Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001520729
Ethics application status
Approved
Date submitted
15/11/2022
Date registered
7/12/2022
Date last updated
21/02/2023
Date data sharing statement initially provided
7/12/2022
Date results information initially provided
21/02/2023
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1b, Open-Label, Parallel Single-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Tinlarebant in Healthy Volunteers Aged 50-85
Scientific title
A Phase 1b, Open-Label, Parallel Single-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Tinlarebant in Healthy Volunteers Aged 50-85
Secondary ID [1] 308085 0
NA
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dry Age related macular degeneration (AMD) 328053 0
Condition category
Condition code
Eye 325112 325112 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase 1b, parallel single-dose study to evaluate the Pharmacokinetics and Pharmacodynamics of tinlarebant when administered as a single oral dose to healthy volunteers aged 50-85. Tinlarebant also known as LBS-008 is being developed as an oral treatment to slow or halt progression of dry age-related macular degeneration (AMD) and juvenile onset macular degeneration, known as autosomal recessive Stargardt disease (STGD1). Both dry AMD and STGD1 are triggered by abnormalities in the retinal pigment epithelium (RPE) that induce secondary degeneration of photoreceptor cells. The ABCA4 gene encodes an ATP-dependent transporter (known as ABCA4, or Rim Protein). This protein resides at the rim of rod and cone photoreceptor disc membranes where it removes light-activated visual chromophore from the retina permitting vitamin A detoxification by a retinaldehyde dehydrogenase (AtRDH) which produces retinol. Retinol liberated from the retina is then taken up by the RPE and is enzymatically re-processed back to a light-sensitive visual chromophore. The RPE also converts dietary vitamin A (retinol) delivered from the blood circulation into visual chromophore and transfers it to the retina in order to maintain light sensitivity and function of the retina. It is important to note that the RPE shows a unique preference for uptake of retinol bound to RBP4. This is due to the unique expression of an RBP4 receptor, which is only expressed in the RPE and brain. In the absence of a functional ABCA4 protein, retinaldehyde accumulates within photoreceptor outer segments where it generates membrane-damaging reactive oxygen species and also spontaneously reacts with cellular lipids. These oxidized membranes and lipid-retinaldehyde species are gradually taken into the RPE through normal phagocytic processing where they form stable bisretinoid compounds, such as A2E. It is theorized that these compounds reach a critical mass within RPE phagolysosomes and cause dysfunction of the metabolic activities of the RPE leading to early accelerated accumulation of lipofuscin which fluoresces due to the high concentration of vitamin A byproducts. Clinically, the presence of autofluorescent lipofuscin precedes the appearance and growth of retinal lesions and VA loss in both GA in dry AMD and STGD1 patients. The LBS-008 drug product for the Phase 1b portion of the Phase 1b/2 study in adolescents with STGD1 is an extemporaneously prepared capsule intended for oral administration.
A total of up to 16 healthy volunteers aged 50-85 are planned to be enrolled into 2 cohorts (8 participants per cohort). Participants will receive a single oral dose of tinlarebant, either 5 mg (Cohort 1) or 10 mg (Cohort 2). Tinlarebant will be administered in tablet form; a single tinlarebant tablet will contain 5 mg of IP. Participants in Cohort 1 will receive 1 tinlarebant tablet (5 mg dose) and participants in Cohort 2 will receive 2 tinlarebant tablets (10 mg dose). Enrolment and dosing of participants in Cohorts 1 and 2 may occur concurrently. Healthy volunteers aged 50-85, will be screened between Day -28 and Day -2, inclusive. Participants will be admitted to the clinical facility on Day -1 with tinlarebant dosing to occur on the following day (Day 1). All participants will be dosed under fasted conditions. Participants will be confined at the clinical facility from Day -1 through to Day 2 , with discharge following completion of all PK and PD blood sample collections and other scheduled assessments on Day 2. Participants will receive a single dose of tinlarebant tablet (s) in the morning of Day 1. 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). Blood samples for PK and PD analysis will be collected pre-dose and at timepoints up to 24 hours (Day 2) post-dose during the confinement period. Participants will be required to attend the clinic as outpatients on Days 3, 4, 6 and 8 for further safety assessments, PK and PD blood sampling. Participants will then return to the clinical facility for final safety assessments at an EOS on Day 15.
In the event of early study termination prior to the End Of Study (EOS) visit (Day 15), participants will be requested to attend the clinic for an early termination (ET) visit.
