Clinical trials of fibryga® in CFD

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Clinical trials of fibryga® in CFD

Control when you need it most: clinical studies of fibryga® in CFD

A doctor in a white coat explains fibryga to a woman and a child, sitting at a desk in a bright, clinical setting.

Summary of fibryga® clinical trials in CFD

The fibryga® clinical trial programme in CFD comprises the FORMA-01, FORMA-02 and FORMA-04 studies.

Design

 Treatment

 Sample size Study population
 Primary objective



 



 Primary endpoint results 


 




 Other efficacy measures 
 

 

 Safety FORMA-01 ¹ , Prospective, randomised, controlled, crossover, across two 45-day study periods phase II trial (70 mg/kg) 
 (fibrinogen concentrate)
 Single IV infusion of Fibryga®or active control (6 adolescents; 16 adults) 22 patients Patients with aged 12 to 53 years congenital afibrinogenaemia as a surrogate marker for haemostatic efficacy

 To determine single-dose PK profiles and MCF 1-hour post-infusion, demonstrating its efficacy in restoring clot strength


 

 MCF Fibryga® demonstrated a significant increase in mean plasma MCF with single-dose administration of fibryga® AEs generally occurred as mostly mild, single events, with similar incidence and severity between arms No deaths, thromboses, viral seroconversions or serious treatment-related AEs occurred There were no safety concerns FORMA-02 , ² Prospective, open-label, uncontrolled, multicentre 
 phase III study to achieve recommended target fibrinogen plasma level Fibryga®, individually dosed (6 adolescents; 19 adults) 25 patients (afibrinogenaemia or hypofibrinogenaemia) aged 12 to 54 years Patients with CFD of acute bleeding episodes (spontaneous or after trauma) and to prevent bleeding during and after surgery To evaluate efficacy of Fibryga® for on-demand treatment of bleeding in patients with CFD in patients with CFD
 On-demand treatment of acute bleeding Prevent bleeding during and after surgery Fibryga® was efficacious for on-demand treatment® was efficacious for surgical prophylaxis Fibryga   (rating of excellent or good) was (90% CI: 0.92–0.99) (Investigator-assessed), and (90% CI: 0.95–1.0) (IDMEAC-assessed) (rated excellent or good) (90% CI: 0.82–1.00) (Investigator- and IDMEAC-assessed) On-demand treatment of acute bleeding Surgical prophylaxis Treatment success96.7%98.9%Intra-operative and post-operative treatment success rate for fibryga®was 100% There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralising antifibrinogen antibodies 
 Fibryga® demonstrated a favourable safety profile FORMA-04 ³ , Prospective, open-label, uncontrolled, multinational, multicentre 
 phase III trial for on‐demand treatment of acute bleeding episodes or surgical prophylaxis Individually dosed fibryga® 11 patients (0–12 years) with CFD
 Paediatric patients in paediatric patients with CFD
 To assess haemostatic efficacy of fibryga® for on-demand treatment of bleeding and surgical prophylaxis for all 10 bleeding episodes (IDMEAC-assessed) (Investigator- and IDMEAC-assessed) On-demand treatment of acute bleeding Prevent bleeding during and after surgery Haemostatic efficacy was 100% successfulHaemostatic efficacy was rated 100% 1-hour post-infusion, demonstrating its efficacy in restoring clot strength
 



 MCF Fibryga® demonstrated a significant increase in mean plasma MCF There were no deaths, no allergic/ hypersensitivity reactions, and no clinical evidence of neutralising antifibrinogen antibodies 
 Fibryga® demonstrated a favourable safety profile AE, adverse event; AUCnorm, area under the curve normalised to the dose administered; CFD, congenital fibrinogen deficiency; CI, confidence interval; IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee; IV, intravenous; MCF, maximum clot firmness; PK, pharmacokinetics.
Design

 Treatment

 Sample size Study population
 Primary objective



 



 Primary endpoint results 


 




 Other efficacy measures 
 

 

 Safety FORMA-01 ¹ , Prospective, randomised, controlled, crossover, across two 45-day study periods phase II trial (70 mg/kg) 
 (fibrinogen concentrate)
 Single IV infusion of Fibryga®or active control (6 adolescents; 16 adults) 22 patients Patients with aged 12 to 53 years congenital afibrinogenaemia as a surrogate marker for haemostatic efficacy

