N e w s & a N a ly s i s

FROM THE ANAlySTS COUCH

The multiple sclerosis market

Trung Huynh
Affecting over 2.5 million people worldwide, multiple sclerosis (MS) is an autoimmune disease in which the central nervous system is attacked by the bodys own immune response, resulting in the steady deterioration of neurological function. At present there is no cure for MS. Current treatment strategies are aimed at enhancing the quality of life of the patient by treating exacerbations and managing symptoms. Over the course of the 1990s, the development of licensed treatments to alter the disease course of relapsing-remitting MS revolutionized the management of this debilitating condition. Interferon-1b (IFN1b) (Betaseron; Bayer Schering) and glatiramer acetate (Copaxone; Teva and SanofiAventis) became the first drugs to delay the progression of the disease. Natalizumab (Tysabri; Biogen Idec and Elan), launched in 2007, has been the only new MS drug to come onto the market in the past 5 years. Now, the market is expected to change dramatically as improved therapies, addressing efficacy and convenience, are in late-stage development. Current therapeutic options Launched in 1993, IFN1b (Betaseron) became the first disease-modifying therapy for MS. It had orphan drug status for 3 years until the launch of IFN1a (Avonex; Biogen Idec) in 1996. It is thought that IFN subtypes act by inhibiting T-cell migration, which consequently reduces demyelination of the nerves1. Newer versions of these IFN therapies, such as Rebif (IFN1a; Merck Serono and Pfizer) and Extavia (IFN1b; Novartis), were launched in 1998 and 2009, respectively. In 1997, glatiramer acetate became the first non-IFN to enter the market. It is an immunomodulator made up of four amino acids found in myelin basic protein and it is thought to act by modifying immune processes associated with the pathogenesis of MS2. The other alternatives to IFN therapies are the cancer drug mitoxantrone (Novantrone; Merck Serono), launched in MS in 2000, a last-line therapy for patients with progressive or worsening relapsing-remitting MS, and natalizumab, a humanized monoclonal antibody against the cellular adhesion
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molecule -integrin. It was initially launched in 2004 but was withdrawn voluntarily in 2005 after three patients developed progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal viral disease. Following evaluation of the safety information and because of its superior efficacy over current therapeutic options, natalizumab was reintroduced in 2006 under a rigorous special prescription programme. By June 2010, there were 55 confirmed cases of PML, still within the 1 in 1,000 patients level noted on the drugs label. However, many neurologists think the benefits of natalizumab outweigh the risks and it has since become the fastest growing MS drug with sales exceeding US$600 million in 2009 across the seven major markets (United States, Japan, France, Germany, Italy, Spain, United Kingdom), up 30% from the previous year. Nevertheless, if more PML cases arise, regulators may choose to withdraw natalizumab again or tighten the restrictions on its use. Unmet need In 2002, the UKs National Institute of Health and Clinical Excellence decided that the four available disease-modifying treatments (IFN1a, IFN1b, natalizumab and glatiramer acetate) provided only modest clinical benefit and with an average price of over $13,000 a year, they were deemed not cost effective for use3. Following this, the UK Department of Health implemented a risk-sharing scheme, involving the National Health Service and drug manufacturers. The scheme allowed patients access to these drugs while they reviewed the long-term cost-effectiveness of the treatment over 10 years. In December 2009, the first set of study results were published, showing that disease progression while on these drugs was far worse than expected. In fact, they were shown to sometimes be inferior to the untreated control group, with deviations varying from 72% to 156% compared to placebo4. Further data analyses, including comparator data sets and long-term follow-up studies of patients are underway. The implication of these results casts doubt over the value of current therapies and their use is expected to decrease markedly over the next decade, particularly as newer drugs enter the market.

Currently all disease-modifying MS treatments are limited to injectable formulations, administered from once a day (glatiramer acetate) to once a month (natalizumab). Patients can suffer painful injection-site reactions and would prefer a less invasive mode of administration. The introduction of oral therapies, therefore, would be a major improvement in the treatment of MS. Key drugs in development Presently, there are seven key agents in late-stage development offering an oral mode of delivery and improved efficacy (TABLE 1). In July 2010, cladribine (Movectro; Merck Serono), a purine nucleoside analogue that interferes with the proliferation of lymphocytes involved in the pathological process of MS, was approved in Russia and became the worlds first oral disease-modifying MS therapy to be granted marketing authorization. However, cladribine is likely to lose out to fingolimod (developed by Novartis and Mitsubishi Tanabe), a sphingosine 1-phosphate receptor 1 agonist, in the race to become the first oral MS therapy in the United States. Despite some safety concerns, fingolimods impressive efficacy5 led to unanimous backing from the US Food and Drug Administration panel and Novartis is expected to win approval for fingolimod as a first-line therapy, with its launch date expected to be at the end of 2010. Other oral therapies in Phase III trials include dimethyl fumarate (developed by Biogen Idec), the first MS drug to activate the nuclear factor erythroid 2-related factor 2 transcriptional pathway to maintain myelin integrity; laquinimod (developed by Teva and Active Biotech), an oral once-daily administration and selective autoimmune suppressant; and teriflunomide (developed by SanofiAventis), a dihydroorotate dehydrogenase and tyrosine kinase inhibitor exerting anti-inflammatory, antiproliferative and immunosuppressive effects. Another highly anticipated therapy is alemtuzumab (Campath; Genzyme, Bayer Schering and BTG), which specifically targets CD52 expressed on the surface of normal and autoreactive T cells, thus depleting the T lymphocytes involved in the degradation of the myelin sheath. Long-term Phase II
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clinical data show that alemtuzumab-treated
12 10

