Safety profile of concizumab: A systematic review and meta-analysis of randomised controlled trials

Masood, Laiba; Akram, Muhammad Bilal; Ashfaq, Noor; Chaudhry, Arib Shafiq; Wasay, Abdul; Javed, Ramsha; Khan, Muhammad Aoun Abbas; Masood, Muhammad Abdullah; Qureshi, Muhammad Abdul Muqtadir; Zahoor, Hafiz Shahbaz; Arshad, Adina; Waseem, Abdul Ahad

doi:10.2478/jhp-2025-0019

Figures & Tables

PRISMA flow diagram for the systematic reviewThe PRISMA flow diagram illustrates the study selection process for this systematic review and meta-analysis, showing the identification, screening, eligibility, and inclusion phases. Numbers at each step represent studies identified through database and other sources, duplicates removed, studies screened, full-text articles assessed for eligibility, and studies included in the final analysis, providing an overview of how studies were selected and reasons for exclusion.

Risk of bias summary for included studies using Cocharane Risk of Bias 2.0 tool

Funnel plot for outcome ‘adverse events’The funnel plot shows evaluation of potential publication bias for the outcome ‘adverse events’. The X-axis represents the risk ratios (RR) between concizumab and placebo; the Y-axis represents the standard error of log risk ratios (SE(log[RR])). Each open circle corresponds with an individual study. The vertical line indicates the null hypothesis (RR=1). The triangle represents the expected 95% confidence interval in the absence of publication bias. Symmetry around the vertical line suggests a low likelihood of publication bias, while asymmetry may indicate potential reporting or small-study effects.

Forest plots highlighting aspects of the included studiesFigure 4a. Mean annualised bleeding rates (ABR) across the included studies

