Intravenous therapy for the treatment of multiple sclerosis. target antigens; they have shown much promise in the treatment of MS

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1 SERVICE PROVISION Intravenous therapy for the treatment of multiple sclerosis Professor Michael Hutchinson, Consultant Neurologist, St Vincent s Hospital, Dublin; Karl Nichol, Biologics Nurse Specialist, Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne; Mhairi Nellis, MS Specialist Nurse, West of Scotland Regional Multiple Sclerosis Service, Department of Neurology, Southern General Hospital; Jeanette Spicer, Multiple Sclerosis Clinical Nurse Specialist, University Hospitals Coventry and Warwickshire NHS Trust; Elspeth Wolfenden, Clinical Nurse Specialist MS, Buckinghamshire Hospitals NHS Trust SPL Multiple Sclerosis (MS) is a multifocal disease of the central nervous system (CNS) that is characterised by inflammation, demyelination and axonal degeneration. In the majority of MS patients, the disease presents with a relapsing remitting course at disease onset. Relapsing remitting MS (RRMS); affects around two thirds of the people in the UK with MS. 1 The aims of treatment in RRMS are not only to prevent the rate of relapse, but also to slow down patients disability progression. Beta interferons (IFN- s) are disease-modifying treatments (DMTs) that are now widely used in MS. Their efficacy in terms of reduction of relapse rates, magnetic resonance imaging (MRI) outcomes and, in some cases, relapserelated disability have been shown in a number of clinical studies. 2 There are four injectable IFN- s licensed for the treatment of MS in Monoclonal antibodies constitute a new class of therapeutic agent designed to interact with specific target antigens; they have shown much promise in the treatment of MS the UK: three preparations of IFN- -1a: Avonex, administered once weekly by intramuscular (IM) injection, and Rebif 22 and Rebif 44, both administered thrice weekly by subcutaneous (SC) injection; one preparation of IFN- -1b: Betaferon, administered every other day by SC injection, and glatiramer acetate: Copaxone, administered once daily by SC injection. IFN- s and glatiramer acetate only partially modify relapse activity and disability progression, and are disappointing in patients with highly active disease. The limitations of current injectable DMTs have been addressed in a number of studies; about one third of patients with RRMS will develop disability progression in the first five years of treatment using current DMTs. 2 4 For this reason, the search for improved treatment regimens and novel therapies has continued. 5 Further research into new DMTs includes trials of combinations of agents, and of immunosuppressive/immunemodulating drugs that are currently used to treat other diseases (eg cytotoxic therapies). NEW DMTS INMS Monoclonal antibodies constitute a new class of therapeutic agent designed to interact with specific target antigens. 6 Through the precise targeting of molecules involved in pathological processes, they have shown much promise in the treatment of many disorders, including MS. 7 Natalizumab (Tysabri) is the first monoclonal FUTURE PRESCRIBER VOL 8(1) 15

2 SERVICE PROVISION antibody licensed for use in patients with MS, specifically those with highly active RRMS. Another monoclonal antibody that has been used, experimentally, in the treatment of MS is alemtuzumab (MabCampath). It was developed, and is licensed, for the treatment of chronic lymphocytic leukaemia but has been prescribed off-label in some UK centres for the treatment of MS. The third new agent in MS, still undergoing clinical trials in centres in the UK, is mitoxantrone; an immune-modulating/ immunosuppressive anti-cancer drug. Although it is licensed in the USA, use in the UK remains experimental and it is currently prescribed off-label for MS. Natalizumab Natalizumab is the only oncemonthly treatment licensed to reduce the frequency of relapses and delay the progression of disability in RRMS. It is administered every four weeks by intravenous (IV) infusion. In the European Union (EU), natalizumab is indicated as monotherapy for patients with RRMS who have high disease activity despite treatment with IFN, and for patients with rapidly evolving severe RRMS. In the former case, patients should have had at least one relapse in the previous year while on therapy and have 9 T2 lesions or 1 Gd+ lesion on cranial MRI; in the latter case, patients should have had two or more disabling relapses in one year and 1 Gd+ lesion or an increase T2 lesion load relative to another recent cranial MRI scan. The manufacturers of natalizumab recommend its use is initiated and supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions. It should be administered in centres with resources for the management of hypersensitivity reactions and timely access to MRI. 8 After receiving approval from the European Agency for the Evaluation of Medicinal Products (EMEA) in June 2006, natalizumab is the first licensed, humanised, monoclonal anti- 4 -integrin antibody in a class known as selective adhesion molecule (SAM) inhibitors. It binds to 4 -integrin on the surface of lymphocytes, preventing their entry to the brain parenchyma, leading to a reduction in the inflammatory process. 