首个杜氏肌营养不良症（DMD）治疗药物Exondys 51（eteplirsen）获美国FDA批准上市 近日，美国食品和药物管理局（FDA）近日有条件批准Sarepta治疗公司的新药Exondys 51，成为首个获批治疗杜氏肌营养不良症（DMD）的药物。 Exondys 51（eteplirsen）专门适用于抗肌营养不良蛋白基因（dystrophin gene）中存在确证突变可导致51号外显子跳跃（exon 51 skipping）的DMD患者；据估计，该类患者约占全部DMD患者的13%。Exondys 51可解决导致该类DMD病例的根本病因，能够产生有功能的抗肌营养不良蛋白，在临床研究中具有广泛良好的安全性、耐受性和疗效。 FDA表示，Sarepta提交的数据证实该类DMD患者（抗肌营养不良蛋白基因中存在可导致51号外显子跳跃的确证突变））经Exondys 51治疗后抗肌营养不良蛋白（dystrophin）水平升高，而这可以合理的预测这些DMD患者中的临床受益。 但FDA也强调，Exondys 51的临床受益还未证实，Sarepta必须开展进一步的临床研究，将有条件批准转变为完全批准。 FDA药物评价及研究中心主任Janet Woodcock表示，此次批准，使DMD群体中一类特殊类型的患者获得了一种重要的治疗选择，标志着DMD临床治疗的一个重大突破；我们将继续利用从药物Exondys 51中获得的科学认识，加速靶向抗肌营养不良蛋白基因其他外显子的新药研发，最终目的是有一天能够治疗携带所有导致外显子跳跃的确证基因突变的DMD患者。 目前，FDA也正在审查来自罕见病药企BioMarin提交的实验性DMD药物drisapersen的上市申请文件，预计将在今年底做出最终审查决定。 杜氏肌营养不良症（DMD）： 杜氏肌营养不良症（DMD）是一种X染色体隐性遗传疾病，主要发生于男孩。该病由抗肌营养不良蛋白基因（dystrophin gene）突变所致，属于进行性肌营养不良症常见类型。据统计，全球平均每3500个新生男婴中就有一人罹患此病。患者在学龄前就会因骨骼肌不断退化出现肌肉无力或萎缩，导致不便行走。大部分DMD患者在3-5岁发病，7-12岁彻底丧失行走能力，20岁左右会因为心肌、肺肌无力死亡。 关于罕见病，世界卫生组织的定义是患病人数占总人口的0.65‰～1‰之间的疾病或病变。据了解，目前已知的罕见病已超过7000种，中国的罕见病患者已达2000万人。在这些罕见病中，神经系统遗传病占到了50%。而排在神经系统遗传病第一大类的遗传性肌肉病中，肌营养不良居第一位。 批准日期：2016年9月26日 公司：Sarepta Therapeutics, Inc. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use EXONDYS 51™ safely and effectively. See full prescribing information for EXONDYS 51. EXONDYS 51 (eteplirsen) injection, for intravenous use Initial U.S. Approval: 2016 INDICATIONS AND USAGE EXONDYS 51 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51 [see Clinical Studies (14)]. A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. (1) DOSAGE AND ADMINISTRATION 30 milligrams per kilogram of body weight once weekly (2.1) Administer as an intravenous infusion over 35 to 60 minutes (2.1, 2.3) Dilution required prior to administration (2.2) DOSAGE FORMS AND STRENGTHS Injection: 100 mg/2 mL (50 mg/mL) in single-dose vial (3) 500 mg/10 mL (50 mg/mL) in single-dose vial (3) CONTRAINDICATIONS None (4) ADVERSE REACTIONS The most common adverse reactions (incidence ≥35% and higher than placebo) were balance disorder and vomiting (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sarepta Therapeutics, Inc. at 1-888-SAREPTA (1-888-727-3782) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Revised: 9/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51 [see Clinical Studies (14)]. A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of EXONDYS 51 is 30 milligrams per kilogram administered once weekly as a 35 to 60 minute intravenous infusion. If a dose of EXONDYS 51 is missed, it may be administered as soon as possible after the scheduled time. 2.2 Preparation Instructions EXONDYS 51 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique. a.Calculate the total dose of EXONDYS 51 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of EXONDYS 51 needed and the correct number of vials to supply the full calculated dose. b.Allow vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake. c.Visually inspect each vial of EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence. Do not use if the solution in the vials is discolored or particulate matter is present. d.With a syringe fitted with a 21-gauge or smaller non-coring needle, withdraw the calculated volume of EXONDYS 51 from the appropriate number of vials. e.Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100-150 mL. Visually inspect the diluted solution for particulates. f.EXONDYS 51 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted EXONDYS 51 solution within 4 hours of dilution. If immediate use is not possible, the diluted solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused EXONDYS 51. 2.3 Administration Instructions Application of a topical anesthetic cream to the infusion site prior to administration of EXONDYS 51 may be considered. EXONDYS 51 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion. Infuse the diluted EXONDYS 51 solution over 35 to 60 minutes. Do not mix other medications with EXONDYS 51 or infuse other medications concomitantly via the same intravenous access line. 3 DOSAGE FORMS AND STRENGTHS EXONDYS 51 is a clear and colorless solution that may have some opalescence, and is available as follows: Injection: 100 mg/2 mL (50 mg/mL) solution in a single-dose vial Injection: 500 mg/10 mL (50 mg/mL) solution in a single-dose vial 4 CONTRAINDICATIONS None. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the EXONDYS 51 clinical development program, 107 patients received at least one intravenous dose of EXONDYS 51, ranging between 0.5 mg/kg (0.017 times the recommended dosage) and 50 mg/kg (1.7 times the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 4 to 19 years. Most (89%) patients were Caucasian. EXONDYS 51 was studied in a double-blind, placebo-controlled study for 24 weeks (Study 1), followed by an open label extension (Study 2). In Study 1, 12 patients were randomized to receive weekly intravenous infusions of EXONDYS 51 (n=8) or placebo (n=4) for 24 weeks. All 12 patients continued in Study 2 and received open-label EXONDYS 51 weekly for up to 208 weeks. In Study 1, 4 patients received placebo, 4 patients received EXONDYS 51 30 mg/kg, and 4 patients received EXONDYS 51 50 mg/kg (1.7 times the recommended dosage). In Study 2, 6 patients received EXONDYS 51 30 mg/kg/week and 6 patients received EXONDYS 51 50 mg/kg/week [see Clinical Studies (14)]. Adverse reactions that occurred in 2 or more patients who received EXONDYS 51 and were more frequent than in the placebo group in Study 1 are presented in Table 1 (the 30 and 50 mg/kg groups are pooled). Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of EXONDYS 51 is not recommended [see Dosage and Administration (2.1)]. The most common adverse reactions were balance disorder and vomiting. Table 1. Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week1 EXONDYS 51 with Incidence at Least 25% More than Placebo (Study 1) Adverse Reactions EXONDYS 51 (N=8) Placebo (N=4) % % Balance disorder 38 0 Vomiting 38 0 Contact dermatitis 25 0 1 50 mg/kg/week = 1.7 times the recommended dosage In the 88 patients who received ≥30 mg/kg/week of EXONDYS 51 for up to 208 weeks in clinical studies, the following events were reported in ≥10% of patients and occurred more frequently than on the same dose in Study 1: vomiting, contusion, excoriation, arthralgia, rash, catheter site pain, and upper respiratory tract infection. There have been reports of transient erythema, facial flushing, and elevated temperature occurring on days of EXONDYS 51 infusion. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no human or animal data available to assess the use of EXONDYS 51 during pregnancy. In the U.S. general population, major birth defects occur in 2 to 4% and miscarriage occurs in 15 to 20% of clinically recognized pregnancies. 8.2 Lactation Risk Summary There are no human or animal data to assess the effect of EXONDYS 51 on milk production, the presence of eteplirsen in milk, or the effects of EXONDYS 51 on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EXONDYS 51 and any potential adverse effects on the breastfed infant from EXONDYS 51 or from the underlying maternal condition. 8.4 Pediatric Use EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping, including pediatric patients [see Clinical Studies (14)]. Intravenous administration of eteplirsen (0, 100, 300, or 900 mg/kg) to juvenile male rats once weekly for 10 weeks beginning on postnatal day 14 resulted in renal tubular necrosis at the highest dose tested and decreased bone densitometry parameters (mineral density, mineral content, area) at all doses. The kidney findings were associated with clinical pathology changes (increased serum urea nitrogen and creatinine, decreased urine creatinine clearance). No effects were observed on the male reproductive system, neurobehavioral development, or immune function. An overall no-effect dose was not identified. Plasma eteplirsen exposure (AUC) at the lowest dose tested (100 mg/kg) was similar to that in humans at the recommended human dose (30 mg/kg). 