RESUMO
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.
Assuntos
Mucopolissacaridose I , Humanos , Mucopolissacaridose I/terapia , Mucopolissacaridose I/tratamento farmacológico , Iduronidase/efeitos adversos , Iduronidase/genética , Iduronidase/metabolismo , Encéfalo/metabolismo , Barreira Hematoencefálica/metabolismo , Receptores da Transferrina/genética , Heparitina Sulfato/metabolismoRESUMO
Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Receptores da Transferrina/antagonistas & inibidores , Proteínas Recombinantes de Fusão/uso terapêutico , Quimioterapia Combinada , Humanos , Mucopolissacaridose II/diagnóstico , Resultado do TratamentoRESUMO
In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Terapia de Reposição de Enzimas/métodos , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Receptores da Transferrina/antagonistas & inibidores , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Brasil/epidemiologia , Criança , Quimioterapia Combinada , Feminino , Humanos , Masculino , Mucopolissacaridose II/epidemiologia , Mucopolissacaridose II/genética , Mucopolissacaridose II/patologia , Receptores da Transferrina/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Whereas significant strides have been made in the treatment of lysosomal storage diseases (LSDs), the neuronopathy associated with these diseases remains impervious mainly because of the blood-brain barrier (BBB), which prevents delivery of large molecules to the brain. However, 100 years of research on the BBB since its conceptualization have clarified many of its functional and structural characteristics, spurring recent endeavors to deliver therapeutics across it to treat central nervous system (CNS) disorders, including neuronopathic LSDs. Along with the BBB, the cerebrospinal fluid (CSF) also functions to protect the microenvironment of the CNS, and it is therefore deeply involved in CNS disorders at large. Recent research aimed at developing therapeutics for neuronopathic LSDs has uncovered a number of critical roles played by the CSF that require further clarification. This review summarizes the most up-to-date understanding of the BBB and the CSF acquired during the development of therapeutics for neuronopathic LSDs, and highlights some of the associated challenges that require further research.
Assuntos
Barreira Hematoencefálica , Doenças por Armazenamento dos Lisossomos , Transporte Biológico , Encéfalo , Sistemas de Liberação de Medicamentos , Humanos , Doenças por Armazenamento dos Lisossomos/tratamento farmacológicoRESUMO
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.
Assuntos
Terapia de Reposição de Enzimas , Iduronato Sulfatase/uso terapêutico , Mucopolissacaridose II/tratamento farmacológico , Animais , Biomarcadores/líquido cefalorraquidiano , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Iduronato Sulfatase/genética , Iduronato Sulfatase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucopolissacaridose II/patologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers' experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews. METHODS: Semi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience. RESULTS: Seven caregivers from 16 trial sites participated, representing seven children aged 8-18 years who had received pabinafusp alfa for 3.3-3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa. CONCLUSION: Caregivers' perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa's potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.
Assuntos
Iduronato Sulfatase , Mucopolissacaridose II , Masculino , Criança , Humanos , Mucopolissacaridose II/tratamento farmacológico , Cuidadores/psicologia , Qualidade de Vida , Japão , Iduronato Sulfatase/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Doenças Raras/tratamento farmacológicoRESUMO
We conducted a randomized phase 3 study to investigate the efficacy and safety of GH treatment in prepubertal Japanese patients with short stature due to SHOX deficiency. The patients were randomly allocated to the GH-GH group (n = 10), in which the patients were treated with GH (0.35 mg/kg/wk) subcutaneously once daily for 24 mo, or the no-treatment (NT)-GH group (n = 9), in which the patients were untreated for the first 12 mo and then administered the same dosage of GH for the next 12 mo. At month 12, the ∆height standard deviation score (SDS) for chronological age (CA) and serum IGF-1 level were significantly higher in the GH-GH group than those in the NT-GH group. In contrast, bone age (BA) and ΔBA/ΔCA were numerically higher in the GH-GH group but were not statistically significant. At month 24, these parameters were comparable between the two groups. The height velocity was significantly larger in the GH-GH group during the first year and in the NT-GH group during the second year. No serious adverse drug reactions were observed; however, one patient in the GH-GH group exhibited increased insulin resistance at month 24. These results indicated that GH is a promising treatment option for short stature in patients with SHOX deficiency.
RESUMO
Enzyme replacement therapy (ERT) has paved the way for treating the somatic symptoms of lysosomal storage diseases (LSDs), but the inability of intravenously administered enzymes to cross the blood-brain barrier (BBB) has left the central nervous system (CNS)-related symptoms of LSDs largely impervious to the therapeutic benefits of ERT, although ERT via intrathecal and intracerebroventricular routes can be used for some neuronopathic LSDs (in particular, mucopolysaccharidoses). However, the considerable practical issues involved make these routes unsuitable for long-term treatment. Efforts have been made to modify enzymes (e.g., by fusing them with antibodies against innate receptors on the cerebrovascular endothelium) so that they can cross the BBB via receptor-mediated transcytosis (RMT) and address neuronopathy in the CNS. This review summarizes the various scientific and technological challenges of applying RMT to the development of safe and effective enzyme therapeutics for neuronopathic mucopolysaccharidoses; it then discusses the translational and methodological issues surrounding preclinical and clinical evaluation to establish RMT-applied ERT.
RESUMO
OBJECTIVE: Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2). DESIGN: A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures. RESULTS: JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to τ (AUC0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues. CONCLUSIONS: Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD. ETHICS: This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.
Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Humanos , Masculino , Fator de Crescimento Insulin-Like I , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento , Método Duplo-Cego , Albuminas , Relação Dose-Resposta a DrogaRESUMO
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked recessive lysosomal storage disease caused by a mutation in the IDS gene and characterized by systemic accumulations of glycosaminoglycans. Its somatic symptoms can be relieved by enzyme replacement therapy (ERT) with idursulfase, but because the enzyme cannot cross the blood-brain-barrier (BBB), it does not address the progressive neurodegeneration and subsequent central nervous system (CNS) manifestations seen in patients with neuropathic MPS-II. However, pabinafusp alfa, a human iduronate-2-sulfatase (IDS) fused with a BBB-crossing anti-transferrin receptor antibody, has been shown to be efficacious against both the somatic and CNS symptoms of MPS II. We report two cases of MPS-II in Japanese siblings sharing the same G140V mutation in the IDS gene, who showed markedly contrasting developmental trajectories following enzyme replacement therapy (ERT). Sibling 1 was diagnosed at 2 years of age, started undergoing conventional ERT shortly afterward, and scored a developmental quotient (DQ) of 53 on the Kyoto Scale of Psychological Development (KSPD) at 4 years of age. Sibling 2 was diagnosed prenatally and received conventional ERT from the age of 1 month through 1 year and 11 months, when he switched to pabinafusp alpha. He attained a DQ of 104 at age 3 years and 11 months, along with significant declines in heparan sulfate concentrations in the cerebrospinal fluid. This marked difference in neurocognitive development highlights the importance of early initiation of ERT with a BBB-penetrating enzyme in patients with neuropathic MPS-II.