This article is the second in a three part series about Array BioPharma Inc. (NASDAQ:ARRY), a biopharmaceutical company that is developing small molecule drug candidates for the treatment of cancers and other diseases. The first article looked at Array's collaboration with Novartis (NYSE:NVS), Amgen (NASDAQ:AMGN), AstraZeneca (NYSE:AZN) and other companies that are developing some promising therapies. This article focuses on several investigational drugs that the company is developing on its own.
In addition to oncology, Array also has an interest in the development of pain and inflammation therapies. Pain therapies continue to evolve and specialize, as the etiology of pain is recognized as being increasingly complex. Although many drugs and devices are marketed for different types of pain, there is still significant unmet need.
According to the research and advisory firm Decision Resources, the pain therapies market will grow at an annual rate of 1.8% over the next 15 years, surpassing $49 billion in sales in 2026.
Formerly known as "pre leukemia," MDS are a group of blood disorders associated with low blood counts. In MDS, the bone marrow does not function effectively to produce one or more types of blood cells, including red blood cells, white blood cells, and platelets.
MDS is treated with blood transfusions, hematopoietic growth factors, chemotherapy, immunosuppressive drugs, and bone marrow transplants.
According to the American Cancer Society, approximately 12,000 people in the United States are diagnosed with MDS each year. About 80% to 90% of those who develop MDS are age 60 or older. Death from MDS is often caused by bleeding and infection from low blood cell counts or if the MDS progresses to acute myeloid leukemia (AML). About one-third of patients with MDS develop AML.
In an initial Phase 1 dose-escalation trial in patients with low or intermediate-1 risk MDS, ARRY-614 achieved a response rate of 38% hematologic improvement at the highest dose evaluated.
Array continued to evaluate an optimized formulation of ARRY-614 in a clinical trial with a similar patient population. This Phase 1 dose-escalation trial, currently in an expansion phase after reaching the maximum tolerated dose, has the goal of identifying the recommended dose for future clinical trials. Researchers have found that this new formulation has demonstrated improved bioavailability and target coverage.
In December 2012, the FDA provided guidance for the future development of ARRY-614, including a discussion of endpoints other than overall survival that could be used as the basis for approval. The FDA also agreed that Low/Int-1 patients who have failed a hypomethylating agent, such as Vidaza, can be considered a high unmet medical need population. Array plans to decide on future study designs for ARRY-614 by the end of 2013.
ARRY-797 is a novel, oral, selective inhibitor with a mechanism of action unique from that of currently approved pain medications. This investigational drug is a non-opioid.
On July 31, 2012, Array announced that ARRY-797 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).
In this trial, ARRY-797 was considered to be well-tolerated at the selected dose of 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. However, 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. Some analysts believe that since heart rhythm are associated with QTC prolongation and liver enzyme elevations with aspartate aminotransferase, the company may have a difficult time obtaining FDA approval.
In November 2012, Array presented data at the 2012 American College of Rheumatology annual meeting assessing biomarkers of cartilage (COMP) and bone (CTX‑I) degradation. Researchers found that ARRY‑797 treatment resulted in statistically significant decreases of 10% for COMP and 38% for CTX‑I versus placebo at week 4,The decrease in CTX‑I was sustained and returned to baseline by the follow‑up visit.
Since Array's focus is on hematology/oncology, the company is seeking a partnership to maximize the value of this drug.
According to the US Centers for Disease Control and Prevention (CDC), approximately 18.9 million adults in the United States have asthma, representing about 8.2% of the population. In addition, about 7.1 million children have asthma, which equates to about 9.5% of all US children.
Severe asthma affects approximately 10% of the asthmatic population. Currently, there are few treatment options for patients with severe asthma.
Array scientists are studying ARRY-502, an oral CRTh2 antagonist, as a treatment for patients with asthma, particularly those with severe disease. In preclinical models of allergic inflammation, ARRY-502 was found to have high anti-inflammatory activity. Array researchers also found that ARRY-502 provided robust, sustained pharmacodynamic activity and was found to be well tolerated by asthma patients in Phase 1 trials. All adverse events were mild.
