This document posted Committee to Evaluate Drugs (CED) Recommendations and Reasons September 2009

Idursulfase Idursulfase (Elaprase) was recently reviewed through Ontario’s new Drugs for Rare Diseases (DRD) evaluation framework. The outcome of this review has resulted in a change in funding status. Please see below under “status” for additional information.

Product: Highlights of Recommendation: such as Hunter syndrome. These IDURSULFASE (Elaprase®) 2 mg/mL ♦ Idursulfase (Elaprase) is a purified form of factors were considered by the vial the iduronate-2-sulfatase enzyme Committee in making the final produced by recombinant DNA technology. recommendation. Given the Class of drugs: It is indicated for the treatment of Hunter limitations with the clinical data, the Enzyme replacement therapy syndrome, also known as potential for life-threatening

Mucopolysaccharidosis (MPS) II. reactions to treatment Indication: administration, and the lack of cost- ♦ Idursulfase (Elaprase) has been shown in Treatment of Hunter syndrome effectiveness, the Committee felt that clinical trials to improve patients’ urinary (Mucopolysaccharidosis II, MPS II) idursulfase (Elaprase) should not be glycosaminoglycans (GAG) levels, liver size funded. Manufacturer: and spleen size. Improvements in walking Shire Human Genetics Therapies, Inc. tests were observed but the results were not significant. There is no evidence that Background: the reported biological effects translate Hunter syndrome, also known as into clinically meaningful benefits, such as Mucopolysaccharidosis (MPS) II, is a rare CED Recommendation prolonged survival, improved quality of and progressive genetic disorder in people life, pain reduction or better physical The CED recommended that idursulfase who do not have enough of an enzyme function. called iduronate-2-sulfatase. The shortage (Elaprase) not be funded through the ♦ Because clinical studies were performed in of this enzyme causes a buildup of Ontario Public Drug Programs. patients with the milder form of Hunter glycosaminoglycans (GAG) in cells and Although preliminary data show that syndrome, evidence is lacking in patients tissues. Hunter syndrome affects multiple the drug demonstrates biological with the more severe form of the disease organ systems in the body. activity, there is no evidence of (sometimes called Hunter syndrome Type meaningful benefits (such as A), which is associated with neurologic The disease varies in severity. In its most improvements in survival, pain, physical involvement. severe form (sometimes called Hunter function or quality of life). Moreover, ♦ Idursulfase (Elaprase) does not penetrate syndrome Type A), a buildup of GAG occurs the brain; therefore, it is unlikely that in the brain, causing progressive the cost of treatment is extremely high. deterioration of brain cells. Children with treatment will prevent the neurological disease seen in patients with Hunter the most severe form of the disorder are

syndrome Type A. usually diagnosed when they are between 18 months and 3 years old. They deteriorate ♦ Idursulfase (Elaprase) is administered by Executive Officer Decision mentally, and death generally occurs before intravenous injection. The most common age 15. People with the mildest form of the side effect with treatment is infusion- disease (sometimes called Hunter syndrome Based on the review of Hunter related reactions, sometimes leading to Type B) are characterized by short stature, Syndrome and idursulfase (Elaprase) severe, life-threatening allergic reactions. stiff joints, osteoarthritis, cardiac valve through the Drugs for Rare Diseases Serious side effects, such as irregular heart disease, and hearing impairment. Other (DRD) evaluation framework, the beats, blood clots in the lung and people may suffer from an intermediate form Executive Officer has decided to fund infections, have also been reported with of the disease. idursulfase (Elaprase) through Ontario treatment. Other side effects include

headache, rash, abdominal pain, joint Public Drug Programs for specific Currently, there is no cure for Hunter pain, anxiety, chest wall pain, back pain, sub-groups of patients. syndrome. Idursulfase (Elaprase) is a and head injury from falls. purified form of the enzyme iduronate-2- ♦ Idursulfase (Elaprase) is dosed according sulfatase produced by recombinant DNA to body weight. The drug costs $4,215 technology. Status per 6mg vial. The treatment cost is about

