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The treatment for multiple sclerosis: emerging oral drugs


Oral treatment may not replace all injectable therapies for multiple sclerosis (MS) but they will provide both the patient and physician an alternative and more user-friendly choice to treat and combat MS.

Claudio Gasperini
Department of Neurosciences
S Camillo Forlanini Hospital

Department of Neurological Sciences
University of Rome “La Sapienza”

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the Central Nervous System (CNS). Disease onset usually occurs in young adults, and it is more common in females. The incidence of the disease varies worldwide, with a prevalence that ranges between 2 and 150 per 100,000 depending on the country or specific population. The disease course varies among patients: most patients present initially with relapsing-remitting (RR) MS, in which partial or complete recovery from neurological function occurs during periods of remission. However a large proportion of patients subsequently develop secondary progressive (SP) MS, in which disability continues to cumulate irrespective of relapse activity.[1]

The immunopathogenesis of MS is complex, heterogeneous and still unclear. Many different immune cells are involved in the pathogenesis of MS, including T cells, B cells and macrophages. In patients with MS, myelin reactive T cells are activated in the periphery by binding to a still unknown antigen and major histocompatibility complex class II molecule on the surface of an antigen-presenting cell. Autoreactive T cells are reactivated within the CNS if they find the appropriate milieu and perceive requisite co-stimulatory signals to initiate a pro-inflammatory immune cascade. This results in a damage of myelin sheaths and injures underlying axons. The accumulation of axonal damage leads to permanent loss of neurological function.[2]

The past 17 years have witnessed the introduction of several therapies for MS. These therapies are thought to work at different levels of the disease, typically consisting of direct symptom management, brief corticosteroid administration for acute exacerbation and the regular use of disease modifying drugs (DMDs). Currently approved immumomodulator treatments for RRMS include glatiramer acetate (GA) and recombinant interferons (IFNß) (IFNß-1a Avonex, IFNß-1a Rebif, IFNß-1b Betaseron) that represent the gold standard in modifying the course of MS. Natalizumab (Tysabri) and Mitoxantrone (Novantrone) are also available for treatment of MS as second line therapy. Natalizumab is used in RRMS patients unresponsive to immunomodulatory treatment or in severe relapsing-remitting forms of the disease. Mitoxantrone is also approved for treatment of relapsing MS, but is generally reserved for secondary progressive and severe relapsing-remitting forms of disease. Nevertheless, in clinical practice DMDs or immunosuppressive treatments are frequently associated with suboptimal response in terms of efficacy and several side-effects leading to poor patient adherence, so the proportion of RRMS patients not adequately responding to disease-modifying therapy has been reported to range from 7 to 49%, depending on the criteria used.[3]

Since MS is a chronic disease DMDs for MS require long term, regular injection or monthly parenteral infusions, which may be uncomfortable and inconvenient for the patient. Thus there is an important need for new therapeutic strategies, especially those that may offer greater patient satisfaction in order to optimise therapeutic outcomes. A number of potential therapies for MS are now in late-stage development. To improve patient compliance with treatment and reduce lack of adherence, most of these are oral compounds and include: fumaric acid (BG12), teriflunomide (A77126 or HMR1726), laquinimod (ABR-215062), cladribine and fingolimod (FTY720).

Final results for three large randomised studies, one regarding cladribine tablets and two about fingolimod, have been recently published. On the strength of these findings cladribine and fingolimod could become the two first orally administered DMDs for patients with RRMS.


Cladribine, a synthetic deoxyadenosine analogue, is an oral immunosuppressive agent that produces targeted, sustained reduction of T and B lymphocytes. Cladribine is already approved for the treatment of leukemias and lymphomas. Short-course therapy with cladribine tablets was investigated for RRMS in the CLARITY study (CLAdRIbine Tablets treating multiple sclerosis orallY). CLARITY was a Phase III, randomised, double-blind, placebo-controlled, multicentre, 96-week study with three parallel groups to assess the efficacy of cladribine tablets in patient with RRMS according to the McDonald’s criteria. The cladribine tablets dosing regimen consisted of two or four short courses per year (cumulative dose of 3.5 and 5.35mg/kg over the 96-week study, respectively). Treatment with 3.5 and 5.25mg/kg cladribine tablets significantly reduced the annualised relapse rate (relative reduction 57.6% and 54.5% vs. placebo, respectively, both p<0.001) and resulted in significantly more relapse-free patients (79.7% and 78.9% vs. 60.9%, respectively; odds ratios: 2.53 and 2.43, both p<0.001).Three measures were detected on MRI activity:T1 gadolinium-enhancing lesions, active T2 lesions and combined unique lesions (all p<0.001 vs. placebo). Lymphopenia occurred more frequently in patients treated with cladribine tablets at both dosages than with placebo. Despite the lymphopenia, the overall incidence of infections was similar across treatment groups. There were no cases of herpes zoster in the placebo group compared with 8 cases and 12 cases of herpes zoster in the 3.5mg/kg group and 5.35mg/kg group respectively. However, all cases were dermatomal and self-limiting. Neoplasms occurred in 10 cases, all of them in cladribine-treated patients at both doses, compared with no patients in the placebo group. On the basis of the small number of neoplasms developed in different solid organs after relatively short intervals from treatment to diagnosis, it is not possible to establish a risk due to the use of cladribine tablets. One patient treated with cladribine tablets had reactivation of latent tuberculosis and died. The use of cladribine may have contributed to this reactivation, and tuberculosis screening measures were immediately introduced subsequently in on-going trials.[5]

