Understanding Real-World Evidence to Advance Patient-Centric Innovation in Bleeding Disorders
Real-world evidence from studies across many of Takeda’s portfolio of treatments for hemophilia demonstrate the cost savings and patient benefits resulting from ongoing personalized treatment. However, in von Willebrand disease, real-world evidence highlights the ongoing unmet clinical need for personalization, as it may enable improved treatment outcomes. Insights presented at ASH include:
- ADYNOVATE ® [Antihemophilic Factor (Recombinant), PEGylated]: In the poster “Real-World Age-Stratified FVIII Consumption and Bleed Outcomes Before and After Switching to Rurioctocog Alfa Pegol in a Retrospective, Observational Study Using US Specialty Pharmacy Data,” (abstract 2411) outcomes found those who switched experienced a significant 40-50% decrease in their annualized bleed rate.
- Hemophilia A: In the poster “Cost-Effectiveness Model of Recombinant FVIII Versus Emicizumab Treatment of Patients With Severe Hemophilia A Without Inhibitors,” (abstract 2102) results found that prophylaxis with rFVIII was estimated to be less costly and more effective over an estimated 70-year lifespan of a patient with severe hemophilia A.
- FEIBA® [Anti-Inhibitor Coagulant Complex]: The poster “Real-World Clinical Management of Patients with Hemophilia and Inhibitors: Effectiveness and Safety of aPCC in Patients with >18 Months’ Follow-up in the FEIBA Global Outcome Study (FEIBA GO)” (abstract 2418) describes the long-term, real-world safety and efficacy of FEIBA in patients with congenital hemophilia A or B with inhibitors across different clinical settings.
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Von Willebrand Disease: Data from two studies that aim to advance scientific knowledge and understanding of von Willebrand disease (VWD), including the following retrospective analyses:
- The poster “Analysis of Bleeding and Treatment Patterns in Children and Adolescents before and after von Willebrand Disease Diagnosis Using Data from a US Medical Claims Database” (abstract 2117) highlights U.S. medical claims data that characterizes the diagnosis, bleeding and treatment patterns in children and adolescents with VWD and points to the need for improved treatment and care of this patient population.
- Additionally, the poster “Estimation of the Economic Burden Associated with Major Surgery Due to von Willebrand Disease Based on Claims Data from the USA” (abstract 4692) assesses the economic burden associated with major surgeries in patients with VWD and found that these patients incur significantly higher costs for health care resources compared to patients without VWD who had similar types of surgery.
“Real-world evidence plays a crucial role in understanding patterns of care that happen in day-to-day medical practice outside of rigorous clinical studies,” said Jonathan Roberts, MD, Associate Medical Director, Bleeding & Clotting Disorders Institute, Peoria, Ill. “The U.S. medical claims data show improvement is needed around management of von Willebrand disease in children and adolescents to optimize treatment and reduce the amount of bleeding episodes following diagnosis.”
Preclinical Scientific Studies Address Challenges of Current AAV Gene Therapies
Takeda also presented data from preclinical scientific studies regarding certain known limitations of AAV gene therapies. These studies will inform Takeda's approach to its own investigational AAV gene therapy programs; TAK-754, an investigational AAV gene therapy for hemophilia A is currently in Phase 1 clinical study, soon to be followed by other potential gene therapies including TAK-748, an investigational gene therapy for hemophilia B.
The treatment goal of gene therapy for hemophilia is to provide sustained therapeutic levels of endogenous clotting factor over multiple years. Hemophilia gene therapies have the potential to provide prolonged, high-level expression of factor, and limit the need for frequent factor infusion.1,2 To deliver gene therapy to a patient, a normal copy of a missing gene is packaged into a delivery vehicle, called a vector.3 Recombinant AAV, particularly those delivered by AAV5 and AAV8 capsid serotypes, serve as the vector in most of the ongoing hemophilia studies.3 The vector delivers the functional gene into a patient’s liver cells, which can then properly produce blood-clotting proteins. 4,5 However, patients’ pre-existing immunity to AAV8 capsid, and other AAV serotypes, can impact the safety and efficacy of these therapies.3
To better understand the prevalence of pre-existing immunity against commonly used AAV2, AAV5 and AAV8 capsid in adult patients with hemophilia, Takeda conducted an international prospective and ongoing epidemiological study, “Co-Prevalence of Pre-Existing Immunity to Different Serotypes of Adeno-Associated Virus (AAV) in Adults with Hemophilia,” (abstract 3349) that found 50% of patients with hemophilia have neutralizing antibodies to AAV2, AAV5 or AAV8 capsid with 40% demonstrating co-prevalence to all three evaluated serotypes. As a result, these patients are not likely to respond to gene therapies based on AAV vectors.3
“As we continue to advance our hemophilia A and hemophilia B investigational gene therapy programs, Takeda is also investigating approaches to overcome the challenges of current AAV gene therapies that could potentially be applied to hemophilia and other rare monogenic diseases,” said Dan Curran, M.D., Head, Rare Diseases Therapeutic Area Unit at Takeda. “Developing new gene therapy approaches – including those capable of treating pre-existing immunity to AAV, enabling re-dosing, lowering doses, enhancing biodistribution and developing alternative gene delivery vehicles – are critical to one day providing functional cures to patients.”
