酶替代治疗药物——α-艾杜糖醛酸酶上市

美国FDA已批准用于治疗Ⅰ型黏多糖病 (MDSI)的一种罕用 (orphan)药———α 艾杜糖醛酸酶 (α Liduronidase ,通用名laronidase ,商品名Aldurazyme)。MDSI(Hurler综合征 )是一种溶酶体贮积障碍 ,因该酶短缺所致。

商品名： Aldurazyme

开发与上市厂商： 本品由美国BioMarin制药厂与 Genzyme公司共同研制，2003年5 月首次在美国上市。

适应证： 适用于Ⅰ型粘多糖增多症（MPS－Ⅰ）及有Scheie形式的中至重度症状患者。

药理作用： 本品为溶酶体水解酶，可催化硫酸软骨素和硫酸乙酰肝素的α－L－艾杜糖酸末端残基的水解。本品作为外源性酶在体内可被溶酶体摄取，催化粘多糖（GAG）的水解。本品被溶酶体摄取可能主要由末端为6－磷酸甘露糖的寡糖链与特异的6-磷酸甘露糖受体结合介导。本品作为外源性酶用于多糖贮积症患者，可缓解其由于多糖贮积引起的多器官功能失调。

本品在12例MPSI－I患者中进行了药动学评价，受试者输注本品4小时，剂量为0．58mg／kg。在第1、第 12和第26周，测得的平均最大血浆浓度（Cmax）为1．2－1．7μg／ml。平均药时浓度曲线下面积（AUC）为4．5－ 6.9（μg·h）/ml；平均分布容积（Vz）为0．24－0.6L/kg：平均血浆清除率（C/）为1.7－2.7ml（min·kg）。平均消除半衰期（t1/2）为1.5－3.6小时。

接受本品一周1次注射，大多数患者12周内可产生抗laronidase流体。在1～12周之间，可观察到某些患者的血浆中药物清除增加，这与其抗体效价成正比。在26周时，本品的血浆清除与1周时的相当，而与抗体效价的增加无关。

临床评价

本品在45例MPS－l患者中进行了随机对照临床研究。其中1例患者临床评价为Hurler形式，37例为Hurler－ Scheie形式，7例为Scheie形式。所有患者的基础用为肺活量（FVC）小于或等于预测的77％。患者采用本品0.58mg／kg或安慰剂治疗，一周1 次，共26周。所有患者在每次输注前，均服用解热药与抗组胺药。治疗结果采用FVC与6分钟行走距离（6MWT）进行评价，结果显示，本品给患者较安慰剂组有明显的改善。

生物活性度是通过肝脏大小和尿 GAG水平的改变来评价。本品组相对于对照组而言，肝脏大小和尿 GAG水平均较低，且在6个月的研究中，本品组无1例患者达到正常的尿GAG水平。

所有45例患者在双盲研究后再接受开放性本品治疗，共36周。先前采用本品治疗的患者与前期相比，平均FVC得到维持，平均6MWT增加。先前采用安慰剂治疗的患者与前期相比，平均FVC和6MWT均得到改善。

不良反应

在临床研究中出现1例过敏反应（荨麻疹和气道阻塞）。

常见的不良反应为上呼吸道感染、潮红和输液反应（潮红、发热、头痛和皮疹）。

注意事项

输注本品前，应让患者服用解热药和（或）抗组胺药。如果出现输液反应，应降低输液速度或暂时停止输液，和（或）给予额外的解热药和（或）抗组胶药可缓解症状。

用法与用量

本品推荐剂量为0.58mg／kg，一周1次，静脉输注，约3－4小时。

解热药和（或）抗组胺药治疗宜在输注开始前60分钟进行。

体重不大于20kg的患者，总输注量为100ml。体重大于20kg的患者总输注量为250ml。开始输注速度为每小时10μg／kg，在开始输注的1小时内可每15分钟调高输注速度，直到达到最大输注速度每小时200μg／kg。然后维持最大速度至输注结束。

