ABSTRACT:Fidanacogene elaparvovec is a single-dose gene therapy designed to express the high-activity factor IX (FIX) variant FIX-R338L. Participants (N = 15) with FIX activity of ≤2% were dosed with 5 × 1011 vector genomes per kilogram infusion of fidanacogene elaparvovec and completed the 1-year dosing trial. After the initial 52 weeks, participants could enroll in long-term follow-up (LTFU) for 5 additional years. This report includes final safety and efficacy data of the LTFU trial through 6 years after gene therapy, with additional patient-reported outcomes (PROs). Of 14 participants enrolled in the LTFU, 11 completed 6 years of follow-up. During years 2 to 6, 9 serious adverse events were reported in 4 participants (28.6%); none were considered treatment-related or resulted in study discontinuation or death. Eight participants had increased alanine aminotransferase levels, and 3 of 8 also had increased aspartate aminotransferase levels; none received corticosteroids. No liver masses, malignancies, thrombotic events, or FIX inhibitors were reported. FIX activity was maintained, with a mean FIX activity of 24.7% at year 2 (n = 14) and 26.1% at year 6 (n = 11). Mean treated annualized bleeding rates remained lower than 1.0 (median, 0.0) during each year of follow-up. Ten participants (71%) had no treated bleeding events. None of the 14 enrolled participants resumed FIX prophylaxis. Improvements relative to before gene therapy in PROs and target joints were observed over the duration of follow-up. Overall, fidanacogene elaparvovec exhibited a favorable safety profile, sustained efficacy, and improved PROs for up to 6 years. This trial is registered at www.clinicaltrials.gov as NCT03307980.

BACKGROUND:Assessing the risk of radiation-induced hematologic cancer from medical imaging in children and adolescents might support informed decisions on the use of imaging. METHODS:We followed a retrospective cohort of 3,724,623 children born between 1996 and 2016 in six U.S. health care systems and Ontario, Canada, until the earliest of cancer or benign-tumor diagnosis, death, end of health care coverage, an age of 21 years, or December 31, 2017. Radiation doses to active bone marrow from medical imaging were quantified. Associations between hematologic cancers and cumulative radiation exposure (vs. no exposure), with a lag of 6 months, were estimated with the use of continuous-time hazards models. RESULTS:During 35,715,325 person-years of follow-up (mean, 10.1 years per person), 2961 hematologic cancers were diagnosed, primarily lymphoid cancers (2349 [79.3%]), myeloid cancers or acute leukemia (460 [15.5%]), and histiocytic- or dendritic-cell cancers (129 [4.4%]). The mean (±SD) exposure among children exposed to at least 1 mGy was 14.0±23.1 mGy overall (for comparison, 13.7 mGy was the exposure from one computed tomographic [CT] scan of the head) and 24.5±36.4 mGy among children with hematologic cancer. Cancer risk increased with cumulative dose, with a relative risk (vs. no exposure) of 1.41 (95% confidence interval [CI], 1.11 to 1.78) for 1 to less than 5 mGy, 1.82 (95% CI, 1.33 to 2.43) for 15 to less than 20 mGy, and 3.59 (95% CI, 2.22 to 5.44) for 50 to less than 100 mGy. The cumulative radiation dose to bone marrow was associated with an increased risk of all hematologic cancers (excess relative risk per 100 mGy, 2.54 [95% CI, 1.70 to 3.51; P<0.001]; relative risk for 30 vs. 0 mGy, 1.76 [95% CI, 1.51 to 2.05]) and most tumor subtypes. The excess cumulative incidence of hematologic cancers by 21 years of age among children exposed to at least 30 mGy (mean, 57 mGy) was 25.6 per 10,000. We estimated that, in our cohort, 10.1% (95% CI, 5.8 to 14.2) of hematologic cancers may have been attributable to radiation exposure from medical imaging, with higher risks from the higher-dose medical-imaging tests such as CT. CONCLUSIONS:Our study suggests an association between exposure to radiation from medical imaging and a small but significantly increased risk of hematologic cancer among children and adolescents. (Funded by the National Cancer Institute and others.).

Damoctocog alfa pegol (BAY 94-9027, Jivi®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate®/Adynovi®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences.