8 Efficacy Data The efficacy of natalizumab in RRMS patients (n=942) was assessed in a phase III, randomised, double-blind, placebo-controlled, multi-centre, parallel-group trial. Patients were randomly assigned to receive natalizumab (n=627) or placebo (n=315) by IV infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year, and the rate of sustained progression of disability at two years. Over the duration of the two-year study, natalizumabtreated patients showed a 68 per cent reduction in annualised relapse rate vs placebo (p<0.001), 9,10 and a 54 per cent reduction in the risk of disability progression (sustained for 6 months and assessed using the Expanded Disability Status Scale [EDSS]) (p<0.001). 9,10 Furthermore, at the end of the study, 28 per cent of patients were free from all of the following measures of disease activity: relapses, Gd+ lesions; T1 weighted hypointense lesions; T2 weighted hyperintense lesions, and sustained disability progression 10 (p<0.001). A subgroup of patients with highly active RRMS ( 2 relapses in the past year and 1 Gd+ lesion on MRI) showed an 81 per cent reduction in annualised relapse rate (p<0.001) and a 64 per cent reduction in the risk of disability progression sustained for six months (n=209, p=0.008). 8 Adverse events In phase III trials, natalizumab was administered as a single infusion, every four weeks, over a period of one hour, immediately followed by a one-hour observation period. 9 Of the patients assigned to receive natalizumab in the aforementioned trial, 23.1 per cent experienced an infusion-related event, compared with 18.7 per cent in the placebo (n=315) group. Adverse events more common in the natalizumab-treated patient group included dizziness, nausea, urticaria and rigors. Of these events 4 per cent were classified as hypersensitivity (1.3 per cent coded as serious; 0.8 per cent of these as anaphylactic/anaphylactoid). The majority of the adverse events were mild-to-moderate, and all cases were successfully treated on-site (they did not require hospitalisation). On the occasions when hypersensitivity reactions did occur, they usually occurred during the infusion or within the following one-hour observation period. 10 Two cases of progressive multifocal leukoencephalopathy (PML), a rare brain disorder, were diagnosed in patients with MS who received natalizumab, in combination with IFN -1a, in the SENTINEL study. 11,12 A third case of PML, previously diagnosed as astrocytoma, was later identified post mortem in a patient with Crohn s disease who had received immunosuppressive treatment in 16 FUTURE PRESCRIBER VOL 8(1)

3 SERVICE PROVISION addition to natalizumab. 13 Natalizumab was withdrawn from the market in February 2005 and ongoing drug trials were suspended; patients who had received natalizumab were invited to participate in screening for other cases of PML. Based on this patient population, who received a mean of approximately 18 monthly doses of natalizumab, it was estimated that the incidence of PML was 1 case per 1000 patients over 18 months (95% CI, ). 14 Managing the risk for PML with natalizumab There is no recommendation for routine laboratory monitoring when using natalizumab. Only neurologists with timely access to magnetic resonance imaging (MRI) should prescribe natalizumab in facilities that are prepared to deal with any hypersensitivity reactions. A MRI of the brain before starting therapy should be performed, to be used for comparison with any future changes if PML is suspected at any stage. Particular care should be taken to review the patient s neurological status and disease pattern, and to assess treatment outcomes regularly at each infusion. If symptoms of new or worsening neurological changes are noted, the patient should be reviewed by the treating neurologist to exclude the possibility of PML or opportunistic infection. If PML is suspected then a MRI Brain should be performed and, if still suspected, a cerebrospinal fluid (CSF) examination for JC virus polymerase chain reaction (PCR) should also be carried out. Neutralising antibodies As natalizumab is a biological agent, the possibility of the treated patients developing neutralising antibodies (NAbs), that can abrogate the efficacy of the agent, should be considered. During the clinical development of natalizumab, 6 per cent of patients were found to be persistently positive for NAbs. The Summary of Product Characteristics recommends that patients whose disease activity is not reduced after six months of treatment should be tested for the presence of persistent NAbs. 8 Alemtuzumab Alemtuzumab is a humanised anti- CD52 monoclonal antibody binds to CD52, a non-modulating, which antigen that is present on the surface of essentially all B and T lymphocytes, a majority of monocytes, macrophages, and NK cells, and a subpopulation of granulocytes. The proposed mechanism of action is antibody-dependent lysis of cells following cell surface binding. It is licensed for the treatment of patients with chronic lymphocytic leukaemia, but its use in MS is currently only experimental. No studies in patients with MS are described in the