We are a clinical-stage biotechnology company engaged in the research and development of innovative cancer therapeutics. Our mission is to produce novel medicines with differentiated mechanisms of action that target the specific biological pathways implicated in a wide range of cancers. We employ novel technologies such as our ArQule Kinase Inhibitor Platform ("AKIP™") to design and develop drugs that have the potential to fulfill this mission.
Our products and programs span a continuum of research and development ranging from drug discovery to advanced clinical testing. They are based on our understanding of biological processes that lead to the proliferation and metastasis of cancer cells, combined with our ability to generate product candidates possessing certain pre-selected, drug-like properties and designed to act specifically against cancer cells. We believe that these qualities, when present from the earliest stages of product development, increase the likelihood of producing safe, effective and marketable drugs.
Our lead product is ARQ 197, a non-adenosine triphosphate ("ATP")-competitive inhibitor of the c-Met receptor tyrosine kinase ("c-Met"). C-Met is a promising target for cancer therapy, as evidence suggests that it plays a key role in cancerous cell proliferation, tumor spread, new blood vessel formation and drug resistance. Our ongoing Phase 2 clinical trial program with ARQ 197 encompasses six tumor types, including non-small cell lung cancer, c-Met-associated soft tissue sarcomas, pancreatic adenocarcinoma, hepatocellular carcinoma, germ cell tumors and colorectal cancer. We believe the trials within the Phase 2 program for ARQ 197 offer the potential for proof-of-principle data that can be generated in one or more indications beginning in early 2010 through 2011, as well as the potential for fast-to-market regulatory pathways in certain indications.
We have licensed commercial rights to ARQ 197 for human cancer indications to Daiichi Sankyo Co., Ltd. ("Daiichi Sankyo") in the U.S., Europe, South America and the rest of the world, excluding Japan and certain other Asian countries, where we have licensed commercial rights to Kyowa Hakko Kirin Co., Ltd. ("Kyowa Hakko Kirin"). Our agreements with these partners provide for possible future milestone payments, royalties on product sales, and development funding, in addition to significant payments that we have already received.
Our proprietary pipeline is directed toward molecular targets and biological processes with demonstrated roles in the development of human cancers. The most advanced candidate in this pipeline is ARQ 621, an inhibitor of the Eg5 kinesin motor protein that is in Phase 1 clinical testing. Additional pipeline assets include ARQ 501 and ARQ 761, activators of the cell's DNA damage response mechanism that we plan to develop further on a partnered basis. We are also pursuing pre-clinical development of an inhibitor of the B-RAF kinase that is in toxicology testing leading to a potential Investigational New Drug ("IND") submission in 2010.
Our drug design efforts are focused primarily on AKIP™, which we are using to generate compounds designed to inhibit kinases without competing with adenosine triphosphate ("ATP") for binding to the target kinase. ATP is a chemical found in all living cells and is involved in a variety of physiological processes. We have assessed AKIP™'s potential to target multiple kinases in oncology and other therapeutic areas, and we are generating and validating compounds that inhibit these kinase targets. With the AKIP™ technology, we have discovered and optimized a series of small molecule inhibitors of fibroblast growth factor receptor inhibitors that are in pre-clinical development, with the potential submission of an IND for a lead product candidate in 2010. We are also pursuing a drug discovery collaboration with Daiichi Sankyo that utilizes the capabilities of the AKIP™ technology to discover compounds that inhibit two kinase targets in the field of oncology.
CLINICAL STAGE PRODUCTS
ARQ 197: c-Met Inhibitor
ARQ 197 is an orally available, small molecule that inhibits the c-Met receptor tyrosine kinase. Abnormal activation of c-Met is believed to play key roles in cancer cell growth, survival, angiogenesis, invasion and metastasis. We believe that the inappropriate expression of c-Met in many cancers and its role in controlling multiple signal transduction pathways involved in tumor growth and metastasis render it a compelling target for cancer therapy.