 To determine single-dose PK profiles and MCF 1-hour post-infusion, demonstrating its efficacy in restoring clot strength


 

 MCF Fibryga® demonstrated a significant increase in mean plasma MCF with single-dose administration of fibryga® AEs generally occurred as mostly mild, single events, with similar incidence and severity between arms No deaths, thromboses, viral seroconversions or serious treatment-related AEs occurred There were no safety concerns FORMA-02 , ² Prospective, open-label, uncontrolled, multicentre 
 phase III study to achieve recommended target fibrinogen plasma level Fibryga®, individually dosed (6 adolescents; 19 adults) 25 patients (afibrinogenaemia or hypofibrinogenaemia) aged 12 to 54 years Patients with CFD of acute bleeding episodes (spontaneous or after trauma) and to prevent bleeding during and after surgery To evaluate efficacy of Fibryga® for on-demand treatment of bleeding in patients with CFD in patients with CFD
 On-demand treatment of acute bleeding Prevent bleeding during and after surgery Fibryga® was efficacious for on-demand treatment® was efficacious for surgical prophylaxis Fibryga   (rating of excellent or good) was (90% CI: 0.92–0.99) (Investigator-assessed), and (90% CI: 0.95–1.0) (IDMEAC-assessed) (rated excellent or good) (90% CI: 0.82–1.00) (Investigator- and IDMEAC-assessed) On-demand treatment of acute bleeding Surgical prophylaxis Treatment success96.7%98.9%Intra-operative and post-operative treatment success rate for fibryga®was 100% There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralising antifibrinogen antibodies 
 Fibryga® demonstrated a favourable safety profile FORMA-04 ³ , Prospective, open-label, uncontrolled, multinational, multicentre 
 phase III trial for on‐demand treatment of acute bleeding episodes or surgical prophylaxis Individually dosed fibryga® 11 patients (0–12 years) with CFD
 Paediatric patients in paediatric patients with CFD
 To assess haemostatic efficacy of fibryga® for on-demand treatment of bleeding and surgical prophylaxis for all 10 bleeding episodes (IDMEAC-assessed) (Investigator- and IDMEAC-assessed) On-demand treatment of acute bleeding Prevent bleeding during and after surgery Haemostatic efficacy was 100% successfulHaemostatic efficacy was rated 100% 1-hour post-infusion, demonstrating its efficacy in restoring clot strength
 



 MCF Fibryga® demonstrated a significant increase in mean plasma MCF There were no deaths, no allergic/ hypersensitivity reactions, and no clinical evidence of neutralising antifibrinogen antibodies 
 Fibryga® demonstrated a favourable safety profile AE, adverse event; AUCnorm, area under the curve normalised to the dose administered; CFD, congenital fibrinogen deficiency; CI, confidence interval; IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee; IV, intravenous; MCF, maximum clot firmness; PK, pharmacokinetics.

FORMA-01 trial

Study design1
A prospective, randomised, controlled, crossover, phase II trial to assess the pharmacokinetic (PK) properties, surrogate efficacy and safety of fibryga® versus active control (alternative fibrinogen concentrate) in 22 patients with congenital afibrinogenaemia ranging from 12 to 53 years of age (6 adolescents and 16 adults). Patients were randomised to receive a single intravenous infusion 70 mg/kg dose of fibryga® or active control in the two 45-day study periods (crossover was performed at the end of the first study period).

Primary objective1
To determine the single-dose pharmacokinetic (PK) profiles and maximum clot firmness (MCF) as a surrogate marker for haemostatic efficacy for fibryga® versus active control.

Results: Fibryga® PK profile1

No significant differences were seen for secondary PK parameters except for as described below, and (Vss). mean clearancevolume of distribution at steady state Fibryga® demonstrated slower clearance compared with active control (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h_1 kg_1; p=0.0002). ¹¹ The clinical impact of this finding has yet to be determined. A recent case report which explored the differential effects of the two concentrates at a clot level showed a strong correlation between . This was attributed to the . ¹⁴ rising fibryga® concentrations, both in vivo and in vitro and longer 50% lysis timehigher concentration of FXIII in fibryga®
No significant differences were seen for secondary PK parameters except for as described below, and (Vss). mean clearancevolume of distribution at steady state Fibryga® demonstrated slower clearance compared with active control (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h_1 kg_1; p=0.0002). ¹¹ The clinical impact of this finding has yet to be determined. A recent case report which explored the differential effects of the two concentrates at a clot level showed a strong correlation between . This was attributed to the . ¹⁴ rising fibryga® concentrations, both in vivo and in vitro and longer 50% lysis timehigher concentration of FXIII in fibryga®

