α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts.

Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 µM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.

Open-label, single-center, clinical study evaluating the safety, tolerability and clinical effects of pentosan polysulfate sodium in subjects with mucopolysaccharidosis I.

Lysosomal enzyme deficiency in mucopolysaccharidosis (MPS) I results in glycosaminoglycan (GAG) accumulation leading to pain and limited physical function. Disease-modifying treatments for MPS I, enzyme replacement, and hematopoietic stem cell therapy (HSCT), do not completely resolve MPS I symptoms, particularly skeletal manifestations. The GAG reduction, anti-inflammatory, analgesic, and tissue remodeling properties of pentosan polysulfate sodium (PPS) may provide disease-modifying treatment for musculoskeletal symptoms and joint inflammation in MPS I following ERT and/or HSCT. The safety and efficacy of PPS were evaluated in four subjects with MPS I aged 14-19 years, previously treated with ERT and/or HSCT. Subjects received doses of 0.75 mg/kg or 1.5 mg/kg PPS via subcutaneous injections weekly for 12 weeks, then every 2 weeks for up to 72 weeks. PPS was well tolerated at both doses with no serious adverse events. MPS I GAG fragment (UA-HNAc [1S]) levels decreased at 73 weeks. Cartilage degradation biomarkers serum C-telopeptide of crosslinked collagen (CTX) type I (CTX-I) and type II (CTX-II) and urine CTX-II decreased in all subjects through 73 weeks. PROMIS scores for pain interference, pain behavior, and fatigue decreased in all subjects through 73 weeks. Physical function, measured by walking distance and dominant hand function, improved at 49 and 73 weeks. Decreased GAG fragments and cartilage degradation biomarkers, and positive PROMIS outcomes support continued study of PPS as a potential disease-modifying treatment for MPS I with improved pain and function outcomes.

Efficacy of a Combination Therapy with Laronidase and Genistein in Treating Mucopolysaccharidosis Type I in a Mouse Model.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood-brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II-thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments.

Laronidase-loaded liposomes reach the brain and other hard-to-treat organs after noninvasive nasal administration.

Mucopolysaccharidosis type I (MPS I) is caused by a lack of the lysosomal enzyme α-L-iduronidase (IDUA), responsible for the degradation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate, leading to multisystemic signs and symptoms. Enzyme replacement therapy (ERT) is a treatment that consists of weekly intravenous administrations of laronidase, a recombinant version of IDUA. However, ERT has limited access to certain tissues, such as bone, cartilage, and brain, and laronidase fails to trespass the BBB. In this sense, this study reports the development and characterization of laronidase-loaded liposomes for the treatment of MPS I mice. Liposomal complexes were obtained by the thin film formation method followed by microfluidization. The main characterization results showed mean vesicle size of 103.0 ± 3.3 nm, monodisperse populations of vesicles, zeta potential around + 30.0 ± 2.1 mV, and mucoadhesion strength of 5.69 ± 0.14 mN. Treatment of MPS I mice fibroblasts showed significant increase in enzyme activity. Nasal administration of complexes to MPS I mice resulted in significant increase in laronidase activity in the brain cortex, heart, lungs, kidneys, eyes, and serum. The overall results demonstrate the feasibility of nasal administration of laronidase-loaded liposomes to deliver enzyme in difficult-to-reach tissues, circumventing ERT issues and bringing hope as a potential treatment for MPS I.

Discovery of allosteric regulators with clinical potential to stabilize alpha-L-iduronidase in mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disease caused by lowered activity of the enzyme alpha-L-iduronidase (IDUA). Current therapeutic options show limited efficacy and do not treat some important aspects of the disease. Therefore, it may be advantageous to identify strategies that could improve the efficacy of existing treatments. Pharmacological chaperones are small molecules that protect proteins from degradation, and their use in combination with enzyme replacement therapy (ERT) has been proposed as an alternative therapeutic strategy. Using the SEE-Tx® proprietary computational drug discovery platform, a new allosteric ligand binding cavity in IDUA was identified distal from the active site. Virtual high-throughput screening of approximately 5 million compounds using the SEE-Tx® docking platform identified a subset of small molecules that bound to the druggable cavity and functioned as novel allosteric chaperones of IDUA. Experimental validation by differential scanning fluorimetry showed an overall hit rate of 11.4%. Biophysical studies showed that one exemplary hit molecule GT-01803 bound to (Kd = 22 µM) and stabilized recombinant human IDUA (rhIDUA) in a dose-dependent manner. Co-administration of rhIDUA and GT-01803 increased IDUA activity in patient-derived fibroblasts. Preliminary in vivo studies have shown that GT-01803 improved the pharmacokinetic (PK) profile of rhIDUA, increasing plasma levels in a dose-dependent manner. Furthermore, GT-01803 also increased IDUA enzymatic activity in bone marrow tissue, which benefits least from standard ERT. Oral bioavailability of GT-01803 was found to be good (50%). Overall, the discovery and validation of a novel allosteric chaperone for rhIDUA presents a promising strategy to enhance the efficacy of existing treatments for MPS I. The compound's ability to increase rhIDUA activity in patient-derived fibroblasts and its good oral bioavailability underscore its potential as a potent adjunct to ERT, particularly for addressing aspects of the disease less responsive to standard treatment.

