Autosomal Dominant Polycystic Kidney Disease
Conditions
Brief summary
This is an exploratory, randomized, double-blind, placebo-controlled, parallel group, multicenter, proof of concept study (Phase 2a), evaluating orally administered GLPG2737 for a double-blind (DB) treatment period of 52 weeks and 4 weeks of follow up as well as an open-label extension (OLE) treatment period of 52 weeks and 4 weeks of follow-up, in participants with rapidly progressing ADPKD.
Interventions
DRUGGLPG2737
Capsules administered orally
DRUGPlacebo
Matching placebo capsules administered orally
Sponsors
Galapagos NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria for the double-blind period of the study: * Documented diagnosis of typical ADPKD, using the Ravine criteria (Ravine, et al., 1994). * Rapidly progressive disease, defined as presence of all of the following: * Total Kidney Volume (TKV) \>750 mL, as determined on imaging not older than 5 years before screening. If historical imaging is not available or older than 5 years, imaging can be performed during the screening period according to local clinical practice (that is, echography, magnetic resonance imaging \[MRI\]) * Mayo ADPKD Classification Classes 1C to 1E. * eGFR at screening between 30 to 90 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) for participants aged 18 to 40 years (inclusive), and between 30 to 60 mL/min/1.73 m\^2 for participants aged 40 to 50 years. * Blood pressure ≤ 150/90 millimeters of mercury (mmHg). In case a participant is treated for hypertension, she/he should be on a stable treatment regimen of antihypertensive therapy for at least 8 weeks prior to the screening visit, and during the screening period. Key Inclusion Criteria for the OLE period of the study: * Male and female participants who completed the 52-week double-blind treatment period on investigational product (IP). * Participant, according to the investigator's judgment, may benefit from long-term treatment with GLPG2737. Key
Exclusion criteria
for the double-blind period of the study: * Congenital absence of 1 kidney, or participant had a previous nephrectomy or has a transplanted kidney or a transplantation is planned in the foreseeable future. * Administration of polycystic kidney disease-modifying agents (for example, tolvaptan, somatostatin analogues) or interventions (such as cyst aspiration or cyst fenestration) within 12 weeks prior to the screening visit and during the screening period. In case tolvaptan is not being administered, this should be because of e.g. non-availability, intolerance, or physician's clinical judgment. * Any condition or circumstances that, in the opinion of the investigator, may make a participant unlikely or unable to complete the study or comply with study procedures and requirements (for example, unable to undergo magnetic resonance imaging (MRI) due to participant's weight exceeds the weight capacity of the MRI, ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, etc.). Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DB Period: Mean Percent Change From MRI Baseline in htTKV | MRI Baseline up to Week 52 | htTKV is used in participants with ADPKD disease to predict the onset of renal insufficiency. htTKV was calculated using TKV (in mL) obtained from MRI divided by height (in m). MRI Baseline: For MRI assessments, all non-missing values before the first study drug administration in the study +14 days (included) was considered as the primary baseline definition. Results were derived by mean of the individual slopes (i.e. using all MRI performed between baseline and Week 52). |
| DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | From first dose to Week 56 | An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study drug, whether or not considered related to it. A serious adverse event (SAE) is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results a congenital anomaly/birth defect or other medically important event. A TEAE was defined as an AE observed after starting administration of the study drug until 30 days after last DB dose or 1 day before OLE dose, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DB Period: Mean Change From Baseline in eGFR | Baseline up to Week 52 | The eGFR is a test that measures level of kidney function and determines the stage of kidney disease. eGFR was based on CKD-EPI formula (2009) calculated from serum creatinine concentrations. Results were derived by mean of the individual slopes (i.e. using data between baseline and Week 52). |
| DB Period: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau) of GLPG2737 and Its Metabolite | Predose (within 30 minutes prior to dosing), 1, 1.5, 2, 3, 4, 5, 6, 7 hours post dose through Week 52 | AUC0-tau described the area under the curve limited to the end of a dosing interval. The metabolite of GLPG2737 is M4. |
| DB Period: Maximum Observed Plasma Concentration (Cmax) of GLPG2737 and Its Metabolite | Predose (within 30 minutes prior to dosing), 1, 1.5, 2, 3, 4, 5, 6, 7 hours post dose through Week 52 | Cmax is the maximum observed plasma concentration of the drug. The metabolite of GLPG2737 is M4. |
Countries
Belgium, Czechia, Germany, Italy, Netherlands, Poland, Spain
Participant flow
Recruitment details
Participants with autosomal dominant polycystic kidney disease (ADPKD) were enrolled. The study was conducted at 20 sites in 7 countries i.e. Belgium, Czech Republic, Germany, Italy, Netherlands, Poland, and Spain. Out of these 20 activated sites, 3 sites did not enroll any participants. 89 participants were screened, out of which 66 were randomized.