ARQ 197 is a specific inhibitor of c-Met and does not compete with ATP for its binding to this kinase. We believe this specificity may help confer an attractive therapeutic profile based on a combination of safety and anti-cancer activity. In clinical studies to date, treatment with ARQ 197 has been well tolerated both as a single agent and in combination with other targeted therapies and cytotoxic agents, and objective tumor responses and prolonged stable disease have been observed across broad ranges of doses and tumors.
Final results of a dose escalation, Phase 1 trial with ARQ 197 conducted at clinical trial sites in the U.S. were presented at the 2009 Annual Meeting of the American Society of Clinical Oncology in June, 2009. The objectives of this trial were to evaluate and establish: safety, maximum tolerated dose, the recommended Phase 2 dose, the pharmacokinetic profile and preliminary anti-tumor activity of ARQ 197.
A total of 74 patients were treated in this trial as of May 1, 2009, with 13 cohorts of patients assessed at doses ranging from 10-360 milligrams twice daily. Adverse events considered drug-related occurred in 30 (40.5 percent) patients, with the most common being fatigue (16.2 percent), nausea (12.2 percent), vomiting (6.8 percent) and diarrhea (5.4 percent). Drug-related serious adverse events occurred in 4 patients. Dose limiting toxicities were reported in 2 patients at 360 milligrams twice daily. These dose limiting toxicities resolved after 6 and 9 days, and treatment continued. No maximum tolerated dose was identified in this trial, although a monotherapy maximum tolerated dose of 360 milligrams twice daily was subsequently determined in a Phase 1 trial conducted at the Royal Marsden Hospital in the U.K.
Investigators concluded that ARQ 197 has a favorable safety profile up to the dose of 360 milligrams twice daily. Although the primary objective of the study was to collect safety data, 61 patients were evaluable for anti-tumor activity. Three patients, with neuroendocrine, prostate and testicular cancers, achieved partial responses per Response Evaluation Criteria In Solid Tumors, or RECIST criteria, for an objective response rate of 4.9 percent in the evaluable population. Thirty-eight patients had a best response of stable disease, and 20 had documented progressive disease. The disease control rate (objective responses and stable disease) among evaluable patients was 67.2 percent, suggesting preliminary evidence of anti-cancer activity and supporting further clinical investigation.
Phase 1 Dosing and Tissue Biopsy Study: Royal Marsden Hospital
Results from a second Phase 1 trial of ARQ 197, conducted at the Royal Marsden Hospital in the U.K. and incorporating serial tumor biopsies and imaging studies investigating the anti-angiogenic activity of selective c-Met inhibition, were also presented at the American Society of Clinical Oncology in June, 2009. The primary objective of this trial was to assess the safety, tolerability and recommended Phase 2 dose of ARQ 197. Secondary objectives included evaluation of pharmacokinetic and pharmacodynamic profiles of ARQ 197, and evaluation of the potential anti-angiogenic activity of selective c-MET inhibition by ARQ 197, a pharmacologic effect suggested by previously reported clinical and pre-clinical data.
A total of 46 patients with advanced solid tumors were enrolled in this trial. The most commonly enrolled tumor types included prostate cancer (12 patients), melanoma (11 patients), gastric cancer (6 patients), sarcoma (4 patients), colorectal cancer (3 patients), and breast cancer (2 patients). The most commonly reported adverse events were fatigue (40.9 percent), nausea (25.0 percent), and vomiting (20.5 percent). The most commonly observed adverse events considered to be at least possibly related to ARQ 197 were fatigue (15.9 percent), nausea (11.4 percent), diarrhea (6.8 percent) and vomiting (6.8 percent). Three patients experienced five dose limiting toxicity events. The recommended Phase 2 dose was established at 360 milligrams twice daily. which reflects an adjustment from a recommended Phase 2 dose of 300 milligrams twice daily based on formulation improvements. Tumor regressions up to 12.4 percent were observed in 2 patients. Stable disease lasting up to 23 weeks was observed in 15 of 24 evaluable patients (62.5 percent), while progressive disease was seen in nine of 24 evaluable patients (37.5 percent).
