International Approvals: Tysabri, Elaprase, Invega

Yael Waknine

July 09, 2007

July 9, 2007 — The UK's Medicines and Healthcare Products Regulatory Agency has approved natalizumab intravenous infusion for the treatment of highly active relapsing-remitting multiple sclerosis, Health Canada has approved idursulfase intravenous infusion for the treatment of Hunter syndrome, and the European Union has approved paliperidone prolonged-release tablets for the treatment of schizophrenia.

Natalizumab (Tysabri) for Highly Active Relapsing-Remitting MS in the UK

On July 3, the UK's Medicines and Healthcare Products Regulatory Agency approved natalizumab intravenous infusion (Tysabri; Biogen Idec and Elan Corporation, PLC) to delay the progression of disability and reduce the frequency of relapses in patients with relapsing-remitting multiple sclerosis. The drug is intended for use in patients with high disease activity despite treatment with a beta-interferon and in patients with rapidly evolving severe disease. According to a company news release, the approval followed a positive recommendation from the National Institute for Health and Clinical Excellence, based on data from two 2-year, randomized, phase 3 studies showing that natalizumab therapy yielded a 68% reduction in the annual rate of clinical relapse and a 54% decrease in the risk for sustained disability relative to placebo.

The monoclonal antibody was first approved for this indication by the US Food and Drug Administration (FDA) in November 2004 and was later withdrawn from market by the manufacturer in February 2005 after 3 patients developed progressive multifocal leukoencephalopathy (PML) during clinical trials. Because 2 of the patients were also taking interferon beta 1 alpha (Avonex, Biogen Idec), a causal role for natalizumab was not established. On June 5, 2006, the FDA allowed the reintroduction of natalizumab into the US market with a restricted distribution program and revised safety labeling to warn of the risk for PML; later that month, the drug was approved for use in the European Union with similar restrictions.

Idursulfase Intravenous Infusion (Elaprase) for Hunter Syndrome in Canada

On June 13, Health Canada approved idursulfase intravenous infusion (Elaprase; Shire Human Genetic Therapies, Inc) for the treatment of mucopolysaccharidosis 2, also known as Hunter syndrome.

According to a company news release, idursulfase had previously been made available on a limited basis to Canadian patients since January 2007 through Health Canada's Special Access Program but will now be available on a more widespread basis across the nation. Hunter syndrome is a rare genetic condition caused by an absence or deficiency of iduronate-2-sulfatase, a lysosomal enzyme. It usually becomes apparent in children aged 1 to 3 years and is characterized by symptoms such as growth delay, joint stiffness, and coarsening of facial features. Severe cases can lead to respiratory and cardiac problems, liver and spleen enlargement, neurologic deficits, and death. Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is produced by recombinant DNA technology in a human cell line. The recommended dose is 0.5 mg/kg of body weight administered every week as an intravenous infusion for 1 to 3 hours.

Health Canada's approval was based on data from a 53-week, randomized, double-blind, phase 2/3 clinical trial (n = 96), showing that weekly idursulfase therapy significantly improved patients' capacity to walk, as demonstrated by an increase of 35 m (38 yd) from baseline in the 6-minute walk test compared with placebo (mean change from baseline, 44 ± 70 m vs 7 ± 54 m; P = .01). A trend toward increased forced vital capacity was also observed in the idursulfase group (mean percentage predicted change from baseline, 3.4% ± 10.0% vs 0.8% ±9.6%; P = .07).

Idursulfase was generally well-tolerated, with mild-to-moderate infusion reactions most commonly reported. Other adverse events observed in more than 30% of patients occurred with similar frequency in the active vs placebo group and included pyrexia (63% vs 59%), headache (19% vs 14%), and arthralgia (10% vs 9%).

Because of the risk for severe and potentially fatal anaphylactic reactions, medical support should be readily available during idursulfase infusions. If a severe reaction occurs, the infusion should be immediately suspended and appropriate treatment initiated. If symptoms resolve, the infusion may be resumed at a lower rate.

Patients who experience a severe infusion reaction can be treated by use of antihistamines and/or corticosteroids prior to or during subsequent infusions, a slower rate of idursulfase administration, and/or early discontinuation of the infusion.

The company notes that patients with compromised respiratory function or acute respiratory disease may be at increased risk for serious acute exacerbation of their respiratory compromise because of infusion reactions and may require additional monitoring. A delay in therapy should be considered for patients with concomitant acute respiratory and/or febrile illness.

Patients and their clinicians are encouraged to participate in a voluntary Hunter Outcome Survey that has been established to monitor and evaluate the safety and efficacy of long-term idursulfase therapy.

Idursulfase was previously approved by the US Food and Drug Administration and the European Commission in July 2006 and January 2007, respectively.

Paliperidone Prolonged-Release Tablets (Invega) for Schizophrenia in EU

On June 28, the European Commission approved paliperidone prolonged-release tablets (Invega; Janssen-Cilag, Ltd), allowing their use for the long-term maintenance and acute treatment of schizophrenia.

According to a company news release, paliperidone differs from the atypical antipsychotic risperidone by the addition of a hydroxyl group. The once-daily formulation, which uses a proprietary osmotic delivery system, is available in 3-, 6-, and 9-mg tablet strengths.

The approval follows a positive recommendation from the European Medicines Evaluation Agency (EMEA) and is based on data from three 6-week trials of nonelderly patients (n = 1665; mean age, 37 years) showing that use of paliperidone at any dose (3, 6, 9, 12, or 15 mg/day) was significantly more effective than placebo for improving symptoms of schizophrenia, as evaluated by validated Positive and Negative Syndrome Scale (PANSS) scores and Personal and Social Performance (PSP) scale scores. "Symptom reduction was seen as early as day 4 after treatment initiation," the companysays in a news release.

PANSS is a multi-item inventory that measures positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. The PSP measures personal and social functioning in socially useful activities (eg, work and study), personal and social relationships, self-care, and disturbing/aggressive behaviors.

"Paliperidone prolonged-release tablets are the first treatment for schizophrenia to receive EMEA approval for inclusion of improved social functioning in the product labeling," the company notes.

These findings were supported by data from a placebo-controlled randomized phase of a long-term study (n = 207) showing that continued use of paliperidone in stabilized patients significantly improved their ability to maintain symptom control and delayed their time to relapse (relapse rate, 48.5% for paliperidone vs 77.9% for placebo). All patients had previously received paliperidone during an 8-week initiation period (3 – 15 mg flexibly dosed, with a 9-mg starting dose) and stabilized with an additional 6 weeks of therapy at the same dose. The trial was terminated early because of findings from an interim analysis that demonstrated the drug's long-term therapeutic efficacy.

Treatment-emergent adverse events (TEAEs) reported in 5% or more of paliperidone-treated patients and occurring at least twice as often as placebo included akathisia and extrapyramidal symptoms. The discontinuation rate due to TEAEs was 5% for active-treatment and placebo groups.

In the 6-week trials, adverse drug reactions occurring in 2% or more of paliperidone-treated patients included headache (13%), akathisia (6.5%), extrapyramidal disorder (5.4%), somnolence (4.9%), dizziness (4.8%), and sedation (4.2%).

The recommended dosing regimen for paliperidone is 6 mg once daily, administered in the morning with or without food. Initial dose titration is not required. Tablets should be swallowed whole with liquids and not chewed, divided, or crushed. Efficacy has been demonstrated only for short-term use. Patients requiring treatment for extended periods should be periodically reevaluated.

For some patients, a dose of 3 mg/day may be sufficient, whereas others may benefit from a higher dose of up to 12 mg/day. Although it has not been systematically established that doses greater than 6 mg have additional benefit, a general trend for increased efficacy was observed at increased doses during clinical trials. However, the potential benefit of such increased doses must be weighed against similarly increased dose-related risks for adverse events. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days and in increments of 3 mg/day.

Dosing adjustments may be required according to renal function status, particularly in elderly patients. The maximum recommended doses for those with mild (creatinine clearance [CrCl], ≥50 to <80 mL/min) and moderate to severe renal impairment (CrCl, 10 to <50 mL/min) are 6 and 3 mg/day, respectively. No dose adjustments are required for those with mild to moderate hepatic impairment.

Paliperidone extended-release tablets previously were approved by the US Food and Drug Administration for the long-term maintenance and acute treatment of schizophrenia.

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