Evaluation of R3R01 for Safety, Tolerability, and Efficacy in Alport Syndrome and Primary Steroid-Resistant Focal Segmental Glomerulosclerosis

Trial ID: 2024-512964-73-00
Protocol: R3R01-ASFSGS-201
Sponsor: River 3 Renal Corp.

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Diseases & Conditions

Focal segmental glomerulosclerosis Alport's syndrome

Objectives

The primary objective of this study is to assess the **tolerability** and safety of R3R01 when administered orally for 12 weeks in patients with Alport Syndrome (AS) and Primary Steroid-Resistant Focal Segmental Glomerulosclerosis (FSGS). Additionally, the study aims to evaluate the efficacy of R3R01 in reducing proteinuria at 12 weeks in both the AS and FSGS patient groups. This is clinically relevant as proteinuria is a key marker of kidney damage and its reduction is associated with improved renal outcomes.

Secondary objectives include:

For all patients: To evaluate improvement in quality of life using the Short Form SF-36 for adults or the Pediatric Quality of Life Inventory (PedsQL) for children and their parents/legal guardians, by assessing changes from baseline to the end of treatment (Day 84) and the end of the follow-up period (Day 168). Additionally, to evaluate the pharmacokinetics of R3R01.
For AS patients: To evaluate proteinuria complete response (UPCR <0.3g/g) and partial response (decrease in proteinuria from baseline of ≥50%) at all timepoints proteinuria is measured.
For FSGS patients: To evaluate proteinuria complete remission (UPCR <0.3g/g), partial remission (decrease in proteinuria from baseline of ≥50% and an absolute value of UPCR < 3.0g/g), and modified partial remission (decrease of ≥40% and UPCR < 1.5g/g) at all timepoints proteinuria is measured.

These secondary objectives aim to provide a comprehensive understanding of the impact of R3R01 on both quality of life and specific renal outcomes in the targeted patient populations.

Participants

The clinical trial involves a total of **40 participants** diagnosed with **Alport Syndrome (AS)** and **Primary Steroid-Resistant Focal Segmental Glomerulosclerosis (FSGS)**. The study population includes both male and female subjects, with an age range of 12 to 75 years for countries enrolling pediatric patients, and 18 to 75 years for those not enrolling pediatric patients. Participants were selected based on their ability to communicate effectively with the investigator and their willingness to comply with study requirements, as well as specific medical criteria such as a confirmed diagnosis of AS or FSGS. The trial includes individuals with an estimated glomerular filtration rate (eGFR) of at least 45 mL/min/1.73m², and those on stable doses of ACE inhibitors or ARBs. Lifestyle considerations include maintaining stable medication doses and, for those who have received a COVID vaccination, ensuring the baseline visit occurs at least one week post-vaccination. The trial population is considered vulnerable, and appropriate consent procedures are in place for minors and their guardians. The study aims to evaluate the tolerability, safety, and efficacy of the investigational drug R3R01 over a 12-week period.

Plans and Procedures

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of the investigational drug R3R01 in patients with **Alport Syndrome** and Primary Steroid-Resistant Focal Segmental Glomerulosclerosis. This is a Phase II, multi-center, open-label study with a primary focus on assessing the reduction in proteinuria over a 12-week treatment period. The trial involves oral administration of R3R01 in tablet form, with a maximum daily dose of 400 mg. The study is expected to conclude by June 2025, with recruitment having commenced in June 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as stable ACEi/ARB therapy and adequate renal function. Following the screening, participants will attend regular follow-up visits at weeks 4, 8, and 12 to monitor safety and efficacy endpoints, including changes in proteinuria and quality-of-life assessments. The end-of-study visit will occur at the conclusion of the 12-week treatment period, with additional follow-up assessments extending to 24 weeks for some endpoints.

The expected duration of participant involvement is approximately 24 weeks, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with study protocols, or withdrawal of consent. The trial's primary endpoints focus on the occurrence of adverse events and changes in clinical parameters, while secondary endpoints include pharmacokinetic analyses and categorical assessments of proteinuria response.

Treatment

The clinical trial involves the administration of the experimental medication **R3R01**, developed by River 3 Renal Corp. This investigational product is formulated as a **tablet** and is intended for oral administration. The active substance, also named R3R01, is of chemical origin. Participants in the study will receive a maximum daily dose of 400 mg, with the total dose not exceeding 400 mg per day. The treatment period is set for a duration of 12 weeks. The primary objective of the trial is to assess the safety, tolerability, efficacy, and pharmacokinetics of R3R01 in patients with Alport Syndrome and Primary Steroid-Resistant Focal Segmental Glomerulosclerosis, particularly focusing on its ability to reduce proteinuria.

In addition to the experimental treatment, participants will continue to receive standard-of-care therapy, which includes ACE/ARB inhibition. This non-experimental treatment is a standard therapeutic approach for managing proteinuria in the specified patient populations. The study does not include a placebo or comparator treatment, as the focus is on evaluating the effects of R3R01 in conjunction with existing standard therapies. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen.

Efficacy

The efficacy of R3R01 in the clinical trial will be assessed primarily by evaluating the change from baseline in **Urinary Protein-to-Creatinine Ratio (UPCR)** at 12 weeks for patients with Alport Syndrome (AS) and Focal Segmental Glomerulosclerosis (FSGS). This primary endpoint will provide a quantitative measure of the drug's impact on proteinuria, a key indicator of disease progression in these conditions. Secondary efficacy endpoints include the number of AS patients achieving complete or partial response for proteinuria at specified timepoints (weeks 4, 8, 12, 16, 20, and 24), and the number of FSGS patients achieving complete, partial, or modified partial remission for proteinuria at the same intervals. These assessments will be conducted using categorical evaluations of proteinuria response.

Data collection will occur at multiple timepoints throughout the study, specifically at weeks 4, 8, 12, 16, 20, and 24, to monitor changes in proteinuria and assess the efficacy of R3R01 over time. The trial will also include a population pharmacokinetic analysis to derive primary and secondary pharmacokinetic parameters, such as absorption rate, apparent clearance, and maximum concentration, which will further inform the drug's efficacy profile. Quality-of-life assessments will be conducted from baseline to the end of treatment and follow-up period to evaluate the broader impact of the treatment on patients' well-being. These comprehensive efficacy assessments will be integral to determining the therapeutic potential of R3R01 in the target patient populations.

Inclusion and Exclusion Criteria

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Inclusion Criteria

All Patients: 1. Patient is able to communicate well with the investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF).
For children to be eligible, one or both parents/legal guardians must sign a parental permission form which provides information contained in the ICF. Children capable of assent must express their willingness to participate by signing an assent form.
If patient has received a COVID vaccination, the baseline visit must occur at least one week or more after the second/booster vaccination.
Patients who have had active symptoms of COVID within 3 months prior to screening and are now asymptomatic for the last 2 weeks but have tested COVID PCR positive. If a patient is asymptomatic at screening but is COVID positive, then rescreening can occur after a minimum of two weeks.
Both female patients, as well as female partners of male patients who are of child-bearing potential must be willing to not become pregnant for the complete duration of the study (>180 days) (90 days after the last dose of study medication).
Males (including sterilized subjects) whose female partners have child-bearing potential, must agree to use male contraception (condoms) during the period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. They must agree to immediately inform the investigator if their partner becomes pregnant during the study.
AS Inclusion Criteria (in addition): 7. Males and females with X-Linked AS and males and females with autosomal inherited AS. a. For countries that are enrolling pediatric patients: patients from age 12 years and older. b. For countries that are not enrolling pediatric patients: patients from age 18 years and older.
Confirmed diagnosis of AS by genetic testing and /or kidney biopsy. For patients enrolled in the US who meet all inclusion and exclusion criteria but have not had their diagnosis confirmed by genetic testing or kidney biopsy, the Sponsor will provide for patient’s genetic testing.
UPCR ≥1.0 g/g.
eGFR ≥ 45 mL/min/1.73m2 (using CKD-EPI equation for adults and Bedside Schwartz equation for children).
ACEi/ARB therapy at maximum tolerated dose stable for at least 4 weeks prior to screening. ACEi/ARB dose should remain stable over the course of the study.
FSGS Inclusion Criteria (in addition): 12. Male or female patients, a. For countries that are enrolling pediatric patients: 12 to 75 years old at the time of signing the informed consent b. For countries that are not enrolling pediatric patients: 18 to 75 years old at the time of signing the informed consent
Primary FSGS (without any identifiable cause, and where the FSGS is confirmed by renal biopsy) or FSGS where there is documentation of a genetic mutation in a podocyte protein associated with FSGS.
Steroid-resistance defined as failure to achieve partial or complete remission, or experienced adverse events without acceptable clinical benefit after at least 8 weeks of adequate corticosteroid therapy for children and 12 weeks for adults.
UPCR between 3.5g/g and 12.0g/g.
eGFR > 45 mL/min/1.73m2 (using CKD-EPI equation for adults and Bedside Schwartz equation for children).
If taking concomitant ACEi and/or ARB treatment, it should remain at a stable dose for a minimum of 28 days prior to enrollment and during the course of the study.

