Patients suffering from multiple sclerosis (MS) have seen their fair share of broken medical promises in recent years. Back
in 2003, biopharma was on a roll, making reassuring strides in the treatment of this chronic, progressive autoimmune disorder.
In the previous decade, FDA had approved five disease-modifying drugs—where previously there had been none. The future was
looking even brighter, with combination therapies, oral treatments, and a powerful first-in-class monoclonal antibody (MAb)
named Tysabri coming out of the pipeline.
But the last five years have largely been a bust. Serious setbacks dampened the optimism of the 400,000 people living with
MS in the US, and the 2.5 million diagnosed worldwide (see "US Patients Living With MS, 2005–2014"). The category is overdue
for an infusion of innovative new products. Fortunately, according to recent AVOS Life Sciences research ("Multiple Sclerosis
Agents: US Market Outlook") into the clinical and commercial dynamics that will shape the MS market through 2015, patients
and their doctors can expect significant change in the form of new treatment options—largely as a result of the introduction
of oral agents to a traditionally biological therapeutic category. Still, a strong sense of uncertainty permeates this medically
challenging disease.
The Troubles of Tysabri
Biogen Idec's Tysabri (natalizumab) has been the decade's big spoiler in MS. Launched in 2004 after FDA fast-tracking, the
MAb was poised to disrupt the market in the best sense: It showed unprecedented efficacy in reducing the frequency of relapses
suffered by MS patients. Then as now, the MS segment is characterized by biologics that require daily or weekly self-administered
injections. In contrast, Tysabri offered a novel mechanism of action, less frequent dosing, fewer side effects, and greater
potency than standard therapies. The drug was widely predicted to be the next gold standard in MS treatment and a sure-fire
blockbuster.
US PATIENTS LIVING WITH MULTIPLE SCLEROSIS, 205-2014
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Instead, Biogen Idec was forced to yank Tysabri from the market in February 2005 after three former trial participants developed
progressive multifocal leukoencephalopathy (PML), a serious brain infection; two of them died. Yet under pressure from MS
patients, Tysabri made an unexpected comeback in 2006 under an FDA-approved restricted access program, on the basis that the
drug's benefits outweighed the risk of developing PML.
That claim is currently being tested. Biogen Idec disclosed the occurrence of two new cases of PML last July, the first since
the drug's reintroduction. But given a worldwide Tysabri patient population of more than 31,000, two new cases of PML may
mean that the danger of developing the brain infection while on the drug is actually lower than the previously estimated risk
of 1 in 1,000 (0.1 percent). Researchers are still seeking to understand why PML occurs, what co-factors encourage PML to
develop in Tysabri patients, and how to further mitigate the PML risk. But barring a breakthrough, the drug's black-box warning
has dimmed its initial promise as a major treatment advance. Still, Tysabri does offer increased efficacy and quality of life,
and for that reason it's likely to remain on the market. In the worst-case scenario, it will have flattened sales and end
up filling a niche for patients who have failed first line treatments.
A Cautious Turn Among Doctors
In the wake of the Tysabri-related PML deaths, physicians have developed not only a much more conservative approach to prescribing,
but also a heightened sensitivity to safety and tolerability in general and a greater appreciation of the true potency of
MS drugs.
The current MS market looks more or less like it did three years ago when Tysabri arrived on the scene. The beta interferon
class, consisting of Biogen Idec's Avonex, Bayer Schering's Betaseron, and Merck Serono's Rebif, remains dominant, accounting
for 69 percent of prescriptions written in the US in 2007. Avonex leads with a little more than a third of market share. Not
far behind is Teva's Copaxone (glatiramer acetate), a polypeptide therapy that was introduced at almost the same time as Avonex
in 1996, and that meets the need for a non-interferon treatment absent neutralizing antibodies and flulike symptoms. Copaxone
has long been the market's No. 2 drug, its growth hindered by the need for daily self-injections.
The Tysabri clinical trials demonstrated the risks of using this disease-modifying MS agent, especially in combination with
beta-interferons. What had been a growing sense of confidence in the first-generation biologicals—which went so far as to
compel the drugmakers to launch dual-therapy Tysabri/Avonex trials during the MAb's clinical development—was shaken when two
of the three cases of PML emerged from those trials. Combination therapy is no longer recommended.
Neurologists are also increasingly wary of switching a patient from a drug that has proved effective to a new treatment that
may offer greater efficacy, but may also expose them to a new set of side effects. Doctors are demanding more extensive, longer
term clinical data before endorsing a new MS drug on a broad basis. This orientation—call it the Tysabri effect—will likely
slow the uptake of the new oral MS drugs as well.
Holding Tysabri back is the physicians' understandable fear that the drug may be too "heavy-handed" for the majority of patients,
who have on-ly mild-to-moderate relapse-remitting MS. (Those using Tysabri, and the ones who cried loudest for its return
to the market, had more aggressive or advanced stages of the disease generally beyond the reach of the beta interferons.)
Tysabri's market share is likely to reach 5 percent this year, despite the new PML scare; the MAb will gain traction through
2014, while the beta interferons slowly decline as they are bested by new treatment options (see "Future Market Trends for
Current Products, 2007–2014").
The Pipeline and Its Promises
FUTURE MARKET TRENDS FOR CURRENT PRODUCTS, 2007-2014
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Several late-stage oral drugs and a novel biological are poised to usher in a new, improved treatment regimen in MS—or at
least promise to. A plethora of pharmas and biotechs are working to develop the next disruptive MS therapy: an oral medication.
This big leap in convenience will drive a value shift in the segment as patients also seek incremental efficacy from these
new mechanisms.
Development delays and failures have made the expectation of an oral MS drug old news for almost a decade. In 2005, Merck
Serono/Teva's cladribine and Sanofi-Aventis' teriflunomide were two oral drugs on track to launch in 2008. Since that analysis,
Teva's oral formulation of the injectable Copaxone got derailed, while cladribine and teriflunomide remain in clinical trials
with filings now targeted for 2009 and 2012, respectively, according to company estimates. But recent positive trial outcomes
suggest that one or more oral formulations may finally reach the market by 2014. The most promising, in addition to cladribine
and teriflunomide, are Teva's laquinimod and Novartis' FTY720. All are late-stage compounds that use a unique mechanism of
action to achieve reductions in relapse rates, in new lesion formation in the brain, and in the risk of disability progression.
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