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Hemophilia is a hereditary blood coagulation dysfunction hemorrhagic disease with the disease gene located on the X chromosome, excluding about a third of spontaneous mutations or genetic changes.
Men are mainly affected, and women are mostly “carriers.”
Common features of hemophilia are active thrombinogenic disorders, prolonged clotting time, and a slight post-traumatic bleeding tendency throughout life.
Spontaneous bleeding can also occur in critically ill patients without obvious trauma. According to the lack of factors, hemophilia is mainly divided into three types: A, B and C. The more common types of hemophilia are A and B types.

Although listed in the list of rare diseases, there are relatively more clinical research drugs for hemophilia than other rare diseases that “nobody cares”. In May, there were several clinical research projects that published notice of progress.

Spark Therapeutics

On May 22, Spark Therapeutics (a gene therapy company that focuses on challenging genetic diseases) and its partner Pfizer Pharmaceuticals released results of a clinical study of hemophilia treatment (SPK-9001), with a cumulative follow-up of more than 18 patient years (5 to 121 weeks).
15 severe or moderately severe (FIX: C ≤ 2%) patients with hemophilia B have stopped routine infusion of Factor IX concentrates and no severe adverse events have occurred by the date of data collection (May 7) Without thrombotic events or factor IX inhibitors.
The overall ABR for all 15 participants decreased by 98% (based on data from Week 4; 97% based on infusion data).
Each participant was equivalent to 0.2 hemorrhages per year, and there were 8.9 bleedings per year before SPK-9001 treatment. Only one participant had bleeding events at least four weeks or longer after the SPK-9001 infusion.
For all 15 participants, overall AIR decreased by 99% (based on data from the fourth week of follow-up; still based on post-infusion data of 99%).
Each participant was equivalent to 0.9 infusions per year, and the infusion before infusion was 57.2.
Six subjects received a factor IX infusion after SPK-9001 administration: two reported spontaneous bleeding, two before surgery, one at the end of the study (at their discretion, according to protocol), and one for Prevent minor traumatic non-bleeding events.
All 13 participants were followed for at least 12 weeks after the SPK-9001 infusion (the time required to reach the steady state factor IX activity level), reaching a stable IX factor ratio of more than 12%.
For a follow-up of 12 weeks or longer for SPK-9001, which was manufactured by three participants using an enhanced procedure, the steady-state factor VIII activity ranged from 38.1% to 54.5%.

SparkTherapeutics Another novel bioengineering-related adenovirus (AAV) vector, SPK-8011 (Spark200), based on the AAV-LK03 capsid, also announced the results of clinical phase 1/2 studies for the treatment of hemophilia A late last year.
The drug received FDA-issued hemophilia A orphan drugs and breakthrough therapies in January and February 2018 respectively. The first four participants of SPK-8011 had a 100% reduction in the overall annual bleeding rate (ABR) at least 12 weeks after the infusion (calculated based on data from week 4; 82% based on infusion data).
By the end of the data (December 6, 2017), the annual average 0 (1) bleeding rate, and the average annual bleeding rate before the single administration of SPK-8011 was 5.5.
Similarly, as data is turned off, their overall annual infusion rate (AIR) decreased by about 98% (calculated from data after 4 weeks; infusion data based on 96%) infused to the average mean of 1.2 the amount of the average annual amount infused before the SPK-8011 treatment was 57.8 times, so far no serious adverse events were observed.

Chugai Pharmaceutical

HEMLIBRA, a Chinese pharmaceutical company, is a bispecific monoclonal antibody. It is a research drug developed using the proprietary antibody engineering technology platform of ChinaPharm.
The drug is designed to bind Factor IXa and Factor X, providing factor VIII cofactor functions for hemophilia A patients, and HEMLIBRA has been approved for listing by the FDA and the European Union respectively.

On May 21st, the leading biotech pharmaceutical company in China, Chuanyi Pharmaceutical announced that it will announce the HEMLIBuma (Emicizumab) clinical phase III multicenter clinical trials HAVEN3 (NCT02847637) and HAVEN 4 (NCT03020160) at the World Federation of Hemophilia Federation 2018 World Congress. The full results of the study.

The HAVEN3 study is a randomized, multi-center, open-label phase III study evaluating the efficacy, safety, and pharmacokinetics of preventive subcutaneous injections of HEMLIBRA once a week and once every two weeks.
The study enrolled had received sporadic or prophylactic treatment of non-factor factor Ⅷ Ⅷ inhibitor aged 12 or above 152 haemophilia A patients, results showed: HEMLIBRA treatment group has significant clinical statistically significant, Prophylactic injection of HEMLIBRA once a week was effective in reducing the bleeding rate by 96% (P<0.0001), effectively reducing the bleeding rate by 97% every two weeks (P<0.0001), and supporting HEMLIBRA for all hemophilia A patients.
The HAVEN 4 study is a single, multi-center, open phase III study.
Among patients 12 years of age and older with or without factor VIII inhibitors, patients receiving HEMLIBRA prophylaxis every four weeks had a median annual bleeding rate of 0.0 (IQR: 0.0; 2.1), of which 56.1% (95%) % CI: 39.7; 71.5) There were no bleeding episodes treated, and 90.2% (95% CI: 76.9; 97.3) had three or fewer bleeding episodes that were treated.