Intervention code [1] 324731 0
Treatment: Drugs
Comparator / control treatment
There will be no comparison between the 2 cohorts. Data from cohort 1 and 2 will be used to determine the optimal dose in this age group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332934 0
To measure the pharmacokinetics (PK) of tinlarebant in plasma following a single oral dose in healthy volunteers aged 50-85. The parameters assessed for the PK endpoints include:
- Area under the plasma concentration versus time curve from time 0 to the last time point with quantifiable concentration (AUC0-t);
- Area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC0-inf);
- Maximum observed plasma concentration (Cmax);
- Time of maximum observed plasma concentration (Tmax);
- Apparent plasma terminal elimination half-life (t1/2);
- Terminal elimination rate constant (lambdaz);
- Apparent total body clearance (CL/F);
- Apparent volume of distribution (Vz/F).
Timepoint [1] 332934 0
PK is assessed at the following timepoints:
- Day 1- Pre dose - 60 min prior to dosing
- Day 1 - Post dose- 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours
- Day 2- post dose- 24 hours
- Day 3- post dose- 48 hours
- Day 4 - post dose- 72 hours
- Day 6-post dose- 120 hours
- Day 8- post dose- 168 hours
Primary outcome [2] 332936 0
To measure the concentrations of retinol-binding protein 4 (RBP4), a pharmacodynamic (PD) biomarker, in plasma following a single oral dose in healthy volunteers aged 50-85. Plasma PD endpoints include:
- Time of minimal RPB4 levels post-dose (Tmin)
- Maximal suppression to RBP4 expressed as minimum concentration of RBP4 (Cmin)
- Maximal suppression to RBP4 expressed as percent (%) of baseline concentration of RBP4 (C%bmin)
- Level of RBP4 at 12 hours as concentration (C12h)
- Level of RBP4 at 12 hours as percent of baseline concentration (C%b12h)
- Level of RBP4 at 24 hours as concentration (C24h);
- Level of RBP4 at 24 hours as percent of baseline concentration (C%b24h)
- Half life for recovery of RBP4 to baseline levels (PDt1/2)
Timepoint [2] 332936 0
PD is assessed at the following timepoints:
- Day 1- Pre dose - 60 min prior to dosing
- Day 1 - Post dose- 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours
- Day 2- Post dose- 24 hours
- Day 3- Post dose- 48 hours
- Day 4- Post dose- 72 hours
- Day 6- Post dose- 120 hours
- Day 8- Post dose- 168 hours
Secondary outcome [1] 415199 0
To investigate the systemic and ocular safety and tolerability of a single oral dose of tinlarebant in healthy adult volunteers aged 50-85.
The parameters assessed for the safety endpoints include
- Incidence, type, severity, and relationship of AEs/Serious AEs (SAEs), including withdrawals due to AEs.
- Changes from baseline in clinical laboratory parameters (haematology, coagulation, serum chemistry and urinalysis)
- Changes from baseline in vital sign measurements (Systolic and diastolic blood pressure (BP), heart rate (HR), respiratory rate, and body temperature). Blood pressure will be measured using sphygmomanometer, body temperature will be measured using a thermometer, Heart rate (HR) is measured using vital sign machine and respiratory rate is measured manually via 60 second count.
- Changes from baseline in electrocardiogram (ECG) parameters
- Changes from baseline in visual acuity scores
- Changes from baseline in colour vision scores
- Ocular examination assessments (slit lamp biomicroscopy, dilated ophthalmoscopy, and intraocular pressure)
Timepoint [1] 415199 0
Assessed at the following time points:
- Adverse events (AEs)- Adverse events will be recorded on and after the first dose of study drug and up to EOS/ET visit, The assessment will be based on the Investigator’s clinical judgement. The severity of each event will be graded using the most current version of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 5) 5-point scale.
- Laboratory tests- Clinical lab tests are performed during screening, Day -1 , on Day 2, Day 8 and at EOS/ET visit. Participants will be requested to fast for at least 8 hours prior to each clinical lab blood and urine sample collection timepoint except at and ET visit.
- Vital Signs - Vital signs will be measured at screening, Day -1, on Day 1 within 60mins pre dose, 1, 4, 8, 12 and 24 hours post dose, on Day 8 and at EOS/ET visit.
- ECGs - Triplicate 12-lead ECG recordings will be made at screening, Day -1, on Day 1 within 60mins prior dosing, 1 hour post dose, Day 2, Day 8 and at EOS/EOT visit.
