——Vimizim(elosufase alfa)注射剂接受罕见儿童疾病优先审评凭证的第一个药物
An open-label extension trial was conducted in 173 patients who completed the placebo-controlled trial [see Clinical Studies (14)]. No new adverse reactions were reported. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. All patients treated with Vimizim 2 mg/kg once per week in the placebo-controlled trial developed anti-drug antibodies by Week 4. Anti-drug antibody titers were sustained or increased for the duration of Vimizim treatment. Because all patients developed anti-drug antibodies, associations between antibody titers and reductions in treatment effect or the occurrence of anaphylaxis or other hypersensitivity reactions could not be determined. All patients treated with Vimizim 2 mg/kg once per week tested positive for neutralizing antibodies capable of inhibiting the drug from binding to the mannose-6-phosphate receptor at least once during the trial. Binding to this receptor is required for Vimizim to be taken into cells where it is active. Neutralizing antibody titers were not determined in the patients. Therefore, the possibility of an association between neutralizing antibody titer and treatment effect cannot be assessed. Assessment of the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Vimizim with the incidence of antibodies to other products may be misleading. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There is a Morquio A Registry that collects data on pregnant women with MPS IVA who are treated with Vimizim. Contact MARS@bmrn.com or call 1-800-983-4587 for information and enrollment [see Patient Counseling Information (17)]. Risk Summary There are no adequate and well-controlled studies with Vimizim in pregnant women. However, animal reproduction studies have been conducted for elosulfase alfa. In these studies, no effects on embryo-fetal development were observed in rats given daily administration of elosulfase alfa up to 33 times the human steady-state AUC (area under the curve) at the recommended human weekly dose pre-mating and through the period of organogenesis. No effects on embryo-fetal development were observed in rabbits given daily administration of elosulfase alfa at doses up to 8 times the human steady-state AUC at the recommended weekly dose during organogenesis, which produced maternal toxicity. A dose-dependent increase in stillbirths was observed when elosulfase alfa was administered daily in rats during organogenesis through lactation at doses 5 times the human steady-state AUC at the recommended human weekly dose. An increase in pup mortality was observed at doses producing maternal toxicity. Vimizim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Disease-associated maternal and embryo/fetal risk Pregnancy can adversely affect the health of females affected with MPS IVA and lead to adverse pregnancy outcomes for both mother and fetus. Animal Data All reproductive studies with rats included pre-treatment with diphenhydramine to prevent or minimize hypersensitivity reactions. The effects of elosulfase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone. Daily intravenous (IV) administration of up to 20 mg/kg elosulfase alfa in rats (33 times the human steady-state AUC at the recommended weekly dose of 2 mg/kg) during a 15-day pre-mating period, mating, and the period of organogenesis, produced no maternal toxicity or effects on embryo-fetal development. Daily intravenous administration of up to 10 mg/kg in rabbits (8 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis had no effects on embryo-fetal development. However, maternal toxicity (gross changes in liver) was observed in rabbits given doses of 1 mg/kg/day and higher (0.1 times the human steady-state AUC at the recommended weekly dose). Elosulfase alfa produced an increase in the percentage of stillbirths when administered daily to rats at doses of 6 mg/kg IV and higher (5 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis through lactation. Daily administration of 20 mg/kg IV (33 times the human steady-state AUC at the recommended weekly dose) produced maternal toxicity and an increase in mortality of offspring during the lactation period. This study lacked a full evaluation of neurodevelopmental milestones; however, no effects of elosulfase alfa were noted in tests for learning and memory. 