Phase 2/3 Adaptive Study of VX-147 in Adults and Pediatric Subjects With APOL1-mediated Proteinuric Kidney Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vertex Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

25 Oct 2022 → ongoing

Decision date (initial)

2024-10-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-515633-15-00

EudraCT number

2021-004762-35

ClinicalTrials.gov

NCT05312879

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

Evaluate efficacy and safety of VX-147 in subjects with AMKD

Secondary objectives 2

1. Part A: •To evaluate the safety and tolerability of VX-147 •To identify the optimal dose from Phase 2 to carry forward to Phase 3 •To characterize the plasma pharmacokinetics (PK) of VX-147 •To evaluate the acceptability of VX-147 in pediatric subjects
2. Part B: To evaluate changes in proteinuria and kidney function after long-term VX-147 treatment in adult and pediatric subjects

Conditions and MedDRA coding

APOL1-mediated Proteinuric Kidney Disease (AMKD)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003368-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 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.
2. 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 2

1. 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.
2. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A: Percent change in UPCR evaluated from baseline at Week 48 (assessed at the IA) • eGFR slope (with ≥48 weeks of eGFR data assessed at the IA and at least 2 years of eGFR data assessed at the final analysis)
2. Part B: Safety and tolerability assessments based on AEs, clinical laboratory values, and vital signs

Secondary endpoints 5

1. Part A: Safety and tolerability based on adverse events (AEs), clinical laboratory values (i.e., hematology, serum chemistry, urinalysis, coagulation studies), standard 12-lead ECGs, and vital signs
2. Part A: Plasma PK parameters of VX-147
3. Part A: Acceptability of tablet formulation of VX-147 in pediatric subjects using the convenience domain of the Treatment Satisfaction Questionnaire for Medication (TSQM)
4. Part B: Percent change in UPCR from baseline over time
5. Part B: eGFR slope

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vertex Pharmaceuticals Inc.

Sponsor organisation

Vertex Pharmaceuticals Inc.

Address

50 Northern Avenue

City

Boston

Postcode

02210-1862

Country

United States

Scientific contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Public contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Locations

2 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 161 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications