The risks of new oral medications for the treatment of multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that usually affects young people with a peak in incidence between 20 and 40 years of age and whose manifestations are focal and diffuse damage from its onset; symptoms vary according to the affected area of the central nervous system. Approximately 85% of patients with multiple sclerosis are affected by the relapsing-remitting type, with an initial course characterized by a continual of relapses followed by remissions and whose recovery can be complete or partial; around 50% of cases evolves within 10 or 20 years to secondary progressive multiple sclerosis, characterized by slowly progressive disability.

New and old drugs

The first medications commercialised for the treatment of multiple sclerosis were interferon beta 1a and 1b, glatiramer acetate and mitoxantrone, substances with different mechanism of action but all aimed at preventing relapses or at least shortening their course (the so-called disease-modifying agents, DMAs). More recently natalizumab (2006) and fingolimod (2011, the first oral medication) have become available; both are to be considered only for patients who did not respond or were intolerant to standard first line treatments (interferon and glatiramer). In fact, although the more recent drugs show better evidences of effectiveness, their safety profile are rather critical (mostly because of cardiovascular toxicity, risk of lethal viral infections, risk of mammary, ovary and thyroid cancer associated to fingolimod and possible onset of progressive multifocal leukoencephalopathy associated to natalizumab). In August 2013, EMA approved teriflunomide as first line therapy for relapsing-remitting multiple sclerosis, an analog of leflunomide that has been used for more than 10 years for the treatment of rheumatoid arthritis. Teriflunomide is an oral drug whose mechanism of action, although not entirely known, is supposed to act by reducing the proliferation and functionality of activated T and B lymphocytes.
In January 2014 EMA approved with the same indications dimethyl fumarate, another oral medication. The drug, used since many years for the treatment of psoriasis, is believed to activate the Nrf2 protein (nuclear factor erythroid 2-related factor 2) that activates different genes genies involved in anti-inflammatory, antioxidant and neuroprotective effects.
Despite the high expectations for these new and more effective drugs, more easily administered (as they are oral instead of injected medications) and without the typical interferon side effects (such as injection-site reactions and flu-like symptoms), teriflunomide and dimethyl fumarate showed since their pivotal trial problematic risk/benefit profiles. For this reason their use is recommended only for selected cases of patients who showed intolerance or no results with first line therapies (glatiramer, interferon) that still hold the most long-term evidences of safety and effectiveness.

Data on teriflunomide

Clinical trials on teriflunomide showed cases of increased empathic liver enzymes, neutropenia, trigeminal neuralgia, diarrhoea, alopecia, nausea and creatine kinase increase. In the light of the sometimes lethal hepatotoxicity known to be associated to leflunomide, the FDA decided to add a warning in the product information sheet to inform patients about the possible onset of hepatotoxicity with teriflunomide treatement treatment.¹
The use of teriflunomide is besides particularly critical in women in reproductive age, since animal studies have shown reproductive toxicity, embryolethality intrauterine death and teratogenicity in rats and rabbits for doses correspondent to those used in humans. For this reason, the drug data sheet contraindicates its use in pregnancy and in women in reproductive age who do not adopt a reliable contraceptive method during the treatment and after it, until the drug blood level remains higher than 0.02 mg/l, values usually reached 8 months after the end of the treatment. In order to reach the recommended concentration more quickly, a procedure for accelerated elimination by cholestyramine or activated charcoal administration can be carried out.
In 2014 a study showed the outcomes of pregnancies where either the woman (83 cases) or her partner (22 cases) had been exposed to teriflunomide during pivotal trials. Since all the children were born healthy and the percentage of spontaneous abortion (18.6% of cases) was in line with the expected physiological one, the authors concluded that there is no risk of teratogenicity associated to teriflunomide. However these are preliminary data, which should be taken with caution as for the limited number of cases and also because the majority of women underwent the procedure of accelerated elimination as soon as they knew about the pregnancy.² Surely the information collected by the drug registers activated in different countries will be able to provide useful data in order to better characterise the risk of teratogenicity associated to teriflunomide, which is very important as the drug is mostly directed to women in reproductive age.³ The principal independent bulletins clearly evaluate teriflunomide negatively, in particular for the absence of direct comparisons with other drugs that for the moment prevent to ascertain its role in the therapy in respect to the current consolidated standard treatments.⁴

Data on dimethyl fumarate

The most common adverse reactions reported in the clinical trials on dimethyl fumarate, especially in the first month of therapy, were blush and gastrointestinal disorders (diarrhoea, nausea, abdominal pain). Renal, hepatic and haematologic toxicity - with onset of leukopenia - were also reported. This last adverse reaction is the most worrying one in the light of the first case of progressive multifocal leukopenia developed by a patient enrolled in the clinical trial ENDORSE as communicated by AIFA in an important informative note published in December 2014. The subject had been under dimethyl fumarate therapy for 4 years, he had never been treated with natalizumab and the adverse reaction arose after 3 years of severe and prolonged lymphocytopenia, a predisposing factor for the onset of progressive multifocal leukopenia.

In the future

Over the next years new drugs for the treatment of relapsing-remitting multiple sclerosis will be commercialised, among whom there are many monoclonal antibodies (daclizubam, ofatumumab, ocrelizumab etcetera). Despite the remarkable progress of the last years, with the commercialisation of disease modifying agents able to positively affect the quality of life for patients with multiple sclerosis, a therapy able to cure the disease has not yet been found. Teriflunomide and dimethyl fumarate showed to be effective but, as their predecessors, show a peculiar risk profile that needs to be accurately evaluated on the basis of the characteristic of the single patient, but also of his expectations, when prescribing this medication.