Results: Fibryga® MCF1

¹ Fibryga® demonstrated a significant increase in clot strength (measured by MCF)
¹ Fibryga® demonstrated a significant increase in clot strength (measured by MCF)

  • As expected, fibryga® demonstrated a significant increase in mean plasma MCF 1-hour post-infusion, demonstrating its efficacy in restoring clot strength. This translates into the potential to promote haemostasis in bleeding situations

Mean (±SD) fibrinogen activity (g/L) during PK assessment after fibryga® and active control administration (N=21*)1

Time (hours) 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 LOQ 0 8 24 48 96 144 216 312 ⁻¹ Fibrinogen activity (g L) Fibryga® Active control *Per-protocol patient analysis set. Fibrinogen activity plotted against time for fibryga® and active control following normalisation to the dose administered and standardisation to 70 mg kg. Mean fibrinogen concentration peaked within 2 hours for both fibrinogen concentrates, with levels well within the recommended target of 1–1.5 g/L (1.161 g/Lfor fibryga® and 1.222 g/L for active control; p=NS). LOQ, limit of quantification; PK, pharmacokinetic; SD, standard deviation. Adapted from Ross et al, 2018. ⁻¹⁻¹ ⁻¹¹
Time (hours) 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 LOQ 0 8 24 48 96 144 216 312 ⁻¹ Fibrinogen activity (g L) Fibryga® Active control *Per-protocol patient analysis set. Fibrinogen activity plotted against time for fibryga® and active control following normalisation to the dose administered and standardisation to 70 mg kg. Mean fibrinogen concentration peaked within 2 hours for both fibrinogen concentrates, with levels well within the recommended target of 1–1.5 g/L (1.161 g/Lfor fibryga® and 1.222 g/L for active control; p=NS). LOQ, limit of quantification; PK, pharmacokinetic; SD, standard deviation. Adapted from Ross et al, 2018. ⁻¹⁻¹ ⁻¹¹

Results: Fibryga® safety profile in the FORMA-01 trial1

  • There were no safety concerns with single-dose administration of fibryga® compared with active control

  • AEs generally occurred as mostly mild, single events, with similar incidence and severity between treatment arms

Summary of AEs in the FORMA-01 trial1

25 30 15 26 9 4 1 0 0 0 5 10 15 20 25 30 35 Number of AEs 2 0 0 0 0 0 2 Fibryga® Active control AE Mild AE Moderate AE Severe AE Probably or possibly
treatment-related AE AE leading to
withdrawal SAE Death N=22. 25 adverse events (AEs) occurred in 11 patients in the fibryga® arm, and 30 AEs occurred in 11 patients in the active control arm. The two AEs occurring in 2 patients potentially attributed to fibryga® were mild pyrexia and a mild allergic reaction. One severe AE (urinary tract infection) occurred 6 days after infusion and 1 patient experienced 2 serious AEs on the same day (abdominal pain and vaginal haemorrhage) 25 days after infusion, but these events were not considered treatment related. There were no deaths or severe allergic reactions in the study nor were there seroconversions (for HIV, HAV, HBV, HCV or parvovirus virus B19) related to either treatment.Adapted from Ross et al, 2018. ¹ ¹
25 30 15 26 9 4 1 0 0 0 5 10 15 20 25 30 35 Number of AEs 2 0 0 0 0 0 2 Fibryga® Active control AE Mild AE Moderate AE Severe AE Probably or possibly
treatment-related AE AE leading to
withdrawal SAE Death N=22. 25 adverse events (AEs) occurred in 11 patients in the fibryga® arm, and 30 AEs occurred in 11 patients in the active control arm. The two AEs occurring in 2 patients potentially attributed to fibryga® were mild pyrexia and a mild allergic reaction. One severe AE (urinary tract infection) occurred 6 days after infusion and 1 patient experienced 2 serious AEs on the same day (abdominal pain and vaginal haemorrhage) 25 days after infusion, but these events were not considered treatment related. There were no deaths or severe allergic reactions in the study nor were there seroconversions (for HIV, HAV, HBV, HCV or parvovirus virus B19) related to either treatment.Adapted from Ross et al, 2018. ¹ ¹