Evidence of anti-angiogenic effect was suggested by declines of circulating endothelial cells up to 100 percent in 19 of 31 evaluable patients (61 percent) following administration of ARQ 197.
Additionally, preliminary imaging data documented statistically significant day 7 decreases in radiographic markers, further suggesting an anti-angiogenic effect mediated by ARQ 197.
Investigators concluded that ARQ 197 was safe and well tolerated up to the recommended Phase 2 dose of 360 milligrams twice daily. Systemic exposure to ARQ 197 increased linearly with dose through the maximum tolerated dose. Inhibition of c-MET phosphorylation in tumor biopsies was observed post-treatment at all doses. Clinical improvement in symptoms was observed, as measured by RECIST stable disease up to 23 weeks and tumor regression.
Phase 2 Program
As described in more detail below, we are currently conducting Phase 2 clinical trials with ARQ 197 as monotherapy and in combination with other agents in six tumor types: (1) non-small cell lung cancer, (2) c-Met-associated soft tissue sarcomas, (3) pancreatic adenocarcinoma, (4) hepatocellular carcinoma, (5) germ cell tumors and (6) colorectal cancer. The dose level of ARQ 197 employed in all of these trials is 360 milligrams twice daily. We and our partners may plan trials in additional tumor types based on our expanding knowledge from the current development programs and the potential broad-spectrum utility of ARQ 197 in c-Met-mediated oncogenic processes, as well as its use in combination with established anti-cancer therapies.
Non-Small Cell Lung Cancer
Scientific data show that the development of resistance in patients with non-small cell lung cancer to therapy with inhibitors of the epidermal growth factor receptor such as erlotinib may be linked to an increase in c-Met signaling. We believe the inhibition of c-Met may offer a new strategy in overcoming this resistance and treating these tumors. In addition, pre-clinical efficacy studies in non-small cell lung cancer cells have demonstrated synergy between ARQ 197 and erlotinib in halting cancer cell proliferation.
In March 2008, we initiated a Phase 1/2 clinical trial program of ARQ 197 administered in combination with erlotinib in non-small cell lung cancer. The Phase 1 lead-in trial in this program was designed to determine the safety, tolerability and recommended Phase 2 dose of ARQ 197 when administered in combination with the approved dose of erlotinib (150 milligrams daily), with particular attention given to non-small cell lung cancer patients. During 2008, we successfully completed the Phase 1 trial, demonstrating that the combination of ARQ 197 and erlotinib was well tolerated at the recommended dose for each drug. In October 2008, we began enrolling patients in a Phase 2, randomized, double-blind trial comparing combination therapy with ARQ 197 plus erlotinib against erlotinib plus placebo, with the primary endpoint being progression-free survival.
At the American Society of Clinical Oncology in June, 2009, we presented results from the Phase 1 lead-in trial with ARQ 197 in non-small cell lung cancer. A total of 32 patients were enrolled and treated with escalating doses of ARQ 197 plus the recommended dose of erlotinib. Tumor types enrolled included non-small cell lung cancer (8 patients), colorectal cancer (3 patients), renal cell carcinoma (3 patients) squamous cell carcinoma (3 patients) and pancreatic cancer (2 patients). Adverse events were reported for 26 patients, including three patients with therapy-related serious adverse events. A dose limiting toxicity of reversible neutropenia was observed in two patients at a dose of 360 milligrams twice daily of ARQ 197. Pharmacokinetic data revealed a proportional increase in exposure of ARQ 197 at doses up to 360 milligrams twice daily and no evidence of ARQ 197-erlotinib drug-drug interaction.