$657,000 per year for a child who weighs 35kg. Without any evidence of meaningful Funding is available through the benefit to justify the high cost, idursulfase Exceptional Access Program (EAP) (Elaprase) does not represent value for according to specific clinical criteria. money. For further information, please see: ♦ Overall, the Committee acknowledged the difficulties http://www.health.gov.on.ca/english/ involved in producing clinical providers/program/drugs/pdf/ evidence and favourable cost- elaprase_reimburse.pdf effectiveness data for rare diseases continued... Detailed Discussion: would be applicable to patients with Hunter CEDAC Recommendation: syndrome Type A. ♦ Idursulfase (Elaprase) does not penetrate the ♦ The Committee considered the funding of (http://www.cadth.ca/index.php/en/cdr/ idursulfase (Elaprase) on two occasions. The blood brain barrier; therefore, it is unlikely that treatment will prevent the neurological disease recommendations ) first review was initiated prior to Health Canada’s approval of this drug and was seen in Hunter syndrome Type A. ♦ The Canadian Expert Drug Advisory Committee completed in June 2007. The second review In terms of safety, infusion related toxicities were the most common adverse event (CEDAC) recommended that idursulfase considered additional information provided by (Elaprase) not be listed. the manufacturer and was completed in associated with idursulfase (Elaprase) therapy. November 2007. Approximately 69% of patients experienced ♦ The evidence for effectiveness of idursulfase infusion reactions, including anaphylactoid (Elaprase) comes from two published trials: a reactions, which may lead to life-threatening small, phase I/II trial involving 12 patients respiratory failure. Serious adverse events, (Muenzer 2007); and a larger, phase II/III trial such as cardiac arrhythmia, pulmonary involving 96 patients (Muenzer 2006). embolism and infections, have also been ♦ In the Muenzer 2007 study, idursulfase reported with treatment. Other adverse (Elaprase) was shown to decrease urinary reactions include headache, urticaria, rash, levels of glycosaminoglycans (GAG), liver abdominal pain, arthralgia, anxiety, chest wall volume and spleen volume. No clear pain, back pain, and head injury from falls. ♦ treatment effect was found for other outcomes IgG antibodies to idursulfase (Elaprase) are including forced vital capacity (FVC), global found in about half of the treated patients; joint range of motion, and sleep quality. however, their occurrence does not appear to ♦ The larger study, Muenzer 2006, compared impact the short-term effects of idursulfase two dose regimens of idursulfase (Elaprase), (Elaprase). Further long-term data are 0.5mg/kg weekly or 0.5mg/kg every other required to assess the potential effects of anti- week, versus placebo. Patients treated with idursulfase antibodies. ♦ idursulfase (Elaprase) 0.5mg/kg weekly, Idursulfase (Elaprase) costs $4,215 per 6mg compared to those on placebo, had a greater vial, or $657,000 per year for a 35kg child improvement in mean distance walked during receiving the recommended dose of 0.5mg/kg the 6-Minute Walk Test (6MWT) of 35 meters. per week. Without evidence of any clinically However, this difference represented a less relevant benefits that could justify the high than 10% improvement over the baseline cost, idursulfase (Elaprase) does not represent mean of over 390 meters at study entry. value for money. ♦ Patients treated with idursulfase (Elaprase) Overall, the Committee acknowledged the also experienced statistically significant difficulties involved in producing clinical reductions in measured liver volume, spleen evidence and favourable cost-effectiveness volume and urinary GAG, compared with those data for rare diseases such as Hunter on placebo. Improvement in FVC with syndrome. These factors were considered by idursulfase (Elaprase) was not statistically the Committee in making the final significant. Global joint range of motion, pain recommendation. However, only preliminary and quality of life were not consistently evidence of biological activity currently exists improved. for idursulfase (Elaprase). Data on clinically ♦ The Committee noted that while idursulfase important measures, such as impact on (Elaprase) has demonstrated treatment effects hospitalization, physical function, quality of life on 6MWT, urinary GAG, splenomegaly and and survival, are lacking. Furthermore, data hepatomegaly, the clinical importance of these supporting the use of this drug in the more reported measures is unknown. Moreover, severe form of Hunter syndrome are not available. Given these limitations with the evidence of benefit is not available for a number of clinically relevant outcomes, such clinical data, the potential for life-threatening reactions to treatment administration, and the as the need for ventilation, hospitalizations, quality of life, and survival. lack of cost-effectiveness, the Committee felt

♦ Evidence is also lacking to support the use of that idursulfase (Elaprase) should not be idursulfase (Elaprase) in Hunter syndrome funded. Ministry of Type A, the more severe variant of the Health and Long-Term Care

disease. Patients in clinical studies were Ontario Public Drug Programs required to cooperate with pulmonary function

tests and, therefore, only patients with the milder form of Hunter syndrome were For more information, please contact: enrolled. It is unclear whether study results Ministry of Health and Long-Term Care Ontario Public Drug Programs Hepburn Block, 9th Floor 80 Grosvenor Street, Queen’s Park Toronto, Ontario M7A 1R3 or click: (http://www.health.gov.on.ca/english/ providers/program/drugs/ced_rec_table.html )