Evaluation of Setanaxib's Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Alport Syndrome: A Phase 2a Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2023-505292-73-00
Protocol: GSN000500
Sponsor: Calliditas Therapeutics Suisse S.A.

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Diseases & Conditions

Alport's syndrome

Objectives

The primary objective of this Phase 2a, randomized, double-blind, placebo-controlled study is to evaluate the **safety** and **tolerability** of setanaxib compared to placebo in patients with **Alport syndrome**. This is clinically relevant as it aims to determine the potential of setanaxib as a therapeutic option for managing this genetic disorder, which affects kidney function, hearing, and vision.

Secondary objectives include:

Assessing the effect of setanaxib on vital signs, 12-lead ECGs, physical examinations, and clinical laboratory parameters compared to placebo.
Evaluating the impact of setanaxib on hearing and urinary protein-to-creatinine ratio (UPCR) compared to placebo.
Assessing the effect on estimated glomerular filtration rate (eGFR) and the plasma exposure of setanaxib and its active metabolite GKT138184.

These objectives aim to provide a comprehensive understanding of the pharmacokinetics, pharmacodynamics, and preliminary efficacy of setanaxib, contributing to the overall assessment of its therapeutic potential in Alport syndrome.

Participants

The clinical trial involves a total of **6 participants** diagnosed with **Alport syndrome**, a genetic condition affecting kidney function. The study population includes both male and female subjects, aged between 12 and 50 years, with a specific age range of 18 to 50 years for sites in the European Union. Participants were selected based on their confirmed diagnosis through genetic testing, ensuring the presence of a mutation in genes associated with Alport syndrome, such as COL4A3, COL4A4, or COL4A5. The trial includes individuals who are on a stable dose of angiotensin-converting enzyme inhibitors or angiotensin II type I receptor blockers for at least 8 weeks prior to consent. Participants are required to have a proteinuria level of at least 90 mg/mmol and maintain a systolic and diastolic blood pressure within specified limits. The study also considers lifestyle factors, requiring female participants of childbearing potential to use highly effective contraception methods and male participants to use condoms and ensure their partners use effective contraception. The trial does not include individuals with a variant of uncertain significance in their genetic testing results. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the NOX1/4 inhibitor **Setanaxib** in patients with **Alport syndrome**. The trial is categorized as a Phase 2a study and is not considered low intervention. The study will involve the administration of Setanaxib in the form of film-coated tablets, with a maximum daily dose of 1600 mg, over a treatment period of up to 24 weeks. The trial is expected to conclude by January 31, 2025, with recruitment starting on December 15, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of Alport syndrome, and stable use of angiotensin-converting enzyme inhibitors or angiotensin II type I receptor blockers. The screening will also include assessments of proteinuria, blood pressure, and estimated glomerular filtration rate. Following randomization, participants will attend regular follow-up visits to monitor safety and efficacy endpoints, including the percentage of patients with serious adverse events and treatment-emergent adverse events of special interest, such as anemia. Secondary endpoints will assess changes in heart rate, blood pressure, ECG, physical examination, laboratory parameters, and hearing tests, as well as pharmacokinetic properties of Setanaxib.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. The study will conclude with an end-of-study visit to evaluate the final outcomes and ensure participant safety. Participants are required to adhere to specific contraceptive measures and are prohibited from donating sperm or eggs during and after the study period. The trial aims to provide valuable insights into the potential benefits and risks of Setanaxib in treating Alport syndrome, contributing to the development of effective therapeutic strategies for this condition.

Treatment

The clinical trial involves the administration of **Setanaxib**, an experimental medication, to evaluate its safety and tolerability in patients with Alport syndrome. **Setanaxib** is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose of **Setanaxib** is 1600 mg, with a total maximum dose of 268.8 grams over the course of the study. The treatment period extends up to 24 weeks. The active substance, **Setanaxib**, is of chemical origin and is developed by Calliditas Therapeutics AB. Participants' compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes the use of **placebo tablets** as a comparator. The placebo is designed to match the **film-coated tablet** form of **Setanaxib** but does not contain any active pharmaceutical ingredients. The placebo is administered in a similar manner to the experimental drug, ensuring the double-blind nature of the study is maintained. The use of placebo allows for the assessment of the true efficacy and safety profile of **Setanaxib** by providing a baseline for comparison.

