Summary. Background: Routine prophylaxis with replacement factor VIII (FVIII) -the standard of care for severe hemophilia A -often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A. Objective: In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on-study (rFVIIIFc) regimens. Methods: We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n = 80), and prior episodic treatment and on-study weekly prophylaxis (n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimens and annualized bleeding rates (ABRs) in the last 3 months on-study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed. Results: As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels of ≥ 1 IU dL À1 (1%) with rFVIIIFc than with equivalent rFVIII regimens. Conclusion: These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL À1 than with rFVIII products requiring more frequent dosing regimens.

IMPORTANCEThe prognostic value of slow vital capacity (SVC) in relation to respiratory function decline and disease progression in patients with amyotrophic lateral sclerosis (ALS) is not well understood.OBJECTIVE To investigate the rate of decline in percentage predicted SVC and its association with respiratory-related clinical events and mortality in patients with ALS. DESIGN, SETTING, AND PARTICIPANTSThis retrospective study included 893 placebo-treated patients from 2 large clinical trials (EMPOWER and BENEFIT-, respectively) and an ALS trial database (PRO-ACT, containing studies completed between 1990 and 2010) to investigate the rate of decline in SVC. Data from the EMPOWER trial (which enrolled adults with possible, probable, or definite ALS; symptom onset within 24 months before screening; and upright SVC at least 65% of predicted value for age, height, and sex) were used to assess the relationship of SVC to respiratory-related clinical events; 456 patients randomized to placebo were used in this analysis. The 2 clinical trials included patients from North America, Australia, and Europe. MAIN OUTCOMES AND MEASURES Clinical events included the earlier of time to death or time to decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) respiratory subdomain, time to onset of respiratory insufficiency, time to tracheostomy, and all-cause mortality.RESULTS Among 893 placebo-treated patients with ALS, the mean (SD) patient age was 56.7 (11.2) years, and the mean (SD) SVC was 90.5% (17.1%) at baseline; 65.5% (585 of 893) were male, and 20.5% (183 of 893) had bulbar-onset ALS. In EMPOWER, average decline of SVC from baseline through 1.5-year follow-up was −2.7 percentage points per month. Steeper declines were found in patients older than 65 years (−3.6 percentage points per month [P = .005 vs <50 years and P = .007 vs 50-65 years) and in patients with an ALSFRS-R total score of 39 or less at baseline (−3.1 percentage points per month [P < .001 vs >39]). When the rate of decline of SVC was slower by 1.5 percentage points per month in the first 6 months, risk reductions for events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months, 22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy or death after 6 months, and 23% for death at any time after 6 months (P < .001 for all). CONCLUSIONS AND RELEVANCEThe rate of decline in SVC is associated with meaningful clinical events in ALS, including respiratory failure, tracheostomy, or death, suggesting that it is an important indicator of clinical progression.Role of the Funder/Sponsor: The study sponsor (Cytokinetics, Inc) was involved in the design and conduct of these analyses, including collection and analysis of data, generation of the statistical tables, and interpretation of this study.

Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T−B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia.

Given the impact of NIV on respiratory function and the importance of respiratory function to quality of life and survival, understanding differences that influence NIV prescribing is critical. This information may inform future study design and identify areas warranting additional research to develop best practices for NIV implementation.

Introduction: Characterize the burden of illness in pediatric patients with congen ital athymia who were receiving supportive care. Methods: This cross-sectional study of adult caregivers of patients with congenital athymia used both a quantitative survey and qualitative

Aims: Congenital athymia is an ultra-rare pediatric condition characterized by the lack of thymus in utero and the naïve T cells critical for infection defense and immune regulation. Patients with congenital athymia receive supportive care to minimize and treat infections, autoimmune phenomena, and autologous graft-versus-host disease (aGVHD) manifestations, but historically, die within the first 3 years of life with supportive care only. We estimated the healthcare resource utilization and economic burden of supportive care over patients' first 3 years of life in the United States. Methods: A medical chart audit by the treating physician was used to collect patient data from birth to age 3 on clinical manifestations associated with congenital athymia (clinical manifestations due to underlying syndromic conditions excluded). Using costs and charges from publicly available sources, the total economic burden of direct medical costs and charges for the first 3 years of life (considered "lifetime" for patients receiving supportive care) and differences in economic burden between patients with higher and lower inpatient hospitalization durations were estimated. Results: All patients (n ¼ 10) experienced frequent infections and aGVHD manifestations; 40% experienced !1 episode of sepsis, and 20% had recurrent sepsis episodes annually. The estimated mean 3year economic burden per patient was US$5,534,121 (2020 US dollars). The annual mean inpatient hospitalization duration was 150.6 days. Inpatient room charges accounted for 79% of the economic burden, reflecting the high costs of specialized care settings required to prevent infection, including isolation. Patients with high inpatient utilization (n ¼ 5; annual mean inpatient hospitalization duration, 289.6 days) had an estimated 3-year economic burden of US$9,926,229. Limitations: The total economic burden may not be adequately represented due to underestimation of some direct costs or overestimation of others. Conclusions: Current treatment of patients with congenital athymia (supportive care) presents a high economic burden to the healthcare system.

Introduction Prophylaxis with factor VIII (FVIII) in patients with severe hemophilia A requires frequent intravenous injections (3–4 per week), impacting compliance and outcomes. A long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) was developed to reduce the frequency of injections. The pharmacokinetics (PK), safety, and efficacy of rFVIIIFc were evaluated in the phase 3 A-LONG study and the primary results were reported recently (Mahlangu J, J Thromb Haemost 2013). To illustrate differences in dosing regimens and clinical outcomes with rFVIIIFc and currently available FVIII products, we compared the prestudy and on-study dose, dose interval, and bleeding rates for subjects in A-LONG who reported receiving a prophylactic regimen with any FVIII product prior to study entry. We also used population PK models to estimate trough FVIII levels on various dosing regimens of rFVIIIFc and rFVIII (Advate®). Methods Previously treated male patients who were ≥12 years old with severe hemophilia A were enrolled in A-LONG and assigned to 1 of 3 treatment arms: Arm 1, individualized prophylaxis with PK-driven dose and dose interval adjustments (25–65 IU/kg every 3–5 days); Arm 2, once weekly prophylaxis (65 IU/kg); and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. A 2-compartmental population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12-65 years old (16 from a phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment). A 2-compartment population PK model of Advate® was developed based on the single-dose PK profiles from 16 subjects in the phase 1/2a study and 30 subjects in the sequential PK subgroup in A-LONG. The population PK estimates for Advate® and rFVIIIFc from A-LONG were used for dosing simulations. We identified Arm 1 subjects who reported use of a prophylactic regimen at least 2 times a week with any FVIII product prior to study entry and compared their dosing regimens and bleeding rate in the 12 months prior to study with their rFVIIIFc dosing regimens and annualized bleed rate (ABR) on study. Only subjects on study for ≥ 6 months were included. The median ABR, dose, and dose interval during the last 3 months on study were analyzed. Results Of 165 total patients, 118 were in Arm 1, of whom 80 received a prophylactic regimen at least 2 times a week prestudy and were in the study for ≥ 6 months. Subjects were grouped by prestudy dosing interval. The table below provides prestudy and on study dose, dose interval, and bleeding rates for these groups. The majority of patients (65/80) reported a dosing interval of 3 times a week, with the most common dose of 25 IU/kg FVIII, and a median of 5.5 bleeding events 12 months prior to study entry. At the end of the study, these same patients were receiving ∼40 IU/kg rFVIIIFc twice a week (every 3.5 days) with a median ABR of 0. Population PK simulation indicated that 76.1% of patients treated with 40 IU/kg of rFVIIIFc twice a week would maintain FVIII levels above 1% at all times. In contrast, population PK simulation indicated that 42.3% of patients treated with 25 IU/kg of Advate® 3 times a week would maintain FVIII levels above 1% at all times. Overall, rFVIIIFc was well tolerated and no inhibitor development was detected during the A-LONG study. Conclusion The results from this descriptive analysis of dose, dose interval, and bleeding rates for subjects with severe hemophilia A who were on prophylaxis suggest that switching from current FVIII products to a rFVIIIFc regimen may allow for less frequent dosing to maintain FVIII activity >1%. Disclosures: Shapiro: Baxter: Consultancy, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Global steering committees, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Inspiration: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding. Ragni:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Smith Kline Glaxo: Consultancy, Research Funding; Tacere Benitec: Consultancy; Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Merck: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity’s Board of Directors or advisory committees. Kulke:Biogen Idec: Employment. Potts:Biogen Idec: Employment. Neelakantan:Biogen Idec: Employment. Nestorov:Biogen Idec: Employment. Dumont:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Brennan:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership.

