Miglustat

本文旨在为读者提供关于范可尼贫血(FA)、戈谢病(GD)、先天性肾上腺皮质增生症(CAH)、原发性肉碱缺乏症(PCD)以及甲基丙二酸血症(MMA)等病症的最新治疗或缓解药物信息。请注意，本文所提供的药物信息仅供参考，并非临床用药依据。若涉及相关病症，请务必及时就医并遵循专业医生的建议。 1.1 【 羟甲烯龙的作用 】 羟甲烯龙属于蛋白同化激素类药物，它能够促进蛋白质的合成并抑制其异生，有助于降低血胆固醇、减少钙磷的排泄，并缓解骨髓抑制，进而促进发育、组织新生以及肉芽的形成。此外，该药物还能预防和对抗因长期使用肾上腺皮质激素所引发的肾上腺皮质功能减退。 1.2 【 艾曲泊帕与RP-L102 】 艾曲泊帕，一种口服血小板生成素，是葛兰素史克与Ligand Pharmaceuticals共同研究的成果。诺华公司在美国以其商品名Promacta进行制造和销售，同时在欧盟以Revolade商品名进行销售。此药物主要用于改善某些个体的中性粒细胞计数，常作为并发疾病期间的支持治疗。 RP-L102是Rocket制药公司研发的一种基于LVV的基因疗法。其治疗流程包括在体外利用CD33+筛选程序对造血干细胞进行筛选和分离，随后通过RP-102进行基因修饰。经过修饰的富含CD34+的造血细胞会被回输至患者体内，以恢复其正常功能。目前，该疗法正在欧盟进行1/2期临床试验研究。 2.1 【 Alglucerase和Elelyso 】 戈谢病的治疗迎来了重大突破，在1991年4月，首个有效治疗药物Alglucerase（Ceredase）获得了FDA的批准。这款药物以人胎盘组织为原料，经过提取和精制，制备出葡糖脑苷脂酶，用于治疗戈谢病。然而，遗憾的是，它已从市场上撤出。 Elelyso（Taliglucerase-α）他利苷酶-alfa，这款由以色列Protalix公司和Pfizer（辉瑞）联合开发的重组葡萄糖脑苷脂酶生物制剂，专为治疗Ⅰ型戈谢病而设计。它不仅是植物细胞表达系统诞生的首个药物，更在美国FDA的严格审批下成为第一种获得批准的植物制剂药。 2.2 【 VPRIV与依利格鲁司特 】 VPRIV（Velaglucerase-α）被称为维葡瑞，是一款专为戈谢病治疗设计的酶替代疗法药物，由Shire公司研发，并经过美国FDA和欧盟EMEA的优先审批，分别于2010年2月26日和2010年8月26日获得批准。它作为一种长期有效的治疗选择，为戈谢病患者带来了新的希望。 依利格鲁司特（Cerdelga），由健赞公司（赛诺菲）研发，是一种专为Ⅰ型戈谢病治疗设计的口服药物。其独特的作用机制在于抑制特异性葡萄糖神经酰胺合酶，从而为患者提供了一种新的治疗选择。 2.3 【 Imiglucerase和Miglustat 】 Imiglucerase（商品名Cerezyme），由Genzyme公司制造，是治疗Ⅰ型和Ⅲ型戈谢病的重要药物。作为西利酶（Ceredase）的改良版，伊米苷酶于1994年5月获得FDA批准，并成功取代了Ceredase。 Miglustat（商品名Zavesca），由英国Oxford GlycoSciences研发并由瑞士生物科技企业Actelion销售，是一种口服小分子药物。当酶替代疗法对轻度至中度Ⅰ型戈谢病（GD1）患者无效时，此药物可作为替代治疗方案。其作用机制在于抑制葡萄糖脑苷脂的形成，这一治疗方法被称为底物还原疗法。 3.1 【 氢化可的松与泼尼松龙 】 对于经典型CAH患者，终身使用糖皮质激素是标准治疗方案，其中氢化可的松是首选药物。在青春期，由于皮质醇的代谢率显著增强，因此一些专家建议在此阶段，特别是对于代谢旺盛的患者，应考虑采用氢化可的松进行治疗。 在婴儿期和儿童期，氢化可的松或液体泼尼松龙常被优先考虑，因为它们与人体自然分泌的皮质醇结构相似，对骨骼生长板的影响相对较小。 3.2 【 地塞米松及氟氢可的松 】 在骨骺闭合后，治疗目标主要转变为预防长期不良的临床特征。考虑到青少年患者的依从性可能较差，且在停止生长后，许多经典型CAH患者会转为长效糖皮质激素治疗。 氟氢可的松是当前唯一可用的盐皮质激素药物，其常用剂量范围为每日0.05至2毫克。在用药过程中，需密切监测电解质、肾素以及血压水平，以确保剂量调整的合理性。 3.3 【 BBP-631的创新疗法 】 这是BridgeBio制药公司最新宣布的一种AAV基因疗法，旨在治疗先天性肾上腺发育不全（CAH）。经过多项动物研究证实，该疗法能有效且持久地将正常产生激素的肾上腺基因传递至患者体内。通过刺激肾上腺增生，使患者能够自主制造皮质醇和醛固酮，从而恢复体内的激素和类固醇平衡。这一创新治疗方法在目前的市场上尚属首次，且有望在2022年下半年启动早期临床数据采集工作。 4.1 【 左旋肉碱的重要功能 】 左旋肉碱，又称左旋肉毒碱，是食物中的一种关键成分，广泛存在于自然界中，尤其在山羊肉中的含量高达2.1g/kg。人体自身也能合成左旋肉毒碱，成人体内大约含有20克左右，主要分布在心肌和骨骼肌中。1958年，Fritz发现左旋肉毒碱能够加速线粒体对脂肪的代谢速度，从而明确了它在脂肪氧化过程中的核心作用。 5.1 【 维生素B12的参与与缺乏 】 在甲基丙二酰辅酶A的代谢过程中，维生素B12扮演着至关重要的角色。它参与了将辅因子甲基丙二酰-CoA转化为琥珀酰-CoA的关键步骤。一旦维生素B12的量不足以完成这一转化，未消耗的甲基丙二酰-CoA便会积累，最终引发甲基丙二酸血症。 5.2 【 左旋肉碱及其他新疗法 】 左旋肉碱，在医学领域被称为“左卡尼汀”，是一种广泛应用于运动食品和功能补剂中的成分。全球范围内，这种物质被广泛销售，且所有MMA患者对左旋肉毒碱治疗都表现出反应。此外，左旋肉碱还有助于清除体内的酰基辅酶A，通过转化为可经尿液排出的酰基肉碱，从而在低蛋白饮食中发挥膳食补充剂的作用。 5.3 【 LB-001与HST5040 】 LB-001是LogicBio Therapeutics公司研发的单次给药基因组编辑疗法，旨在为甲基丙二酸血症（MMA）患儿提供新的治疗选择。近期公布了一项重大临床试验成果，标志着首次在儿童患者身上进行的基因编辑疗法取得了突破。 HST5040是由HemoShear公司研发的一款药物，旨在降低甲基丙二酸血症（MMA）和丙酸血症（PA）患者体内积累的有毒代谢物。HST5040作为一种小分子药物，能够轻松分布到患者体内的所有受影响组织，从而在全身范围内发挥作用。 5.4 【 mRNA-3705的探索 】 Moderna公司已成功完成对首位患者的给药，这是在评估其研究性mRNA疗法mRNA-3705的安全性和耐受性的1/2期研究中的重要一步。该疗法针对的是甲基丙二酸血症（MMA），一种通过静脉输注给药的罕见代谢性疾病。研究将探索多达五种不同的给药方案，以确定每种方案的安全性和耐受性。在收集足够的安全性和药理学数据后，将选出最佳剂量，并允许更多患者加入可选择的扩展队列，接受进一步治疗。

Long-Term Data Adds to the Growing Body of Evidence Supporting the Compelling Clinical Profile of Pombiliti® + Opfolda®PRINCETON, N.J., Sept. 08, 2025 (GLOBE NEWSWIRE) -- Amicus Therapeutics (Nasdaq: FOLD), today announced the presentation of new 4-year muscle function, muscle strength and biomarker endpoints from the PROPEL open-label extension (OLE) study of cipaglucosidase alfa-atga + miglustat (cipa+mig) in adults with late-onset Pompe disease (LOPD) at the International Congress of Inborn Errors of Metabolism (ICIEM) in Kyoto, Japan. The