Thursday, January 21, 2010

NEJM publishes studies for two Oral MS drugs.

Yesterday, the New England Journal of Medicine published results from three clinical trials testing oral medications for the treatment of MS. One for Cladribine, one for Fingolimod, and one for Fingolimod vs. Avonex. Scroll down this post to find an editorial which was published concurrently with these findings.

Directly below, please find an article written by the BMJ Group (British Medical Journal) and published at The Guardian which clearly points out the basic information regarding these findings.

Two new drugs for multiple sclerosis that can be taken as tablets rather than injected have been shown to reduce flare-ups of this nervous system disease. One type worked better than the current standard treatment, injections of beta interferon. But the drugs have potentially serious side effects. What do we know already?

If you have multiple sclerosis (MS), the nerves in your brain and spinal cord slowly lose their coating. Over time, these nerves get damaged and may stop working properly. This can affect you in all sorts of ways. The most common symptoms are feeling very tired and weak and having numb or 'tingling' areas.

The most common type of MS is called 'relapsing remitting multiple sclerosis'. This means you have periods without any symptoms, then periods when you get a flare-up of symptoms, called a relapse. The condition is caused by a problem with the immune system, which mistakenly attacks the coating of the nerves. So, most treatments work to change the way your immune system works.

The treatment used most often is called beta interferon. It has to be injected. It's intended to reduce the number of relapses you have, and prevent you from becoming disabled. But it doesn't work for everyone. In studies, around 55 in 100 people still had a relapse over the course of two years, despite taking beta interferon. Another injected treatment, glatiramer acetate, works about as well as beta interferon.

Doctors have been investigating new drugs for MS that can be taken as tablets, instead of injected. We now have results from three big trials (each with over 1000 patients) looking at how well they work. The new drugs studied are called fingolimod and cladribine.

What do the new studies say?

The studies show that these new drugs work better than no treatment, and one of them works better than beta interferon.

Three studies have been published. They compare:

  • Fingolimod with a dummy (placebo) drug, over two years. Between 70 and 75 in 100 people taking fingolimod didn't have a relapse during the study, compared with only 46 in 100 taking the placebo drug.
  • Fingolimod with beta interferon, over one year. Between 80 and 83 in 100 people taking fingolimod didn't have a relapse, compared with 70 in 100 people taking beta interferon.
  • Cladribine with a placebo drug, over almost two years. About 80 in 100 people taking cladribine didn't have a relapse, compared with 61 in 100 people taking the placebo.

Both drugs were tested at two different doses. Higher doses worked slightly better for fingolimod, but there wasn't much difference between high and low doses of cladribine. People were more likely to get unwanted side effects with higher doses.

The side effects were serious in some cases. Two people taking fingolimod died after catching serious herpes virus infections. Four people had breast cancer, and five had a type of skin cancer. People taking cladribine were also more likely to have serious infections or cancers than people taking placebo pills. Overall, serious problems affected 8 to 9 percent of people taking cladribine and about 5 to 10 percent of people taking fingolimod.

People taking drugs that affect the immune system are at higher risk of infections and cancers, because their immune system is weakened by the drugs. Both these drugs reduce the amount of white blood cells (lymphocytes), which protect against infection.

How reliable are the findings?

The findings from these studies should be reliable. They were carried out as randomised controlled trials, which is the best way to find out whether a treatment works. It's important not to compare the results between trials, though (for example, to compare fingolimod with cladribine), because different groups of patients can have different results. We can see this in the difference in numbers of patients having relapses between the two studies that included a placebo drug.

Also, it's important to remember that these studies lasted only one or two years. We need to see long-term results, especially to find out whether they are safe to take for longer than two years.

Where do the studies come from?

Both drugs have been tested by international groups of researchers and doctors, some of whom worked directly for the drugs companies that make the drugs (Novartis Pharma for fingolimod and Merck Serono for cladribine). It's common for drugs companies to fund research into their own drugs, especially while they are under development. The studies were published in the New England Journal of Medicine.

