Safety Concerns Unlikely to Delay FDA Approval of Novartis' MS Drug Gilenia
Novartis AG (NVS) said the FDA extended the review period for its investigational multiple sclerosis (MS) drug Gilenia by three months. Given the unexplained "refuse-to-file" letter received by a competitor last December from U.S. regulators for their own experimental oral drug for relapsing forms of MS treatment, Novartis' insistence that safety concerns did not trigger the delay is less-than assuring news.
"The announcement of this revised timeline is in line with our expectations, and reflects the comprehensive clinical program and resulting large amount of data to be reviewed in the NDA," said Trevor Mundel, Global Head of Development at Novartis Pharma. The FDA's review status for Gilenia (fingolimod) was set to expire on June 21, 2010.
In my opinion, the efficacy of Gilenia -- or its competitor's drug -- is not in doubt. Data presented at the 2010 American Academy of Neurology (AAN) held in April reinforced -- and added to -- an accumulating body of evidence demonstrating once daily, oral Gilenia could be a breakthrough disease-modifying treatment option for relapsing-remitting MS (the most prevalent form of the disease), irrespective of prior treatment history.
Gilenia (fingolimod) binds to a docking site (sphingosine-1-phosphate receptor, or S1P-receptor) on immune cells, including the T-cells and B-cells implicated in inflammatory damage to the nervous system found in MS. The once-a-day pill essentially sequesters white blood cells in lymph nodes, preventing these cells from migrating into the brain and spinal cord.
In addition to its anti-inflammatory effects, Gilenia may also have a direct beneficial effect on cells in the central nervous system (CNS), such as repairs to myelin sheath, the oft-damaged insulation (surrounding axon fibers) prevalent in progressive MS. Currently, no marketed treatments for MS can produce remyelination.
Novartis is jockeying with EMD Serono, the U.S. affiliate of Germany's Merck KgaA, for first-mover advantage in the $8.7 billion global MS market. Merck KGaA's horse in the race, oral cladribine, has also shown promise in terms of efficacy: Treatment with cladribine tablets significantly reduced relapse rates by 55-58 percent compared to placebo at the 2-year mark, according to published results from its late-stage Clarity trial. Cladribine also demonstrated reductions in the risk of disability progression and MRI measures of disease activity at 96 weeks.
In late 2009, EMD Serono received a refuse-to-file (RTF) letter for its oral cladribine NDA. The FDA and the company are not required to disclose the contents of the RTF, but such a regulatory decision has historically been based on submission of data insufficient for a substantive and meaningful review, such as: noncompliance with study protocol, omission of critical data (such as evidence of efficacy), or administrative errors with the filing.
As of late May, Merck KGaA still hadn't disclosed when it would be meeting with the FDA to discuss what deficiencies need be redressed before it could resubmit the NDA for cladribine. The FDA usually requires independent data from two separate Phase 3 trials as supportive data on a drug's efficacy. When EMD Serono submitted its original NDA application, only CLARITY results were included. Although an injectable form of the drug is available (marketed by Ortho Biotech under the name Leustatin) as a treatment for leukemia, the FDA will likely request additional long-term efficacy data for MS.
The FDA's concerns with cladribine had to do with "tabulation," or how the data were counted, and with certain documents Merck filed, according to a Reuters'recounting of a Merck presentation to investors at a JPMorgan healthcare conference on Jan. 11.
Nonetheless, the real concern of regulators and physicians is how to balance efficacy and the drug's long-term safety profile. Similar to Gilenia, Merck KgaA's cladribine interferes with the proliferation of certain white blood cells, particularly circulating lymphocytes (T cells, such as helper CD4-cells, and B-cells), which are thought to be involved in the immune-mediated and inflammatory pathological process of MS. The immune suppression activities of both experimental drugs could leave the MS-treated patients vulnerable to opportunistic infections and cancers.
Acknowledging that drug-drug comparisons are difficult -- no head to head trials exist -- each drug has exhibited notable drug-related health risks, including: fatal infections, nonfatal herpes and skin cancers with Gilenia; lymphocytopenia and shingles with cladribine.
An adverse-events assessment from the pivotal Transforms trial found that skin cancers were more common in the Gilenia-treated group: eight cases versus two reported cases in MS patients treated with Biogen-Idec's (BIIB) once-weekly, intramuscular interferon beta1-a (Avonex). Two fatal infections also occurred in the group taking the higher dose (1.25-mg/day) of Gilenia.
However, Jeffrey Cohen of the Mellen Center at the Cleveland Clinic Foundation and lead investigator for the TRANSFORMS study, told me that no conclusive role for Gilenia in the deaths of two trial patients could be identified. Additionally, all of the skin malignancies proved to be localized and were excised successfully.
At the 2010 ANN meeting, "extension data from Transforms revealed no new safety issues not already seen in the core study," said Dr. Cohen. "When data from all the fingolimod studies are combined, there was no apparent increase in cancer."
Gilenia has been well studied in one of the largest-ever clinical trial programs conducted in MS. "The full program, including completed as well as on-going studies in MS, now has more than 6600 patient years of experience, with some patients now in their sixth year of treatment," said a Novartis spokeswoman.
Despite the growing body of clinical experience, the Novartis PR team did presciently note in separate correspondence with me several weeks back that since Gilenia's active ingredient, fingolimod, was a "New Molecular Entity," the FDA would likely need additional time to evaluate Novartis' required safety monitoring protocols (Risk Management Program) -- resulting in the now acknowledged pushback of Gilenia's approval timeline.
Cladribine, in my opinion, is dead in the water for now: where Gilenia reversibly bottles up white blood cells in lymph nodes, cladribine kills off many circulating CD4+ T-cells -- which can take up to a year to recover. Ergo, there are concerns that if serious infections were to arise in MS-treated patients on cladribine, there wouldn't be a viable way to rebuild the patients' immune systems.
In November 2009, Merck KGaA began recruiting participants for its PREMIERE Trial, a prospective, long-term safety registry of cladribine-treated people with MS who have enrolled in cladribine studies. However, the follow-up time for PREMIERE is two years minimum.
The FDA has scheduled a meeting of its Peripheral and Central Nervous System Drugs Advisory Committee for June 10, 2010, to discuss the benefit/risk profile of Gilenia. Assuming no new evidentiary surprises with safety, Gilenia will likely become the first oral MS drug to hit pharmacy shelves.
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