- Visual Acuity Scores- Visual acuity will be measured at screening, Day 2, Day 4, and at the EOS/ET visit, using the ETDRS assessment scale (Method 2). The visual acuity examination will occur first, followed by a colour vision examination, and then an ocular examination, if applicable.
- Colour Vision Scores - Colour vision will be tested at screening, Day 2, Day 4, and at the EOS/ET visit, using the D-15 dichotomous test.
- Ocular Examinations - Ocular examinations will be performed at screening, Day 4, and at the EOS/ET visit. Ocular examinations will include slit lamp biomicroscopy, dilated ophthalmoscopy, and intraocular pressure.
Secondary outcome [2] 415203 0
Exploratory Outcome: To measure the concentration of retinol, a PD biomarker , in serum following a single oral dose of tinlarebant in healthy volunteers aged 50-85.
Serum retinol concentration for each participant will be calculated for each timepoint.
Timepoint [2] 415203 0
Serum retinol concentration is assessed at the following time points:

- Day 1- Pre dose - 60 min prior to dosing
- Day 1 - Post dose- 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours
- Day 2- Post dose- 24 hours
- Day 3- Post dose- 48 hours
- Day 4- Post dose- 72 hours
- Day 6- Post dose- 120 hours
- Day 8- Post dose- 168 hours

Eligibility
Key inclusion criteria
1. 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.
2. Healthy adult male or female, or adult male or female with a stable chronic disease or condition aged 50-85 years of age, inclusive. Adults with stable chronic disease or condition includes adults with no new diagnosis, hospitalisation or changes In medication in the 3 months prior to first dose of study drug on Day 1. Ongoing concomitant medications associated with the stable disease or condition, including over-the-counter (OTC) medications and herbal/vitamin supplements taken by volunteers, will be recorded and reviewed by the PI (or delegate) to determine whether the volunteer is suitable for inclusion in the study.
3. The volunteer is considered by the Investigator to be in stable health
Minimum age
50 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Presence of clinically significant (CS) cardiovascular, pulmonary, hepatic, renal, haematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, orpsychiatric disease, or any other condition that, in the opinion of the Investigator, would jeopardise the safety of the participant or the validity of the study results.
2. Point no 2 updated in public notes.
3. A history of uncontrolled hypertension, coronary artery disease, or any other significant cardiovascular disease.
4. A history of uncontrolled diabetes. Volunteers with fully resolved gestational diabetes will be eligible to participate in the study.
5. A history of unexplained loss of consciousness, epilepsy or other seizure disorder, or cerebrovascular disease.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
All study participants who sign an informed consent form at screening will receive a unique sequential number (i.e., a screening number). Participants who meet the study eligibility criteria will then be assigned a participant number on Day 1 and receive either 5 or 10 mg IP (in an open-label manner).
Participants who withdraw for any reason without completing all screening evaluations successfully will be considered screen failures.
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Detailed methodology for summaries and statistical analyses of the data collected will be documented in a separate Statistical Analysis Plan (SAP).
1. Sample Size Considerations
A sample size of 8 healthy male or female participants (aged 50-85) per cohort in this 2-cohort parallel study is based on clinical and practical considerations and not on a formal statistical power calculation. The sample size is considered sufficient to evaluate the objectives of the study.
2. Analysis Sets
a. Safety Analysis Set- The safety analysis set will include all participants who receive at least one dose of study drug (tinlarebant).
b. Pharmacokinetic Analysis Set - The PK analysis set will include all participants who received tinlarebant and who have at least one tinlarebant plasma concentration data point.
c. Pharmacodynamic Analysis Set- The PD analysis set will include all participants who received tinlarebant and who have at least one RBP4 plasma concentration data point.
3. Demographic and Baseline Data
Demographic data (including gender, age, race, and ethnicity), height weight and BMI will be summarised using descriptive statistics tabulated by cohort and overall.Screening serology results (HIV, HBsAg and HCV) will be listed only.
Medical history will be coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). The number of participants reported with conditions/procedures and the number of conditions/procedures reported will be summarised by dose level and overall, grouped according to system organ class and preferred term, using descriptive statistics.
