Optimizing Liver Health Before and After Gene Therapy for Hemophilia A.

Gene therapy for severe hemophilia A employs an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in FVIII activity. Thus, hepatocyte health is an essential aspect of safe and successful gene therapy. Many people living with hemophilia A have current or past chronic hepatitis C virus infection, metabolic dysfunction-associated steatosis or steatohepatitis, or other conditions that may compromise the efficacy and safety of AAV-mediated gene therapy. In addition, gene therapy may induce an immune response to transduced hepatocytes, leading to liver inflammation and reduced FVIII activity. The immune response can be treated with immunosuppression, but close monitoring of liver function tests and factor levels is necessary. The long-term risk of hepatocellular carcinoma associated with gene therapy is unknown. Routine screening by imaging for hepatocellular carcinoma, preferable every 6 months, is essential in patients at high risk and recommended in all recipients of hemophilia A gene therapy. This paper describes our current understanding of the biologic underpinnings of how liver health affects hemophilia A gene therapy, and provides practical clinical guidance for assessing, monitoring, and managing liver health both before and after gene therapy.

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A.

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and F8-mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The F8-mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with CTLA4 assigned SNPs (p=2.2E-5). The F8-mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of F8-mutation-effects and non-F8-genetics.

Early real-world experience with emicizumab and concomitant factor VIII replacement products in adult males with Hemophilia A without inhibitors.

AIMS: To assess real-world use of emicizumab in adult people with hemophilia A (PwHA) without inhibitors including healthcare resource utilization (HCRU) and costs. MATERIALS AND METHODS: Adult, male PwHA without inhibitors initiating emicizumab (index date) were identified using IBM MarketScan after 4 October 2016. Patients were required to have continuous health insurance coverage for ≥180 days prior to and ≥90 days after index date and have ≥90 days of continuous use of emicizumab. Patients were followed until treatment gap, disenrollment, or end of data. Results were reported overall and among a subgroup with prior factor VIII (FVIII) prophylaxis. Emicizumab use, concomitant FVIII treatment use, HCRU, and costs were assessed separately over baseline, the emicizumab induction period, emicizumab maintenance period, and annualized. RESULTS: Among the 71 emicizumab patients (FVIII prophylaxis subgroup: 52) included in the study, the mean age was 35 (subgroup: 34) years and mean follow-up was 12 (subgroup: 11.1) months. At baseline, the annualized mean total healthcare cost was $532,948 (subgroup: $645,727). After emicizumab initiation, per-patient-per-month (PPPM) HCRU was higher in the emicizumab induction period compared to the maintenance period with higher monthly FVIII fills/in-office administrations (0.37 vs 0.17), non-FVIII outpatient visits (2.23 vs 1.55), and emergency department visits (0.06 vs 0.03). The FVIII prophylaxis subgroup yielded similar HCRU trends. Hemophilia treatment costs accounted for over 95% of total healthcare costs. The annualized mean cost was $50,491 (subgroup: $61,512) for concomitant FVIII treatment and $777,171 (subgroup: $793,168) for emicizumab and concomitant FVIII treatment for the first year of emicizumab treatment. CONCLUSION: This study represented experience with emicizumab after the approval for PwHA without inhibitors. The study cohort may not be representative of all PwHA taking emicizumab. The findings highlight the continued burden of treatment and healthcare cost for PwHA without inhibitors despite advances in treatment options.

Safety of a pasteurized plasma-derived Factor VIII and von Willebrand factor concentrate: analysis of 33 years of pharmacovigilance data.

BACKGROUND: Haemate-P/Humate-P (Humate-P) is a pasteurized human plasma-derived concentrate containing both Factor VIII and von Willebrand factor for treatment of hemophilia A and von Willebrand disease (VWD). STUDY DESIGN AND METHODS: We analyzed the safety of Humate-P based on more than 33 years of postmarketing pharmacovigilance data, representing an estimated exposure of approximately 25,000 patient-years. The analysis comprises reports of potential adverse drug reactions (ADRs) from all sources, reported as part of routine pharmacovigilance at CSL Behring. ADRs considered clinically relevant or potential risks of Humate-P were identified based on defined and standardized Medical Dictionary for Regulatory Activities queries. Recognizing the limitations of spontaneous reporting, we also reviewed the literature, including clinical trials with mandatory reporting. RESULTS: From 1982 to 2015, a total of 670 postmarketing cases had been reported via pharmacovigilance, for an overall reporting rate of approximately one ADR per 3900 administered standard doses. Of these cases, 343 involved ADRs considered clinically relevant risks (33 thromboembolic complications, 97 inhibitor formation, 110 hypersensitivity or allergic reactions) or potential risks (103 suspected virus transmissions) for Humate-P. Most thromboembolic complications occurred in patients undergoing surgery or with other known risk factors. Inhibitor formation occurred mostly in patients with hemophilia A (24 cases were high titer). Most patients with hypersensitivity or allergic reactions had VWD. None of the reported suspected virus transmission cases were confirmed to be associated with Humate-P. Reported results of company-sponsored studies showed a low incidence of adverse events possibly or probably related to Humate-P. CONCLUSIONS: More than 33 years of pharmacovigilance data continue to support the safety of Humate-P.