FORMA-02 trial

Study design2

  • A prospective, open-label, uncontrolled, multicentre phase III study to assess the efficacy and safety of fibryga® for on-demand treatment of acute bleeding and to prevent bleeding during and after surgery in 25 patients aged ≥12 years with CFD (afibrinogenaemia or hypofibrinogenaemia), ranging from 12 to 54 years of age (6 adolescents and 19 adults)

  • Fibryga® was individually dosed to achieve recommended target fibrinogen plasma level, dependent on bleed type (minor/major) or type of surgery (minor/major). Of the 25 treated patients, 24 experienced one or more bleeding episodes and 9 underwent surgery

  • Treatment of bleeding events was assessed using an objective four-point haemostatic efficacy scale based on criteria such as bleeding cessation, changes in haemoglobin and use of any other haemostatic means

  • MCF was assessed as a surrogate measure of haemostatic efficacy

Primary objective2
To evaluate the efficacy of fibryga® for on-demand treatment of acute bleeding episodes (spontaneous or after trauma) and to prevent bleeding during and after surgery

Results: Fibryga® efficacy in on-demand treatment of bleeding episodes2

  • With respect to the primary outcome, fibryga® was efficacious for on-demand treatment of bleeding in patients with CFD. The high success rate for treatment of bleeding demonstrated here is comparable with that previously reported for other fibrinogen concentrates

  • Treatment success (rating of excellent or good) was 96.7% (90% CI: 0.92–0.99) according to the Investigator, and 98.9% (90% CI: 0.95–1.0) according to the Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) (See Table below)

  • Haemostatic efficacy was further demonstrated through a significant increase in mean (± SD) MCF (measured using ROTEM) from 0 mm (at baseline) to 5.79 (± 2.53) mm (p<0.001) at 1 hour following the first fibryga® infusion. This was consistent with the 98.9% successful efficacy rating given by the IDMEAC, utilising an objective 4-point scale

Efficacy of fibryga® for on-demand treatment of bleeding episodes in adults and adolescents in FORMA-022

Four-Point Efficacy Scale [%] Excellent Good Moderate None Missing Investigator 78.7 18.0 1.1 0 2.2 IDMEAC 91.0 7.9 1.1 0 0 A total of 89 bleeding events were treated in 24 patients. There were 87 bleeding events defined as minor (mild joint bleeding and superficial muscle, soft tissue or oral bleeding) and 2 defined as major (spontaneous intracranial haemorrhage and spontaneous occult gastrointestinal bleed). Most bleeding episodes (83/89; 93.3%) required a single infusion of fibryga®, with a mean (± SD) dose of 61.88 (± 11.73) mg/kg for the first infusion. IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee.  Adapted from Lissitchkov et al, 2020. ²
Four-Point Efficacy Scale [%] Excellent Good Moderate None Missing Investigator 78.7 18.0 1.1 0 2.2 IDMEAC 91.0 7.9 1.1 0 0 A total of 89 bleeding events were treated in 24 patients. There were 87 bleeding events defined as minor (mild joint bleeding and superficial muscle, soft tissue or oral bleeding) and 2 defined as major (spontaneous intracranial haemorrhage and spontaneous occult gastrointestinal bleed). Most bleeding episodes (83/89; 93.3%) required a single infusion of fibryga®, with a mean (± SD) dose of 61.88 (± 11.73) mg/kg for the first infusion. IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee.  Adapted from Lissitchkov et al, 2020. ²

Results: Fibryga® efficacy for surgical prophylaxis2

  • With respect to the primary outcome, fibryga® was efficacious for surgical prophylaxis in patients with CFD

  • Intra-operative and post-operative treatment success rate for fibryga® (i.e. a rating of excellent or good) was 100% (90% CI: 0.82–1.00) by the Investigator (surgeon or haematologist) and the IDMEAC assessment (See Table below)

Efficacy of fibryga® in surgical prophylaxis treatment of bleeding episodes in adults and adolescents in FORMA-023