本品在0．9％氯化钠注射液配制的0．1%人血清白蛋白中稀释，且应使用PVC容器制备与输注，并使用线性、低蛋白结合的0．2μm过滤器。

制剂

无菌、澄清度1级溶液，每瓶5ml 溶液含本品2．9mg。

首个遗传性代谢病治疗药Aldurazyme获FDA批准上市

BioMarinPharmaceuticals公司的Aldurazyme(laronidase)于5月6日获得FDA许可，成为首个用于治疗罕见的遗传性疾病MPS-I的某些类型，包括Hurler综合征(赫尔利综合征，粘脂沉积症Ⅰ型，脂肪软骨营养障碍，HurlerSyndrome)的药物。

该病是由于细胞内一种可降解葡糖胺聚酶(GAG)的酶缺乏或障碍所致的。MPS-I病人细胞内GAG的累积会导致细胞累进性受损，进而影响机体外表、体质、器官功能，及某些情况下的心理发展。这一新的生物技术产品就是人体所缺乏的这种酶的一种制剂，可有助于防止细胞内GAG的累积，并已显示能改善肺功能和运动能力。

本品获得FDA优先审查权。此次获得用于MPS-I的Hurler和Hurler-Scheie型病人，以及中至重度症状的Scheie病患者。Hurler综合征是MPS-I病一种最严重的类型。患病儿童常常早早地因呼吸系统疾病和心脏并发症而死亡。Hurler-Scheie综合征则是一种较不严重的类型，但病人常常活不过20岁。

而Scheie综合征是最轻型的，许多病人可活至成年，但这些病人仍存在有畸形、心脏疾病和呼吸困难。据美国国立卫生研究院报道，加拿大的研究估计新生儿中Hurler综合征的患病率为1/100000，Hurler-Scheie综合征为1/115000，而Scheie综合征为1/500000。

本品在45例MPS-I病人中进行了一项随机安慰剂对照研究，这些病人大多为Hurler-Scheie综合征。26周后，本品组病人肺功能和6分钟步行测试的行走功能改善。尚无证据显示，本品对中枢神经系统症状(发育延迟和脑积水)有任何积极作用。

本品最严重的不良反应为过敏反应，约在输液后3小时发生，有严重肺功能问题的病人需要进行紧急气管切开术。最常见的不良反应为上呼吸道感染、出疹和注射部位反应。与输液反应相关的主要安全性问题是潮红、发热、头痛和出疹。此外，本品还是一个罕用药物，拥有7年市场独占权。

Aldurazyme
Generic Name: laronidase
Dosage Form: injection, solution, concentrate

FULL PRESCRIBING INFORMATION

Indications and Usage for Aldurazyme

Aldurazyme® (laronidase) is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms.  The risks and benefits of treating mildly affected patients with the Scheie form have not been established.

Aldurazyme has been shown to improve pulmonary function and walking capacity.  Aldurazyme has not been evaluated for effects on the central nervous system manifestations of the disorder.

Aldurazyme Dosage and Administration

Recommended Dose

 The recommended dosage regimen of Aldurazyme is 0.58 mg/kg of body weight administered once weekly as an intravenous (IV) infusion.  Pretreatment is recommended 60 minutes prior to the start of the infusion and may include antihistamines, antipyretics, or both [see Warnings and Precautions (5)].

Each vial of Aldurazyme provides 2.9 milligrams (mg) of laronidase in 5.0 milliliters (mL) of solution and is intended for single use only.  Do not use the vial more than one time.  The concentrated solution for infusion must be diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL or 250 mL, using aseptic techniques.  The final volume of the infusion is determined by the patient’s body weight.  Patients with a body weight of 20 kg or less should receive a total volume of 100 mL.  Patients with a body weight greater than 20 kg should receive a total volume of 250 mL [see Dosage and Administration (2.2)].  For patients with underlying cardiac or respiratory compromise and weighing up to 30 kg, physicians may consider diluting Aldurazyme in a volume of 100 mL and administering at a decreased infusion rate [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Adverse Reactions (6.3)].

Instructions for Use

 Prepare and use Aldurazyme according to the following steps. Use aseptic techniques. Prepare Aldurazyme using low-protein-binding containers and administer with a low-protein-binding infusion set equipped with an in-line, low-protein-binding 0.2 micrometer (µm) filter. There is no information on the compatibility of diluted Aldurazyme with glass containers.