prescribing information for alemtuzumab; the studies that are referred to involve small numbers of patients for other, unrelated, conditions. As its use in MS is currently experimental, efficacy and safety data should be taken into consideration, but used as guidance only. 15 Adverse events and safety issues The manufacturers of alemtuzumab recommend its administration as an IV infusion over a period of up to two hours. Infusion-related adverse events associated with alemtuzumab include hypotension, rigors, fevers, shortness of breath, bronchospasm and rash. Acute infusion-related events were most common during the first week of treatment. Post-marketing reports of serious adverse events include syncope, pulmonary infiltrates, adult respiratory distress syndrome (ARDS), respiratory arrest cardiac arrythmias, myocardial infarction (MI) and cardiac arrest. Careful monitoring of blood pressure and hypotensive symptoms and signs should be incorporated into the infusion procedure. 15 The manufacturers, therefore, offer additional guidance: that alemtuzumab is administered in gradual increments, and that adjunctive therapies (such as oral anti histamines and acetaminophen) should be used to manage the side-effects. 15 Treatment with alemtuzumab has resulted in profound lymphopenia during clinical trials. 15 A variety of opportunistic infections (bacterial, viral and parasitic) have been reported, and the use of prophylactic anti-infective therapy may be warranted depending on the dose and duration of treatment. Severe and prolonged myelosuppression, bone marrow aplasia and hypoplasia have been seen and are thought to be dose related. Other autoimmune disorders recorded may also be treatment related. In September 2005, a three-year, phase II trial of comparing alemtuzumab with IFN- - 1a in RRMS was suspended after two years. The suspension was due to the emergence of three cases (one fatal) of idiopathic thrombocytopenic purpura (ITP); a further three cases have, subsequently, been discovered. 16 Alemtuzumab has also been associated with a 27 per cent incidence of Graves Disease 17 and Goodpasture s Syndrome. 17 As a minimum, it is therefore recommended that weekly laboratory investigations (full blood count FUTURE PRESCRIBER VOL 8(1) 17

4 SERVICE PROVISION SPL and chemistry) are carried out, and that the frequency of monitoring is adjusted to the clinical condition of the patient. With various unresolved questions relating to the safety of alemtuzumab, the manufacturer discourages use of the agent outside a clinical trial setting in which procedures are in place for managing ITP risk. 16 At least 1.9 per cent of alemtuzumab-treated patients were found to have antibodies against the agent, although this figure may underestimate the true incidence due to the method of detection chosen. 15 As with other immunogenic agents, the infusion service provision must have adequate resources available to manage hypersensitivity reactions. Mitoxantrone Mitoxantrone is a synthetic anthracenedione derivative that was developed in the 1970s as an A hosptial-based specialist neurology infusion clinic can benefit both patients and healthcare teams antineoplastic agent. 18 In MS, mitoxantrone acts by suppressing the activity of the T-cells, B-cells and macrophages that are thought to lead the attack on the myelin sheath. Mioxantrone is licensed by the Food and Drug Administration (FDA) in USA for the treatment of Secondary Progressive (SP) MS and for refractory RRMS with accumulating disability. It is not licensed for the treatment of MS in the UK, although it is used in some patients for the treatment of SPMS with superimposed relapses, or aggressive MS. However, data from randomised, double-blinded, placebo-controlled trials are limited. A recent systematic review by the Cochrane Collaboration identified five papers relating to four studies. 19 Patients suitable for treatment should be carefully selected and should have evidence of disease activity both clinically (relapses) and by MRI (Gadolinium enhancing lesions). Patients with SPMS without such evidence are unlikely to benefit from mitoxantrone. Adverse events In clinical trials of mitoxantrone, the common adverse events that resulted in treatment discontinuation included nausea, alopecia, cutaneous mycosis and menstrual disorders (amenorrhea and menorrhagia). The proportion of mitoxantrone-treated patients who experienced infections ranged between per cent, compared with 67 per cent of patients in the placebo group. Approximately 6 per cent of patients in the mitoxantrone group required hospitalisation due to treatment-related infections. 