FROM THE ANALYST’S COUCH
`Rheumatoid arthritis market
`Claire Mount and James Featherstone
`
`In patients who suffer from rheumatoid
`arthritis (RA), the body, for unknown reasons,
`directs a hostile autoimmune response against
`joint cavities, which results in progressive,
`painful destruction of joint tissues. World-
`wide, approximately 1–2% of the population
`is thought to be affected by RA, and one in
`three patients is likely to become severely
`disabled within 20 years. Onset often occurs
`between the ages of 25 and 50 years and is
`three times more prevalent in women than
`men. There are currently three major product
`classes being used for the treatment of RA that
`offer significant clinical and quality-of-life
`improvements for sufferers.
`
`Treatment trends
`Early therapeutics treated the symptoms of the
`disease and maintained the patient’s quality of
`life, and were generally non-steroidal anti-
`inflammatory drugs (NSAIDs), such as aspirin,
`naproxen and the cyclooxygenase 2 (COX2)
`inhibitors, all of which reduce pain and inflam-
`mation. However, the recent high profile volun-
`tary withdrawal of Merck's COX2 inhibitor
`Vioxx, due to the increased risk of cardiovasu-
`lar events, and the temporary withdrawal of
`Novartis’ Prexige, casts a shadow over the entire
`COX2 inhibitor class. Steroids were often used
`in conjunction with NSAIDs to further reduce
`inflammation, and this combination offered
`the most potent short-term anti-inflammatory
`activity. However, clinical benefit seems to
`diminish over time, which is problematic given
`the chronic nature of RA.
`During the past 20 years, the poor prognosis
`for chronic RA sufferers has spurred a more
`aggressive approach to the treatment of RA,
`and has led to the development of disease-
`modifying antirheumatic drugs (DMARDS)
`that attempt to halt disease progression. The
`most popular DMARD is methotrexate, origi-
`nally used in the treatment of cancer, and
`others include gold salts, antimalarials, sulpha-
`salazine, tetracyclines and cyclosporine. These
`are generic products and together consistently
`generate approximately US $600 million per
`year in sales. Evidence of early structural dam-
`age in RA has lead to a shift in the treatment
`paradigm, and physicians now prescribe
`DMARDs at disease onset; moderate-to-severe
`RA suffers are given NSAIDs, corticosteroids
`and DMARDs concurrently.
`
`Although methotrexate is effective in the
`majority of RA patients, many cannot tolerate
`the side effects of the drug, and roughly 50%
`of patients eventually fail treatment, subse-
`quently becoming eligible for more recent treat-
`ment innovations, such as biologic response
`modifiers. Leflunomide (Arava; Aventis) was
`launched in 1998, and was the first drug specif-
`ically approved for RA in more than a decade.
`Leflunomide is similar in mechanism and
`side effects to methotrexate and is used as a
`second-line agent in patients that have failed
`methotrexate therapy.
`The most successful of the novel RA thera-
`pies are the tumour-necrosis factor-α (TNFα)
`inhibitors such as etanercept (Enbrel; Amgen),
`infliximab (Remicade; J&J/Centocor) and adal-
`imumab (Humira; Abbott). Overall, TNFα
`inhibitors generated more than US $4 billion in
`sales in 2003, and growth in excess of 30% in
`2004 is expected. The market is projected at US
`$7 billion by 2007, as approximately 30% of the
`moderate-to-severe patient population will be
`receiving anti-TNF therapy, with increasing
`penetration in mild-to-moderate patients.
`Amgen’s second biologic RA treatment,
`anakinra (Kineret), an interleukin-1 receptor
`antagonist (IL-1ra), was approved for the treat-
`ment of RA in 2001, although uptake has been
`
`Rural Africa 0.0026% Japan 0.2%
`China 0.3%
`Italy 0.33%
`Spain 0.5%
`Norway 0.5%
`Sweden 0.5%
`France 0.53%
`Finland 0.8%
`United Kingdom 0.81%
`USA 1.0%
`
`Figure 1 | Population prevalence. The prevalence
`of rheumatoid arthritis is relatively constant in many
`populations at between 0.5 and 1%. There are,
`however, exceptions, indicating the need for further
`elucidation of both genetic and environmental risk
`factors and their interactions.
