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 TysabriBiogen 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.
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
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.