Enzyme Replacement Research Articles

Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case–control study

BackgroundExocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause.MethodsIn this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c and body mass index (BMI).Results48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects (p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA1c and BMI evolution did not differ between the groups.ConclusionsPERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders.Trial registration Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047

Plain language summary of a study looking at the long-term benefits of enzyme replacement therapy in children and teenagers with Gaucher disease type 3

What is this study about? Gaucher disease is a rare genetic condition. There are three types of Gaucher disease: type 1, type 2, and type 3 (GD3). Symptoms of GD3 include problems with the brain and spinal cord, bones, blood, enlarged liver and spleen, and slow growth. Symptoms have a great impact on the quality of life of people with GD3 and are known to cause loss of life in childhood. In Gaucher disease, people have two non-working copies of a gene called GBA, which tells the body how to make an enzyme called beta-glucosidase (which breaks down excess fats called sphingolipids). In Gaucher disease, people do not make enough beta-glucosidase enzyme, meaning sphingolipids build up inside cells, affecting many organs and systems of the body. Enzyme replacement therapy (ERT) is a treatment for Gaucher disease. Previous studies looking at ERT showed that treatment can greatly improve most symptoms and quality of life in people with Gaucher disease. How ERT may help people with GD3 is only available in small studies. What was the aim of this study? Researchers looked at long-term changes in the blood, spleen, liver, and growth in children and teenagers living with GD3 and how long they survived once they had started an ERT called imiglucerase. Researchers used data from a large global database called the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The aim was to investigate if imiglucerase could improve long-term symptoms and prevent early loss of life. What were the results of this study? Low red blood cell counts (causing a condition called anaemia), low platelet (specialised blood cells that stop bleeding and bruising) counts, enlarged liver and spleen, and slow growth were the most common symptoms in people with GD3 before treatment. People with GD3 who had received imiglucerase had improved symptoms after 5 years of treatment. They also had a greater chance of living longer, with 92% of people alive after 5 years of treatment. These results show that the ERT imiglucerase helps to improve blood, spleen, liver, and growth symptoms, and most importantly that it is a life-prolonging treatment.

Long-Term Outcomes of Disease Modifying Therapies in Gaucher Disease.

To study clinical response to treatment with enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) in a cohort of Gaucher disease. Retrospective data of 8 patients of Gaucher disease was compiled. The treatment included all three currently available enzyme replacement therapies as well as substrate reduction therapy with Eliglustat. The relevant blood investigations were done in follow-up visits. The assessment of the effects of long-term treatment over varying periods up to 13 y was done with various issues related to the course of therapy documented. Improvement in hematological parameters was seen in all patients. Reduction of spleen size occurred in 7 of 8 patients (87.5%). One patient had 2 successful pregnancies while on therapy. A distinct patient with type 3 Gaucher disease developed complication in the form of Gaucheroma within the spleen. Awareness about the disease and the efficacy of the therapies amongst pediatricians will help in early diagnosis and better outcomes. The available therapies have changed the outcome of the patients and improved the quality of life in patients with Gaucher disease. The data of Indian patients is important at this juncture when under Rare Disease Policy, government funding has become available for ERT for Gaucher disease patients in India.

Reducing agalsidase beta infusion time in Fabry patients: low incidence of antibody formation and infusion-associated reactions in an Italian multicenter study

BackgroundFabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated.ResultsTwenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study’s end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved.ConclusionsThe study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.

Real-life impacts of olipudase alfa: The experience of patients and families taking an enzyme replacement therapy for acid sphingomyelinase deficiency

BackgroundAcid Sphingomyelinase Deficiency (ASMD) is an ultra-rare autosomal recessive lysosomal storage disorder characterized by intracellular lipid accumulation resulting from reduced function of acid sphingomyelinase. Olipudase alfa, an enzyme replacement therapy, was recently approved in several countries for the treatment of the non-neurologic manifestations of ASMD. Studies demonstrate improvement in organomegaly, pulmonary function and lipid profiles with olipudase alfa, yet little is known about its impact on quality of life (QoL) for patients and caregivers. The purpose of this study is to better understand the real-life impact of ASMD on patients and caregivers and assess how olipudase alfa impacts QoL for pediatric patients and their caregivers.MethodsCaregivers of pediatric patients (≤ 18 years of age) with a confirmed diagnosis of ASMD that received olipudase alfa for at least 12 months were recruited in early 2022 through national patient organizations to participate in a global online questionnaire followed by semi-structured interviews. Ten caregivers of patients with ASMD who utilized olipudase alfa as an experimental therapy for pediatric patients participated in the study. Quantitative analysis of the results was undertaken, and qualitative data was analyzed using an inductive thematic approach.ResultsTen eligible participants completed questionnaires, and 8 of the 10 went on to participate in structured interviews. Symptom burden of ASMD and impact on symptomatology and quality of life after olipudase alfa use are reported here. Five themes emerged from analysis: (1) ASMD is a systemic disease with a wide array of manifestations that significantly impact QoL; (2) Olipudase alfa was associated with improvements in all non-neurologic manifestations of ASMD; (3) Participants perceived the risk associated with olipudase alfa to be low and the benefits to greatly outweigh any risk or burden; (4) Participants reported an unmet need to treat the neurologic manifestations of the disease despite the benefits of olipudase alfa in the management of non-neurological symptoms; (5) Participants felt all patients with ASMD need access to olipudase alfa based on the life-changing experience they perceived.ConclusionsThese findings highlight the sustained positive impact olipudase alfa had in many domains that are deemed important to patients and families living with ASMD and outline the extensive unmet need for patients and families living with ASMD.

