Array BioPharma Announces Top-Line Results from Rheumatoid Arthritis Phase 2 Trial

BOULDER, Colo.--(BUSINESS WIRE)--Sep. 3, 2009-- Array BioPharma Inc. (Nasdaq: ARRY) today announced its preliminary analysis of results from a study examining ARRY-162, a small molecule MEK inhibitor, in a 12-week Phase 2 clinical trial with 201 patients. The patients had active rheumatoid arthritis (RA) that was not completely responsive to methotrexate. This study included a placebo group and three different dose groups of ARRY-162, all on a stable background of methotrexate. None of the treatment groups demonstrated a statistically significant ACR20 response rate compared to the placebo group at 12 weeks (p=0.459), therefore the study did not meet the primary endpoint.

Overall, the placebo response rates in this study were higher than expected for this patient population and showed regional differences, with patients in South America (99 patients) having substantially higher placebo response rates than those in Eastern Europe (101 patients). In Eastern Europe when patients in the three active treatment arms were combined, there was a trend towards efficacy, as measured by DAS28-4(CRP) (p=0.067), "Good" EULAR response (p=0.105) and ACR20 response rate (p=0.115). Array is conducting a full analysis of safety, efficacy and pharmacokinetic data from this study and expects to present complete results at a medical conference in 2010.

"This is the first clinical trial evaluating the modulation of the MEK pathway for the treatment of chronic inflammatory disease," said Kevin Koch, Ph.D., President and Chief Scientific Officer. "While we are disappointed in the overall efficacy outcome, we were pleased with the confirmation of the favorable safety profile and are continuing to evaluate the regional results. Previously we announced our strategy to rapidly advance ARRY-162 for the treatment of cancer patients. We initiated a Phase 1 oncology trial last month and patient dosing is underway."

Array will host a conference call on Friday, September 4, 2009, at 9:00 a.m. ET to discuss these results (see conference call details below). Array has also posted additional slides discussing these results on the Investor Relations section of Array's website at www.arraybiopharma.com.

Efficacy Results

The table below shows the ACR20 response rates at 12 weeks evaluated overall and by region in the efficacy evaluable population using last observation carried forward method.

ACR20 Response Rates at 12 weeks - Overall and by Region

 

Placebo

 

10 mg
BID

 

40 mg
QD

 

20 mg
BID

 

Global
P value*

 

All Treated
vs. Placebo
P value

 
Overall

46.9%
(N=49)

 

60.4%
(N=48)

 

61.2%
(N=49)

 

54.0%
(N=50)

  0.457   0.185  
Eastern Europe

34.6%
(N=26)

 

53.8%
(N=26)

 

58.3%
(N=24)

 

47.8%
(N=23)

  0.351   0.115  
South America

60.9%
(N=23)

 

68.2%
(N=22)

 

64.0%
(N=25)

 

59.3%
(N=27)

  0.936   0.810  

*Global P value compares all four treatment arms.

Safety Results

Consistent with earlier studies of up to 28 days with ARRY-162, the most common drug-related adverse events (AEs) observed in the study were skin-related (e.g., rash, dermatitis) and diarrhea. The incidence of these findings were most common in the 20 mg BID and 40 mg QD dose groups, and were generally mild-to-moderate in intensity. There were no drug-related serious adverse events. The table below shows the most frequently reported drug-related adverse events in the safety population.

Most Commonly Reported Drug-Related Adverse Events

Adverse Event  

Placebo
N=49

 

10 mg BID
N=49

 

40 mg QD
N=50

 

20 mg BID
N=50

 
Rash*   4%   12%   28%   42%  
Diarrhea   4%   4%   24%   18%  
Abdominal Pain   4%   2%   4%   4%  

Abnormal Liver
Function Tests**

  2%   2%   2%   8%  
Nausea   0%   0%   6%   4%  
Peripheral Edema   0%   0%   4%   4%  

Drug-related as assessed by investigators, blinded to treatment.
* includes any event of rash, rash pustular, rash erytematous, rash papular, folliculitis, acne, dermatitis acneiform, eczema, prurigo, rosacea, urticaria and erythema.
** includes any event of alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, liver function test abnormal and transaminases increased. All events were Grade 1 in severity.

About Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a debilitating autoimmune disease that affects more than two million Americans, and as many as 1% of the global population, and hinders the daily activities of sufferers. The damage that occurs in RA is a result of the immune system attacking joint tissue, causing painful chronic inflammation, often resulting in irreversible destruction of cartilage, tendons and bones. Common RA symptoms include inflammation of the joints, swelling, fatigue, stiffness and pain. Additionally, since RA is a systemic disease, it can have effects in other tissues such as the lungs and eyes.

ARRY-162 Phase 2 RA Trial Design

This was a Phase 2, randomized, double-blind, placebo-controlled, 12-week, parallel treatment trial of ARRY-162 in patients with active RA on stable doses of methotrexate. Patients entering the study had an inadequate response to methotrexate (≥6 swollen and ≥6 tender joints with C-reactive protein ≥1 mg/dL at screening) and had been on a stable dose of methotrexate for at least 6 weeks prior to study entry. Prior therapy with biologics was not allowed. 201 patients were enrolled in this study. Patients were randomized 1:1:1:1 to one of three dosing regimens of ARRY-162 (10 mg BID, 20 mg BID, 40 mg QD) or placebo. The study enrolled 100 patients in Eastern Europe (99) and North America (1), and 101 patients in South America.

About ARRY-162 in Inflammatory Diseases

ARRY-162, an orally active MEK inhibitor, has shown significant efficacy and is well tolerated in preclinical models of human arthritis and other inflammatory diseases. In preclinical combination studies with standard of care RA treatments, including methotrexate, dexamethasone, ibuprofen, and etanercept, ARRY-162 was well tolerated and demonstrated at least additive efficacy, even with the maximally efficacious dose of etanercept. ARRY-162 was well-tolerated in preclinical studies for up to 9 months of daily dosing. Phase 1 clinical trials with ARRY-162 have demonstrated selective and dose-dependant inhibition of IL-1, IL-6 and TNF with convenient oral dosing, as well as good tolerability when used in combination with methotrexate.

About ARRY-162 in Cancer

Array believes ARRY-162 is particularly well-suited for use in cancer treatment and has advantages over other MEK inhibitors currently in development, including greater potency, and improved safety and pharmacokinetics. ARRY-162 has been administered to more than 230 patients/healthy subjects in clinical trials for either safety assessment or the treatment of inflammatory disease. The drug has been well-tolerated and demonstrated significant pharmacodynamic responses in the completed trials. In addition, the Company has completed long-term preclinical regulated safety studies and has identified a commercially viable synthetic process and oral formulation for ARRY-162.

About MEK

MEK is a key protein kinase in the RAS/RAF/MEK/ERK pathway, which mediates production of key proinflammatory cytokines, including TNFα, IL-1β and IL-6, as well as cellular proliferation and survival. It also has a role in pathogenic bone remodeling through direct effects on osteoclasts, the cells responsible for bone resorption. MEK inhibition therefore has the potential to be a novel and safe approach to treating chronic, progressive inflammatory diseases because of its observed anti-inflammatory and bone anti-resorptive effects. In addition, MEK is frequently activated in cancer, in particular in tumors that have mutations in the RAS and RAF oncogenes. Preclinical data show that MEK inhibitors are additive or synergistic in combination with other agents. In particular, the PI-3K/AKT/mTOR pathway interacts with the RAS/RAF/MEK/ERK pathway in response to growth factor signaling. Simultaneous inhibition of both these pathways has significantly greater preclinical anti-tumor activity compared to inhibition of either pathway alone. Because these pathways are commonly activated in many tumors, we believe that dual MEK and PI3K/AKT/mTOR inhibition could have broad anti-tumor activity.

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