| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe Hypertriglyceridemia (SHTG) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe Hypertriglyceridemia (SHTG) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020870 |
| E.1.2 | Term | Hypertriglyceridemia |
| E.1.2 | System Organ Class | 100000004861 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the effect of BIO89-100 on serum TG levels in subjects with SHTG (TG ≥500 mg/dL) |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the effect of BIO89-100 on selected serum lipids and lipoproteins
• To determine the effect of BIO89-100 on highsensitivity C-reactive protein (hsCRP)
• To determine the effect of BIO89-100 on metabolic markers
• To characterize BIO89-100 pharmacokinetics (PK)
• To characterize BIO89-100 PD profile as assessed by MRI-PDFF |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Intensive PK substudy (subgroup of patients, optional participation, only in US)
- Objective is to characterize BIO89-100 PK
PK parameters in Intensive PK subgroup
o Cmax within a dosing interval
o AUC0-tau within a dosing interval
o tmax
o t½
MRI-PDFF substudy (subgroup of patients, optional participation, worldwide)
- Exploratory objective: Percentage change and change from baseline in hepatic steatosis using Magnetic Resonance Imaging – Whole Liver Proton Density Fat Fraction (MRI-PDFF) (optional)
- Percentage change and change from baseline in hepatic steatosis using MRI-PDFF
Pharmacogenomic assessment (subgroup of patients, optional participation, worldwide)
- Exploratory objective:
• Genetic analyses related to BIO89-100, including associations of deoxyribonucleic acid (DNA) variations with clinical treatment responses to BIO89-100 (e.g., PK, tolerability, and safety features or disease susceptibility and severity features)
• Apolipoprotein E (ApoE) genotype will be determined to investigate association between ApoE genotype and PD responses/disease state |
|
| E.3 | Principal inclusion criteria |
1. Subject understands the study design and has been informed of the investigational nature of the study. Subject has given voluntary, written, informed consent to take part in this study.
2. Subject agrees to be compliant and is capable of completing the required study assessments.
3. Male or female age ≥21 to ≤75 years at time of signing informed consent.
4. All subjects (male or female) who are of childbearing potential must agree to use highly-effective, double contraception (with male/female partners) during the study. Double contraception is defined as use of a condom by the male partner, combined with use of 1 of the following forms of highly-effective contraception by the female partner:
a. Oral contraceptive pills
b. Depot or injectable contraceptive
c. Intrauterine device (IUD)
d. Contraceptive patch (e.g., Xulane®) or NuvaRing®
e. Documented evidence of tubal ligation at least 6 months prior to the screening visit).
Male subjects with a history of vasectomy should also use condoms as double contraception during the study. Use of highly-effective, double contraception must continue for 30 days or 5 half-lives (whichever is longer) after the last dose of IP. Female subjects must not donate oocytes during this time. Male subjects must not donate sperm during this time. Rhythm methods are not considered as highly-effective methods of birth control. Subject abstinence for the duration of the study and 30 days or 5 half-lives (whichever is longer) after last dose of IP is acceptable if it is the subject’s regular practice.
5. Females of childbearing potential must have a negative serum pregnancy test at screening V2 and agree to undergo a urine pregnancy test at V3/3.1, V4, V8 and V12, and a serum pregnancy test at end of the study (V13).
6. Females not of childbearing potential will be defined for this study as postmenopausal (defined as cessation of regular menstrual periods for at least 12 months) and confirmed by follicle-stimulating hormone (FSH) level OR surgically sterile (e.g., total hysterectomy, partial hysterectomy, or oophorectomy).
7. Serum TG criteria meeting all of the following criteria:
a. A historical documented TG ≥400 mg/dL (4.52 mmol/L) in the past 5 years from screening V1, or currently on lipid-modifying therapy due to SHTG at screening V1.
b. Mean of 2 screening fasting serum TGs ≥ 500 mg/dL (5.65 mmol/L) and ≤2000 mg/dL (22.60 mmol/L). The target for the study is 500 mg/dL. Due to TG variability, up to 10% of subjects enrolled may have a mean qualifying TG level between 475 and 500 mg/dL. Mean screening fasting serum TG is defined as the mean of TG at V2 and V3, or V3 and V3.1 if the average of TG at V2 and V3 is <500 mg/dL, or >2000 mg/dL. The repeat measure of TG is permitted at a minimum of 7 days apart at V3.1.
c. If 1 of the 2 qualifying TGs is <400 mg/dL, the difference between 2 TG should be <300 mg/dL. Note: If a subject has an individual fasting TG value of <350 mg/dL at any one visit or mean of two fasting TG levels <475 mg/dL, they will be considered a screen fail and not eligible to be re-screened.
8. Willing to maintain current eating and exercise habits from time of signing the informed consent and for the duration of the study. (See also Inclusion Criterion #11 and Exclusion Criterion #10 regarding alcohol consumption and Exclusion Criterion #4 regarding weight changes.).
9. Concomitant medication may include prescription fish oil (including purified eicosapentaenoic acid [EPA] with or without docosahexaenoic acid [DHA]) and/or statin with or without ezetimibe (none of which will be supplied as part of study) as long as the subject has been clinically stable (per Principal Investigator [PI] judgment) while on stable dose for ≥4 weeks before screening V1.
10. Medicines known to exacerbate hypertriglyceridemia (such as certain beta blockers, thiazides, estrogens, bile acid sequestrants) should be stable (≥4 weeks before screening V1) and remain stable during the study.
11. Subject is willing to refrain from alcohol consumption for ≥48 hours before each study visit.
12. MRI-PDFF of ≥6.0% for subjects screened for the fibrate expansion cohort. Note: Those who cannot undergo MRI for any reason (e.g., claustrophobia, metal implants) cannot participate in the fibrate expansion cohort. |
|
| E.4 | Principal exclusion criteria |
1.Females who are pregnant or breastfeeding, or planning to become pregnant, or breastfeed while enrolled in the study or within 30 days or 5 half-lives (whichever is longer) after last dose of IP.
2.Uncontrolled or newly diagnosed (< 3 months since diagnosis at time of Screening) hypertension. Subjects with well controlled hypertension who are clinically stable may enroll if they have been on a stable dose of antihypertensive medications for at least 2 months before Screening. Subjects who are taking >2 antihypertensive medications may be eligible with Medical Monitor (or designee) approval.
3.Body mass index (BMI) >45 kg/m2 at screening V1.
4.Weight change ≥5% in 3 months prior to screening V1 or weight change ≥5% between screening V1 and V3.
5.Central laboratory hemoglobin levels below the lower limit of normal (<12.0 g/dL for males, <11.0 g/dL for females), or dialysis, lipid apheresis, plasma exchange, blood transfusion, or blood donation/blood loss of ≥400 mL at least a month prior to and during the screening period or anticipation of these procedures during the period of the study and up to 30 days afterwards
6.A history of symptomatic gallstone disease unless treated with cholecystectomy and/or pancreatitis within 5 years from screening will be excluded from the study.
7.ALT or AST >3× upper limit of normal (ULN) at screening V1.
8.Total bilirubin exceeds ULN at screening V1, unless prior diagnosis and documentation of Gilbert’s syndrome in which case total bilirubin must be ≤3 mg/dL.
9.Creatine kinase (CK) >5× ULN at screening V1.
10.Risky drinking (defined as alcohol intake >14 standard drink units per week or 4 standard drinks on a single occasion in men; and alcohol intake >7 standard drink units per week or 3 standard drinks on a single occasion in women) within the 24 months before screening V1 or had positive alcohol test at screening V3 or at V4. A unit of alcohol is defined as 14 gram or as 355 mL of beer (5% alcohol by volume [ABV]), 1 glass of wine (150 mL; 12% ABV), or 1 shot of hard liquor (45 mL; 40% ABV). During the study, subjects will receive counseling and will be encouraged to abstain from alcohol. Alcohol intake will be limited to 2 units of alcohol per day for men and 1 unit of alcohol per day for women. Subjects must be willing to abstain from alcohol use 48 hours prior to study visits.