new analysis, “208-week efficacy and safety of cipaglucosidase alfa plus miglustat in patients with late-onset Pompe disease treated from PROPEL baseline: muscle function and biomarkers,” was conducted on the 82 patients (62 ERT-experienced and 20 ERT-naïve) who were randomized to cipa+mig in PROPEL and who enrolled in the open label extension (OLE). Pombiliti + Opfolda is indicated in the U.S. for the treatment of adult patients with LOPD weighing ≥40 kg and who are not improving on their current ERT. In the U.S., Pombiliti + Opfolda is not indicated for patients naïve to ERT treatment. The data summarized below are from the ERT-experienced group in the OLE. Pulmonary function data from the PROPEL OLE will be presented separately at an upcoming conference. The mean age was 48.8 years and the median duration of prior ERT in the ERT-experienced cohort at PROPEL baseline was 7.5 years. In the ERT-experienced group, the measures of muscle function, muscle strength and biomarkers improved and/or were sustained out to 208 weeks. Mean change from PROPEL baseline to week 208 were as follows: Percent predicted six-minute walk distance (6MWD), +2.3%;Lower extremity manual muscle test (MMT) score, +1.6 points;Gait-Stairs-Gowers-Chair (GSGC) score, +0.1 points;PROMIS® physical function score, +1.2 points;Serum creatine kinase (CK) levels, -160.0 serum CK; and,Urine hexose tetrasaccharide (Hex4), -1.9 mmol/mol creatinine. No new safety signals were identified. Up to week 208, 41 patients experienced treatment-related treatment-emergent adverse events (TEAEs), leading to four cipa+mig discontinuations, and two patients experienced serious treatment-related TEAEs, leading to two cipa+mig discontinuations. One patient experienced a TEAE (worsening of Lewy body disease) unrelated to study treatment, which led to death; the patient had discontinued from the study prior to death. “Durability of effect is important for evaluating the impact of treatments for individuals with LOPD. In this new analysis assessing the long-term outcomes from the open label extension of PROPEL, the improvements in muscle function, muscle strength, and biomarkers observed in patients receiving Pombiliti and Opfolda were maintained for four years,” said Priya Kishnani, MD, Chief, Division of Medical Genetics, Chen Family Distinguished Professor of Pediatrics, Chief, Division of Medical Genetics, Duke University Medical Center. “This new analysis adds to the growing body of evidence supporting the compelling clinical profile of Pombiliti and Opfolda in ERT-experienced adults,” said Jeff Castelli, PhD, Chief Development Officer, Amicus Therapeutics, Inc. “To observe these sustained improvements and stability in the patients in the open label extension at four years is very encouraging given the progressive nature of LOPD. We look forward to presenting long-term extension data across pulmonary measures soon and will continue to closely study Pombiliti and Opfolda as part of our commitment to make a meaningful difference in the lives of people living with late-onset Pompe disease.” Other abstracts at ICIEMIn addition to this analysis, the following abstracts related to Pombiliti + Opfolda based on Amicus studies were also presented at ICIEM: Abstract Title: Cipaglucosidase alfa and alglucosidase alfa enzymes have similar stability at neutral pH and can be stabilized with miglustat Presenter: Filip Cosmanescu, Amicus Therapeutics Inc., Princeton, NJ, U.S.A. Abstract