Prevention, individualized prevention, and emerging therapies continue to develop hemophilia A treatment

Hemophilia is a rare group of bleeding disorders inherited in recessive X chromosome.
It is divided into hemophilia A (FVIII deficiency) and hemophilia B (FIX deficiency), of which hemophilia A is the main one
.
1
In recent years, individualized preventive treatment 2 and PK-guided individualized preventive treatment 3 have gradually become a hot topic in the field of hemophilia diagnosis and treatment
.

Emerging treatment methods such as gene therapy have also been advancing continuously, and exciting progress has been made4.
As a result, patients with hemophilia usher in more hope
.

In this issue, the editor will share with you the relevant progress of hemophilia A treatment, and hope it will be helpful to your clinical work
.

Preventive treatment-the key to improving the survival of patients.
Preventive treatment is an important part of the standard treatment of hemophilia.
It is a treatment aimed at maintaining normal joint and muscle function.
5, the new version of the guidelines ("Haemophilia Treatment Chinese Guidelines (2020 Edition)) 》) The importance of preventive treatment is emphasized again: China has the basic conditions for preventive treatment of hemophilia, and preventive treatment should be actively promoted in order to reduce the disability rate of hemophilia patients in China and improve the quality of life 6
.

In 2012, the third-generation recombinant human full-length coagulation factor VIII rAHF-PFM (recombinant human coagulation factor VIII for injection) was approved for the treatment and prevention of bleeding in patients with hemophilia A in China
.

A prospective, multi-center, open-label, post-marketing intervention study7, conducted in 11 research centers in China from June 2014 to May 2016, to evaluate the use of rAHF-PFM standard preventive treatment and on-demand treatment in the past China after treatment (PTP) efficacy and safety of severe / moderate haemophilia a patients
.

The study included 72 Chinese male patients with hemophilia A (FVIII level ≤ 2%), who first received 6 months of rAHF-PFM on-demand treatment, and then received 6 months of rAHF-PFM preventive treatment (20-40 IU/kg , Once every 48±6 hours), evaluate the patient’s annual bleeding rate (ABR) and the hemostatic efficacy and safety of rAHF-PFM
.

The results showed that: rAHF-PFM preventive treatment can significantly reduce bleeding.
Among 72 patients receiving rAHF-PFM treatment, 61 patients met the requirements.
The analysis results showed that the average total ABR of the on-demand treatment group was higher than that of the preventive treatment group (58.
3 vs.
2.
5), the average ABR decreased by 95.
9% (as shown in Figure 1)
.

 Figure 1 Comparison of bleeding between patients in the on-demand treatment group and the preventive treatment group.
The effect of rAHF-PFM bleeding treatment was good.
96.
1% of patients rated the bleeding treatment effect of rAHF-PFM as "excellent" or "good"
.

 The safety of rAHF-PFM was relatively good.
Four patients found transient low-titer FVIII inhibitors (0.
6-1.
7 BU), which were eliminated before the end of the study
.

No other unexpected safety issues were observed
.

Individualized preventive treatment-available and effective options.
With the improvement of China's economic and medical conditions, and there are differences between individuals with hemophilia, it is recommended to start implementation in children with hemophilia who are economically feasible.
Pathways, bleeding phenotypes, pharmacokinetics (PK) characteristics, and availability of coagulation factor preparations, and formulate the best individualized plan6,8
.

Among the many individualized preventive treatment plans, PK-guided individualized preventive treatment is an effective plan for successful preventive treatment3
.

As a currently well-documented and feasible individualized treatment strategy, PK-guided individualized preventive treatment can reduce bleeding and effectively reduce the number of infusions9 and the infusion dose10.
At the same time, the PK-guided individualized preventive treatment results in higher factor trough concentrations , The treatment cost is lower 11
.

In order to calculate PK parameters more conveniently and quickly, Takeda has developed a dose calculation software for recombinant human coagulation factor VIII for injection (hereinafter referred to as "PK software")
.

The PK software has been approved by the National Medical Products Administration (NMPA) in 2020 and is suitable for patients with hemophilia A who are 16 years old and above (weight 45 kg and above) receiving rAHF-PFM treatment
.

With the help of PK software, the clinical outcome of individualized preventive treatment using rAHF-PFM has been significantly improved
.

 Individualized preventive treatment of rAHF-PFM assisted by PK software can improve the clinical outcome of patients The PK parameters are adjusted to the preventive treatment plan
.

