By David Orange and Timothy Vollmer, MD, FAAN

Several new medications are emerging for the treatment of multiple sclerosis (MS), including five orally-administered drugs. Many of these medications are nearing FDA approval and could reach the market as early as the summer of 2010. Others have had expedited review, called being fast-tracked, by the FDA and could become available over the next few years. Below, we describe some of the most promising of these new drugs, their modes of action, research into their function and safety and the status of their progress toward FDA approval.

Gilenia

Formerly known as FTY720, or Fingolimod, Gilenia^® is an oral agent—the first of a new class of potential MS medications known as “S1P receptor agonists,” which appear to induce immune cells to remain in the lymph nodes and spleen rather than migrating into the brain and spinal cord. Thus, if patients stop this medication, their immune systems should quickly return to normal. As of this writing, Gilenia has been approved for FDA Priority Review, meaning that it could win final approval in as little as 6 months (summer, 2010).  It is currently unavailable outside of clinical trials.

As FTY720, Gilenia has been researched in three Phase III clinical trials: TRANSFORMS, FREEDOMS and FREEDOMS II, which, collectively, involve more than 3,400 patients from around the world. Results of FREEDOMS and FREEDOMS II (both two-year placebo-controlled studies) should be available soon. Recently reported results of the TRANSFORMS study show that it is more effective than interferon beta-1a (Avonex^®), which is currently a standard MS treatment. TRANSFORMS calculated the annualized relapse rate after 1 year in patients given 0.5 mg or 1.25 mg of Gilenia or an injection of interferon beta-1a. Patients on 0.5 mg of Gilenia exhibited a 52% reduction in relapse while those on the 1.25 mg dose showed a 38% reduction in relapse, compared to interferon beta-1a. Both doses showed benefit and no statistically significant difference was seen between them, indicating that the higher dose did not seem to provide greater benefit than the lower dose.

In studies, Gilenia has been generally well tolerated. Side-effects included fatigue and headache. However, Gilenia does affect other organs, including the heart, liver, and eyes. The therapy suppresses the immune system and there are concerns about development of potentially serious infections. In the TRANSFORMS trial, 7 cases of localized skin cancer lesions were seen and all were successfully removed. Recent studies, published in the New England Journal of Medicine, January 20, 2010 (www.nejm.org), showed significantly lower annualized relapse rates compared to both intramuscular interferon beta-1a and placebo. However, at higher dosages, two fatal infections occurred. The benefit to risk factor of Gilenia is still being researched.

Laquinimod

A once-daily oral therapy, laquinimod is now being studied in two Phase III clinical trials: Allegro and Bravo.  This therapy received Fast Track designation from the FDA in February, 2009 and may be available on the market as soon as late 2011. The results from a Phase II trial for relapsing-remitting MS, released in June 2008, found that a daily 0.6 mg dose of laquinimod significantly reduced MRI disease activity in study participants by a median of 60% compared with placebo. While there was no statistical difference, there was a favorable trend toward reduced annual relapse rates, as well as a higher number of relapse-free patients versus placebo. With the conclusion of Phase II trials, an encouraging safety profile is emerging: to this point, laquinimod has been well tolerated and no severe side effects have been observed. However, many adverse effects are not detected until Phase III trials. More concrete information on the safety profile will become available through the Allegro and Bravo trials, which will each last between 24 and 30 months. Comparing laquinimod to placebo, Allegro involves over 152 sites in North America, Europe, and Asia. Bravo is also a placebo-controlled study but will additionally compare laquinimod’s risk-to-benefit factor to injectable Interferon Beta 1-A (Avonex).

Exactly how laquinimod works in MS is not understood, but it appears to induce some neuroprotective mechanisms. Investigators do know that laquinimod does not suppress the immune system in any significant way. Consequently, in addition to its possible role as a monotherapy in MS, it may be good for combination therapy.

Cladribine

Cladribine^® is a small molecule that can both kill and alter the function of certain white blood cells, particularly T and B lymphocytes. As such, it is approved by FDA as a chemotherapy treatment, most often used for leukemia and lymphoma; however, because the T and B lymphocytes it affects are thought to play key roles in the progression of MS, cladribine has been designated for Fast Track FDA review as an MS treatment and may be approved in 2010 as the first available oral MS treatment.

A phase III clinical trial, CLARITY, compared a low and a higher dose of cladribine to placebo. Participants in the cladribine groups took the agent between 8 and 20 days per year and experienced approximately 50% fewer relapses than those on placebo. No significant difference in benefit was seen between the two cladribine doses:  the lower 8-day dose resulted in relapse reduction rates of 58%, essentially equal to the 55% reduction seen in higher dose participants. Additionally, 80% of patients treated with low-dose cladribine and 79% of those on the high-dose regimen experienced no clinical relapse, compared with 61% in the placebo group. Thus, the lower dose appears adequate to treat MS and may be safer than the higher dose. Cladribine patients also exhibited a more than 30% reduction in the risk of disability progression compared to placebo over the two years of the study.

