A Study of Lanadelumab (SHP643) in Chinese Participants With Hereditary Angioedema (HAE)

TEAE is defined as an adverse event (AE) with onset at the time of or following initial dosing with study drug (lanadelumab), or medical conditions present prior to the start of study drug but increasing in severity or relationship at the time of or following the start of treatment, up to the last follow-up visit. An SAE is any untoward clinical manifestation of signs, symptoms or outcomes whether considered related to investigational product or not and at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, congenital abnormality/birth defect, an important medical event. Hypersensitivity reactions and events of disordered coagulation were considered as AESIs. Adverse events were classified as HAE attack and non-HAE attack reported AEs and are categorized accordingly in this outcome measure. A participant could be counted in more than one category.

Laboratory parameters included clinical chemistry, hematology, coagulation, urinalysis, and serology. Clinically meaningful laboratory parameters assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in laboratory parameters (including clinical chemistry, hematology, coagulation, urinalysis, and serology) were reported.

Vital signs included measurement of blood pressure, heart rate, body temperature, and respiratory rate. Clinically meaningful vital signs assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in vital signs were reported.

ECG included heart rate, PR interval, QRS duration, QT interval, corrected QT interval (QTc) interval, QT corrected for heart rate by Fridericia's cube root formula (QTcF) interval, and QT corrected for heart rate by Bazett formula (QTcB) interval. Clinically meaningful ECG assessment was based on investigator interpretation. Number of participants with clinically meaningful changes in ECG were reported.

Physical examination findings by body system were classified as height and weight, general appearance, ears, nose and throat, head and neck, ophthalmological, respiratory, cardiovascular, abdomen, neurological, extremities, dermatological, and lymphatic. Number of participants with clinically significant changes in physical examination findings per investigator interpretation were reported. Only categories with at least one participant with event are reported.

pKal activity was measured by cleaved high molecular weight kininogen (cHMWK) level (i.e., plasma concentrations of cHMWK).

An HAE attack was confirmed by following symptoms or signs consistent with an attack in at least one of the following locations: 1) Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region; 2) Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea; 3) Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx. Treatment period attack rate per month is calculated as the number of investigator-confirmed HAE attacks occurring during that treatment period divided by number of days the participant contributed to that treatment period multiplied by 28 days.

An HAE attack was confirmed by following symptoms/signs consistent with an attack in atleast one of the following locations:1)Peripheral angioedema:cutaneous swelling involving an extremity,the face,neck,torso,and/or genitourinary region;2)Abdominal angioedema:abdominal pain,with/without abdominal distention,nausea,vomiting,or diarrhea;3)Laryngeal angioedema:stridor,dyspnea, difficulty speaking,difficulty swallowing,throat tightening,or swelling of the tongue,palate,uvula,or larynx.Acute HAE attacks were managed per the investigator's usual care, including use of individualized acute therapy/rescue medications.Acute therapy/rescue medications included Firazyr, fresh frozen plasma (FFP), or other local standard of care.Treatment period attack rate per month is calculated as the number of investigator-confirmed HAE attacks requiring acute treatment occurring during that treatment period divided by number of days the participant contributed to that treatment period multiplied by 28 days.

The severity of the investigator-confirmed HAE attacks was defined per the HAE attack assessment and reporting procedures (HAARP) definitions: severe (marked limitation in activity, assistance required), moderate (mild to moderate limitation in activity, some assistance needed). Treatment period attack rate per month is calculated as the number of moderate or severe investigator-confirmed HAE attacks occurring during that treatment period divided by number of days the participant contributed to that treatment period multiplied by 28 days.

Number of participants with maximum HAE attack severity during the efficacy evaluation period was assessed. HAE attack severity was calculated per participant based on the severity categories as follows: No attack, Mild, Moderate, and Severe.

Time to the first investigator-confirmed HAE attack (days) was calculated from the date and time of the first dose of study drug for that efficacy evaluation period to the date and time of the first investigator-confirmed HAE attack after the first dose for the efficacy evaluation period. The time to the first HAE attack was summarized using Kaplan-Meier (KM) estimates.

An HAE attack was confirmed by following symptoms or signs consistent with an attack in at least one of the following locations: 1) Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region; 2) Abdominal angioedema: abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea; 3) Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx. A participant was considered as attack free if the participant had no investigator-confirmed HAE attacks during the efficacy evaluation period. Number of participants who achieved attack-free status for the efficacy evaluation periods were assessed.

A run-in period of 4 weeks was included to determine the participant's baseline attack rate. This period may be extended up to 8 weeks. The normalized number of investigator-confirmed HAE attacks during efficacy evaluation period was expressed as a monthly (28 days) HAE attack rate relative to the run-in period NNA. Number of participants who achieved at least 50 percent (%), 70%, 90% and 100% reduction in the investigator-confirmed NNA per 4 weeks relative to the run-in period normalized NNA for the efficacy evaluation periods was assessed.

The normalized number of investigator-confirmed HAE attacks during the efficacy evaluation period was expressed as a monthly (28 days) HAE attack rate. Attack rate was calculated for each participant as the number of attacks occurring during the specified period divided by the number of days the participant contributed to the specified period multiplied by 28 days. Number of participants who achieved NNA <1.0 per 4 weeks for the efficacy evaluation period were assessed.

Number of participants with neutralizing or non-neutralizing ADA in plasma were assessed.

The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the lanadelumab plasma concentrations was assessed.

The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the cHMWK levels was assessed.

The number of investigator-confirmed HAE attacks during the efficacy evaluation period was expressed as a normalized monthly (4 weeks, i.e., 28 days). Treatment period attack rate per month is calculated as the number of investigator-confirmed HAE attacks occurring during that treatment period divided by number of days the participant contributed to that treatment period multiplied by 28 days. The effect of presence or absence of neutralizing or non-neutralizing ADA in plasma on the investigator-confirmed HAE attacks during the efficacy evaluation period was assessed.