Efficacy and Safety Evaluation of Inaxaplin (VX-147) in APOL1-Mediated Proteinuric Kidney Disease: A Phase 2/3 Adaptive, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-515633-15-00
- Protocol
- VX21-147-301
- Sponsor
- Vertex Pharmaceuticals Inc.
Trial statistics
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of VX-147 in subjects with **APOL1-mediated Proteinuric Kidney Disease (AMKD)**. This is clinically relevant as AMKD is a condition that can lead to significant kidney damage and progression to end-stage renal disease, necessitating effective treatment options to manage and potentially mitigate disease progression.
Secondary objectives include:
- Evaluating the efficacy of VX-147 to decrease the risk of the composite clinical outcome.
- Assessing the safety and tolerability of VX-147.
- Identifying the optimal dose from Phase 2 to carry forward to Phase 3.
- Characterizing the plasma pharmacokinetics (PK) of VX-147.
- Evaluating the acceptability of VX-147 in pediatric subjects.
Participants
The clinical trial for evaluating the efficacy and safety of VX-147 in subjects with **APOL1-mediated Proteinuric Kidney Disease (AMKD)** includes a total of 633 participants. The study population comprises both male and female subjects, with an age range of 12 to 65 years. Participants were selected based on specific genetic criteria, requiring an APOL1 genotype of G1/G1, G2/G2, or G1/G2. The trial does not include a vulnerable population. Participants are required to have a body mass index (BMI) between 18 and 45 kg/m² and a total body weight of at least 40 kg. They must also have a urine protein-to-creatinine ratio (UPCR) of 0.7 to less than 10 g/g and an estimated glomerular filtration rate (eGFR) of 25 to less than 75 mL/min/1.73 m². Subjects are expected to be on a stable dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for at least four weeks prior to screening, unless intolerant. Additionally, those taking sodium glucose co-transporter-2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), or permitted immunosuppressants must have maintained a stable dose for four weeks before screening. Participants must be affiliated with a social security scheme. The trial does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed as a **Phase 2/3 adaptive, double-blind, placebo-controlled study** to evaluate the efficacy and safety of VX-147 in subjects with **APOL1-mediated Proteinuric Kidney Disease (AMKD)**. The trial will involve adult and pediatric participants, with the primary objective of assessing the percent change in urine protein-to-creatinine ratio (UPCR) from baseline at Week 48 and the slope of estimated glomerular filtration rate (eGFR) over time. Secondary endpoints include the time to a composite clinical outcome, safety and tolerability assessments, plasma pharmacokinetic parameters of VX-147, and the acceptability of the tablet formulation in pediatric subjects.
The trial will commence with a screening visit to confirm eligibility based on inclusion criteria such as age, genotype, body mass index, and baseline kidney function. Participants will be randomized to receive either the VX-147 film-coated tablet or a placebo, administered orally. The trial will span an estimated duration from March 2022 to May 2028, with participant involvement expected to last up to 108 weeks, depending on individual response and study phase progression.
Study visits will be scheduled at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. These visits will include clinical assessments, laboratory tests, and evaluations of adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all collected data. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse events that compromise participant safety.
Treatment
The clinical trial involves the administration of **VX-147**, a film-coated tablet containing the active substance **inaxaplin**. This investigational medication is chemically synthesized and is provided by Vertex Pharmaceuticals, Incorporated. The pharmaceutical form is a film-coated tablet, designed for **oral use**. The maximum daily dose of VX-147 is 45 mg, with a total maximum dose of 4860 mg over the course of the study. The treatment period extends up to 108 days. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the trial to ensure accurate assessment of the drug's efficacy and safety in subjects with APOL1-mediated proteinuric kidney disease.
In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind study. The placebo is a coated tablet that mimics the appearance of the VX-147 film-coated tablet but does not contain the active substance. The placebo is administered in the same manner as the experimental drug, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This design helps to maintain the integrity of the study by minimizing bias and allowing for a clear evaluation of the investigational drug's effects compared to the placebo.
Efficacy
Efficacy in this clinical trial will be assessed using specific primary and secondary endpoints. The primary endpoints include the percent change in **urine protein-to-creatinine ratio (UPCR)** evaluated from baseline at Week 48 and the slope of the estimated glomerular filtration rate (eGFR) with at least 48 weeks of eGFR data assessed at the interim analysis and at least two years of eGFR data assessed at the final analysis. Secondary endpoints will measure the time to a composite clinical outcome, which includes a sustained decline of ≥30% from baseline in eGFR, the onset of end-stage kidney disease (ESKD), or death. ESKD is defined as maintenance dialysis for ≥28 days, kidney transplantation, or a sustained eGFR of <15 mL/min/1.73 m², with confirmation by a second measurement after ≥28 days.