Four-Point Efficacy Scale [%] Excellent Good Moderate None Intra-operative Surgeon 91.7 8.3 0 0 IDMEAC 91.7 8.3 0 0 Post-operative Surgeon 100.0 0 0 0 IDMEAC 91.7 8.3 0 0 Nine patients received fibryga® during 12 surgeries (11 were minor surgeries). The mean (± SD) pre-operative loading dose was 77.39 (± 20.22) mg/kg (11 surgeries) and the mean (± SD) maintenance dose was 20.13 (± 7.49) mg/kg. IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee. Adapted from Lissitchkov et al, 2020. ²
Four-Point Efficacy Scale [%] Excellent Good Moderate None Intra-operative Surgeon 91.7 8.3 0 0 IDMEAC 91.7 8.3 0 0 Post-operative Surgeon 100.0 0 0 0 IDMEAC 91.7 8.3 0 0 Nine patients received fibryga® during 12 surgeries (11 were minor surgeries). The mean (± SD) pre-operative loading dose was 77.39 (± 20.22) mg/kg (11 surgeries) and the mean (± SD) maintenance dose was 20.13 (± 7.49) mg/kg. IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee. Adapted from Lissitchkov et al, 2020. ²

Results: Fibryga® safety profile in the FORMA-02 trial1

A favourable safety profile for fibryga® was demonstrated in this study
A favourable safety profile for fibryga® was demonstrated in this study

Summary of AEs (safety population)* in the FORMA-02 trial2

AEs occurring Patients with AE, N (%) Relatedness to treatment (Probably or Possibly related)    Non serious (Mild)    Serious (Moderate) AE leading to discontinuation Death Number of AEs † 91 19 (76.0) 3 2 ‡ 1 § 0 0 †‡§ *N=25 patients. Unless otherwise indicated, numbers are the number of AEs. A total of 91 AEs in 19 patients (76.0%) were reported. Three AEs in 3 patients were considered possibly related to treatment: a moderate AE reported as exacerbation of a pre-existing condition of peripheral ischaemia due to digital microthrombi, a mild skin reaction, and a mild AE reported as peripheral phlebitis of the upper limbs, all of which resolved. No deaths or severe allergic reactions were reported, nor were clinical evidence of neutralising anti-fibrinogen antibodies. AEs include TEAEs (occurring between the start of the first fibrinogen concentrate infusion and the end of each 30-day observation and follow-up period) and non-TEAEs (AEs occurring outside of the follow-up period). Mild skin reaction (itchiness and redness), peripheral phlebitis of the upper limbs. Ischaemia due to digital microthrombi. Adapted from Lissitchkov et al, 2020. ²
AEs occurring Patients with AE, N (%) Relatedness to treatment (Probably or Possibly related)    Non serious (Mild)    Serious (Moderate) AE leading to discontinuation Death Number of AEs † 91 19 (76.0) 3 2 ‡ 1 § 0 0 †‡§ *N=25 patients. Unless otherwise indicated, numbers are the number of AEs. A total of 91 AEs in 19 patients (76.0%) were reported. Three AEs in 3 patients were considered possibly related to treatment: a moderate AE reported as exacerbation of a pre-existing condition of peripheral ischaemia due to digital microthrombi, a mild skin reaction, and a mild AE reported as peripheral phlebitis of the upper limbs, all of which resolved. No deaths or severe allergic reactions were reported, nor were clinical evidence of neutralising anti-fibrinogen antibodies. AEs include TEAEs (occurring between the start of the first fibrinogen concentrate infusion and the end of each 30-day observation and follow-up period) and non-TEAEs (AEs occurring outside of the follow-up period). Mild skin reaction (itchiness and redness), peripheral phlebitis of the upper limbs. Ischaemia due to digital microthrombi. Adapted from Lissitchkov et al, 2020. ²

FORMA-04 trial

Study design3

  • A prospective, open-label, uncontrolled, multinational, multicentre phase III trial to assess the clinical efficacy, PK and safety of fibryga® for the treatment of on-demand acute bleeding episodes and surgical prophylaxis in paediatric patients (<12 years) with CFD

  • Of the 11 patients who completed the study, eight were treated for 10 bleeding episodes, and three for surgical prophylaxis. Evaluation of the haemostatic efficacy for on-demand and surgical prophylaxis was conducted using an objective 4-point efficacy scale (excellent, good, moderate and none), based on criteria such as bleeding cessation, changes in haemoglobin and use of any other haemostatic means

Primary objective3
To assess haemostatic efficacy of fibryga® for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients (0–12 years) with CFD

