The most frequently reported adverse reactions (>15%) were epistaxis, headache and gingivalbleeding. Seven patients (7%) in the CABLIVI group experienced an adverse reaction leading to

study drug discontinuation. None of the adverse reactions leading to discontinuation wereobserved in more than 1% of patients.

Among 106 patients treated with CABLIVI during the TITAN and HERCULES studies, serious

bleeding adverse reactions reported in ≥2% patients included epistaxis (4%) and subarachnoid

hemorrhage (2%).

Adverse reactions that occurred in ≥2% of patients treated with CABLIVI and more frequentlythan in those treated with placebo across the pooled data from the two trials are summarized in

Table 1. Urticaria was seen during plasma exchange.

Table 1: Adverse Reactions in ≥2% of Patients Treated with CABLIVI and More Frequentthan Placebo during the Blinded Periods of aTTP Studies (HERCULES and TITAN)

Adverse Reaction by Body System

CABLIVI

(N=106)

n (%)

Placebo

(N=110)

n (%)

Gastrointestinal disorders

Gingival bleeding 17 (16) 3 (3)

Rectal hemorrhage 4 (4) 0 (0)

Abdominal wall hematoma 3 (3) 1 (1) 

Adverse Reaction by Body System

CABLIVI

(N=106)

n (%)

Placebo

(N=110)

n (%)

General disorders and administration site conditions

Fatigue 16 (15) 10 (9)

Pyrexia 14 (13) 12 (11)

Injection site hemorrhage 6 (6) 1 (1)

Catheter site hemorrhage 6 (6) 5 (5)

Injection site pruritus 3 (3) 0 (0)

Musculoskeletal and connective tissue disorders

Back pain 7 (7) 4 (4)

Myalgia 6 (6) 2 (2)

Nervous system disorders

Headache 22 (21) 15 (14)

Paresthesia 13 (12) 11 (10)

Renal and urinary disorders

Urinary tract infection 6 (6) 4 (4)

Hematuria 4 (4) 3 (3)

Reproductive system and breast disorders

Vaginal hemorrhage 5 (5) 2 (2)

Menorrhagia 4 (4) 1 (1)

Respiratory, thoracic and mediastinal disorders

Epistaxis 31 (29) 6 (6)

Dyspnea 10 (9) 5 (5)

Skin and subcutaneous tissue disorders

Urticaria 15 (14) 7 (6)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibodyformation is highly dependent on the sensitivity and specificity of the assay. Additionally, the

observed incidence of antibody (including neutralizing antibody) positivity in an assay may beinfluenced by several factors including assay methodology, sample handling, timing of sample

collection, concomitant medications, and underlying disease. For these reasons, comparison ofthe incidence of antibodies to caplacizumab-yhdp in the studies described below, with the

incidence of antibodies in other studies, or to other products, may be misleading.

The preva lence of pre-existing antibodies binding to caplacizumab-yhdp observed during clinicalstudies and during eva luation of commercially available human samples varied between 4% and

63%. In aTTP patients, pre-existing antibodies can be produced by the patient or can originatefrom donor plasma during plasma exchange. No clinically apparent impact of these pre-existing