The poster “AAV8-Specific Immune Adsorption Column: A Treatment Option for Patients with Pre-Existing Anti-AAV8 Neutralizing Antibodies,” (abstract 5922) reported pre-clinical data on one potential approach to overcoming pre-existing AAV immunity.6 In the study, an AAV8-specific immune adsorption column (IAC) was used to mimic the processing of patients’ plasma in an in vitro setting by applying different treatment cycles to plasma reservoirs which shows anti-AAV8 titers could be depleted.6 Insights from this study will be applied to Takeda’s research to determine if an IAC could enable the administration of AAV8 gene therapies to patients with pre-existing immunity and potentially facilitate the re-administration of gene therapy.6
ADYNOVATE Professional Important Information
ADYNOVATE [Antihemophilic Factor (Recombinant), PEGylated] Important Information
Indications and Limitation of Use
ADYNOVATE is a human antihemophilic factor indicated in children and adults with hemophilia A (congenital factor VIII deficiency) for:
- On-demand treatment and control of bleeding episodes
- Perioperative management
- Routine prophylaxis to reduce the frequency of bleeding episodes
ADYNOVATE is not indicated for the treatment of von Willebrand disease.
DETAILED IMPORTANT RISK INFORMATION
CONTRAINDICATIONS
Prior anaphylactic reaction to ADYNOVATE, to the parent molecule (ADVATE [Antihemophilic Factor (Recombinant)]), mouse or hamster protein, or excipients of ADYNOVATE (e.g. Tris, mannitol, trehalose, glutathione, and/or polysorbate 80).
WARNINGS & PRECAUTIONS
Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with other recombinant antihemophilic factor VIII products, including the parent molecule, ADVATE. Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema, chest tightness, dyspnea, wheezing, urticaria, and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to factor VIII can occur following administration of ADYNOVATE. Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected, or if bleeding is not controlled with expected dose.
ADVERSE REACTIONS
The most common adverse reactions (≥1% of subjects) reported in the clinical studies were headache and nausea.
Click here for Full Prescribing Information https://www.shirecontent.com/PI/PDFs/ADYNOVATE_USA_ENG.pdf
FEIBA [Anti-Inhibitor Coagulant Complex] Indications and Detailed Important Risk Information
Indications for FEIBA
FEIBA is an Anti-Inhibitor Coagulant Complex indicated for use in hemophilia A and B patients with inhibitors for:
- Control and prevention of bleeding episodes
- Perioperative management
- Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
FEIBA is not indicated for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX.
Detailed Important Risk Information for FEIBA
WARNING: EMBOLIC AND THROMBOTIC EVENTS
- Thromboembolic events have been reported during post-marketing surveillance following infusion of FEIBA, particularly following the administration of high doses (above 200 units per kg per day) and/or in patients with thrombotic risk factors.
- Monitor patients receiving FEIBA for signs and symptoms of thromboembolic events.
CONTRAINDICATIONS
FEIBA is contraindicated in patients with:
- History of anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components, including factors of the kinin generating system
- Disseminated intravascular coagulation (DIC)
- Acute thrombosis or embolism (including myocardial infarction)
WARNINGS AND PRECAUTIONS
Thromboembolic events (including venous thrombosis, pulmonary embolism, myocardial infarction, and stroke) can occur, particularly following the administration of high doses (>200 units/kg/day) and/or in patients with thrombotic risk factors.
Patients with DIC, advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with recombinant factor VIIa have an increased risk of developing thrombotic events due to circulating tissue factor or predisposing coagulopathy. Potential benefit of treatment should be weighed against potential risk of these thromboembolic events.
Infusion should not exceed a single dose of 100 units/kg and daily doses of 200 units/kg. Maximum injection or infusion rate must not exceed 2 units/kg/minute. Monitor patients receiving >100 units/kg for the development of DIC, acute coronary ischemia and signs and symptoms of other thromboembolic events. If clinical signs or symptoms occur, such as chest pain or pressure, shortness of breath, altered consciousness, vision, or speech, limb or abdomen swelling and/or pain, discontinue FEIBA and initiate appropriate diagnostic and therapeutic measures.
Safety and efficacy of FEIBA for breakthrough bleeding in patients receiving emicizumab has not been established. Cases of thrombotic microangiopathy (TMA) were reported in a clinical trial where subjects received FEIBA as part of a treatment regimen for breakthrough bleeding following emicizumab treatment. Consider the benefits and risks with FEIBA if considered required for patients receiving emicizumab prophylaxis. If treatment with FEIBA is required for patients receiving emicizumab, the hemophilia treating physician should closely monitor for signs and symptoms of TMA. In FEIBA clinical studies TMA has not been reported.
Hypersensitivity and allergic reactions, including severe anaphylactoid reactions, can occur. Symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension. Reactions can be severe and systemic (e.g., anaphylaxis with urticaria and angioedema, bronchospasm, and circulatory shock). Other infusion reactions, such as chills, pyrexia, and hypertension have also been reported. If signs and symptoms of severe allergic reactions occur, immediately discontinue FEIBA and provide appropriate supportive care.
Because FEIBA is made from human plasma it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
FEIBA contains blood group isohemagglutinins (anti-A and anti-B). Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D, may interfere with some serological tests for red cell antibodies, such as antiglobulin test (Coombs test).
ADVERSE REACTIONS
Most frequently reported adverse reactions observed in >5% of subjects in the prophylaxis trial were anemia, diarrhea, hemarthrosis, hepatitis B surface antibody positive, nausea, and vomiting.
Serious adverse reactions seen are hypersensitivity reactions and thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis.
DRUG INTERACTIONS
Consider possibility of thrombotic events when systemic antifibrinolytics such as tranexamic acid and aminocaproic acid are used with FEIBA. No adequate and well-controlled studies of combined or sequential use of FEIBA and recombinant factor VIIa, antifibrinolytics, or emicizumab, have been conducted. Use of antifibrinolytics within approximately 6 to 12 hours after FEIBA is not recommended.
Clinical experience from an emicizumab clinical trial suggests that a potential drug interaction may exist with emicizumab.
Please see FEIBA full Prescribing Information, including BOXED
WARNING on Embolic and Thrombotic Events
About Hemophilia
Hemophilia is a challenging chronic disease that causes longer-than-normal bleeding due to absent or deficient clotting factor in the blood.7 Hemophilia A is more common than hemophilia B;7 hemophilia A affects about 158,225 people, whereas hemophilia B affects about 31,247 people worldwide.8
People with hemophilia, working closely with their healthcare professionals, can live healthy lives with proper care and adequate treatment.7 Treatment regimens typically include on-demand and/or regular prophylactic infusions of factor replacement therapy to control or prevent the risk of bleeding.7,8
About Takeda Hematology
Following its recent acquisition of Shire, Takeda is a leader in hemophilia with the longest heritage and market-leading portfolio, backed by established safety and efficacy profiles with decades of real-world experience. We have 70+ years driving innovation for patients9 and a broad portfolio of 11 products across multiple bleeding disorders.10 Our experience as leaders in hematology means we are well prepared to meet today’s needs as we pursue future developments in the care of bleeding disorders. Together with the hematology community, we are raising expectations for the future, including earlier diagnosis, earlier and full protection against bleeds, and more personalized patient care.
About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience and Rare Diseases. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.
For more information, visit https://www.takeda.com.
References
1. National Hemophilia Foundation. Future Therapies. Accessible at: https://www.hemophilia.org/Bleeding-Disorders/Future-Therapies. Accessed: November 2019.
2. Wong, T. & Recht, M. Drugs (2011) 71: 305.
3. Rajavel, K et al. Co-Prevalence of Pre-Existing Immunity to Different Serotypes of Adeno-Associated Virus (AAV) in Adults with Hemophilia. Data on File.
4. Doshi BS, Arruda VR. Gene Therapy for Hemophilia: What Does the Future Hold? Therapeutic Advances in Hematology. 2018; 9(9):273-293.
5. Pipe, SW. Gene therapy for hemophilia. Pediatric Blood Cancer. 2018; 65(2): e26865.
6. Kruzik, A et al. AAV8-specific immune adsorption column: A treatment option for patients with pre- existing anti-AAV8 neutralizing antibodies. Data on File.
7. World Federation of Hemophilia. “What is hemophilia?” World Federation of Hemophilia website. http://www.wfh.org/en/page.aspx?pid=646. Last Accessed April 2019.
8. World Federation of Hemophilia. Report on the Annual Global Survey 2017. World Federation of Hemophilia website. http://www1.wfh.org/publications/files/pdf-1714. pdf Last Accessed April 2019.
9.World Federation of Hemophilia. “About Bleeding Disorders: Treatment.” World Federation of Hemophilia website. https://www.wfh.org/en/page.aspx?pid=642. Last Accessed April 2019.
10. Shire Website. Product List. Website: https://www.shire.com/products/product-list?t=. Last Accessed June 2019.
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