Pre-assignment details
Participants who met protocol eligibility criteria were assigned to GLPG2737 or placebo in the double-blind (DB) treatment period and open-label extension (OLE) period. The study was prematurely terminated on 02 March 2023, due to the lack of efficacy of GLPG2737, making the expected benefit-risk balance negative.
Participants by arm
| Arm | Count |
|---|---|
| GLPG2737 During DB Participants received 150 mg GLPG2737 capsules orally once daily for 52 weeks in the DB treatment period. | 44 |
| Placebo During DB Participants received placebo matched to GLPG2737 capsules orally once daily for 52 weeks in the DB treatment period. | 22 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Treatment Period (52 Weeks) | Lost to Follow-up | 1 | 1 |
| Double-blind Treatment Period (52 Weeks) | Non Compliance with study drug | 1 | 1 |
| Double-blind Treatment Period (52 Weeks) | Withdrawal by Subject | 1 | 0 |
| Open-Label Treatment Period (52 Weeks) | Adverse Event | 1 | 1 |
| Open-Label Treatment Period (52 Weeks) | Study terminated by sponsor | 34 | 15 |
| Open-Label Treatment Period (52 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | GLPG2737 During DB | Total | Placebo During DB |
|---|---|---|---|
| Age, Continuous | 40.6 years STANDARD_DEVIATION 6.3 | 40.3 years STANDARD_DEVIATION 6.3 | 39.6 years STANDARD_DEVIATION 6.2 |
| Estimated Glomerular filtration rate (GFR) | 55.5 mL/min/1.73 m^2 STANDARD_DEVIATION 16.3 | 54.2 mL/min/1.73 m^2 STANDARD_DEVIATION 16.1 | 51.6 mL/min/1.73 m^2 STANDARD_DEVIATION 15.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 11 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 55 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height-Adjusted Total Kidney Volume(htTKV) | 1069.18 mL/m STANDARD_DEVIATION 438.06 | 1190.51 mL/m STANDARD_DEVIATION 575.26 | 1439.23 mL/m STANDARD_DEVIATION 737.67 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 66 Participants | 22 Participants |
| Sex: Female, Male Female | 24 Participants | 32 Participants | 8 Participants |
| Sex: Female, Male Male | 20 Participants | 34 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 22 | 0 / 20 |
| other Total, other adverse events | 44 / 44 | 22 / 22 | 15 / 20 |
| serious Total, serious adverse events | 3 / 44 | 3 / 22 | 2 / 20 |
Outcome results
Primary
DB Period: Mean Percent Change From MRI Baseline in htTKV
htTKV is used in participants with ADPKD disease to predict the onset of renal insufficiency. htTKV was calculated using TKV (in mL) obtained from MRI divided by height (in m). MRI Baseline: For MRI assessments, all non-missing values before the first study drug administration in the study +14 days (included) was considered as the primary baseline definition. Results were derived by mean of the individual slopes (i.e. using all MRI performed between baseline and Week 52).