Implantación y resultados de un programa de riesgo compartido para terapias de sustitución enzimática en enfermedades de depósito lisosomal / Implementation and results of a risk-sharing scheme for enzyme replacement therapy in lysosomal storage disease

Objetivo: Describir la implantación y los resultados de un programa de riesgo compartido para el tratamiento enzimático sustitutivo de enfermedades lisosomales. Método: Se diseñó y aplicó el programa en un hospital de referencia para enfermedades congénitas del metabolismo. La consecución de los acuerdos requirió las siguientes fases: 1) Definir y consensuar las variables y criterios de respuesta al tratamiento; 2) asignar el porcentaje de descuento a cada escalón de efectividad; 3) elaborar y firmar el acuerdo por todas las partes; 4) implantar el acuerdo; 5) individualizar la gestión de compras; 6) evaluar los resultados clínicos, y 7) emitir un informe anual. Resultados: Se incluyeron ocho pacientes en el programa (cuatro con enfermedad de Hurler, dos con enfermedad de Pompe y dos con enfermedad de Gaucher), siendo cinco de ellos mujeres y tres varones. Tras analizar las variables y criterios de respuesta definidos, todos los pacientes presentaron efectividad plena tras dos o tres años de seguimiento, excepto uno de ellos que no se pudo evaluar. Dada la efectividad alcanzada, el hospital realizó el pago íntegro de todos los tratamientos administrados. Conclusiones: El programa de riesgo compartido implantado es la primera experiencia publicada de pago por resultados clínicos en medicamentos huérfanos en España. El impacto económico ha sido limitado y la implantación del programa no ha estado exenta de complejidad de formulación y de gestión. Sin embargo, el mayor logro ha sido reducir la brecha de conocimiento entre eficacia y efectividad, constatando que las terapias administradas han mostrado los beneficios óptimos por los que está dispuesto a pagar el financiador

Objective: To describe a risk-sharing program's implementation and results on enzyme replacement therapy for lysosomal diseases. Method: The program was designed and implemented in a referral hospital for congenital metabolic diseases. The conclusion of agreements required the following phases: 1) To define and agree on response variables and criteria to treatment; 2) to assign discount percentage to each stage of effectiveness; 3) to prepare and sign the agreement by all parties; 4) to implement the agreement; 5) to individualize purchases management; 6) to evaluate clinical results, and 7) to issue an annual report. Results: Eight patients were included in the program (four with Hurler's disease, two with Pompe and two with Gaucher), five of them were women and three were men. After analyzing the defined variables and response criteria, all patients presented full effectiveness after two or three years of follow-up except one of them that could not be evaluated. Given the effectiveness achieved, the hospital made full payment of all administered therapies. Conclusions: The implanted risk-sharing program is Spain's first published event of paying for clinical results using orphan drugs. Economic impact has been limited, and program implementation has gone through a complex process of formulation and management. However, the greatest achievement has been to reduce the knowledge gap between efficacy and effectiveness, stating that the therapies administered have shown the optimal benefits for which the funder is willing to pay

Case series of patients under biweekly treatment with laronidase: a report of a single center experience / Série de casos de pacientes em tratamento com laronidase quinzenal: relato da experiência de um centro

ABSTRACT Objective: To report the stabilization of urinary glycosaminoglicans (GAG) excretion and clinical improvements in patients with mucopolysaccharidosis type I (MPS I) under an alternative dose regimen of laronidase of 1.2 mg/kg every other week. Methods: We participated in a dose-optimization trial for laronidase in MPS-I patients using four alternative regimens: 0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every week and 1.8 mg/kg every other week (EOW). After the trial ended, the patients resumed the recommended dose and regimen of 0.58 mg/kg every week. Under this regimen, some patients presented difficulties in venous access and were unable to commute weekly to the treatment center. Therefore, we used an alternative regimen that consisted of 1.2 mg/kg EOW in eight patients. A retrospective study of medical records of MPS-I patients who underwent both enzyme replacement therapy (ERT) regimens, of 0.58 mg/kg every week and 1.2 mg/kg EOW, was done. Results: Patients remained clinically stable under the alternative regimen, did not present elevation of urinary GAG nor any adverse event. Conclusions: The switch of dose regimen to 1.2 mg/kg EOW of laronidase was safe, and did not cause any clinical worsening in patients who had been previously under standard dose ERT.