Introduction Prophylactic regimens with coagulation factor in patients with hemophilia A have been designed to maintain FVIII activity above 1 IU/dL, based on previous studies demonstrating that joints can be preserved and bleeding is minimized when circulating factor levels remain above this level (Nilsson IM, et al. J Intern Med 1992). Collins and colleagues confirmed this observation and demonstrated that increasing time spent under 1 IU/dL FVIII activity in patients on prophylaxis with recombinant FVIII (rFVIII) was associated with an increase in bleeding episodes and hemarthroses (Collins PW, et al. J Thromb Haemost 2009). The pharmacokinetics (PK), safety, and efficacy of rFVIII Fc fusion protein (rFVIIIFc) have been evaluated in the A-LONG study and recently reported (Mahlangu J, et al. J Thromb Haemost 2013). Briefly, previously treated male patients, ≥12 years old with severe hemophilia A, were enrolled in A-LONG and allocated to 1 of 3 treatment arms: Arm 1) individualized prophylaxis with dose and dosing interval adjustments (25–65 IU/kg every 3–5 days) based on PK and clinical indications, Arm 2, fixed dose (65 IU/kg) weekly prophylaxis, and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. The median annualized bleeding rates for individualized prophylaxis and weekly prophylaxis were 1.6 and 3.6, respectively, and 33.6 for episodic treatment. In this analysis, we evaluated the bleeding tendency in relation to predicted FVIII activity levels in 163 subjects in the A-LONG study. Methods A 2-compartment population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12 – 65 years old (16 from a Phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment) (Neelakantan S, et al. J Thromb Haemost 2013). Individual post-hoc PK parameters were derived to construct continuous FVIII activity-time profiles for each dose administered over the course of the study for 163 subjects in A-LONG. The cumulative time under 1IU/dL FVIII levels for each individual on study was calculated and normalized to obtain annualized time under 1IU/dL. Negative binomial regression models were used to evaluate associations between the number of bleeding episodes (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1IU/dL FVIII activity. Models were adjusted for age, body mass index, baseline HIV and HCV status, baseline von Willebrand factor, number of bleeding episodes in the 12 months prior to study entry, and each subject’s time on study. Results The predicted median annualized time under 1IU/dL FVIII activity for subjects on episodic treatment was 224.81 days, which was shortened to 51.55 days in subjects on a fixed prophylactic dose of 65 IU/kg of rFVIIIFc once weekly, and further reduced to 2.17 days in subjects on tailored prophylactic regimens (25 – 65 IU/kg, every 3 – 5 days). Multivariable negative binomial regression analysis showed that the number of overall bleeding episodes increased with increased time spent under 1IU/dL of FVIII activity level (p<0.001). A significant association was also observed for the time under 1IU/dL and the individual bleed types (spontaneous, traumatic, and joint) when analyzed separately. In addition, across all subtypes of bleeding, there was a significant decrease in the odds of being bleed-free for each one day increase in the time spent under 1IU/dL of FVIII activity. Conclusions In subjects treated with rFVIIIFc in the A-LONG study, there was a significant association between increased time spent under 1IU/dL of FVIII activity and increased bleeding tendency, as well as decreased odds of being bleed-free. The findings reinforce the importance of a therapeutic threshold of 1 IU/dL of FVIII activity as reported previously, and contribute to building a stronger foundation for designing effective rFVIIIFc prophylactic dosing regimens based on population PK simulations of FVIII activity. Disclosures: Pasi: Bayer: Membership on an entity’s Board of Directors or advisory committees; Bio Products Laboratory Ltd: Membership on an entity’s Board of Directors or advisory committees; OctaPharma : Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Wang:Biogen Idec: Employment. Kulke:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.