`
`N E W S & A N A L Y S I S
`
`‘Cub’, courtesy of Daniel Michalik, danielmichalik@mac.com
`Photographer, Mark Johnston. All work is 100% recycled cork
`
`slow due to inferior efficacy compared with
`anti-TNFα therapies. Kineret is generally
`restricted to use in the 30–40% of cases in
`which patients fail to respond to anti-TNFα
`therapies and is then given as a monotherapy
`or in combination with methotrexate or other
`non-TNF-targeting DMARDs.
`
`What’s in the pipeline?
`The RA market is set to become more competi-
`tive in the medium term with the introduction
`of a number of drugs based on new mecha-
`nisms of action that have potential advantages
`over existing TNFα inhibitors, including
`longer half-lives and reduced dosing schedules.
`The most advanced pipeline products are
`new-generation TNFα inhibitors such as
`UCB/Celltech’s CDP-870 pegylated TNFα anti-
`body fragment, and Biogen Idec/Genentech/
`Roche’s MabThera/Rituxan, which is currently
`approved for the treatment of non-Hodgkin’s
`lymphoma. CDP-870 is produced in Eschericha
`coli, which reduces the cost of goods to approxi-
`mately one-quarter of that of the other TNFα
`drugs, and MabThera has a highly differentiated
`dosing regime that could reduce the cost of
`treatment to less than half that of existing bio-
`logic therapies, which is currently upwards of
`US $10,000 per patient per year.
`Other development programmes include
`Roche’s atlizumab (Actemra) treatment, a
`humanized anti-IL-6 receptor antibody; Bristol-
`Myers Squibb’s CTLA4Ig (Abatacept), a soluble
`immunosuppressant antibody that is the first
`in a new class of co-stimulation blockers; and
`BMS’s 561392 (DPC 333), a TNFα-converting
`enzyme inhibitor which, based on its mecha-
`nism of action, has the added advantage of
`being orally available.
`In the longer-term, small-molecule inhibi-
`tors of proteases and enzymes will begin to
`emerge as RA treatments. Examples include
`Angiotech Pharma’s protease inhibitor Paxceed;
`Wyeth’s cell-cycle inhibitor CCI-779; J&J’s
`(Scios) p38 MAPK inhibitor SCIO-469; and
`AtheroGenics TNF-response-genes modulator
`AGIX-4207. These products could be comple-
`mentary to anti-TNFs or target refractory
`patients, and be easier to administer. Other
`key areas of interest include further anti-TNF
`agents, novel cytokines, angiogenic molecules,
`cell adhesion molecules and IL-1β-converting
`enzyme inhibitors.
`
`▲
`
`NATURE REVIEWS | DRUG DISCOVERY
`
`VOLUME 4 | JANUARY 2005 | 1 1
`
`Medac Exhibit 2046
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
`Page 00001
`
`

`

`N E W S & A N A L Y S I S
`
`RHEUMATOID ARTHRITIS MARKET | MARKET INDICATORS
`
`Table 1 | Performance of key marketed brands and products 2003/2008*
`Key products
`2003
`2008‡
`Marketed brands
`Arava
`Enbrel (Amgen)
`Enbrel (Wyeth)
`Remicade (Johnson & Johnson)
`Remicade (Schering-Plough)
`Kineret
`Humira
`Remicade (Tanabe)
`Development products
`CTLA4-Ig (Abatacept)
`CDP870
`*Figures in US $ millions. ‡Estimated.
