GRWD0715 is an orally administered, selective inhibitor of the Endoplasmic Reticulum Aminopeptidase 1 \[ERAP1\] enzyme being explored as a potential new treatment for axial spondyloarthritis (axSpA), a long term condition caused by inflammation predominantly affecting the sacroiliac joints (SIJs) and spine.
GRWD0715 is an orally administered, selective inhibitor of the Endoplasmic Reticulum Aminopeptidase 1 \[ERAP1\] enzyme being explored as a potential new treatment for axial spondyloarthritis (axSpA), a long term condition caused by inflammation predominantly affecting the sacroiliac joints (SIJs) and spine. ERAP1 is involved in trimming antigens from foreign bodies (e.g. bacteria, viruses) which are presented on the surface of a cell to trigger an immune response. In axSpA, it is thought an antigen from the person's own body, called a 'self-peptide' is presented by the ERAP1 processing pathway and incorrectly recognised by the immune system. The hypothesis is that stimulation of the immune system by the presentation of this self-peptide causes the inflammatory symptoms experienced by people living with axSpA. As an inhibitor of ERAP1, GRWD0715 aims to prevent the generation of the antigenic self-peptide, and thus remove the stimulus of the immune system. If the immune system is not activated, the immune attack on the sacroiliac joint (SIJ) and spine would stop, halting the axSpA disease progress. The study will consist of 4 parts: Part A conducted in healthy human volunteers, and Part B, Part C and/or D in participants with axSpA. The primary goal of Parts A, B and C is to assess whether GRWD0715 is safe and well tolerated in healthy human volunteers and participants with axSpA. The primary goal of Part D is to review whether GRWD0715 is efficacious when compared to placebo.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
140
Participants in Part A will receive a single dose of GRWD0715 on Day 1 only.
Participants in Part B will receive GRWD0715 for 28 days
Participants in Part C will receive GRWD0715 for 12 weeks
University of the Sunshine Coast (UniSC)
Birtinya, Australia
RECRUITINGUniversity of the Sunshine Coast (UniSC)
Morayfield, Australia
Parts A, B and C: Incidence of treatment emergent (TEAE) and treatment related adverse events (TRAEs)
Any adverse event AE reported or observed after the start of dosing with any study treatment until completion of the last study related procedure (includes follow-up for safety assessments) will be recorded as a treatment-emergent AE (TEAE). If the TEAE is considered related to the study drug as per the definitions of relatedness listed in ('possibly', 'probably' or 'definitely' related) it will be considered a treatment-related AE (TRAE).
Time frame: Immediately after the first dose of GRWD0715 through to study completion after 4-12 weeks.
Parts A and B: Incidence and nature of dose limiting events (DLEs).
DLEs are on Grade 2 (moderate) events that are classified as related to study drug and are not resolved within 7 days. Any Grade 2 events lasting longer than 7 days, events of a higher grade, events that require study drug discontinuation or which meet the criteria for Seriousness and are related to study drug are counted as DLEs.
Time frame: Part A: the DLE period will be 15 Days from the start of dosing Part B: the DLE period will be 35 days from the start of dosing
Analysis of clinical response per Assessment of SpondyloArthritis International Society (ASAS) core outcome set compared to placebo. Higher scores mean worse outcome: Continuous Calculated Scores
The ASAS core outcome set (COS) will be conducted in participants and includes the following questionnaires which use Continuous Calculated Scores: Ankylosing Spondylitis Disease Activity Score (ASDAS)- A specific mathematically weighted index that combines patient-reported outcomes and blood inflammatory markers. Bath Ankylosing Spondylitis Function Index (BASFI) - A mean score derived from 10 individual visual/numeric questions regarding physical function. Assessment of SpondyloArthritis (ASAS) Health Index - A composite health and functioning score calculated from a specific 17-item questionnaire.
Time frame: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
Analysis of clinical response per Assessment of SpondyloArthritis International Society (ASAS) core outcome set compared to placebo. Higher scores mean worse outcome: Numeric Rating Scales
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Participants in Part D will receive GRWD0715 or placebo-to-match for 12 weeks
The Colin Bayliss Research and Teaching Unit
Perth, Australia
RECRUITINGPioneer Clinical Research
Sydney, Australia
RECRUITINGUniversity Ghent
Ghent, Belgium
RECRUITINGUZ Leuven
Leuven, Belgium
RECRUITINGRheumazentrum Ruhrgebiet, Ruhr-University Bochum
Bochum, Germany
RECRUITINGUniversitätsklinikum Erlangen - Medizinische Klinik 3
Erlangen, Germany
NOT_YET_RECRUITINGAmsterdam University Medical Center
Amsterdam, Netherlands
RECRUITINGLeids Universitair Medisch Centrum (LUMC) (Leiden University Medical Center)
Leiden, Netherlands
NOT_YET_RECRUITING...and 6 more locations
The ASAS core outcome set (COS) will be conducted in participants and includes the following questionnaires which use numeric rating scales (0-10): NRS Patient Global Assessment of Disease Activity (PGA-DA): A single 0-10 scale rating overall disease impact. NRS total back pain (BASDAI Q2): A single 0-10 scale rating spinal pain. NRS fatigue (BASDAI Q1): A single 0-10 scale rating tiredness levels. NRS average duration and severity of morning stiffness (BASDAI \[Q5+Q6\]/2): An average calculation derived from two separate 0-10 numeric rating scales.