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Exclusion Criteria

All Patients: 1. Uncontrolled diabetes mellitus as evidenced by an HbA1c ≥ 11%. For Germany: HbA1c ≥ 8.5%.
Uncontrolled hypertension a. Adults: (SBP ≥ 180mmHg and/or DBP ≥ 100mmHg). For Germany: (SBP ≥ 140mmHg and/or DBP ≥ 100mmHg). b. Children: ≥ 95th percentile or ≥ 130/80 mm Hg, whichever is lower, as defined in Appendix 13.8.
Moderate or severe hepatic impairment as per Child Pugh score (See Section 9.5.4.7), except if (a) decreased serum albumin is directly related to the renal disease (resulting in a Child Pugh score of 7), and (b) no other Child-Pugh Score parameters are increased and (c) patient has no liver pathology in medical history.
Presence of any active (i.e., with symptoms) and/or uncontrolled infection (including COVID).
Presence of Human immunodeficiency virus (HIV).
BMI > 40. For Germany: BMI > 35 (Obesity Class II).
History of malignancy other than treated basal cell or squamous cell skin cancer within the past 5 years.
History of alcohol abuse in the last 5 years or currently drinks in excess of 21 and 14 units per week for males and females, respectively.
Received an investigational agent within 30 days or 5 half-lives prior to screening (whichever is longer).
History of non-compliance such that patient is unlikely to be compliant with study visits, procedures or drug administration.
Patient has had an organ transplant, is currently on an organ transplant waiting list or there is a reasonable possibility that the patient will have an organ transplant in the 6 months after screening.
Participation in an interventional trial within the previous 3 months prior to screening or concurrent participation in a research trial.
Patient is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of noncompliance with study visits, procedures, or drug administration) in the opinion of the investigator.
Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception as described in Section 13.3.
Females that are lactating.
History of hypersensitivity to study drug and/or any of its excipients
Patients with hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
Required concomitant use of bardoxolone, rituximab, cyclophosphamide, abatacept or sparsentan.
AS Exclusion Criteria (in addition): 19. Kidney disease apart from AS, e.g., diabetic nephropathy or lupus nephritis.
Use of Bardoxolone or sparsentan treatment in the 30 days prior to screening. SGLT2 inhibitors are allowed if the patient is on a stable dose for at least 3 months prior to screening.
FSGS Exclusion Criteria (in addition): 21. Patient has collapsing variant of FSGS on renal biopsy.
Patient has FSGS secondary to another condition (e.g., obesity, cardiovascular, infectious, or autoimmune disorder).
Use of Rituximab, cyclophosphamide or abatacept treatment in the 120 days prior to screening. If taking other chronic immune-modulatory medications that are small molecules, the dosage must be stable for 4 weeks prior to screening.
If previous Rituximab treatment is greater than 120 days from screening, CD20 cell count should be within normal limits.
If previous other antibody treatment on a stable dose is greater than 120 days from screening, the investigator must deem administration of study drug to be safe.
Use of sparsentan in the 30 days prior to screening. SGLT2 inhibitors are allowed if the patient is on a stable dose for at least 3 months prior to screening.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	27 Jun 2022	5
France	Not Recruiting	27 Jun 2022	5
Germany	Not Recruiting	27 Jun 2022	5
The Netherlands	Not Recruiting	27 Jun 2022	—
Netherlands	—	—	5