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A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary Angioedema Type I or II

A Randomized, Double-Blind, Placebo-Controlled, Phase 3, Three-way Crossover Trial to Evaluate the Efficacy and Safety of Two Dose Levels of KVD900, an Oral Plasma Kallikrein Inhibitor, for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients with Hereditary Angioedema Type I or II

136

The median age of the patients in the Safety Set was 39.5 years and ranged from 13 to 74 years. This included 13 adolescents (ages 13-17 years) and 97 adult (ages 18-74 years) patients. More females were enrolled than males (60% versus 40%). The majority of patients enrolled were White (92 [83.6%] patients) by race and non-Hispanic or Latino (95 [86.4%] patients) by ethnicity. Mean weight was 77.86 kg (range: 41 to 140.3 kgs) and mean BMI was 27.44 kg/m2.

A total of 136 patients were randomly assigned to receive the IMP, of which a total of 110 patients treated at least 1 attack with IMP and therefore were included in FAS and Safety Set, and 86 patients were included in PPS. Of the 110 patients included in the FAS and Safety Set, this included 13 adolescent patients that were evaluable for the primary analysis. Sixty-eight (61.8%) of 110 patients completed the trial and 42 (38.2%) of 110 patients were discontinued from the trial. The primary reason for trial discontinuation was that the specified number of attacks for trial completion was reached and ongoing patients were terminated. This was recorded as trial termination by sponsor (32 [29.1%] patients) in the EDC. All 110 patients treated their first attack with IMP, 86 patients treated their second attack with IMP, and 68 patients treated their third attack with IMP for a total of 264 treated attacks.

Overall, 20 TEAEs were reported for 17 (19.8%) patients in the 300 mg KVD900 group, 18 TEAEs were reported for 14 (15.1%) patients in the 600 mg KVD900 group, and 24 TEAEs were reported for 17 (20.5%) patients in the placebo group. Two treatment-related TEAEs were reported for 2 (2.3%) patients in the 300 mg KVD900 group, and 4 treatment-related TEAEs in 3 (3.2%) patients in the 600 mg KVD900 group, and 5 treatment-related TEAEs in 4 (4.8%) patients in the placebo group. The most common TEAEs (i.e., TEAEs that occurred in more than 2% of patients [3 or more, regardless of treatment group]) reported by preferred term were headache (4 [3.4%] patients in the 600 mg KVD900 group, and 1 [1.2%] patients each in the 300 mg KVD900 and placebo groups), and vomiting (1 [1.1%] patient in the 600 mg KVD900 group and 1 [1.2%] patient each in the 300 mg KVD900 and placebo groups). All other TEAEs occurrences were reported in 1 patient in any given treatment group. The majority of TEAEs were mild (24 events) or moderate (37 events) in severity; 1 severe event was reported (intervertebral disc protrusion for 1 patient in the 300 mg KVD900 group; this event was also an SAE considered unrelated to treatment). The most common treatment-related TEAEs (i.e., TEAEs that occurred in more than 1% of patients [2 or more regardless of treatment group]) were nausea (1 treatment-related TEAE each was reported for 1 [1.1%] patient in the 600 mg KVD900 group and 1 [1.2%] patient in the placebo group), dyspepsia (1 treatment-related TEAE each was reported for 1 [1.2%] patient in the 300 mg KVD900 group and 1 [1.1%] patient in the 600 mg KVD900 group), and headache (1 treatment-related TEAE each was reported for 1 [1.1%] patient in the 600 mg KVD900 group and 1 [1.2%] patient in the placebo group). None of the TEAEs resulted in IMP discontinuation or trial discontinuation, or death. Three SAEs were reported in 3 (2.7%) patients: intervertebral disc protrusion in 1 patient in the 300 mg KVD900 group, and anisocoria and hereditary angioedema (reported term: HAE exacerbation) in 1 patient each in the 600 mg KVD900 group. All 3 SAEs led to hospitalization. The SAE in the 300 mg KVD900 group was also reported as a Grade 3 (severe) AE. None of the SAEs were considered to be related to the IMP. There were no clinically significant trends observed in mean values after baseline through the end of the trial in the laboratory safety parameters, vital signs, or ECG parameters. Physical examination assessments were reported to be normal, not clinically significant in majority of the patients and abnormal, not clinically significant at final/ET visit in a few patients, except for 3 patients whose assessments [body systems: neurological, extremities, general appearance, and dermatological] were reported to be abnormal, clinically significant.

