Safety first: Tracking adverse events associated with new therapies for people with hemophilia

Abstract

The year 1992 was momentous for individuals affected by hemophilia. Eight years after the successful cloning of the factor VIII gene and 5 years after clinical trials assessing the safety and efficacy of recombinant factor VIII concentrates commenced, Food and Drug Administration approval was granted to recombinant factor VIII concentrates.1.Schwartz R.S. Abildgaard C.F. Aledort L.M. et al.Human recombinant DNA‐derived antihemophilic factor (factor VIII) in treatment of hemophilia A. Recombinant factor VIII study group.N Engl J Med. 1990; 323: 1800-1805Crossref PubMed Scopus (215) Google Scholar, 2.Inwood M. Lusher J. Clinical trials of the recombinant factor VIII product, Kogenate.Transfusion Med Rev. 1992; 6: 261-262Crossref PubMed Scopus (5) Google Scholar The cloning of factor IX, first reported in 1982, resulted in a licensed recombinant factor IX concentrate in 1997.3.Hemophilia: From plasma to recombinant factors. http://www.hematology.org/about/history/50‐years/hemophilia. Accessed October 11, 2020.Google Scholar The development of these medications was driven by the scourge of HIV and hepatitis C virus (HCV) infection of the plasma‐derived factor concentrates in the 1970s and 1980s.4.Gringeri A. Factor VIII safety: plasma‐derived versus recombinant products.Blood Transfus. 2011; 9: 366-370PubMed Google Scholar The year 1992 was also momentous for me as I first participated in the care of children with hemophilia. Working with Diana Beardsley at the Hemophilia Treatment Center at Yale University, I learned the physiology of hemostasis and thrombosis as well as the true human cost of hemophilia, not only on the affected children but also on their parents and family members as they watched their children live in pain during bleeding episodes and grieved as many succumbed to HIV infection. It was during this formative period of my training when I pledged my professional life to ensuring the safe and effective care for all those affected by bleeding disorders. Fast forward 28 years. The hemophilia community is in the midst of a therapeutic transformation as stunning as the development of recombinant factor concentrates. Extended half‐life factor concentrates, with their ability to target higher trough levels, are making significant inroads. Emicizumab, a factor VIII mimetic, has been Food and Drug Administration‐approved for use in people of all ages with hemophilia A with or without FVIII inhibitors.5.Oldenburg J. Mahlangu J.N. Kim B. et al.Emicizumab prophylaxis in hemophilia A with inhibitors.N Engl J Med. 2017; 31: 809-818Crossref Scopus (595) Google Scholar, 6.Young G. Liesner R.I. Chang T. et al.A multicenter, open‐label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.Blood. 2019; 134: 2127-2138Crossref PubMed Scopus (167) Google Scholar, 7.Mahlangu J. Oldenburg J. Paz‐Priel I. et al.Emicizumab prophylaxis in patients who have hemophilia A without inhibitors.N Engl J Med. 2018; 30: 811-822Crossref Scopus (365) Google Scholar Multiple medications inhibiting hemostatic inhibitors are in late‐phase clinical trials.8.Wayand A.C. Pipe S.W. New therapies for hemophilia.Blood. 2019; 133: 389-398Crossref PubMed Scopus (87) Google Scholar Gene therapy vectors have been shown to increase endogenous factor levels, with one factor IX vector demonstrating durability for over 8 years.9.Nathwani A.C. Gene therapy for hemophilia.Hematology Am Soc Hematol Educ Program. 2019; 2019: 1-8Crossref PubMed Scopus (65) Google Scholar With these advances in the available treatment options for people with hemophilia, our commitment to ensuring the safety and effectiveness of these new therapeutic modalities must redouble. That is why the series of papers in this month's issue of JTH are so interesting and important. Written by a consortium of the most respected and published investigators in our field (with all three manuscripts supported by Roche/Genentech, the manufacturer of emicizumab) we are walked through: (a) a review of contemporary data describing mortality for people with congenital hemophilia;10.Hay C.R.M. Nissen F. Pipe S.W. Mortality in congenital hemophilia A ‐ a systematic literature review.J Thromb Haemost. 2021; 19: 6-20Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar (b) a proposal for more thoroughly assessing the cause of death in people with congenital hemophilia;11.Pipe S.W. Kruse‐Jarres R. Mahlangu J.N. et al.Establishment of a framework for assessing mortality in persons with congenital hemophilia A and its application to an adverse event reporting database.J Thromb Haemost. 2021; 19: 21-31Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar and (c) an analysis of the Roche Emicizumab Global Safety Database using the proposed mortality assessment framework.12.Peyvandi F. Mahlangu J. Pipe S.W. et al.Application of a hemophilia mortality framework to the Emicizumab Global Safety Database.J Thromb Haemost. 