Long-term Safety Evaluation of Sebetralstat (KVD900) for On-demand Treatment of Angioedema Attacks in Hereditary Angioedema Type I or II Patients

Trial ID: 2023-505904-41-00
Protocol: KVD900-302
Sponsor: Kalvista Pharmaceuticals Limited

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Diseases & Conditions

Hereditary angioedema with C1 esterase inhibitor deficiency

Objectives

The primary objective of this study is to assess the **safety** of long-term administration of KVD900 in adolescent and adult patients with **Hereditary Angioedema** (HAE) type I or II. This is clinically relevant as ensuring the safety of long-term treatment options is crucial for managing chronic conditions like HAE, which can significantly impact patients' quality of life.

Secondary objectives include:

To assess the long-term efficacy of KVD900 in the treatment of attacks in adolescent and adult patients with HAE type I or II.
To assess the safety and efficacy of KVD900 when used as short-term prophylaxis in adolescent and adult patients with HAE types I or II.

Participants

The clinical trial involves a total of **75 participants** diagnosed with **Hereditary Angioedema Type I or II**. The study population includes both male and female subjects aged 12 years and older. Participants were selected based on their confirmed diagnosis of Hereditary Angioedema Type I or II, with a requirement of having experienced at least two documented attacks within three months prior to the enrollment visit. The trial includes individuals who may have rolled over from a previous study, KVD900-301, and those on stable long-term prophylactic treatment with protocol-allowed therapies. Participants must be able to swallow trial tablets whole and meet specific contraception requirements. The trial population is considered vulnerable, and all participants must provide signed informed consent or assent, with additional consent from a parent or legally authorized representative when applicable. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are capable of adhering to protocol requirements, including the ability to appropriately receive, store, and document their experiences with the investigational medicinal product (IMP) in an electronic diary (eDiary).

Plans and Procedures

The clinical trial is designed to evaluate the long-term safety of **KVD900**, an oral plasma kallikrein inhibitor, for the on-demand treatment of angioedema attacks in adolescent and adult patients with **Hereditary Angioedema** (HAE) Type I or II. This trial follows a randomized, open-label extension design, allowing patients to roll over from a previous study, KVD900-301. The trial is expected to run until August 31, 2026, with recruitment having commenced on December 27, 2022. The trial involves the administration of KVD900 in two pharmaceutical forms: film-coated tablets and orodispersible tablets, with a maximum daily dose of 1200 mg and 900 mg, respectively, and a maximum treatment period of 24 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of HAE Type I or II, a history of at least two documented HAE attacks within three months prior to enrollment, and the ability to swallow trial tablets whole. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with primary endpoints including the frequency and percentage of patients experiencing adverse events (AEs), serious AEs, and AEs leading to premature discontinuation. Secondary endpoints will assess the time to symptom relief and attack resolution.

The expected length of participant involvement is up to 24 weeks, with conditions for early termination including the occurrence of serious AEs or the inability to adhere to protocol requirements. The trial aims to provide comprehensive data on the safety profile of KVD900, contributing to the understanding of its long-term use in managing HAE attacks. Participants will be required to adhere to contraception requirements and demonstrate the ability to manage and store the investigational medicinal product (IMP) appropriately. The trial's design ensures rigorous monitoring of laboratory and vital sign results at each scheduled visit, ensuring participant safety and data integrity throughout the study duration.

Treatment

The clinical trial involves the administration of **KVD900**, an experimental medication developed by KalVista Pharmaceuticals, Ltd. The active substance in KVD900 is **sebetralstat**, a chemical compound with the 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. KVD900 is available in two pharmaceutical forms: a film-coated tablet and an orodispersible tablet. The film-coated tablet is administered orally with a maximum daily dose of 1200 mg and a maximum total dose of 1800 mg over a treatment period of up to 24 hours. The orodispersible tablet is also administered orally, with a maximum daily and total dose of 900 mg over the same treatment period. Both formulations are designed for on-demand treatment of angioedema attacks in patients with Hereditary Angioedema (HAE) Type I or II.