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 an important role in asthma symptoms such as coughing, difficult breathing, lower lung function and possibly exacerbations.
Based on the role of CRTh2 in mediating the actions of PGD2, Array scientists believe that the selective antagonism of CRTh2 presents an attractive therapeutic approach for the treatment of allergic diseases. 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.
Array has completed recruitment of a 182-patient Phase 2a trial with ARRY-502 in mild to moderate persistent asthma. Array expects top-line results from this trial during the summer of 2013 and intends to seek a partner for further development of ARRY-502 in this large market disease indication.
Array is studying ARRY-520 as a potential treatment for multiple myeloma (MM). This Array owned investigational drug is a potent, selective kinesin spindle protein (KSP) inhibitor. ARRY-520's mechanism of action is distinct from other drugs used to treat MM
In preclinical studies, ARRY-520 treatment resulted in a rapid onset of apoptosis in tumor cells that depend on the MCL-1 survival protein. MM and other hematologic cancers frequently depend on MCL-1 as a key survival protein.
In clinical studies, ARRY-520 demonstrated durable, single agent activity in patients with MM that is refractory to both Takeda Pharma's (OTCPK:TKPYY)/Millenium Pharmaceuticals' Velcade (bortezomib) and Celgene's (NASDAQ:CELG) Revlimid (lenalidomide). ARRY-520 was found to be highly active in animal models of MM and synergy was observed when combined with Velcade or Revlimid. Array scientists believe that these data support the ongoing investigation of ARRY-520 in combination with Velcade and Onyx Pharmaceuticals' (NASDAQ:ONXX) Kyprolis (carfilzomib), which may enable development opportunities in earlier lines of therapy.
Array presented Phase 1 and Phase 2 clinical data for ARRY-520 at the December 2011 American Society of Hematology (ASH) annual meeting. In these studies, ARRY-520 showed preliminary clinical activity in heavily pre-treated patients with MM and was found to be generally well-tolerated.
In the Phase 2 trial, ARRY-520 demonstrated promising activity in patients with relapsed or refractory MM who had received both a proteasome inhibitor and an IMiD-based regimen. Objective responses were observed in six patients (19%), with four confirmed partial responses and two minor responses. ARRY-520 demonstrated an 18% response rate (minor response or better) in patients with MM refractory to both Revlimid and Velcade.
On April 4, 2013, Array announced results from two ongoing ARRY-520 clinical trials in MM were presented at the 2013 International Myeloma Workshop in Kyoto, Japan.
ARRY-520 demonstrated single agent activity in heavily pretreated patients, with 19 months median overall Survival and a 16% Overall Response Rate. These results are similar to those for recently approved products Kyprolis (carfilzomib) and Pomalyst (pomalidomide) as single agents in a similar patient population.
ARRY-520 was generally well tolerated, with the predominant adverse events being transient and non-cumulative neutropenia and thrombocytopenia that were readily managed with growth factors and supportive care.
Consistent with other reported ARRY-520 study results, there was a low-incidence of non-hematologic adverse events with no treatment-related neuropathy observed.
Further data on a potential patient selection marker was also presented. Patients with normal levels of alpha-1-acid glycoprotein (AAG) had a longer median Overall Survival (20.2 months vs 4.5 months), improved median Event Free Survival (5.3 months vs. 2.4 months) and greater Overall Response Rate (24% vs 0%) compared to patients with elevated AAG. The identification of this marker may enable more precise targeting of patient populations who will benefit from ARRY-520.
In another trial studying ARRY-520 plus Velcade (bortezomib) combination treatment was generally well-tolerated. Neutropenia was the most common adverse event and non-hematologic grade 3 or 4 toxicity was infrequent. Neutropenia was well managed by the use of growth factor support.
Researchers noted initial signs of activity, including responses and prolonged stable disease, were observed in this heavily pretreated population. The majority were refractory to prior Velcade treatment.