1.  Determine the number of vials to be diluted based on the patient's weight and the recommended dose of 0.58 mg/kg, using the following equation:
   Patient's weight (kg) x 1 mL/kg of Aldurazyme = Total number mL of Aldurazyme
   Total number of mL of Aldurazyme ÷ 5 mL per Vial = Total number of Vials.
   

2.  Round up to the next whole vial.  Remove the required number of vials from the refrigerator to allow them to reach room temperature.  Do not heat or microwave vials.

3. Before withdrawing the Aldurazyme from the vial, visually inspect each vial for particulate matter and discoloration.  The Aldurazyme solution should be clear to slightly opalescent and colorless to pale yellow.  Some translucency may be present in the solution.  Do not use if the solution is discolored or if there is particulate matter in the solution.

4. Withdraw and discard a volume of the 0.9% Sodium Chloride Injection, USP from the infusion bag, equal to the volume of Aldurazyme concentrate to be added.

5. Slowly withdraw the calculated volume of Aldurazyme from the appropriate number of vials using caution to avoid excessive agitation. Do not use a filter needle, as this may cause agitation. Agitation may denature Aldurazyme, rendering it biologically inactive.

6. Slowly add the Aldurazyme solution to the 0.9% Sodium Chloride Injection, USP using care to avoid agitation of the solutions. Do not use a filter needle.

7. Gently rotate the infusion bag to ensure proper distribution of Aldurazyme. Do not shake the solution.

8. The entire infusion volume (100 mL for patients weighing 20 kg or less and 250 mL for patients weighing greater than 20 kg) should be delivered over approximately 3 to 4 hours. The initial infusion rate of 10 µg/kg/hr may be incrementally increased every 15 minutes during the first hour, as tolerated, until a maximum infusion rate of 200 µg/kg/hr is reached. The maximum rate is then maintained for the remainder of the infusion (2-3 hours), as outlined in Tables 1  and 2.

Table 1:  Incremental Rates for 100 mL Aldurazyme® Infusion (For use with Patients Weighing 20 kg or Less)

Infusion Rate	Criteria for Increasing Infusion Rate
2 mL/hr x 15 minutes (10 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
4 mL/hr x 15 minutes (20 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
8 mL/hr x 15 minutes (50 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
16 mL/hr x 15 minutes (100 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
32 mL/hr x ~3 hours (200 μg/kg/hr)	For the remainder of the infusion.

Table 2: Incremental Rates for 250 mL Aldurazyme® Infusion (For use with Patients Weighing Greater than 20 kg)

Infusion Rate	Criteria for Increasing Infusion Rate
5 mL/hr x 15 minutes (10 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
10 mL/hr x 15 minutes (20 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
20 mL/hr x 15 minutes (50 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
40 mL/hr x 15 minutes (100 μg/kg/hr)	Obtain vital signs, if stable then increase the rate to...
80 mL/hr x ~3 hours (200 μg/kg/hr)	For the remainder of the infusion.

Aldurazyme does not contain any preservatives; therefore, after dilution with saline, the infusion bags should be used immediately.  If immediate use is not possible, the diluted solution should be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 36 hours.  Other than during infusion, room temperature storage of diluted solution is not recommended.  Any unused product or waste material should be discarded and disposed of in accordance with local requirements.

Aldurazyme must not be administered with other medicinal products in the same infusion. The compatibility of Aldurazyme in solution with other products has not been evaluated.

Dosage Forms and Strengths

Aldurazyme is supplied as a sterile solution in 5 mL vials (2.9 mg per 5 mL).

Contraindications

None.

Warnings and Precautions

Anaphylaxis and Allergic Reactions

[see Boxed Warning]

 Anaphylaxis and severe allergic reactions have been observed in patients during or up to 3 hours after Aldurazyme infusions. Some of these reactions were life-threatening and included respiratory failure, respiratory distress, stridor, tachypnea, bronchospasm, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria. If anaphylactic or other severe allergic reactions occur, immediately discontinue the infusion of Aldurazyme and initiate appropriate medical treatment. Caution should be exercised if epinephrine is being considered for use in patients with MPS I due to the increased prevalence of coronary artery disease in these patients. Interventions have included resuscitation, mechanical ventilatory support, emergency tracheotomy, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids [see Adverse Reactions (6)].