In this open-label extension trial, the primary objective is to evaluate the long-term safety of KVD900 in adolescent and adult patients with HAE Type I or II. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The administration of KVD900 is monitored to ensure participant compliance with the dosing schedule. The trial is designed to assess the safety profile of KVD900 when used as an on-demand treatment for angioedema attacks, with a focus on the pharmacokinetics in adolescent patients participating in the KVD900-302 trial.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints focus on safety parameters, including the frequencies and percentages of patients experiencing adverse events (AEs), serious AEs, and AEs leading to premature discontinuation. Additionally, the number and percentage of patients with normal or abnormal laboratory and vital sign results at each scheduled visit will be evaluated. These assessments will be conducted throughout the trial to monitor the safety profile of the investigational medicinal product (IMP), **KVD900**.

The secondary endpoints are designed to evaluate the efficacy of **KVD900** in providing symptom relief for patients with Hereditary Angioedema (HAE) Type I or II. These include the Patient Global Impression of Change (PGI-C) and Patient Global Impression of Severity (PGI-S) scales. The PGI-C will measure 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 initial dose. The PGI-S will assess the time to the first incidence of a two-time-point decrease from baseline within 12 hours of the initial dose, as well as the time to HAE attack resolution, defined as "none" within 24 hours of the initial dose. These efficacy parameters will be collected and analyzed to determine the therapeutic benefit of **KVD900** in managing angioedema attacks.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients may roll over from KVD900-301.
Confirmed diagnosis of HAE type I or II at any time in the medical history
Patient has had at least 2 documented HAE attacks within 3 months prior to the Enrollment Visit
If a patient is receiving long-term prophylactic treatment with one of the protocol-allowed therapies, they must have been on a stable dose and regimen for at least 3 months prior to the Enrollment Visit
Male or female patients 12 years of age and older.
Patients must meet the contraception requirements.
Patients must be able to swallow trial tablets whole.
Patients, as assessed by the Investigator, must be able to appropriately receive and store IMP, and be able to read, understand, and complete the eDiary.
Investigator believes that the patient is willing and able to adhere to all protocol requirements.
Patient provides signed informed consent or assent (when applicable). A parent or LAR must also provide signed informed consent when required.

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Exclusion Criteria

Discontinued from the KVD900-301 trial for reasons of non-compliance, withdrawal of consent, or safety.
Presence of any safety concerns that would preclude participation in the open-label trial as determined by the investigator.
Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1 inhibitor deficiency, HAE with normal C1-INH (previously known as HAE type III), 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.
Use of attenuated androgens (e.g., stanozolol, danazol, oxandrolone, methyltestosterone, testosterone), or anti-fibrinolytics (e.g., tranexamic acid) within 28 days prior to the Enrollment Visit.
Use of ACE inhibitors within 7 days prior to the Enrollment Visit.
Any estrogen-containing medications with systemic absorption (such as oral contraceptives including ethinylestradiol or hormonal replacement therapy) within 7 days prior to the Enrollment Visit.
Inadequate organ function, including but not limited to: a) Alanine aminotransferase (ALT) >2x ULN b) Aspartate aminotransferase (AST) >2x ULN c) Bilirubin direct >1.25x ULN d) INR >1.2 e) Clinically significant hepatic impairment defined as a Child-Pugh B or C
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.
History of substance abuse or dependence that would interfere with the completion of the trial, as determined by the Investigator.
Known hypersensitivity to KVD900 or to any of the excipients.
Participation in any gene therapy treatment or trial for HAE.
Participation in any interventional investigational clinical trial, including an investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of investigational drug prior to the Enrollment Visit.
Any pregnant or breastfeeding patient.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	27 Dec 2022	3
Bulgaria	Not Recruiting	27 Dec 2022	3
France	Not Recruiting	27 Dec 2022	10
Germany	Not Recruiting	27 Dec 2022	12
Greece	Not Recruiting	27 Dec 2022	8
Hungary	Not Recruiting	27 Dec 2022	2
Italy	Not Recruiting	27 Dec 2022	8
The Netherlands	Not Recruiting	27 Dec 2022	—
Poland	Not Recruiting	27 Dec 2022	8
Portugal	Not Recruiting	27 Dec 2022	4