Title: Integrating clinical evidence on cipaglucosidase alfa plus miglustat and alglucosidase alfa via a multi-level network meta-regression Presenter: William Kerr, Amicus Therapeutics Ltd, Marlow, U.K. Abstract Title: PROPEL Japan subpopulation: efficacy and safety of cipaglucosidase alfa plus miglustat versus alglucosidase alfa in patients with late-onset Pompe disease Presenter: Hiroshi Kobayashi, The Jikei University School of Medicine, Tokyo, Japan Abstract Title: ATB200-19: an open-label, expanded access study of the safety and effectiveness of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease in Japan Presenter: Aya Narita, ISEIKAI International General Hospital, Osaka, Japan Abstract Title: PROPEL Australia subpopulation: efficacy and safety of cipaglucosidase alfa plus miglustat versus alglucosidase alfa in patients with late-onset Pompe disease Presenter: Michel Tchan, Westmead Hospital, Westmead, NSW, Australia The following abstract related to Pombiliti + Opfolda from a non-Amicus study was also presented at ICIEM: Abstract Title: Real World Study: Assessing the impact of switching from alpha-glucosidase to cipaglucosidase alfa with miglustat on disease progression in adults with Pompe disease Lead author: Sara Lucas Del Pozo, National Hospital for Neurology and Neurosurgery, UCLH, London, U.K.Presenter: Robin Lachmann, National Hospital for Neurology and Neurosurgery, UCLH, London, U.K. About the PROPEL StudyPROPEL was a 52-week, double-blind randomized global study designed to assess the efficacy, safety, and tolerability of cipaglucosidase alfa-atga + miglustat compared to non-U.S. approved alglucosidase alfa + placebo (the comparator). The study enrolled 123 adult LOPD patients who still had the ability to walk and to breathe without mechanical ventilation. Patients enrolled in PROPEL were randomized 2:1 so that for every two patients randomized to be treated with cipaglucosidase alfa-atga + miglustat, one was randomized to be treated with the comparator. Of the patients enrolled in PROPEL, 77% were being treated with alglucosidase alfa (n=95) for at least 2 years at study entry and 23% had never been treated with any ERT (n=28). 117 of the 123 patients (>95%) completed the PROPEL study. Efficacy endpoints of the study included primary endpoint of change from baseline to week 52 in 6-minute walk distance (6MWD) for comparison of superiority and key secondary endpoint of change from baseline to week 52 in forced vital capacity (FVC). PROPEL did not achieve statistical significance for the primary endpoint of superiority in change from baseline to week 52 in 6MWD in the overall population. After 52 weeks, ERT-experienced patients treated with cipaglucosidase alfa-atga + miglustat (n=61) walked an estimated 17 meters (95% CI, 0.2, 33) farther than the comparator group (n=29). After 52 weeks, ERT-experienced patients treated with cipaglucosidase alfa-atga + miglustat (n=55) showed an estimated treatment difference of 3.5% (95% CI, 1.0, 6.0) in FVC compared with the comparator group (n=29). About the PROPEL Open-label Extension StudyThe Phase 3 open-label extension (OLE) study (ATB200-07) is a multicenter, international study designed to evaluate the long-term safety and efficacy of cipaglucosidase alfa-atga + miglustat in adult subjects with LOPD who completed the Phase 3 PROPEL Study (ATB200-03). Of the 118 patients treated in the OLE, 81 continued cipa+mig treatment from PROPEL (cipa+mig group; 61 