Introduction The phase 2/3 PROTECT VIII study demonstrated long-term efficacy and safety of damoctocog alfa pegol (BAY 94-9027; Jivi (R)), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to improve its pharmacokinetic profile. Aim We report a post hoc assessment of bleeding and safety outcomes in the subgroup of patients, aged 12-<18 years at enrolment. Method PROTECT VIII was a multicentre, open-label study of previously treated males aged 12-65 years with severe haemophilia A (FVIII<1%). Twelve patients were included in this analysis. All received damoctocog alfa pegol prophylaxis for the total time in study (median [range] time in study 4.0 [1.3-6.2] years). Results Overall median (Q1; Q3) total and joint ABRs were 1.8 (0.4; 5.1) and 0.7 (0.2; 1.8), respectively for the entire study. During the last 6 months of treatment, eight (66.7%) and ten (83.3%) out of twelve patients experienced zero total and joint bleeds, respectively. No patient developed FVIII inhibitors. No deaths or thrombotic events were reported. Conclusion Efficacy and safety of damoctocog alfa pegol was confirmed in adolescent patients with haemophilia A, with data for up to 6 years supporting its use as a long-term treatment option in this group as they transition into adulthood.

BACKGROUND:The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq® ) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A.METHODS:Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study.RESULTS:Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%-88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0-0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0-1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported.CONCLUSION:No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.

Objective To evaluate the frequency of medical imaging or estimated associated radiation exposure in children with Down syndrome.Methods This retrospective cohort study included 4,348,226 children enrolled in six U.S. integrated healthcare systems from 1996-2016, 3,095 of whom were diagnosed with Down syndrome. We calculated imaging rates per 100 person years and associated red bone marrow dose (mGy). Relative rates (RR) of imaging in children with versus without Down syndrome were estimated using overdispersed Poisson regression.Results Compared to other children, children with Down syndrome received imaging using ionizing radiation at 9.5 times (95% confidence interval[CI] = 8.2-10.9) the rate when age <1 year and 2.3 times (95% CI = 2.0-2.5) between ages 1-18 years. Imaging rates by modality in children <1 year with Down syndrome compared with other children were: computed tomography (6.6 vs. 2.0, RR = 3.1[95%CI = 1.8-5.1]), fluoroscopy (37.1 vs. 3.1, RR 11.9[95%CI 9.5-14.8]), angiography (7.6 vs. 0.2, RR = 35.8[95%CI = 20.6-62.2]), nuclear medicine (6.0 vs. 0.6, RR = 8.2[95% CI = 5.3-12.7]), radiography (419.7 vs. 36.9, RR = 11.3[95%CI = 10.0-12.9], magnetic resonance imaging(7.3 vs. 1.5, RR = 4.2[95% CI = 3.1-5.8]), and ultrasound (231.2 vs. 16.4, RR = 12.6[95% CI = 9.9-15.9]). Mean cumulative red bone marrow dose from imaging over a mean of 4.2 years was 2-fold higher in children with Down syndrome compared with other children (4.7 vs. 1.9mGy).Conclusions Children with Down syndrome experienced more medical imaging and higher radiation exposure than other children, especially at young ages when they are more vulnerable to radiation. Clinicians should consider incorporating strategic management decisions when imaging this high-risk population.