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .

Inhibition Effect of Pancreatic Exocrine Insufficiency on Immune Checkpoint Inhibitor Treatment in Pancreatic Cancer: A Retrospective Study.

Chemotherapy combined with immune checkpoint inhibitors (ChIM) is used to treat advanced pancreatic ductal adenocarcinoma (PDAC). However, the efficacy of ChIM is similar to that of chemotherapy alone. To assess potential factors affecting the effectiveness of ChIM, we analyzed the clinical data of 359 patients with PDAC who visited the hospital during June 2017 to December 2022. Surgical resection, diabetes, and ChIM were risk factors for pancreatic exocrine insufficiency (PEI). The adjusted odds ratio of ChIM was 2.63 (95% confidence interval (CI) 1.492-4.626) (P = 0.001). The incidence of PEI in the ChIM group (76.9%) was significantly higher than that of the chemotherapy group (60.2%) (P = 0.004). Survival analysis showed that ChIM did not improve the survival rate of patients with PDAC (hazard ratio (HR) 0.92, 0.707-1.197) (P = 0.534) in comparison with that of the chemotherapy group. However, in patients without PEI, those receiving ChIM showed a higher 1-year overall survival (OS) rate of 70.8% (two-sided, P = 0.045) and a median OS of 22.0 months (95% CI 11.5-32.5). Moreover, pancreatic enzyme replacement therapy significantly improved the OS of patients with PDAC (HR = 0.73, 95% CI = 0.561-0.956) (P = 0.022). Immune checkpoint inhibitors (ICIs) increased the incidence of PEI in patients with PDAC. The OS was not different between patients receiving chemotherapy and ChIM due to irregular PERT treatment. The finding show that pancreatic enzyme replacement therapy may improve the response rate of patients with PDAC to ICIs.

Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS®) physical function questionnaire in late-onset Pompe disease using PROPEL phase 3 data

BackgroundThe construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT).MethodsIn the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers’ maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients’ age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods.Results123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively.ConclusionsPROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD.Trial registrationClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www.clinicaltrials.gov/search?term=NCT03729362.

Baseline physiotherapy composite profile assessment (PCPA) as a predictor of functional outcomes in infantile-onset Pompe disease (IOPD) treated with enzyme replacement therapy in a UK paediatric centre

Baseline physiotherapy composite profile assessment (PCPA) as a predictor of functional outcomes in infantile-onset Pompe disease (IOPD) treated with enzyme replacement therapy in a UK paediatric centre

A phase III clinical trial of GC1111 as an enzyme replacement therapy in previously untreated mucopolysaccharidosis type II (Hunter syndrome) patients: A double-blind, randomized, active-controlled (part 1) and open-labeled, historical placebo-controlled (part 2) study

A phase III clinical trial of GC1111 as an enzyme replacement therapy in previously untreated mucopolysaccharidosis type II (Hunter syndrome) patients: A double-blind, randomized, active-controlled (part 1) and open-labeled, historical placebo-controlled (part 2) study

Experience with enzyme replacement therapy in children with late-onset Pompe disease diagnosed via newborn screening in the United States

Experience with enzyme replacement therapy in children with late-onset Pompe disease diagnosed via newborn screening in the United States

Enzyme replacement therapy with a blood brain barrier-penetrating antibody-fused alpha-L-iduronidase prevents bone deformities in a mouse model of mucopolysaccharidosis type I

Enzyme replacement therapy with a blood brain barrier-penetrating antibody-fused alpha-L-iduronidase prevents bone deformities in a mouse model of mucopolysaccharidosis type I

Glycosphingolipid evaluation for Fabry disease patients receiving migalastat after switching from enzyme replacement therapy

Glycosphingolipid evaluation for Fabry disease patients receiving migalastat after switching from enzyme replacement therapy

Therapeutic potential of intracerebroventricular recombinant human heparan-N-sulfatase enzyme replacement therapy in MPS IIIA mice

Therapeutic potential of intracerebroventricular recombinant human heparan-N-sulfatase enzyme replacement therapy in MPS IIIA mice

Integrated long-term efficacy and safety data on enzyme replacement therapy with pabinafusp alfa for neuronopathic mucopolysaccharidosis type II (MPS II): Updated clinical data from Japan and Brazil

Integrated long-term efficacy and safety data on enzyme replacement therapy with pabinafusp alfa for neuronopathic mucopolysaccharidosis type II (MPS II): Updated clinical data from Japan and Brazil

Hypersensitivity reactions and enzyme replacement therapy: Outcomes and safety of rapid desensitization in 5132 infusions

Hypersensitivity reactions and enzyme replacement therapy: Outcomes and safety of rapid desensitization in 5132 infusions

Enzyme replacement is associated with better long-term cognitive outcomes in Hurler syndrome

Enzyme replacement is associated with better long-term cognitive outcomes in Hurler syndrome

Tolerability of pegunigalsidase alfa across the clinical program: Integrated analysis of infusion-related reactions by prior enzyme replacement therapy

Tolerability of pegunigalsidase alfa across the clinical program: Integrated analysis of infusion-related reactions by prior 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

Changes in CSF GAG after intravenous enzyme replacement therapy

Changes in CSF GAG after intravenous enzyme replacement therapy