In clinical studies and postmarketing safety experience with Aldurazyme, approximately 1% of patients experienced severe or serious allergic reactions.  In patients with MPS I, pre-existing upper airway obstruction may have contributed to the severity of some reactions.  Due to the potential for severe allergic reactions, appropriate medical support should be readily available when Aldurazyme is administered.  Because of the potential for recurrent reactions, some patients who experience initial severe reactions may require prolonged observation.

 The risks and benefits of re-administering Aldurazyme following an anaphylactic or severe allergic reaction should be considered.  Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.

Acute Respiratory Complications Associated with Administration

 Patients with an acute febrile or respiratory illness at the time of Aldurazyme infusion may be at greater risk for infusion reactions.  Careful consideration should be given to the patient’s clinical status prior to administration of Aldurazyme and consider delaying Aldurazyme infusion.  One patient with acute bronchitis and hypoxia experienced increased tachypnea during the first Aldurazyme infusion that resolved without intervention.  The patient’s respiratory symptoms returned within 30 minutes of completing the infusion and responded to bronchodilator therapy.  Approximately 6 hours after the infusion, the patient experienced coughing, then respiratory arrest, and died.

 Sleep apnea is common in MPS I patients.  Evaluation of airway patency should be considered prior to initiation of treatment with Aldurazyme.  Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an infusion reaction, or extreme drowsiness/sleep induced by antihistamine use.

 5.3 Risk of Acute Cardiorespiratory Failure

 Caution should be exercised when administering Aldurazyme to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated.  These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions.  Appropriate medical support and monitoring measures should be readily available during Aldurazyme infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient [see Adverse Reactions (6.3)].

 5.4 Infusion Reactions

Because of the potential for infusion reactions, patients should receive antipyretics and/or antihistamines prior to infusion.  If an infusion reaction occurs, regardless of pre-treatment, decreasing the infusion rate, temporarily stopping the infusion, or administering additional antipyretics and/or antihistamines may ameliorate the symptoms [see Adverse Reactions (6)].

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 clinical practice.

The most serious adverse reactions reported with Aldurazyme treatment during clinical trials were anaphylactic and allergic reactions.  Most adverse reactions reported in clinical trials were considered disease-related and unrelated to study drug.  The most common adverse reactions were infusion reactions.  The frequency of infusion reactions decreased over time with continued use of Aldurazyme, and the majority of reactions were classified as being mild to moderate in severity.  Most infusion reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, with or without administering additional treatments including antihistamines, antipyretics, or both.

Clinical Trials in Patients 6 Years and Older

A 26-week, double-blind, placebo-controlled clinical study (Study 1) of Aldurazyme was conducted in 45 patients with MPS I, ages 6 to 43 years old, gender evenly distributed (N=23 females and 22 males).  Of these 45 patients, 1 was clinically assessed as having Hurler form, 37 Hurler-Scheie, and 7 Scheie.  Patients were randomized to receive either 0.58 mg/kg IV of Aldurazyme per week for 26 weeks or placebo.  All patients were treated with antipyretics and antihistamines prior to the infusions.  Infusion reactions were reported in 32% (7 of 22) of Aldurazyme-treated patients. The most commonly reported infusion reactions regardless of treatment group were flushing, pyrexia, headache, and rash.  Flushing occurred in 5 patients (23%) receiving Aldurazyme; the other reactions were less frequent.  Less common infusion reactions included angioedema (including face edema), hypotension, paresthesia, feeling hot, hyperhidrosis, tachycardia, vomiting, back pain, and cough.  Other reported adverse reactions included bronchospasm, dyspnea, urticaria and pruritus.

Table 3 enumerates adverse reactions and selected laboratory abnormalities that occurred during the placebo-controlled study (Study 1) that were reported in at least 2 patients more in the Aldurazyme group than in the placebo group.

