What is hemophilia?
Hemophilia is a rare X-linked congenital bleeding disorder. The disorder is characterized by a deficiency of coagulation factor VIII (FVIII) in hemophilia A or factor IX (FIX) in hemophilia B.
Who and how is affected
Hemophilia A and B occur in 1 in 10,000 and 1 in 50,000 of the population, respectively. Type A is estimated to account for 80-85% of all cases, while type B is estimated to account for 15-20% of all cases.
Patients are highly susceptible to spontaneous bleeding and bleeding following injuries or surgery. Living with a chronic disease impairs their quality of life (Qol). Τhe only accepted way to change the natural history of bleeding is prophylaxis.
CFC replacement therapy: Does it meet patients’ medical needs?
Today CFC replacement therapy is the standard treatment for hemophilia. It involves regularly replacing the deficient clotting factor by infusing it through a vein (ΙV administration) to prevent bleeds (prophylactic care).
Though replacement therapy has significantly changed the life of patients, hemophilia remains a disease with significant unmet needs. The following limitations result in reduced QoL and treatment compliance and worsen the prognosis.
6 biggest challenges of CPC replacement therapy for hemophilia
1. Risk of nAb (inhibitor) development
About 15-20 percent of people with hemophilia develop inhibitors that prevent the treatment from working. A patient with an inhibitor will require special treatment either with a larger amount of clotting factor or a different type of clotting factor.
2. IV administration
The infusion of the clotting factor is particularly challenging in those with difficult venous access.
3. Frequency of administration
Currently, available replacement therapy requires intravenous injections up to three times a week to maintain protective levels.
4. High treatment cost
In patients with inhibitors, care costs increase significantly due to special treatment requirements and higher chances of hospitalization.
5. Not always effective
Ιn cases of severe Hemophilia, replacement therapy is not always effective.
6. Prophylaxis treatment does not limit joint damage risk
Aside from spontaneous bleeding, the main complication of hemophilia is hemarthrosis. Bleeding within joints is a common symptom of hemophilia and can lead to chronic joint disease and pain.
Current research trends for hemophilia therapies. What do they bring to the table?
The challenges mentioned above call for novel treatments for patients. Current research trends for improved hemophilia therapies that may alleviate current challenges include:
1. Extended half-life recombinant products
Extended half-life (EHL) products (Recombinant FVII for hemophilia A and Recombinant FIX for hemophilia B) are efficient and require less frequent injections. Reducing dose frequency can result in increased patient compliance.
2. Rebalancing coagulation by targeting natural anticoagulants
An alternative treatment methodology is to rebalance the activities of pro- and anticoagulant factors through inhibition of the natural anticoagulants antithrombin and tissue factor pathway inhibitor (TPFI). Fitusiran targets antithrombin, and Concizumab targets TFPI.
- Are Fitusiran and Concizumab the future of hemophilia therapy?
Fitusiran by Alnylam Pharmaceuticals/Sanofi is an investigational small interference RNA (si RNA) therapeutic designed to lower antithrombin, a protein that inhibits blood clotting, in order to increase clotting ability.
Concizumab by Novo Nordisk is a monoclonal antibody (mAb) that functions as a hemostatic rebalancing agent and decreases the TFPI inhibitory activity. Hence, allowing the production of sufficient FXa by the FVIIa-tissue factor complex to achieve hemostasis.
Both Fitusiran and Concizumab are subcutaneously administered prophylactic therapies for people with hemophilia A or B, with or without inhibitors.
3. Mimicking of factor VIII cofactor activity (Emicizumab)
A recombinant, humanized, bispecific monoclonal antibody restores the function of missing activated factor VIII (FVIII) by bridging FIXa and FX to facilitate effective hemostasis in patients with hemophilia A.
- Is the Bispecific Antibody Emicizumab a breakthrough for patients with inhibitors?
Emicizumab is designed to address the unmet needs οf replacement therapy (intravenous infusion and the high burden of treatment associated with prophylaxis) and to provide an alternative to conventional FVIII replacement products in patients with hemophilia A, regardless of the presence or absence of inhibitors.
4. Targeted production of endogenous factors
The hemophilias (Τype A and B) are suited for gene therapy because a small increment in blood factor levels is associated with significant amelioration of bleeding phenotype in severely affected patients.
- AAV–FVIII/FIX
Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following transfer of a functional gene to replace the hemophilic patient’s own defective gene.
- HSC-LV-FVIII
Lentiviral vector (LV)-mediated gene transfer into hematopoietic stem cells (HSCs) results in stable integration of FVIII gene into the host genome, leading to persistent therapeutic effect.
- Gene editing
Gene editing is a group of technologies that give scientists the ability to change an organism’s DNA. These technologies allow genetic material to be added, removed, or altered at particular locations in the genome.
Past, current, and future trends in prescribing practices for hemophilia
The Lucidquest team reviewed research available up to March 2022 and identified these prescribing trends so far.
Did you know that…?
1. According to a US survey held from 1999 to 2021, the prescribing of high doses of factor (>40 units/kg) has increased while the ITI prescribing practices remained similar over time.
2. >91% of clinicians prescribed emicizumab to treat HA with inhibitors. Emicizumab was more frequently prescribed with inhibitors than without. Reasons for switching from FVIII to emicizumab were fewer injections and improved QoL.
3. Approximately 1/3 of clinicians had patients in a GT clinical trial.
Key Takeaways
Today’s hemophilia treatments have changed the lives of patients. But there is no cure yet. People with hemophilia can experience complications that come with their chronic, debilitating condition (such as joint disease and inhibitors). Pharmacological research and clinical studies on novel gene and non-gene therapies promise a better understanding of hemophilia, fewer compilations, and improved QoL for patients.
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Sources:
https://www.cdc.gov/ncbddd/hemophilia/treatment.html
https://www.cdc.gov/ncbddd/hemophilia/facts.html
https://www.cdc.gov/ncbddd/hemophilia/inhibitors.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682782/
https://pubmed.ncbi.nlm.nih.gov/33577709/
https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-14-15-00-00-2351761
https://pubmed.ncbi.nlm.nih.gov/33570646/
https://pubmed.ncbi.nlm.nih.gov/32717759/
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913446/
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