RESUMO Objetivo: Descrever a manutenção dos níveis de glicosaminoglicano (GAG) excretados na urina e da estabilização clínica em pacientes com mucopolissacaridose do tipo I (MPS I) com o uso da laronidase num regime de dose alternativo de 1,2 mg/kg a cada duas semanas. Método: Alguns pacientes do nosso serviço participaram de um estudo de otimização de dose da laronidase para o tratamento da MPS I no qual foram comparados quatro esquemas terapêuticos: 0,58 mg/kg/semana, 1,2 mg/kg a cada duas semanas, 1,2 mg/kg/semana e 1,8 mg/kg a cada duas semanas. Após o término do estudo, todos os pacientes passaram a receber a terapia de reposição enzimática (TRE) na dose padrão de bula, que é de 0,58 mg/kg/semana, e nesse regime alguns pais se queixaram da dificuldade em comparecer ao centro todas as semanas, além da dificuldade de se obter acesso para punção venosa. Com base nessas queixas, oito pacientes passaram a receber a TRE no regime alternativo de 1,2 mg/kg a cada duas semanas. Foi feito o estudo retrospectivo de dados de prontuário de pacientes com MPS I que fizeram TRE com laronidase nas doses 0,58 mg/kg/semana e 1,2 mg/kg a cada duas semanas. Resultados: Os pacientes mantiveram-se clinicamente estáveis, não apresentaram aumento dos níveis de GAG urinários nem eventos adversos durante o regime alternativo de dose. Conclusões: A mudança para o esquema de 1,2 mg/kg de laronidase a cada duas semanas foi segura e não acarretou piora clínica nos pacientes que já estavam em TRE na dose padrão.

The impact of laronidase treatment in otolaryngological manifestations of patients with mucopolysaccharidosis / Impacto do tratamento com laronidase nas manifestações otorrinolaringológicas de pacientes com mucopolissacaridose

ABSTRACT INTRODUCTION: Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by deficiency of a-l-iduronidase. The otolaryngological findings include hearing loss, otorrhea, recurrent otitis, hypertrophy of tonsils and adenoid, recurrent rhinosinusitis, speech disorders, snoring, oral breathing and nasal obstruction. OBJECTIVE: To evaluate the impact of enzymatic replacement therapy with laronidase (Aldurazyme(r)) in patients with mucopolysaccharidosis (MPS I), regarding sleep and hearing disorders, and clinical manifestations in the upper respiratory tract (URT). METHODS: Nine patients with MPS I (8 Hurler-Scheie, and 1 Scheie phenotypes) of both sexes, ages ranging between 3 and 20 years, were included in this study. Patients were evaluated between seven and 11 months before the treatment and between 16 and 22 months after the onset of the enzymatic replacement. They were all submitted to a clinical and otolaryngological evaluation, including nasofibroscopical, polysomnographic and audiologic exams. RESULTS: The results' data showed decreasing of the frequency of ear, nose and throat infections, with improvement of the rhinorrhea and respiratory quality. No remarkable changes were observed regarding macroglossia and tonsil and adenoid hypertrophy. Audiometric and polysomnographic evaluations did not show statistical significance. CONCLUSION: Enzymatic replacement therapy in patients with mucopolysaccharidosis I provides control of recurrent URT infections, rhinorrhea and respiratory quality, however it is does not seem to improve audiologic and polisomnographic parameters, with no effect on adenoid and tonsils hypertrophy and macroglossia.

Resumo Introdução: Mucopolissacaridose (MPS) é uma doença de depósito lisossômico causada pela deficiência de a-l-iduronidase. Os achados otorrinolaringológicos incluem perda auditiva, otorreia, otites de repetição, hipertrofia adenotonsilar, rinossinusite recorrente, distúrbios da fala, roncos, respiração bucal e obstrução nasal. Objetivo: Avaliar o impacto da terapia de reposição enzimática com laronidase (Aldurazyme(r)) em pacientes com mucopolissacaridose I (MPS I) em relação ao sono, distúrbios auditivos e manifestações clínicas do trato respiratório superior (TRS). Método: Nove pacientes com MPS I (oito com fenótipo Hurler-Scheie e um com fenótipo Scheie), de ambos os sexos, com idades variando entre 3 e 20 anos, foram incluídos neste estudo. Os pacientes foram avaliados entre 7 e 11 meses antes do tratamento e entre 16 e 22 meses após o início da substituição enzimática. Todos foram submetidos a uma avaliação clínica e otorrinolaringológica, incluindo nasofibroscopia, polissonografia e exames radiológicos. Resultados: Os dados dos resultados mostraram diminuição da frequência de infecções de orelha, nariz e garganta, com melhora da rinorreia e da qualidade respiratória. Mudanças significativas não foram observadas em relação à macroglossia e à hipertrofia adenotonsilar. Avaliações audiométricas e polissonográficas não apresentaram significância estatística. Conclusão: A terapia de reposição enzimática em pacientes com mucopolissacaridose I fornece controle de infecções recorrentes do TRS, rinorreia e qualidade respiratória, porém, não parece melhorar os parâmetros audiológicos e polissonográficos, ou exercer efeito sobre a hipertrofia adenotonsilar e macroglossia.