Results: Fibryga® efficacy in on-demand treatment of bleeding in paediatric patients3

  • Overall, haemostatic efficacy as assessed by the IDMEAC was 100% successful for all 10 bleeding episodes. The high success rate for haemostatic efficacy in treating bleeding events in paediatric patients with CFD is comparable to that reported for other fibrinogen concentrates in several mixed age and paediatric studies

Efficacy of fibryga® for on-demand treatment of bleeding episodes in children in FORMA-043

Four-Point Efficacy Scale [%] Four-Point Efficacy Scale [%] Excellent Good Moderate None Investigator N (%) 7 (70.0%) 1 (10.0%) 1 (10.0%) 1 (10.0%)* IDMEAC N (%) 8 (80.0%) 2 (20.0%) 0 (0.0%) 0 (0.0%) A total of 10 bleeding episodes were treated in 8 patients. *For one patient, the haemostatic efficacy assessment was missing. As per the statistical analysis plan, the rating by the investigator was designated as ‘None’. Of the 10 treated bleeding episodes, five were spontaneous and five were trauma-induced; with reference to their severity, 80% of bleeds were major and 20% were minor. For all minor bleeds, a single infusion of fibryga® was sufficient to achieve control. The median dose of fibryga® per infusion for treatment of all bleeding events was . Adapted from Djambas Khayat et al, 2020.  70 mg/kg ³
Four-Point Efficacy Scale [%] Four-Point Efficacy Scale [%] Excellent Good Moderate None Investigator N (%) 7 (70.0%) 1 (10.0%) 1 (10.0%) 1 (10.0%)* IDMEAC N (%) 8 (80.0%) 2 (20.0%) 0 (0.0%) 0 (0.0%) A total of 10 bleeding episodes were treated in 8 patients. *For one patient, the haemostatic efficacy assessment was missing. As per the statistical analysis plan, the rating by the investigator was designated as ‘None’. Of the 10 treated bleeding episodes, five were spontaneous and five were trauma-induced; with reference to their severity, 80% of bleeds were major and 20% were minor. For all minor bleeds, a single infusion of fibryga® was sufficient to achieve control. The median dose of fibryga® per infusion for treatment of all bleeding events was . Adapted from Djambas Khayat et al, 2020.  70 mg/kg ³

Results: Fibryga® efficacy in surgical prophylaxis in paediatric patients3

Overall, was rated by both the investigator and (see Table below) heamostatic efficacy100%IDMEAC
Overall, was rated by both the investigator and (see Table below) heamostatic efficacy100%IDMEAC

Efficacy of fibryga® in surgical prophylaxis treatment of bleeding episodes in paediatric patients in FORMA-043

Efficacy rating Intra-operative efficacy 4-point Efficacy Scale Excellent Good Moderate None Two-Point Efficacy Scale* Success Failure Post-operative efficacy Four-point Efficacy Scale Excellent Good Moderate Investigator N (%) 3 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) 0 (0.0) 95% CI † 29.24-100.00 IDMEAC N (%) 3 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) 0 (0.0) 95% CI † 29.24-100.00 ®† Three surgeries were carried out in three paediatric patients. Of the three surgical interventions, one was major, and two were minor. A loading dose was administered prior to the three surgeries. As with the bleeding episodes arm, a single infusion of fibryga was sufficient to achieve bleeding control. The patient undergoing major surgery received a total of six infusions. The mean dose per infusion was . *Efficacy rating of excellent or good indicated success and efficacy rating of moderate or none indicated failure. 95% CI for the success was calculated by the Clopper Pearson method.  CI, confidence interval; IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee. Adapted from Khayat et al, 2020. ³ 79 mg/kg
Efficacy rating Intra-operative efficacy 4-point Efficacy Scale Excellent Good Moderate None Two-Point Efficacy Scale* Success Failure Post-operative efficacy Four-point Efficacy Scale Excellent Good Moderate Investigator N (%) 3 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) 0 (0.0) 95% CI † 29.24-100.00 IDMEAC N (%) 3 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) N (%) 3 (100.0) 0 (0.0) 0 (0.0) 95% CI † 29.24-100.00 ®† Three surgeries were carried out in three paediatric patients. Of the three surgical interventions, one was major, and two were minor. A loading dose was administered prior to the three surgeries. As with the bleeding episodes arm, a single infusion of fibryga was sufficient to achieve bleeding control. The patient undergoing major surgery received a total of six infusions. The mean dose per infusion was . *Efficacy rating of excellent or good indicated success and efficacy rating of moderate or none indicated failure. 95% CI for the success was calculated by the Clopper Pearson method.  CI, confidence interval; IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee. Adapted from Khayat et al, 2020. ³ 79 mg/kg

