Intravenous Enzyme Replacement Therapy Research Articles

Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program

BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII.MethodsThis disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022.ResultsAs of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and − 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died.ConclusionsTo date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

AAV-GAA Gene Therapy Clears Long Chain Length Neuronal Glycogen in a Pompe Disease Rat Model

Pompe disease is due to mutations in the acid a-glucosidase (GAA) gene. GAA protein degrades lysosomal glycogen and dysfunctional or absent protein leads to cellular glycogen accumulation. In recent years, it has become clear that glycogen accumulation in the central nervous system (CNS) needs to be targeted in Pompe disease. However, the standard of care — intravenous enzyme replacement therapy using recombinant GAA does not effectively target the CNS. Here, we investigated the ability of neonatal AAV-GAA therapy to clear neuronal glycogen in the Pompe ( Gaa−/−) rat. On post-natal day one, male Gaa−/− rats received an administration of AAV9-DES-hGAA (1x1014 vector genomes/kg) via the temporal vein injection or sham injection (1xPBS). Rats were euthanized at age 9 months, and spinal cords and the diaphragm muscle were harvested and glycogen biochemistry was evaluated by matrix-assisted laser desorption/ionization mass spectrometry glycogen imaging (MALDI) and immunohistochemistry (GAA antibody). MALDI imaging reveal significant reduction in glycogen accumulation in the cervical spinal cord, and AAV9-DES-hGAA selectively targeting longer glucose chains within glycogen. Immunohistochemistry verified GAA expression in spinal cord neurons of rats treated with AAV-GAA. In the diaphragm muscle, MALDI revealed that the expected increase glycogen in the untreated Pompe diaphragm was associated with a decrease in n-linked glycans, a potential biomarker of the disease. Strikingly, glycogen content and glycans in the AAV-GAA treated diaphragm were indistinguishable from wild type. We conclude the neonatal gene therapy with AAV9-DES-hGAA can drive functionally relevant GAA expression in the adult rat CNS, and also effectively targets the diaphragm. R01HD052682 (DDF and BJB), R01AG066653 (RCS), R01CA266004 (RCS), R01AG078702 (RCS), RM1NS133593 (RCS), R35NS116824 (MSG). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in CSF GAG after intravenous enzyme replacement therapy

Changes in CSF GAG after intravenous enzyme replacement therapy

Anti-IDUA IgG alters cortical bone structure of mucopolysaccaridosis type I mice treated with intravenous enzyme replacement therapy

Anti-IDUA IgG alters cortical bone structure of mucopolysaccaridosis type I mice treated with intravenous enzyme replacement therapy

Safety outcomes and patients’ preferences for home-based intravenous enzyme replacement therapy (ERT) in pompe disease and mucopolysaccharidosis type I (MPS I) disorder: COVID-19 and beyond

BackgroundThe Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting.ResultsWe report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease − 32 patients) and cohort B (MPS I − 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as “good” (cohort A: 50%; cohort B: 83.3%).ConclusionsEvidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Neonatal gene therapy restores breathing in a rat model of Pompe disease

Pompe disease is a neuromuscular disorder resulting from mutations in the gene for acid a-glucosidase (GAA) – an enzyme necessary to degrade lysosomal glycogen. Early-onset disease occurs in the absence of functional GAA, which leads to cardiorespiratory failure early in life. Late-onset disease is associated with reduced GAA activity and gradual respiratory failure with preserved cardiac function. The standard of care – intravenous enzyme replacement therapy (ERT) using recombinant GAA does not effectively target the central nervous system, and can delay but not prevent respiratory failure. We used a Pompe rat model ( Gaa null) to test the hypothesis that a single intravenous AAV-GAA dose in neonate Pompe rats can drive persistent and widespread GAA expression and prevent respiratory decline over the lifespan. Male Gaa -/- rats received a single intravenous administration of AAV9-DES-hGAA (1x1014 vector genomes/kg; n=6), temporal vein injection) or sham injection (1xPBS; n=6) on post-natal day one. Ventilation was measured using a whole-body plethysmograph at age 3-, 6-, and 9-months. Rats treated with the gene therapy vector showed a striking increase in body mass over the duration of the study (2-way repeated measures analyses of variance, treatment effect, p<0.001). At age 9 mo, treated rats weighed 402±25 g and sham rats weighed 293±27 g. As rats progressed from 3- to 9-months age, tidal volume, minute ventilation, and the ratio of minute ventilation to CO2 production (i.e., V E /VCO 2 ) were all greater in the gene therapy treated rats as compared to sham (each of these variables showed an age x treatment interaction, all p<0.001). We conclude the neonatal gene therapy with AAV9-DES-hGAA can prevent decline in body mass and preserve breathing ability over the lifespan of a Pompe rat model. Gene therapy is a promising approach for treating Pompe disease. Funding: R01HD052682 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The patients` perspective on home-based infusion: A longitudinal observational study in the German healthcare setting for patients with lysosomal storage disorders treated with enzyme replacement therapy

BackgroundLysosomal storage diseases (LSDs), metabolic disorders resulting in build-up of endogenous waste and progressive organ damage, can be treated with intravenous enzyme replacement therapy (ERT). ERT can be administered either in specialized clinics, at a physician's office or in the home care setting. Legislative goals in Germany strive to shift to more outpatient care while maintaining treatment objectives. This study investigates the patient perspective on home-based ERT in terms of acceptance, safety, and treatment satisfaction in LSD patients. MethodsThis was a longitudinal observational study, carried out under real-world conditions in patients' home environment, covering 30 months from January 2019 to June 2021. Patients with LSDs who were deemed suitable for home-based ERT by their physicians were recruited to the study. Patients were interviewed before the start of the first home-based ERT and then at regular intervals thereafter using standardized questionnaires. ResultsData from 30 patients were analyzed: 18 with Fabry disease, 5 with Gaucher disease, 6 with Pompe disease and 1 with Mucopolysaccharidosis type I (MPS I). Age ranged from 8 to 77 years (mean age 40). The reported average waiting time prior to infusion of more than half an hour decreased from 30% of the patients affected at baseline to 5% across all follow-up time points. All patients felt adequately informed about home-based ERT throughout follow-ups and reported that they would choose home-based ERT again. At almost each time point, patients indicated that home-based ERT had improved their ability to cope with the disease. All but one patient indicated feeling safe at each follow-up time point. Compared to 36.7% at baseline, only 6.9% of patients reported a need for improvement in their care after 6 months of home-based ERT. Mean treatment satisfaction increased by approximately 1.6 scale points after 6 months of home-based ERT compared to baseline, and by another 0.2 scale points after 18 months. In terms of quality of care, all but one patient rated home-based ERT as an equivalent alternative throughout follow-ups. Patients would recommend home-based ERT to other suitable LSD-patients. ConclusionHome-based ERT increases patients' treatment satisfaction, and patients perceive the quality of care as an equivalent alternative, compared to ERT in a center, clinic, or at a physician's office.

Airway Findings in Patients with Hunter Syndrome Treated with Intravenous Idursulfase.

People with Hunter syndrome are known to be affected by a variety of airway pathologies. Treatment of Hunter syndrome with the enzyme replacement therapy (ERT) idursulfase is now the standard of care. However, it is not known how ERT changes the progression of airway involvement. To evaluate this, we performed a retrospective analysis of bronchoscopies performed on children with Hunter syndrome who were part of intrathecal ERT trials. Findings for airway pathology were extracted from bronchoscopy reports and analyses were performed for cross-sectional and longitudinal changes in airway disease. One-hundred and thirty bronchoscopies from 23 subjects were analyzed. Upper airway disease (adenoid hypertrophy and/or pharyngomalacia) was reported in 93% and 87% of bronchoscopies, respectively. Laryngeal abnormalities were recognized in 46% of cases. There were lower airway (tracheal and or bronchial) findings in 64% of all bronchoscopies and prevalence increased with age. Evaluations over time adjusted for repeat evaluations showed that increasing airway involvement was associated with older age (p = 0.0007) despite ongoing ERT. No association was discovered between age of intravenous ERT initiation and progression of airway disease. Individuals with Hunter syndrome who are receiving intravenous enzyme replacement therapy showed the progression of airways disease supporting the need for regular airway monitoring and intervention.

Dose-dependent effects of enzyme replacement therapy on skeletal disease progression in mucopolysaccharidosis VII dogs

Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme β-glucuronidase. Skeletal abnormalities are common in patients and result in diminished quality of life. Enzyme replacement therapy (ERT) for MPS VII using recombinant human β-glucuronidase (vestronidase alfa) was recently approved for use in patients; however, to date there have been no studies evaluating therapeutic efficacy in a large animal model of MPS VII. The objective of this study was to establish the effects of intravenous ERT, administered at either the standard clinical dose (4mg/kg) or a high dose (20mg/kg), on skeletal disease progression in MPS VII using the naturally occurring canine model. Untreated MPS VII animals exhibited progressive synovial joint and vertebral bone disease and were no longer ambulatory by age 6months. Standard-dose ERT-treated animals exhibited modest attenuation of joint disease, but by age 6months were no longer ambulatory. High-dose ERT-treated animals exhibited marked attenuation of joint disease, and all were still ambulatory by age 6months. Vertebral bone disease was recalcitrant to ERT irrespective of dose. Overall, our findings indicate that ERT administered at higher doses results in significantly improved skeletal disease outcomes in MPS VII dogs.

Efficacy of Intravenous Elosulfase Alfa for Mucopolysaccharidosis Type IVA: A Systematic Review and Meta-Analysis

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were −0.260, −0.102, −0.182, −0.360, −0.408, −0.587, −0.293, −0.311, and −0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.

Newborn Screening Program for Mucopolysaccharidosis Type II and Long-Term Follow-Up of the Screen-Positive Subjects in Taiwan.

Background: Mucopolysaccharidosis II (MPS II) is an X-linked disorder resulting from a deficiency in lysosomal enzyme iduronate-2-sulfatase (IDS), which causes the accumulation of glycosaminoglycans (GAGs) in the lysosomes of many tissues and organs, leading to progressive cellular dysfunction. An MPS II newborn screening program has been available in Taiwan since 2015. The aim of the current study was to collect and analyze the long-term follow-up data of the screen-positive subjects in this program. Methods: From August 2015 to April 2022, 548,624 newborns were screened for MPS II by dried blood spots using tandem mass spectrometry, of which 202 suspected infants were referred to our hospital for confirmation. The diagnosis of MPS II was confirmed by IDS enzyme activity assay in leukocytes, quantitative determination of urinary GAGs by mass spectrometry, and identification of the IDS gene variant. Results: Among the 202 referred infants, 10 (5%) with seven IDS gene variants were diagnosed with confirmed MPS II (Group 1), 151 (75%) with nine IDS gene variants were classified as having suspected MPS II or pseudodeficiency (Group 2), and 41 (20%) with five IDS gene variants were classified as not having MPS II (Group 3). Long-term follow-up every 6 months was arranged for the infants in Group 1 and Group 2. Intravenous enzyme replacement therapy (ERT) was started in four patients at 1, 0.5, 0.4, and 0.5 years of age, respectively. Three patients also received hematopoietic stem cell transplantation (HSCT) at 1.5, 0.9, and 0.6 years of age, respectively. After ERT and/or HSCT, IDS enzyme activity and the quantity of urinary GAGs significantly improved in all of these patients compared with the baseline data. Conclusions: Because of the progressive nature of MPS II, early diagnosis via a newborn screening program and timely initiation of ERT and/or HSCT before the occurrence of irreversible organ damage may lead to better clinical outcomes. The findings of the current study could serve as baseline data for the analysis of the long-term effects of ERT and HSCT in these patients.

Chaperone Therapy in Fabry Disease.

Fabry disease is an X-linked lysosomal multisystem storage disorder induced by a mutation in the alpha-galactosidase A (GLA) gene. Reduced activity or deficiency of alpha-galactosidase A (AGAL) leads to escalating storage of intracellular globotriaosylceramide (GL-3) in numerous organs, including the kidneys, heart and nerve system. The established treatment for 20 years is intravenous enzyme replacement therapy. Lately, oral chaperone therapy was introduced and is a therapeutic alternative in patients with amenable mutations. Early starting of therapy is essential for long-term improvement. This review describes chaperone therapy in Fabry disease.

Difficulties Associated with Enzyme Replacement Therapy for Mucopolysaccharidoses.

Background:Mucopolysaccharidoses are extremely rare, progressive, often severe multisystem disorders, some of which are managed by weekly intravenous enzyme replacement therapy. This study aimed to determine the difficulties faced by the patients with mucopolysaccharidosis and their families due to enzyme replacement therapy.Methods:A questionnaire about demographics, enzyme replacement therapy-related characteristics, and specific enzyme replacement therapy-related difficulties was conducted over the telephone with mucopolysaccharidosis patients (or their parents) followed at a referral center in Turkey, who have been on enzyme replacement therapy for ≥12 months. The responses were analyzed with chi-square, Mann–Whitney U, Kruskal–Wallis tests, Spearman's rank correlation, and binary logistic regression.Results:A total of 54 patients (median age: 13 years) participated, who had been receiving enzyme replacemnt therapy for a median of 5.02 years, 83.3% of whom had mucopolysaccharidosis-IVA or -VI. About 72.2% went to school or work, 64.1% of whom missed a full day every week due to enzyme replacement therapy. About 63% missed at least 1 dose in the past 6 months, mostly due to not being able to obtain doses or having intercurrent infections. Significantly more enzyme replacement therapy doses were missed or unobtained in Central (non-Ankara) and Eastern Anatolia, but enzyme replacement therapy-related disruption to family life was more severe in families living in Ankara.Conclusions:We provide the first Turkish data about mucopolysaccharidosis patients’ subjective enzyme replacement therapy experience, which is influenced by actionable inequalities and hurdles, partially related to geographical factors. Access to the drugs can be facilitated, and the clash of enzyme replacement therapy infusions with school and work should be avoided. Multi-center studies using more objective data sources are needed.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Considerations for Home-Based Treatment of Fabry Disease in Poland during the COVID-19 Pandemic and Beyond.

Current therapy for Anderson–Fabry disease in Poland includes hospital or clinic-based intravenous enzyme replacement therapy with recombinant agalsidase alpha or beta, or oral pharmacological chaperone therapy with migalastat. Some countries around the world offer such treatment to patients in the comfort of their own homes. The 2020–2021 COVID-19 pandemic has pushed global healthcare providers to evolve their services so as to minimize the risk of COVID-19 exposure to both patients and providers; this has led to advances in telemedicine services and the increasing availability of at-home treatment for various procedures including parenteral drug administration. A total of 80% of surveyed Anderson–Fabry disease patients in Poland would prefer home-based treatment, which would be a safe and convenient alternative to clinic-based treatment if patient selection is based on our proposed algorithm. Our recommendations for home-based treatments appear feasible for the long term care of Anderson–Fabry disease patients during the COVID-19 pandemic and beyond. This may also serve as a basis for home-based treatment programs in other rare and ultra-rare genetic diseases.

Therapy-type related long-term outcomes in mucopolysaccaridosis type II (Hunter syndrome) – Case series

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare, X-linked recessive multisystem lysosomal storage disease due to iduronate-2-sulfatase enzyme deficiency. We presented three unrelated Slovenian patients with the severe form of MPS II that received three different management approaches: natural course of the disease without received specific treatment, enzyme replacement therapy (ERT), and hematopoietic stem cell transplantation (HSCT). The decision on the management depended on disease severity, degree of cognitive impairment, and parent's informed decision. The current benefits of MPS II treatments are limited. The lifelong costly intravenous ERT brings significant benefits but the patients with severe phenotypes and neurological involvement progress to cognitive decline and disability regardless of ERT, as demonstrated in published reviews and our case series. The patient after HSCT was the only one of the three cases reported to show a slowly progressing cognitive development. The type of information from the case series is insufficient for generalized conclusions, but with advanced myeloablative conditioning, HSCT may be a preferred treatment option in early diagnosed MPS II patients with the severe form of the disease and low disease burden at the time of presentation.

Reduction in Intravenous Infusion Duration of Enzyme Replacement Therapy to Ten Minutes with Velaglucerase Alfa in Adult Patients with Type 1 Gaucher Disease