2021; 19: 32-41Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar I suspect one driver behind the production of these manuscripts is the recent focus on individuals who had received emicizumab and died, both in medical literature as well as in the lay press.13.Aledort L.M. Deaths associated with emicizumab in patients with hemophilia A.N Engl J Med. 2019; 381: 1878-1879Crossref PubMed Scopus (13) Google Scholar, 14.https://www.drug-injury.com/druginjurycom/2019/12/hemlibra-adverse-events-reports-deaths-patients-hemophilia-drug-safety-issues.html. Accessed October 12, 2020.Google Scholar In an attempt to provide “balanced, peer‐reviewed, and scientifically rigorous clinical information about emicizumab‐kxwh,” Roche had set up a website, www.emicizumabinfo.global, containing a curated collection of publications and scientific presentations, guidelines and recommendations, and medical resource links (including a link to the US Food and Drug Administration's searchable Adverse Event Reporting System (FAERS) database).15.https://www.emicizumabinfo.global/us/en/homepage.html. Accessed October 12, 2020.Google Scholar Of note, the quarterly updates on thrombotic microangiopathy, serious thrombotic events, and reported fatalities previously available on this website were last reported on June 30, 2020, and are no longer being updated. Rather, Roche/Genentech has elected to share data on the safety and effectiveness of emicizumab through peer‐reviewed publications and presentations to the scientific community. So, what are the important conclusions from this series of papers? From the Hay manuscript,10.Hay C.R.M. Nissen F. Pipe S.W. Mortality in congenital hemophilia A ‐ a systematic literature review.J Thromb Haemost. 2021; 19: 6-20Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar we learned mortality in people with congenital hemophilia has generally decreased over time, despite an increase in deaths associated with HIV and HCV infections in the 1980s and 1990s, with mortality strongly correlated with age and hemophilia severity. Even with incomplete and heterogenous reporting, bleeding, infections with HIV and HCV, and liver disease were the leading causes of death in people with hemophilia. In the Pipe et al manuscript,11.Pipe S.W. Kruse‐Jarres R. Mahlangu J.N. et al.Establishment of a framework for assessing mortality in persons with congenital hemophilia A and its application to an adverse event reporting database.J Thromb Haemost. 2021; 19: 21-31Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar the authors propose a framework for assessing the cause of death in people with congenital hemophilia, separating out those causes of mortality definitely linked to hemophilia (hemorrhage and non‐HCV‐related liver causes), hemophilia‐related but potentially overlapping with non‐hemophilia‐related causes (HIV/HCV and thrombosis), non‐hemophilia‐related but potentially overlapping with hemophilia‐related causes (other infections and nonthrombotic cardiovascular disease) and non‐hemophilia related (trauma/suicide, diabetes, malignancy, and pulmonary disease). The authors apply their framework to the 519 fatalities of people with congenital hemophilia A in the FAERS database. Of all the deaths reported, more than one‐third were directly related to an individual's diagnosis of hemophilia. As is often the case when analyzing registry data, particularly registry data allowing free text input, a causality of death could not be assigned in more than one‐third of the deaths. In the Peyvandi et al manuscript,12.Peyvandi F. Mahlangu J. Pipe S.W. et al.Application of a hemophilia mortality framework to the Emicizumab Global Safety Database.J Thromb Haemost. 2021; 19: 32-41Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar the authors applied the framework proposed by Pipe et al to the 31 deaths of those individuals with congenital hemophilia A receiving emicizumab known the Roche Emicizumab Global Safety Database. They found no unique risk of death associated with emicizumab use in people with congenital hemophilia A. The important takeaway messages from these manuscripts are:•People with congenital hemophilia A die earlier than the population in general.•A majority of deaths with a reported cause in people with congenital hemophilia are associated with hemophilia‐related causes.•The deaths in people with congenital hemophilia A receiving emicizumab appear to mirror the causes of death in people with congenital hemophilia A not receiving emicizumab.•Rather than relying on isolated reports of fatalities, a more exacting, harmonized, and prospective approach to reporting the cause of death in people with congenital hemophilia is an international priority. At the American Thrombosis and Hemostasis Network (ATHN), we have anticipated this call to action. The primary aim of ATHN 7: Hemophilia Natural History Study (NCT03619863) (currently transitioning into the hemophilia cohort of ATHN Transcends [NCT04398628]) is collecting safety data around current therapies for hemophilia, concentrating on European Haemophilia Safety Surveillance (EUHASS) endpoints, including deaths. By harmonizing our data collection methodologies with those collected by EUHASS, we are able to capture emerging safety signals of any new therapy, including nonfactor molecules and gene therapy, in people with hemophilia in a timely manner. Looking back on 1992 and the beginning of my career caring for those affected by bleeding disorders, I could not have predicted the astonishing advances in the breadth of therapies available to my patients currently and in the future. That said, my pledge for avoiding the tragedies of the past has strengthened. Only through long‐term national and international collaboration (such as ATHN Transcends and EUHASS) will providers, researchers, hemophilia research organizations, industry, and those affected by hemophilia be able to recognize potential safety signals for new therapies currently in clinical trials and those approved by national regulatory agencies. The framework proposed by Pipe et al should be applied to all therapies for hemophilia using ATHN Transcends in the United States and harmonized national data collection organizations worldwide. Research funding to the author’s employers: Bayer, BioMarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma Sanofi, Spark, Takeda, uniQure. Consulting/advisory boards: Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, Novo Nordisk, Pfizer, Sanofi, Takeda, uniQure. Board of Directors: Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders. Employment: American Thrombosis and Hemostasis Network, Oregon Health & Science University.