8.3 Nursing Mothers It is not known if Vimizim is present in human milk. Elosulfase alfa is present in milk from treated rats [see Use in Specific Populations (8.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Vimizim and any potential adverse effects on the breastfed child from the drug or from MPS IVA. Exercise caution when administering Vimizim to a nursing mother. There is a Morquio A Registry that also collects data on breastfeeding women with MPS IVA who are treated with Vimizim. Contact MARS@bmrn.com or call 1-800-983-4587 for information and enrollment [see Patient Counseling Information (17)]. 8.4 Pediatric Use Safety and effectiveness of Vimizim have been established in pediatric patients 5 years of age and older. Use of Vimizim in patients 5 years of age and older is supported by an adequate and well-controlled trial in pediatric and adult patients. Clinical trials with Vimizim were conducted in 176 patients (median age 12 years, range 5 to 57 years old) with the majority of patients in the pediatric age group (53% aged 5 to 11 years, 27% aged 12 to 17 years) [see Clinical Studies (14)]. Safety and effectiveness in pediatric patients below 5 years of age have not been established. 8.5 Geriatric Use Clinical studies of Vimizim did not include any patients aged 65 and over. It is not known whether they respond differently from younger patients. 10 OVERDOSAGE There is no experience with overdose with Vimizim. 11 DESCRIPTION Vimizim is a formulation of elosulfase alfa, which is a purified human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. Human N-acetylgalactosamine-6-sulfatase (EC 3.1.6.4) is a hydrolytic lysosomal glycosaminoglycan-specific enzyme that hydrolyzes sulfate from either galactose-6-sulfate or N-acetyl-galactosamine-6-sulfate on the non-reducing ends of the glycosaminoglycans keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Elosulfase alfa is a soluble glycosylated dimeric protein with two oligosaccharide chains per monomer. Each monomeric peptide chain contains 496 amino acids and has an approximate molecular mass of 55 kDa (59 kDa including the oligosaccharides). One of the oligosaccharide chains contains bis-mannose-6-phosphate (bisM6P). bisM6P binds a receptor at the cell surface and the binding mediates cellular uptake of the protein to the lysosome. Elosulfase alfa has a specific activity of 2.6 to 6.0 units/mg. One activity unit is defined as the amount of the enzyme required to convert 1 micromole of sulfated monosaccharide substrate D-galactopyranoside-6-sulfate (Gal-6S) to de-sulfated-galactose (Gal) and free sulfate per minute at 37°C. Vimizim is intended for intravenous infusion and is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted with 0.9% Sodium Chloride for Injection, USP prior to administration. Vimizim is supplied in clear Type 1 glass 5 mL vials. Each vial provides 5 mg elosulfase alfa, 31.6 mg L-arginine hydrochloride, 0.5 mg polysorbate 20, 13.6 mg sodium acetate trihydrate, 34.5 mg sodium phosphate monobasic monohydrate, and 100 mg sorbitol in a 5 mL extractable solution with a pH between 5.0 to 5.8. Vimizim does not contain preservatives. Each vial is for single use only. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mucopolysaccharidoses comprise a group of lysosomal storage disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis IVA (MPS IVA, Morquio A Syndrome) is characterized by the absence or marked reduction in N-acetylgalactosamine-6-sulfatase activity. The sulfatase activity deficiency results in the accumulation of the GAG substrates, KS and C6S, in the lysosomal compartment of cells throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Vimizim is intended to provide the exogenous enzyme N-acetylgalactosamine-6-sulfatase that will be taken up into the lysosomes and increase the catabolism of the GAGs KS and C6S. Elosulfase alfa uptake by cells into lysosomes is mediated by the binding of mannose-6-phosphate-terminated oligosaccharide chains of elosulfase alfa to mannose-6-phosphate receptors. In the absence of an animal disease model that recapitulates the human disease phenotype, elosulfase alfa pharmacological activity was evaluated using human primary chondrocytes from two MPS IVA patients. Treatment of MPS IVA chondrocytes with elosulfase alfa induced clearance of KS lysosomal storage from the chondrocytes. 12.2 Pharmacodynamics The pharmacodynamic effect of Vimizim was assessed by reductions in urinary KS levels. The relationship of urinary KS to other measures of clinical response has not been established [see Clinical Studies (14)]. No association was observed between antibody development and urinary KS levels. 12.3 Pharmacokinetics The pharmacokinetics of elosulfase alfa were evaluated in 23 patients with MPS IVA who received intravenous infusions of Vimizim 2 mg/kg once weekly, over approximately 4 hours, for 22 weeks. Eleven patients were aged 5 to 11 years, six were aged 12 to 17 years, and six were aged 18 to 41 years. Table 2 summarizes the pharmacokinetic parameters at Week 0 and Week 22. Mean AUC0‑t and Cmax increased to 2.8- and 2.9-fold, respectively, at Week 22 compared to Week 0. Mean t1/2 increased from 7.5 min at Week 0 to 35.9 min at Week 22. These changes are likely related to the development of neutralizing antibodies in all patients. Table 2: Pharmacokinetic Parameters
AUC0-t, area under the plasma concentration-time curve from time zero to the time of last measurable concentration; Cmax, observed maximum plasma concentration; Tmax, time from zero to maximum plasma concentration; CL, total clearance of drug after intravenous administration; N = 15; N = 20 Vdss, apparent volume of distribution at steady-state; N = 14; t1/2, elimination half-life 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with elosulfase alfa. Based on the mechanism of action, elosulfase alfa is not expected to be tumorigenic. Daily intravenous administration of elosulfase alfa in rats at doses up to 20 mg/kg (55 times the human steady-state AUC in male rats and 33 times the human steady-state AUC in female rats at the recommended human weekly dose) had no effects on fertility or reproductive performance. 14 CLINICAL STUDIES The safety and efficacy of Vimizim were assessed in a 24-week, randomized, double-blind, placebo-controlled clinical trial of 176 patients with MPS IVA. The age of patients ranged from 5 to 57 years. The majority of the patients (82%) presented with a medical history of musculoskeletal conditions, which includes knee deformity (52%), kyphosis (31%), hip dysplasia (22%), prior spinal fusion surgery (22%) and arthralgia (20%). At baseline, all enrolled patients could walk more than 30 meters (m) but less than 325 m in six minutes. Patients received Vimizim 2 mg/kg once per week (n=58), Vimizim 2 mg/kg once every other week (n=59), or placebo (n=59). The primary endpoint was the change from baseline in the distance walked in six minutes (six minute walk test, 6-MWT) at Week 24. The other endpoints included changes from baseline in the rate of stair climbing in three minutes (three-minute stair climb test, 3-MSCT) and changes from baseline in urine KS levels at Week 24. The treatment effect in the distance walked in 6 minutes, compared to placebo, was 22.5 m (CI95, 4.0, 40.9; p=0.0174) in patients who received Vimizim 2 mg/kg once per week. There was no difference in the rate of stair climbing between patients who received Vimizim 2 mg/kg once per week and those who received placebo. Patients who received Vimizim 2 mg/kg once every other week performed similarly in the 6-MWT and 3-MSCT as those who received placebo. The reduction in urinary KS levels from baseline, a measure of pharmacodynamic effect, was greater in the Vimizim treatment groups compared to placebo. The relationship between urinary KS and other measures of clinical response has not been established. Table 3: Results from Placebo-Controlled Clinical Trial
