Evaluation of Efficacy and Safety of Transitioning from Anti-C5 Antibody Therapy to Iptacopan in Patients with Atypical Hemolytic Uremic Syndrome

Trial ID: 2023-504550-35-00
Protocol: CLNP023F12302
Sponsor: Novartis Pharma AG

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Diseases & Conditions

Atypical haemolytic uraemic syndrome

Objectives

The primary objective of this study is to assess the proportion of participants with **Atypical Hemolytic Uremic Syndrome (aHUS)** who remain free of Thrombotic Microangiopathy (TMA) manifestations during 12 months of treatment with **iptacopan** following a switch from anti-C5 antibody therapy. This is clinically relevant as it evaluates the efficacy of iptacopan in maintaining disease control in patients transitioning from existing therapies, potentially offering a new therapeutic option for managing aHUS.

Secondary objectives include:

Assessing the proportion of participants free of TMA manifestation during 12 months of iptacopan treatment in those with functionally significant mutations in complement genes or positive for anti-FH antibodies.
Evaluating the time to TMA manifestation following the switch to iptacopan treatment.
Assessing the effect of iptacopan on hematologic parameters (platelets, LDH, hemoglobin) and kidney function (serum creatinine, UPCR, eGFR, CKD stage) at Month 12.
Evaluating the effect of iptacopan on dialysis requirement status.
Assessing the safety and tolerability of iptacopan treatment.
Evaluating the proportion of participants with TMA-related events.

These objectives aim to provide comprehensive data on the clinical benefits and safety profile of iptacopan, contributing to the understanding of its role in the management of aHUS.

Participants

The clinical trial involves a total of **16 participants** diagnosed with **Atypical Hemolytic Uremic Syndrome (aHUS)**. The study population includes both male and female subjects who are **18 years of age or older**. Participants were selected based on their current treatment with a weight-based dosage regimen of anti-C5 antibody treatment, such as eculizumab or ravulizumab, for at least three months prior to the screening visit. The trial population is characterized by individuals who have shown clinical evidence of response to anti-C5 antibody treatment, with hematological normalization and stable or improving kidney function. Participants are required to have been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae infections prior to the start of treatment with iptacopan. The study includes a vulnerable population, and participants must be willing and able to comply with the study visit schedule. The selection criteria ensure that other types of thrombotic microangiopathy (TMA) and non-aHUS kidney diseases have been excluded.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of switching from anti-C5 antibody therapy to **iptacopan** therapy in participants with **Atypical Hemolytic Uremic Syndrome (aHUS)**. This is a multicenter, single-arm, open-label study. The primary objective is to assess the proportion of participants free of thrombotic microangiopathy (TMA) manifestation during 12 months of iptacopan treatment. The trial is expected to commence recruitment on January 1, 2025, and conclude by July 19, 2029.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a confirmed diagnosis of aHUS and prior treatment with anti-C5 antibody therapy. Following the screening, participants will transition to iptacopan treatment, administered orally in the form of hard gelatin capsules. The maximum daily dose is 400 mg, with a treatment period extending up to 24 months. Regular follow-up visits will be scheduled to monitor safety and efficacy, including assessments of hematologic parameters and kidney function. The end-of-study visit will conclude the participant's involvement, summarizing the treatment outcomes and any adverse events.

Participant involvement is expected to last for 12 months, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that necessitate discontinuation. The study will not employ a randomized or double-blind design, as it is an open-label trial. Safety evaluations will be conducted throughout the study, focusing on adverse events, laboratory parameters, and vital signs. The trial aims to provide comprehensive data on the transition from anti-C5 antibody therapy to iptacopan, contributing valuable insights into the management of aHUS.

Treatment

The clinical trial involves the administration of **Iptacopan**, a chemical compound developed by Novartis Pharma AG. Iptacopan is provided in the form of hard gelatin capsules, with each capsule containing the active substance known as Iptacopan. The pharmaceutical form is designed for oral administration. The maximum daily dose of Iptacopan is 400 mg, and the total dose should not exceed 400 mg per day. The treatment period is set for a maximum of 24 months. The primary objective of the trial is to evaluate the efficacy and safety of switching from anti-C5 antibody therapy to Iptacopan therapy in participants with atypical hemolytic uremic syndrome (aHUS).

