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disease. Based on these early results, we believe selumetinib has the potential to treat patients with
RAI-refractory thyroid cancer.
Pain and Inflammatory Diseases Market
Pain and inflammation are closely interrelated, yet present distinct challenges and opportunities. Pain
remains one of the most pressing as well as largest therapeutic areas to address, including a wide
spectrum of acute, sub-acute and chronic pain conditions ranging from acute postoperative pain to
chronic osteoarthritis pain. Although well established, the pain field continues to evolve and specialize, as
the etiology of pain is recognized as being increasingly complex. Many medications, procedures and
devices are marketed to address different forms of pain exist, yet pain remains an area of significant
unmet need. In recent years, with the exception of the introduction of antidepressant drugs such as
Cymbalta
(duloxetine) and the antiepileptics Neurontin (gabapentin) and Lyrica (pregabalin), drug
development in pain has been rather limited. Instead, drug development has focused largely around
reformulations and alternate delivery mechanisms to provide improved safety/tolerability/drug abuse
prevention among the leading existing classes of opioids and non-steroidal anti-inflammatory drugs, or
NSAIDs.
Inflammation is a natural biologic response to injury or infection that, under normal conditions, resolves
during healing or clearing. Unregulated inflammation results in a broad range of conditions, most of which
are classified by the tissue or organ where the inflammation occurs. These conditions include: respiratory
diseases such as asthma, allergic rhinitis, and chronic obstructive pulmonary disease; dermatological
conditions such as psoriasis and atopic dermatitis; gastrointestinal disorders such as Crohn's disease
and ulcerative colitis; musculoskeletal disorders such as rheumatoid arthritis, systemic lupus
erythematosus, gout and spondyloarthropathies such as psoriatic arthritis and ankylosing spondylitis.
Similar to the pain market, there are a wide range of drug treatment options and delivery mechanisms
depending on the specific condition. Yet even in acknowledged ``crowded'' disease areas such as
asthma, there still remains significant unmet need in specific populations such as those with severe,
refractory and difficult-to-control asthma.
Pain (ARRY-797 -- p38 inhibitor)
Patients are treated for almost 320 million cases per year of acute and sub-acute pain in the U.S. alone.
Acute and sub-acute pain occurs under a broad set of circumstances including bone fractures,
postoperative pain in planned surgical or trauma/emergency settings, severe migraine attacks, arthritis
flares, and breakthrough cancer pain. For example, surgical patients typically experience moderate to
severe pain up to a few weeks after the procedure.
Chronic pain presents perhaps an even more significant burden, with about half of all adults experiencing
chronic pain in their lifetime. According to a recent report to the U.S. Department of Health and Human
Services by the Institute of Medicine, chronic pain affects an estimated 116 million adults in the U.S. and
costs the nation up to $635 billion per year in medical treatment and lost productivity. Chronic pain,
variously defined as a pain condition which persists or recurs for a duration of greater than three or
greater than six months depending on the specific condition, includes a wide range of conditions including
arthritic pain, inflammatory pain, chronic low back pain, fibromyalgia, neuropathic pain (e.g., post-herpetic
neuralgia, painful diabetic neuropathy), chronic headache, and cancer pain.
The major analgesic pain therapies currently on the market, including opioids, NSAIDs and selective
COX-2 inhibitors, have side effect and efficacy issues. Opioids are the most commonly prescribed drug
class in the U.S., with 15% to 20% of doctor visits involving an opioid prescription, and four million
Americans per year prescribed a long-acting opioid. Opioids are efficacious in the management of pain,
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but have considerable side effects including nausea, vomiting, constipation, respiratory depression and
cognitive dysfunction. Perhaps even more significant, opioid drug abuse is a major concern. Since 1999,
deaths in the U.S. involving opioids have more than tripled to 14,800 in 2008, accounting for over 40% of
all drug poisoning deaths. In addition, for every unintentional overdose death related to an opioid
analgesic, nine persons are admitted for substance abuse treatment, 35 visit emergency departments,
161 report drug abuse or dependence, and 461 report nonmedical uses of opioid analgesics. NSAIDs
have demonstrated pain reduction which is modest but less efficacious than opioids. Although NSAIDs
have overall a more favorable safety profile than opioids, renal toxicity and gastrointestinal bleeding are
associated with their use. COX-2 inhibitors, though possibly offering less gastrointestinal toxicity than
NSAIDs, still result in other side effects associated with NSAIDs, most notably adverse cardiovascular
effects. Most drugs in this class have been withdrawn from the U.S. market, with the notable exception of
Celebrex
(celecoxib).
Market growth of drug therapies used in acute, sub-acute and chronic pain settings is expected to be
moderate. Sales across the seven major pharmaceutical markets for acute and sub-acute pain are
forecasted to grow annually by 3% from $17.4 billion in 2010 to $22.1 billion in 2018. Sales for chronic
pain are forecasted to grow annually by 4% from $21.1 billion in 2010 to $29.0 billion in 2018.
Few innovative pain therapeutics have successfully emerged from clinical development in recent years.
We believe there is an opportunity for a novel drug with efficacy comparable to opioids, NSAIDs and
COX-2 inhibitors for the treatment of patients who are intolerant of or refractory to these classes of drugs.
Further, there is an opportunity in several inflammatory pain conditions affecting large populations, such
as RA and ankylosing spondylitis, to offer additional pain relief over and above what current targeted
therapeutics, such as tumor necrosis factor alpha, or TNF , inhibitors, may provide.
Array is currently developing ARRY-797, a p38 inhibitor. p38 is well-known for its role in the regulation of
the production of pro-inflammatory cytokines such as TNF and IL-1, as well as PGE2, a significant pain
modifier. Based on several past clinical studies and positive results from the recently completed 28-day
study evaluating the analgesic efficacy of ARRY-797 in patients with pain due to osteoarthritis of the knee
despite the use of NSAIDs, we believe ARRY-797 has good potential to treat a broad range of pain
conditions in acute and chronic settings.
Asthma (ARRY-502 -- CRTh2 antagonist)
Asthma is a chronic condition of the airways that currently poses one of the more significant public health
burdens. According to the American Lung Association, in 2009 an estimated 25 million individuals have
asthma, resulting in approximately 3,500 deaths per year and nearly $56 billion in medical treatment and
lost productivity.
Asthma is a heterogeneous disease, caused by a combination of environmental and genetic factors,
which can wax and wane, with varying frequency and severity among individual patients. The majority of
asthma patients suffer from allergic asthma, whereby the patient's immune system produces an
exaggerated response to allergens (e.g. pollens, pets, dust). This type of asthma is often termed
Th2-mediated asthma (T-helper 2 cells). Mast cells, activated by IgE, release histamine and various other
mediators that cause immediate bronchospasm, or a constriction of the muscles of the airway walls, and
vasoconstriction, or narrowing of bronchial blood vessels, thereby resulting in coughing and difficulty
breathing. Mast cells also promote tissue damage in the airways through release of other mediators,
notably cytokines, chemokines, and prostanoids such as the mediator prostaglandin D2, or PGD2, which
results in the attraction of more inflammatory cells to the lungs. In severe allergic asthma, there is
emerging evidence suggesting that a greater presence of PGD2 and an upregulation of CRTh2, the
biologically relevant receptor for PGD2-mediated allergic disease that is expressed on Th2 cells,
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