Seventeen patients were evaluable for tumor responses, with one unconfirmed partial response, as measured by RECIST, in head and neck cancer, stable disease in 14 patients (82.4 percent) and progressive disease in 3 patients (17.6 percent). The duration of stable disease ranged from 5.9 to 45.4 weeks, with a median duration of 17.1 weeks. Tumor regressions of between 2.3 percent to 33.3 percent were observed in 5 patients after 8 to 26 weeks on therapy. Eight patients had non-small cell lung cancer, 6 of whom had prior treatment with erlotinib. Five patients who had prior therapy with erlotinib had stable disease lasting more than 17 weeks. The median duration of progression-free survival in non-small cell lung cancer patients in this trial was 26.3 weeks, or more than 6 months, greater than previously published median progression-free survival of 9.7 weeks in 2nd/3rd line non-small cell lung cancer patients with erlotinib monotherapy.
A subsequent presentation of updated data from this trial at the 13th World Lung Conference (July 31 – August 4, 2009) showed significantly longer durations of stable disease for non-small cell lung cancer patients and provided insights into key genetic factors independently associated with non-small cell lung cancer disease outcome and prognosis, and with the likelihood of benefit from treatment with epidermal growth factor receptor inhibitors such as erlotinib. Among the three remaining active patients with non-small cell lung cancer for whom data was presented, time on treatment increased from previously reported data, as follows: from 33.6 weeks to 47 weeks; 32.7 weeks to 46 weeks; and 17.6 weeks to 31 weeks.
New genetic information was presented at the World Lung Conference on six of the non-small cell lung cancer patients who had samples available for analysis. Biologic profiles were presented relating to three factors: c-Met gene amplification, epidermal growth factor receptor mutation status, and K-Ras mutation status. All of these factors are independently associated with non-small cell lung cancer disease outcome and prognosis, as well as with the likelihood of therapeutic benefit from epidermal growth factor receptor inhibitors, including erlotinib.
Specifically, three of six evaluated patients were c-Met-amplified (previously associated with poor outcome in non-small cell lung cancer), five of five evaluated patients were epidermal growth factor receptor wild-type (previously associated with poorer response to epidermal growth factor receptor inhibitors), and one of five evaluated patients harbored a K-Ras mutation (previously associated with poorer response to epidermal growth factor receptor inhibitors and extremely unfavorable prognosis in non-small cell lung cancer). Furthermore, of the three non-small cell lung cancer patients who were still being treated with the ARQ 197-erlotinib combination, two of three were c-Met amplified, all were epidermal growth factor receptor wild-type, and one was positive for the K-Ras mutation.
We completed recruitment in the Phase 2 trial in September, 2009 with approximately 170 patients enrolled in the U.S. and Europe. We plan to complete data analyses and announce the results of this trial in the first half of 2010.
C-MetAssociated Soft Tissue Sarcomas
C-Met-associated soft tissue sarcomas included in our trials are clear cell sarcoma, alveolar soft parts sarcoma and translocation-associated renal cell carcinoma. They are linked biologically through a common chromosomal abnormality that drives the over-expression of c-Met and the development of cancer. These tumors are generally resistant to all conventional therapies. We have demonstrated the ability of ARQ 197 to inhibit activation of c-Met and to kill clear cell sarcoma cells in vitro.
In October, 2007, we initiated a Phase 2 trial in c-Met associated soft tissue sarcomas that employed an original dose of 120 milligrams twice daily. The dose was increased to 360 milligrams twice daily in October, 2008 following the identification of a maximum tolerated dose in the Royal Marsden trial. The primary objective of the trial was to determine the overall response rate in patients treated with ARQ 197. Secondary objectives include the evaluation of progression-free survival time, as well as six-month and one-year overall survival in these patients.