A terapia de reposição enzimática pode mudar a frequência de intervenções médicas na mucopolissacaridose tipo I? Um estudo retrospectivo e exploratório / Can enzyme replacement therapy change the frequency of medical interventions in mucopolysaccharidosis type I? An exploratory retrospective study

Introdução: A mucopolissacaridose tipo I (MPS I) é uma doença lisossômica (DL) para a qual está disponível a terapia de reposição enzimática (TRE) com laronidase. Objetivo: caracterizar o efeito da TRE em pacientes com MPS I avaliados por um único centro de referências para DL a partir da análise da frequência de intervenções médicas. Métodos: Estudo retrospectivo e exploratório com comparações pré e pós-intervenção. O número/ano/paciente de consultas, medicamentos usados, internações, cirurgias e exames realizados, foi obtido por meio de revisão de prontuário médico. Essas variáveis foram, então, comparadas entre dois períodos: pré-TRE e pós-TRE. Resultados: Nove pacientes (graves=3, atenuados=6) foram incluídos no estudo. A mediana de idade de início da TRE foi 9 anos e a mediana de duração da TRE foi 4 anos. Em média, os pacientes realizaram 90% das infusões previstas para o período. Somente o número de cirurgias/ano/paciente foi dependente do tempo de doença (p=0,0004) e da gravidade do fenótipo (p=0,014). Com relação às comparações pré e pós-TRE, as variáveis que apresentaram diferença significativa (média do número/ano/paciente) foram: exames (pré-TRE=10,2±2,7; pós-TRE=22,5±2,1; p=0,005) e internações (pré-TRE=0,05±0,04; pós-TRE=0,30±0,11; p=0,013). Conclusão: Nossos dados sugerem que a TRE não alterou a história natural da MPS I em relação aos desfechos analisados. Este achado pode ser devido à idade relativamente avançada de início do tratamento no nosso centro.

Background: Mucopolysaccharidosis type I (MPSI) is a lysosomal disorder (LSD) which can be treated with enzyme replacement therapy (ERT) with laronidase. Aim: To describe the effect of ERT on MPSI patients evaluated at a single referral center for LSD by assessing the frequency of medical interventions. Methods: An exploratory, retrospective study with pre- and post-intervention assessments. We reviewed medical records to collect data on the number of medical appointments/year/patient, medications used, hospital admissions, surgeries, and exams performed. These variables were then compared between the pre- and the post-ERT periods.Results: Nine patients (severe=3; attenuated=6) were included in the study.The median age for the start of ERT was 9 years, and the median time on ERT was 4 years. On average, patients received 90% of the infusions predicted for the study period. Only the number of surgeries/year/patient was found to be dependent on length of disease (p=0.0004) and on severity of phenotype (p=0.014). Regarding pre- and post-ERT comparisons, there was a significant difference (mean number/year/patient in exams (pre-ERT, 10.2±2.7; post-ERT, 22.5±2.1; p=0.005) and hospital admissions (pre-ERT, 0.05±0.04; post-ERT, 0.30±0.11; p=0.013). Conclusion: Our data suggest ERT didn’t alter the natural history of MPSI the outcomes assessed in this study. This may be due to the relatively advanced age of patients when they started treatment at our Center.

Mucopolisacaridosis de tipo I Hurler: Informe de un caso / Mucopolysaccharidosis I, Hurler syndrome: A case report

La mucopolisacaridosis de tipo I (MPS I), es una enfermedad genética autosómica recesiva de origen lisosomal, caracterizada por la deficiencia de la enzima a-L-iduronidasa. La deficiencia en el catabolismo de los glucosaminoglucanos resulta en su acumulación en diferentes tejidos y órganos. La incidencia global de la MPS I es de 0,99-1,99/100 000 nacidos vivos. Existen tres presentaciones clínicas: Hurler (grave), Hurler-Scheie (moderada) y Scheie (leve). Presentamos el caso de un niño de 10 años de edad a quien se le diagnosticó MPS I, de variedad grave en el año 2006, mediante medición de la actividad enzimática de a-L-iduronidasa en leucocitos. Este caso es el único con diagnóstico confirmado y tratamiento enzimático hasta el momento, en el Perú. Presenta infecciones respiratorias recurrentes, hernia umbilical, opacidad corneal, rasgos toscos, macroglosia, hipoacusia, rigidez articular, estenosis de la válvula pulmonar leve-moderada, manos en garra, retardo mental y retraso del crecimiento. Recibe terapia de reemplazo enzimático desde el año 2008, mostrando mejoría de los síntomas viscerales, más no del daño neurológico.

