ARTICLE IN BRIEF
Investigators said the study results for the oral therapies — fingolimod and cladribine — were promising, but more research is needed to address safety concerns that emerged in the trials.
Two oral therapies — fingolimod and cladribine — were found to be significantly more effective in reducing relapsing-remitting MS at the end of one or two years (depending on the study design) and fewer lesions were seen on repeated MRI scans.
But while the investigators said the results for these oral therapies — reported in three separate papers online Jan. 20 in the New England Journal of Medicine (NEJM) — were promising, they noted that more research is needed to address safety concerns that emerged in the trials.
In phase 3 trials, investigators randomized patients to fingolimod, or placebo; fingolimod and injectable interferon; and cladribine and placebo. [For study details, see “Oral Therapies for MS: The Findings.”]
All of the oral therapies are immunosuppressants. Fingolimod, originally known by number as FTY720, is a sphingosine-1-phosphase-receptor modulator that prevents lymphocyte egress from lymph nodes. Cladribine destroys B cells and T cells of the immune system and also has potent anti-inflammatory effects.
Jeffrey A. Cohen, MD, director of Experimental Therapeutics at the Mellen MS Center at the Cleveland Clinic, who led the TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) study, said the problem for moving towards approval of any of these medicines is safety. But those problems are being examined in ongoing studies.
Dr. Cohen explained that in the initial phase 2 study of fingolimod, which followed 281 patients over a six-month time period, the main side effects were slowing of heart rate with the initial dose and mild elevations in liver enzymes. But those effects dissipated after the first dose.
While there were no cases of skin cancer seen during the six-month core study of the phase 2 trial, two cases of melanoma were identified in the five-year extension study. This finding sparked the addition of a dermatologic monitoring system in the phase 3 studies.
In the phase 3 trial, which randomized 1,292 patients to 0.5 mg or 1.25 mg of fingolimod, 10 localized skin cancers were reported; five basal cell carcinomas (two in the 1.25-mg group and three in the 0.5-mg group) and one in the interferon group; three melanomas (all limited to the epidermis) in the group receiving the 0.5-mg dose of fingolimod; and one squamous-cell carcinoma in the interferon group. Breast cancer was reported in two patients in each of the fingolimod groups; three cases were diagnosed within four months after the initiation of the drug, and one was diagnosed 11 months after enrollment.
In addition to the increased risk for skin cancers, those taking fingolimod had more infections and other side effects. There were two deaths due to herpes infections, as well as macular edema with vision loss, pulmonary function deterioration, mild hypertension, liver enzyme elevation, and transient bradycardia when therapy was started. Concerns about adverse effects actually led to the higher 1.25 mg dose of fingolimod being dropped from development plans.
The doctors participating in the larger phase 3 trials were aware of the possible problems. So was the FDA. The agency worked with the drug company, Novartis, to add dermatological exams through the study.
A third study of fingolimod, FREEDOM2 (FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) will be completed in 2011. The drug is also being studied in patients with primary progressive MS.
In the cladribine study, which randomized 1.326 patients to 3.5 mg or 6.26 mg of the experimental drug or placebo, more people on the active drug had adverse effects: 21.6 percent taking 3.5 mg and 31.5 percent on 5.25 mg had lymphocytopenia, compared with 2.8 percent on placebo. Eight patients on the lower dose and 12 on the higher dose had herpes zoster, compared with none on placebo.
The rate of herpes zoster was 2.3 percent in the medication group versus none in the controls, and there was one unusual death due to disseminated tuberculosis. Benign or malignant neoplasms occurred in 1.1 percent of the cladribine treated patients compared to none of controls.
“Further studies will be necessary to determine whether these medications are associated with increased risk of serious infection or cancer and the magnitude of that risk,” Dr. Cohen said.
“Until we know more about the safety profile, I don't think we should put the majority of MS patients on this drug as a first line therapy,” said Peter Calabresi, MD, the lead investigator in the ongoing FREEDOMS2 study. If someone is doing well I would not switch them because a pill is easier to take, said Dr. Calabresi, associate professor of neurology at Johns Hopkins School of Medicine and director of the Johns Hopkins Multiple Sclerosis Center.
EXPERTS: CAUTIOUS OPTIMISM
MS specialists who were not involved with the trials agreed. Bruce A. Cohen, MD, professor of neurology and director of the MS program at the Feinberg School of Medicine at Northwestern University, said that the potential side effects observed in these studies may require a monitoring program of some kind. “Like any new agent, we won't know all the issues we may confront until it is in general use in the population.” For instance, the initial cardiac side effect that is seen only at the first dose led investigators to avoid entering study patients with heart problems. But once the drug is in use, patients with cardiovascular disease may experience other cardiac problems that have not been seen so far. The problems with macular edema and skin cancers also suggest that monitoring for certain potential problems may be critical to the success of these medicines, he said.
These studies have shown surprisingly excellent efficacy and good short term tolerability, said Patricia K. Coyle, MD, professor and acting chair in the department of neurology at State University of New York-Stony Brook. “There is great excitement that one or both of these agents —cladribine or fingolimod — may be available in the near future to treat MS. At the same time, there are concerns that have been raised about these more convenient therapies, and how to determine their true risk-benefit ratio.”
Both drugs have a novel mechanism of action for MS, Dr. Coyle continued, but they lack long-term safety and efficacy data. “Although parenteral cladribine has been available for some years, it has not been used for MS except by a handful of physicians. It is not clear how many courses of cladribine can be given safely or how many years fingolimod can be used.”
“The extent of monitoring that may be required for both these new agents may create additional burdens for the practicing neurologist,” said Dr. Coyle. “Nevertheless, no one can question the trial results indicating their significant benefits in controlling the MS disease process.”
ORAL THERAPIES FOR MS: THE FINDINGS
The TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis) study randomly assigned 1,292 patients to 0.5mg daily or 1.25 mg of fingolimod or interferon beta 1A for one year.
Among findings, there was a 52 percent reduction in relapse rates for patients taking the 0.5 mg daily dose and 38 percent reduction in the larger 1.25 mg dose compared to interferon. There was also reduced lesion activity and a slowing of brain atrophy.
At one year, the neurologists could find no difference in the clinical progression of the disability in those on the medicine and those on interferon.
The FREEDOMS (FTY720 Oral in Relapsing-Remitting Multiple Sclerosis), a 24-month, double-blind, randomized study largely conducted in Europe, randomized MS patients to 0.5 mg or 1.25 mg fingolimod or placebo.
Led by Ludwig Kappos, MD, of the departments of neurology and biomedicine at the University of Basel in Switzerland, the investigators reported that of 1,033 patients, the annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.15 with 1.25 mg of fingolimod, and .40 with placebo. Both doses were superior to placebo with regard to new or enlarged lesions.
The Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study compared efficacy and safety of cladribine in a 96-week, double blind, placebo controlled trial involved 1.326 patients.
Patients receiving either 3.5 mg or 6.25 mg cladribine had a significantly lower annual relapse rate than the placebo group — .14 and .15 respectively, versus .33 for placebo; a higher relapse-free rate — 79.7 percent and 78.9 percent, respectively, versus 60.9 percent — and had significant reductions in brain lesions on MRI.
The CLARITY Study Group was led by Gavin Giovannoni, MBBCh, of the Neuroscience Center at the Blizard Institute of Cell and Molecular Science of Queen Mary University London.