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Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known.In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment.Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir.Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).

Background Immune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors. Methods The functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry. Results Preclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies. Conclusions AGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients. Trial Registration NCT03860272

Background The phenomenon of pseudoprogression (PsP) may appear with cancer immunotherapy. The underlying etiology is not fully elucidated, tumor flare is the suspected mechanism of early pseudoprogression that may resolve gradually while continuing treatment. Further, immunotherapy-induced sarcoidosis may mimic PsP. Here we present examples of 3 observed patterns of PsP in cervical cancer (CC) patients treated with balstilimab (BAL; anti-PD-1), alone or in combination with zalifrelimab (ZAL; anti-CTLA-4). Methods The evaluated patients received either BAL 3 mg/kg every 2 weeks alone (NCT03104699) or in combination with ZAL dosed at 1 mg/kg every 6 weeks (NCT03495882). PsP was defined as radiologic disease progression per RECIST1.1 followed by a significant reduction of measurable baseline lesions, disappearance of the non-measurable lesions, or no further progression for at least two tumor assessments after initial progressive disease (PD) by Independent Evaluation Review Committee (IERC). PsP was divided into 3 categories – early (before or at week 12 of treatment), delayed (after week 12) and serial (at least 2 PsP occurrences). Results Overall, 313 patients with post-chemotherapy recurrent CC with baseline measureable disease were treated with either BAL (n=160) or in combination with ZAL (n=143). Early PsP was observed in 7 patients treated with BAL and 8 with BAL/ZAL while 5 patients experienced delayed PsP (BAL (n=1); ZAL(n=4)). Serial PsP was observed in 1 patient (BAL only) and another (n=1) BAL treated experienced showed PsP (new Mediastinal lesions) present in 2 consecutive CT scan evaluations before disappearance – hence were classified as PD even by iRECIST. Immune-related sarcoidosis was confirmed histologically in 2 patients following confirmation by mediastinal lymph node biopsy. PsPs were accompanied with clear clinical benefit of disease improvement and weight stabilization, improvement in performance status, and decreased painPsP BAL (N=160)) BAL/ZAL (N=143)Early 7 (4%) 8 (6%)Delayed 1 ( Conclusions This is the first report of PsP in CC population. PsP-confounded IERC evaluation of tumor response was seen in some CC patients treated with BAL or combination of BAL and ZAL. The differentiation of PD and PsP has important consequences for disease assessment in clinical trials and disease management and outcomes. Further efforts to elucidate the underlying mechanisms and clearly define the characteristics of PsP are crucial for better treatment management of affected patients. Standard response evaluation systems including iRECIST may need further refinement to recognize the importance of PsP. Trial Registration NCT03104699 and NCT03495882 Ethics Approval C-700-01 : The WIRB Study # is 1173375 and the site IRB approval # is 20170314. and for C-550-01: ICON Cancer Center in South Brisbane, Queensland, Australia.- IRB approval # is 2017-10-766.

Background CD137 (4-1BB) represents a costimulatory pathway that promotes T, NK, and dendritic cell effector functions favorable for antitumor immunity. The extracellular domain of CD137, comprised of four cysteine-rich domains (CRD-I, CRD-II, CRD-III, CRD-IV), trimerizes upon binding to CD137 ligand (CD137L) to induce cell stimulatory transcriptional and epigenetic changes.1 2 The investigation of CD137-targeting agonist antibody, urelumab (CRD-I-binding, IgG4), in human subjects showed immunologic and pharmacodynamic effects, but poor efficacy due to dose-limiting liver toxicity.3 Preclinical studies using a murine surrogate antibody, clone 3H3 (CRD-I-binding, rIgG2a), also demonstrated hepatotoxicity that correlated with activation of CD137-expressing myeloid cells and memory CD8+ T cells.4 5 In contrast, utomilumab (CRD-II/III-binding, IgG2) showed acceptable tolerability, but limited clinical efficacy.6 7 These and more recent findings implicate epitope and Fc gamma receptor (FcγR)-dependent antibody cross-linking as critical factors for CD137 therapeutic antibody design. Methods We investigated the molecular and cellular effects of AGEN2373 (CRD-IV-binding, IgG1), a conditionally active CD137-targeting agonist antibody designed to bind and induce CD137 signaling upon FcγR cross-linking while permitting ligand binding to CD137. The role of epitope and FcγR binding as critical factors for anti-CD137 therapeutic activity were elucidated in primary cell-based assays and syngeneic tumor-bearing mouse models using anti-mouse antibody clones S3B1 (CRD-IV-binding) and 3H3, surrogates of AGEN2373 and urelumab, respectively. In an ongoing phase 1 trial (NCT04121676), we evaluated the safety and tolerability of AGEN2373. Results AGEN2373 bound with high-affinity to CD137 CRD-IV and promoted potent agonist activity of CD137 that was conditionally dependent on Fc-dependent antibody cross-linking. AGEN2373 surrogate, S3B1, showed comparable binding and cross-link dependent agonist activity. In CT26 tumor-bearing mice, S3B1 and 3H3 demonstrated complete tumor control that was not reproducible with a Fc-silent S3B1 antibody. The Fc-dependent activity of S3B1 correlated with induced immunologic changes in the TME including CD8 T cell expansion, NK cell activation, and Treg depletion. Patients with advanced solid cancers, treated with AGEN2373 up to 1 mg/kg every 4 weeks, demonstrate clinical activity with no evidence of hepatotoxicity. Conclusions Conditional and potent agonist activity of AGEN2373 is dependent on binding to CD137 CRD-IV and FcγR. Preclinically, our data demonstrate that AGEN2373-like murine surrogate antibodies promote potent immune activation and anti-tumor immunity. Phase 1 clinical trials investigating the safety and efficacy of AGEN2373, alone or combination with balstilimab (anti-PD-1), are underway. Trial Registration NCT04121676 References Wen TJ, Bukczynski and Watts TH. 4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function. J Immunol 2002;168(10): p. 4897–906. Bitra A, et al. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. J Biol Chem 2018;293(26): p. 9958–9969. Segal NH, et al., Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23(8): p. 1929–1936. Bartkowiak T, et al., Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27-dependent pathway. Clin Cancer Res 2018;24(5): p. 1138–1151. Lin GH, et al., GITR-dependent regulation of 4-1BB expression: implications for T cell memory and anti-4-1BB-induced pathology. J Immunol 2013;190(9): p. 4627–39. Segal, N.H., et al., Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 2018;24(8): p. 1816–1823. Li Y, et al., Limited Cross-Linking of 4-1BB by 4-1BB ligand and the agonist monoclonal antibody utomilumab. Cell Rep 2018;25(4): p. 909–920 e4.

Background Zalifrelimab is a fully human monoclonal antibody against cytotoxic T-lymphocyte -associated protein 4 (CTLA-4). Preliminary data demonstrated clinical benefit and tolerability, as monotherapy, in patients with recurrent solid tumors including rare tumor types. Previously presented Phase I data reported one durable complete response in recurrent cutaneous angiosarcoma (cAS).1 Here we report additional clinical responses from an ongoing Phase 2 study of zalifrelimab monotherapy including clinical benefit in rare solid tumors. Methods In an ongoing, phase 2 study (NCT03104699), the safety and efficacy of zalifrelimab, as monotherapy, was evaluated in patients who progressed on prior anti-PD-1/L1 treatment. All patients were treated intravenously (IV) with zalifrelimab at 1 mg/kg every 3 weeks until disease progression or up to 2 years. Results Overall, 44 patients were treated and 29 patients were response-evaluable at the time of report. In patients with refractory solid tumors treated with zalifrelimab, we report a disease control rate (CR, PR, and SD) of 51.7%, objective response rate (ORR) of 10.3% (3/29), disease stabilization of 41.3% (12/29). Clinical activity was observed in five solid tumors considered rare, including; cAS (N=1), glucagonoma (N=1), chondrosarcoma (N=1), spindle-cell sarcoma (N=1) and fibroblastic sarcoma (N=1). In these rare tumors, durable partial responses of 45 and 30 weeks were observed in cAS of the scalp with lymph node metastases and glucagonoma, respectively. Both patients remain on zalifrelimab with no evidence of disease progression. Additionally, durable disease stabilization was observed in a patient with spindle-cell sarcoma. Patients with chondrosarcoma and fibroblastic sarcoma progressed on therapy. Zalifrelimab was well tolerated with the most commonly reported treatment-related adverse events including fatigue, nausea, anemia, diarrhea and vomiting, consistent with the drug class. Most events were mild or moderate and resolved with standard treatments. Conclusions Our data demonstrates the potential for Zalifrelimab to promote meaningful clinical benefit in difficult to treat tumors, including patients that progress on prior PD-1/PD-L1 therapy or chemotherapy. Notably, responses were observed in rare tumor types such as recurrent cutaneous angiosarcoma and glucagonoma. Treatment with zalifrelimab is safe and well tolerated in patients with advanced malignancies. Trial Registration NCT03104699. Reference Vaia Florou, Andrew E Rosenberg, Eric Wieder, Krishna V. Komanduri, Despina Kolonias, Mohamed Uduman, John C Castle, Jennifer S. Buell, Jonathan C. Trent and Breelyn A. Wilky Journal for Immunotherapy of Cancer 2019 7:213.

In this multicenter, dose-ranging study of maribavir for the treatment of cytomegalovirus (CMV) infections deemed refractory or resistant to current antivirals, 67% of patients achieved clearance of CMV viremia within 6 weeks, with responses maintained for up to 24 weeks., Background Cytomegalovirus (CMV) infections that are refractory or resistant (RR) to available antivirals ([val]ganciclovir, foscarnet, cidofovir) are associated with higher mortality in transplant patients. Maribavir is active against RR CMV strains. Methods Hematopoietic-cell or solid-organ transplant recipients ≥12 years old with RR CMV infections and plasma CMV deoxyribonucleic acid (DNA) ≥1000 copies/mL were randomized (1:1:1) to twice-daily dose-blinded maribavir 400, 800, or 1200 mg for up to 24 weeks. The primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment. Safety analyses included the frequency and severity of treatment-emergent adverse events (TEAEs). Results From July 2012 to December 2014, 120 patients were randomized and treated (40 per dose group): 80/120 (67%) patients achieved undetectable CMV DNA within 6 weeks of treatment (95% confidence interval, 57–75%), with rates of 70%, 63%, and 68%, respectively, for maribavir 400, 800, and 1200 mg twice daily. Recurrent on-treatment CMV infections occurred in 25 patients; 13 developed mutations conferring maribavir resistance. Maribavir was discontinued due to adverse events in 41/120 (34%) patients, and 17/41 discontinued due to CMV infections. During the study, 32 (27%) patients died, 4 due to CMV disease. Dysgeusia was the most common TEAE (78/120; 65%) and led to maribavir discontinuation in 1 patient. Absolute neutrophil counts

AGEN1181 is a novel, Fc-engineered monoclonal antibody that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with enhanced FcyR-dependent functionality designed to improve T cell priming and activation, deplete intratumoral regulatory T cells (Treg), and improve memory T cell response. AGEN1181 is currently undergoing Phase I clinical evaluation, both as a single agent and in combination with the anti-PD-1 antibody balstilimab, in patients with advanced solid tumors (NCT03860272). Encouraging signals of clinical benefit have emerged as part of this ongoing study, including complete and durable responses in patients that would traditionally be considered unresponsive to conventional CTLA-4/PD-1 therapy. Here we report on pharmacodynamic analyses associated with AGEN1181 exposure in patients on study in this trial. As monotherapy, AGEN1181 was administered on a once every 3 or once every 6 week cycle (doses escalated from 0.1 - 4 mg/kg). Alternatively, AGEN1181 was dosed once every six weeks in combination with balstilimab (3 mg/kg once every 2 weeks). Tumor mutational burden (TMB) and gene expression were assessed from pre-treatment and on-treatment biopsies by whole exome sequencing (WES) and RNASeq, respectively. Multiplex immunohistochemistry was used to assess Treg depletion and CD8 T-cell activation in response to AGEN1181. TCR repertoire was analyzed in PBMCs collected on-treatment with AGEN1181. FcγRIIIA genotyping was performed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry. Consistent with its proposed mechanism of action, dose-dependent pharmacodynamic effects have been observed in patients while on-treatment with AGEN1181. Peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T cells increased over baseline in response to monotherapy. This effect was further enhanced in subjects treated with AGEN1181 when given in combination with balstilimab. Responders expressed either the low affinity FcγRIIIA allele or were heterozygous - suggesting that AGEN1181 has the potential to expand clinical activity to patients with low affinity Fc binding, in contrast to conventional CTLA-4 inhibitors. Additionally, we show that AGEN1181 induced selective Treg depletion within the tumor microenvironment with concomitant increases in CD8 T cell infiltration. TCRSeq analysis demonstrated increased clonality and decreased downsampled diversity, providing further evidence that the Fc-enhanced activity of AGEN1181 can promote improved T cell priming and Treg depletion. In summary, the pharmacodynamic analyses presented here are consistent with the Fc-enhanced design of AGEN1181 and its potential to broaden the therapeutic reach of CTLA-4-based immunotherapy. Citation Format: Irina Shapiro, Min Lim, Simarjot Pabla, Steven J. O'Day, Anthony El-Khoueiry, Chethan Ramamurthy, Andrea J. Bullock, Michael S. Gordon, Jennifer Buell, Dhan Chand, Anna Wijatyk. Characterization of the pharmacodynamic activity of AGEN1181, an Fc-enhanced CTLA-4 antibody, alone and in combination with the PD-1 antibody balstilimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1677.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

TPS3157 Background: AGEN1181 is a novel Fc-optimized anti-CTLA4 antibody, currently being evaluated in an ongoing multi-center, open-label, phase 1 study in all advanced solid tumors as mono-therapy and combination with anti-PD-1 antibody, AGEN2034 (NCT03860272). AGEN1181 is Fc-engineered to harness a novel mechanism for enhanced FcγR-dependent functionality relative to first-generation CTLA-4 antibodies. In pre-clinical models, AGEN1181 enhances T cell priming, depletion of intratumoral regulatory T cells (Treg) and improved memory formation compared to first-generation anti-CTLA-4 antibodies. Most notably, AGEN1181 demonstrates improved binding to FcyRIIIA and superior T cell responsiveness in populations that only express the low affinity FcγRIIIA receptor relative to first-generation IgG1 CTLA-4 antibodies. The combination of AGEN1181 and AGEN2034 further enhances T cell activation and effector function. Methods: This phase 1 study is an open-label, multi-center dose-escalation designed to evaluate the safety, tolerability, dose limiting toxicity (DLT) PK, and pharmacodynamic profiles of patients with refractory advanced solid tumors who did not receive an anti-CTLA4 previously. The study is being conducted in 3 arms; with patients assigned using a standard 3+3 dose escalation design in the mono-therapy arms with AGEN1181 and an accelerated design in the combination with AGEN2034 arm. AGEN1181 is administered as IV infusion as mono-therapy on Day 1 of every 3 weeks (0.1,0.3,1,2,4 mg/kg), every 6-weeks (1,2,4 mg/kg) in parallel cohorts and every 6-weeks (0.1,0.3,1,2,4 mg/kg) in combination with AGEN2034 (3mg/kg Q2Weeks) until disease progression or unacceptable toxicity (maximum 2 years). All 3 Arms are open and enrolling patients. The study is expected to enroll approximately 80 evaluable patients with solid tumors. Dose reductions are not allowed in the event of AGEN1181-related toxicities. Currently 3 cohorts have been completed, first cohort in the combination arm and the fourth cohort in the monotherapy arm are enrolling. Preclinical and clinical assessment of AGEN1181 supports continued development as a potential therapy for refractory or relapsed advanced solid tumors. Clinical trial information: NCT03860272 .

