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In a Phase 1 dose-escalation/expansion trial of 44 evaluable patients, ARRY-614 demonstrated activity
as a single agent in patients with low or intermediate-1 risk MDS under the International Prognostic
Scoring System (IPSS) and for whom treatments with approved therapies have failed, including
hypomethylating agents and Revlimid. There was a 38% response rate for hematologic improvement in
patients receiving the highest dose of 1200 mg daily (n=16). At this dose, ARRY-614 demonstrated
multilineage hematologic improvement in 67% of the responders, improving more than one cytopenia
(neutropenia, thrombocytopenia and/or anemia).
Hematologic improvement with ARRY-614 was durable (five-month median response duration), with
multiple patients remaining on therapy for over twelve months. Clinically significant hematologic toxicity
was minimal. Observed changes in pharmacodynamic markers included p38-dependent normalization of
plasma erythropoietin, as well as decreases in phospho-p38 and disease-related apoptosis in the bone
marrow.
Development Status: During fiscal 2012, we initiated a second dose-escalation Phase 1 trial using an
optimized formulation in patients with MDS. During the next fiscal year, we plan to meet with the FDA to
discuss the development plan to support registration, finish the ongoing Phase 1 trial and, given
continued positive results, initiate a potential registration study in patients with MDS.
3.
ARRY-797 -- p38 Program for Pain
p38 regulates production of the pro-inflammatory cytokines TNF and IL-1, both mediators of
inflammation, and PGE2, a significant mediator of pain. ARRY-797 is a novel, oral, selective p38 inhibitor
with a mechanism of action unique from that of currently approved pain medications. Compared to other
p38 inhibitors, ARRY-797 has distinct properties: it is highly selective, has exceptional potency in whole
blood samples, has a differentiated pharmacokinetic profile and is highly water soluble.
In two Phase 2 acute dental pain studies, ARRY-797 achieved statistically significant analgesic effects. In
the course of clinical development to date, over 450 subjects/patients have received at least one dose of
ARRY-797. In these mostly short-duration studies, ARRY-797 was generally well-tolerated with common
adverse events including dizziness, headache, diarrhea and nausea, mostly mild in severity and with no
clear relation to dose or duration of exposure. Post-hoc analyses of a 28-day rheumatoid arthritis study
and a 12-week ankylosing spondylitis study of ARRY-797 in a small number of patients conducted in
2009 suggested pain relief with ARRY-797.
In July 2012, Array announced that ARRY-797, a non-opioid, met its primary endpoint in a randomized,
placebo-controlled and active-controlled (oxycodone ER) Phase 2 clinical trial in 157 osteoarthritis
patients suffering from moderate to severe knee pain despite the use of non-steroidal anti-inflammatory
drugs (NSAIDs). Patients in all treatment groups continued using NSAIDs throughout the trial. Treatment
with ARRY-797 resulted in a statistically significant reduction in pain over a 28-day period compared to
placebo, as measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC )
pain subscale (a 0 - 10 numerical pain rating scale). Patients receiving ARRY-797 experienced a mean
reduction in the WOMAC pain subscale score at day 28 vs. baseline that was 0.8 greater than those
receiving placebo (2.4 vs. 1.6; one-sided p = 0.0247). Oxycodone ER was used as the active control for
the trial and achieved improvement of 0.28 versus placebo due to a higher discontinuation rate.
ARRY-797 also showed improvement relative to placebo or oxycodone ER in additional measures
including, WOMAC physical function, WOMAC stiffness and the Patient's Treatment Satisfaction
Measure. The discontinuation rate due to adverse events was higher in patients treated with oxycodone
ER (34%) than for either the ARRY-797 (6%) or placebo (8%) treatment groups. In patients completing
the trial, the reduction in WOMAC pain observed for ARRY-797 was comparable to that seen with
oxycodone ER. In this trial, ARRY-797 was considered overall to be well-tolerated at the selected dose of
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400 mg twice-daily. The most common adverse events observed in patients treated with ARRY-797 were
dizziness, diarrhea and nausea, which were mainly mild in severity. ARRY-797 treatment was associated
with sporadic, transient increases in creatine kinase and aspartate aminotransferase. Mild prolongations
of the QTc interval and sustained decreases in systolic and diastolic blood pressure were also observed.
To further explore the safety and tolerability of ARRY-797, Array is currently conducting a multiple
ascending dose trial in healthy volunteers at doses up to 2.5-fold higher than those evaluated in the
osteoarthritis pain trial. ARRY-797 has been well-tolerated in this trial to date, and greater QTc
prolongations were observed at these higher dose levels. No subject in either trial exhibited an absolute
QTc interval greater than 500 msec or a change from baseline greater than 60 msec, two values cited by
regulatory authorities, including the FDA, as thresholds of particular concern for cardiac arrhythmia. We
believe these QTc observations warrant further evaluation.
Development Status: Array believes ARRY-797 has an opportunity to address a significant unmet
medical need in both acute and chronic pain. Given the scope of a development program in pain, Array
will seek an appropriate partner to maximize the value of this drug.
4.
ARRY-502 -- CRTh2 Program for Asthma
ARRY-502, an oral CRTh2 antagonist, has the potential to be an effective treatment for patients with
asthma, particularly those with severe disease, and may have advantages over competitor molecules in
development. In various preclinical models of allergic inflammation, ARRY-502 has demonstrated a high
level of anti-inflammatory activity. In a randomized, double-blind, 14-day multiple ascending dose
Phase 1 trial when ARRY-502 was dosed to healthy subjects, ARRY-502 was well-tolerated at all doses
evaluated, with all treatment-related adverse events being mild. Dose proportional increases in
ARRY-502 exposure were observed with overall low inter-subject variability. ARRY-502 provided robust
and sustained pharmacodynamic activity in this Phase 1 trial.
Inappropriate inflammatory responses to environmental allergens underlie allergic reactions such as
allergic asthma, allergic rhinitis and atopic dermatitis, which collectively affect up to 20% of the United
States population. Despite the range of treatments used to treat allergic asthma, there remains a
significant need for patients with severe asthma as well as for more convenient, safe and effective
therapies for those with mild to moderate persistent asthma. Although severe asthma affects only
approximately 10% of the asthmatic population, the condition results in approximately 60% of total
healthcare costs associated with asthma. Currently, few treatment options exist for patients with severe
asthma.
In severe allergic asthma, there is emerging evidence suggesting that a greater presence of the mediator
prostaglandin D2, or PGD2, and an upregulation of CRTh2, the biologically relevant receptor for
PGD2-mediated allergic response, that is expressed on inflammatory cells, may play a particularly
important role in more pronounced symptoms of asthma such as coughing, difficulty breathing, lower lung
function and possibly exacerbations. Activation of CRTh2 has been shown to result in chemotaxis and
activation of inflammatory cells and stimulate the production of cytokines that are thought to drive asthma
pathophysiology, particularly in the Th2-signature population.
Based on the role of CRTh2 in mediating the actions of PGD2, selective antagonism of CRTh2 presents
an attractive therapeutic approach to the treatment of allergic diseases spanning the severity spectrum. In
addition, there is a potential for patient selection in allergic asthmatics which would increase the likelihood
of successful treatment. There are selective antagonists of CRTh2 in various stages of clinical
development with compounds currently being evaluated in Phase 2 studies in allergic rhinitis, asthma and
eosinophilic esophagitis.
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