It’s been a while since i wrote last post, but NeuroImmunology has been busy with several other projects. It’s been a while too since i decided to write a monographic post about the different oral treatments that are already available or are about to arrive but i postponed it until i had enough time to do it carefully. I will try to clarify the different pros and cons of the oral treatments in general and of each one in particular. It’s also an attempt to organize my ideas about the subject.

Until very recently the only disease-modifying treatments available for MS were injected therapies (I say disease-modifying because steroids are only used for relapses and do not modify the course of the disease in the long-term). Interferon and glatiramer acetate (subcutaneous or intramuscular), mitoxantrone (intravenous) and, more recently, natalizumab (intravenous) were the only available options for MS. In some countries people used intravenous immunoglobulins (IVIg), azathioprine (oral) and cyclophosphamide (oral or intravenous) but the evidence for their use in MS is very weak and they were not considered standard treatments for MS. Several major claims and complaints of patients with MS related to the treatment route of administration. Needles, need for portable fridges, problems in the airports and customs, an injection every two days, subcutaneous nodules, risk of infections… So, research on oral therapies was one of the main targets of researchers and companies and one of the things patients are more interested and askabout more often. And oral therapies finally arrived.

At this moment there is only one treatment fully available in Europe, fingolimod (Gilenya), four more laquinimod, BG-12 (dimethyl fumarate) teriflunomide and cladribine have completed phase III trials and another one, firategrast, is still on phase II trials but shows promising results.

The first and most obvious advantage of oral therapies is that they overcome the annoying need of injections. That adds one important thing, the adherence to treatment, that was far from optimal with injectable standard therapies (interferon and glatiramer acetate), will probably improve substantially. However, being less annoying does not mean that they are free of adverse events. Some patients tend to think that oral therapies are “less strong” than injected ones. In this case, specially with some of the above-mentioned treatments, is not true at all and that has to be taken in account when deciding which treatment use for each patient. It’s not the same having an aggressive MS than a “benign” one. Regarding adherence and tolerance one important thing is that some treatments, despite being oral, will have also immediate side effects: skin rashes, diarrhea, hair thinning or loss… that may not be important overall but can be for some patients. In some cases the balance of effectiveness/side effects might balance in favor of intravenous therapies. For example, the benefit of receiving natalizumab might outweight the need of visiting once a month the hospital if that prevents relapses, need for steroids, etc. The best thing of the new scenario is that the options increase significantly and so are the chances of finding the appropriate treatment for every patient in terms of both effectivenes and safety.

So, let’s start:

Fingolimod

Fingolimod is currently available in the US and Europe. We’ve wrote about it before. Is quite effective, clearly better than interferon and glatiramer acetate but, in my opinion, the safety profile, despite not being very bad, raises some concerns.

Profile: Fingolimod is a sphingosine-1 phosphate receptor (SP1R) inhibitor. SP1R function is necessary for lymphocytes to leave the lymph nodes. Fingolimod, then, exerts its function by preventing the egress of pathogenic lymphocytes from lymph nodes. In that way, autoreactive lymphocytes can not get into the central nervous system and attack the myelin. The standard treatment regimen is a 0.5mg pill daily.

Effectiveness: Annualized relapse rate showed a 50% reduction in comparison to placebo and a 40% when compared to interferon beta 1a (intramuscular). Despite that benefit in relapse rate, disability progression only showed a modest reduction with fingolimod when compared to placebo and there was no difference compared to interferon.

Safety: As a consequence of lymphocyte sequestration in the lymph node, there’s an important peripheral lymphopenia. Risk of severe infections is higher in fingolimod (as it is with all immunosuppressive drugs). In the pase 3 trials there were 2 deaths that could be related to the treatment. One was an herpes simplex encephalitis and the other one a varicella-zoster systemic infection. Both deaths occurred with the higher doses (1.25 mg), but none with the dose that has been approved (0.5 mg) and now, varicella serologies are routinely performed before starting treatment. Other important side effects to take in account are cardiovascular events. Fingolimod can cause bradycardia, so the first dose has to be administered monitored in the hospital. It’s not recommended to use fingolimod in patients with known cardiopathies or arrythmias or under treatment with drugs that can cause bradycardia (such as beta-blockers or calcium antagonists). One post-commercialization death is probably related with this side effect of the drug. Other side effects that can be concerning but that are carefully monitored are skin neoplasms (basal-cell carcinomas) and macular edema (which was also more frequent in the higher doses and not with the approved dose).

Conclusion: Fingolimod is a powerful oral therapy but the safety issues can make it less desirable than some other oral treatments that are to come. If MS is very aggressive patients and doctors will tend to prescribe monoclonal therapies with a better efficacy (natalizumab, rituximab/ocrelizumab, alemtuzumab…). And for patients with a milder MS the safety issues can be an important pitfall.

Cladribine

Phase III trial testing cladribine in multiple sclerosis were published in the New England Journal of Medicine the same day that fingolimod results were reported. Despite a similar effectiveness compared to fingolimod, the increased frequency of neoplasms, severe infections and deaths compared to placebo, led to negative reports of FDA and EMEA and was not approved.

Profile: Cladribine is a chemotherapeutic drug that is used in a rare leukemia. It’s a purine analog, so it interferes in DNA synthesis. Usually cells can metabolize it easily, but not blood cells, so it acts as a cytotoxic drug in those cells. The treatment regimen consists of 4 doses monthly (aproximately) for 4 months and two more doses at weeks 48 and 52.

Effectiveness: Very similar to fingolimod. A decrease of 50% in annualized relapse rate and a slight decrease in the rate of disability progression compared to placebo.

