FDA-Approved Medications: New Data
- 0.5 mg capsule given orally once per day
- Approved in 2010 for RMS in adults; approved in 2018 for RMS in pediatric MS
Gilenya is the first in a class of immuno-modulatory drugs called “S1P-receptor modulators.” It is similar in structure to a naturally occurring component of cell-surface receptors on white blood cells. (White blood cells are produced by the immune system to fight infection and disease.) Gilenya blocks potentially damaging T cells from leaving lymph nodes, lowering their number in the blood and tissues. It may reduce damage to the CNS and enhance the repair of damaged nerves within the brain and spinal cord.
Gilenya was approved for RMS in adults in 2010, and in May 2018, became the first medication approved to treat pediatric MS. The FDA approved Gilenya to treat RMS in children and adolescents ages 10 through 17 years on the basis of the Phase III PARADIGMS study. The trial, which included 214 children and adolescents with RMS, compared Gilenya to Avonex® (interferon beta-1a). Eighty-six percent of the individuals in the Gilenya group were relapse-free after 24 months of treatment, compared to 46 percent in the interferon beta-1a group. In PARADIGMS, the side effects of Gilenya experienced by pediatric patients were similar to those seen in adults.
The most commonly reported adverse effects were headache, elevated liver enzymes, diarrhea, cough, flu, sinusitis, back pain, abdominal pain, and pain in the extremities.19 This first FDA approval of a medication to treat pediatric MS is a very important and exciting development, and hopefully will be followed in the years ahead by the approval of other medications with demonstrated efficacy and safety profiles in children and adolescents with MS.
Returning to studies with adults, the 36-month INFORMS trial evaluated the effect of Gilenya relative to placebo on delaying the time to sustained disability progression in people with primary-progressive MS. The enrollment of 969 PPMS patients into the INFORMS trial was completed in 2011, and the trial’s data analysis was completed in 2014. Novartis announced in December 2014 that unfortunately, the primary outcome of the study was not met. Gilenya did not show a significant difference from placebo on a combination of disability measures. Interestingly, a medication in the same class as Gilenya, siponimod, was able to show a benefit in SPMS.
Meanwhile, three studies examining the long-term efficacy and safety of Gilenya in RRMS all generated favorable results. The findings from these three studies were reported at the ECTRIMS-ACTRIMS Meeting in October 2017.
LONGTERMS, an open-label, single-arm extension study, followed more than 3,100 people who had received Gilenya in Phase II and Phase III trials of the medication and who continued to receive the DMT for up to 10 years. Researchers found that the annualized rate of relapse declined with longer use of Gilenya, from 0.26 for those who used the agents for up to one year to 0.19 for individuals who stayed on Gilenya for up to 10 years.
Seventy-nine percent of patients remained free of confirmed disability progression through five years of treatment, and 68 percent avoided disability progression through 10 years. MRI assessments also showed that ongoing use of Gilenya was associated with stability in brain volume. Importantly, long-term use of Gilenya did not see new safety concerns emerge over time. The most common adverse events reported were viral upper respiratory tract infection (15 percent of individuals), headache (12 percent), and hypertension (9 percent).20
PANGAEA is a non-interventional study designed to investigate the long-term safety, effectiveness, and patient-reported outcomes of the medication for up to five years in daily clinical practice. The German study has enrolled more than 4,200 participants, and by January 2017, had accumulated long-term data on 474 of those individuals.
The annual rate for discontinuing Gilenya was 10 percent to 12 percent, and the main reasons for stopping therapy included patient’s decisions (33 percent), adverse event (27 percent), switch of physician (12 percent), and disease progression (11 percent). Common adverse events included low levels of lymphocytes (white blood cells with important immune system functions), nasopharyngitis, and elevated liver enzyme values.21
The third long-term study on the effects of Gilenya reported at the 2017 ECTRIMS-ACTRIMS Meeting found that after eight years of treatment, 50 percent of individuals receiving the DMT had seen their degree of MS-related disability remain stable or improve. Another 20 percent had fluctuating scores on the Expanded Disability Status Scale (EDSS), and 30 percent had worse scores, compared to baseline.
No differences were seen between those with an improved or stable EDSS score and those with fluctuating or worsening scores in terms of the number of relapses they had experienced before entering the trial, suggesting that the differences seen in the study were due to the effect of Gilenya.
The investigators noted that people in the improved disability group were more likely to have had shorter disease duration. They concluded that this finding shows that early diagnosis and initiation of therapy is important to help reduce long-term disability.22
Meanwhile, another Gilenya-related study reported at the 2017 ECTRIMS-ACTRIMS Meeting sought to better understand how the DMT provides its beneficial effects. Investigators enrolled 77 people with MS in a two-year, Phase IV study. Thirty-seven of these individuals were treated with Gilenya; the other 40 did not receive treatment. All participants had a neurological examination every six months, and MRI imaging at the start of the study and after 12 and 24 months.
At the end of two years, 89 percent of the untreated patients had new lesions in the cortical region of the brain, compared with just 13.5 percent of patients receiving Gilenya. Individuals in the Gilenya-treated group also had less loss of volume in several – but not all – areas of the brain. While the relatively small sample and short duration of the study require that its results be replicated in a longer, larger trial, the research nonetheless provides valuable insights.23