Introduction Simoctocog alfa (Nuwiq (R)) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors.Aim To report the efficacy and safety results from the NuProtect study.Methods PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study.Results Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events.Conclusion Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Introduction : The burden of the management and clinical sequelae of hemophilia B (HB) negatively impacts health-related quality of life (HRQoL), including chronic pain and mental health. Fidanacogene elaparvovec (PF-06838435, formerly SPK-9001) is an adeno-associated virus-based gene therapy vector transferring the high activity variant of human factor IX (FIX), FIX-R338L, aimed at enabling endogenous FIX expression in individuals with hemophilia B. We present descriptive data on the impact on HRQoL for participants in the fidanacogene elaparvovec phase 1/2a study. Methods : Fifteen participants with moderately severe to severe hemophilia B (FIX activity ≤2%) received a single infusion of fidanacogene elaparvovec 5e11 vg/kg as part of a phase 1/2a study (NCT02484092). The study was 52 weeks in duration, after which participants were eligible to enroll in a long-term follow-up (LTFU) study for up to 5 years (NCT03307980). All 15 participants completed the phase 1/2a study and 14 subsequently enrolled in the LTFU study (1 participant declined participation). Participants in both studies completed patient-reported outcome (PRO) HRQoL assessments, including the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), the visual analog scale of the EQ-5D (EQ-VAS), and the Change in Level of Activity questionnaire, every 6 months through Week 156 post infusion and then once annually during the LTFU study. The Haem-A-QoL questionnaire consists of 46 items pertaining to 10 domains to assess HRQoL, and domains scores and the Total Score ranging from 0-100 based on the individual items (high scores indicate high impairment in HRQoL). In the EQ-VAS, participants rate their current health state for endpoints of 100 (best imaginable health) to 0 (worst imaginable health). In the Change in Level of Activity questionnaire, participants assess whether they have been doing more/fewer/the same amount or intensity of physical activities in the past month. The data cutoff date was August 2, 2022. Results : For 14 participants (aged 20 to 63 years), the mean (SD) age at entry to the LTFU study was 42 (13.7) years, body mass index was 26.4 (4.4) kg/m 2, and 85.7% were White. Of the 14 participants, 13 had HRQoL data available through Week 156; beyond this time point, there were 10 or fewer participants with both post- and pre-vector infusion (baseline) values. For the Haem-A-QoL assessment, the mean (SD) Total Score at Week 156 (n=12) decreased by 15.2 (10.3) from pre-vector infusion, indicating an improvement in HRQoL ( Fig. 1). A 7-point reduction in the total score has been shown to be clinically meaningful in previous studies (Von Mackensen S et al, Haemophilia 2020;26:1019-30; Wyrwich KW et al, Haemophilia 2015;21:578-84). Of the 12 participants with data at Week 156, 8 had Total Score decreases of 7 or more at each visit through Week 156. Similarly, participant scores for each individual domain decreased over time (implying an improvement in HRQoL) from pre-vector infusion in all instances except for the Dealing with Hemophilia domain ( Fig. 1). Mean EQ-VAS scores were above mean baseline score and were consistently greater than baseline by 7 to 8 points during Year 2 onward, suggesting an improvement in overall health status. At Week 156, the EQ-VAS score increased from baseline by mean (SD) 7.2 (6.2): baseline 83.7 (7.3), n=13; Week 156 91.5 (5.4), n=12. An EQ-VAS score change of 7 points has been shown to be clinically meaningful (Pickard AS et al. Health Qual Life Outcomes 2007;21:5:70). Responses in the Change in Level of Activity questionnaire showed that a greater proportion of participants at each visit (n=12-14) reported doing the same or more intensive physical activities up to Week 156 than reported at baseline ( Fig. 2). No participant reported a reduction in the amount or intensity of physical activities at Week 156 (n=13) ( Fig. 2). Conclusion : HRQoL improvements after gene therapy are an indicator that fidanacogene elaparvovec can reduce the burden associated with hemophilia. PRO assessments will be a part of BENEGENE-2, an ongoing pivotal phase 3 study to demonstrate the efficacy of fidanacogene elaparvovec and will provide additional insights via the analyses of secondary endpoints into HRQoL benefits for participants with HB following gene therapy with fidanacogene elaparvovec.

Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older.