Mucopolysaccharidosis I (MPS I) is a rare, recessively inherited, lysosomal storage disorder caused by deficiency on the enzyme a-L-iduronidase. This defect results in accumulation of heparan and dermatan sulfate in different tissues and organs due to a deficiency in the catabolism of glycosaminoglycans. The overall incidence of MPS I is 0.99-1.99/100.000 live births. There are three clinical presentations: Hurler (severe), Hurler Scheie (mild) and Scheie (mild). We report the case of a 10-years-old male patient diagnosed with Hurler syndrome, the severe presentation, 5 years ago by enzyme a-L-iduronidase activity measurement in leukocytes; with a history of recurrent respiratory infections, umbilical hernia, corneal opacity, coarse facial features, macroglossia, hearing loss, stiffness of joints, cardiac compromise, claw hands, mental retardation and stunted growth. After enzyme replacement therapy the patient has shown improvement of visceral symptoms, but the neurological damage continuous in progress.

Mucopolisacaridosis de tipo I Hurler: Informe de un caso / Mucopolysaccharidosis I, Hurler syndrome: A case report

La mucopolisacaridosis de tipo I (MPS I), es una enfermedad genética autosómica recesiva de origen lisosomal, caracterizada por la deficiencia de la enzima a-L-iduronidasa. La deficiencia en el catabolismo de los glucosaminoglucanos resulta en su acumulación en diferentes tejidos y órganos. La incidencia global de la MPS I es de 0,99-1,99/100 000 nacidos vivos. Existen tres presentaciones clínicas: Hurler (grave), Hurler-Scheie (moderada) y Scheie (leve). Presentamos el caso de un niño de 10 años de edad a quien se le diagnosticó MPS I, de variedad grave en el año 2006, mediante medición de la actividad enzimática de a-L-iduronidasa en leucocitos. Este caso es el único con diagnóstico confirmado y tratamiento enzimático hasta el momento, en el Perú. Presenta infecciones respiratorias recurrentes, hernia umbilical, opacidad corneal, rasgos toscos, macroglosia, hipoacusia, rigidez articular, estenosis de la válvula pulmonar leve-moderada, manos en garra, retardo mental y retraso del crecimiento. Recibe terapia de reemplazo enzimático desde el año 2008, mostrando mejoría de los síntomas viscerales, más no del daño neurológico.(AU)

Mucopolysaccharidosis I (MPS I) is a rare, recessively inherited, lysosomal storage disorder caused by deficiency on the enzyme a-L-iduronidase. This defect results in accumulation of heparan and dermatan sulfate in different tissues and organs due to a deficiency in the catabolism of glycosaminoglycans. The overall incidence of MPS I is 0.99-1.99/100.000 live births. There are three clinical presentations: Hurler (severe), Hurler Scheie (mild) and Scheie (mild). We report the case of a 10-years-old male patient diagnosed with Hurler syndrome, the severe presentation, 5 years ago by enzyme a-L-iduronidase activity measurement in leukocytes; with a history of recurrent respiratory infections, umbilical hernia, corneal opacity, coarse facial features, macroglossia, hearing loss, stiffness of joints, cardiac compromise, claw hands, mental retardation and stunted growth. After enzyme replacement therapy the patient has shown improvement of visceral symptoms, but the neurological damage continuous in progress.(AU)

Medicamentos de alto custo para doenças raras no Brasil: o exemplo das doenças lisossômicas / High cost drugs for rare diseases in Brazil: the case of lysosomal storage disorders

Este artigo aborda, de forma crítica, aspectos das políticas públicas brasileiras para medicamentos, com ênfase nos de alto custo dirigidos às doenças raras. As doenças lisossômicas foram utilizadas como exemplo pela sua raridade e pela tendência mundial para o desenvolvimento de novos fármacos para seu tratamento. Três doenças foram abordadas: doença de Gaucher, doença de Fabry e mucopolissacaridose tipo I. Embora todas tenham medicamentos registrados no Brasil, a doença de Gaucher é a única com protocolo clínico e diretrizes de tratamento balizadas pelo Ministério da Saúde. Os autores almejam, com este artigo, fomentar a discussão sobre o papel da avaliação de tecnologias em saúde para o tratamento das doenças raras no Brasil, enfatizando a necessidade de políticas legitimadas dirigidas especialmente a elas. A despeito das dificuldades de se estabelecer uma política de saúde específica para cada doença rara, é possível o estabelecimento de modelos racionais para lidar com esse crescente desafio.

This paper approaches in a critical way aspects of Brazilian public policies for drugs, emphasizing those classified as high cost and for rare diseases. The lysosomal storage diseases was taken as an example because of their rarity and the international trend for the development of new drugs for their treatment, all at high costs. Three lysosomal storage diseases were approached: Gaucher disease, Fabry disease and mucopolysaccharidosis type I. Gaucher disease has its treatment drug licensed in Brazil and guidelines for its use are established through a clinical protocol by the Ministry of Health. The others have their drug treatments registered in Brazil; however, no treatment guidelines for them have been developed by the government. The objective of the paper was to foster the discussion on the role of health technology assessment for high-cost drugs for rare diseases in Brazil, emphasizing the need for establishing health policies with legitimacy towards these diseases. Despite the difficulties in establishing a health policy for each rare disease, it is possible to create rational models to deal with this growing challenge.