Results: Fibryga® safety profile in the FORMA-04 trial3

Treatment with fibryga® showed a safety profile. favourable
Treatment with fibryga® showed a safety profile. favourable

Summary of AEs (safety population)* in the FORMA-04 trial3

AE, n Patients with AE, N (%) Severity of AE, n Mild Moderate Severe Probably or possibly related AE, n AEs leading to discontinuation, n SAE, n Death, n AE severity (PT) Mild Abdominal pain Pyrexia ‡ Ecchymosis (n = 3) Influenza-like illness Tonsillitis Moderate Procedural pain Haemarthrosis AEs 10 4 (28.6) 7 2 1 2 1 † 1 0 Severe PVT ‡ A total of 10 AEs were reported in 4 patients (28.6%). Two AEs in one patient were considered possibly related to treatment: portal vein thrombosis (PVT) and fever (pyrexia). The PVT was rated as an SAE and occurred after a splenectomy for spontaneous spleen rupture. The SAE was assessed as possibly related to fibryga® while taking into consideration that PVT is a regular complication of splenectomy. The SAE led to the discontinuation of the patient from the study. No deaths or severe allergic reactions were reported, nor were clinical evidence of neutralising anti-fibrinogen antibodies.  AE, adverse event; N, number of patients; PT, preferred term; PVT, portal vein thrombosis; SAE, serious adverse event.  Adapted from Khayat et al, 2020. ³
AE, n Patients with AE, N (%) Severity of AE, n Mild Moderate Severe Probably or possibly related AE, n AEs leading to discontinuation, n SAE, n Death, n AE severity (PT) Mild Abdominal pain Pyrexia ‡ Ecchymosis (n = 3) Influenza-like illness Tonsillitis Moderate Procedural pain Haemarthrosis AEs 10 4 (28.6) 7 2 1 2 1 † 1 0 Severe PVT ‡ A total of 10 AEs were reported in 4 patients (28.6%). Two AEs in one patient were considered possibly related to treatment: portal vein thrombosis (PVT) and fever (pyrexia). The PVT was rated as an SAE and occurred after a splenectomy for spontaneous spleen rupture. The SAE was assessed as possibly related to fibryga® while taking into consideration that PVT is a regular complication of splenectomy. The SAE led to the discontinuation of the patient from the study. No deaths or severe allergic reactions were reported, nor were clinical evidence of neutralising anti-fibrinogen antibodies.  AE, adverse event; N, number of patients; PT, preferred term; PVT, portal vein thrombosis; SAE, serious adverse event.  Adapted from Khayat et al, 2020. ³

UK-FIB-2500024 | May 2026

Abbreviations 
AE, adverse event; AFD, acquired fibrinogen deficiency; AUC, area under the curve; AUCnorm, area under the curve normalised to the dose administered; CFD, congenital fibrinogen deficiency; CI, confidence interval; FXIII, factor XIII; HAV; hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDMEAC, Independent Data Monitoring and Endpoint Adjudication Committee; LOQ, limit of quantification; MCF, maximum clot firmness; N, number of patients; PK, pharmacokinetic; POC(T), point-of-care testing; PT, preferred term; PVT, portal vein thrombosis; ROTEM, rotational thromboelastometry; SAE, serious adverse event; SD, standard deviation; TEAE, treatment-emergent adverse event; Vss, volume of distribution at steady state.

References

  1. Ross C, et al. Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency. J Thromb Haemost. 2018;16:253–61.

  2. Lissitchkov T, et al. Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients. J Thromb Haemost. 2020;18:815–24

  3. Djambas Khayat C, et al. Efficacy and safety of fibrinogen concentrate for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency. Haemophilia. 2021;27(2):283–92

  4. Goodarzi S, et al. Are all fibrinogen concentrates the same? The effects of two fibrinogen therapies in an afibrinogenemic patient and in a fibrinogen deficient plasma model. A clinical and laboratory case report. Front Med (Lausanne). 2024;11:1391422

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