Lubor Goláň,1 Ozlem Goker-Alpan,2 Myrl Holida,3 Ikka Kantola,4 Mariusz Klopotowski,5 Johanna Kuusisto,6 Aleš Linhart,1 Jacek Musial,7 Kathleen Nicholls,8 Derlis Gonzalez-Rodriguez,9 Reena Sharma,10 Bojan Vujkovac,11 Peter Chang,12 Anna Wijatyk12 1First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic; 2Lysosomal Research and Treatment Unit, Fairfax, VA, USA; 3Stead Family Department of Pediatrics, Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; 4Division of Medicine, Turku University Hospital, Turku, Finland; 5Institute of Cardiology, Warsaw, Poland; 6Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; 7Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland; 8Department of Nephrology, Royal Melbourne Hospital and the University of Melbourne, VIC, Australia; 9Instituto Privado de Hematologia E Investigacion Clinica (IPHIC), Asuncion, Paraguay; 10Salford Royal NHS Foundation Trust, Salford, UK; 11General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia; 12Shire, Lexington, MA, USA Purpose: Efficacy and safety of agalsidase alfa at 0.2mg/kg weekly were compared with 0.2mg/kg every other week (EOW). Exploratory analyses were performed for 0.4mg/kg weekly.Patients and methods: This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height>50g/m2.7 for males and >47g/m2.7 for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti–agalsidase alfa antibodies.Results: Twenty patients were randomized to 0.2mg/kg EOW (mean age, 50.3years; 70% male), 19 to 0.2mg/kg weekly (51.8years; 53% male), and 5 to 0.4mg/kg weekly (49.4years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2g/m2.7 and 0.5g/m2.7, with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classi­fication. No significant differences were found between 0.2mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21mL/min/1.73 m2 vs -3.32mL/min/1.73m2) or plasma globotriaosylceramide (-1.05nmol/mL vs -2.13nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti–agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status.Conclusion: No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4mg/kg weekly showed similar results. Keywords: adverse events, exercise tolerance, left ventricular hypertrophy, lysosomal storage disorder, quality of life, renal functionA Letter to the Editor has been received and published for this article.

Background Signs and symptoms of the X-linked disorder, Fabry disease (FD), can occur early during childhood with heterogeneous clinical manifestations including potential cardiac and renal dysfunction. Several studies support the efficacy of the enzyme replacement therapy (ERT) agalsidase alfa, in adults with FD, though published data on the long-term safety and efficacy of agalsidase alfa in children are limited. As early treatment with ERT has the potential to reduce complications arising from disease progression, children in particular could benefit. The objective of this study was to evaluate the safety and efficacy of long-term agalsidase alfa ERT in children with FD. Methods TKT029 was a 6.5-year open-label, multicenter, extension study of children who completed TKT023 (26-week, open-label, every-other-week, intravenous 0.2 mg/kg agalsidase alfa). TKT029 was divided into two phases (before and after an agalsidase alfa manufacturing process change); only patients who participated in both phases were included in the analysis. Primary endpoints included safety, tolerability, and heart rate variability (HRV). Additional efficacy parameters included left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and plasma/urine globotriaosylceramide (Gb3). Results Eleven patients participated (phase 1 baseline median [range] age: 10.8 [8.6–17.3] years; 10 [90.9%] males). During TKT029 (6.5 years), all patients experienced ≥1 treatment-emergent adverse event (AE); eight patients had ≥1 possibly/probably drug-related AE. Six patients experienced infusion-related AEs, but none discontinued due to AEs. Eight serious AEs arose (two patients); none were deemed drug-related. No deaths occurred. Three patients developed anti-agalsidase alfa antibodies, with IgG antibodies in one patient that were agalsidase alfa neutralizing, but without apparent clinical impact. Renal (eGFR) endpoints remained generally in normal range. Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV, although some patients experienced a reduction in heart rate. Plasma and urinary Gb3 reductions were maintained. Conclusions TKT029 represents the longest assessment of ERT in children with FD in a clinical trial setting. Overall, agalsidase alfa was well tolerated and demonstrated a stabilizing clinical effect. Agalsidase alfa may be a useful clinical therapeutic option for long-term treatment initiated during childhood in patients with FD. Trial registration http://ClinicalTrials.gov identifier NCT00084084. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0169-6) contains supplementary material, which is available to authorized users.

