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ArQule, Inc. (ARQL)

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ArQule, Inc. is a biotechnology company that is focused on the research and development of cancer therapeutics. It currently has three product candidates in clinical trials, ARQ 501, which is in Phase II, ARQ 197 and ARQ 171, that are in phase I trials.

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Company Analysis

Woburn, MA based ArQule is a biotechnology company engaged in the research and development of Cancer therapeutics.

The company was initially focused on providing chemistry services to collaborators and customers for their discovery programs. However this operation was terminated in may 2006 and the company is currently focused on developing its oncology portfolio transitioned to become an integrated research and development company. In 2003, ArQule acquired Cyclis Pharmaceuticals, Inc. (“Cyclis”), an early stage cancer therapeutics company.

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Clinical Trials

The following information was summarized from the company website and latest annual report [1]


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ARQ 197

ARQ 197 is an orally administered small molecule inhibitor of the c-Met receptor tyrosine kinase. c-Met that plays multiple key roles in human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis (the spread of cancer from one part of the body to another). c-Met is inappropriately expressed in almost all types of human cancer, with an established role in tumor development.

Phase 1 clinical trial with ARQ 197 was initiated in early 2006. This open label, dose escalation trial includes patients with multiple metastatic tumor types who have had disease progression when treated with available therapy or for whom no standard systemic therapy exists.

The primary objectives of the trial are to determine tolerability, safety and a recommended dosing regimen for Phase 2 trials pending the successful completion of Phase 1. Additionally, the trial will seek to define the pharmacokinetic profile of ARQ 197 and to collect preliminary data on anti-tumor activity.

The company have completed dose escalation in this trial. Utilizing a regimen of two weeks of twice daily therapy followed by one week off therapy, maximum systemic patient exposure to ARQ 197 has been achieved in the absence of dose-limiting toxicity. The optimal dose of ARQ 197 when given orally, twice daily, two weeks out of three, has been identified as 120 mg per dose. Based on the observed safety profile and pharmacokinetics, we are exploring a twice daily ongoing dosing schedule with no off-therapy period. Prior to initiation of Phase 2 testing with ARQ 197 anticipated in the second quarter of 2007, and as part of our Phase 1 trial, we are enrolling a small number of patients who are being dosed on this schedule.

The company is also initiating a new study to investigate biomarkers of activity in both tumor tissue and peripheral blood. This trial will be conducted at the Royal Marsden Hospital in the United Kingdom. The Marsden study is being designed to provide findings that will help correlate anti-tumor activity with changes in biomarker activity and establish dosing parameters for Phase 2 clinical testing. Pending these findings, we expect to employ the twice daily ongoing dosing regimen for Phase 2, as compared to the twice daily dosing two of every three weeks initially employed in Phase 1.

Phase 1 Interim Data with ARQ 197

Interim data from this trial were presented on November 10, 2006 at the 18th EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics. These data demonstrate clinical tolerability, pharmacokinetics and signs of anti-tumor activity in cancer patients with a broad range of metastatic solid tumor types who had failed prior treatment regimens.

Data were presented on 31 evaluable patients, of whom 15 achieved a best response of stable disease or better, ranging from six-plus to 33 weeks. Two of these patients achieved a partial response, according to RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. ARQ 197 was administered orally at doses ranging from 10 mg to 180 mg twice daily (20 mg to 360 mg daily), for 14 days, followed by seven days with no treatment. This 21-day cycle was repeated as long as the patient tolerated the drug. Adverse event data were collected on 27 patients. Dose escalation has been well tolerated, with no dose limiting toxicity observed. Adverse events have been generally mild, with the most common being fatigue. Enrollment is continuing in this trial.


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ARQ 501

ARQ 501 is ArQule's lead candidate, currently in Phase II. The drug is developed in collaboration with Roche using ArQule's Activated Checkpoint Therapy (ACT) development platform. A checkpoint is a cell's natural defense mechanism that ensures genomic integrity. A depressed checkpoint function may result in cancer. ArQule’s ACT technology platform seeks to restore or reactivate checkpoint functions that are lost in cancer cells.

ARQ 501 is currently undergoing three separate Phase II trials. These include monotherapy trials in leiomyosarcoma and in head and neck cancer, and a combination therapy trial with gemcitabine in pancreatic cancer.

The company have completed patient recruitment in all three Phase 2 trials. The enrollment targets were as follows: 30 patients in the leiomyosarcoma study, 53 patients in the head and neck cancer study and 66 patients in the pancreatic cancer study. The Phase 2 dose employed in the leiomyosarcoma and head and neck cancer trials is 450 milligrams per meter squared (mg/m 2 ), and the Phase 2 dose in the pancreatic cancer trial is 400 mg/m 2 .

A number of data presentations from Phase 1 monotherapy and combination therapy trials with ARQ 501 were made during 2006. Summaries of these presentations follow.

* Phase 1 Monotherapy Results with ARQ 501
On April 4, 2006, the company reported results from a Phase 1 monotherapy trial with ARQ 501 at the 97th Annual Meeting of the American Association for Cancer Research (AACR) that provided evidence of clinical tolerability and anti-tumor activity in cancer patients with advanced solid tumors who had failed prior treatments with chemotherapy.
Subjects in this trial received either one or three-hour infusions of ARQ 501 as monotherapy. Infusions were repeated weekly, every other week or two out of three weeks. Dose escalation was conducted to explore and evaluate the effects of both doses and infusion regimens. Tumor response was evaluated according to RECIST guidelines.
ARQ 501 was administered to 64 patients with late-stage cancer who had received prior regimens of chemotherapy. Doses ranged from 10 to 660 mg/m 2 . Tumor regression or prolonged disease stabilization was observed in a broad spectrum of cancer types, including pancreatic cancer, head and neck cancer, ovarian cancer, colorectal cancer and leiomyosarcoma.
Evidence of anti-tumor activity was observed in 18 out of 38 patients evaluable for efficacy. Of these 18 patients, evidence of tumor regression was observed in five patients, two of whom had partial responses and three of whom had minor responses (tumor regression by more than 15% but less than 30% per RECIST). In addition, 13 of these patients achieved disease stabilization.
The data also demonstrated the clinical tolerability and favorable pharmacokinetics of ARQ 501. Drug-related serious adverse events included destruction of red blood cells resulting in lower levels of hemoglobin and the presence of higher than normal levels of bilirubin (also known as hemolytic anemia and hyperbilirubinemia), although these were transient and clinically manageable. Hemolytic anemia was identified as the dose-limiting toxicity associated with administration of ARQ 501. Based on these findings, as well as pre-clinical data, the Phase 2 dose employed in the ARQ 501 monotherapy trials in leiomyosarcoma and head and neck cancer is 450 mg/m 2 .
*Phase 1b Combination Therapy Results with ARQ 501 and Gemcitabine
On June 15, 2006, ArQule announced data from a Phase 1b combination therapy trial with ARQ 501 and gemcitabine that demonstrated clinical tolerability, favorable pharmacokinetics and signs of anti-tumor activity in cancer patients with a range of advanced solid tumors who had failed prior treatments with chemotherapy. These data were collected as of May 19, 2006.
The objectives of this Phase 1b study were to determine the maximum tolerated dose, safety and tolerability, pharmacokinetics and preliminary anti-tumor activity of this combination therapy in patients with advanced solid tumors. All patients enrolled in the study had failed prior courses of chemotherapy.
ARQ 501 was administered once weekly for all cycles of treatment, 30 minutes after the end of the gemcitabine infusion. Gemcitabine was administered once weekly for the first four weeks of cycle 1 and then 3 out of 4 weeks for each successive cycle.
A total of 36 patients were enrolled in this study, with 34 receiving the combination regimen. Of these, 26 patients were evaluable for efficacy, defined as having completed eight weeks of study and one post-baseline tumor assessment. Of these, 14 patients (54 percent) achieved a response of stable disease or better, ranging from 8 to 33 weeks, including one minor response in a patient with colorectal cancer who achieved a 28 percent reduction in tumor mass over 33 weeks on study.
A recommended Phase 2 regimen of 400 mg/m2 of ARQ 501 in combination with gemcitabine has been determined in this study. A total of 11 patients have been enrolled at this dose level, with 7 considered evaluable for efficacy. Of these, 5 patients have achieved a best response of stable disease ranging from 10+ to 16+ weeks and all 5 continue on study, while 2 patients had progressive disease. Of the remaining 4 patients enrolled at this dose level, 1 has withdrawn for an adverse event after receiving one dose of the combination, and 3 other patients have recently enrolled, all of whom remain on study.
Although 400 mg/m2 was established as the recommended Phase 2 dose, 6 patients received a dose of 450 mg/m2 of ARQ 501 in combination with gemcitabine. While dose-limiting toxicity was observed at the 450 mg/m 2 dose level, 3 of these 6 patients achieved stable disease ranging from 20+ to 27+ weeks, with all 3 patients continuing on study, at the time data were reported.
The data also demonstrated the clinical tolerability of ARQ 501 in combination with gemcitabine. The most common adverse events were anemia, fatigue and constipation. Based on these findings, combined with pre-clinical data, a regimen of weekly administration of 400 mg/m 2 of ARQ 501 is being employed in the Company’s Phase 2 trial with ARQ 501 and gemcitabine in patients with pancreatic cancer.
* Phase 1 Combination Therapy Results with ARQ 501 and Docetaxel
Several presentations of data from a Phase 1b combination therapy trial with ARQ 501 and docetaxel were made during the year 2006.
These data, demonstrated clinical tolerability and promising signs of anti-tumor activity in cancer patients with a range of advanced solid tumors who had failed prior treatments with a range of anti-cancer therapies. A total of 43 patients have received the combination therapy of ARQ 501 and docetaxel in this trial, with doses of ARQ 501 ranging from 140 to 550 mg/m 2 , infused over one or three hours. Promising anti-tumor activity has been observed over the range of doses administered. Of 36 patients evaluable for efficacy, 20 have achieved disease stabilization, and evidence of tumor regression was observed in 4 of these patients, 3 of whom had a partial response and 1 of whom had a minor response.
The objectives of this study were to determine the maximum tolerated dose, dose-limiting toxicity, safety, tolerability and preliminary anti-tumor activity of the combination of ARQ 501 and docetaxel. All patients enrolled in the study except for one had received and failed prior courses of therapy.
Two dosing schedules were investigated in this combination therapy protocol. In the first, ARQ 501 was administered for five consecutive days, with a single docetaxel infusion administered on day three. In the second, a single dose of ARQ 501 was administered in combination with a single docetaxel infusion on day one. Once tolerated, additional weekly infusions of ARQ 501 were administered. Both schedules were repeated every three weeks. Dose escalation of ARQ 501 was conducted to explore and evaluate the effects of both doses and infusion regimens.
A total of 11 patients were enrolled and received the first dosing schedule. Of these, 9 patients were evaluable for efficacy, defined as having completed 6 weeks of the study and at least one post-baseline tumor assessment. Of these, 5 patients (56 percent) achieved a best response of stable disease or better, ranging from 9.4 to 23.6 weeks. Two patients with ovarian cancer achieved a partial response based on reduction in the levels of the tumor marker CA-125. One of these also showed an unconfirmed 42 percent reduction in tumor burden according to guidelines.
A total of 32 patients were enrolled and received the second dosing schedule. Twenty-seven of these were evaluable for efficacy, as defined above. Of the 27 patients, 15 (55 percent) achieved a response of stable disease or better, ranging from 12 to more than 41 weeks. Two patients achieved a partial response (one unconfirmed), including one with head and neck cancer and one with melanoma. In addition, a minor response was seen in a pancreatic cancer patient.
The data also demonstrated the clinical tolerability and favorable pharmacokinetics of ARQ 501 in combination with docetaxel. The most common adverse events were anemia, fatigue, hyperbilirubinemia and leucopenia.
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ARQ 171

