Table 2

Overall Treatment-Emergent Adverse Event Incidence and Selected Adverse Events of Interest in Patients With at Least 2 Consecutive Low-Density Lipoprotein Cholesterol Values <25 or <15 mg/dl (Pooled Safety Population)

Pooled Control (n = 1,894)Alirocumab
Overall Alirocumab (n = 3,340)LDL-C ≥25 mg/dl (n = 2,501)LDL-C <25 mg/dl (n = 839)LDL-C <15 mg/dl (n = 314)
Patients with any TEAEs77.1 (1,461)77.8 (2,599)76.6 (1,917)72.7 (610)71.7 (225)
Patients with any treatment-emergent SAEs15.4 (291)16.0 (534)15.4 (386)15.4 (129)13.1 (41)
Patients with any TEAEs leading to death1.2 (22)0.7 (22)0.7 (18)0.5 (4)0.3 (1)
Patients with any TEAEs leading to permanent treatment discontinuation7.2 (137)6.9 (232)7.9 (197)4.2 (35)5.4 (17)
AEs of interest
 Neurologic events (CMQ)3.7 (71) [3.1]4.0 (134) [3.1]4.2 (105) [3.4]2.4 (20) [1.9]2.9 (9) [2.3]
 Peripheral neuropathy (SMQ)3.3 (63) [2.7]3.2 (106) [2.4]3.4 (84) [2.7]1.7 (14) [1.3]2.2 (7) [1.8]
 Neurocognitive disorders (CMQ)§0.9 (17) [0.7]1.0 (32) [0.7]1.0 (26) [0.8]0.6 (5) [0.5]0.3 (1) [0.3]
 Amnesia (PT)0.3 (5) [0.2]0.2 (6) [0.1]0.2 (5) [0.2]0.1 (1) [0.1]0
 Aphasia (PT)0<0.1 (2) [<0.1]<0.1 (1) [<0.1]0.1 (1) [0.1]0
 Confusional state (PT)0.2 (3) [0.1]0.2 (8) [0.2]0.3 (7) [0.2]0.1 (1) [0.1]0
 Dementia (PT)0.1 (2) [0.1]<0.1 (1) [<0.1]00.1 (1) [0.1]0
 Frontotemporal dementia (PT)0<0.1 (1) [<0.1]00.1 (1) [0.1]0.3 (1) [0.3]
 Musculoskeletal (CMQ)17.3 (328) [15.6]16.7 (559) [14.1]16.5 (413) [14.6]13.8 (116) [12.1]14.3 (45) [12.9]
 Myalgia (PT)5.0 (95) [4.1]5.2 (174) [4.0]5.4 (136) [4.4]3.1 (26) [2.5]3.8 (12) [3.2]
 Ophthalmological TEAEs (SMQ)1.3 (25) [1.1]1.9 (64) [1.4]1.9 (47) [1.5]1.5 (13) [1.2]1.6 (5) [1.3]
 Hepatic disorders (SMQ)2.4 (45) [1.9]2.8 (95) [2.2]3.0 (75) [2.4]2.0 (17) [1.6]2.2 (7) [1.8]
 Hepatic steatosis (PT)0.6 (11) [0.5]0.2 (7) [0.2]0.2 (6) [0.2]0.1 (1) [0.1]0.3 (1) [0.3]
 Cataract (CMQ)1.1 (21) [0.9]1.3 (43) [1.0]0.8 (19) [0.6]2.5 (21) [2.0]2.9 (9) [2.3]
 Cataract (PT)1.0 (19) [0.8]1.0 (35) [0.8]0.7 (17) [0.5]1.9 (16) [1.5]2.5 (8) [2.1]
 Lenticular opacities (PT)0<0.1 (3) [0.1]00.4 (3) [0.3]0.3 (1) [0.3]
 Cataract nuclear (PT)<0.1 (1) [<0.1]0.1 (5) [0.1]<0.1 (2) [0.1]0.2 (2) [0.2]0
TEAEs related to diabetes mellitus or diabetic complications (CMQ)#, according to baseline diabetes status
 Patients with diabetes at baseline, n559998688310129
 Diabetes mellitus or diabetic complications (CMQ)10.4 (58) [8.7]10.6 (106) [8.5]9.0 (62) [7.7]11.9 (37) [10.1]11.6 (15) [9.9]
 Diabetes mellitus (PT)2.5 (14) [2.0]3.6 (36) [2.8]3.3 (23) [2.7]4.2 (13) [3.3]6.2 (8) [5.1]
 Type 2 diabetes mellitus (PT)1.6 (9) [1.3]1.5 (15) [1.1]1.0 (7) [0.8]2.3 (7) [1.8]0
 Diabetes mellitus inadequate control (PT)2.0 (11) [1.6]1.5 (15) [1.1]1.0 (7) [0.8]2.6 (8) [2.0]1.6 (2) [1.2]
 Patients without diabetes at baseline, n1,3352,3421,813529185
 Diabetes mellitus or diabetic complications (CMQ)2.5 (33) [2.0]2.0 (46) [1.5]1.8 (32) [1.4]2.3 (12) [1.8]2.2 (4) [1.8]
 Type 2 diabetes mellitus (PT)1.2 (16) [1.0]1.3 (31) [1.0]1.2 (21) [0.9]1.7 (9) [1.4]2.2 (4) [1.8]
 Diabetes mellitus (PT)0.5 (7) [0.4]0.4 (9) [0.3]0.4 (7) [0.3]0.4 (2) [0.3]0

Values are % (n) or % (n) [rate per 100 patient-years]. TEAEs were encoded as PTs using the MedDRA (version 18.0) according to the verbatim account entered by the investigator. TEAEs were further categorized according to standard MedDRA definitions (HLT, HLGT, and SMQ) or using custom groupings (CMQs) as defined by the study sponsors. Rate per 100 patient-years was calculated as number of patients with an events divided by total patient-years. For patients with events, number of patient-years was calculated up to the date of the first event; for patients without events, it was calculated up to the end of the TEAE period. For patients with LDL-C <25 mg/dl, the number of patient-years was calculated from the time of the first such value.

AE = adverse event; CMQ = Company MedDRA Query; HLGT = high-level group term; HLT = high-level term; LDL-C = low-density lipoprotein cholesterol; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; SMQ = Standardized MedDRA Query; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

  • p = 0.0018 for comparison of LDL-C ≥25 versus <25 mg/dl groups in pool of phase 3 studies. All other comparisons of AEs of interest were not significant (Table 3).

  • Only TEAEs that occurred, worsened, or became serious on the day or after the first of 2 consecutive LDL-C values <25 or <15 mg/dl were considered.

  • Selection of PTs based on SMQs: “demyelination” (broad + narrow), “peripheral neuropathy” (broad + narrow) and “Guillain-Barre syndrome” (broad + narrow) excluding the following PTs (“acute respiratory distress syndrome,” “asthenia,” “respiratory arrest,” and “respiratory failure”).

  • § Selection of PTs is based on the HLGTs “deliria (including confusion),” “cognitive and attention disorders and disturbances,” “dementia and amnestic conditions,” “disturbances in thinking and perception,” and “mental impairment disorders.”

  • Selection of PTs is based on the SMQs “optic nerve disorders” (broad + narrow), “retinal disorders” (narrow), and “corneal disorders” (narrow).

  • Selection of PTs is based on the HLT “cataract conditions.”

  • # Selection of PTs is based on HLGT “diabetic complications,” HLT “diabetes mellitus,” and HLT “carbohydrate tolerance analyses (including diabetes),” excluding PT “blood glucose decreased” and PT “hyperglycemia.”