Rheumatoid arthritis is a chronic inflammatory disease that leads
to pain, stiffness, swelling and limitation in the motion and function
of multiple joints. If left untreated, rheumatoid arthritis can produce
serious destruction of joints that frequently leads to permanent disability.2 Though the joints are the principal body part affected by rheumatoid
arthritis, inflammation can develop in other organs as well.2
In 2010, approximately 4.6 million people suffered from rheumatoid arthritis in the seven major markets (US, Japan, France, Germany, Italy, Spain, and the UK) creating an estimated pharmaceutical market of over $15 billion in 2012.1 More than half of these cases in 2010 were in the US alone (2.7 million).1 The disease is two to three times more prevalent in women and onset can occur at any point in life, but is most frequent in the fourth and fifth decades of life, with most patients developing the disease between the ages of 35 and 50.2 The prevalence of rheumatoid arthritis in the major markets is predicted to modestly increase to 5.2 million patients by 2020 in line with corresponding growth of ageing populations.1 By all accounts, this patient population will remain sustainable, presenting long term market opportunities for emerging anti-rheumatic drugs.
The main symptom of rheumatoid arthritis is the persistent inflammation
of the joints, usually in a symmetric distribution.2 This inflammation
causes destruction of cartilage, bone erosion and structural changes
in the joint, which might range from minimal joint damage to debilitating
disease.2,3 Patients’ symptoms typically wax and wane, often making
early diagnosis and treatment difficult.2 Some patients also experience
the effects of rheumatoid arthritis in places other than the joints.2 It is estimated that 40% of patients have extraarticular manifestations, and these symptoms are classifiable as severe in approximately 15% of patients.2
Current Rheumatoid Arthritis Treatments There are many different drugs that are used to treat rheumatoid arthritis, including hormones, small molecules and biologics, which are manufactured using recombinant technology. Typically, rheumatoid arthritis is initially treated with a nonsteroidal anti-inflammatory drug (NSAID), for pain relief, and a disease modifying anti-rheumatic drug (DMARD), with selective use of low-dose oral or intra-articular glucocorticoids.3,4 Dihydroorotate dehydrogenase (DHODH) inhibitors and biologics may also be added and finally, reconstructive joint surgery may be warranted for patients failing all pharmacotherapies who exhibit severe pain and functional impairment.3,4 DMARDs are the only drugs that have been shown to alter the course of the disease.3
Antifolates
Methotrexate (MTX), a classical antifolate, was originally used as a chemotherapy drug to treat certain kinds of cancer, but was also found to be beneficial in treating inflammatory arthritis and psoriasis. MTX is generic and marketed in both injectable and oral formulations by multiple companies.4 The administration of MTX is known to cause serious side effects such as pulmonary fibrosis and elevations in liver enzymes, which can be indicative of early liver and kidney damage.4 Other traditional oral DMARDs include leflunomide, auranofin, sulfasalazine, cyclosporine, hydroxychloroquine, azathioprine and penicillamine.4
Biologics
EnbrelTM (entanercept), HumiraTM (adalimumab) and RemicadeTM (infliximab) are anti-tumor necrosis factor (anti-TNF) therapies that have been approved by the FDA and are the top selling biologics for rheumatoid arthritis.1 These three anti-TNF compounds are administered to patients by injection and can be used alone or in combination with other DMARDs, such as MTX, or NSAIDs such as aspirin or ibuprofen.4 Although there have been positive results for biologics, their use may be limited due to associated high costs and side effect profile, including increased risk of opportunistic infections.1,4
Development Status
CH-1504 has completed Phase I and Phase II clinical trials for the potential treatment in rheumatoid arthritis. CH-4051 has completed a Phase I clinical trial and a Phase II clinical trial is ongoing, investigating its utility in the treatment of rheumatoid arthritis. Descriptions of the completed clinical trials may be viewed here. (top)
Psoriasis
Psoriasis is a non-contagious, chronic immune-mediated skin disease
affecting approximately 14.5 million patients in the seven major markets in 2012, with 6.5 million patients in the US alone. With approximately $4.6 billion spent on psoriasis therapeutics across the seven major markets in 2012, the market is expected to reach $5.4 billion by the year 2020.5
Psoriasis is a very diverse skin disease that appears in a variety
of forms. Plaque psoriasis is the most prevalent form of the disease,