20 During the studies, common laboratory abnormalities included leukopenia, liver enzyme abnormalities, granulocytopenia and anaemia. Other adverse events include significant myelosuppression and leukaemia, which is estimated to occur in 0.25 per cent (1 in 400) of patients. In the clinical trial setting, neutropenia generally occurred days after administration and was reversible. Additional resources may be required for the provision of antibiotics, regular blood tests and blood products, in addition to standard resuscitation equipment. Other serious adverse events noted include cardiotoxicity; estimated to occur in 2.6 per cent (more than 1 in 20) of patients receiving up to a 140mg/m 2 total cumulative dose (although experience has resulted in total doses of 100mg over one year now being used 21 ). The manufacturers recommend baseline monitoring of cardiac function, in particular left ventricular ejection fraction (LVEF), by echocardiography or multigated acquisition (MUGA). In addition, a thorough history and clinical examination should be undertaken regularly, noting any changes in cardiovascular signs or symptoms. Frequent monitoring of laboratory values (haematological and blood chemistry), LVEF and relevant clinical parameters should also be undertaken before each successive dose in order to manage the risk of adverse events. Women of child-bearing potential should have a negative pregnancy test before each dose. 20 DESIGNATED INFUSION SERVICES The advent of novel agents may increase the expectation of treatment outcomes. In order to optimise the treatment benefits afforded by, and minimise adverse events related to, new agents administered by IV infusion, planning and resource should be considered for the development of 18 FUTURE PRESCRIBER VOL 8(1)

5 SERVICE PROVISION infusion services to meet new demands. Administration of IV infusions in the hospital outpatient setting is not new, and the planning of further such services should draw on the experience gained in rheumatology and oncology. Implicit to the safe and effective administration of IV MS agents, is the establishment of specialist neurology infusion services. There are other benefits associated with such a services, for both patients and staff. Patients benefit from experienced and dedicated staff, improved quality of care, and regular contact and support from the MS team and other patients. In addition, patients gain the opportunity to ask questions and discuss their disease management regularly. For the healthcare professionals, advantages of a designated neurology infusion service include continuity of patient care within the unit, regular and structured patient monitoring and the ability to administer other neurology therapies, such as IntraVenous Immune Globulin (IVIG) and intravenous steroids, within same the facility. It is prudent to set up specialist infusion centres for the administration of IV MS agents within a hospital neurology department: staff already have experience in the management of MS and are therefore better able to assist in the treatment of their patients. There are, of course, many factors that need to be taken into consideration when setting up such a service, such as service planning, the resource required and implementation. Service planning There are a number of practical, clinical and financial issues that need to be factored into the planning stage of setting up an IV infusion service. An accurate estimate of the anticipated number of RRMS patients who will use the service is crucial in determining the necessary space, staff, equipment, funding and other resources required. Required resources can be determined, in part, by the particular characteristics of the agents being administered. In line with this estimate, assessment should be made of existing resources, capacity and service infrastructure. In this way, any gaps in resource can be identified. This assessment process should also highlight any key financial considerations, such as the need for IT resources, funding for staff and drugs and equipment. In addition, consideration of future service expansion may need to be addressed. It is important to factor in possible expansions, the impact of which can be assessed by considering several scenarios involving varying patient numbers. Again, this should be undertaken in conjunction with senior members of the MS specialist team and finance department. Resource Physical resource Resources that could be shared should also be identified, such as a rheumatology day-care unit, or an oncology unit. Necessary prerequisites of the department in which the service will be situated are: the presence of resuscitation equipment, vital signs monitoring equipment, and the ability to take bloods. Provision must also be made for: infusion chairs (beds are not required); infusion pumps and stands; refrigeration; dilutents; labels and patient comforts (such as a television or magazines). In terms of where the drugs will be administered, space is needed for patient pre-assessment, administration and subsequent patient monitoring. Human resource Consideration should also be given to the staff necessary (including a qualified nurse in charge of the unit) who will: admit patients, carry out pre-infusion investigations, administer the drug, monitor and discharge the patient. Many trusts also require a second trained nurse to check the infusion set up before administration. In addition, a prescribing consultant will be needed to sign prescriptions. Clear definition of roles and responsibilities within the infusion team is very important. There should not, for example, be any ambiguity over who is responsible for mixing the drug, who administers the drug, etc. Anticipation of product-specific requirements Data from clinical trials can assist in anticipation of the resources required for each agent and how such resources should be deployed. Factors to consider include the method of administration; observation periods; anticipated frequency and characteristics of adverse events; rate and severity of hypersensitivity reactions; and routine monitoring requirements. The caveat to using trial results to anticipate service requirements is that agents may have been tested in different patient populations, and so the findings should only be used as a guide. For a detailed explanation of the data associated with each agent, reference to the relevant Summary of Product Characteristics is also recommended. FUTURE PRESCRIBER VOL 8(1) 19