An alternate treatment regimen with the addition of low-dose dexamethasone will be evaluated in the study.
During 2013, Array plans to report results from the Phase 2 study of ARRY-520 in combination with dexamethasone, interim results from the Phase 1b study of ARRY-520 in combination with Velcade and dexamethasone and interim results from the Phase 1b study of ARRY-520 in combination with Kyprolis. If there are positive results in either of these trials, the company plans to define a path to late stage development for ARRY-520 in MM
In MDS patients, p38 and Tie2 are dysregulated in the bone marrow. ARRY-614 enables the repopulation of red blood cells, platelets and neutrophils and is believed to restore bone marrow function by blocking myelosuppression.
ARRY-614 was found to inhibit inflammation and cytokine-dependent tumor growth in preclinical models.
MDS are diseases characterized by over-production of myelosuppressive cytokines leading to aberrant apoptosis in hematologic progenitor cells and peripheral cytopenias. p38 MAP kinase (p38) is implicated in dysregulation of apoptosis and myelosuppressive cytokine signaling and production. Tie2 may affect this process by promoting cytokine production and altering stromal cell quiescence. It is hypothesized that disrupting cytokine-driven apoptosis in the normal progenitors and stromal cells may improve hematopoiesis in MDS patients.
According to the American Cancer Society, MDS is at a rate of 4.5 cases for every 100,000 people. That works out to about 12,000 new cases of MDS each year in the United States. The number of new cases diagnosed each year seems to be increasing as the average age of the population has increased. About 80% to 90% of all patients with MDS are older than 60 years.
Array presented positive clinical data for ARRY-614 at the December 2011 ASH and June 2012 European Hematology Association (EHA) meetings. ARRY-614 demonstrated activity as measured by hematologic improvement (increased neutrophils, platelets and/or red blood cells) in patients with MDS and was generally well-tolerated.
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 had 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. 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 had a 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.
During fiscal 2012, Array initiated a second dose-escalation Phase 1 trial using an optimized formulation in patients with MDS.
In an initial Phase 1 dose-escalation trial in patients with low or intermediate-1 risk MDS, ARRY-614 achieved a response rate of 38% hematologic improvement at the highest dose evaluated.
Array continued to evaluate an optimized formulation of ARRY-614 in a clinical trial with a similar patient population. This Phase 1 dose-escalation trial, currently in an expansion phase after reaching the maximum tolerated dose, has the goal of identifying the recommended dose for future clinical trials. This new formulation has demonstrated improved bioavailability and target coverage, including higher peak plasma concentrations and overall exposures, as compared to the original formulation.
At the end of 2012, the FDA provided guidance to Array for the future development for this program, including a discussion of endpoints other than overall survival that could be used as the basis for approval. The FDA also agreed that Low / Int-1 patients who have failed a hypomethylating agent, such as Vidaza, can be considered a high unmet medical need population. Since the company now has guidance on a potential path to registration and, pending additional data from the ongoing study, it plans to make decisions on future study designs by the end of 2013.
The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years, p38 has been considered a promising target for the development of new anti-inflammatory drugs to treat RA and other chronic immune-mediated inflammatory diseases. p38 regulates production of the pro-inflammatory cytokines TNF and IL-1, both mediators of inflammation, and PGE2, a significant mediator of pain.
Another Array owned program, ARRY-797, a non-opioid, 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. This investigational drug 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 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. Researchers found that 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 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. Array believes these QTc observations warrant further evaluation.
The research and advisory firm, Decision Resources, forecasts that the acute pain drug market will increase to $17.4 billion through 2021 in the United Sates, France, Germany, Italy, Spain, the United Kingdom and Japan, and that in 2010, sales of pharmacological therapies for the treatment of chronic pain exceeded $20 billion in the seven major pharmaceutical markets.
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.
I hope you will check out the third article in this series that looks at Array's financing and whether or not the drug is a wise investment.