"Safety Investigator" Sees Bloodborne vs. Restructuring FVIII Safety

Introduction For many years, "safety" has been one of the most concerned issues in the treatment of hemophilia
.

The emergence of blood-derived coagulation factor VIII (FVIII) has greatly reduced the risk of death of patients, but there is a risk of viral infection, prompting the development of safer FVIII products 1
.

The advent of recombinant FVIII is a major advance in the treatment of hemophilia A 2
.

In this issue, "Safety Investigator" is launched to analyze the safety of Restructured FVIII compared to Bloodborne FVIII
.

Investigation item 1: Risk of viral infection The use of blood-derived FVIII carries the risk of viral infection, and once infection occurs, the treatment cost and social burden of virus-positive hemophilia patients will far exceed those of ordinary hemophiliacs 3
.

Blood-derived FVIII known risk of viral infection Common blood-borne viruses include human immunodeficiency virus, hepatitis C virus, hepatitis B virus,
etc.

In addition to possible immunodeficiency and liver cirrhosis, infection with these viruses can lead to an increased incidence of tumors 1
.

Limitations of virus inactivation technology: Current virus inactivation technology (such as heat treatment, etc.
) cannot fully ensure the safety of blood-derived products4
.

The risk of blood-derived FVIII unknown virus infection There are many unknown viruses: with the improvement of laboratory diagnosis and research technology, viruses that can infect humans are constantly being reported and discovered 5
.

Limited by current technology and cognition, many unknown pathogenic viruses may exist in the blood
.

There are limitations in virus screening methods: blood products virus screening methods have limitations, virus screening methods still have the problem of "window period", missed detection caused by differences in reagent sensitivity, and limitations of virus detection types, etc.
, all lead to blood products.
There is a great risk in the application of 6
.

Insufficient supply of blood-derived FVIII In addition to known and unknown risks of viral infection, blood-derived FVIII is limited by the supply of blood, and the supply is limited, which cannot meet the needs of hemophilia patients for preventive treatment 3
.

Recombinant FVIII came into being to reduce the risk of viral infection: The risk of viral infection in blood-derived FVIII prompted the development of safer FVIII products7
.

Recombinant FVIII is expressed through gene cloning technology and does not contain any blood components.
The use of recombinant FVIII to replace blood-derived FVIII greatly reduces the risk of viral infection and greatly improves the safety of the treatment of hemophilia A patients 6
.

Continuous improvement of production process: The continuous improvement of the virus inactivation/clearance process of recombinant FVIII makes its safety more effectively guaranteed, and can eliminate the risk of infection by known and unknown pathogens6
.

Adequate supply: Production and supply are more secure than blood products, helping to help more hemophiliacs achieve preventive treatment3
.

Investigation Item 2: Risk of Inhibitors In addition to viral infection, inhibitors, as the most challenging complication in the current treatment of hemophilia A patients, will also greatly increase the economic burden of hemophilia patients7
.

Although factors such as the type and severity of hemophilia A, the nature of the genetic defect, ethnicity, factor exposure at surgery, and prophylactic or as-needed treatment regimens are known to influence the risk of inhibitor development, the use of replacement therapy FVIII type may also affect inhibitor production 7
.

Meta-analysis found no significant difference in the incidence of inhibitors between blood-derived FVIII and recombinant FVIII A systematic review and meta-analysis of published prospective studies in previously untreated patients with severe hemophilia A (PUP) ) were evaluated for the incidence of inhibitors
.

The analysis included 25 prospective studies published between 1990 and 2007, with a total of 800 patients, and the results showed 8: There was no significant difference in the incidence of total inhibitors between patients receiving blood-derived FVIII and recombinant FVIII (weighted mean: 21% vs.
27%)
.

There was no significant difference in the incidence of high titer inhibitors between patients receiving blood-derived FVIII and recombinant FVIII (weighted mean: 14% vs.
16%)
.