Primary endpoint There was a statistically significant improvement in the time to the beginning of symptom relief between 300 mg KVD900 (adjusted p<0.0001) versus placebo group and between 600 mg KVD900 (adjusted p=0.0013) versus placebo group. The median (95% CI) time to the beginning of symptom relief was 1.61 hours (95% CI: 1.28, 2.27) for 300 mg KVD900 group, 1.79 hours (95% CI: 1.33, 2.27) for 600 mg KVD900 group, and 6.72 hours (95% CI: 2.33, not evaluable) for placebo group. More attacks reached beginning of symptom relief within 12 hours of first IMP administration in the KVD900 treatment groups than placebo group (300 mg KVD900 group: 66 [75.9%] attacks and 600 mg KVD900 group: 71 [76.3%] attacks versus placebo group: 41 [48.8%] attacks). Key Secondary endpoints There was a statistically significant improvement in the time to reduction in severity between 300 mg KVD900 (adjusted p=0.0036) versus placebo group and 600 mg KVD900 (adjusted p=0.0032) versus placebo group. The median (95% CI) time to reduction in severity in PGI-S score was 9.27 hours (95% CI: 4.08, not evaluable) for 300 mg KVD900 group, 7.75 hours (95% CI: 3.27, not evaluable) for 600 mg KVD900 group, and not evaluable i.e., >12 hours for placebo group. More attacks achieved the time to reduction in severity in the 300 mg KVD900 (44 [50.6%] attacks) and 600 mg KVD900 groups (49 [52.7%] attacks) than placebo group (26 [31.0%] attacks). There was a statistically significant improvement in the complete HAE attack resolution between the 300 mg KVD900 group (adjusted p=0.0022) versus placebo group and 600 mg KVD900 group (adjusted p<0.0001) versus placebo group. The median (95% CI) time to complete HAE attack resolution was not evaluable (95% CI: 16.60, not evaluable) for 300 mg KVD900 group, 24.00 hours (95% CI: 10.6, not evaluable) for 600 mg KVD900 group, and not evaluable i.e., >24 hours for placebo group. More number of attacks reached complete HAE attack resolution within 24 hours of the first IMP administration in the 300 mg KVD900 (37 [42.5%] attacks) and 600 mg KVD900 groups (46 [49.5%] attacks) than placebo group (23 [27.4%] attacks). The treatment effects for 300 mg KVD900 and 600 mg KVD900 groups were similar to the full FAS across all subgroups analyzed (including but not limited to baseline attack severity, initial attack location, use of long-term prophylactic treatment, and age of patient). For secondary and exploratory endpoints, time taken to achieve efficacy was consistent and supportive of the primary and key secondary endpoints.

The primary and key secondary endpoints in this trial were all met. A statistically significant and clinically meaningful improvement was observed in the results of the primary and key secondary endpoints (time to the beginning of symptom relief, time to reduction in severity, and complete HAE attack resolution) for attacks treated with 300 mg KVD900 or 600 mg KVD900 compared with placebo. KVD900 was safe and well tolerated at both dose levels in adult and adolescent patients 12 years and older.

June. 11, 2024

May. 31, 2024

https://www.nejm.org/doi/full/10.1056/NEJMoa2314192?utm_source=conf&utm_medium=qr&utm_campaign=EAACI2024

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2051220178

Smith Michael

KalVista Pharmaceuticals, Ltd.

Porton Science Park, Bybrook Road, Porton Down, Salisbury, SP4 0BF, United Kingdom

clinicalstudies@kalvista.com

Kanmuri Kazuhiro

Ascent Development Services, Inc.