Fingolimod is a structural analogue of sphingosine that interferes with cell traffic between organs and blood. The FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) was a Phase III, 24-month, double-blind, randomised, placebo controlled study to detect the efficacy of fingolimod in patients with RRMS, in term of relapse rate, time to disability progression and MRI activity. Patients were randomly assigned, in a 1:1:1 ratio, to receive oral fingolimod capsules in a dose of 0.5mg or 1.25mg or matching placebo, once daily for 24 months. All clinical (table 2) and MRI-related efficacy end points significantly favoured both doses of fingolimod over placebo, and there were no significant differences in efficacy between the two fingolimod doses.

On MRI measures, both doses of fingolimod were superior to placebo for outcomes, including new or enlarged lesions on T2-weighted images, gadolinium-enhancing lesions, and brain volume loss, with a p<0.001 for all comparisons.[6]

In a 12-month, PHASE III, multicentre, randomised, double-blind, double-dummy, parallel group study, called The Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS), they compared the efficacy and safety of fingolimod with that of intramuscular interferon beta-1a. Patients were randomised to receive oral fingolimod, in the same doses of 0.5mg/day or 1.25mg/day, or interferon beta-1a (Avonex, Biogen Idec), 30µg given intramuscularly once a week. There was a significantly greater reduction in the annualised relapse rates in both fingolimod groups than in the interferon group (see Table 3). Patients in the two fingolimod groups had significantly fewer new or enlarged hyperintense lesions on T2-weighted images and gadolinium-enhancing lesions on T1-weighted images at 12 months than did those in the interferon group (p<0.001).[7]


The adverse event observed with fingolimod was similar for both studies. The overall incidence of infections was similar across the treatment and placebo groups respectively, and it was the same between the fingolimod group and interferon ß-1a in the TRANSFORM study. There was a transient, dose-dependent reduction in the heart rate that developed within 1 hour after the initial administration of fingolimod, which is consistent with the findings in previous clinical trials. Key safety observations included transient bradyarrhythmias, macular edema, infections and possibly cancers. In the TRANSFORM study herpesvirus infections were most common in the 1.25mg group and were fatal in two patients, both in the group receiving fingolimod, 1.25mg/daily: one patient with disseminated primary varicella zoster and the other with herpes simplex encephalitis. On the contrary in the FREEDOM study herpesvirus infection was reported in similar proportions of patients across the three study groups. The actual data from these studies do not suggest an increased risk of cancer with the use of fingolimod. However, further long-term observation is necessary, since the risk of cancer is potentially increased by the use of any immunomodulatory agent.[6-7]

Maintaining adherence to DMDs is a daily challenge to those who manage and coordinate care for MS patients. It has been widely reported that patients who have more positive feelings towards prescribed therapy adhere more closely to their therapeutic regimen.[8] The development of drugs with easier administration, such as oral agents like fingolimod and cladribine, would further promote adherence and could increase the number of patients with MS in treatment, reducing discomfort and inconvenience, making it easier for patients to adhere to their treatment regimen and thus improving efficacy. The most challenging aspect for physicians will be making their patients understand the need of balancing for each case, pro and cons of new oral treatment, where serious side-effects may outweigh benefits in certain individuals. With currently available agents, the main complaints are injection-site reactions and flu-like symptoms, compared with the higher stakes with fingolimod and cladribine, those side-effects seem to be more acceptable. Safety is likely to become the most important factor in future clinical practice while prescribing MS drugs, certainly more research is also needed to compare escalation, different treatment combinations and induction treatment strategies. These oral therapies may not replace definitely all injectable therapy, but they’ll provide patient and physician with an alternative and more user-friendly choice to treat and combat MS.

1. Weinshenker BG. Neurol Clin 1995;13:119-146.
2. Lassmann et al. Brain Pathol 2007;17:210-218.
3. Rio J, Nos C et al. Ann Neurol 59,344-352 (2006).
4. Kottil W. Rammohan et al. Neurol 2010 5;74 Suppl 1:S47-53.
5. Giovannoni G, Cook S, et al. N Engl J Med 2010 4;362(5):416-26.
6. Kappos L et al. N Engl J Med 2010;362(5):387-401.
7. Cohen JA et al. N Engl J Med 2010;362(5):387-40.
8. Fallowfield L et al. Ann Oncol 2006;17:205-210.

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