Time frame: MRI Baseline up to Week 52
Population: Full Analysis Set (FAS): All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| GLPG2737 During DB | DB Period: Mean Percent Change From MRI Baseline in htTKV | 8.18 percent change |
| Placebo During DB | DB Period: Mean Percent Change From MRI Baseline in htTKV | 9.17 percent change |
Comparison: Based on a random coefficient regression model (linear slope model) on htTKV log-transformed values with time (in weeks) as a continuous variable, treatment, time-by-treatment interaction and a random intercept and slope. The treatment effect was determined by using estimated slopes for each treatment group on the basis of the time-by-treatment interaction term from the mixed model.p-value: 0.60695% CI: [-4.34, 2.64]Random coefficient regression model
Primary
DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the study drug, whether or not considered related to it. A serious adverse event (SAE) is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results a congenital anomaly/birth defect or other medically important event. A TEAE was defined as an AE observed after starting administration of the study drug until 30 days after last DB dose or 1 day before OLE dose, whichever occurred first.
Time frame: From first dose to Week 56
Population: SAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GLPG2737 During DB | DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 44 participants |
| GLPG2737 During DB | DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 1 participants |
| Placebo During DB | DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 22 participants |
| Placebo During DB | DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 3 participants |
Secondary
DB Period: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau) of GLPG2737 and Its Metabolite
AUC0-tau described the area under the curve limited to the end of a dosing interval. The metabolite of GLPG2737 is M4.
Time frame: Predose (within 30 minutes prior to dosing), 1, 1.5, 2, 3, 4, 5, 6, 7 hours post dose through Week 52
Population: Pharmacokinetic Analysis Set (PKAS): All randomized participants who received at least one dose of study drug for which plasma concentration data was available to facilitate development of the Population PK model and for whom the time of the dose on the days of PK sampling was known.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| GLPG2737 During DB | DB Period: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau) of GLPG2737 and Its Metabolite | GLPG2737 | 18500 nanogram* hour per milliliter (ng*h/mL) |
| GLPG2737 During DB | DB Period: Area Under the Plasma Concentration-Time Curve During a Dosing Interval (AUCtau) of GLPG2737 and Its Metabolite | Metabolite M4 | 18700 nanogram* hour per milliliter (ng*h/mL) |
Secondary
DB Period: Maximum Observed Plasma Concentration (Cmax) of GLPG2737 and Its Metabolite
Cmax is the maximum observed plasma concentration of the drug. The metabolite of GLPG2737 is M4.
Time frame: Predose (within 30 minutes prior to dosing), 1, 1.5, 2, 3, 4, 5, 6, 7 hours post dose through Week 52
Population: PKAS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| GLPG2737 During DB | DB Period: Maximum Observed Plasma Concentration (Cmax) of GLPG2737 and Its Metabolite | GLPG2737 | 1160 ng/mL |
| GLPG2737 During DB | DB Period: Maximum Observed Plasma Concentration (Cmax) of GLPG2737 and Its Metabolite | Metabolite M4 | 873 ng/mL |
Secondary
DB Period: Mean Change From Baseline in eGFR
The eGFR is a test that measures level of kidney function and determines the stage of kidney disease. eGFR was based on CKD-EPI formula (2009) calculated from serum creatinine concentrations. Results were derived by mean of the individual slopes (i.e. using data between baseline and Week 52).
Time frame: Baseline up to Week 52
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GLPG2737 During DB | DB Period: Mean Change From Baseline in eGFR | -5.44 mL/min/1.73 m^2 |
| Placebo During DB | DB Period: Mean Change From Baseline in eGFR | -3.13 mL/min/1.73 m^2 |
Comparison: Least-squares mean difference (95% CI) from a random coefficient regression model (linear slope model) on eGFR values with time (in weeks) as a continuous variable, the time-by-treatment interaction and a random intercept and slope. The treatment effect was determined by using estimated slopes for each treatment group on the basis of the time-by-treatment interaction term from the mixed model.p-value: 0.17195% CI: [-5.64, 1.02]Random coefficient regression model