During the first stage of the study, 23 patients were enrolled and treated with the 120 milligram dose. As announced in October, 2008, among 14 patients evaluable for efficacy, a partial response was observed in a patient with clear cell sarcoma, and 10 patients demonstrated stable disease. We subsequently proceeded to the second stage of the study, where additional patients were enrolled at the 360 milligram dose level. We also increased the dose administered to several patients from the first stage who continued to participate in this trial.
We completed recruitment in the Phase 2 trial in February, 2010 with a total of approximately 50 patients enrolled in North America and Europe. We plan to complete final data analyses and announce the results of this trial in the first half of 2010. These final data will be evaluated by Daiichi Sankyo, regulatory authorities and us in formulating decisions about whether to proceed with Phase 3 clinical testing.
In pancreatic cancer, between 78 and 88 percent of tumor tissue samples from patients are estimated to over-express c-Met, indicating that the c-Met signaling pathway may play a role in the development of this disease and that inhibition of this pathway may represent a viable therapeutic intervention. ARQ 197 has shown anti-cancer activity in animal models of human pancreatic cancer.
In October, 2007, we initiated an open-label, randomized Phase 2 trial in Eastern Europe in which approximately 72 patients with pancreatic adenocarcinoma were expected to be treated with either ARQ 197 or gemcitabine. Eligible patients were randomized to receive either 120 milligrams of ARQ 197 orally twice daily or intravenous infusion of gemcitabine at a dose of 1000 milligrams per meter squared and evaluated for overall survival, progression-free survival and overall response rate.
A review of interim data from this trial conducted in 2008, supported by discussions with key opinion leaders, suggests that chemotherapy is a preferable approach to monotherapy kinase inhibition among the late-stage patients in this trial. We believe, therefore, that targeted therapy such as ARQ 197 may be best employed in the context of combination therapy in pancreatic cancer. Consequently, we have modified the original pancreatic clinical trial protocol by adding a combination arm consisting of ARQ 197 at 360 milligrams twice daily in combination with gemcitabine. To proceed with this plan, we are testing the safety of this combination compared to both individual arms, and we have been dosing patients with gemcitabine-treated tumors, including pancreatic adenocarcinoma. Based on a review of data generated in all arms, we will make a decision about adding a combination arm to the Phase 2 randomized study that will evaluate gemcitabine alone against gemcitabine in combination with ARQ 197 at 360 milligrams twice daily in pancreatic cancer patients.
Scientific literature provides evidence of the aberrant activation of the c-Met cell signaling pathway in hepatocellular carcinoma. The dysregulation of c-Met and hepatocyte growth factor expression has been shown to be common in this disease and associated with poor prognoses in patients with hepatocellular carcinoma. We believe that ARQ 197 offers a new therapeutic approach which may have clinical utility as monotherapy and in combination with existing therapies.
We initiated a Phase 1-2 clinical trial program of ARQ 197 in hepatocellular carcinoma in March, 2009. This program includes trials of ARQ 197 both as a single agent and in combination with sorafenib. We dosed the first patient in the Phase 1 ARQ 197 monotherapy safety trial in hepatocellular carcinoma in March, 2009, and we dosed the first patient in the Phase 1 ARQ 197-sorafenib combination therapy safety trial in June, 2009.
Following the evaluation of patients in the Phase 1 monotherapy trial, we initiated enrollment in a Phase 2 monotherapy trial with ARQ 197 in hepatocellular carcinoma in September, 2009. We expect to enroll approximately 100 patients with unresectable hepatocellular carcinoma who have failed one prior systemic therapy in this randomized, double-blind trial comparing patients treated with ARQ 197 to those treated with placebo, with the primary endpoint being time to progression. A Phase 2 ARQ 197-sorafenib combination therapy trial in hepatocellular carcinoma will be initiated pending the evaluation of safety data in the Phase 1 run-in trial.
Data from the Phase 1 single agent safety trial in hepatocellular carcinoma were presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium in January, 2010. ARQ 197 was shown to be well tolerated in this patient population, and no drug related worsening of liver function was observed.