 uniQure N.V

uniQure N.V is a leading gene therapy company that aims to advance conversion therapies for patients with severe medical needs.
uniQure is advancing a potential Best-in-class gene therapy program for hemophilia B, AMT-061, which consists of the AAV5 viral vector carrying the Factor IX Padua variant (FIX-Padua) gene cassette, AMT 2018 061 will advance dose confirmation and critical studies in patients with severe and moderately severe hemophilia B.
Phase I/II studies have shown that AAV5-based gene therapy is safe, effective, and long-lasting, with no loss of efficacy over a period of up to 18 months.
The patient did not experience any loss of Factor IX (FIX) activity or a capsid-specific T cell mediated immune response during the study.

On May 19th, uniQure Chief Scientific Officer Dr. Anna Majowicz stated at the American Gene and Cell Therapy Association in Chicago that uniQure performed re-analysis of pre-treatment serum samples from 10 patients who participated in AMT-060 Phase I/II clinical trials. There is no apparent relationship between the presence of anti-AAV5 NABs and the clinical efficacy of AMT-060 in patients with hemophilia B prior to treatment.
In a previous clinical trial of gene therapy using adeno-associated virus (AAV) vectors, patients with anti-AAVNAB levels were excluded from treatment due to concerns that the efficacy of AAV vector delivery may have a negative effect due to the presence of anti-AAV5 NABs. outer.

“uniQure’s mission is to provide patients with advanced gene therapy, and current findings indicate that AAV5-based gene therapy may be applicable to all or almost all hemophilia patients, Huntington’s disease and other life-changing disease patients,” said uniQure Chief Executive Officer Matthew Karpstad said “We have a wealth of expertise in gene therapy based on AAV5, including many years of clinical experience and proprietary technologies that produce these gene therapies on a commercial scale.” We believe that AAV5 may become A potential best-in-class carrier that can more effectively and safely apply more gene therapy to patients in need of treatment.


Sanover’s Bioverativ, which focuses on rare blood diseases, announced at the World Federation of Hemophilia 2018 World Congress in May that a low dose of severe hemophilia among 18-65-year-olds Or preliminary safety and pharmacokinetic data for high dose BIVV001 (rFVIIIFc-VWF-XTEN). BIVV001 is a new type of therapy developed for the treatment of hemophilia von Willebrand disease (vWF) independent factor VIII. A single low dose of BIVV001 prolongs the half-life of Factor VIII with a high factor activity level to 37 hours and is lost. The average factor VIII activity reached 13.0% on the 5th day after injection.
And it is generally well tolerated and there is no development of inhibitors.
BIVV001 may offer full protection in all treatment situations, including management of acute bleeding, perioperative care, emergencies, and preventative use.
The role of factors also exceeds the coagulation cascade and may play a role in the joint and bone health of hemophiliacs.

BIVV001 is based on Bioverativ’s innovative Fc fusion technology, which adds a region of von Willebrand factor and XTEN polypeptide that may extend its circulation time.
It is the only treatment that has been shown to exceed the upper limit of von Willebrand factor. In August 2017, BIVV001 was awarded the title of Orphan Drug by the U.S. Food and Drug Administration.

Catalyst Biosciences

Catalyst Biosciences is a clinical-phase biopharmaceutical company focused on the development of new drugs to address blood-related indications. At the World Federation of Hemophilia 2018 World Congress in May, CatalystBiosciences announced the subcutaneous administration of hemophilia B patients. Safety and Pharmacokinetics of Applied Factor IX Variant ISU304 / CB2679d.

ISU304/CB2679d has received double orphan drug certification in the United States and the European Union. In February of this year, ISU304/CB2679d published top-line data of clinical phase 1/2 study of subcutaneous drug ISU304/CB 2679d for type B hemophilia. The test results showed that after a single daily dose of CB2679d for six days, the activity level of factor IX (FIX) continued to increase linearly.

Since ISU304/CB2679d is a Factor IX variant, it has a 22-fold enhanced potency due to its resistance to ATIII inhibition, increasing catalytic activity and affinity for FVIIIa, which makes subcutaneous injection (SQ) possible.
In the results of the published safety and pharmacokinetic studies, it was shown that ISU304/CB2679d administered subcutaneously showed an extended half-life of 1.4 to 4.8 times compared to intravenous administration.
After SQ injection, some patients experience the expected mildly extensive or localized adverse events.
Even with a slight adverse reaction, previous studies have shown that CB 2679d is also advantageous compared to currently approved all-IV therapy for hemophilia B.

In conclusion, innovative antibodies and gene therapy have brought hope for better treatment for hemophilia patients. It is expected that, with the publication of rare disease catalogs and the guidance of relevant policies, more and more rare drugs are no longer ” alone”.

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