Proportion of patients experiencing one or more bleeding episodes

Frequency of bleeding events involving joints

Incidence of all reported adverse events

Characteristics of studies included in the systematic review and meta-analysis

STUDY	STUDY DESIGN	STUDY LOCATION	TREATMENT DURATION	INCLUSION CRITERIA	MEAN AGE	INTERVENTION GROUP	CONTROL GROUP	OUTCOMES MEASURED
Chowdary 2015 [12]	Prospective, multi-centre, open-label, randomised phase 3a trial	69 investigational sites in 31 countries	24 weeks for group 1 (no prophylaxis) 32 weeks for group 2 (concizumab prophylaxis) 38 weeks on the previous prophylaxis regimen (in the intra-patient analysis set) 24 weeks on the concizumab maintenance dose (in the intra-patient analysis set)	Male Aged 12 years or older Congenital severe haemophilia A or moderate/severe haemophilia B without inhibitors Documented treatment with clotting factor concentrate in the 24 weeks prior to screening Participation in the prior phase 2 concizumab trial (explorer5) allowed	25.3 ± 3.1	Group 2, who received concizumab prophylaxis	Group 1, who received no prophylaxis and continued on-demand clotting factor treatment	Treated spontaneous and traumatic bleeding episodes, assessed at confirmatory analysis cutoff (N) Treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis vs. previous prophylaxis, in intra-patient comparison (N) Secondary outcomes: Treated spontaneous bleeding episodes (N) Treated spontaneous and traumatic joint bleeds (N) Treated spontaneous and traumatic target joint bleeds (N) Safety measures (e.g., thromboembolic events, hypersensitivity reactions, anti-drug antibodies)
Shapiro 2019 [9]	explorer4 (inhibitor trial): multi-centre, open-label, randomised controlled trial explorer5 (non-inhibitor trial): multi-centre, single-arm, open label phase 2 trial	explorer4 (inhibitor trial): multiple sites across 12 countries explorer5 (non-inhibitor trial): multiple sites across 11 countries	At least 24 weeks for those receiving concizumab (in both trials)	Male patients Aged 12 years or older Congenital severe haemophilia A or moderate/severe haemophilia B without inhibitors Documented treatment with clotting factor concentrate in the 24 weeks prior to screening Participation in the prior phase 2 concizumab trial (explorer5) allowed	N/A	Participants who received concizumab prophylaxis (both trials)	explorer4 (inhibitor trial): participants with haemophilia A or B with inhibitors, who received on-demand treatment with eptacog alfa activated (rFVIIa) instead of concizumab prophylaxis	Bleeding episodes during at least 24 weeks of treatment with subcutaneous concizumab (N) Secondary outcomes: assessment of concizumab safety and immunogenicity safety of administering rFVIIa when exposed to concizumab supportive PK and PD endpoints
Chowdary 2024 [11]	First human dose, phase 1, multi-centre, randomised, double-blind, placebo-controlled, single-dose, dose-escalation trial	Multiple sites in 9 countries: Austria, Denmark, Germany, Malaysia, South Africa, Spain, Switzerland, Thailand, UK	43 days	Age 18–65 years Body weight 50–100 kg Body mass index 18–30 kg/m²	30–36 years	Participants who received concizumab	Participants who received placebo, with 1:3 ratio of placebo to concizumab within each dose cohort	Safety, including adverse events, local tolerability, and various clinical laboratory assessments Pharmacokinetics of concizumab, including plasma concentrations Pharmacodynamics of concizumab, including free TFPI levels, TFPI functionality, and markers of procoagulant effect (D-dimer and prothrombin F1+2)
Matsushita 2023 [10]	Prospective, multi-centre, open-label, phase 3a trial, comparing concizumab prophylaxis with no prophylaxis	N/A	At least 24 weeks for the no prophylaxis group (Group 1) At least 32 weeks for the concizumab prophylaxis group (Group 2), including a 5–8 week dose-adjustment period Extension period of 128–136 weeks after the main part of the trial (Groups 3 and 4)	Congenital haemophilia A or B with inhibitors (of any severity) Aged 12 years or older when providing written informed consent Body weight ≥25 kg at screening Previously treated with bypassing agents in the 24 weeks before screening (if not transferring from explorer4)	N/A	Group 2, who received concizumab prophylaxis Groups 3 and 4 also received concizumab prophylaxis	Group 1, who received no prophylaxis (on-demand treatment with bypassing agents).	Treated spontaneous and traumatic bleeding episodes (N), comparing the concizumab prophylaxis group vs. no prophylaxis group Key secondary outcomes: changes in bodily pain and physical functioning scores on SF-36v2 Additional secondary and exploratory endpoints, including safety outcomes

Product comparison data for three patients who received a SHL FIX product for a prior surgery

CERTAINTY ASSESSMENT							PATIENTS (N;%)		EFFECT		CERTAINTY	IMPORTANCE
STUDIES (N)	STUDY DESIGN	RISK OF BIAS	INCONSISTENCY	INDIRECTNESS	IMPRECISION	OTHER CONSIDERATIONS	CONCIZUMAB	STANDARD	RELATIVE (95% CI)	ABSOLUTE (95% CI)	CERTAINTY	IMPORTANCE
Bleeding joint
2	RCT	NS	NS	NS	NS	publication bias strongly suspecteda	15/30 (50.0%)	10/13 (76.9%)	RR 0.66 (0.45 to 0.96)	262 fewer per 1,000 (from 423 fewer to 31 fewer)	Moderate^a
Adverse events
4	RCT	S	NS	NS	NS	none	74/99 (74.7%)	21/38 (55.3%)	RR 1.17 (0.89 to 1.54)	94 more per 1,000 (from 61 fewer to 298 more)	Moderate^b
Upper respiratory tract infection
2	RCT	S	NS	NS	NS	publication bias strongly suspecteda	4/69 (5.8%)	2/28 (7.1%)	RR 0.75 (0.15 to 3.85)	18 fewer per 1,000 (from 61 fewer to 204 more)	Low^a
Serious adverse events
3	RCT	S	NS	NS	NS	none	7/81 (8.6%)	6/32 (18.8%)	RR 0.46 (0.06 to 3.53)	101 fewer per 1,000 (from 176 fewer to 474 more)	Moderate^b

Safety profile of concizumab: A systematic review and meta-analysis of randomised controlled trials

Figures & Tables

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Figure 4e.

Characteristics of studies included in the systematic review and meta-analysis

Product comparison data for three patients who received a SHL FIX product for a prior surgery

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