A multicenter, single arm, open-label trial to evaluate efficacy and safety of oral, twice daily iptacopan in adult PNH patients who have Hb≥10 g/dL in response to anti-C5 antibody and switch to iptacopan

Trial ID: 2022-502148-10-00
Protocol: CLNP023C12303
Sponsor: Novartis Pharma AG

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Diseases & Conditions

Paroxysmal nocturnal haemoglobinuria

Objectives

The primary objective of this clinical trial is to evaluate whether **iptacopan** treatment is equally effective compared to the standard of care in patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** who have a hemoglobin level of ≥10 g/dL in response to anti-C5 antibody therapy and are switching to iptacopan. This is clinically relevant as it aims to determine if iptacopan can maintain or improve the therapeutic outcomes achieved with current standard treatments, potentially offering a new oral treatment option for PNH patients.

Secondary objectives include assessing whether iptacopan demonstrates superior effectiveness compared to the standard of care treatment. This evaluation is crucial for understanding the potential benefits of iptacopan over existing therapies, which could lead to improved management strategies for PNH.

Participants

The clinical trial involves a total of **25 participants** diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their stable regimen of anti-C5 antibody treatment for at least six months prior to screening and a mean hemoglobin level of at least 10 g/dL. The trial population is characterized by individuals who have been vaccinated against Neisseria meningitidis and S. pneumoniae infections, with additional recommendations for vaccination against Haemophilus influenzae infections. Participants are required to have a PNH clone size of white blood cells (WBCs) of at least 10% based on historical data. The trial includes a vulnerable population, and participants must be able to communicate effectively with the investigator to comply with study requirements.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **iptacopan** in adult patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** who have a hemoglobin level of at least 10 g/dL in response to anti-C5 antibody treatment and are transitioning to iptacopan. This is a multicenter, single-arm, open-label trial. The trial will involve oral administration of iptacopan in the form of hard gelatin capsules, with a maximum daily dose of 400 mg. The trial is expected to last until March 2025, with recruitment having started in May 2023. The primary endpoint is the change in hemoglobin levels from baseline to Day 126 and Day 168 of treatment.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment stability. The inclusion criteria require participants to be at least 18 years old, have a confirmed diagnosis of PNH with a white blood cell clone size of at least 10%, and have been on a stable anti-C5 antibody regimen for at least six months prior to screening. Additionally, participants must have a mean hemoglobin level of at least 10 g/dL, confirmed by central laboratory testing during the screening period. Vaccinations against **Neisseria meningitidis**, **S. pneumoniae**, and, if applicable, **Haemophilus influenzae** are required prior to the start of iptacopan treatment, with specific guidelines for timing and prophylactic antibiotic use if vaccinations are administered close to the start of treatment.

Following the screening visit, participants will attend regular follow-up visits to monitor hemoglobin levels and assess safety and efficacy outcomes. The end-of-study visit will conclude the trial for each participant, with the overall duration of individual participation expected to be approximately 24 weeks. Conditions that may lead to early termination from the study include non-compliance with study procedures, adverse events, or withdrawal of consent. The trial aims to provide valuable data on the potential of iptacopan as a treatment option for PNH, contributing to the understanding of its role in managing this rare disease.

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 chemically as 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid. The pharmaceutical form is designed for oral administration. Participants in the trial will receive a maximum daily dose of 400 mg, administered in two divided doses, ensuring a consistent therapeutic level of the drug. The treatment period is set for a maximum of 24 weeks, during which the efficacy and safety of Iptacopan will be evaluated in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have a hemoglobin level of at least 10 g/dL in response to anti-C5 antibody therapy and are transitioning to Iptacopan.

In this open-label, single-arm trial, Iptacopan is the sole experimental medication being tested. There are no non-experimental treatments, such as a placebo or comparator treatment, included in the study design. The trial aims to assess whether Iptacopan is equally effective as the standard of care when patients switch from anti-C5 antibody therapy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial's design does not include a pediatric formulation, and the drug is classified as an orphan drug under the designation EU/3/20/2281, highlighting its intended use for a rare condition.

Efficacy

Efficacy in this clinical trial will be assessed by evaluating the change in **hemoglobin** levels in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who switch from anti-C5 antibody treatment to iptacopan. The primary endpoint involves measuring the change in hemoglobin levels before the start of iptacopan treatment and comparing it to the mean hemoglobin levels at Day 126 and Day 168. This assessment will be conducted using laboratory tests to ensure accurate and reliable data collection. The trial is designed to determine if iptacopan treatment is equally effective compared to the standard of care. The trial will follow a multicenter, single-arm, open-label design, focusing on adult PNH patients with a hemoglobin level of at least 10 g/dL in response to anti-C5 antibody treatment. The efficacy assessments will be conducted at specified time points to monitor the treatment's impact on hemoglobin levels over the course of the trial.

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 ICF signatures and with a diagnosis of PNH confirmed by PNH clone size WBCs ≥ 10% based on historical data.
Stable regimen (dose and intervals) of anti-C5 antibody treatment (either eculizumab or i.v. ravulizumab) for at least 6 months prior to screening
Mean hemoglobin level ≥10 g/dL, documented by the mean of all available Hb assessments (minimum 2 measurements) over a period of 6 months before screening visit, collected at any laboratory. In addition to fulfill the Hb eligibility criterion, participants must have two different samples collected during the screening period and tested by the central laboratory with the mean >10 g/dL, prior to starting iptacopan.
Vaccination against Neisseria meningitidis and S. pneumoniae infection are required prior to the start of iptacopan treatment. If the patient has not been previously vaccinated, or if a booster is required, vaccine are to be given according to local regulations, at least 2 weeks prior to first dosing. However, administration of these vaccines less than 2 weeks prior to start of iptacopan treatment is at the discretion of the investigator. If iptacopan treatment is started less than 2 weeks post-vaccination, participant must be given prophylactic antibiotic at the start of iptacopan and for at least 2 weeks after vaccination.
If not received previously, vaccination against Haemophilus influenzae infections is recommended, if available and according to local regulations. The vaccines should be given at least 2 weeks prior to initiation of iptacopan treatment. However, administration of these vaccines less than 2 weeks prior to start of iptacopan treatment, is at the discretion of the investigator. If iptacopan treatment is started less than 2 weeks post-vaccination, participant must be given prophylactic antibiotic at the start of iptacopan and for at least 2 weeks after vaccination.
Able to communicate well with the investigator, to understand and comply with the requirements of the study

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Exclusion Criteria

Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment
Patients requiring red blood cell transfusion in the 6 months prior to screening or during screening
History of stem cell transplantation or any solid organ transplantation
Active systemic bacterial, viral (incl. COVID-19) or fungal infection within 14 days prior to study drug administration
Presence of fever ≥ 38.0 °C (100.4 °F) within 7 days prior to study drug administration
Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for HIV antibody at Screening)
A history of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus
Unstable medical condition including, but not limited to, myocardial ischemia, active gastrointestinal bleeding, coexisting chronic anemia unrelated to PNH, or unstable thrombotic event not amenable to active treatment as judged by the investigator at Screening.
History of cancer of any part of the body within the past 5 years
Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial.
Any medical condition deemed likely to interfere with the patient's participation in the study
Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study