Time frame: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
Analysis of clinical response per Assessment of SpondyloArthritis International Society (ASAS) core outcome set compared to placebo. Higher scores mean worse outcome: Direct Anatomical Counts
The ASAS core outcome set (COS) will be conducted in participants and includes the following assessments which use direct anatomical counts: 44 swollen joint count (Part D): A literal tally of how many joints out of 44 are actively swollen. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) (Part D only): A tally of painful areas out of 13 specific enthesitic insertion sites. Dactylitis count: A literal tally of the number of digits (fingers and toes) exhibiting uniform swelling (Part D only) ASAS20 and ASAS 40 scores will be calculated from constituent questions within the ASAS COS clinical outcome measures and patient reported outcome measures.
Time frame: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
Analysis of clinical response per SPARCC MRI (magnetic resonance imaging) Activity of the sacroiliac joints and spine in the core outcome set compared to placebo
The SPARCC Scoring System measures active inflammation and structural joint damage in the sacroiliac joints using MRI, through the following: Inflammation Scoring (Bone Marrow Edema): Slice selection: Evaluates six consecutive, specialized coronal MRI slices through the joint. Joint quadrants: Divides each sacroiliac joint into four distinct quadrants (upper and lower iliac, upper and lower sacral). Basic scoring: Gives 1 point for the presence of bone marrow edema in each quadrant. Intensity and depth bonuses: Adds extra points for lesions that show very high signal intensity or great depth (\>1 cm). Maximum score: Reaches a total high score of 72 points for inflammation Structural Damage Scoring: Erosions: Measures loss of bone at the joint surface. Fat lesions: Tracks areas where bone marrow is replaced by fat. Backfill and ankylosis: Detects tissue repair and joint fusion
Time frame: This will be conducted at Screening, Week 1, Week 4, Week 8, Week 12 and the 15 Day End of Study visit
Parts A, B and C: PK - trough concentrations (Cmin)
PK samples will be collected during the study to measure the to measure how the study drug moves into, through, and out of the body over time, and how its concentration in the body changes over time. Whole blood will be collected for the determination of GRWD0715 levels in plasma. The trough is the lowest concentration of a drug reached in the body, it is collected from a blood sample drawn immediately before administering the next scheduled dose.
Time frame: Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8
Parts A, B and C: PK - maximum observed concentration (Cmax)
The Cmax is the highest measured drug concentration in the blood or plasma after a dose and is measured or identified directly as the highest peak data point on the experimental concentration-time graph.
Time frame: Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8
Parts A, B and C: PK - time to Cmax (Tmax)
This is the exact time elapsed from drug administration until the peak concentration (Cmax) is reached and is found by looking at the time value on the x-axis that corresponds directly to the peak concentration of the drug in the blood.
Time frame: Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8
Parts A, B and C: PK - area under the concentration-time curve (AUC0-t)
A measure of the total drug exposure in the body from time zero up to the timepoints specified below for each study Part.
Time frame: Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8
Parts A, B and C: PK - half-life (t1/2)
The time required for the GRWD0715's plasma concentration to decrease by exactly 50% during the final elimination phase.
Time frame: Part A: From first dose to Day 4 Part B: From first dose to Day 28 Part C: Immediate Rollover: Week 4, 8 and 10 Returning Rollover: Week 1, 4 and 8
Part B: A Biologically Active Dose (BAD) will be identified
A BAD is defined as a dose level with evidence supporting a biological effect of GRWD0715. A BAD will be identified based on meeting at least one of the following pre-specified criteria: Steady state pharmacokinetics: Dose levels achieving mean steady-state Cavg concentration at or above a predefined threshold of 1166 ng/ml will be considered to provide sufficient target engagement to meet the definition of a BAD. This threshold corresponds to the predicted IC50 as a relative Cavg concentration and is supported by human PK-PD modelling of a related oral ERAP1 inhibitor (GRWD5769) in oncology, which demonstrated that significant immunopeptidome shifts occur at levels that achieve PK exposures ≥ predicted IC50 as a relative Cavg concentration. Preliminary signals of clinical activity, including clinically important improvements in validated disease activity measures (e.g., ASDAS). Other supporting evidence may be considered including evidence of pharmacodynamic activity.
Time frame: The Biologically Active Dose will be assessed every 3 months in Part B on the completion of each of the 6 dose cohorts for up to a total of 14 months.
Parts A, B and C: Maximum tolerated dose (MTD): the MTD will be determined by the incidence of DLEs according to the MTD evaluation process.
Multiple ascending doses will be evaluated in this study. The MTD will be decided using a BOIN design escalation/de-escalation/elimination criteria model. If the true DLE rate is greater than 0.22 for a dose level, no future participants can be dosed at that level or higher.
Time frame: MTD will be assessed on the completion of each dose level cohort.