11.Concomitant use of PCSK9 inhibitors, niacin, or any supplements, including non-prescription, non-pharmaceutical strength fish oils, used to alter lipid metabolism. Previous treatment with a PCSK9 inhibitor will need to have ceased >12 weeks before screening with no intention to reinitiate treatment for the duration of the trial. Other lipid-modifying supplements including, but not limited to, red rice yeast supplements, garlic supplements, soy isoflavone supplements, sterol/stanol products, or policosanols are not permitted.
a.Subjects participating in the main cohort previously treated with a fibrate will need to agree to cease fibrate treatment for the duration of this trial.
b.Subjects enrolled in the fibrate expansion cohort will need to maintain their current stable dose of fibrate therapy (≥4 weeks before screening V1).
12.Previous long-term (>4 weeks) use of systemic steroid (glucocorticoid) medications such as prednisone within 12 months of screening V1. Inhaled or topical corticosteroids are permitted.
13.Reduced renal function (eGFR ≤55 mL/min/1.73 m2 calculated using chronic kidney disease epidemiology collaboration [CKD-EPI] equation).
14.Positive for hepatitis b virus (HBV), hepatitis c virus (HCV) or human immunodeficiency virus (HIV). HIV, HBV and HCV determined by antibodies first and, if positive, confirmed by DNA/ribonucleic acid (RNA). Subjects who have tested positive for COVID-19 who are asymptomatic or who have active COVID-19 infection are excluded. Note: subjects who had COVID-19 and recovered without sequelae or tested positive without symptoms at least 8 weeks prior to screening may be included.
15.History of substance use disorder, or any other substance dependence (with the exception of caffeine) as defined by the Diagnostic and Statistical Manual of Mental Disorders 4th edition Text Revision (DSM-IV-TR) in the past 2 years prior to Screening. Subjects without a history of substance use disorder who have a positive drug screen test at screening V1 may be considered for enrollment with Medical Monitor (or designee) approval.
16.Participation in a previous clinical trial or exposure to another investigational drug within 12 weeks or 5 half-lives, whichever is longer, prior to screening.
17.Previous exposure to an FGF21 analog (e.g., BIO89-100, LY2405319, LY3025876, BMS-986036, [pegbelfermin], BMS-986171, PF-05231023, PF-06645849, AKR-001)[efruxifermin]) or FGFR1 activating product, or known sensitivity to PEG or any of the excipients.
18.Type 1 diabetes mellitus (T1DM).
19.Diagnosis of Type 2 diabetes mellitus (T2DM) <6 months prior to screening.. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage change in serum TG from baseline to Week 8 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Achieve TG <500 mg/dL at Week 8
• Percentage change in very low density lipoprotein cholesterol (VLDL-C) , low density lipoprotein cholesterol (LDL-C), non-high density lipoprotein
cholesterol (non-HDL-C), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein triglycerides (VLDL-TG), apolipoprotein B100
(ApoB), remnant lipoprotein cholesterol (RLP-C) from baseline to Week 8
• Percentage change in hsCRP from baseline to Week 8
• Percentage change in fasting plasma glucose, adiponectin, and body weight from baseline to Week 8
• Serum BIO89-100 concentration
• PK parameters in Intensive PK subgroup
o Maximal observed serum concentrations (Cmax) within a dosing interval
o Area under the serum drug concentration by time curve within a dosing interval (AUC0-tau)
o Time to achieve Cmax (tmax)
o Terminal elimination half-life (t½)
• Additional PK parameters may be calculated if also deemed appropriate.
•Percentage change and change from baseline in hepatic steatosis using MRI-PDFF |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Week 8
• From baseline to Week 8 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, Tolerability |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Poland |
| Czechia |
| Hungary |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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