On November 30, U.S. regulators issued a "refusal to file letter" to Merck Serono, the U.S. subsidiary. Company spokesman Gangolf Schrimpf told me the FDA preliminary action of the cladribine submission was not an assessment of the efficacy and safety of the compound. Nonetheless, the agency obviously felt the deficiencies in the filing were material enough -- scientific or legal -- to delay its formal review of the tablet.
Initial results from Novartis' two-year FREEDOMS FTY-720 study show that once-daily oral fingolimod reduced the relapse rate by 54 percent for the 0.5 mg dose in patients with relapsed MS. Novartis looks to file its new drug application with the FDA within next few months, followed fast track approval and launch in summer 2010.
Though efficacy over standard-of-care interferon-beta treatments is similar for the two oral agents, I suspect that neurologists' prescribing behaviors might be more favorably disposed towards cladribine, which offers a more convenient â€"- a short-course regimen -- five-day dosing, twice a year. Merck's setback is thus Novartis' gain, as it affords a window of time for providers â€"- and patients -â€" to gain clinical experience with fingolimod therapy.
In my opinion, the FDA being circumspect about cladribine did have more to do with safety than efficacy. Abnormal low blood levels of white blood cells (called lymphopenia) and four cases of malignant tumors were reported in cladribine -treated patients in the pivotal CLARITY trial. No surprise, as the drug reduces circulating levels of white blood cells (lymphocytes, which are involved in the pathogenesis of MS) and inhibits DNA synthesis and repair (parenteral cladribine was approved as a chemotherapeutic for Hairy Cell Leukemia back in the 1990s).
Concerns exist, too, that cladribine can affect the immune system many years after cessation of treatment. Merck Serono would not answer my question on whether or not the rejection had to do with the company's post-marketing safety protocol, its Risk Management and Mitigation Strategy (RiskMap). "We will work closely with the FDA to fully understand FDA's concerns and define a path forward for a successful resubmission of this application at the earliest point in time," is all spokesman Schrimpf would diplomatically say.
No disease-modifying agent is without risk. Fingolimod, first in a new class of immunomodulatory drugs called S1P-receptor modulators, also reduces circulating levels of white blood cells (by bottling them up in lymph nodes). Skin cancer is a risk associated with fingolimod treatment. The FDA will likely weigh the drugs promising efficacy, however, against this adverse event by requiring Novartis to develop a RiskMap protocol.
With the expected loss of its blockbuster blood pressure drug Diovan in 2012 (more than $4 billion in expected 2009 sales), Novartis is looking to fingolimod to launch a successful new franchise in MS. Although injection-based interferon therapies are likely to remain the preferred choice (due to patient years of experience), discomfort with having to take injections daily or weekly will ensure a step on the treatment paradigm for oral drugs. And, in a market that had global sales of more than $6 billion last year -- expected to exceed $9 billion by 2015 -- there is room for two blockbuster oral formulations.
If approved, Novartis should have two years to cement fingolimod's position as a preferred oral treatment. Come 2012, the oral MS market could get more crowded, as Teva Pharmaceuticals (laquinimod), Sanofi-Aventis (teriflunomide) and Biogen-Idec (BG-12) all have oral formulations in late stage clinical development.