Vía aérea difícil en un paciente pediátrico con mucopolisacaridosis tipo i (síndrome de Hurler) / Difficult airway in a pediatric patient with mucopolysaccharidosis type i (Hurler syndrome)

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Laronidasa para el tratamiento de pacientes con mucopolisacaridosis tipo 1 / Laronidase for the treatment of patients with mucopolysaccharidosis type 1

INTRODUCCIÓN: a) Cuadro clínico: La mucopolisacaridosis tipo I (MPS I) es una enfermedad autosómica recesiva dentro del grupo de errores innatos del metabolismo con depósito lisosomal de diversos tipos de glucosaminoglucanos (GAG). Este cúmulo de GAG (dermatán sulfato y heparan sulfato) puede darse en cualquier órgano y es provocado por la deficiencia de la enzima -L-iduronidasa, conllevando a síntomas progresivos multisistémicos y potencialmente mortales. b) Tecnología sanitaria: Laronidasa (Aldurazyme®, BioMarin Pharmaceutical Inc) es una variante polimórfica de la enzima humana -L-iduronidasa que se produce mediante tecnología de ADN recombinante. Su objetivo es sustituir la -L-iduronidasa ausente en MPS I proporcionando una enzima exógena para la absorción en los lisosomas. De esta forma aumenta el catabolismo de GAG y disminuye su acumulación. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura de laronidasa para pacientes con mucopolisacaridosis tipo I. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE (PubMed), LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. En primer lugar se seleccionaron ensayos clínicos aleatorizados (ECAs) y revisiones sistemáticas (RS) que evalúen la eficacia y seguridad de la tecnología. Debido a la escasez de estudios, se incluyen también estudios observacionales. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de enfermedades raras; y agencias que realizan RS, evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se seleccionaron dos RS, dos GPC, un consenso y cinco ETS. Una RS publicada en el año 2017, incluyó dos ECAs y siete estudios no aleatorizados que incluyeran más de cinco pacientes. El primer ECA seleccionado compara laronidasa en dosis de 100 U/kg (0,58 mg/kg) endovenosa y placebo en niños de con una edad promedio de 15,5 años (rango: 6 a 43 años) teniendo como desenlaces primarios a la capacidad vital forzada (CVF) y la prueba de caminata de 6 minutos (PC6m). Los autores reportan que después de 26 semanas, los pacientes que recibieron laronidasa mostraron mejoras estadísticamente significativas en la CVF, mas no en la distancia de PC6m. También redujo significativamente la hepatomegalia y los niveles de GAG urinarios y, en pacientes más gravemente afectados, mejoró la apnea/hipopnea del sueño y la flexión del hombro. En el segundo ECA se compararon distintas dosis de laronidasa, no encontrando diferencias significativas en la reducción de la excreción urinaria de GAG o el volumen hepático. En ambos estudios laronidasa tuvo un perfil de seguridad aceptable. Debido a la heterogeneidad de estos dos ECAs, no se pudo realizar un meta-análisis. CONCLUSIONES: La evidencia con respecto a la eficacia y seguridad de laronidasa en MPS-I es escasa y de baja calidad metodológica; se basa en dos ECAs comparando laronidasa frente a placebo o distintas dosis de laronidasa entre sí. Si bien se ha intentado analizar los desenlaces clínicos combinando los resultados de los ECAs y estudios observacionales, la calidad de estos resultados es cuestionable y tiene que ser tomada con precaución. Los beneficios demostrados con la evidencia disponible son moderados, sin incluir un beneficio en desenlaces primordiales como mortalidad o calidad de vida. La mayoría de GPC y consensos consideran el uso de laronidasa después del trasplante de células hematopoyéticas. No existe consenso en las recomendaciones de las ETS seleccionadas, dos de ellas consideran justificable el reembolso de laronidasa después de la evaluación de la evidencia y análisis presupuestarios. Las cinco ETS coinciden en que la evidencia disponible es de baja calidad metodológica.