Safe and effective intravenous enzyme replacement therapy (ERT) has been available for more than 25 years for patients with Gaucher disease (GD). The safety of the several ERTs for GD has also afforded the possibility of home infusions. Yet, ERT is usually a life-long commitment to infusions and many patients find the every-other-week (EOW) hourly infusions onerous. Previous experience with rapid intravenous infusion of biological materials, in particular monoclonal antibodies, have defined a variable potential for reactions, ranging from mild local irritations at the access site to life-threatening hypersensitivities and anaphylactoid reactions as well as various inflammatory and immunological responses. Particularly in the home environment, these reactions could conceivably occur too quickly for an effective response by a medical team. Thus, we designed a “change in practice” study to assess the safety and efficacy of rapid infusions in adult with type I GD who had already been treated for at least 3 months with velaglucerase alfa. The switch from infusion time of 60 minutes to 10 minutes was done using a step-wise reduction.Methods: Fifteen patients, (8 female), mean age 32 (range 22-44) years, genotype N370S homozygous (n=7) or heterozygous, stable on treatment for a mean of 9.6 (range: 2.5-17) years at doses of treated at 15-60 units/kg body weight/infusion were recruited. Study was started with three months at the standard infusion time of 60 minutes EOW in the home setting. Next was a rate change with one infusion at 30 minutes, one infusion at 20 minutes, and then four infusions over 10 minutes, all in the hospital clinic setting. The final stage was infusions over 10 minutes at home with every three months study evaluations in the clinic. Safety was determined by adverse events (AEs) during or directly after infusions as monitored by an experienced nurse. Efficacy parameters included hemoglobin concentration and platelet counts, spleen and liver volume estimation by ultrasound, the biomarker LysoGb1 (Centogene, Rostock Germany ) and anti-velaglucerase alfa antibodies formation. Seven visual analogue scales were used to assess disease related impact including [1] dependence on others; [2] fatigue; [3] bone pain; [4] depression ; [5] satisfaction with treatment; [6] family impact [7] pessimistic/optimistic view of the future. Local investigational review board approval was granted for the study and all participating patients provided written informed consent before commencing study procedures.Results: Patients were followed for a mean±SD of 60±19 weeks on this study. No serious AEs associated with the 10 minute infusions, in the clinic or at home, were reported. The only mild AE was a single patient who experienced discomfort (feeling cold) in the infused arm during two 10 minute infusions. All patients maintained stability in the key disease features including the hematological parameters and organ volumes. Mean (range) LysoGb1 levels at baseline and last evaluation were 80.8 (11.5-246) ng/mL and 84 (13.8-200) ng/mL, respectively. A single patient showed increased values of LysoGb1, yet her platelet counts were unaffected. On week 36 evaluation - no patient developed antibodies. Twelve patients completed the disease impact questionnaire; mean responses to the specific questions and mean score, ranging from 5.3-9.4 at baseline and 7.6-9.7 on 10 minute infusion, were not altered over the study period. Pharmacokinetics studies are pending.Discussion: With this study protocol, we established that step-wise shortening of infusion duration, from one hour to 10 minutes in three stages and as home infusions, did not compromise the safety or efficacy of treatment in adult patients with type 1 GD receiving velaglucerase alfa EOW at dosages ranging from 15-60 units/kg body weight. Rapid administration of velaglucerase alfa was generally well tolerated and disease-specific parameters were maintained over the course of the study. Willingness of patients to continue with 10 minute infusion confirms the importance of convenience, specifically decreased infusion duration, to patients for whom ERT infusions are currently envisioned to be a life-long commitment. Moreover, this approach may also have wider implications for healthcare providers and payers because of the possibility of reducing the costs engendered by prolonged intravenous administrations and the reliance on a hospital setting. DisclosuresZimran:Shire: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding. Elstein:Shire: Consultancy. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding.

PRO61 Health-Related Quality of Life (HRQOL) and Healthcare Resource Use (HCRU) Associated with the Treatment of Pompe Disease (PD): Targeted Literature Reviews

