Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Tysabri (Biogen-Idec)
glass vials containing 300 mg antibody in 15 mL liquid
Approved indication: monotherapy for relapsing-remitting multiple sclerosis
Australian Medicines Handbook section 14.1.4

Multiple sclerosis is characterised by the development of inflammatory lesions in the brain and spinal cord resulting in progressive disability for the patient. This process is mediated by immune cells that cross into the central nervous system. In most patients, the disease initially follows a relapsing-remitting course but eventually develops into a secondary progressive phase.

In Australia, there are currently two treatments for this disease, interferon beta and glatiramer, which act by modulating the immune system. Both of these drugs have been shown to reduce relapse rates by approximately 30% and retard disease progression by 12-18 months.1

Natalizumab, a humanised mouse monoclonal antibody, acts by binding to integrins present on the surface of leucocytes. This interaction stops the leucocytes from migrating into the central nervous system. Natalizumab may also suppress ongoing inflammation by preventing leucocytes from binding to ligands within the extracellular matrix.

Following the repeat intravenous administration of a 300 mg dose of natalizumab every four weeks, the serum concentration reaches a steady state after 24 weeks. The mean half-life of the drug is 11 days but clearance increases with body weight. After discontinuation, natalizumab stays in the blood for about 12 weeks, therefore a washout period may be appropriate before starting other treatments.

There have been three phase II trials and one phase III trial investigating natalizumab as a monotherapy for multiple sclerosis. In a placebo-controlled phase II trial, natalizumab (3 mg or 6 mg/kg) was given intravenously every four weeks for six months to patients with relapsing-remitting disease or secondary progressive multiple sclerosis. In the placebo group, 15 of 71 (21.1%) patients had at least one relapse compared with only 3 of 68 (4.4%) patients given natalizumab 3 mg/kg and 8 of 74 (10.8%) patients given natalizumab 6 mg/kg.2

Two other phase II trials also assessed natalizumab in patients with relapsing-remitting disease or secondary progressive multiple sclerosis. In the larger trial of 180 patients, a single dose of natalizumab (1 or 3 mg/kg) did not significantly improve the clinical course of acute relapses. Although natalizumab reduced the gadolinium-enhancing lesion volume in patients (observed by MRI) at 1 and 3 weeks after the beginning of treatment, by 14 weeks there were no differences in lesion volume between the treatment and placebo groups.3

In the other phase II trial of 72 patients, the number of new gadolinium-enhancing lesions was less in the treatment group (two doses of natalizumab 3 mg/kg four weeks apart) compared to the placebo group over the first 12 weeks. However in the second 12-week period there were no significant differences in the number of new lesions between the two groups.4

A phase III trial enrolled only patients with relapsing-remitting disease who had had a documented relapse in the previous 12 months. They received either a 300 mg dose of natalizumab or placebo every four weeks for up to 116 weeks. Of the 627 patients randomised to receive natalizumab, 72% remained relapse-free after two years compared with 46% of 315 patients randomised to the placebo group. Similarly after an MRI evaluation, no new or enlarging hyper-intense lesions were detected in 57% of patients in the natalizumab group compared with 15% of patients in the placebo group.5

During the phase III trial, 6% of natalizumab patients and 4% of placebo patients discontinued the study because of adverse effects. Infusion reactions occurred in 148 patients in the natalizumab group compared with 55 patients in the control group. Hypersensitivity reactions, which included urticaria, allergic dermatitis and anaphylaxis, were reported by 25 patients receiving natalizumab. There were five cases of cancer reported in the treatment group compared to one in the placebo group. Two deaths occurred during the trial. Both were in the natalizumab group; one was from malignant melanoma and the other was alcohol intoxication.5

Persistent antibodies to natalizumab developed in 37 patients who also had an increase in infusion-related adverse events and loss of efficacy of the study drug.5It is known that the presence of such antibodies increases the clearance of natalizumab three-fold.

In 2005 natalizumab was voluntarily withdrawn in the USA following reports of progressive multifocal leukoencephalopathy, a serious viral infection of the brain, in approximately 1 in 1000 patients taking the drug. After confirming that there were no additional cases of the infection, natalizumab was re-released in the USA through a restricted prescribing program. The drug also comes with a warning to doctors and patients that it increases the risk of progressive multi focal leukoencephalopathy.

Natalizumab is contraindicated for patients who have an increased risk of opportunistic infections. It should not be given in combination with other drugs that modulate the immune system.

The safety and efficacy of natalizumab beyond two years is unknown. During treatment there is a possibility that patients will develop antibodies to this drug that may reduce its efficacy and cause a hypersensitivity reaction.

Natalizumab should only be given by a neurologist who has timely access to MRI facilities. Patients should be evaluated three and six months after the first infusion and then every six months. If there is no sign of clinical benefit after six months, consider discontinuing treatment.

manufacturer provided the product information

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.