4. Pharmacokinetic Data
All parameters will be calculated using Phoenix® WinNonlin® Version 8.0 or later or SAS® . Pharmacokinetic parameters will be summarised for each dose level using descriptive statistics (n, mean, SD, CV, median, minimum, maximum, geometric mean, and geometric %CV). Geometric mean and geometric %CV will be reported for AUC0-t, AUC0-inf, and Cmax only.
5. Pharmacodynamic Data
All parameters will be calculated using Phoenix® WinNonlin® Version 8.0 or later or SAS®. Pharmacodynamic parameters will be summarised for each dose level using descriptive statistics. Additional exploratory analysis may be conducted as needed to establish concentration response relationships between tinlarebant concentrations and RBP4 levels.
Serum retinol for each participant will be calculated for each timepoint and time interval respectively.
6. Safety/Tolerability Data
Safety evaluations will be based on the incidence, severity and relationship of AEs, vital signs, clinical laboratory results and ECGs.
a. Adverse event data - All AEs will be coded using the latest version of MedDRA by system organ class (SOC) and preferred term, classified from verbatim terms. The number of treatment-emergent AEs (TEAEs) as well as the number and percentage of participants with at least one TEAE, will be summarised by SOC and preferred term and tabulated for each cohort. Summaries of TEAEs by severity and relationship will also be presented. Summaries will also be presented for SAEs leading to death or study withdrawal. The duration of such events will be determined and included in the listings.
b. Prior and Concomitant Medication Data- Prior and concomitant medications will be coded using the latest version of the World Health Organisation Drug Dictionary (WHO DD). The number and percentage of participants taking prior medication, and concomitant medication will be summarised using frequency tables according to WHO Drug Anatomical Therapeutic Chemical Level 1 Code Description and the WHO DD preferred name. If a participant has more than one prior or concomitant medication coded to the same category, the participant will be counted only once.
c. Physical Examination Data
Physical examination data will be listed only. Any post-dose CS findings will be reported as AEs.
d. Visual Acuity- Observed values and changes from baseline for visual acuity scores will be summarised at each scheduled timepoint using descriptive statistics and tabulated for each cohort.
e. Colour Vision Examination Data
Observed values and changes from baseline for colour vision scores will be summarised at each scheduled timepoint using descriptive statistics and tabulated for each cohort.
f. Ocular Examination Data
Ocular examination assessments (including slit lamp biomicroscopy, dilated ophthalmoscopy, and intraocular pressure) will be summarised at each scheduled timepoint using descriptive statistics and tabulated for each cohort. Where appropriate, observed values and changes from baseline using descriptive statistics will be presented at each scheduled visit by cohort.
g. Vital Signs Data
Observed values and changes from baseline for vital signs (systolic and diastolic BP, HR, body temperature and respiratory rate) will be summarised at each scheduled timepoint using descriptive statistics and tabulated for each cohort.
h. Electrocardiogram Data
The following ECG parameters will be analysed: ventricular HR, RR interval, PR interval, QRS width, QT interval, QTcB and QTcF. Observed values and changes from baseline for ECG parameters will be summarised at each scheduled timepoint using descriptive statistics andtabulated for each cohort. The mean value for the triplicate at each timepoint will be utilised in these summaries. msec or an increase from baseline of at least 30 (and 60) msec will also be presented, in accordance with ICH E14.
i. Clinical Laboratory Safety Data- Clinical laboratory safety data will be summarised by the laboratory parameter. Normal reference ranges and abnormal results will be used in the summary of laboratory data. Observed values and changes from baseline for continuous clinical laboratory parameters will be summarised at each scheduled timepoint using descriptive statistics and tabulated for each cohort.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/12/2022
Actual
9/12/2021
Date of last participant enrolment
Anticipated
14/12/2022
Actual
14/12/2022
Date of last data collection
Anticipated
27/01/2023
Actual
19/01/2023
Sample size
Target
16
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23464 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 38864 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 312337 0
Commercial sector/Industry
Name [1] 312337 0
RBP4 Pty Ltd
Country [1] 312337 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
RBP4 Pty Ltd
Address
RBP4 Pty Ltd
58 Gipps Street, Collingwood Victoria 3066
Country
Australia
Secondary sponsor category [1] 313899 0
Commercial sector/Industry
Name [1] 313899 0
Belite Bio, Inc
Address [1] 313899 0
Belite Bio, Inc
5820 Oberlin Drive, Suite 101, San Diego, CA 92121
Country [1] 313899 0
United States of America
Other collaborator category [1] 282488 0
Commercial sector/Industry
Name [1] 282488 0
Avance Clinical Pty Ltd
Address [1] 282488 0
Avance Clinical Pty Ltd
Level 1, Ann Nelson Drive
Thebarton, SA 5031, Australia
Country [1] 282488 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311705 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 311705 0
Bellberry Limited
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 311705 0
Australia
Date submitted for ethics approval [1] 311705 0
12/10/2022
Approval date [1] 311705 0
11/11/2022
Ethics approval number [1] 311705 0

Summary
Brief summary
This is a Phase 1b, parallel single-dose study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of tinlarebant when administered as an oral dose to healthy volunteers aged 50-85. Tinlarebant (previously called LBS-008) is being developed as an oral treatment to slow or halt the progression of dry age-related macular degeneration (AMD) and juvenile onset macular degeneration, known as Stargardt disease (STGD). Accumulation of lipofuscin bisretinoids in the retina is associated with several retinal degenerative diseases including dry AMD and STGD. A total of up to 16 healthy volunteers aged 50-85 are planned to be enrolled into 2 cohorts (8 participants per cohort). Participants will receive a single oral dose of tinlarebant, either 5 mg (Cohort 1) or 10 mg (Cohort 2). The total maximum study duration for participants in this study is 45 days, inclusive of visit windows. This includes a screening period of up to 27 days (Day -28 to Day -2), confinement to the clinical facility over 2 nights (Day -1 to Day 2) and 5 outpatient visits including the EOS visit or Day 15. Tinlarebant will be administered in tablet form; a single tinlarebant tablet will contain 5 mg of IP. Participants in Cohort 1 will receive 1 tinlarebant tablet (5 mg dose) and participants in Cohort 2 will receive 2 tinlarebant tablets (10 mg dose). Enrolment and dosing of participants in Cohorts 1 and 2 may occur concurrently. Healthy volunteers aged 50-85, will be screened between Day -28 and Day -2, inclusive. Participants will be admitted to the clinical facility on Day -1 with tinlarebant dosing to occur on the following day (Day 1). All participants will be dosed under fasted conditions. Participants will be confined at the clinical facility from Day -1 through to Day 2 with discharge following completion of all PK and PD blood sample collections and other scheduled assessments on Day 2. 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). Blood samples for PK and PD analysis will be collected pre-dose and at timepoints up to 24 hours (Day 2) post-dose during the confinement period. Participants will be required to attend the clinic as outpatients on Days 3, 4, 6 and 8 for further safety assessments, PK and PD blood sampling. Participants will then return to the clinical facility for final safety assessments,
In the event of early study termination prior to the EOS visit (Day 15), participants will be requested to attend the clinic for an early termination (ET) visit.
Trial website
Trial related presentations / publications
Public notes
Exclusion Crietria- 2. Had a CS new illness within 1 month prior to the screening visit, with the exception of fully resolved gastrointestinal illness at least 14 days prior to the screening visit, fully resolved minor colds (e.g., only cold and flu-like symptoms) that occurred within 1 month prior to the screening visit, and fully resolved corona virus disease2019 (COVID-19) infections if resolved at least 14 days prior to the screening visit and 30 days prior to confinement to the clinical facility.

Contacts
Principal investigator
Name 122066 0
Dr Sam Francis
Address 122066 0
Nucleus Network Melbourne
Level 5, Burnet Tower, 89 Commercial Rd, Melbourne 3004, Victoria
Country 122066 0
Australia
Phone 122066 0
+614 66640801
Fax 122066 0
Email 122066 0
s.francis@nucleusnetwork.com.au
Contact person for public queries
Name 122067 0
Miss Lisa Liang
Address 122067 0
Belite Bio, Inc
36F, No.68, Sec.5, Zhongxiao E. Rd, Taipei
Country: Taiwan
Country 122067 0
Taiwan, Province Of China
Phone 122067 0
+886 227255355
Fax 122067 0
Email 122067 0
clinicaltrial@belitebio.com
Contact person for scientific queries
Name 122068 0
Miss Lisa Liang
Address 122068 0
Belite Bio, Inc
36F, No.68, Sec.5, Zhongxiao E. Rd, Taipei
Country: Taiwan
Country 122068 0
Taiwan, Province Of China
Phone 122068 0
+886 227255355
Fax 122068 0
Email 122068 0
clinicaltrial@belitebio.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Privacy and Intellectual property rights considerations


What supporting documents are/will be available?

No Supporting Document Provided



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