Safety: There were 4 deaths in the cladribine group and two in the placebo group, although none of them seem to be related to the treatment. However, the rate of infections and, more importantly, the rate of neoplasms of any kind was higher among cladribine-treated patients. These facts, added to the duration of the effect (lasts for months), that prevents a quick withdrawal if any serious adverse reaction appears, were determinant in its rejection as a standard therapy in MS.

Teriflunomide

Two phase III trials have been developed to test teriflunomide in MS. The TEMSO trial, comparing it with placebo, resulted positive, with a good safety profile. However, when comparing teriflunomide with interferon, despite a better safety and tolerance with teriflunomide, there was no difference in effectiveness. Nevertheless applications for approval have been filed and awaiting decision. Teriflunomide is administered once daily.

Profile: Teriflunomide is the active metabolite of leflunomide, a drug used since the late nineties in rheumatoid arthritis. It acts halting the division of rapidly growing cells, including inflammatory cells.

Effectiveness: The effectiveness of teriflunomide is a step lower than fingolimod and cladribine. It decreases the relapse rate approximately a 30% and the disability progression between a 21% and a 29% depending on the dose. Those results, that are in the range of interferon effectiveness, are dissapointing when compared with other treatments such as fingolimod or natalizumab.

Safety: The main advantage of teriflunomide compared to currently available treatments is the safety and tolerability profile. With an important add-on: it has been used (leflunomide) in rheumatoid arthritis and the experience is huge (around 2 million patients-year exposed). In the trials there were no deaths and the rate of serious adverse events was similar to that of placebo. Diarrhea and hair thinning or loss were the only adverse events that were more frequent in teriflunomide than in placebo. However those adverse events did not lead to discontinuation. In rheumatoid arthritis patients leflunomide caused two progressive multifocal leukoencepaholopathies  (but the rate is extremely low).

Laquinimod

Laquinimod, as teriflunomide, is also a step below fingolimod and cladribine. However, again, its safety profile makes it appropriate for patients with low disease activity with a good risk-benefit balance. It has a surprisingly good performance on disability considering the por results in relapse rate reduction. Results of the ALLEGRO phase III trial were recently reported in the New England Journal of Medicine. It’s administered once daily.

Profile: Laquinimod is a quinoline derivative that acts reducing inflammatory infiltrates in the central nervous system and decreasing demyelination and axonal loss.

Effectiveness: Despite a very modest decrease (23%) in relapse rates compared to placebo, surprisingly disability progression was almost a 30% lower than for placebo. Usually the performance on relapses (related to inflammatory attacks) is much better than on disability (related to stablished neuronal loss). This is not the case, what has led to several studies to assess the “neuroprotective effect” of laquinimod. So, despite a dissapointing effect on relapses, the overall effectiveness in disability is similar to that of interferon, fingolimod and other “more powerful” drugs.

Safety: As in teriflunomide, no deaths occurred with laquinimod and the rate of severe adverse events was similar to placebo. Among the frequent adverse events, abdominal and back pain were significantly higher in the laqinimod group. However, overall tolerance was good.

Dimethyl Fumarate (or BG-12)

Phase III trials with fumarate have not been published yet but the results from the DEFINE trial have been reported in the last ECTRIMS meeting. It yields a very good effectiveness (in the range of fingolimod) with an also good safety profile. It’s curently under review by FDA and EMEA. The only important disadvantage is that it needs to be taken twice or three times a day, influencing adherence and, then, effectiveness.

Profile: BG-12 is a immunomodulatory drug that has been tested in psoriasis. Its mechanism of action is not understood but it decreases the levels of some inflammatory cells and cytokines in animal models. It has been suggested that it acts in both, inflammatory lessions and preventing axonal/neuronal loss. It’s administered daily, twice or thrice.

Effectiveness: The annualized relapse rate and the risk of relapse is around 50% lower compared to placebo. It also decreased disability progression by 38%.

Safety: No deaths, serious adverse events, infections or neoplasms were reported. The most frequent adverse events in the fumarate group were flushing and gastrointestinal symptoms, which were higher the first month of treatment and then decreased.

Firategrast

Firategrast has been studied only in a phase II trial. However, the good results of that trial and the features of the molecule make it an interesting treatment that deserves attention.

Profile: Firategrast is a small molecule that inhibits the alpha4 intergins. This is the same molecular target of natalizumab, but natalizumab is a monoclonal antibody, with a half-life of 11-12 days, while firategrast half-life is around 4 hours. This is important if a serious adverse event appears because it allows a faster reaction to prevent further progression of the adverse event. It’s administered twice a day.

Effectiveness: Phase II trials usually are not powered to detect differences in clinical parameters and so, no significant differences were detected when compared to placebo. It decreased significantly the rate of gadolinium-enhancing lessions (meaning the rate of new inflammatory lessions in the MRI) by 50% (in the high dose group). A trend towards lower relapse rates in the firategrast group was found but those differences were not statistically significant.

Safety: Firategrast was well tolerated and no significant adverse events were reported comparing with placebo.

So, in summary, a handful of new oral therapies (and another handful of parenteral therapies) is about to come. With the important advantage of improving the tolerability of the treatments, keeping, in the worst case, the effectiveness of the traditional therapies. Moreover, the appearence of this variety will improve the individualization of care. Patients with low disease activity could benefit from teriflunomide or laquinimod, patients with higher activity could use fingolimod or BG-12…patients not tolerating or responding to one of them can switch to another one or to one of the old treatments…. and combination therapies can be used to increase the options when suboptimal responses are achieved. And that’s only for the oral therapies… if we add the highly effective alemtuzumab, natalizumab, rituximab, ocrelizumab… the therapy of MS is experiencing an exponential progress that benefits first and most importantly MS patients, except those with progressive forms. Hope the research efforts on progressive forms can lead soon to a similar variety in therapies for them too.

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