Table 3: Summary of Adverse Reactions that Occurred in 2 Patients More in the Aldurazyme® Group than in the Placebo Group in the 26-Week Placebo-controlled Study (Study 1)

MedDRA System Organ Class (SOC)          MedDRA Preferred Term	(N=22) Aldurazyme n (%)	(N=23) Placebo n (%)
Blood and lymphatic system disorders
Thrombocytopenia	2 (9) )	0
Eye disorders
Corneal opacity	2(9)	0
General disorders and administration site conditions
Chest pain	2 (9)	0
Face edema	2 (9)	0
Gravitational edema	2 (9)	0
Injection site pain	2 (9)	0
Injection site reaction	4 (18)	2 (9)
Hepatobiliary disorders
Hyperbilirubinemia	2 (9)	0
Infections and infestations
Abscess	2 (9)	0
Upper respiratory tract infection	7 (32)	4 (17)
Nervous system disorders
Hyperreflexia	3 (14)	0
Paresthesia	3 (14)	1 (4)
Rash	8 (36)	5 (22)
Vascular disorders
Hypotension	2(9)	0
Poor venous access	3 (14)	0

All 45 patients who completed the placebo-controlled study (Study 1) continued treatment in an open-label, uncontrolled extension study (Study 2).  All patients received Aldurazyme 0.58 mg/kg of body weight once weekly for up to 182 weeks.  The most serious adverse reactions reported with Aldurazyme infusions in Study 2 were anaphylactic and allergic reactions [see Warnings and Precautions (5)]. The most common adverse reactions requiring intervention were infusion reactions reported in 49% (22 of 45) of patients treated with Aldurazyme.  The most commonly reported infusion reactions included rash (13%), flushing (11%), pyrexia (11%), headache (9%), abdominal pain or discomfort (9%), and injection site reaction (9%).  Less commonly reported infusion reactions included nausea (7%), diarrhea (7%), feeling hot or cold (7%), vomiting (4%), pruritus (4%), arthralgia (4%), and urticaria (4%).  Additional common adverse reactions included back pain and musculoskeletal pain.

Clinical Trials in Patients 6 Years and Younger

Study 3 was a 52-week, open-label, uncontrolled study of 20 MPS I patients, ages 6 months to 5 years old (at enrollment).  Sixteen patients were clinically assessed as having the Hurler form, and 4 had the Hurler-Scheie form.  All 20 patients received Aldurazyme at 0.58 mg/kg of body weight once weekly for 26 weeks and up to 52 weeks.  All patients were treated with antipyretics and antihistamines prior to the infusions.

The most commonly reported serious adverse events (regardless of relationship) reported with Aldurazyme infusions in Study 3 were otitis media (20%), and central venous catheterization required for Aldurazyme infusion (15%).

The nature and severity of infusion reactions were similar between the older and less severely affected patients in Studies 1 and 2, and the younger, more severely affected patients in Study 3.  The most commonly reported adverse reactions in Study 3 were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%).  Other commonly reported infusion reactions occurring in ≥ 5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritis, and rash.

Immunogenicity

In clinical trials, 99 of 102 patients (97%) treated with Aldurazyme were positive for IgG antibodies to Aldurazyme.  The clinical significance of antibodies to Aldurazyme, including the potential for product neutralization, is not known.  Potential for antibody neutralization of cellular uptake has not been assessed.

The data reflect the percentage of patients whose test results were considered positive for antibodies to Aldurazyme using an enzyme-linked immunosorbent assay (ELISA) for Aldurazyme-specific IgG binding antibodies reported as titers (57 patients) or optical density units per uL (OD/uL) (42 patients), and confirmed by radio-immunoprecipitation (RIP).  The relationship of Aldurazyme antibody concentration in titer units and OD/uL units has not been established.

Nine patients in Study 1 and Study 2, collectively, who experienced severe infusion reactions were tested for Aldurazyme-specific IgE antibodies and complement activation.  IgE testing was performed by ELISA, and complement activation was measured by the Quidel Enzyme Immunoassay.  One of the nine patients had an anaphylactic reaction consisting of urticaria and airway obstruction and tested positive for both Aldurazyme-specific IgE binding antibodies and complement activation.  None of the patients in the open-label clinical study of patients 5 years old or younger (Study 3) tested positive for IgE.

Other allergic reactions were also seen in patients receiving Aldurazyme [see Adverse Reactions (6)].