8.5 Geriatric Use DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with EXONDYS 51. 8.6 Patients with Renal or Hepatic Impairment EXONDYS 51 has not been studied in patients with renal or hepatic impairment. 10 OVERDOSAGE There is no experience with overdose of EXONDYS 51.  11 DESCRIPTION EXONDYS 51 (eteplirsen) injection is a sterile, aqueous, preservative-free, concentrated solution for dilution prior to intravenous administration. EXONDYS 51 is clear and colorless, and may have some opalescence. EXONDYS 51 is supplied in single dose vials containing 100 mg or 500 mg eteplirsen (50 mg/mL). EXONDYS 51 is formulated as an isotonic, phosphate buffered saline solution with an osmolality of 260 to 320 mOsm and a pH of 7.5. Each milliliter of EXONDYS 51 contains 50 mg eteplirsen; 0.2 mg potassium chloride, 0.2 mg potassium phosphate monobasic, 8 mg sodium chloride, and 1.14 mg sodium phosphate dibasic, anhydrous, in water for injection. The product may contain hydrochloric acid or sodium hydroxide to adjust pH. Eteplirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Eteplirsen contains 30 linked subunits. The molecular formula of eteplirsen is C364H569N177O122P30 and the molecular weight is 10305.7 daltons. The structure and base sequence of eteplirsen are: 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein, which was evaluated in Study 2 and Study 3 [see Clinical studies (14)]. 12.2 Pharmacodynamics All EXONDYS 51-treated patients evaluated (n=36) were found to produce messenger ribonucleic acid (mRNA) for a truncated dystrophin protein by reverse transcription polymerase chain reaction. In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy subjects). Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1. In Study 3, the average dystrophin protein level was 0.16% of normal before treatment, and 0.44% of normal after 48 weeks of treatment with EXONDYS 51 [see Clinical studies (14)]. The median increase in truncated dystrophin in Study 3 was 0.1% [see Clinical Studies (14)]. 12.3 Pharmacokinetics Following single or multiple intravenous infusions of EXONDYS 51 in male pediatric DMD patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline. The majority of drug elimination occurred within 24 hours. Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for eteplirsen Cmax and AUC range from 20 to 55%. Following single or multiple intravenous infusions of EXONDYS 51, the peak plasma concentrations (Cmax) of eteplirsen occurred near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week). Distribution In vitro investigation suggested that plasma protein binding of eteplirsen in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss) of eteplirsen was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg. Twenty-four hours after the end of the infusion, mean concentrations of eteplirsen were 0.07% of Cmax. Accumulation of eteplirsen during once weekly dosing has not been observed. Elimination The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. Metabolism Eteplirsen did not appear to be metabolized by hepatic microsomes of any species tested, including humans. Excretion Renal clearance of eteplirsen accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration. Elimination half-life (t1/2) of eteplirsen was 3 to 4 hours. Specific Populations Age: The pharmacokinetics of eteplirsen have been evaluated in male pediatric DMD patients. There is no experience with the use of EXONDYS 51 in patients 65 years of age or older. Sex: Sex effects have not been evaluated; EXONDYS 51 has not been studied in female patients. Race: Potential impact of race is not known because 89% of the patients in studies were Caucasians. Renal or Hepatic Impairment: EXONDYS 51 has not been studied in patients with renal or hepatic impairment. Drug Interaction Studies In vitro data showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP, MRP2 and BSEP). Based on in vitro data on plasma protein binding, CYP or drug transporter interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for drug-drug interactions in humans. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies have not been conducted with eteplirsen. Mutagenesis Eteplirsen was negative in in vitro (bacterial reverse mutation and chromosomal aberration in CHO cells) and in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility Fertility studies in animals were not conducted with eteplirsen. No effects on the male reproductive system were observed following intravenous administration of eteplirsen (0, 5, 40, or 320 mg/kg) to male monkeys once weekly for 39 weeks. Plasma eteplirsen exposure (AUC) in monkeys at the highest dose tested was 20 times that in humans at recommended human dose (30 mg/kg).  14 CLINICAL STUDIES EXONDYS 51 was evaluated in three clinical studies in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. In Study 1, patients were randomized to receive weekly infusions of EXONDYS 51 (30 mg/kg, n=4); EXONDYS 51 (50 mg/kg, n=4), or placebo (n=4) for 24 weeks. The primary endpoint was dystrophin production; a clinical outcome measure, the 6-minute walk test (6MWT), was also assessed. The 6MWT measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. Patients had a mean age of 9.4 years, a mean 6-minute walk distance (6MWD) at baseline of 363 meters, and were on a stable dose of corticosteroids for at least 6 months. There was no significant difference in change in 6MWD between patients treated with EXONDYS 51 and those treated with placebo. All 12 patients who participated in Study 1 continued treatment with open-label EXONDYS 51 weekly for an additional 4 years in Study 2. The 4 patients who had been randomized to placebo were re-randomized 1:1 to EXONDYS 30 or 50 mg/kg/week such that there were 6 patients on each dose. Patients who participated in Study 2 were compared to an external control group. The primary clinical efficacy outcome measure was the 6MWT. Eleven patients in Study 2 had a muscle biopsy after 180 weeks of treatment with EXONDYS 51, which was analyzed for dystrophin protein level by Western blot. Study 2 failed to provide evidence of a clinical benefit of EXONDYS 51 compared to the external control group. The average dystrophin protein level after 180 weeks of treatment with EXONDYS 51 was 0.93% of the dystrophin level in healthy subjects. Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1. In Study 3, 13 patients were treated with open-label EXONDYS 51 (30 mg/kg) weekly for 48 weeks and had a muscle biopsy at baseline and after 48 weeks of treatment. Patients had a mean age of 8.9 years and were on a stable dose of corticosteroids for at least 6 months. Dystrophin levels in muscle tissue were assessed by Western blot. In the 12 patients with evaluable results, the pre-treatment dystrophin level was 0.16% ± 0.12% (mean ± standard deviation) of the dystrophin level in a healthy subject and 0.44% ± 0.43% after 48 weeks of treatment with EXONDYS 51 (p < 0.05). The median increase after 48 weeks was 0.1%. Individual patient dystrophin levels from Study 3 are shown in Table 2. Patient Number Baseline % normal dystrophin Week 48 % normal dystrophin Change from Baseline % normal dystrophin 1 0.13 0.26 0.13 2 0.35 0.36 0.01 3 0.06 0.37 0.31 4 0.04 0.10 0.06 5 0.17 1.02 0.85 6 0.37 0.30 -0.07 7 0.17 0.42 0.25 8 0.24 1.57 1.33 9 0.11 0.12 0.01 10 0.05 0.47 0.43 11 0.02 0.09 0.07 12 0.18 0.21 0.03 Mean 0.16 0.44 0.28; p=0.008 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied EXONDYS 51 injection is supplied in single-dose vials. The solution is clear and colorless, and may have some opalescence. Single-dose vials containing 100 mg/2 mL (50 mg/mL) eteplirsen  NDC 60923-363-02  Single-dose vials containing 500 mg/10 mL (50 mg/mL) eteplirsen NDC 60923-284-10  16.2 Storage and Handling Store EXONDYS 51 at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light and store EXONDYS 51 in the original carton until ready for use. 完整处方来源附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=33bff678-7829-479e-9110-b8e33a0bc0aa

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