Observed Vimizim mean change – Placebo mean change ANCOVA Model-based Vimizim mean change – Placebo mean change, adjusted for baseline 6MWT categories (less than or equal to 200 meters, greater than 200 meters) and age groups (5-11, 12-18, 19 or older) p-value based on the model-based difference in means Extension Trial Patients who participated in the placebo-controlled trial were eligible to continue treatment in an open-label extension trial. One hundred seventy-three of 176 patients enrolled in the extension trial in which patients received Vimizim 2 mg/kg once per week (n=86) or Vimizim 2 mg/kg once every other week (n=87). In patients who continued to receive Vimizim 2 mg/kg once per week for another 48 weeks (for a total of 72-week exposure), walking ability showed no further improvement beyond the first 24 weeks of treatment in the placebo-controlled trial. 16 HOW SUPPLIED/STORAGE AND HANDLING Vimizim is supplied as a concentrated solution for infusion (1 mg per mL) requiring dilution. One vial of 5 mL contains 5 mg Vimizim. NDC 68135-100-01, 5 mL vial Store Vimizim under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Diluted Vimizim should be used immediately. If immediate use is not possible, diluted Vimizim may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) followed by up to 24 hours at 23°C to 27°C (73°F to 81°F) during administration. 17 PATIENT COUNSELING INFORMATION Anaphylactic Reactions Advise the patients and caregivers that reactions related to administration and infusion may occur during Vimizim treatment, including life-threatening anaphylaxis. Patients who have experienced anaphylactic reactions may require observation during and after Vimizim administration. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. The risks and benefits of re-administering Vimizim following a severe reaction should be considered. Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions. Pre-medication and reduction of infusion rate may alleviate those reactions associated with the infusion [see Warnings and Precautions (5.1, 5.2)]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0caa2565-12b2-0ad0-1f9a-273e81c3d4cc FDA批准Vimizim用于治疗儿童罕见病 2014年2月14日,美国FDA批准Vimizim (elosulfase alfa)上市,这是FDA批准的首款粘多糖贮积症IVA型(Morquio综合征A型)治疗药物。 粘多糖贮积症IVA型是一种罕见的、常染色体隐性遗传性溶酶体贮积病,由N-乙酰半乳糖胺-6-硫酸酯酶(GALNS)缺乏引起。Vimizim旨在替代该酶的功能。GALNS的缺失可导致骨生长发育问题。在美国大约有800名Morquio综合征A型患者。 Vimizim被授予了优先审评权。FDA优先审评权为严重疾病或病症治疗可能提供重要改善的药物提供了一种加快的审评途径。Vimizim也是首款获得罕见儿科疾病优先评审权的药物,罕见儿科疾病优先评审权旨在鼓励用于罕见儿科疾病预防和治疗的新药和生物制剂开发的一个条款。 “这次的批准及罕见儿科疾病优先评审权凸显了FDA让罕见病患者获得治疗药物的承诺,”FDA药物评价与研究中心(CDER)胃肠病学和先天缺陷产品部门副主任、医学博士Andrew E. Mulberg说。 Vimizim的安全性和有效性基于一项由176名Morquio综合征A型患者参与的临床试验,患者年龄从5岁到57岁不等。经由Vimizim治疗的受试者在6分钟行走试验中,与安慰剂治疗患者相比显示出更大的改善。临床试验显示,Vimizim用药患者6分钟行走与安慰剂治疗患者相比平均多走22.5米。 临床试验期间,Vimizim最常见的副作用有发热、呕吐、头痛、恶心、腹痛、寒战和疲劳。Vimizim对5岁以下儿科患者的安全性和有效性尚未确定。Vimizim获得批准时带有一项黑框警告,提示有过敏性风险。临床试验期间,危及生命的过敏反应在一些患者输注Vimizim时发生。 Vimizim由加利福尼亚州诺瓦托的BioMarin制药公司上市销售。 ---------------------------------------- 产地国家:美国 原产地英文商品名: VIMIZIM 5ml/VIAL 原产地英文药品名: elosulfase alfa 中文参考商品译名: VIMIZIM注射剂 5毫升/瓶 中文参考药品译名: 重组人N-乙酰半乳糖胺-6-硫酸硫酸酯酶(rhGALNS) 生产厂家中文参考译名: BioMarin 生产厂家英文名: BioMarin ---------------------------------------- 产地国家:德国 原产地英文商品名: Cerezyme 5ml/VIAL 原产地英文药品名: elosulfase alfa 中文参考商品译名: VIMIZIM注射剂 5毫升/瓶 中文参考药品译名: 重组人 N-乙酰半乳糖胺-6-硫酸硫酸酯酶(rhGALNS 生产厂家中文参考译名: BioMarin 生产厂家英文名: BioMarin |