What does this mean for me?

If you have multiple sclerosis, you'll be keen to hear about any new treatments that might help your condition. But these drugs have not yet been licensed and so will not be widely available yet. If and when they are licensed, they may be more suitable for some people than others. You'll need to weigh up the risks of getting serious side effects, with the potential benefits of fewer relapses.

What should I do now?

If you are interested in finding out about research into new MS drugs, speak to your specialist or to the Multiple Sclerosis Society (


Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. New England Journal of Medicine. Published online 20 January 2010.

Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine. Published online 20 January 2010.

Kappos L, Radue E-W, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine. Published online 20 January 2010.

To find out more about treatments for MS, see our information on multiple sclerosis.

© BMJ Publishing Group Limited ("BMJ Group") 2010

The New England Journal of Medicine Editorial

Oral Therapy for Multiple Sclerosis — Sea Change or Incremental Step?
William M. Carroll, M.B., B.S., M.D., F.R.A.C.P.

The long-awaited arrival of oral formulations for the treatment of relapsing–remitting multiple sclerosis is welcome news for the estimated 2.5 million people worldwide who have this chronic, disabling disease. Since the publication of the first pivotal trial of interferon beta-1b in 1993, practitioners and patients alike have been anticipating the approval of oral therapies because of the relative ease of administration, which should improve adherence and reduce restrictions on lifestyle.

In this issue of the Journal, researchers report the results of three well-conducted trials of the first two oral agents, cladribine and fingolimod, in the treatment of multiple sclerosis. The researchers studied cladribine in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial and fingolimod in the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trial and the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS). Although these two drugs differ in their mechanisms of action, both reduce the number of potentially autoaggressive lymphocytes that are available to enter the central nervous system. The articles, which report that the agents are effective and have manageable adverse- effect profiles, raise three questions: How do these therapies measure up against the existing treatments? Are all the longer-term adverse effects known? What do these drug trials tell us about multiple sclerosis and our treatment goals?

Both cladribine (in the CLARITY trial) and fingolimod (in the FREEDOMS trial) were highly effective against placebo over a 2-year period, and fingolimod was more effective than intramuscular interferon beta-1a over a 12-month period (in the TRANSFORMS trial). Each of the three studies involved more than 130 centers in up to 32 countries, and the enrollments of 1272 to 1326 patients ensured that the trials were sufficiently powered to detect an effect of two doses of the active oral agent. Patients had active relapsing disease with durations of 7 to 9 years. On the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), patients had a median score of 2.0 in the fingolimod trials and mean scores ranging from 2.9 to 3.0 in the cladribine trial.

All three studies used the annualized rate of relapse as the primary end point, and high and low doses of cladribine and fingolimod were shown to be superior to both placebo and interferon beta-1a. For cladribine versus placebo, the relative risk reduction in the annualized relapse rate was 57.6% for the group receiving 3.5 mg per kilogram of body weight and 54.5% for those receiving 5.25 mg per kilogram. For fingolimod versus placebo, the relative risk reduction was 54% for the 0.5-mg dose and 60% for the 1.25-mg dose. For fingolimod versus interferon beta-1a, the relative risk reduction was 52% for the 0.5-mg dose and 39% for the 1.25-mg dose. Both agents were superior to the comparators with respect to secondary end points, including measures on magnetic resonance imaging and a number of clinical end points, including the time to the progression of sustained disability at 3 months.

Furthermore, although only fingolimod was tested against the widely used interferon beta-1a, it is likely that the two oral therapies will be at least as effective as other currently available disease- modifying therapies. In this regard, head-to-head trials of subcutaneous interferon beta-1b and interferon beta-1a versus intramuscular interferon beta-1a showed advantages of both subcutaneous regimens over the latter. More recent trials were unable to separate the clinical efficacy of the two subcutaneously administered forms of interferon beta from that of glatiramer acetate.

