At a special satellite symposium at ECTRIMS 2011, attendees heard how the first oral agent approved for relapsing forms of multiple sclerosis represents a new era in the disease’s management
One of the most popular sessions at the recent 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) was a satellite symposium on the first of the new oral compounds in multiple sclerosis (MS): fingolimod (Gilenya).
Opening the symposium, Professor Frederik Barkhof, Professor in Neuroradiology at Vrije University Medical Centre, Amsterdam, said neurologists and MS patients are finally beginning to reap the benefits of an improved understanding of the disease’s pathology.
“These are exciting times in multiple sclerosis,” said Prof Barkhof. “Many novel agents are emerging and it is important that we understand how these new mechanisms translate into clinical profiles. Critically, as we embrace this new treatment landscape, sharing clinical experiences will ensure the potential benefits of new drugs are realised in our patients.”
Fingolimod leads a novel class of therapeutic compounds, the sphingosine 1-phosphate receptor (S1PR) modulators, and is the first oral agent to gain approval in the EU for the treatment of highly active relapsing-remitting MS (RRMS) in patients with high disease activity despite treatment with a beta-interferon or patients with rapidly evolving severe RRMS.
“By acting on S1PRs located on the surface of lymphocytes, fingolimod causes reversible and selective retention of circulating autoreactive lymphocytes in the lymph nodes, reducing their infiltration into the central nervous system (CNS),” Prof Barkhof explained. “However, there is growing preclinical evidence to suggest that fingolimod may also interact with S1PRs on neural cells.”
The fingolimod clinical trial programme demonstrated improvements in clinical, MRI and brain atrophy endpoints compared with placebo and the standard of care interferon beta-1a, he continued.
In addition, with more than 20,000 patient years’ of exposure to date, the safety profile of fingolimod in clinical trials has been well studied.
“There are a number of approved injectables on the market, most of which target the immune system,” Prof Barkhof said. “But most current disease-modifying therapies (DMTs) for MS primarily target the immunological inflammatory component of the disease without acting directly on the CNS. Beyond the injectables, there are oral agents being developed, most of which have an effect on both the systemic compartment within the immune system and within the CNS.
“Fingolimod is one that acts on the immune system, very specifically, and also, as we will see later, potentially in the CNS.”
Describing the importance of MRI in MS management, Prof Barkhof said it is vital when determining disease activity.
“MRI is especially important when it comes to brain atrophy, providing an objective and sensitive measure of MS pathology; it is a window into the brain and a measure of tissue integrity. Atrophy measurement is probably the best measurement of long-term clinical outcome,” said the professor.
“When it comes to deciding treatment for our patients, there are two main dimensions: Efficacy and burden. With efficacy we’re looking at clinical outcomes, MRI disease activity, and so on; and with burden we need to know how much the patient is willing to accept in terms of side effects, and how ready the patient is to take any potential risks and weigh them against treatment benefit. We basically want to maximise efficacy while minimising the burden.”
A targeted MS treatment: The importance of the central nervous system
Dr Amit Bar-Or, Associate Professor of Neurology and Associate in Microbiology and Immunology at McGill University, Canada, next focused on the mechanism of action of fingolimod, and explained how this impacts on its efficacy.
“As we have heard, fingolimod is the first in a new class of immunomodulatory drugs called S1P-receptor modulators,” said Dr Bar-Or.
He explained that fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring S1P, an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors.
“There are at least five S1P receptor subtypes, known as S1P1–5, four of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS,” he continued.
“S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding, yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the CNS. S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology and migration. Fingolimod crosses the blood–brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies,” he said.
So what does this all mean for clinical practice?
“Fingolimod has an early and sustained effect on the rate of brain atrophy. We have identified, with fingolimod, a rapid and reversible non-cytotoxic effect on retaining cells that are functioning in the lymphatic tissue,” said Dr Bar-Or. “Within one to two-and-a-half months off the drug we see a recovery back to normal lymphocyte levels.”
This early and sustained effect of fingolimod on the rate of brain atrophy may reflect a combination of its biological impact on the immune system as well as on the CNS, he concluded.
Sharing clinical experiences to support the patient journey
Next, two specialists from different sides of the Atlantic shared their experiences with fingolimod. Dr Bernd Kieseier, Head of the MS Outpatient Clinic at Heinrich-Heine University, Dusseldorf, Germany and Dr Barry Singer, Director of the MS Centre for Innovations in Care at Missouri Baptist Medical Centre, US, both have MS patients being treated with fingolimod. The labelling of fingolimod is slightly different around the world, and both speakers discussed its use from their country’s perspective.
Dr Kieseier was heavily involved in the phase II and III development stages of fingolimod, and said the drug has been available for about half a year in Germany and throughout Europe.