Additional secondary endpoints will evaluate safety and tolerability based on adverse events, clinical laboratory values, standard 12-lead ECGs, and vital signs. Plasma pharmacokinetic (PK) parameters of VX-147 will also be assessed. For pediatric subjects, the acceptability of the tablet formulation of VX-147 will be evaluated using the convenience domain of the Treatment Satisfaction Questionnaire for Medication (TSQM). These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the effectiveness of VX-147 in treating APOL1-mediated proteinuric kidney disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part A: 1.Subject (or their legally appointed representative) will sign and date informed consent form (ICF) and, when appropriate, an assent form. 2.Willing and able to comply with scheduled visits, treatment plan, study restrictions (Section 9.5) laboratory tests, contraceptive guidelines, and other study procedures. 3.Subject has an APOL1 genotype of G1/G1, G2/G2, or G1/G2 obtained with a Vertex designated investigational clinical study assay. 4.For Phase 2, subjects must be between the ages of 18 and 65 years at time of signing first ICF, inclusive. For Phase 3, subjects must be between the ages of 12 and 65 years at time of signing first ICF, inclusive. Subjects must be <66 years of age at time of randomization. Pediatric subjects may be enrolled only after IDMC review of Phase 2 data is completed, the Phase 3 dose is selected, and a recommendation by the IDMC on the inclusion of pediatric subjects is made. Up to approximately 15% of the total number of subjects planned for enrollment may be >61 to ≤65 years of age at time of signing first ICF, inclusive. 5. A BMI of 18 to 45 kg/m2, inclusive, and a total body weight ≥40 kg. 6. A UPCR of ≥0.7 g/g to <10 g/g in the first morning void based on the average of 3 measurements collected on 3 separate days within a 7-day period, during the Screening Period. 7.Estimated glomerular filtration rate (eGFR) ≥25 to < 75 mL/min/1.73 m2 during the Screening Period, based on the Modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation without the race adjustment26 for subjects ≥18 years on Day 1 and the Chronic Kidney Disease in Children Under 25 (CKiD U25) equation21 for subjects <18 years on Day 1. 8.On a stable, maximum tolerated labeled dose (at least 4 weeks before screening) of an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), but not both concomitantly, unless documented to be intolerant to ACE inhibitor/ARB. 9.Subjects taking sodium glucose co transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonist (GLP 1a), mineralocorticoid receptor antagonists (MRAs), endothelin antagonists, sparsentan, or permitted immunosuppressants (prednisone ≤10 mg or steroid equivalent, mycophenolate, tacrolimus, cyclosporine, or azathioprine) must have been on a stable dose for 4 weeks before screening.
- Part B: 1. Subject (or their legally appointed representative) will sign and date informed consent form (ICF) and, when appropriate, an assent form. 2.Subject is willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures through the Safety Follow-up visit (or EDV if applicable). Alternatively, the subject’s legally appointed and authorized representative must be able to understand protocol requirements, restrictions, and instructions, and should be able to ensure that the subject will comply with, and is likely to complete, Part B of the study as planned. 3.Subject did not withdraw consent during Part A of the study. 4.Completion of Treatment Period in Part A (Section 9.1.3.3) and no permanent discontinuation of study drug.
Exclusion Criteria
- Part A: 1. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject. 2. Evidence of FSGS with a known cause other than due to APOL1 mutations. 3. History of diabetes mellitus. A diagnosis of prediabetes is permitted. 4. Known underlying cause of kidney disease 5. Abnormal laboratory values at screening that present a risk to subject safety in the opinion of the investigator, or any of the following abnormal laboratory values at screening: • Serum albumin <1 g/dL • Total bilirubin ≥1.5 × upper limit of normal (ULN) • Aspartate transaminase (AST) or alanine transaminase (ALT) ≥2 × ULN • Hemoglobin <9 g/dL. 6. Risk factors for Torsade de Pointes (e.g., familial long QT syndrome, chronic hypokalemia, heart failure) or concomitant medications that prolong the QT/QTc interval or any history of cardiac disorders 7. Any clinically significant ECG abnormality (as determined by the investigator) or median QTcF of triplicate standard 12-lead ECGs >450 msec at screening. 8. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or positive HIV test 9. Screening blood pressure, based on the average of 3 measurements, of ≥180 mm Hg (systolic) or ≥100 mm Hg (diastolic). 10. Pregnant or nursing female subjects. Females of childbearing potential must have a negative pregnancy test at screening (serum test) and Day 1 (urine test). 11. Known hypersensitivity to investigational medicinal product or to any of its excipients.
- Part B: 1. ESKD as defined in Section 9.10.1, in Part A. 2. History, new onset, or worsening of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. 3.Pregnant or breastfeeding females. Female subjects of childbearing potential must have a negative urine pregnancy test on Day 1 of Part B before receiving the first dose of study drug. 4.Any clinically significant laboratory abnormalities before Day 1 of Part B that would interfere with the study assessments or pose an undue safety risk for the subject, as deemed by the site investigator. 5.Ongoing or planned participation in another interventional, therapeutic clinical trial other than Part A of the study. Participation in a noninterventional study, including observational and registry studies, is permitted. 6.Any condition or circumstances, which in the opinion of the site investigator or Vertex, may make a subject unlikely or unable to complete the study or comply with study procedures and requirements of Part B, including study restrictions as defined in Section 9.5. 7.Subject, or close relative or a caregiver of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site. An adult (aged 18 years or older) who is a relative of a study staff member may be enrolled in the study provided the following: • The adult lives independently of and does not reside with the study staff member; and • The adult participates in the study at a site other than the site at which the family member is employed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 29 Mar 2022 | 2 |
 France | Recruiting | 29 Mar 2022 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VX-147 film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 45 | 108 | PRD10397323 |
VX-147, Coated Placebo Tablet | Placebo | N/A | — | — | — | N/A |