Laronidase como terapia de reposição enzimática na mucopolissacaridose tipo I / Laronidase as enzyme replacement therapy in mucopolysaccharidosis type I

CONTEXTO: A mucopolissacaridose tipo I (MPS I) é uma doença lisossômica (DL) crônica, progressiva, causada pela atividade deficiente da alfa-L-iduronidase (IDUA). A IDUA é responsável pela clivagem dos resíduos de ácido idurônico dos glicosaminoglicanos (GAGs) heparan e dermatan sulfato. Na MPS I, ocorre o acúmulo desses GAGs parcialmente degradados no interior dos lisossomos e o aumento da sua excreção na urina. Em consequência, os pacientes apresentam comprometimento dos sistemas respiratório, nervoso, musculoesquelético, gastrointestinal (fígado e baço), cardiovascular, dentre outros. A MPS I é herdada de forma autossômica recessiva, sendo uma doença rara. A sua incidência mundial é bastante variável, sendo estimada entre 0,69 e 1,66 por 100.000 pessoas. Está associada a três formas clássicas, que diferem entre si com base na presença de comprometimento neurológico, na velocidade de progressão da doença e na gravidade do acometimento dos órgãos-alvo. Não existe tratamento curativo para a MPS I. O manejo clínico dos pacientes envolve equipe multidisciplinar e inclui intervenções realizadas no nível do fenótipo clínico (como cirurgias para correção de hérnias) e no nível da proteína mutante (transplante de células hematopoiéticas (TCTH) e terapia de reposição enzimática (TRE), conduzida com laronidase, enzima produzida por tecnologia de DNA recombinante). TECNOLOGIA: Laronidase. INDICAÇÃO: Reposição enzimática na mucopolissacaridose tipo I. PERGUNTA: O uso da laronidase como TRE em pacientes com MPS tipo I é eficaz e seguro na melhora clínica e da qualidade de vida dos pacientes? EVIDÊNCIAS CIENTÍFICAS: Foram realizadas buscas nas seguintes bases de dados: PubMed, Embase, Lilacs, Cochrane e ClinicalTrials.gov. Treze estudos foram incluídos nesse relatório, sendo nove ensaios clínicos controlados e randomizados, 4 revisões sistemáticas, os quais foram avaliados pelos desfechos, classificados, por sua vez, como de maior ou menor relevância clínica no tratamento da doença. Dentre os quatro desfechos considerados de maior relevância avaliados, o tratamento com laronidase trouxe benefício clinicamente significativo na capacidade de flexão do ombro que reflete um efeito positivo nas doenças osteoarticulares. Para os outros desfechos avaliados, qualidade de vida, manifestações cardiológicas e doença ocular não foi possível determinar com precisão a existência de benefício. Entre os desfechos de menor relevância, o uso de laronidase demonstrou ter impacto benéfico na diminuição da excreção de GAGs urinários e diminuição do crescimento hepático, mas com efeito incerto na capacidade respiratória, e no crescimento e estado nutricional. O uso de laronidase foi considerado seguro, não se relatando efeitos adversos importantes que pudessem comprometer o tratamento. Em estudos não controlados ou randomizados observaram-se maior probabilidade de sobrevida e menor impacto em órgãosalvo em participantes que fizeram o tratamento de reposição enzimática, principalmente quando se iniciava o tratamento de forma mais precoce. Recomendam-se que sejam implementadas políticas de saúde e educacionais no Brasil, que permitam o diagnóstico precoce dos pacientes, a fim de possibilitar a realização de TCTH, quando indicado, o início precoce da TRE e o aconselhamento genético. Da mesma forma, Protocolo Clínico e Diretrizes Terapêuticas deve estabelecer os critérios para início e interrupção do tratamento. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A estimativa de impacto orçamentário decorrente da incorporação de laronidase estaria entre R$ 29 milhões a R$ 44 milhões no primeiro ano de incorporação. RECOMENDAÇÃO INICIAL: A CONITEC recomendou preliminarmente a incorporação no SUS da laronidase para reposição enzimática em pacientes com mucopolissacaridose tipo I. CONSULTA PÚBLICA: Foram recebidas 348 contribuições, sendo 340 pelo formulário de experiência ou opinião e 8 pelo formulário técnico-científico. No que diz respeito às características das 340 contribuições pelo formulário de experiência ou opinião analisadas, 337 contribuições foram de pessoa física e 3 de pessoa jurídica. O percentual de concordância com a recomendação da CONITEC foi de 100%. Dos 08 formulários técnico-cientifico enviados e analisados, 7 foram de pessoa física (4 de profissionais de saúde, 2 interessados e 1 familiar) e 1 de pessoa jurídica. Todas as 8 contribuiçoes recebidas pelo formulário técnico-científico se declaravam favoráveis à recomendação da CONITEC e apenas 1 apresentou argumentos ciêntíficos. DELIBERAÇÃO FINAL: Os membros presentes na 57ª reunião do Plenário da CONITEC, nos dias 5 e 6 de julho, deliberaram por unanimidade recomendar a incorporação da laronidase para reposição enzimática em pacientes com mucopolissacaridose tipo I. Foi assinado o Registro de Deliberação nº 275/2017.(AU)

Mucopolisacaridosis tipo I: evolución clínica de 2 pacientes tras 30 meses de tratamiento enzimático sustitutivo / Mucopolysaccharidosis type I: clinical courses of two patients after 30 months of enzyme replacement therapy

