Phase 2a Study of VX 147 in Adults With APOL1-mediated Focal Segmental Glomerulosclerosis.

Phase 1

Conditions: APOL1-mediated Focal segmental glomerulosclerosis (FSGS)
MedDRA version: 21.1Level: PTClassification code 10067757Term: Focal segmental glomerulosclerosisSystem Organ Class: 10038359 - Renal and urinary disorders
Therapeutic area: Body processes [G] - Genetic Phenomena [G05]

Registration Number: EUCTR2020-000185-42-GB

Lead Sponsor: Vertex Pharmaceuticals Incorporated

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 20

Inclusion Criteria

The following criteria are applicable for Cohort 1 and Cohort 2:
1. Willing to sign and date an informed consent form (ICF).
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines and other study procedures.
3. An APOL1 genotype of G1/G1, G2/G2, or G1/G2 obtained with a Vertex-approved clinical study assay. After enrollment, if the genotype result obtained with the investigational assay is not confirmed to be eligible by Sanger sequencing, the subject must
be discontinued from the study.
4. Between the ages of 18 and 65 years, inclusive.
5. Body mass index (BMI) of 18.0 to 40.0 kg/m2, inclusive, and a total body weight >50 kg.
6. FSGS diagnosed by kidney biopsy, with the exception of the tip variant, as confirmed through the eligibility review process.
7. There should be no plan to start, stop, or modify dosing for an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), neprilysin inhibitor, sodium-glucose co-transporter-2 (SGLT2) inhibitor, renin inhibitor, systemic corticosteroids, tacrolimus, or mycophenolate from 28 days before Screening through the
Follow-up Period.
8. Subjects who are on low-dose corticosteroids (prednisone = 10 mg per day or prednisone equivalent) or on an allowed immunosuppressant (i.e. tacrolimus or mycophenolate) must
be on a stable dose for 28 days before screening.

The following criterion is applicable for Cohort 1:
9. A UPCR ratio of =3 g/g (±10%) and <10 g/g in the first morning void on 3 measurements collected on at least 3 separate days within a 7-day period, during the Screening Period. All 3 measurements must meet this criterion.
10. Estimated glomerular filtration rate (eGFR) =45 mL/min/1.73 m2 (±10%) based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.

The following criterion is applicable for Cohort 2:
11. A UPCR ratio of =1 g/g and <2.7 g/g in the first morning void on 3 measurements collected on at least 3 separate days within a 7-day period, during the Screening Period. All 3 measurements must meet this criterion.
12. Estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m2 based on the CKD-EPI equation.
13. Subjects with eGFR =30 to <40 mL/min/1.73 m2 must have tubulointerstitial fibrosis =50% or described as no, mild, or moderate on their kidney biopsy.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 19
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1

Exclusion Criteria

The following criteria are applicable for Cohort 1 and Cohort 2:
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
• Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator
• Clinically significant liver disease
• Ongoing alcohol or drug abuse as determined by the investigator
• Any condition possibly affecting drug absorption (e.g., gastrectomy, gastrointestinal tract surgery except appendectomy and cholecystectomy)
• Stroke or myocardial infarction within 6 months before Day 1
2. Evidence of non-APOL1-mediated FSGS. 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.
• Evidence of another underlying kidney disease that can cause FSGS, including evidence of congenital anomaly of the kidney or urinary tract (CAKUT) on renal ultrasound, history of CAKUT, history of nephrectomy.
• 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. Evidence of kidney disease other than FSGS on kidney biopsy, as assessed by the eligibility review process.
4. Kidney biopsy showing the tip variant of FSGS, as assessed by the eligibility review process.
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:
• Total bilirubin =1.5 × upper limit of normal (ULN)
• Aspartate transaminase (AST) or alanine transaminase (ALT) =2 ULN
Serum albumin <1 g/dL
• Hemoglobin <10 g/dL.
6. Positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) nucleic acid during screening.
7. 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.
8. Any clinically significant ECG abnormality (as determined by the investigator) or median QTcF of triplicate standard 12 ECGs >450 msec at screening.
9. Screening blood pressure =160 mm Hg (systolic) or =100 mm Hg (diastolic), based on the average of 3 measurements.
10. Pregnant or nursing female subjects.
11. Subjects of reproductive potential who are not willing to follow the contraception requirements outlined in Section 11.6.5.1.
12. Plan to travel to countries where sleeping sickness is endemic, from the Screening Visit through 1 week after the last dose of study drug.
13. Subject, or close relative of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly i

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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