At Last: Peer Review of MS Pill Trials

In the neck-and-neck race to market the first-ever disease-modifying pill for multiple sclerosis, both Novartis and Merck Serono scored by getting their respective pivotal trials of fingolimod and cladribine published in the venerable NEJM this week. (For background, start at last year's No. 8 story.)

And because I like to make comparative tables, here's another one providing the salient features of the 3 studies—all of which enrolled patients with relapsing-remitting MS.

Study Features	FREEDOMS	TRANSFORMS	CLARITY
Phase	3	2	3
Drug	Fingolimod 0.5 or 1.25 mg/d	Fingolimod 0.5 or 1.25 mg/d	Cladribine 3.5 or 5.25 mg/kg*
Comparator drug	Placebo	IM interferon-beta 1a 30 µg/wk	Placebo
Duration	24 months	12 months	96 weeks
Enrollees	1272	1292	1326
Completers	1033 (81%)	1153 (89%)	1184 (89%)
Annualized relapse rate (primary outcome)	55% or 60% ↓	39% or 51% ↓	54% or 58% ↓
Major secondary outcomes	26% or 31% ↓ disability progression; significant ↓ MRI lesions	No difference in disability progression	~30% higher relapse-free rate; significantly ↓ 3-month disability progression and MRI lesion burden
Notable drug-related adverse events	Bradycardia, AV block, macular edema, high liver enzymes, mild HTN	Fatal infections,** nonfatal herpes, bradycardia, AV block, HTN, macular edema, skin cancer, high liver enzymes	Lymphocytopenia, herpes zoster

* 2-4 "short" courses for the first 48 weeks, then 2 short courses starting at weeks 48 and 52 (total treatment, 8-20 days/year).
** Two in high-dose group: disseminated primary varicella zoster and herpes encephalitis.

What's the take-home?

Although trial-to-trial comparisons are problematic, both drugs appear to have comparable and significant efficacy. Novartis, developer of fingolimod, has an edge owing to its phase 2 study with the standard MS treatment of interferon beta.

But the uptake of these drugs, once they are approved (and I predict they will be...eventually), will likely depend on their safety profiles. Fingolimod, in particular, is associated with some wicked side effects.

AV = atrioventricular; CLARITY = Cladribine Tablets Treating Multiple Sclerosis Orally; FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; HTN = hypertension; TRANSFORMS = Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis.