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This study is being done to learn more about the safety and effectiveness of the investigational drug VX-147 in participants with APOL1-Mediated Chronic Kidney Disease.

People of recent African ancestry are more likely to have certain APOL1 variants and are more at risk for CKD. Currently, treatment for CKD exists only to control some aspects of the disease, such as high blood pressure. However, it is important to also treat the worsening of the kidney function as well as the underlying cause of CKD. VX-147 is being studied to determine if it can slow or stop the worsening of kidney function as well as target the underlying cause of this disease.

Inclusion Criteria

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 10 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 adjustment25 for subjects ≥18 years on

Day 1 and the Chronic Kidney Disease in Children Under 25 (CKiD-U25) equation2 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, mineralocorticoid

receptor antagonists (MRAs) 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.

 

Exclusion Criteria

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. This includes, but is not limited to, the following:

• Solid organ or bone marrow transplantation

• Cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical

carcinoma in situ (each being disease-free for the last 5 years)

• Clinically significant and active bacterial, viral, fungal, or parasitic infection

• Clinically significant liver disease

• Ongoing alcohol abuse or illicit drug use

• Any condition possibly affecting drug absorption (e.g., gastrectomy, gastrointestinal tract

surgery except appendectomy and cholecystectomy)

• Stroke or myocardial infarction within 6 months before screening

2. Evidence of FSGS with a known cause other than due to APOL1 mutations. This includes but

is not limited to the following:

• FSGS occurring concomitantly to administration of drugs known to induce FSGS,

including but not limited to lithium, interferon, and bisphosphonates (e.g., pamidronate),

or FSGS occurring in a subject using intravenous illicit drugs at the time of diagnosis.

• FSGS occurring in a subject with known sickle cell disease.

• Known genetic mutation other than APOL1 G1 or G2 that is associated with FSGS.

• Positive serology for human immunodeficiency virus-1 (HIV-1) or human

immunodeficiency virus-2 (HIV-2).

3. History of diabetes mellitus. A diagnosis of prediabetes is permitted.

4. Known underlying cause of kidney disease in the opinion of the investigator including but

not limited to biopsy-confirmed or suspected cases of the following: lupus nephritis,

myeloma kidney, glomerular basement membrane disease, membranoproliferative

glomerulitis, polycystic kidney disease, sickle cell disease, diabetic nephropathy, HIV

nephropathy, autoimmune-induced nephropathy, amyloidosis, anti-phospholipase A2 receptor-mediated nephropathy, monoclonal gammopathy related kidney disease,

complement related glomerulonephritis, thrombotic microangiopathy or hemolytic uremic

syndrome, Alport syndrome, immunoglobulin A (IgA) nephropathy, post-streptococcal

glomerulonephritis, or acute kidney injury within the past 3 months if eGFR is not at

pre-injury baseline.

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 that, in the opinion of the investigator, might put the subject at risk or may

confound the results of the study.

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 during screening.

9. Screening blood pressure, based on the average of 3 measurements, of ≥180 mm Hg

(systolic) or ≥100 mm Hg (diastolic) for subjects ≥12 years old, and ≥30 mm Hg above the

95th percentile based on age, sex and height for subjects 10 to <12 years old.

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. Participation in another interventional clinical study within 28 days or 5 half-lives, whichever

is longer, before the first dose of study drug.

12. Inability to adhere to the study restrictions defined in Section 9.5, including restrictions

before the first dose of study drug for strong CYP3A4 inhibitors or moderate and strong

inducers, cyclophosphamide, rituximab, or high dose systemic corticosteroids (>10 mg/day

of prednisone or prednisone equivalent).

13. 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.

14. Known hypersensitivity to investigational medicinal product or to any of its excipients.