In the postmarketing setting, approximately 1% of patients experienced severe or serious infusion allergic reactions and tested positive for IgE.  Of these IgE-positive patients, some have discontinued treatment, but some have been successfully re-challenged.  The clinical significance of IgE antibodies has not been established.

As with all the therapeutic proteins, there is potential for immunogenicity.  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 Aldurazyme with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Aldurazyme.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with Aldurazyme, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock [see Boxed Warning and Warnings and Precautions (5)].

Adverse reactions resulting in death reported in the postmarketing setting with Aldurazyme treatment included cardio-respiratory arrest, respiratory failure, cardiac failure, and pneumonia.  These events have been reported in MPS I patients with significant underlying disease.

Additional common adverse reactions included erythema and cyanosis.

There have been a small number of reports of extravasation in patients treated with Aldurazyme.  There have been no reports of tissue necrosis associated with extravasation.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B.

A developmental toxicity study has been performed in rats at doses up to 6.2 times the human dose and has revealed no evidence of impaired fertility or harm to the fetus due to Aldurazyme.  However, there are no adequate and well-controlled studies of Aldurazyme in pregnant women.  Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Pregnant women with MPS I should be encouraged to enroll in the MPS I Registry. For more information, visit www.MPSIregistry.com or call (800) 745-4447 [see Patient Counseling Information (17)].

Nursing Mothers

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Aldurazyme is administered to a nursing woman.

Pregnant women with MPS I should be encouraged to enroll in the MPS I Registry.  For more information, visit www.MPSIregistry.com or call (800) 745-4447 [see Patient Counseling Information (17)].

Pediatric Use

The safety and effectiveness of Aldurazyme was assessed in a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old, and was found to be similar to the safety and effectiveness of Aldurazyme in pediatric patients 6 to 18 years, and adults [see Adverse Reactions (6) and Clinical Studies (14)].

Geriatric Use

Clinical studies of Aldurazyme did not include patients aged 65 and over.  It is not known whether they respond differently from younger patients.

Overdosage

There have been no reports of overdose with Aldurazyme.  In clinical studies, a small number of patients received doses up to 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week.  Adverse events reported in patients receiving 1.2 mg/kg body weight once weekly or 1.8 mg/kg body weight every other week were similar to the adverse events reported by patients treated with 0.58 mg/kg body weight once weekly.

Aldurazyme Description

Aldurazyme (laronidase) is a polymorphic variant of the human enzyme α‑l‑iduronidase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line.  α-l-iduronidase (glycosaminoglycan α-l-iduronohydrolase, EC 3.2.1.76) is a lysosomal hydrolase that catalyzes the hydrolysis of terminal α-l-iduronic acid residues of dermatan sulfate and heparan sulfate.

Laronidase is a glycoprotein with a molecular weight of approximately 83 kD. The predicted amino acid sequence of the recombinant form, as well as the nucleotide sequence that encodes it, are identical to a polymorphic form of human α-L-iduronidase. The recombinant protein is comprised of 628 amino acids after cleavage of the N-terminus and contains 6 N-linked oligosaccharide modification sites. Two oligosaccharide chains terminate in mannose-6-phosphate sugars. Aldurazyme has a specific activity of approximately 172 U/mg.

Aldurazyme, for IV infusion, is supplied as a sterile, nonpyrogenic, colorless to pale yellow, clear to slightly opalescent solution that must be diluted prior to administration in 0.9% Sodium Chloride Injection, USP. The solution in each vial contains a nominal laronidase concentration of 0.58 mg/mL and a pH of approximately 5.5. The extractable volume of 5.0 mL from each vial provides 2.9 mg laronidase, 43.9 mg sodium chloride, 63.5 mg sodium phosphate monobasic monohydrate, 10.7 mg sodium phosphate dibasic heptahydrate, and 0.05 mg polysorbate 80. Aldurazyme does not contain preservatives; vials are for single use only.

Aldurazyme - Clinical Pharmacology

Mechanism of Action

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAG). Mucopolysaccharidosis I (MPS I) is characterized by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyzes the hydrolysis of terminal α-L-iduronic acid residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAG substrates, dermatan sulfate and heparan sulfate, throughout the body and leads to widespread cellular, tissue, and organ dysfunction.

