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Hospital pharmacists will have a key role in educating patients and fellow healthcare professionals in the correct dosing, administration and monitoring of oral therapies for multiple sclerosis
Charles Tugwell
BPharm MSc MRPharmS
Specialised Clinical Pharmacist
Barts and The London NHS Trust
The Royal London Hospital
Gavin Giovannoni
MBBCh PhD
Centre Lead Neuroscience and Trauma
Barts and The London School of Medicine and Dentistry
Queen Mary University of London
London
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) that affects around 2.5 million people worldwide.[1] It is the most common non-traumatic disabling neurological disease of young adults,[2] and relapsing–remitting MS (RRMS) is the most prevalent form of the disease. Whereas the cause of MS is unclear, there is consensus that a dysregulated immune system plays a critical role in the pathogenesis of MS.
Disease-modifying drugs (DMD) represent the cornerstone of medical management for RRMS, and a growing body of evidence highlights the importance of early intervention with these drugs following diagnosis.[3] Once diagnosed, the patient’s status is monitored by recording the rate and severity of relapses, and by assessing progression of disability using the Expanded Disability Status Scale (EDSS). In the past few years, magnetic resonance imaging (MRI) has also proved to be an important objective measure of disease activity and severity, and may help to predict the course of the disease. Beneficial effects on all three of these measures of disease activity are required to confirm the efficacy of a DMD.
Clear need for new treatment options in MS
Currently available DMDs for the treatment of RRMS include glatiramer acetate and the recombinant beta-interferons (IFNß). Natalizumab and mitoxantrone are also available as second-line therapies, although mitoxantrone is not licensed in many countries for MS. While currently available therapies have been shown to reduce disease activity and the progression of disability, responses are often suboptimal. Furthermore, the need for regular intravenous (IV) infusions or subcutaneous (SC)/intramuscular (IM) injections confers a burden of side-effects and inconvenience that many patients find troublesome, which can in turn lead to poor adherence and consequent reductions in efficacy. There is a clear need for therapies with improved efficacy and that are easy for patients to take.
New therapies will be welcomed
Several agents are in Phase III clinical development for the treatment of RRMS, and it is anticipated that some of these will be licensed over the next few years. Alemtuzumab, rituximab and daclizumab are three monoclonal antibodies in development for MS, all of which have to be administered parenterally. These will not be discussed in this review, which focuses on oral agents under investigation.
Much attention has been directed at five oral agents in late-stage clinical development. These are cladri
bine tablets, fingolimod, teriflunomide, laquinimod and BG00012. It is anticipated that at least two of these – cladribrine tablets and fingolimod – may be approved for RRMS in the near future. Phase III efficacy results for cladribine and fingolimod were published in the New England Journal of Medicine earlier this year,[4–6] and regulatory submissions are underway for both treatments. Pivotal trial data for the other three agents are awaited, with anticipated regulatory submissions in 2011/2012. It will be vital for pharmacists and other healthcare professionals involved in the care of patients with MS to have a thorough understanding of these emerging therapies in preparation for their potential availability.
A comparison of oral treatments in late-stage development
The five oral treatments in late-stage development target various steps of the immunopathological pathway that gives rise to MS. The availability of agents with differing mechanisms of action is important given the variability in both the response to treatment and the course of the disease. With the exception of therapy with cladribine tablets, which is given in an annual short-course regimen, all oral agents are given as daily treatments (one to three times daily). Table 1 provides an overview of the five oral therapies, summarising efficacy and safety data and dosing information from clinical trials.[4–11] The table also lists the study populations included in completed and ongoing clinical trials for each agent, providing some insight into the potential indications that may be sought for each therapy.
Cladribine tablets
Cladribine is believed to exert its immunomodulatory effects by the related sustained reductions in peripheral lymphocytes, particularly T cells, while sparing other immune cells and haematological components.[12] Treatment with cladribine tablets (Merck Serono S.A.) has shown promising results in late-stage clinical trials (Table 1); its efficacy indicates relative reductions in MS annualised relapse rates (ARR) of 55–58% relative to placebo in the CLARITY study.[4]
In the 96-week Phase III CLARITY study, adverse events (AEs) reported more frequently with cladribine tablets than placebo included lymphopenia and leukopenia, as expected from the mechanism of action of cladribine.[4] Lymphopenia was reported by investigators as an AE in 21.6%, 31.5% and 1.8% of patients treated with cladribine tablets 3.5mg/kg, 5.25mg/kg and placebo, respectively.[4] AEs reported by at least 10% of patients that were comparable with placebo included headache, nasopharyngitis, nausea and upper respiratory tract infections.[4] Despite the lymphopenia observed in patients treated with cladribine, the overall incidence of infections was similar to placebo (47.7%, 48.9% and 42.5% of patients treated with cladribine tablets 3.5mg/kg, 5.25mg/kg and placebo, respectively).[4] Three isolated malignancies occurred during the study across different organ systems (an ovarian carcinoma, a pancreatic carcinoma and a malignant melanoma) in the 3.5mg/kg cladribine group, and one case of cervical carcinoma in situ in the 5.25mg/kg group. A choriocarcinoma was diagnosed in one patient in the cladribine 5.25mg/kg group 9 months after study completion. All cases were considered by investigators as unlikely to be treatment related.[4] A Phase IIb trial of cladribine tablets as add-on therapy to IFNß in patients with RRMS is ongoing (ONWARD study). Regulatory submissions are underway.