In a multicenter, open-label, treatment protocol (HGT-REP-059; NCT01031173), clinical effects and tolerability of agalsidase alfa (agalα; 0.2 mg/kg every other week) were evaluated in patients with Fabry disease who were treatment naïve or switched from agalsidase beta (switch). Over 24 months, data were collected on the safety profile; renal and cardiac parameters were assessed using estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and midwall fractional shortening (MFS).Enrolled patients included 71 switch (median [range] age, 46.6 [5-84] years; male to female [M:F], 40:31) and 29 treatment naïve (38.7 [12-74] years; M:F, 14:15). Adverse events (AEs) were consistent with the known safety profile of agalα. Two switch patients had hospitalization due to possibly/probably drug-related serious AEs (one with transient ischemic attack, one with infusion-related AEs). One switch and two treatment-naïve patients discontinued treatment because of AEs. Three patients (one each switch, treatment naïve, and previous agalα) died; no deaths were considered drug-related. There was no significant change from baseline in LVMI or MFS in either group. Similarly, eGFR remained stable; mean ± standard error annualized change in eGFR (mL/min/1.73 m(2)) was -2.40 ± 1.04 in switch and -1.68 ± 2.21 in treatment-naïve patients.This is the largest cohort of patients with Fabry disease who were started on or switched to agalα in an FDA-accepted protocol during a worldwide supply shortage of agalsidase beta. Because this protocol was primarily designed to provide access to agalα, there were limitations, including not having stringent selection criteria and the lack of a placebo group.

Introduction Les resultats a cinq ans des patients inclus dans le registre FOS (Fabry Outcomes Survey ; Shire) atteints de la maladie de Fabry et traites par agalsidase alfa ont ete compares aux resultats publies des patients non traites [1] , [2] , [3] Materiels et methodes Les taux de changement du debit de filtration glomerulaire estime (DFGe) et de la masse du ventricule gauche indexee a la taille (iMVG) ont ete evalues, ainsi que la morbidite (temps jusqu’a l’apparition des evenements) et le deces. Resultats Les donnees de 740 patients traites etaient disponibles. Apres environ 5 ans de suivi, les patients traites et qui presentaient un DFGe initial inferieur a 60 mL/min/1,73 m2 ont demontre une baisse moyenne annuelle du DFGe plus faible (−2,86 [SEM 0,53] mL/min/1,73 m2/an) que ceux non traites (−6,8 [1,5]). Les taux moyens annuels du changement de l’iMVG etaient inferieurs chez les patients traites (hommes 0,33 [SEM 0,10] g/m2,7/an ; femmes 0,48 [0,09]) que ceux non traites (hommes 4,07 [1,03] ; femmes 2,31 [0,81]). Les evenements indiquant une progression de la maladie vers une insuffisance organique sont survenus plus tard sous agalsidase alfa (risque ∼15 % apres 24 mois contre ∼45 % chez les patients non traites), de meme que les deces (chez les hommes, la mediande de survie est estimee a 77,5 ans contre 60 ans chez les patients non traites). Conclusion Ces resultats demontrent les effets benefiques sur le long terme d’un traitement par agalsidase alfa, en ralentissant la progression de la maladie renale/cardiaque et en retardant significativement la morbidite/mortalite dans la maladie de Fabry. D’autres etudes sont necessaires pour confirmer ces resultats.