The rationale of Aldurazyme therapy in MPS I is to provide exogenous enzyme for uptake into lysosomes and increase the catabolism of GAG. Aldurazyme uptake by cells into lysosomes is most likely mediated by the mannose-6-phosphate-terminated oligosaccharide chains of laronidase binding to specific mannose-6-phosphate receptors.

Because many proteins in the blood are restricted from entry into the central nervous system (CNS) by the blood brain barrier, effects of intravenously administered Aldurazyme on cells within the CNS cannot be inferred from activity in sites outside the CNS. The ability of Aldurazyme to cross the blood brain barrier has not been evaluated in animal models or in clinical studies.

Pharmacodynamics

The pharmacodynamic effect of Aldurazyme was assessed by reductions in urinary GAG levels. The responsiveness of urinary GAG to dosage alterations of Aldurazyme is unknown, and the relationship of urinary GAG to other measures of clinical response has also not been established [see Clinical Studies (14)].

Pharmacokinetics

The pharmacokinetics of laronidase were evaluated in 6 year old or older patients (N = 10 to 12) with MPS I who received 0.58 mg/kg of body weight once weekly of Aldurazyme as a 4-hour infusion in the placebo-controlled clinical study (Study 1). After the 1st, 12th, and 26th weekly infusions, the mean maximum plasma concentrations (Cmax) ranged from 1.2 to 1.7 μg/mL for the 3 time points. The mean area under the plasma concentration-time curve (AUC∞) ranged from 4.5 to 6.9 μg • hour/mL. The mean volume of distribution (Vz) ranged from 0.24 to 0.6 L/kg. Mean plasma clearance (CL) ranged from 1.7 to 2.7 mL/min/kg, and the mean elimination half-life (t1/2) ranged from 1.5 to 3.6 hours.

Most patients who received once weekly infusions of Aldurazyme in Study 1 developed antibodies to laronidase by Week 12. Between Weeks 1 and 12, increases in the plasma clearance of laronidase were observed in some patients and appeared to be proportional to the antibody titer. At Week 26, plasma clearance of laronidase was comparable to that at Week 1, in spite of the continued and, in some cases, increased titers of antibodies.

The pharmacokinetics of Aldurazyme have not been established in patients 6 years and younger.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to assess the mutagenic and carcinogenic potential of laronidase have not been conducted.

Laronidase at IV doses up to 3.6 mg/kg (6.2 times the human dose) was found to have no effect on the fertility and reproductive performance of male and female rats.

Clinical Studies

The safety and efficacy of Aldurazyme were assessed in three clinical studies.

Clinical Studies in Patients 6 Years and Older

Study 1 was a randomized, double-blind, placebo-controlled study in 45 patients with MPS I, ages 6 to 43 years old, including 1 patient with the Hurler form, 37 patients with Hurler-Scheie form, and 7 patients with Scheie form of MPS I.  All patients had a baseline percent predicted forced vital capacity (FVC) less than or equal to 77%.  Patients received Aldurazyme at 0.58 mg/kg of body weight once weekly or placebo once weekly for 26 weeks.  All patients were treated with antipyretics and antihistamines prior to each infusion.

The primary efficacy outcome assessments were percent predicted FVC and distance walked in 6 minutes (6-minute walk test).  After 26 weeks, patients treated with Aldurazyme showed improvement in percent predicted FVC and in 6-minute walk test compared to placebo-treated patients (see Table 4).

Table 4: Primary Efficacy Outcomes in the Placebo-controlled Study (Study 1)

		Aldurazyme®  (N = 22)	Placebo (N = 23)
By Wilcoxon Rank Sum Test
Forced Vital Capacity (percent of predicted normal)
Pre-treatment Baseline	Mean ± s.d.	48 ± 15	54 ± 16
Week 26	Mean ± s.d.	50 ± 17	51 ± 13
Change from Baseline to Week 26	Mean ± s.d.	1 ± 7	-3 ± 7
	Median	1	-1
Difference in Change from Baseline to Week 26 Between Groups	Mean	4
	Median (95% CI)	2 (0.4, 7), p=0.02*
6-Minute Walk Distance (meters)
Pre-treatment Baseline	Mean ± s.d.	319 ± 131	367 ± 114
Week 26	Mean ± s.d.	339 ± 127	348 ± 129
Change from Baseline to Week 26	Mean ± s.d.	20 ± 69	-18 ± 67
	Median	28	-11
Difference in Change from Baseline to Week 26 Between Groups	Mean	38
	Median (95% CI)	39 (-2, 79), p=0.07*

