Phase 2 Multicenter Open-Label Study of Mitapivat on Albumin-Creatinine Ratio in Sickle Cell Disease with Nephropathy

Trial ID: 2023-510289-28-00
Protocol: AG348-C-026
Sponsor: Agios Pharmaceuticals Inc.

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Diseases & Conditions

Sickle cell disease

Objectives

The primary objective of this study is to evaluate the effect of **mitapivat** on the albumin creatinine ratio (ACR) response in subjects with **Sickle Cell Disease (SCD)** and nephropathy. This is clinically relevant as ACR is a critical marker for kidney function, and its management is essential in patients with SCD, who are at increased risk for nephropathy.

Secondary objectives include:

Evaluating the effect of mitapivat on the cystatin C and creatinine-based estimated glomerular filtration rate (eGFRcr-cys), which provides additional insights into kidney function.
Assessing the effect of mitapivat on ACR, further supporting the primary objective.
Evaluating the effect of mitapivat on efficacy measures related to nephropathy, which may offer a broader understanding of its therapeutic potential.
Assessing the safety of mitapivat, ensuring that the treatment is not only effective but also safe for patients.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **Sickle Cell Disease (SCD) and Nephropathy**. The study population includes both male and female subjects, aged 16 years and older, with a documented diagnosis of SCD, specifically HbSS or HbS/β0-thalassemia. Participants are required to have a hemoglobin concentration between 5.5 and 10.5 g/dL during the screening period. The trial includes individuals who may be considered part of a vulnerable population. Participants must have stable doses of hydroxyurea, ACE inhibitors, or ARB therapy if applicable, for at least 90 days prior to the study. Lifestyle considerations include the requirement for women of childbearing potential to use effective contraception methods throughout the study. The selection process ensured that participants had specific urine albumin creatinine ratio (ACR) results within defined parameters during the screening period. The trial aims to evaluate the effect of mitapivat on ACR response in this specific patient population.

Plans and Procedures

The clinical trial is a **Phase 2**, open-label, multicenter study designed to evaluate the effect of **mitapivat** on the albumin creatinine ratio (ACR) response in subjects with **sickle cell disease** (SCD) and nephropathy. The trial will involve the administration of mitapivat in tablet form, taken orally, with a maximum daily dose of 200 mg. The study is expected to span a period of approximately 97 weeks, with participant involvement beginning from the screening visit and continuing through to the end-of-study visit.

Participants will first undergo a screening visit to confirm eligibility based on specific inclusion criteria, such as age, documented diagnosis of SCD, and stable hemoglobin concentration. The screening will also involve the collection of urine samples to assess ACR levels. Following successful screening, participants will be enrolled in the study and will attend regular follow-up visits to monitor their response to the treatment and any potential adverse events. The primary endpoint of the study is a ≥30% decrease in ACR from baseline to Month 6, with secondary endpoints including changes in estimated glomerular filtration rate (eGFR) and the annualized rate of emergency room visits and hospitalizations.

The study will conclude with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact of mitapivat on the participants' condition. Participants are expected to remain in the study for its entire duration unless specific conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial is not categorized as low intervention, and it aims to provide insights into the potential benefits of mitapivat in improving anemia and reducing kidney damage in patients with SCD and nephropathy.

Treatment

The clinical trial involves the administration of **Mitapivat**, a chemical compound developed by Agios Pharmaceuticals. **Mitapivat** is provided in the form of a **tablet** and is intended for oral administration. The maximum daily dose of **Mitapivat** is 200 mg, with a total maximum dose of 146,700 mg over the course of the study. The treatment period is set to a maximum of 97 days. The active substance in **Mitapivat** is chemically synthesized and is identified by the chemical name N-(4-((4-(cyclopropylmethyl)-1-piperazinyl)carbonyl)phenyl)-8-quinolinesulfonamide, also known by its sponsor product code AG-348. The trial aims to evaluate the effect of **Mitapivat** on the albumin creatinine ratio (ACR) response in subjects with sickle cell disease and nephropathy.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of **Mitapivat**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the therapeutic potential of **Mitapivat** in the specified patient population, with careful monitoring of dosage and administration to optimize safety and efficacy outcomes.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **albumin creatinine ratio (ACR) response**, defined as a ≥30% decrease in ACR from baseline to Month 6. This primary endpoint will be measured to evaluate the effect of mitapivat in subjects with sickle cell disease and nephropathy. Secondary endpoints include changes from baseline in estimated glomerular filtration rate (eGFRcr-cys) and ACR, stable ACR defined as Month 6 ACR within ±20% of baseline ACR, and the annualized rate of visits to the emergency room (ER) and days of hospitalizations. Additionally, the type, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) and their relationship to the study drug will be monitored. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study to determine the therapeutic impact of mitapivat on the target population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Aged ≥16 years at the time of providing informed consent/assent (except in France where subjects must be aged ≥18 years at the time of providing informed consent). a. Females must be post-menarche. 2. Documented diagnosis of SCD (HbSS or HbS/β0-thalassemia). 3. Hemoglobin concentration ≥5.5 and ≤10.5 g/dL during the Screening Period. If more than one measurement is collected during the Screening Period, the average must be ≥5.5 and ≤10.5 g/dL. 4. If taking hydroxyurea, the dose of hydroxyurea must have been stable for at least 90 days before Study Day 1 with no planned dose adjustment during the study and no sign of hematologic toxicity. a. Discontinuation of hydroxyurea requires a 90-day washout before providing informed consent/assent. 5. Two urine ACR results collected during the Screening Period, both of which must be ≥100 and <2000 mg/g. One ACR result can be from an untimed urine sample collected as part of a clinic visit. The other ACR result must be from a urine sample that is the first (or second) morning void on another day. 6. One ACR result >100 mg/g within 24 weeks before providing informed consent/assent. 7. If taking ACE inhibitor or ARB therapy, must have been on stable dose for at least 90 days before providing informed consent/assent with no planned dose adjustment during the study. 8. Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed consent/assent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can include an acceptable barrier method (see Appendix 1). 9. Written informed consent/assent (for subjects aged <18 years, or younger than the age at which a subject is considered legally an adult per local regulations, parental permission and child assent will be obtained) must be obtained before any study-related procedures are conducted, and subjects must be willing to comply with all study procedures for the duration of the study.

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Exclusion Criteria

Currently receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or VOC is permitted. 2. Have received an RBC transfusion within 60 days before providing informed consent/assent or during the Screening Period. 3. Hospitalized within 14 days before providing informed consent/assent or during the Screening Period either for an SCPC (defined in Section 8.2.1) or other vaso-occlusive event. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an ER or outpatient clinic visit. A visit to an ER that does not result in an in-patient admission does not meet the definition of hospitalization. 4. More than10 SCPCs (defined in Section 8.2.1) in the 52 weeks before providing informed consent/assent. 5. History of stroke or meeting criteria for primary stroke prophylaxis (history of 2 transcranial Doppler [TCD] measurements ≥200 cm/s by nonimaging TCD or ≥185 cm/s by imaging TCD) at any time. 6. Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), except for hydroxyurea. The last dose of such therapies must have been administered at least 90 days before Study Day 1. 7. History of malignancy (active or treated) ≤5 years before providing informed consent/assent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. 8. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before Study Day 1, including but not limited to: a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% d. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right heart failure, and oxygen indicated
Hepatobiliary disorders including but not limited to: a. Liver disease with histopathological evidence or clinical diagnosis of cirrhosis or severe fibrosis at any time b. Clinically symptomatic cholelithiasis or cholecystitis within 60 days before study drug administration (subjects with prior cholecystectomy are eligible) c. History of drug-induced cholestatic hepatitis within 90 days before study drug administration d. Aspartate aminotransferase >2.5× the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5× the ULN (unless due to hepatic iron deposition) within 60 days before study drug administration 10. Renal dysfunction as defined by an eGFR <45 mL/min/1.73 m² by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (National Kidney Foundation, 2021b) at Screening. 11. History of renal disease due to another disorder (eg, diabetes, hypertension, primary focal segmental glomerulosclerosis, autoimmune) unrelated to SCD at any time. 12. Evidence of acute kidney injury (in the opinion of the Investigator) within 4 weeks before informed consent/assent or during Screening Period. 13. Currently undergoing renal replacement therapy (ie, hemodialysis, peritoneal dialysis, hemofiltration, kidney transplantation). 14. History of kidney transplant at any time. 15. Nonfasting triglycerides >440 mg/dL (5 mmol/L) at Screening. 16. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mm Hg or diastolic BP >90 mm Hg) refractory to medical management. Please refer to Protocol, Section 5.2. for detailed list of Exclusion Criteria.