Shibuya SOLASTA 3F, 1-21-1, Dogen-zaka, Shibuya-ku, Tokyo, Japan 150-0043

+81-3-4590-9005

kazuhiro.kanmuri@ascent-dev.com

Complete

Feb. 24, 2023

Interventional

randomized controlled trial

double blind

placebo control

crossover assignment

treatment purpose

1) Male or female patients 12 years of age and older.
2) Confirmed diagnosis of HAE Type I or II at any time in the medical history:
a) Documented clinical history consistent with HAE (sc or mucosal, nonpruritic swelling episodes without accompanying urticaria) AND EITHER
i) Diagnostic testing results obtained prior to randomization that confirm HAE Type I or II: C1-INH functional level <40% of the normal level. Patients with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. Testing may be obtained from central or local laboratories or obtained from documented historical testing results. Patients may be retested at any time prior to randomization if results are incongruent with clinical history or believed by the Investigator to be confounded by recent prophylactic or therapeutic C1-INH use, OR
ii) Documented genetic results that confirm known mutations for HAE Type I or II.
3) Patient has access to and ability to use conventional on-demand treatment for HAE attacks.
4) 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 Screening Visit and be willing to remain on a stable dose and regimen for the duration of the trial.
5) Patients last dose of attenuated androgens was at least 28 days prior to randomization.
6) Patient:
a) has had at least 2 documented HAE attacks within 3 months prior to screening or randomization; or
b) is a completer of the KVD824-201 trial within 3 months prior to randomization and meets all other entry criteria to enroll in KVD900-301.
7) Patients must meet one of the following contraception requirements as follows:
a) Female patients who are fertile and heterosexually active must agree to use contraception from the Screening Visit until the Final or Early Termination (ET) Visit. Acceptable methods of contraception include one or more of the following:
i) Intrauterine device.
ii) Intrauterine hormone-releasing system.
iii) Bilateral tubal occlusion.
iv) Vasectomized partner (provided that the partner is the sole heterosexual partner of the female patient of childbearing potential and that the vasectomized partner has received medical assessment of surgical success).
v) Male condom.
b) Patients who are not fertile or not heterosexually active, as defined below, do not require contraception. If the patients status changes during the course of the trial, they will be required to meet the requirements specified in Inclusion Criterion 7a).
i) Female patients who refrain from heterosexual intercourse during the trial if the reliability of the heterosexual abstinence has been evaluated in relation to the duration of the clinical trial and is the preferred and usual lifestyle of the patient.
ii) Female patients who are surgically sterile (e.g. status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months.
iii) Female patients who are premenarche and remain premenarcheal until the end of the trial.
c) Male patients (including female partners) do not require contraception.
8) Patients must be able to swallow trial tablets whole.
9) Patients, as assessed by the Investigator, must be able to appropriately receive and store IMP, and be able to read, understand, and complete the electronic diary (eDiary).
10) Investigator believes that the patient is willing and able to adhere to all protocol requirements.
11) Patient provides signed informed consent or assent (when applicable). A parent or legally authorized representative must also provide signed informed consent when required.

1) Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1-inhibitordeficiency, HAE with normal C1-INH (previously known as HAE Type III), idiopathic angioedema, or angioedema associated with urticaria.
2) A clinically significant history of poor response to bradykinin receptor 2 (BR2) blocker, C1-INHtherapy, or plasma kallikrein inhibitor therapy for the management of HAE, in the opinion of the Investigator.
3) Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening Visit or within 7 days prior to randomization.
4) 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.
5) Patients who require sustained use of strong cytochrome P450 3A4 (CYP3A4) inhibitors orinducers.
Note: These medications include but are not limited to the following:
Inhibitors: boceprevir, clarithromycin, cobicistat, dasabuvir, denoprevir, elvitegravir, idelalisib,indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir ombitasvir, paritaprevir,posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, andvoriconazole.
Inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. Johns Wort.
6) Inadequate organ function, including but not limited to:
a) Alanine aminotransferase (ALT) >2x upper limit of normal (ULN)
b) Aspartate aminotransferase (AST) >2x ULN
c) Bilirubin direct >1.25x ULN
d) International normalized ratio (INR) >1.2
e) Clinically significant hepatic impairment defined as a Child-Pugh B or C.
7) 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.
8) History of substance abuse or dependence that would interfere with the completion of the trial, as determined by the Investigator.
9) Known hypersensitivity to KVD900 or placebo or to any of the excipients.
10) Prior participation in trial KVD900-201.
11) Participation in any gene therapy treatment or trial for HAE.
12) Participation in any interventional investigational clinical trial (with the exception of KVD824-201), including an investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of investigational drug prior to screening.
13) Any pregnant or breastfeeding patient.

Both

Hereditary Angioedema

- 300 mg KVD900 (1 x 300 mg tablet plus 1 matching placebo tablet)
- 600 mg KVD900 (2 x 300 mg tablets)
- 2 matching placebo tablets

To demonstrate the clinical efficacy of KVD900 compared with placebo for the on-demand treatment of HAE attacks.

To investigate the safety and tolerability of KVD900.

+81-72-683-1221

Feb. 01, 2023

United States/Canada/Australia/New Zealand/Bulgaria/France/Germany/Greece/Hungary/Israel/Italy/Netherlands/North Macedonia/Poland/Puerto Rico/Romania/Spain/United Kingdom