`
`287
`1,300
`299
`1,169
`378
`68
`280
`2
`
`0
`0
`
`385
`2,808
`545
`2,068
`815
`150
`2,537
`66
`
`340
`225
`
`Rituxan
`
`Antibody against CD20
`
`Phase III Genentech/
`Roche/
`Biogen Idec
`
`Table 2 | Selected rheumatoid arthritis (RA) products in clinical trials
`Product
`Target/mechanism
`Status Company
`Comments
`Abatacept
`Inhibits T-cell activation
`Phase III Bristol-Myers
`First in new class of co-
`Squibb
`stimulation modulators;
`also being (CTLA4Ig)
`tested in combination
`with Enbrel
`Currently used in
`treatment of B-cell
`lymphoma; for patients
`refractory to other
`DMARDs; IV infusion
`every 12 weeks
`IL-6 significantly
`increased in RA
`Once per month dosing
`due to longer half-life;
`cheaper manufacturing
`
`R1569/MRA
`
`CDP-870
`
`Antibody against IL-6
`receptor
`Antibody against TNF
`
`Phase III Roche/Chugai
`
`Phase III Celltech/UCB
`
`Pegsunercept Pegylated TNF receptor
`type I
`Antibody against IL-15
`
`AMG 714/
`HuMax-IL15
`Paxceed
`
`SCIO-469
`
`Phase II Amgen
`
`Phase II
`
`Phase II
`
`ISIS
`
`Phase II Amgen/
`Genmab
`Small-molecule protease Phase II Angiotech
`inhibitor
`Pharma
`Small molecule p38
`J&J (Scios)
`MAPK inhibitor
`ISIS 104838 Antisense molecule
`against TNFα
`Antibody against
`vitronectin receptor
`
`Vitaxin
`
`Phase II MedImmune
`
`Oral administration
`
`In patients with
`suboptimal response to
`other drugs
`Oral administration
`
`▲
`
`The treatment of RA is dominated in volume by
`older, generic drugs, but the market for new
`biologics is growing rapidly (FIG. 2). Indeed, with
`roughly 165 million sufferers worldwide, and
`given that only an estimated 15% of US patients
`with RA are currently being treated with bio-
`logics, the market has tremendous potential for
`growth.Although penetration of the anti-TNFs
`is likely to increase in the near-term, growth of
`this class should ultimately begin to tail off,
`particularly following the approval of the non-
`TNF-targeted competitors including MabThera
`and MRA; in addition, novel drug targets are set
`to influence the future of RA treatment in the
`next decade (TABLE 1). New product classes have
`made significant improvements to the treat-
`ment of RA and promising developmental
`candidates have led to much optimism sur-
`rounding the chance to control disease pro-
`gression (TABLE 2). With significant unmet
`clinical need, there is room for further growth
`in the RA market. The current growth potential
`2003–2008 is predicted to be a 12% increase,
`with a market size of US $10 billion by 2008.
`
`Claire Mount and James Featherstone are
`Pharmaceuticals and Biotechnology Consultants
`at Wood Mackenzie, 5th Floor, Tower 42,
`Old Broad Street, London EC2N 1HN, UK.
`e-mail: claire.mount@woodmac.com
`doi:10.1038/nrd1611
`
`Online links
`
`FURTHER INFORMATION
`The Arthritis foundation: http://www.arthritis.org
`National Institutes of Health: http://www.nih.gov/
`National Rheumatoid Arthritis Society:
`http://www.rheumatoid.org.uk/
`Access to this interactive links box is free online.
`
`10,469
`
`9,320
`
`8,121
`
`6,906
`
`5,537
`
`4,370
`
`3,018
`
`2,441
`
`1,844
`
`1,559
`
`13
`
`12
`
`11
`
`10
`
`0123456789
`
`Sales (US $ millions)
`
`1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
`Figure 2 | Forecast growth rates for the
`rheumatoid arthritis (RA) market. 2003–2008
`forecast compound annual growth rate = 24.4%.
`The RA market is expected to expand rapidly, driven
`by technological advances, increased competition
`and significant unmet need.
`
`AGIX-4207
`
`Antegren
`
`CCI-779
`
`Humira
`
`Phase II Atherogenics
`
`Phase II Elan/Biogen Idec
`
`Small molecule that
`modulates TNF-
`response genes
`Antibody against
`adhesion molecules
`Small-molecule cell-cycle Phase II Wyeth
`inhibitor
`Antibody against TNF
`
`Developed for Japanese
`market by Eisai
`DMARD, disease-modifying antirheumatic drug; IL, interleukin; IV, intravenous; MAPK, mitogen-activated protein
`kinase; TNF, tumour-necrosis factor.
`
`Phase II Eisai/Abbott
`
`12 | JANUARY 2005 | VOLUME 4
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