ERT-experienced prior to PROPEL; 20 ERT-naïve) and 37 switched from alg+pbo to cipa+mig (switch group; 29 ERT-experienced; 8 ERT-naive). Efficacy endpoints of the study included primary endpoint of change from PROPEL baseline to approximately 4 years in 6-minute walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. About Pombiliti + OpfoldaPombiliti® + Opfolda®, is a two-component therapy that consists of cipaglucosidase alfa-atga, a bis-M6P-enriched rhGAA that facilitates high-affinity uptake through the M6P receptor while retaining its capacity for processing into the most active form of the enzyme, and the oral enzyme stabilizer, miglustat, that’s designed to reduce loss of enzyme activity in the blood. U.S. INDICATIONS AND USAGEPOMBILITI in combination with OPFOLDA is indicated for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg and who are not improving on their current enzyme replacement therapy (ERT). SAFETY INFORMATION HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS: Appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available. If a severe hypersensitivity reaction occurs, POMBILITI should be discontinued immediately and appropriate medical treatment should be initiated. INFUSION-ASSOCIATED REACTIONS (IARs): If severe IARs occur, immediately discontinue POMBILITI and initiate appropriate medical treatment. RISK OF ACUTE CARDIORESPIRATORY FAILURE IN SUSCEPTIBLE PATIENTS: Patients susceptible to fluid volume overload, or those with acute underlying respiratory illness or compromised cardiac or respiratory function, may be at risk of serious exacerbation of their cardiac or respiratory status during POMBILITI infusion. See PI for complete Boxed Warning. CONTRAINDICATION: POMBILITI in combination with Opfolda is contraindicated in pregnancy. EMBRYO-FETAL TOXICITY: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for at least 60 days after the last dose. Adverse Reactions: Most common adverse reactions ≥ 5% are headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia. Please see full PRESCRIBING INFORMATION, including BOXED WARNING, for POMBILITI (cipaglucosidase alfa-atga) LINK and full PRESCRIBING INFORMATION for OPFOLDA (miglustat) LINK. About Late-Onset Pompe DiseaseLate-onset Pompe disease is an inherited lysosomal disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA). Reduced or absent levels of GAA lead to accumulation of glycogen in cells, which is believed to result in the clinical manifestations of Pompe disease. Late-onset Pompe disease can be severe and debilitating with progressive muscle weakness throughout the body that worsens over time, particularly skeletal muscles and muscles that control breathing. About Amicus Therapeutics Amicus Therapeutics (Nasdaq: FOLD) is a global, patient-dedicated biotechnology company focused on discovering, developing and delivering novel high-quality medicines for people living with rare diseases. With extraordinary patient focus, Amicus Therapeutics is committed to advancing and expanding a pipeline of cutting-edge, first- or best-in-class medicines for rare diseases. For more information please visit the company’s website at www.amicusrx.com, and follow on X and LinkedIn. NP-AT-ALL-00010825 CONTACTS: Investors: Amicus Therapeutics Andrew Faughnan Vice President, Investor Relations afaughnan@amicusrx.com(609) 662-3809 Media: Amicus Therapeutics Diana Moore Vice President, Corporate Communications dmoore@amicusrx.com(609) 662-5079 FOLD-G