Potential monitoring requirements for cladribine tablets in clinical practice will involve periodic full blood profiles. The dosing regimen for cladribine tablets is based on body weight, which in practice translates into a simple short-course dosing regimen, with two or four courses (totalling 8–20 days of treatment) needed over a 48-week period followed by two courses over a second 48-week period of treatment. Pharmacists will have a key role in ensuring accuracy of dosing and providing clear guidance to patients.
Fingolimod (FTY720)
Fingolimod (Novartis AG) is a sphingosine-1-phosphate (S1P)-receptor modulator that sequesters activated lymphocytes in lymph nodes and the thymus, thereby preventing their migration into the bloodstream.[13] This reduces the circulation of disease-relevant autoreactive T cells to the CNS,[14] and as a consequence, interrupts the inflammatory processes that give rise to MS. Results from the recently published Phase III FREEDOMS trial5 indicate reductions in ARRs of 54–60% relative to placebo (Table 1). TRANSFORMS, a Phase III head-to-head comparison of fingolimod versus IM IFNß-1a showed that fingolimod was significantly more effective than IFNß-1a over a 12-month period.6 Regulatory submissions are underway.
Adverse events reported more frequently with fingolimod than placebo included bradycardia, atrioventricular (AV) block, macular oedema, hypertension and elevated liver function tests (LFTs). As seen with cladribine tablets, fingolimod treatment was associated with lymphopenia.[5] In the FREEDOMS study, malignant neoplasms were reported in four patients receiving 0.5mg of fingolimod, four receiving 1.25mg of fingolimod and ten receiving placebo.[5] This included four cases of breast cancer, three in the placebo group and one in the 1.25mg fingolimod group. There was one case each of endometrial cancer, prostate cancer and cervical cancer (stage 0), all in the placebo group. All 11 skin cancers (BCC, malignant melanoma or Bowen’s disease) that occurred (three cases with 1.25mg fingolimod, four with 0.5mg fingolimod and four with placebo) were removed successfully.
Dosing is one capsule taken daily (0.5mg or 1.25mg), with fast-track regulatory submission underway for the 0.5mg dose for the indication of RRMS. In the Phase III trials, patients were observed for 6 hours following the first dose, with assessments including monitoring of heart rate and AV conduction. This monitoring requirement may translate into clinical practice.
Teriflunomide
Teriflunomide (Sanofi Aventis) is the active metabolite of leflunomide, a treatment approved in many countries for rheumatoid arthritis and active psoriatic arthritis. The exact mechanism of action of teriflunomide remains unclear, but it is known to possess both anti-proliferative and anti-inflammatory actions.[8] Its ability to inhibit dihydroorotate dehydrogenase (DHODH), a key cellular enzyme involved in de novo pyrimidine synthesis appears to dominate its therapeutic effect. Inhibition of DHODH mediates a cytostatic effect on proliferating T and B lymphocytes.[8]
Phase III trials of teriflunomide (7mg and 14mg tablet once daily) versus placebo or IFNß-1a are underway in patients with RRMS, with one scheduled for completion in late 2010. A Phase II trial reported significant improvements on MRI measures of disease activity (Table 1) and although ARRs in actively treated patients were not significantly lower than in those patients receiving placebo, disability progression was significantly reduced in the teriflunomide 14mg group.[7] The role of teriflunomide as a possible combination therapy with IFNß or glatiramer acetate (GA) is also under investigation. Preliminary data indicate that improvements are seen over IFNß alone on MRI measures of disease activity and clinical measures of disability (EDSS),[15] and over GA alone on MRI measures of disease activity.[16]
AEs reported more frequently in patients treated with teriflunomide than those in the placebo group included neutropenia, nasopharyngitis, alopecia, nausea, alanine transaminase (ALT) increase, paraesthesia, back and limb pain, diarrhoea and arthralgia.[7] Animal studies indicate that teriflunomide has hepatotoxic, teratogenic and myelosuppressive effects. Consequently, a washout regimen is recommended prior to stopping contraception,[7] and monthly or bimonthly LFTs are recommended during treatment.[8]
Laquinimod
A derivative of linomide, laquinimod (Teva & Active Biotech) is an immunomodulatory agent thought to exert its therapeutic effect in MS by inducing the release of transforming growth-factor-ß and by favouring the production of other Th2 cytokines.[17] Two Phase III laquinimod trials are underway in patients with RRMS, so efficacy data are presently limited, but Phase IIb results indicate good efficacy on MRI measures of disease activity (Table 1).[9] Main safety concerns include a possible pro-inflammatory effect and potential hepatotoxicity,[10] possibly giving rise to elevated LFTs. A case of Budd-Chiari syndrome has highlighted the possibility of an increased risk of thrombosis in patients with pre-existing thrombophilia exposed to laquinimod.[9]
The laquinimod efficacy and safety profile emerging to date has enabled this agent to be granted a Fast Track designation from the FDA,[17] which may help to facilitate the drug’s entry to the market as soon as late 2011.