PD is a rare, progressive neuromuscular disease caused by deficiency of lysosomal enzyme acid alpha-glucosidase. PD is now considered to be a continuous spectrum of phenotypes. The severe classic infantile onset form (IOPD) is rapidly progressing: symptoms appear before 12 months characterized by significant and progressive cardiac hypertrophy with death by 24 months, if untreated. A slower, less severe progressive phenotype is often termed late onset (LOPD). Current standard of care is biweekly intravenous enzyme replacement therapy (ERT) with alglucosidase alfa. The present study was undertaken to better understand the landscape and evidence gaps relating to HRQoL (including utilities) and HCRU associated with the treatment of PD. Targeted literature reviews following defined search protocols retrieved interventional and non-interventional studies on PD published in English from the year 2000 onwards. 9 databases and 4 technology assessment/regulatory agency websites were searched in June/July 2020. One reviewer selected records with a second reviewer checking a 25% sample, and one extracted data. Searches identified 2505 unique records; 15 studies (in 15 documents) met the inclusion criteria and reported HRQoL data (n=14; utilities and SF-36) and/or HCRU data (n=6). Utility data were not well reported. For SF-36, the best evidence came from a single trial that reported no differences between ERT and placebo for the physical component scores. For HCRU data, the economic costs of ERT varied across the studies, and the impact of indirect costs were reported in only one study. Data on other healthcare and non-healthcare costs were reported in a small number of studies. The impact of PD on patient utility has not been robustly established, highlighting a knowledge gap that merits further research. HCRU for management of PD depends on several key factors including form of disease, country-specific cost of ERT, and indirect costs.

Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice

Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with recombinant IDS (idursulfase) is ineffective for CNS manifestations due to its inability to cross the blood-brain barrier (BBB). Here, we demonstrate that the clearance of heparan sulfate (HS) deposited in the brain by a BBB-penetrable antibody-enzyme fusion protein prevents neurodegeneration and neurocognitive dysfunctions in MPS II mice. The fusion protein pabinafusp alfa was chronically administered intravenously to MPS II mice. The drug reduced HS and attenuated histopathological changes in the brain, as well as in peripheral tissues. The loss of spatial learning abilities was completely suppressed by pabinafusp alfa, but not by idursulfase, indicating an association between HS deposition in the brain, neurodegeneration, and CNS manifestations in these mice. Furthermore, HS concentrations in the brain and reduction thereof by pabinafusp alpha correlated with those in the cerebrospinal fluid (CSF). Thus, repeated intravenous administration of pabinafusp alfa to MPS II mice decreased HS deposition in the brain, leading to prevention of neurodegeneration and maintenance of neurocognitive function, which may be predicted from HS concentrations in CSF.

Mucopolysaccharidoses I and II: Brief Review of Therapeutic Options and Supportive/Palliative Therapies.

Purpose. Mucopolysaccharidoses (MPS) are group of inherited lysosomal storage diseases caused by mutations of enzymes involved in catalyzing different glycosaminoglycans (GAGs). MPS I and MPS II exhibit both somatic and neurological symptoms with a relatively high disease incidence. Hematopoietic stem cell therapy (HSCT) and intravenous enzyme replacement therapy (ERT) have had a significant impact on the treatment and comprehension of disease. This review is aimed at providing a comprehensive evaluation of the pros and cons of HSCT and ERT, as well as an up-to-date knowledge of new drugs under development. In addition, multiple disease management strategies for the uncontrollable manifestations of MPS I and MPS II to improve patients' quality of life are presented. Findings. Natural history of MPS I and MPS II shows that somatic and neurological symptoms occur earlier in severe forms of MPS I than in MPS II. ERT increases life expectancy and alleviates some of the somatic symptoms, but musculoskeletal, ophthalmological, and central nervous system (CNS) manifestations are not controlled. Additionally, life-long treatment burdens and immunogenicity restriction are unintended consequences of ERT application. HSCT, another treatment method, is effective in controlling the CNS symptoms and hence has been adopted as the standard treatment for severe types of MPS I. However, it is ineffective in MPS II, which can be explained by the relatively late diagnosis. In addition, several factors such as transplant age limits or graft-versus-host disease in HSCT have limited its application for patients. Novel therapies, including BBB-penetrable-ERT, gene therapy, and substrate reduction therapy, are under development to control currently unmanageable manifestations. BBB-penetrable-ERT is being studied comprehensively in the hopes of being used in the near future as a method to effectively control CNS symptoms. Gene therapy has the potential to “cure” the disease with a one-time treatment rather than just alleviate symptoms, which makes it an attractive treatment strategy. Several clinical studies on gene therapy reveal that delivering genes directly into the brain achieves better results than intravenous administration in patients with neurological symptoms. Considering new drugs are still in clinical stage, disease management with close monitoring and supportive/palliative therapy is of great importance for the time being. Proper rehabilitation therapy, including physical and occupational therapy, surgical intervention, or medications, can benefit patients with uncontrolled musculoskeletal, respiratory, ophthalmological, and neurological manifestations.