Background: BAX 335 is an adeno-associated virus serotype 8 (AAV8)-based clotting factor IX (FIX) Padua (R338L) gene therapy for the treatment of hemophilia B. A phase 1/2 safety and efficacy study dosed 8 participants with BAX 335 between 2013 and 2015 (NCT01687608). Infusions with BAX 335 were generally well tolerated; however, 7 of 8 participants did not achieve significant levels of durable transgene expression despite the use of glucocorticoids and resumed FIX replacement by 52 weeks (Konkle et al, Blood 2021;137:763-74). A root-cause analysis identified CpG content in the vector as a potential immunogenic trigger for the innate immune response, resulting in loss of expression. One participant demonstrated high levels of durable FIX expression, with detectable FIX activity levels between 0.1 and 0.4 IU/mL after 4 years and was found to have a missense variant in the IL6R gene. This study is the longest ongoing clinical gene therapy trial using a FIX R338L transgene. Aims: (1) To report long-term safety and participant disposition; (2) to describe persistence of endogenous FIX R338L transgene expression; and (3) to report long term persistence of neutralizing anti-capsid antibodies. Methods: Eight adult male participants with hemophilia B (FIX activity ≤2%) received BAX 335 in 1 of 3 intravenous dose cohorts (2.0 x 1011, 1.0 x 1012, or 3.0 x 1012 vector genomes/kg). The primary study objective was to assess the safety of BAX 335. Secondary assessments included the kinetics of plasma FIX activity, the need for exogenous FIX replacement, and systemic immune responses to BAX 335 and vector transgene protein. FIX clotting activity was measured using the one-stage clotting assay at the central laboratory. Serum neutralizing antibodies against the AAV8 and AAV2 capsids were measured to Year 5 following BAX 335 infusion using an in vitro transduction inhibition assay. Laboratory and in-person assessments were conducted for the first 5 years after BAX 335 infusion (one unscheduled visit was made at 7.2 Years). This was followed by annual liver ultrasound scans and telephone questionnaires assessing health status with the aim of completing 15 years of follow-up per participant. The study was approved by the institutional review boards of all participating sites, and all participants provided written informed consent. Results: Of 8 participants enrolled (aged 20-69 years), 2 discontinued from the study approximately 1 and 3 years after receiving BAX 335 infusion, and another participant withdrew consent 2 weeks prior to the data cutoff of May 6, 2022. Data from the 6 participants who had >5 years of long-term safety follow-up were included in this analysis. At data cutoff, 176 adverse events (AEs) were reported in all 8 dosed participants, most (72%) occurred in Years 1 and 2. In total, 6 serious adverse events (SAEs) were reported in 3 participants, of these 2 SAEs (post-procedural hemorrhage, arthritis) were reported after the interim analysis reported by Konkle et al. 2021. None were considered to be related to BAX 335 and all resolved. Although long-term hemostatic protection from bleeds was not observed in most of the participants in this analysis, 1 participant had continued FIX activity (Figure 1), with a most recent value of 0.078 IU/mL at 7.2 years after BAX 335 infusion. This participant has neither experienced any bleeds nor needed FIX replacement therapy after the second week of vector infusion. No FIX inhibitors have been observed. At Year 5, AAV neutralizing antibodies persisted at high titers in most participants (reciprocal of serum dilution: AAV2, <5 to 10,240; AAV8, 80 to 40,960). Conclusions: No additional BAX 335-related AEs, malignancy or thrombosis were reported in this long-term follow-up analysis of a phase 1/2 study. One participant achieved persistent FIX transgene activity in the circulation for 7.2 years and remains free from bleeding and the need for FIX replacement therapy. This is the longest duration of FIX R338L expression reported. Consistent with other studies, AAV neutralizing antibodies remained persistent at titers that would limit re-dosing with current AAV platforms. Future studies should explore patient-specific factors that may predict persistent transgene expression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

INTRODUCTION:FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. METHODS:The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL-1 (≥0.6 to <5 low-titre, ≥5 high titre). RESULTS:A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. CONCLUSION:In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.

Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses.

Objective To assess leukemia risks among children with Down syndrome in a large, contemporary cohort. Study design Retrospective cohort study including 3 905 399 children born 1996-2016 in 7 US healthcare systems or Ontario, Canada, and followed from birth to cancer diagnosis, death, age 15 years, disenrollment, or December 30, 2016. Down syndrome was identified using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes. Cancer diagnoses were identified through linkages to tumor registries. Incidence and hazard ratios (HRs) of leukemia were estimated for children with Down syndrome and other children adjusting for health system, child's age at diagnosis, birth year, and sex. Results Leukemia was diagnosed in 124 of 4401 children with Down syndrome and 1941 of 3 900 998 other children. In children with Down syndrome, the cumulative incidence of acute myeloid leukemia (AML) was 1405/100 000 (95% CI 1076-1806) at age 4 years and unchanged at age 14 years. The cumulative incidence of acute lymphoid leukemia in children with Down syndrome was 1059/100 000 (95% CI 755-1451) at age 4 and 1714/100 000 (95% CI 1264-2276) at age 14 years. Children with Down syndrome had a greater risk of AML before age 5 years than other children (HR 399, 95% CI 281-566). Largest HRs were for megakaryoblastic leukemia before age 5 years (HR 1500, 95% CI 555-4070). Children with Down syndrome had a greater risk of acute lymphoid leukemia than other children regardless of age (<5 years: HR 28, 95% CI 20-40, >= 5 years HR 21, 95% CI 12-38). Conclusions Down syndrome remains a strong risk factor for childhood leukemia, and associations with AML are stronger than previously reported.

Objective Bleeding events (BEs) in persons with hemophilia A or B with inhibitors (PwHABI) impair musculoskeletal structure and function with consequent poor quality of life. An early bleed treatment and resolution is a primary goal in optimal haemophilia management. Eptacog beta (EB - HEMA Biologics and LFB) is a new bypassing agent approved in the USA for the treatment and control of BEs in adult and adolescent PwHABI. In the PERSEPT 1 clinical trial (NCT#02020369), we evaluated efficacy and safety of EB in home treatment in adults and adolescent (age ≥12 years) in different dosages. The aim was to assess the efficacy of 2 initial dose regimens of EB in the treatment of BE in the home setting in PwHABI.