ARQ 171 is another drug that was developed using ArQUle's ACT technology platform in collaboration with Roche. It is currently in Phase I clinical trial.

The company initiated patient recruitment in a Phase 1 trial with ARQ 171 in December 2006. ARQ 171, which is believed to have the same mechanism of action as ARQ 501, has been shown to have greater potency in preclinical tests. We estimate completion of patient recruitment in our Phase 1 trial with ARQ 171 by the end of 2007, depending upon the achievement of dose-limiting toxicity and the identification of a recommended Phase 2 dose.

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Leadership


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News Feed

11/23/08 10:11 am Navigating the Micro-Cap Biotech Minefield (at Seeking Alpha)
11/15/08 9:11 am ARQULE INC Financials (EDGAR Online Financials)
11/14/08 8:11 am ArQule, Inc. to Present at Lazard Capital Markets Healthcare Conference (Business Wire)
11/12/08 7:11 am Zacks #1 Rank Additions for Wednesday (Zacks.com)
11/11/08 11:11 am ArQule Joins Forces with Daiichi Sankyo to Fight Cancer (at Seeking Alpha)
11/11/08 9:11 am New Star Analyst Rankings for ArQule, Inc. (StarMine)
11/10/08 4:11 pm ArQule, Inc. Q3 2008 Earnings Call Transcript (at Seeking Alpha)
11/10/08 2:11 pm ARQULE INC Files SEC form 8-K, Results of Operations and Financial Condition, Financial Statements and Exhibits (EDGAR Online)
11/10/08 9:11 am ArQule, Inc. Earnings Call scheduled for 9:00 am ET today (CCBN)
11/10/08 8:11 am UPDATE - ArQule and Japan's Daiichi to develop cancer drugs (at Reuters)
More News...
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Risks

  • The company is still cash flow negative. It may need to raise capital in the future, that may result in dilution to current shareholders.
  • The company's products are still in the early stages of clinical trials. There is high risk that the company's products may fail trials in the future.
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Research Links

ArQule, Inc. Snapshot
ArQule, Inc. Leadership
ArQule, Inc. Fundamentals
ArQule, Inc. Technical Analysis
ArQule, Inc. Message Boards
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Notes

  1. ↑ "Form 10-k, Annual report for period ended in december 31, 2006," filed on March 13, 2007. Accessed on may 22, 2007.
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