The type of FVIII product (ie, blood-derived FVIII versus recombinant FVIII) does not appear to affect the incidence of inhibitors in PUP patients with severe hemophilia
A.

Whether the incidence of recombinant FVIII inhibitors is higher than that of blood-derived FVIII is inconclusive.
Differences: there are differences in study time, inhibitor detection frequency, and median follow-up time, so it is not clear whether the incidence of blood-derived FVIII inhibitors is low.
in recombinant FVIII9
.

Uncertainty: Different patterns of inhibitor detection, differences in study populations, different severity of FVIII deficiency in enrolled patients, race, type of gene mutation, age at first treatment, etc.
may all be related factors for the production of inhibitors9
.

Investigation item 3: Clinical safety evidence In addition to the risk of viral infection and inhibitors, whether the clinical safety evidence is sufficient is also an important indicator for evaluating "safety"
.

Many blood-derived FVIII are produced by local companies, some are only used domestically, and there is insufficient global experience.
However, most recombinant FVIII has undergone large prospective, multi-center studies, and most are undergoing post-marketing studies in different countries.
The generation of recombinant FVIII-rAHF-PFM, its long-term safety has been verified
.

Long-Term Safety A large global multicenter, non-interventional, real-world study11 enrolled more than 1000 patients with moderate-to-severe hemophilia A who received rAHF-PFM globally
.

The observation period of each patient is ≥4 years.
Up to now, the 6-year interim analysis results show: Safety: The 6-year interim safety analysis is consistent with the safety outcomes reported in previous related studies, confirming the long-term safety of rAHF-PFM treatment
.

Safety in Chinese Patient Population A phase 4 clinical study12 explored the safety of rAHF-PFM prophylaxis in Chinese patients with previously treated moderate and severe hemophilia A, including 72 Chinese men with hemophilia Patient A, first received 6 months of rAHF-PFM as-needed treatment, followed by 6 months of rAHF-PFM prophylaxis (20-40 IU/kg, once every 48 ± 6 hours), the results showed: rAHF-PFM is safe Good performance: Transient low-titer FVIII inhibitors (0.
6-1.
7 BU) were found in 4 patients and resolved by the end of the study
.

No other unexpected safety issues were observed
.

Compared with blood-derived FVIII, recombinant FVIII greatly reduces the risk of viral infection, and can eliminate the risk of infection by known and unknown pathogens6
.

The meta-analysis did not find a significant difference in the incidence of inhibitors of blood-derived FVIII and recombinant FVIII in PUP7, and whether the incidence of inhibitors of recombinant FVIII is higher than that of blood-derived FVIII is inconclusive9
.

The safety of recombinant FVIII (eg rAHF-PFM) has been validated by studies 11,12
.

References: 1.
Alessandro Gringeri.
Blood Transfus 2011;9:366-70.
2.
Key NS, et al.
Lancet.
2007 Aug 4;370(9585):439-48.
3.
Yang Renchi.
Journal of Clinical Drug Therapy.
2019.
17(11) :11-13.
4.
Di Minno G, et al.
Blood Rev.
2016 Jan;30(1)35-48.
5.
Woolhouse M, et al.
Philosophical Transactions of the Royal Society of London, 2012, 367(1604):2864- 71.
6.
Huo Jiping, et al.
Drug Evaluation.
2018.
15; 14-19.
7.
Iorio A, et al.
J Thromb Haemost.
2010 Jun; 8(6):1256-65.
8.
Massimo Franchini, et al.
;81(1):82-93.
9.
Gringeri A, et al.
Blood Transfus.
2011 Oct;9(4):366-70.
10.
Hermans Cedric, et al.
Crit.
Rev.
Oncol.
Hematol, 2012, 83 11- 20.
11.
MC Ozelo, et al.
Presented at the 28th International Society on Thrombosis and Haemostasis (ISTH), 2020; Abstracts PB0900.
12.
Y.
Zhao, et al.
Presented at the 28th International Society on Thrombosis and Haemostasis (ISTH), 2020; Abstracts PB0876.
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