Evaluations of bioactivity were changes in liver size and urinary GAG levels.  Liver size and urinary GAG levels decreased in patients treated with Aldurazyme compared to patients treated with placebo.  No patient in the group receiving Aldurazyme reached the normal range for urinary GAG levels during this 6-month study.

Study 2 was a 182-week, open-label, uncontrolled extension study of all 45 patients who completed Study 1.  Patients received Aldurazyme at 0.58 mg/kg body weight once weekly.  For patients treated with Aldurazyme, the mean increase in 6-minute walk test distance was maintained for an additional 182 weeks through completion of Study 2.

At the end of Study 2, the decrease in mean urinary GAG was similar to the decrease in urinary GAG reported in Aldurazyme treated patients at the end of Study 1.  The relationship of urinary GAG to other measures of clinical response has not been established.

Clinical Studies in Patients 6 Years and Younger

Study 3 was a 52-week, open-label, uncontrolled clinical study in 20 patients with MPS I, ages 6 months to 5 years old (at enrollment), including 16 patients (80%) with the Hurler form and 4 patients (20%) with the Hurler-Scheie form.  All 20 patients received Aldurazyme at 0.58 mg/kg of body weight once weekly for 26 weeks.  After 26 weeks of treatment, 16 patients continued to receive 0.58 mg/kg of body weight once weekly through Week 52, and 4 patients received 1.16 mg/kg of body weight once weekly from Week 26 through Week 52.

Reduction in mean urinary GAG was demonstrated at Week 13 and was maintained through Week 52.  No patient receiving Aldurazyme reached the normal range for urinary GAG levels during this 52-week study.  Changes in urinary GAG levels in children 6 years and younger were similar to changes reported in older patients in Studies 1 and 2 (6 through 43 years old).  The relationship of urinary GAG to other measures of clinical response has not been established.

How Supplied/Storage and Handling

Aldurazyme is supplied as a sterile solution in single-use, clear Type I glass 5 mL vials, containing 2.9 mg laronidase per 5 mL solution.  The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.

NDC 58468-0070-1, 5 mL vial

Refrigerate vials of Aldurazyme at 2° to 8°C (36° to 46°F).  Do not freeze or shake.  Protect from light.  Do not use Aldurazyme after the expiration date on the vial.  This product contains no preservatives.

Patient Counseling Information

Patients should be counseled that allergic reactions may occur during Aldurazyme treatment, including life-threatening anaphylaxis.  Premedication and reduction of infusion rate may alleviate those allergic reactions associated with the infusion.  The appropriate length of post-infusion monitoring is to be determined by the treating physician based on the individual patient’s clinical status and infusion history [see Warnings and Precautions (5)].

Patients should be advised to report any adverse reactions experienced while on Aldurazyme treatment.

It is unknown how Aldurazyme affects women during pregnancy, labor and delivery or while nursing, as no adequate and well-controlled clinical studies have been conducted in these patient populations [see Use in Specific Populations (8)].

The full benefits of Aldurazyme may not be evident for several months to years of treatment. To maintain treatment benefit, Aldurazyme should be administered on a weekly basis as indicated.

Patients should be informed that a registry for MPS I patients has been established in order to better understand the MPS I disease, and to track clinical outcomes of patients with MPS I over time. Patients should be encouraged to participate, and advised that their participation is voluntary and may involve long-term follow-up. Information regarding the registry program may be found at www.MPSIregistry.com or by calling (800) 745-4447.

Aldurazyme is manufactured by: 

          BioMarin Pharmaceutical Inc. 
          105 Digital Drive
          Novato, CA 94949

          US License Number 1649

Aldurazyme is distributed by:

          Genzyme Corporation 
          500 Kendall Street 
          Cambridge, MA 02142