Cladribine may also be suitable for combination therapy. It is now being studied in another Phase III trial, ONWARD, to measure its effectiveness with injectable interferon beta-1a (Rebif^®, Avonex, or Betaseron^®). While remaining on their interferon therapy, study participants will be assigned to also receive cladribine or placebo, administered two to four times each year for four to five days.

Cladribine’s safety profile has been reported as acceptable. A great deal is known about the agent as a treatment for other diseases. As a chemotherapy and immunosuppressive, it does pose significant risk of complications including toxic effects on organs such as the liver. The therapy reduces white blood cell counts in patients’ blood and bone marrow, which can increase the risk of infection. In addition, the drug causes long term, possibly permanent, changes in white blood cells, the consequences of which are not fully understood. It may also cause a blood-related cancer, such as leukemia or lymphoma. Further research is needed in order to evaluate the effects of long-term use and expand knowledge of the safety profile.

Teriflunomide

A once-daily oral therapy, teriflunomide demonstrated beneficial effects in MS patients in a Phase II clinical trial. Now in Phase III, the therapy continues to show an encouraging safety profile. An immunomodulator, teriflunomide is chemically and functionally related to leflunomide, an FDA-approved rheumatoid arthritis treatment.  Technically, it inhibits rapidly dividing cells, including activated T cells, thought to drive the disease process in MS. Unlike similar drugs, teriflunomide is not thought to affect other immune functions, possibly providing patients with a decreased risk of infections and other complications linked to chemotherapy-like drugs.

The safety profile of teriflunomide is still being investigated. In Phase II, it was well tolerated. Side effects, seen more among higher-dose teriflunomide participants, included upper respiratory tract infections, nausea, headaches, diarrhea, and limb pain. There is also some concern regarding liver function. A Phase III study called TEMSO further explored teriflunomide’s effectiveness and safety profile with principal interest in frequency of relapse and progression of disability. Published results of the TEMSO study are expected in 2010.

Phase II studies have also evaluated teriflunomide as an add-on treatment to interferon-beta or glatiramer acetate in relapsing remitting MS patients and the effect of teriflunomide on people at high risk for MS—those who have experienced a single neurological event suggestive of demyelination and MRI findings suggestive of MS.

The sponsor could apply for approval of teriflunomide as an oral MS treatment within the next year.

BG-12    

BG-12 (dimethyl fumarate) is the fifth emerging oral therapy in our consideration. Now in late stage Phase III clinical trials, BG-12 has thus far demonstrated encouraging results and minimal side affects. It has been shown to activate the Nrf2 transcriptional pathway thought to defend against oxidative-stress induced neuronal death, protect the blood-brain barrier, and support maintenance of myelin integrity in the central nervous system—all key elements in treating MS. In addition to its use as individual therapy, the fact that it does suppress the immune system makes BG12 a potential candidate for combination therapy.

In Phase II studies, side-effects included flushing, gastrointestinal disorders, headache, nausea and nasal inflammation. The infection rate for BG-12 was the same as for placebo, and thus far the emerging safety profile is rather positive.

Fampridine-SR

Finally, in January 2010, the U.S. FDA approved Fampridine-SR, now called Ampyra^® (dalfampridine), extended release tablets to improve walking in patients with multiple sclerosis (MS). This medication has the same active ingredient as 4-AP, so they should not be taken at the same time.   Ampyra is not a therapy to slow the progression of MS but it addresses a common, debilitating aspect of the disease: as MS progresses, walking can become a challenge and many people with MS are forced to use a cane, walker or wheelchair. According to recent research, 70% of MS sufferers report this to be the greatest symptomatic challenge they face. A sustained-release formulation of 4-amino-pyridine (4AP), Ampyra is a selective neuronal potassium (K+) channel blocker . The idea is that by blocking these channels, the conduction of nerve signals through nerve fibers is improved, despite the myelin damage that characterizes MS. Improved nerve communication facilitates nerve connections vital for mobility. Ampyra will function as an add-on symptomatic treatment option for those with difficulty walking.

Because the effect of Ampyra on increasing conduction velocity is not restricted to motor pathways but is a general effect, it may also be useful for other symptoms of MS. Whether or not this is true will probably be determined by patients and their physicians as they carefully try the medication for other important MS symptoms. Throughout various studies, investigators have struggled to find the most efficient dosage of Ampyra. When given a lower dose, patients demonstrated no improvement; but higher doses were associated with increased risk of epileptic seizures. Other common adverse reactions reported by patients taking Ampyra in clinical trials include urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling in the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling or itching of skin.

For more information on any of these medications, speak with your Neurologist.

Clinical Trial Phases – from www.clincialtrials.gov

Phase I – researchers test a drug or treatment in a small group of people (20-80) for the first time to evaluate safety, find a safe dose range, and identify side effects.

Phase II – the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate safety.

Phase III – the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the study drug or treatment to be used safely.

Phase IV – post marketing studies look for additional information including the drug’s risks, benefits, and optimal use.

This entry was posted on Thursday, July 29th, 2010 at 10:51 am and is filed under Featured. You can follow any responses to this entry through the RSS 2.0 feed.