La mucopolisacaridosis tipo I (MPS I) es una enfermedad lisosomal hereditaria producida por un déficit enzimático de a-Liduronidasa, que da lugar a una acumulación de los glucosaminglucanos (GAG) dermatán y heparán sulfato en los órganos y los tejidos, así como a un aumento de su excreción urinaria. Hay tres subtipos: la enfermedad de Hurler (MPS IH) es la más grave, la enfermedad de Scheie (MPS IS) es la más leve y la enfermedad de Hurler-Scheie (MPS IHS) es la forma intermedia. Es una enfermedad crónica y progresiva, con manifestaciones multisistémicas. La disminución de la capacidad pulmonar y los síntomas de obstrucción de las vías altas (síndrome apnea- hipopnea del sueño), la afectación cardiovascular y los problemas articulares son los que causan mayor morbimortalidad. El trasplante de médula ósea o de células madre hematopoyéticas, junto con el tratamiento enzimático sustitutivo, constituyen los principales pilares del tratamiento. Presentamos 2 casos de MPS I que han recibido tratamiento sustitutivo con enzima recombinante a-L-iduronidasa durante 30 meses y un tercer caso de un paciente que lo ha iniciado hace 3 meses. Ninguno ha presentado complicaciones atribuibles al tratamiento

Mucopolysaccharidosis type I is an inherited lysosomal storage disease caused by deficiency of the enzyme a-L-iduronidase that leads to a progressive accumulation of dermatan sulfate and heparan sulfato glycosaminoglycans in organs and tissues and to increased urinary excretion. There are three clinical syndromes in decreasing order of severity: Hurler (MPS IH), Hurler-Scheie (MPS IHS) and Scheie (MPS IS). Mucopolysaccharidosis I is a chronic, progressive, multisystemic disease. Respiratory insufficiency and sleep apnea- hypopnea syndrome, together with cardiovascular compromise and joint problems, are the main causes of morbidity and mortality. Bone marrow or hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) are the mainstays of treatment of these patients. We report the clinical courses of two patients who have been treated with recombinant human a-L-iduronidase (laronidase) for 30 months and a third patient who began ERT 3 months ago. None of these patients has presented adverse events related to ERT

Síndrome de Hurler-Scheie: seguimiento de la terapia de recambio enzimático durante dos años / No disponible

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Evolución de dos pacientes con síndrome de Hurler en tratamiento con enzima recombinante humana α -L-iduronidasa / Outcome replacement of two patients with Hurler´s syndrome under enzyme replacement therapy with human recombinant α -L-iduronidase

Estudio prospectivo de 2 pacientes con enfermedad de Hurler (de 4,8 años y 17 meses de edad al inicio de la intervención) en tratamiento enzimático sustitutivo con enzima recombinante humana α -L-iduronidasa durante 52 y 28 semanas, respectivamente, con el objetivo de analizar la eficacia y seguridad de la intervención durante dicho período de tiempo. Se realizaron para ello diversas pruebas diagnósticas por imagen, exámenes clínicos y analíticos seriados que demostraron en ambos casos ser una terapia efectiva. En el caso 1 (varón de 4,8 años, homocigoto W402X) la intervención se planteó con fines paliativos desde el comienzo debido a su estado clínico muy evolucionado. En el caso 2 (mujer de 17 meses, heterocigota para W402X) la intervención se realizó de forma precoz y se observó una estabilización clínica posterior sin la adquisición de factores regresivos. Posteriormente se realizó con éxito un trasplante de médula ósea de donante no emparentado. Actualmente, ante la carencia de donantes de médula ósea histocompatibles, se está realizando trasplante de células madre hematopoyéticas procedentes de cordón o de sangre periférica con resultados satisfactorios. La terapia génica se considera el tratamiento futuro capaz de prevenir la enfermedad asociada al síndrome de Hurler y detener el deterioro neurocognitivo característico de estos pacientes.

We performed a prospective study of two patients with Hurler's syndrome (aged 4.8 years and 17 months at the beginning of the intervention) under enzyme replacement therapy with human recombinant α -L-iduronidase for 452 and 28 weeks respectively. The aim of this study was to analyze the safety and efficacy of the intervention during the treatment periods. Several diagnostic imaging tests, clinical examinations, and serial laboratory determinations were performed to demonstrate the effectiveness of the therapy in both patients. In patient 1 (a boy aged 4.8 years, homozygote W402X), the treatment was always intended to be palliative because of the advanced stage of the disease. In patient 2 (a 17-month-old girl, heterozygote W402X) the treatment was initiated early with subsequent clinical stabilization without acquisition of regressive factors. Bone marrow transplantation from an unrelated donor was successful. Currently, because of the lack of histocompatible bone marrow donors, transplantation of hematopoietic stem cells from umbilical cord blood or peripheral blood are being performed with satisfactory results. In the future, gene therapy may be able to prevent the diseases associated with Hurler's syndrome and halt the neurocognitive deterioration characteristic of these patients