6 SERVICE PROVISION Service protocols The next stage of planning is the establishment of clear service protocols, adequate patient coding for each aspect of the service, and a hospital visit form, such as short-stay admission forms for patient visits. Systems should be defined (even simple phone calls and letters to remind patients of appointments) that will help avoid unnecessary and costly cancellations. Implementation Once the neurology infusion service is established there are a number of ongoing service and communication needs to consider. For example, the hospital finance department, IT department and commissioners require regular updates on the progress of the infusion service. From a patient satisfaction point of view, regular feedback should be sought from the facility s users regarding the service and audit of the centre. CONCLUSION It is anticipated that new biological agents that require IV infusion will change the future outcomes of MS treatment. 22 Many such agents will require administration in specialist hospital centres and will require space, staffing and other resources. A hospital-based specialist neurology infusion clinic can be a highly rewarding service offering benefiting both patients and healthcare teams. With careful planning and a review of existing resources, it is anticipated that the use of these new agents will be resource-efficient, and will improve the treatment offering for MS patients, especially those with more severe forms of the disease. Conflict of interest: Prof. Hutchinson reports having received the following: consulting fees from Biogen Idec; lecture fees from Serono, Schering AG, and Biogen Idec; and grant support from Serono, Schering AG, and Biogen Idec. REFERENCES 1. Multiple Sclerosis Trust website ( mstrust.org.uk/information/types.jsp; accessed ). 2. Rudick RA, Lee JC, Simon J, Ransohoff RM, Fisher E. Defining interferon beta response status in multiple sclerosis patients. Ann Neurol 2004;56: Waubant E,Vukusic S,Gignoux L, et al. Clinical characteristics of responders to interferon therapy for relapsing MS. Neurology 2003;61: O Rourke K, Walsh C, Antonelli G, et al. Predicting beta-interferon failure in relapsingremitting multiple sclerosis. Multiple Sclerosis 2006;12: Kappos L, Kuhle J, Gass A, et al. Alternatives to current disease-modifying treatment in MS: what do we need and what can we expect in the future? J Neurol 2004;251(Suppl 5):v57 v Cree B. Emerging monoclonal antibody therapies for multiple sclerosis. Neurologist 2006; 12: Hohlfeld R, Wekerle H. Drug Insight: using monoclonal antibodies to treat multiple sclerosis. Nat Clin Pract Neurol 2005;1: Biogen Idec Ltd. Summary of Product Characteristics: Tysabri 300mg. 18 July Polman CH, O Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: Biogen Idec Ltd. Data on file. 11. Kleinschmidt-DeMasters BK, Tyler KL Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med, 353: Langer-Gould A, Atlas SW, Bollen AW, et al Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med, 353: Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn s disease. N Engl J Med, 353: Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354: Genzyme Corporation. Campath (Alemtuzumab) Prescribing Information. ( berlex.com/html/products/pi/campath_pi.pdf; accessed ). 16. Genzyme Canada Inc. Press release: Genzyme Reports Interim Results from Trial of Campath for Multiple Sclerosis: Two-Year, Pre-Planned Interim Analysis Demonstrates Robust, Statistically Significant Treatment Effect of Campath Compared to Rebif. 14 September 2006 ( GENZ%20PR asp; accessed ). 17. Coles AJ, Cox A, Le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253: Debouverie M, Vandenberghe N, Morrissey SP, et al. Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis. Multiple Sclerosis 2004;10: Martinelli Boneschi F, Rovaris M, Capra R, et al. Mitoxantrone for multiple sclerosis. The Cochrane Database of Syst Rev 2005; 19:CD Serono. Novatrone (mitoxantrone for injection concentrate) Prescribing Information. ( accessed ). 21. Boggild M. Rationale and experience with combination therapies in multiple sclerosis. J Neurol 2006;253(Suppl 6):vi Pender MP. Neurology. 4: Multiple sclerosis. Med J Aust 2000;172: Letters We would be pleased to receive any comments you may have on articles published in this issue of Future Prescriber, and will consider publishing them on the letters page. Please send your comments to: The Editor, Future Prescriber, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ. 20 FUTURE PRESCRIBER VOL 8(1)