Before and after treatment adjustment, the patient’s annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) were evaluated.
The results showed that 12: PK software assisted individualized rAHF-PFM preventive treatment, ABR and AJBR were significantly reduced (PK software assisted Before vs.
PK software assisted: average ABR=2.
2 vs.
1.
5; P=0.
018, average AJBR=1.
3 vs.
0.
7; P=0.
012)
.

The bleeding situation before and after PK software assistance is shown in Figure 2: Figure 2 PK software assisted individualized rAHF-PFM prevention and treatment of bleeding outcome changes.
Emerging therapy-hemophilia treatment continues to extend the half-life of factor therapy in alternative therapy Because of the short half-life of FVIII products, the currently widely used preventive treatment program also requires about 2-3 infusions per week, and even repeated intravenous infusions once a day in some cases, which brings inconvenience to treatment.
It has also prompted researchers to develop recombinant FVIII (EHL rFVIII) with an extended half-life, thereby reducing the frequency of intravenous infusions and preventing patients from bleeding for a longer period of time 13
.

To define EHL rFVIII, the following three criteria need to be met: 1.
Using technology to extend the half-life of circulating organisms; 2.
Compared with standard rFVIII, most patients meet the "biological difference" standard: the lower limit of AUC ratio of 90% CI is higher than that of biological Equivalent cut-off value (1.
25 or 125%); 3.
Based on the model, the half-life is extended by ≥1.
3 times14
.

Methods to extend half-life include pegylation and fusion modification of coagulation factor fusion protein 15
.

Gene therapy Because hemophilia is a single-gene genetic disease, gene therapy is the most ideal way for hemophilia, and it is also the only way to cure hemophilia
.

Gene therapy is to transfer the normal FVIII gene into the patient's body through a vector
.

Vectors can be divided into viral vectors and non-viral vectors.
Commonly used viral vectors include retroviral vectors, adenovirus vectors, and adeno-associated virus vectors4
.

However, gene therapy still faces a series of issues such as immunogenicity and safety.
In addition, gene therapy is expensive
.

Summary With the continuous development of science and technology, the treatment of hemophilia is constantly enriched, optimized, and iterated
.

Preventive treatment is the basis for improving the quality of life of hemophilia, and individualized treatment is an effective treatment option for patients
.

In the context of the digital era, PK-guided individualized preventive treatment will help the treatment of hemophilia
.

Emerging treatment methods such as gene therapy indicate that there will be more possibilities for the treatment of hemophilia in the future
.

I believe that the treatment of hemophilia will continue to move towards a higher goal
.

References: 1.
Srivastava A .
et al.
Haemophilia.
2020;0011–158.
2.
Carcao MD,et al.
Semin Thromb Hemost.
2015 Nov;41(8):864-713.
Álvarez-Román MT,et al.
Haemophilia 2017 Jan;23(1)4.
Sun Boyang, Yang Renchi.
Chinese Journal of Hematology.
2018;39(10):873-8765.
Thrombosis and Hemostasis Group of Hematology Branch of Chinese Medical Association.
Chinese Journal of Hematology, 2017,38( 05):364-3706.
Thrombosis and Hemostasis Group, Chinese Hematology Branch, Chinese Hemophilia Collaborative Group.
Chinese Journal of Hematology.
2020;41(4):265-2717.
Zhao YQ, et al.
Clin Appl Thromb Hemost.
Jan-Dec 2021;27:1076029621989811.
8.
Petrini P, et al.
Expert Rev Hematol 2015 Apr;8(2)9.
LA VALENTINO et al.
J Thromb Haemost.
2012 Mar;10(3)359-6710.
Lissitchkov T et al.
Haemophilia.
2017;23:697–70411.
Iannazzoa S et al.
Blood Coagul Fibrinolysis.
2017Sep;28(6):425-43012.
Mingot-Castellano ME,et al.
Haemophilia 2018 Sep;24(5) :e338-e34313.
Yang Lingxiao.
Chongqing Medicine.
2018;47(24):3216-3219.
14.
Mahlangu J, et al.
Haemophilia.
2018 May;24(3):348-358.
15.
Puthenveetil G, et al.
Indian J Pediatr.
2020;87(2):134-140 Approval Number: VV-MEDMAT-57835 Approval Time: 11/24/2021 Expiration Time: 11/24/2023 Statement This information is intended to help medical and health professionals better understand the latest developments in the field of related diseases
.

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.

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.

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