Natalizumab
Summary: Natalizumab (Nz) is a first-in-class selective adhesion molecule blocker and works by reducing the trafficking of lymphocytes into the central nervous system. Nz is very high efficacy DMT capable of achieving long-term NEDA in the majority of treated MSers with a large impact on end-organ damage (brain volume loss). Once rebaselined, average annual brain volume loss is the range one would expect normal people to have. One result of reduced trafficking of lymphocytes in the brain is reduced immune surveillance, which puts MSers on Nz at high risk of PML (if they have been infected with the JC virus that causes PML). The risk of PML is variable and can be reduced by using extended interval dosing (EID). Nz is given as a 4-weekly infusion and is very well tolerated. A small number of MSers (<5%) may develop infusion reactions, which can be serious. Infusion reactions typically come on with the 2nd, 3rd or 4th infusion and are associated with the development of so called neutralizing antibodies (NABs). Nz has a rapid onset of action and when used early a large number of MSers notice an improvement in disability and often report improvement in fatigue.
Trade Names: Tysabri
Mode of action: Nz is an immunosuppressive as it is associated with opportunistic infections and possibly secondary malignancies of the central nervous system. Nz is a monoclonal antibody that targets VLA-4 or α4β1 integrin on lymphocytes, preventing them from crossing the blood brain barrier. A good analogy of how the lymphocytes cross the blood brain barrier is Velcro. The lymphocyte has to stick to the wall of the blood vessel before it can cross. Nz blocks one of the surfaces (or Velcro) so the lymphocytes are unable to cross the wall of the blood vessel. The following video explain Nz's mode of action. MSers on Nz treatment have increases in the number of circulating white blood cells in their blood. The reason this occurs is that pool of cells that tend to be stuck or rolling on blood vessel walls (marginating cells) are now found in the blood.
Efficacy: Very high, particularly in MSers with rapidly evolving severe MS
Class: Maintenance, immunosuppressive
Immunosuppression: Yes, but limited to the CNS
Posology: Nz 300 mg is administered by intravenous infusion once every 4 weeks
Main adverse events:
Adverse events of special interest:
Infusion reactions: These tend to mild and occur in ~20% of MSers and may be associated with headache, dizziness, nausea, urticaria and rigors.
Hypersensitivity reactions: these occur in approximately 5% of MSers. In about a quarter of MSers these can be anaphylactoid in nature and typically occur during the infusion or within an hour of completing the infusion. Hypersensitivity reactions are associated with either a low or high blood pressure, chest pain, chest discomfort, shortness of breath, swelling of the throat, rash, urticaria, rigors, nausea, vomiting and flushing. Most hypersensitivity reactions occur on the 2nd, 3rd or 4th infusion and are associated with the development of anti-drug antibodies, i.e. your own body rejects the drug by making antibodies against Nz. Persistent anti-natalizumab antibodies develop in approximately 5-6% of MSers on Nz and decrease the effectiveness of Nz and cause hypersensitivity reactions.
Infections: In general Nz is not associated with systemic infections. As an immunosuppressive therapy Nz has been associated with opportunistic infections, in particular progressive multifocal leukoencephalopathy (PML). Other opportunistic infections include cryptosporidium diarrhoea and cryptococcal meningitis. Herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occur more frequently on Nz. Serious life-threatening encephalitis and meningitis caused by herpes simplex or varicella zoster can occur on Nz. The presentation of these infections is atypical in that Nz reduces trafficking of cells into the CNS and hence the associated inflammation is less intense and so the presentations are more indolent and subacute over weeks. Rarely these viruses may infect the retinae and lead to acute retinal necrosis and loss of vision.
PML and granule cell neuronopathy: JCV is the commonest opportunistic infection in seropositive natalizumab treated MSers. JCV cause PML and granule cell neuronopathy (GCN). PML is the commonest and its management is described separately. GCN is characterised by lytic infection of the cerebellar granule cell layer and presents with a cerebellar ataxia and cerebellar atrophy and white matter changes in the cerebellum and brainstem on MRI. Many cases of GCN also have white matter changes elsewhere suggesting an overlap between GCN and PML.
Abnormal liver function tests: Autoimmune hepatitis, increased liver enzymes and hyperbilirubinaemia can rarely occur on Nz.
Anaemia: Anaemia and haemolytic anaemia have been rarely reported in Nz-treated MSers.
Malignancies: Several cases of CNS lymphoma have been reported in MSers treated with Nz. The risk of CNS lymphoma is likely to be increased based on the mode of action of Nz, i.e. it blocks immune surveillance of the CNS and hence there will be an increased risk of CNS tumours.
Neutralizing Antibodies (NAbs): Yes, in approximately 5% of Nz-treated MSers
Pharmacovigilance monitoring requirements:
Baseline: FBC, U&E, LFTs, JCV-serology and pregnancy test. Follow-up: LFTs 3 monthly for a year. NABs at 12 months. JCV serology 6-monthly.
Follow-up: LFTs 3 monthly for the first year, NABs at 12 months and JCV serology every 6-months. In MSers at high risk of PML 3-monthly MRI otherwise annual MRI monitoring for disease activity monitoring.
Self-monitoring: All MSers should be warned about opportunistic infections and informed to look-out for symptoms suggestive of infections. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or HPV testing done 3 yearly.
Rebaselining: A rebaseline MRI needs to be done after Nz has had sufficient time to work. As Nz works very quickly I recommend 3-6 months after starting treatment and to include Gd-enhancement as part of the rebaselining MRI.
Pregnancy: Animal studies have shown no toxicity from Nz and data from clinical trials and post-marketing studies suggest Nz exposure has no adverse effect on pregnancy outcomes. Babies born to MSers on Nz have a transient mild to moderate low platelet count and anaemia, which disappear within weeks. Most neurologists are now allowing their female patients to fall pregnant whilst on Nz and then offer to stop it after they have become pregnant. Because of the emerging safety profile of Nz in pregnancy some neurologists are letting patients continue Nz throughout pregnancy. The decision to this is based on the risk of rebound MS activity when natalizumab washes out.
Breastfeeding: The amount of natalizumab that crosses over into the breast milk is very small and likely to be digested by the babies digestive enzymes, therefore, it is safe to breastfeed on Nz.
Male Fertility: Safe
Vaccination: Safe for component or inactivated vaccines. Live vaccines are contraindicated. Live viruses, particularly ones that can infect the central nervous system, are potentially dangerous.
Summary of Product Characteristics (SmPC): Tysabri