patients experienced a 71% reduction in the risk of progression to clinically-defined disability6. The other important monoclonal antibody is daclizumab (Zenapax; Biogen Idec and Abbott Laboratory), which selectively binds to the chain (CD25) of the interleukin-2 receptor on activated T cells and inhibits their activation. In a Phase II trial, investigators reported that daclizumab (2 mg per kg) in combination with IFN1a reduced lesion formation by 72% versus IFN alone7. These treatments have highly superior efficacy compared with that of currently marketed products. market outlook The MS market is entering a crucial stage. Because of the low level of competition, existing market players have periodically increased prices. However, this trend is expected to change as a result of growing pressure from payers and launches of new agents and biosimilars. The introduction of more effective and less invasive therapies is expected to drive growth in the mid term from $7.3 billion in 2009 to peak at $9.7 billion in 2014 across the seven major markets8 (FIG. 1). In the long term, however, market growth will be offset by biosimilar incursion, which will create heightened cost competition over the forecast period. with spiralling health-care expenditure, the scope for cost savings by switching away from the expensive MS drugs to the cheaper IFN and glatiramer acetate biosimilars will become key resistors causing the market to decline and plateau at an estimated $9.6 billion by 2019 (REF. 8). Fingolimod is expected to become the market-leading therapy at the end of the forecast period (2019), achieving sales of $2.4 billion across the seven major markets.

Sales value (US$ billions)

8 6 4 2 0 2009 2010f 2011f 2012f 2013f 2014f 2015f 2016f 2017f 2018f 2019f

Avonex Rebif Betaseron

Extavia Copaxone Novantrone

Tysabri Gilenia Movectro

Panaclar Laquinimod Teriflunomide

Campath Zenapax Generics

Figure 1 | shifting composition for the multiple sclerosis market. Data are for the seven major markets. The launch of pipeline oral drugs is forecasted (f) to grow the market by|a compound Nature Reviews Drug Discovery annual growth rate of 5.5% over the 20092014 period. As a result of biosimilar incursion of the interferon- subtypes and glatiramer acetate the market growth is expected to decline with a compound annual growth rate of 0.8% over the 20142019 period8.

In total, pipeline drugs are forecast to account for $5 billion (or a 52% share) of the MS market in 2019, whereas current brand revenue is expected to fall by 75% from 2009, capturing $2.2 billion across the seven major markets. As the MS market becomes saturated in the next 10 years, drug developers will need to look at alternative ways to grow the market. Currently, most existing and pipeline treatments only work for the relapse-remitting form of MS, which accounts for around 55% of the patient population. The greatest unmet need is for effective treatments for the remaining 45% of patients who suffer from the more severe progressive forms of MS.
1. Yong, V. W. et al. Interferon in the treatment of multiple sclerosis: mechanisms of action. Neurology 51, 682689 (1998). 2. Copaxone. Copaxone prescribing information. Copaxone website [online], http://www.copaxone.com/pdf/ PrescribingInformation.pdf (2010).

3. National Institute for Health and Clinical Excellence. Multiple sclerosis interferon and glatiramer acetate. NICE website [online], http://www.nice.org.uk/guidance/ index.jsp?action=byID&r=true&o=11441 (2002). 4. Boggild, M. et al. Multiple sclerosis risk sharing scheme: two year results of clinical cohort study with historical comparator. BMJ 339, b4677 (2009). 5. Novartis. Two-year Phase III study shows Novartis oral MS therapy FTY720 significantly reduces relapses and disability progression. Novartis website [online], http://www.novartis.com/newsroom/media-releases/ en/2009/1344775.shtml (2009). 6. The CAMMS223 trial investigators. Alemtuzumab vs. interferon -1a in early multiple sclerosis. N. Engl. J. Med. 359, 17861801 (2008). 7. Wynn, D. et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, doubleblind, placebo-controlled, add-on trial with interferon . Lancet Neurol. 9, 381390 (2010). 8. Datamonitor. Commercial insight: multiple sclerosis next generation therapies signal the start of a new era. (Datamonitor, 2010).

Trung Huynh, Ph.d., is an analyst at Datamonitor, 119 Farringdon Road, London EC1R 3DA, UK. e-mail: THuynh@Datamonitor.com doi:10.1038/nrd3272 Competing interests statement
The author declares no competing financial interests.

Table 1 | overview of key compounds in late-stage development for multiple sclerosis

Molecule
Fingolimod Oral cladribine Laquinimod Teriflunomide Alemtuzumab Daclizumab

Brand name Mechanism or code

Gilenia Movectro ABR215062 HMR1726 Campath Zenapax Adenosine deaminase inhibitor Activates Nrf pathway Unknown DHODH inhibitor CD52 inhibitor IL-2 receptor antagonist

Administration company route

Novartis Merck Serono Biogen Idec Teva Genzyme Biogen Idec Oral Oral Oral Oral Injection Injection

Partner

stage of development
Filed Phase III Phase III Phase III Phase III Phase III

Selective S1P receptor 1 agonist Oral

Mitsubishi Tanabe (Japan) Approved* Not applicable Not applicable Active Biotech Bayer Schering and BTG Abbott Laboratory

Dimethyl fumarate Panaclar

SanofiAventis Not applicable

DHODH, dihydroorotate dehydrogenase; IL-2, interleukin-2; Nrf, nuclear factor erythroid 2-related factor 2; S1P, sphingosine 1-phosphate. *Russia.

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