Evaluation of Long-term Safety and Efficacy of Deucrictibant Extended-Release Tablets for Prophylactic Management of Hereditary Angioedema in Adolescents and Adults

Trial ID: 2024-516248-24-00
Protocol: PHA022121-C307
Sponsor: Pharvaris Netherlands B.V.

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Diseases & Conditions

Hereditary angioedema

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of deucrictibant 40 mg extended-release (XR) tablet in the long-term prophylactic treatment of **hereditary angioedema** (HAE). This is clinically relevant as ensuring the safety and tolerability of a medication is crucial for its use in preventing angioedema attacks, which can be life-threatening and significantly impact patients' quality of life.

Secondary objectives include:

Evaluating the efficacy of deucrictibant 40 mg XR tablet in long-term prophylactic treatment of HAE.
Assessing the impact on health-related quality of life (HRQoL) of deucrictibant 40 mg XR tablet in long-term prophylactic treatment of HAE.
Evaluating the pharmacokinetics (PK) of deucrictibant 40 mg XR tablet in long-term prophylactic treatment of HAE.

Participants

The clinical trial involves a total of **73 participants** diagnosed with **Hereditary Angioedema** (HAE). The study population includes both male and female subjects, with an age range starting from 12 years and above. Participants were selected based on their previous involvement in HAE studies with deucrictibant or through confirmed diagnosis by a central laboratory. The trial includes individuals who have a documented clinical history consistent with HAE and meet specific diagnostic criteria. Participants are required to have reliable access to standard of care on-demand treatments for managing acute HAE attacks. The study also considers lifestyle factors such as the ability to adhere to protocol requirements, including data recording into an eDiary. The trial population includes vulnerable groups, ensuring comprehensive representation across different demographics. The sponsor has not provided specific information regarding the general health status or lifestyle habits such as diet and physical activity of the participants.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and tolerability of deucrictibant, an extended-release tablet, in the long-term prophylactic treatment of **hereditary angioedema** (HAE). This study is a phase 3, open-label trial, which means that both the researchers and participants know which treatment is being administered. The trial is expected to commence on January 13, 2025, and conclude by November 10, 2028, with the total duration of participant involvement being up to 130 days. Participants will be administered deucrictibant orally, with a maximum daily dose of 40 mg.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as a documented clinical history consistent with HAE and diagnostic testing results. Participants who have previously participated in HAE studies with deucrictibant may be eligible for screening. The primary endpoints of the study include monitoring treatment-emergent adverse events, clinical laboratory tests, vital signs, and electrocardiogram parameters. Secondary endpoints focus on the frequency and severity of HAE attacks, quality of life assessments, and deucrictibant plasma concentration levels.

Participants will be required to attend follow-up visits throughout the treatment period to assess the efficacy and safety of the treatment. These visits will involve clinical evaluations, laboratory tests, and completion of questionnaires related to quality of life and treatment satisfaction. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to ensure participant safety and gather comprehensive data on the treatment's impact.

Participants may be withdrawn from the study early if they experience serious adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The study aims to provide valuable insights into the long-term use of deucrictibant for the prevention of angioedema attacks in individuals with hereditary angioedema, contributing to the understanding and management of this condition.

Treatment

The clinical trial involves the administration of **Deucrictibant (PHA-022121)**, an experimental medication formulated as an extended-release **tablet**. The active substance, **deucrictibant**, is of chemical origin and is intended for oral administration. The trial aims to evaluate the safety and efficacy of deucrictibant in the prophylactic treatment of **hereditary angioedema** (HAE) in both adolescents and adults. The maximum daily dose of deucrictibant is 40 mg, with a total maximum dose of 36,400 mg over a treatment period of up to 130 days. The medication is not a pediatric formulation and is not classified as an orphan drug. The pharmaceutical form is a tablet, and the route of administration is oral, ensuring ease of use for participants.

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 long-term administration of deucrictibant to assess its prophylactic potential against angioedema attacks. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is conducted under the sponsorship of PHARVARIS NETHERLANDS B.V, with the product being authorized for use in this clinical setting.

Efficacy

The efficacy of the clinical trial evaluating the safety and efficacy of orally administered Deucrictibant extended-release tablet for prophylaxis against angioedema attacks in adolescents and adults with **Hereditary Angioedema** (HAE) will be assessed using both primary and secondary endpoints. The primary endpoints include the assessment of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), adverse events of special interest (AESIs), and TEAEs leading to study drug discontinuation. Additionally, clinical laboratory tests, vital signs, and electrocardiogram (ECG) parameters will be monitored.

Secondary endpoints focus on the time-normalized (per 4 weeks) number of Investigator-confirmed HAE attacks during the treatment period, including those treated with on-demand medication. The study will also evaluate the time-normalized number of moderate or severe HAE attacks, the proportion of time without angioedema symptoms, and various patient-reported outcomes. These include the Angioedema Quality of Life (AE-QoL) questionnaire, Patient Global Assessment of Change (PGA-Change), Angioedema Control Test 4-week version (AECT-4wk), Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP), and the Abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9). Additionally, Deucrictibant plasma concentration pre-dose (Ctrough) will be measured to assess drug exposure.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Provision of written informed consent. At the time of signing informed consent, male and female participants must be aged ≥12 years. If the participant is an adolescent (ie, aged ≥12 to <18 years or as determined by local law, ≥40 kg), written assent will be obtained from the participant and consent will be obtained from the participant’s parent/legal guardian. A participant who is an adolescent will sign the informed consent form if they reach the age of 18 or as determined by local law during their participation in the study
Participants who previously participated in HAE studies with deucrictibant on-demand or prophylactic treatment may be eligible to be screened for this study. Participants in Study PHA022121-305 must have completed all study drug treatment and assessments in the double-blind Treatment Period of the previous study
Participants who have not previously had their HAE diagnosis confirmed by a central laboratory in a Pharvaris-sponsored study with deucrictibant must meet the following requirements: a. Diagnosis of HAE type 1/2: • Documented clinical history consistent with HAE (cutaneous or submucosal, nonpruritic swelling without accompanying urticaria) • At least one of the following: 1. Age at reported onset of first angioedema symptoms ≤30 years 2. Family history consistent with HAE 3. C1q above the lower limit of the normal range b. Diagnostic testing results to confirm HAE: • C1 esterase inhibitor (C1INH) functional level <50% of the normal level must be shown by chromogenic assay performed by the central laboratory as part of the Screening procedures. Participants with functional C1INH level 40% to <50% of the normal level must also have a C4 level below the lower limit of the normal range. 3. Diagnosis of HAE type 3: a. Recurrent angioedema attacks with diagnostic testing results obtained during Screening to confirm C1INH function ≥50% of normal and C4 level not below the lower level of the normal range performed by the central laboratory. b. Documented genetic mutation associated with HAE type 3. c. Attacks not responding to treatments with high-dose antihistamine and no clinical attack symptom relief if treated with corticosteroid, montelukast, or omalizumab. d. Documented effective attack symptom relief with on-demand icatibant treatment
For Non rollover participants: History of at least 1 attack in the last 3 consecutive months prior to Screening
Participant is assessed by the Investigator to have reliable access and ability to use standard of care on-demand treatments to effectively manage acute HAE attacks
Investigator considers that the participant (and parent/caregiver for adolescent participants) is willing and able to adhere to all protocol requirements, including the participant being capable of and compliant with data recording into an eDiary
Female participants of childbearing potential (or who become of childbearing potential during the study) must agree to the protocol specified pregnancy testing and use an acceptable contraception method defined in the protocol from enrollment until 30 days after the last study drug administration

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Exclusion Criteria

Any diagnosis of angioedema other than HAE
History of epilepsy and/or other significant neurological diseases
Any clinically significant and uncontrolled gastrointestinal dysfunction (eg, chronic diarrhea, inflammatory bowel disease) which impacts study drug absorption
History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse
Use of concomitant medications with systemic absorption and foods that are moderate and strong inhibitors of cytochrome P450 (CYP)3A4 such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, and grapefruit juice or strong inducers of CYP3A4 such as carbamazepine, phenytoin, and rifampin within the last 30 days or within 5 half-lives (whichever is longer) of the time of enrollment
Known hypersensitivity to deucrictibant or any of the excipients of study drug
Participation in a clinical study with any other investigational drug within the last 30 days or within 5 half-lives of the investigational drug at ICF signature (whichever was longer) or prior gene therapy for any indication at any time
Participants who discontinued from previous studies with deucrictibant prophylactic and/or on demand treatment due to safety reasons or compliance issues that, in the opinion of the Investigator, would interfere with the participant’s safety or compliance to participate in the study. Participants who previously received deucrictibant prophylactic and/or on-demand treatment and recently completed a pregnancy may be eligible to participate in this study. Participants may be eligible for this study if the previous study with deucrictibant prophylactic and/or on-demand treatment has been terminated by the Sponsor prior to their completion of the study
Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks of Screening
For Rollover participants who have completed participation in studies with deucrictibant prophylactic treatment prior to Screening and Non rollover participants: Receiving prophylactic treatment for HAE within the time periods before Screening as indicated below: a. Long-term prophylactic therapy for HAE (C1INH, oral kallikrein inhibitors, or anti-fibrinolytics) within 2 weeks prior to Screening b. Long-term prophylactic therapy for HAE with attenuated androgens within 4 weeks prior to Screening c. Long-term prophylactic monoclonal antibody therapy for HAE (ie, lanadelumab) within 5 half-lives prior to Screening d. Short-term prophylaxis for HAE within 7 days prior to Screening
Any females who are pregnant, plan to become pregnant, or are currently breast-feeding
Abnormal hepatic function (aspartate aminotransferase [AST] >2× upper limit of normal [ULN], alanine aminotransferase [ALT] >2× ULN, or total bilirubin >1.5× ULN or any hepatic impairment via Child-Pugh Scoring System. Participants with Gilbert’s syndrome, defined as isolated increase of total bilirubin ≤3× ULN and AST and ALT within the normal range, are not excluded
Moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2)
Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, uncontrolled hypertension, bradycardia, or any other clinically significant cardiovascular abnormality within the previous year that, in the opinion of the Investigator, would interfere with the participant's safety or ability to participate in the study
Any other clinically significant comorbidity or systemic dysfunction that, in the opinion of the Investigator, could interfere with the participant’s safety or ability to participate in the study

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	13 Jan 2025	2
Bulgaria	Recruiting	13 Jan 2025	10
France	Recruiting	13 Jan 2025	5
Germany	Recruiting	13 Jan 2025	10
Hungary	Recruiting	13 Jan 2025	5
Ireland	Recruiting	13 Jan 2025	5
Italy	Recruiting	13 Jan 2025	15
Poland	Recruiting	13 Jan 2025	10
Romania	Not Recruiting	13 Jan 2025	5
Slovakia	Recruiting	13 Jan 2025	5