Adverse effects were similar in all three trials of cladribine and fingolimod, and rates of events leading to discontinuation of a study drug were low but still at least twice as frequent with highdose cladribine (7.9% for the 5.25-mg dose) and fingolimod (10% and 14% for the 1.25-mg dose). Herpetic infections occurred among patients receiving both cladribine and fingolimod. The rate of herpes infections among patients receiving the 1.25-mg dose of fingolimod was 5.5%; such infections were serious in three of these patients, two of whom died. Twenty cases of cutaneous herpes zoster were recorded among patients receiving cladribine, three of which were serious. Three solid tissue cancers (pancreatic, ovarian, and melanoma) occurred among patients receiving lowdose cladribine (3.5 mg per kilogram). Basal-cell carcinoma, melanoma, and breast cancer were all more common among patients receiving fingolimod than among those receiving interferon beta-1a. Macular edema was confirmed in 13 patients, 11 of whom received high-dose fingolimod (7 in the FREEDOMS trial and 4 in the TRANSFORMS trial). Of these 13 patients, 11 recovered within 1 to 6 months after discontinuation of therapy, and the condition of the other 2 patients stabilized. Transient bradycardia and first- and second-degree heart block occurred more frequently among patients receiving high-dose fingolimod than in the comparator groups. Lymphocytopenia was frequent in patients receiving both agents, more so with higher doses. Clinicians and patients will need to evaluate the risks and benefits of each of these drugs. Given the recent studies documenting the development of progressive multifocal leukoencephalopathy among patients receiving natalizumab, a monoclonal antibody against α4-integrin, close postmarketing surveillance will be important to detect any increase in these or other unexpected adverse effects.

The mechanism of action of both oral agents represents a major change from those of currently available drugs for multiple sclerosis. Among a number of actions that are claimed for current therapies is that they change the emphasis of the immune response from activation of proinflammatory type 1 helper T cells to activation of antiinflammatory type 2 helper T cells. Even though cladribine is administered in two or four short courses annually, whereas fingolimod is given daily, both drugs were associated with persistent lymphocytopenia. Cladribine is resistant to the enzyme adenosine deaminase, which causes an accumulation of toxic deoxyribonucleotides in lymphocytes, resulting in relatively selective longterm depletion of CD4+ and CD8+ T cells. Fingolimod is a synthetic analogue of myriocin that is derived from a fungus (Isaria sinclairii). Once phosphorylated, the drug acts to down-regulate the sphingosine-1-phosphate receptor required for antigen-activated lymphocytes to egress, effectively locking them in the nodes. Thus, both cladribine and fingolimod are targeting inflammation, the key driver of immune injury in multiple sclerosis. Similarly, both natalizumab, which blocks lymphocyte access to endothelium in the central nervous system, and the anti-CD52 monoclonal antibody alemtuzumab, which destroys T and B cells, have shown impressive reductions in disease activity. Insights from these trials and others treating the initial stages of disease suggest that early direct targeting of the immune system offers the best hope for the prevention of later disability.

The studies in this issue of the Journal provide a new horizon for patients with relapsing–remitting multiple sclerosis and a welcome increase in the range of treatment options. Although current therapies remain very effective, particularly when they are administered early, and have welldefined side-effect profiles, oral therapies further support a change in treatment approach to directly prevent immune-mediated injury. This approach will probably be followed until the next step in the therapeutic advance occurs, but such a change in strategy highlights the final question: What are the long-term goals of this new phase of therapy?
The question will not be fully answered until the underlying cause of multiple sclerosis is better understood, but the lack of a definable end point remains a contentious issue for clinicians and health care funders alike. Time will determine the long-term effectiveness of these treatments in delaying the development of irreversible disability, and as ongoing, real-life experiments, they will contribute to our understanding of this enigmatic disease.

Copyright © 2010 Massachusetts Medical Society. All rights reserved.

No comments:

Post a Comment