which characterized by raised, inflamed, red lesions covered by a silvery
white scale. It is typically found on the elbows, knees, scalp and
lower back. About 80 percent of all those who have psoriasis have this
form.6
There are a broad range of treatments to help control psoriasis including
topical treatments, phototherapy (exposing the skin to wavelengths
of ultraviolet light under medical supervision), and systemic medications.6
In a series of eight survey panels conducted by the National Psoriasis Foundation from 2003 to 2006, more than 80% of respondents reported their disease to have a moderate to large problem in everyday life. Psoriasis may have a negative impact on a number of rudimentary daily activities that are often taken for granted with those without disease. Nearly one-half of respondents reported sleeping problems in the past month due to their condition. Nearly one-third of respondents reported that their condition interfered with sexual activities. Approximately one-third of respondents reported problems using their hands, walking, sitting and standing for long periods of time in the past month. More than 10% of respondents reported challenges in performing daily activities for 15 days of the past month. Less than one-third of respondents indicated they were very satisfied with their psoriasis treatment.7 (top)
Inflammatory Bowel Disease (IBD)
IBD is an umbrella term encompassing a number of chronic, relapsing inflammatory diseases involving the gastrointestinal tract, including Crohn's Disease and Ulcerative Colitis. Crohn's Disease is an inflammatory process that can affect any portion of the digestive tract, but is most commonly seen in the last part of the small intestine. Ulcerative Colitis is an inflammatory disease of the large intestine, commonly called the colon. The disease causes inflammation and ulceration of the inner lining of the colon and rectum. Because they behave similarly and may at times be difficult to differentiate, the two disorders are grouped together as IBD.8
In 2009, there were 890,000 patients with Crohn’s disease and approximately 1.4 million cases of ulcerative colitis in the seven major markets, over half of which were in the US. Prevalence of both diseases is predicted to incrementally increase in these markets through 2019 as a result of improved diagnosis, management and survival of IBD patients. The IBD pharmaceutical market is estimated at values of $3.4 billion in the US, $328,000 in Japan and $1 billion in the 5 major European markets (France, Germany, Italy, Spain and the UK).8
Both forms of IBD are chronic and onset occurs most frequently in early adult life, requiring management over a lifetime, most frequently with immunosuppressant therapy.8,9 This consists of mesalazine, steroids, and later of steroid-sparing agents (such as azathioprine, methotrexate or 6-mercaptopurine) or biologics.9 Refractory cases may require surgery, such as bowel resection, strictureplasty or a temporary or permanent colostomy or ileostomy.10 Current therapies are by and large considered inadequate by healthcare providers.9 Thus, there is a substantial market of IBD patients with unmet medical needs. (top)
Additional Research
In addition to the aforementioned disease states, further potential applications in which metabolically inert antifolate therapies, such as CH-4051, may play a significant role include uveitis, ankylosing spondylitis, cancer and other immunological disorders. Chelsea plans to continue working with key opinion leaders to identify and evaluate additional potential therapeutic areas for CH-4051. (top)
References
1. Disease Modification in Rheumatoid Arthritis Market Forecast, Interactive Model. 8 Sep 2011. Datamonitor- Pharmaceuticals & Healthcare. 5 Jan 2012.
2. Lipsky, P. (2006). Chapter 5: Rheumatoid Arthritis. In A. Fauci, Harrison's Rheumatology (pp. 82-99). McGraw-Hill Professional.
3. Muller D, Rindfleisch JA. Diagnosis and Management of Rheumatoid Arthritis. Am Fam Physician. 2005 Sep; 72(6):1037-1047.
4. Rheumatoid arthritis- Treatment and drugs. 2 Nov 2011. Mayo Clinic. 12 Jan 2012
5. Psoriasis Market Forecast, Interactive Model. 30 Nov 2011. Datamonitor- Pharmaceuticals & Healthcare. 6 Jan 2012.
6.
Lawley LP, McCall CO, Lawley TJ. Chapter 52. Eczema, Psoriasis, Cutaneous Infections, Acne, and Other Common Skin Disorders. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
7.
Epidemiology: Inflammatory Bowel Disease. Stable incidence but high prevalence due to early diagnosis and improved survival. 25 March 2011. Datamonitor- Pharmaceuticals & Healthcare. 10 Jan 2012.
9.
Wallace JL, Sharkey KA. Chapter 47. Pharmacotherapy of Inflammatory Bowel Disease. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011.
10. Roses RE, Rombeau JL. Recent trends in the surgical management of inflammatory bowel disease. World J Gastroenterol. 2008 January 21; 14(3): 408–412.