Participants in the study will be monitored for compliance with the dosing schedule, which involves the oral intake of the medication. The trial is structured as a multicenter, single-arm, open-label study, focusing on the proportion of participants who remain free of thrombotic microangiopathy (TMA) manifestations during the 12 months following the switch to Iptacopan treatment. No additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The study aims to provide comprehensive data on the safety and efficacy of Iptacopan in the specified patient population.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint, which is the **absence of TMA (Thrombotic Microangiopathy) manifestation** without the use of anti-C5 antibody during 12 months of treatment with iptacopan following the switch from anti-C5 antibody therapy. Secondary endpoints include the time to TMA manifestation during the 12 months of iptacopan treatment, changes from baseline in hematologic parameters such as platelets, LDH, and hemoglobin, as well as kidney function indicators like serum creatinine, UPCR, eGFR, and CKD stage at Month 12. Additionally, the dialysis requirement status will be monitored through the 12-month period.

Safety evaluations will also be conducted throughout the 12 months of iptacopan treatment, including monitoring adverse events, serious adverse events, safety laboratory parameters, and vital signs. TMA-related events will be documented, defined as irreversible reduction in eGFR by ≥20%, episodes of acute kidney injury requiring renal replacement therapy, or non-renal manifestations requiring hospitalization or causing irreversible organ damage or death. These efficacy parameters will be collected and analyzed at specified timepoints to determine the overall effectiveness of iptacopan in the treatment of atypical Hemolytic Uremic Syndrome (aHUS).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent must be obtained prior to participation in the study
Male and female participants ≥ 18 years of age at the time of consent.
Willing and able to comply with the study visit schedule
Participants with diagnosis of aHUS for whom etiologies of other types of TMA (eg., Thrombotic Thrombocytopenic Purpura (TTP), Shiga Toxin producing Escherichia Coli (STEC)-TMA, Pneumococcal hemolytic uremic syndrome, TMA secondary to cobalamin C defect, TMA related to Diacylglycerol kinase ε (DGKE) nephropathy) and non-aHUS kidney disease have been excluded.
Currently on the recommended (as per label) dosage regimen of anti-C5 antibody treatment (eg., eculizumab or ravulizumab), for at least 3 months prior to entering the screening period .
In the opinion of the investigator the participant has responded to anti-C5 antibody treatment prior to screening and has clinical evidence of response (in absence of PE/PI) during the Screening period. Clinical evidence of response to anti-C5 antibody treatment (in absence of PE/PI) confirmed during the Screening period by central laboratory at two visits 12 weeks apart. Clinical evidence of response is defined as: • Hematological normalization in platelet count ≥150 x 109/L and LDH below upper limit of normal [ULN], and Stable kidney function as defined by serum creatinine values within ±15% during the Screening period .
Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is required prior to the start of treatment with iptacopan. If the participant has not been previously vaccinated or if a booster is required, the vaccine(s) should be given, according to local regulations, at least 2 weeks prior to first iptacopan dosing. If iptacopan treatment has to start earlier than 2 weeks post-vaccination, prophylactic antibiotic treatment must be initiated at the start of iptacopan study treatment and for at least 2 weeks after vaccination
If not received previously or if a booster is required, vaccination against Haemophilus influenzae infection, should be given, if available and according to local regulations, at least 2 weeks prior to first iptacopan dosing.

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Exclusion Criteria

History of aHUS disease relapse while on anti-C5 antibody treatment.
Liver disease, such as active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection defined as hepatitis B virus surface antibody (HBsAg) positive or HCV RNA positive, or liver injury as indicated by abnormal liver function tests at Screening as defined below: • Any single parameter of alanine amino transferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase must not exceed 3×upper limit of normal (ULN).
Any medical condition deemed likely to interfere with the participant’s participation in the study.
Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations.
History of hypersensitivity to iptacopan or any of its excipients or to drugs of similar chemical classes.
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer) treated or untreated within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
Female participants who are pregnant or breastfeeding, or intending to conceive during the course of the study.
Women of child-bearing potential (WCBP), defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of iptacopan and for 1 week after stopping of iptacopan.
eGFR < 30 ml/min/1.73m2.
Uncontrolled arterial hypertension (systolic blood pressure >160 mmHg).
Active infection or history of recurrent invasive infections caused by encapsulated bacteria, i.e. meningococcus, pneumococcus (eg., N. meningitidis, S. pneumoniae) or H. influenzae.
Participants with sepsis or active systemic bacterial, viral (including COVID-19) or fungal infection within 14 days prior to study treatment administration.
Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for HIV at screening).
Kidney, bone marrow transplant (BMT)/hematopoietic stem cell transplant (HSCT), heart, lung, small bowel, pancreas, liver transplantation or any other cell or solid organ transplantation.
History of drug or alcohol abuse within the 12 months prior to dosing.
Women of child-bearing potential (WCBP), defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they are using effective methods of contraception during dosing of iptacopan and for 1 week after stopping of iptacopan. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., hormonal profile confirming menopause and/or age-appropriate history of vasomotor symptoms).
Participants committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
Participants dependent on the sponsor, the study site or the Investigator