BG00012 (fumaric acid)
Fumaric acid esters in topical formulations have been used for the treatment of psoriasis for many years, and an oral formulation is approved for this use in Germany. In MS, oral BG00012, or fumaric acid (Biogen Idec) is thought to have both anti-inflammatory and immunomodulatory effects, although its mechanism of action is not wholly understood. Two Phase III trials of BG00012 in patients with RRMS are underway, with one of these expected to complete in late 2010.
Phase II trials indicate good efficacy on MRI measures of disease progression (see Table 1).[11] As for the Phase II teriflunomide and laquinimod studies, reduction in ARR in the Phase II BG00012 study showed a positive trend, but did not reach statistical significance. Flushing was the most commonly reported AE, but rarely resulted in patients withdrawing from the study.[11] Flushing and gastrointestinal effects improved over the first few weeks of treatment and did not appear to be dose dependent. The two dosing regimens under investigation consist of two 120mg capsules taken two or three times daily. It is possible that patients may find a three-times-daily regimen difficult to adhere to over the long term.
Practical issues
In terms of day-to-day practice for hospital pharmacists, the potential addition of oral MS medications to the hospital formulary will bring many practical issues to consider, including:
- As the dosing regimens of these agents vary and are not all simple, the pharmacist will have a key role in ensuring appropriate dosage; tracking adherence and compliance; and counselling and advising patients who lose their tablets or miss one or more scheduled doses.
- Cladribine is classified as a cytotoxic drug, so tablet storage and disposal guidelines will need to be observed, and patients counselled appropriately regarding handling.
- Drug–drug interactions and adverse effects will be defined as these agents move through the clinical development process, and familiarisation with these will be vital for pharmacists. Risk management programmes will form an essential part of safety monitoring.
- Patients switching from one DMD to another may require a wash-out period.
- All these drugs will carry pregnancy warnings, and patients will need counselling to avoid pregnancies during and for a yet-to-be-defined period after treatment.
- The role of the hospital pharmacist will vary between European Union countries.
Conclusions
There is a clear need for new therapies for MS that offer improved efficacy and safety and that can offer alternative mechanisms of action to current DMDs. Additionally, they should be easy for healthcare professionals to administer and for patients to take.
The risk–benefit profiles of the five oral agents in late-stage development have yet to be defined, but will become clearer over the coming years as Phase III trial data are published. As yet, it is unknown whether these therapies, if approved, will be indicated for first- or second-line treatment, and much depends upon the long-term safety data. The role of combination therapy will also need to be determined. Funding and reimbursement issues will need to be navigated on a country-by-country basis as more data become available.
The concept of annual short-course therapy with cladribine tablets provides intriguing possibilities. Unlike the other oral agents in development, this treatment modality is based on a sustained reduction in T lymphocytes that extends far beyond the systemic availability of the drug. The impact of such a short course of treatment on adherence and on patients’ lifestyles in general is expected to be positive, but the sustained effect which appears to persist beyond drug clearance must be balanced against concerns relating to management of AEs or the need to switch to another DMD.
The arrival of oral therapies for MS has been long awaited by patients, but will also serve to galvanise the healthcare profession to reflect upon treatment approaches and goals, with a view to providing patients with early, individualised treatment.
Hospital pharmacists will have a key role in educating patients and fellow healthcare professionals in the correct dosing, administration and monitoring of oral therapies, and in influencing and helping to formulate MS treatment policies and procedures within their own institutions.
[[HPE51.45]]
Since the writing of this article, cladribine tablets therapy has been granted marketing authorisation for use in MS in Russia (July 2010).
Acknowledgements
Editorial assistance and writing support were provided by ACUMED (Tytherington, UK), funded by Merck Serono S.A., Geneva, Switzerland, an affiliation of Merck KGaA, Darmstadt, Germany.
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