Evaluation of Safety, Pharmacokinetics, and Efficacy of Sebetralstat in Pediatric Patients with Hereditary Angioedema Type I or II

Trial ID: 2023-507591-44-00
Protocol: KVD900-303
Sponsor: Kalvista Pharmaceuticals Limited

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Diseases & Conditions

Hereditary angioedema with C1 esterase inhibitor deficiency

Objectives

The primary objective of this clinical trial is to evaluate the **safety** and tolerability of **sebetralstat** in pediatric patients aged 2 to less than 12 years with **Hereditary Angioedema** (HAE) Type I or II. This is clinically relevant as it aims to ensure that the treatment is safe for use in a vulnerable population, potentially leading to improved management of HAE in children.

Secondary objectives include:

Evaluating the pharmacokinetics (PK) of sebetralstat in pediatric patients with HAE Type I or II, which is crucial for understanding the drug's absorption, distribution, metabolism, and excretion in this specific age group.
Assessing the clinical efficacy of sebetralstat for the on-demand treatment of HAE attacks in pediatric patients with HAE Type I or II, which is important for determining the therapeutic benefit and effectiveness of the drug in managing acute episodes of the condition.

Participants

The clinical trial involves a total of **23 participants** diagnosed with **Hereditary Angioedema (HAE) Type I or II**. The study population consists of both male and female pediatric patients aged 2 to less than 12 years. Participants were selected based on a confirmed diagnosis of HAE Type I or II, with additional criteria for those weighing 20 kg or more, requiring at least one documented HAE attack in the year prior to screening. The trial includes a vulnerable population, as it involves children. Caregivers must be capable of managing the investigational medicinal product and maintaining a diary, ensuring adherence to protocol requirements. The study does not specify particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and tolerability of **sebetralstat** in pediatric patients aged 2 to 11 years with **Hereditary Angioedema** (HAE) Type I or II. This is an open-label, Phase III trial, which will involve the administration of **sebetralstat** in the form of an orodispersible tablet. The trial will be conducted over an estimated period from September 2024 to August 2027. Participants will be randomly assigned to receive either a 450 mg or 900 mg dose of **sebetralstat**, with the maximum treatment period being 12 months. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess overall outcomes.

The inclusion criteria require participants to be male or female patients aged 2 to 11 years with a confirmed diagnosis of HAE Type I or II. Participants must have experienced at least one documented HAE attack in the year prior to screening if they weigh 20 kg or more. Caregivers must be capable of storing and administering the investigational medicinal product (IMP) and completing a diary. The primary endpoint is the proportion of pediatric patients experiencing any adverse events (AEs) during the study. Secondary endpoints include the time to symptom relief and attack resolution, as well as the time to use of conventional on-demand treatment.

Participants are expected to be involved in the study for up to 12 months, with conditions for early termination including the occurrence of significant adverse events or non-compliance with the study protocol. The trial aims to provide valuable data on the use of **sebetralstat** in a pediatric population, contributing to the understanding of its safety and efficacy in managing HAE Type I or II.

Treatment

The clinical trial involves the administration of **KVD900**, an experimental medication formulated as an **orodispersible tablet**. The active substance in KVD900 is **sebetralstat**, a chemical compound also known by its chemical name, N-[(3-fluoro-4-methoxypyridin-2-yl) methyl]-3-(methoxymethyl)-1-({4-[(2-oxo-1,2-dihydropyridin-1-yl) methyl]phenyl}methyl)-1H-pyrazole-4-carboxamide. The medication is produced by KalVista Pharmaceuticals, Ltd. and is designated as an orphan drug under the number EU/3/22/2625. The trial includes two formulations of KVD900: a pediatric formulation with a maximum daily dose of 450 mg and a non-pediatric formulation with a maximum daily dose of 900 mg. Both formulations are administered orally, with a maximum treatment period of 12 weeks.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided in the source data. The administration of KVD900 is monitored to ensure participant compliance with the dosing schedule. The trial aims to evaluate the safety, pharmacokinetics, and efficacy of sebetralstat in pediatric patients aged 2 to 11 years with **hereditary angioedema** Type I or II. The study is designed to assess the tolerability of the medication in this specific patient population.

Efficacy

The efficacy of **sebetralstat** in the clinical trial will be assessed using several secondary endpoints. These include the time to the beginning of symptom relief, defined as at least "a little better" at two consecutive time points within 12 hours of the first investigational medicinal product (IMP) administration, as measured by the Caregiver Global Impression of Change (CaGI-C) scale. Additionally, the time to the first incidence of a decrease from baseline, also at two consecutive time points within 12 hours of the first IMP administration, will be evaluated using the Caregiver Global Impression of Severity (CaGI-S) scale. Another parameter is the time to resolution of a **Hereditary Angioedema (HAE)** attack, defined as "none" within 24 hours of the first IMP administration, again assessed by the CaGI-S scale. Furthermore, the time to the use of conventional on-demand treatment within 12 hours of the first IMP administration will be recorded. These efficacy parameters will be collected and analyzed at specified time points to determine the therapeutic impact of sebetralstat in pediatric patients with HAE Type I or II.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female patients 2 to 11 years of age.
Confirmed diagnosis of HAE Type I or II at any time in the medical history.
For patients ≥20 kg at screening, patient has had at least 1 documented HAE attack in the last year prior to screening.
Caregiver, as assessed by the Investigator, must be able to appropriately store and administer IMP and be able to read, understand, and complete the diary.
Investigator believes that the patient and caregiver are willing and able to adhere to all protocol requirements.
Parent or LAR provides signed informed consent and patient provides assent (when applicable).

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Exclusion Criteria

Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1 inhibitor deficiency, HAE with normal C1-INH, idiopathic angioedema, or angioedema associated with urticaria.
A clinically significant history of poor response to bradykinin receptor 2 (BR2) blocker, C1-INH therapy, or plasma kallikrein inhibitor therapy for the management of HAE, in the opinion of the Investigator.
Patient weighs <9.5 kg.
Use of angiotensin-converting enzyme (ECA) inhibitors after the Screening Visit.
Any estrogen-containing medications with systemic absorption (such as oral contraceptives including ethinylestradiol or hormonal replacement therapy) within 7 days prior to the Screening Visit.
Patients who require sustained use of strong cytochrome CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers.
Any clinically significant comorbidity or systemic dysfunction, which in the opinion of the Investigator, would jeopardize the safety of the patient by participating in the trial.
Known hypersensitivity to sebetralstat or to any of the excipients.
Participation in any interventional investigational clinical trial within 4 weeks of the last dosing of investigational drug prior to the Screening Visit.