Two drugs in a race to become the first oral treatment for relapsing forms of multiple sclerosis have high safety hurdles to overcome, obstacles that may knock them both out of the running as first-line treatments.

Both Merck Serono and Novartis presented data associated with their highly anticipated oral MS drugs at the American Academy of Neurology meeting in Seattle this past week. Currently it appears Merck Serono, which presented cladribine data late on April 30, has an early lead to being first to market given its plans to file an NDA in the U.S. and EU by mid-year. Novartis plans similar filings for fingolimod by year's end.

But it seems increasingly likely that fingolimod's safety will be the subject of careful scrutiny from regulators. On May 1, Novartis announced that yet another patient who participated in its 1,292-patient TRANSFORMS study had died, bringing the total number of deaths associated with the drug to three.

The patient, whom Novartis characterized as having a "severe neurologic condition," died in February from an aspiration pneumonia, six months after discontinuing treatment with fingolimod. In a May 1 investor call, Global Head of Development Trevor Mundel said there was a question of whether this patient had other autoimmune diseases or metabolic conditions because of some unusual features on the individual's MRI.

Last year two patients died during the study, one of primary disseminated varicella and one of herpes encephalitis. Mundel noted, however, that the data safety monitoring board, which is overseeing the entire fingolimod program, not just individual studies, considered all these cases in February and voted to continue the study unchanged.

Skin cancer may also be a serious side-effect of the drug. To date, seven cases of localized skin cancer have been reported in fingolimod-treatment groups. Mundel said the firm switched in July 2007 from having neurologists do a cursory skin check to requiring a formal dermatology annual exam. "I think that led to a burst of cases. We have had no new cases since July of last year," he noted.

Mundel pointed out that following the Phase II trial, a group of 281 patients continued on an extension study. In this population, no new skin malignancies and no new cases of serious infections were observed. That's cold comfort to analysts who believe the side effects mean the drug will be reserved for only the most severe cases.

If and when fingolimod is approved, Bernstein Research analyst Ronny Gal believes its risk profile will likely relegate it to a third-line therapy, or at best a second-line competitor to Biogen-Idec's Tysabri (natalizumab) , which has struggled to grow in market share due to concerns about progressive multifocal leukoencephalopathy associated with the medicine's use (¹ Also see "Biogen Idec Says Tysabri Patient Counts Are On The Upswing" - Pink Sheet, 17 April, 2009.). A more restrictive REMS for fingolimod would also increase the hassle-factor associated with taking or prescribing the drug, stripping the oral medicine of some of its dosing advantage.

Cancer concerns dog Merck Serono's drug

Safety concerns also blight enthusiasm for Merck Serono's cladribine Tablets, but to date, the risk profile seems a bit more manageable. Indeed, Bernstein's Gal believes "cladribine's most natural place in clinical practice seems to be as a second-line competitor to [Biogen Idec's] Tysabri." And as safety data accumulates, there's "the potential to capture share from [current therapies] in 1 line with time," he says.

At AAN, Merck Serono provided an update on cladribine, including the occurrence of four malignancies during its pivotal Phase III CLARITY study, which enrolled 1,326 patients. In addition, a cladribine-treated patient who became pregnant six months after completing the study developed a case of choriocarcinoma when her fetus was at week 14 of gestation (² Also see "Side Effects Dampen Neurologists’ Enthusiasm For Novel MS Drugs" - Pink Sheet, 16 February, 2009., p. 9).

Cladribine-caused immunosuppression may have allowed the observed tumors to grow more quickly, but oncogenesis is a relatively slow process, explained lead investigator Gavin Giovannoni, a professor at the London School of Medicine and Dentistry. Cladribine, an antineoplastic drug, is already approved in the U.S. as an injection to treat active hairy cell leukemia.

Both cladribine and fingolimod showed exceedingly good reduction in relapse rates. Cladribine showed as much as a 58 percent reduction in annualized relapse rate compared to placebo. New Phase III data presented by Novartis showed as many as 83 percent of patients on fingolimod were free of relapse at one year. That compared with 69 percent of patients on interferon beta-1a (Biogen Idec's Avonex ) (³ Also see "Good News, Bad News For Novartis’ Oral MS Drug, But REMS Could Help" - Pink Sheet, 23 December, 2008.).

- Pamela Taulbee (p.taulbee@elsevier.com)

Safety Remains Front Line Concern For Oral MS Drugs

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