“How do we translate the clinical data that are out there into clinical practice? We need a treatment option that is efficacious and safe at the same time, and one that is convenient and easily to implement into daily life,” he said.
Dr Kieseier then outlined the FREEDOMS data on fingolimod. The FREEDOMS study showed that fingolimod reduced relapse rates in MS by 54-60 per cent compared to placebo, and disability progression by 30-32 per cent.
This result built on previous data showing superior efficacy to interferon beta-1a in the TRANSFORMS trial, which on its publication was the largest head-to-head phase III study against a standard of care treatment in MS.
“In Europe the label we received from the EMEA was possibly a bit different than what was expected,” said Dr Kieseier. “Gilenya received a second-line label and so we therefore had the possibility of using this drug in patients who were non-responders to interferon beta-1a and still had ongoing disease activity. Patients who have at least two disabling relapses, however, are recommended to receive fingolimod first-line.”
“In Europe, given the label we have here, we are interested in how fingolimod compares to the injectables in MS,” Dr Kieseier told the symposium. “The TRANSFORMS study used an active comparator and showed that fingolimod is superior to interferon beta 1-a in reducing the relapse rate over one year. Even more interesting from a clinical perspective is looking at patients who are switched from interferon to fingolimod (the TRANSFORM extension study). These patients’ disease activity was reduced when switched. So we know that switching from an interferon to fingolimod is a relevant and sensible option in our daily practice.”
He continued: “It is helpful to look at the existing data and see why the US label was approved as it was. If we look at the patients randomised to either placebo or fingolimod we see there is a significant decrease in the annualised relapse rate with fingolimod. We also know that we see effects on disease activity very early on with fingolimod. In both FREEDOMS and TRANSFORMS we see this in comparison to either placebo or the active drug interferon beta 1-a.
“So whatever way we look at it-- from the US or the EU labelling perspectives-- the clinical data shows we have a very effective drug with fingolimod. The question again is, how do we communicate this to our patients?”
Dr Singer explained that it has been one year since the drug was launched in the US, where it is recommended in all patients with relapsing forms of MS as first-line therapy.
He said his priority when discussing treatment is explaining to patients the reduction in relapse rate and the importance of this.
“This is what my patients mostly ask about in the clinic. Compared to an interferon injectable, the reduction in attacks is more than half. Also important to these patients is disability down the line. We can tell them that over the course of two years on fingolimod, disease activity has lessened considerably. When I go over MRI results with patients I talk about the reduction in T2 lesions and in enhancing lesions, and we also talk about how brain shrinkage happens quite quickly in MS but that with this treatment, we may be able to prevent that to a better degree,” Dr Singer said.
Dr Kieseier added that the drug’s safety is very important to patients.
“We can tell them, in a nutshell, that in comparison to placebo overall adverse incidents were generally about the same. We have to manage patient expectations – the overall burden with fingolimod is managable.”
Dr Singer agreed, saying that he explains any possible adverse events in detail to his patients. “When I sit down with individual patients I talk about safety risks in detail, and with family members if they are available, such as macular oedema and how to manage it, for example. Patients might think they’re going to take fingolimod and immediately be better or improve, so they must have realistic expectations and be told that what we are trying to do is prevent further damage,” he said.
Dr Singer also spoke about what doctors have learned while using fingolimod in the US.
“Right now about 20,000 patients in the US have been exposed to fingolimod and in addition, over 200 patients have been on the treatment for over two years. Some of the initial clinical trial patients are now seven years on the drug. So we are rapidly accumulating safety data, and very importantly there have been no new safety signals. There have been no cases of progressive multifocal leukoencephalopathy (PML) and no opportunistic infections to date either.
“We’re looking at further studies, such as the Post Approval Safety Study (PASS), as continued surveillance is important,” Dr Singer said.
Regarding initiating therapy, again there are different recommendations from the US and Europe; however, as Dr Singer explained: “We are the doctors and specialists, and can decide what is best for our individual patients.
“In the US the stepwise approach to treatment initiation includes a baseline eye exam, determining antibody status, an ECG in certain patients, and an assessment of foetal risk – you don’t want patients to conceive on fingolimod if we can prevent it.”
The European approach is similar, although ophthalmic exams are only recommended in patients with diabetes or a history of eye disease.
“The ECG is also not mandatory although in some countries it may be done,” said Dr Kieseier.
On both sides of the Atlantic it is recommended that the first dose is monitored for six hours.
“I personally have over 100 patients on this treatment and all the patients are doing well clinically. We had no clinical issues in the six-hour observation period. I had one case of macular oedema in a patient who was at higher risk for it but who had failed all other treatments. So I can say that fingolimod is definitely a good option for patients; in our clinics we see lots of different patients and we do need new options. Having an oral option is a big plus,” Dr Singer said.
This report was published in association with Novartis