Efficacy

Efficacy in this clinical trial will be assessed through several secondary endpoints. These include the evaluation of the **urine protein to creatinine ratio (UPCR)** at 24 weeks compared to baseline, and the percentage of patients achieving a 25% reduction in UPCR at 24 weeks. Additionally, the ratio of estimated glomerular filtration rate (eGFR) at 24 weeks compared to baseline will be measured. Pharmacokinetic properties of setanaxib, such as pre-dose and post-dose plasma concentrations, will also be assessed. These properties include the area under the concentration-time curve over 24 hours at steady state (AUC0-24-ss), minimum plasma concentration at steady state (Cmin-ss), and maximum plasma concentration at steady state (Cmax-ss). The collection and analysis of these parameters will be conducted at specified timepoints throughout the trial to determine the preliminary efficacy of setanaxib in patients with Alport syndrome.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients aged 12 to 50 years inclusive, at the time of informed consent/assent; For sites in the EU: Male or female patients aged 18 to 50 years, inclusive, at the time of informed consent;
Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated with Alport syndrome [ie, COL4A3, COL4A4, or COL4A5]); Patients with a variant of uncertain significance should not be included in the study;
Weight ≥40 kg;
Willing and able to give informed consent (and assent, where applicable), in accordance with local age requirements, and to comply with the requirements of the study;
Female patients of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥4 weeks before randomization and must agree to continue strict contraception (as specified in 5c) up to 90 days after the last dose of investigational medicinal product (IMP); For the purposes of this study, women of childbearing potential (WOCBP) are defined as “fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy”; b. Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In female patients who are not using hormonal contraception or hormonal replacement therapy but with suspected menopause and less than 12 months of amenorrhea, a high follicle-stimulating hormone (FSH) level in the postmenopausal range will be required at Screening to confirm a postmenopausal state; c. Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. These methods include the following: Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); Intrauterine device; Intrauterine hormone-releasing system; Bilateral tubal occlusion; Vasectomized partner; and Sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associated with the study treatments, ie, up to 90 days after the last dose of IMP). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, or post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception.
Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Visit 3 (after randomization and before dosing);
Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use a highly effective contraceptive method (as defined in the list in inclusion criterion 5c). Female condom and male condom should not be used together. This requirement begins at the time of informed consent/assent and ends 90 days after receiving the last dose of IMP;
Male patients must be willing not to donate sperm and female study patients must be willing not to donate eggs from baseline until 90 days after the last dose of IMP;
Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at Study Visit 1 or 2, calculated at the central laboratory using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for patients ≥18 years of age and the revised bedside Schwartz formula for patients 12 to 17 years of age;
Proteinuria (urine protein to creatinine ratio [UPCR] ≥90 mg/mmol [0.8 g/g]) at 2 consecutive measurements (24-hour urine sampling), separated by at least 2 weeks and calculated by the central laboratory;
Receiving maximum allowed dose or maximum-tolerated daily dose of an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin II type I receptor blocker (ARB) that has been stable for at least 8 weeks prior to consent/assent; and
Systolic and diastolic blood pressure ≤95th percentile, based on the patient’s age and weight for patients 12 to 17 years of age or with ≤130 mmHg systolic blood pressure and ≤80 mmHg diastolic blood pressure for patients ≥18 years of age.

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Exclusion Criteria

Has ongoing chronic hemodialysis or peritoneal dialysis;
Has a positive pregnancy test at Study Visit 2 (Screening) and/or Study Visit 3 (Day 1) (WOCBP only) or is breastfeeding;
Has evidence of any of the following cardiac conduction abnormalities at Screening or Day 1 (pre-dose): a QTcF interval >450 milliseconds for male patients or >470 milliseconds for female patients, or a PR interval ≥220 milliseconds
Has a history of aplastic anemia, or any current marked anemia, defined as hemoglobin <10.0 g/dL;
Has uncontrolled hypothyroidism. Patients with subclinical hypothyroidism may be included. Subclinical hypothyroidism is defined biochemically as a normal serum free thyroxine (T4) concentration in the presence of an elevated serum thyroid-stimulating hormone (TSH) concentration;
Has any laboratory abnormality or condition that, in the opinion of the Investigator, could interfere with or compromise a patient’s treatment, assessment, or compliance with the Protocol and/or study procedures;
Has any other condition that, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the patient in the study, or that could interfere with the study objectives, conduct, or evaluation;
Uses medications known to be potent cytochrome P450 (CYP) 3A4 inhibitors (itraconazole, lopinavir/itonavir, telaprevir, clarithromycin, ritonavir, ketoconazole, indinavir/ritonavir, conivaptan, and voriconazole), potent CYP3A4 inducers (avasimibe, carbamazepine, enzalutamide, mitotane, nevirapine, phenobarbital, phenytoin, rifabutin, rifampicin, rifapentine, and St John’s wort), or potent uridine 5'-diphospho-glucuronosyltransferase 1A9 inhibitors and inducers (mefenamic acid and rifampicin) within 21 days prior to study drug administration;
Has known psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent/assent; or
Has known hypersensitivity or intolerance to setanaxib or to any of its excipients.
Has a history of kidney transplant;
Has other causes of chronic kidney disease (CKD) (even if not yet on hemodialysis), including but not limited to other heritable disorders leading to CKD, diabetic nephropathy, hypertensive nephropathy, lupus nephritis, and immunoglobulin A nephropathy;
Has been treated with any investigational agent within 12 weeks of signing informed consent/assent or 5 half-lives of the investigational agent (if known), whichever is longer, or current enrollment in an interventional clinical study;
Has had prior treatment with setanaxib;
Has known malignancy that is progressing or requires active treatment, with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer that has undergone potentially curative therapy, or malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of study drug and of low potential risk for recurrence;
Positive urine drug screen (if not due to prescription use of a concomitant medication, as confirmed by the Investigator) at Screening. Patients on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol products are not exclusionary and may be allowed if the prescription and diagnosis are reviewed and approved by the Investigator;
Has an active HIV infection or acute or chronic hepatitis B or C infection, confirmed at Screening;
Has had a surgery (eg, gastric bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator);
Has a history of chronic liver disease (eg, primary biliary cholangitis, alcoholic liver disease, chronic viral hepatitis including hepatitis B and C, non-alcoholic fatty liver disease, and hemochromatosis);
Has plasma alanine aminotransferase and/or aspartate aminotransferase >3 x the upper limit of normal (ULN) at Study Visit 1 or 2 (Screening);
Has total bilirubin >2 x ULN at Study Visit 1 or 2 (Screening); or
Has international normalized ratio >1.2 at Study Visit 1 or 2 (Screening) (criterion not applicable for patients on anticoagulant therapy).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	15 Dec 2023	5
Czechia	Not Recruiting	15 Dec 2023	6
France	Not Recruiting	15 Dec 2023	6
Lithuania	Not Recruiting	15 Dec 2023	3
Slovakia	Not Recruiting	15 Dec 2023	2
Spain	Not Recruiting	15 Dec 2023	6