosing in each cohort will start with two sentinel participants with one of the two sentinels randomized to receive OLX75016 and the other randomized to receive placebo. Dosing for healthy volunteers in SAD Cohort 6 only, will require sentinel participants being administered pre-medication. Pre-medication will consist of paracetamol (1000 mg) and ibuprofen (400mg). Pre-medications will be administered 30 minutes prior to OLX75016 dose administration and continue as needed. The safety and tolerability of each sentinel participant will be monitored in the clinic until Day 3. Following completion of Day 3 assessments for sentinel participants, all available safety/tolerability information (including Day 3 clinical blood and urine safety laboratory results), will be reviewed by the PI, prior to making the decision to dose the remaining participants in each cohort. Participants will be required to return to the clinic for additional outpatient safety/tolerability assessments on Day 4, 7, 14, 28 and 42. Participants will be discharged from each visit following completion of all safety assessments, the end of study (EoS) visit will be on Day 56. 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). After at least 6 out of 8 participants have completed the Day 28 visit, the SRC will review all available safety/tolerability data (including safety/tolerability data collected on Day 28), discuss the findings, and decide to: • Enrol the next dose cohort in Part A at the protocol-defined dose level. • Enrol the next dose cohort at an intermediate dose level not defi ned in the protocol; or • Terminate enrolment in Part A of the study. In conjunction with the above, following completion of SAD Cohort 3, the SRC may also determine a starting dose level for Part B (MAD) and determine whether sentinel dosing should be used for the first cohort in Part B (MAD). If the SRC determines sentinel dosing is required, the SRC will advise on the minimum length of time for participants to be followed prior to dosing the remaining participants in the cohort. Part B- Multiple Ascending Dose (MAD) HV: For healthy volunteers, up to 1 dose level (as determined from Part A [SAD]) is planned to be evaluated. At the discretion of the study Sponsor, in consultation with the SRC (an) additional cohort(s) may be added in order to evaluate (an) additional dose level(s), based on the results of the SAD part of the study. Upto 10 participants over 1 dose cohort will be enrolled into the study. Healthy participants to be cleared from safety standpoint by the PI (or delegate), prior to discharge on Day 3 and Day 87 from the clinic. If HV 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). At the discretion of the study Sponsor, in consultation with the SRC (an) additional cohort(s) may be added in order to evaluate (an) additional dose level(s), based on the results of the SAD part of the study.