On November 10, 2015 Exelixis, Inc. (Nasdaq: EXEL) reported financial results for the third quarter of 2015 and provided an update on progress toward delivering upon its key 2015 corporate objectives and clinical development milestones (Press release, Exelixis, NOV 10, 2015, View Source;p=RssLanding&cat=news&id=2111224 [SID:1234508190]).

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Key Priorities and Corporate Updates

Following release of positive results from the pivotal METEOR trial, Exelixis is focused on expediting its regulatory submissions and augmenting its commercial infrastructure to support the potential launch of its lead compound, cabozantinib, in advanced renal cell carcinoma (RCC) in the United States. At the same time, in support of its collaboration partner, Genentech, a member of the Roche Group, Exelixis is rolling out its portion of the U.S. sales force promoting COTELLICTM (cobimetinib), a second Exelixis-discovered compound, following recent regulatory approvals for the compound in combination with vemurafenib for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma in the United States and Switzerland.

Cabozantinib Highlights

METEOR Trial Delivers Positive Results in Advanced RCC; Cabozantinib Granted Breakthrough Therapy Designation. In July 2015, Exelixis announced that METEOR met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) for cabozantinib versus everolimus in a population of patients with advanced RCC who have experienced disease progression following treatment with at least one prior VEGFR tyrosine kinase inhibitor. Based on these data, the FDA granted Breakthrough Therapy Designation to cabozantinib as a potential treatment for patients with advanced RCC who have received one prior therapy. In September 2015, detailed data from METEOR were published in The New England Journal of Medicine and also presented during the Presidential Session I at the European Cancer Congress in Vienna, Austria.

Progress on U.S. and EU Regulatory Filings for Cabozantinib in Advanced RCC. Based on the data from the METEOR trial, in October 2015, Exelixis initiated the rolling submission of its New Drug Application (NDA) in the United States. Exelixis expects to complete the U.S. filing before the end of 2015. In the European Union, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has granted accelerated assessment to cabozantinib for advanced RCC. As a result, when filed, the company’s Marketing Authorization may be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when written or oral information is requested from CHMP). Exelixis expects to complete the EU filing in early 2016.

Results from a Randomized Phase 2 Trial in First-Line RCC Expected in the First Half 2016. The randomized phase 2 trial comparing cabozantinb versus sunitinib in the treatment of first-line intermediate or poor risk RCC patients, CABOSUN, completed enrollment in early 2015 and results for the primary endpoint of PFS are now expected in the first half of 2016. CABOSUN is being conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP).

Trial Underway Evaluating Cabozantinib with Immunotherapies. In July 2015, Exelixis’ collaborators at NCI-CTEP initiated a phase 1 trial of cabozantinib in combination with nivolumab alone, or in combination with nivolumab plus ipilimumab, in patients with genitourinary tumors, including bladder cancer and RCC. The primary endpoint of the trial is the determination of dose-limiting toxicities and a recommended phase 2 dose for the combinations. Exelixis believes that there is a strong rationale for combining cabozantinib with immunotherapies, including clinical evidence of cabozantinib’s ability to create a more immune-permissive environment, as well as preclinical data suggesting cabozantinib increases T-cell infiltration into tumors. Data from this trial could have relevance in other disease settings, including non-small cell lung cancer (NSCLC).

Cobimetinib Highlights

Regulatory Progress for COTELLIC in Europe, Including Approval in Switzerland and Positive Opinion Issued by the European Medicines Agency’s CHMP. On August 27, 2015, Exelixis announced that Swissmedic, the Swiss licensing and supervisory authority, approved COTELLIC for use in combination with vemurafenib as a treatment for patients with advanced melanoma. In September 2015, the European Medicines Agency’s CHMP adopted a positive opinion of Roche’s Marketing Authorization Application for COTELLIC in combination with vemurafenib for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma. The European Commission is expected to release its final opinion by the end of 2015. Under the terms of the collaboration agreement with Roche and Genentech, Exelixis will receive royalties on sales of COTELLIC outside of the United States.

Positive Overall Survival Data for Cobimetinib in Combination with Vemurafenib in Advanced Melanoma. In October 2015, Exelixis announced that the phase 3 coBRIM trial of cobimetinib in combination with vemurafenib met its secondary endpoint of demonstrating a statistically significant and clinically meaningful increase in overall survival for patients with unresectable locally advanced or metastatic melanoma carrying the BRAF V600 mutation. These data will be the subject of a presentation at the Society for Melanoma Research 2015 Congress taking place in San Francisco, November 18-21, 2015.

Regulatory Approval for COTELLIC in the United States. Today, Exelixis announced that the U.S. FDA approved cobimetinib for use in combination with vemurafenib as a treatment for patients with BRAF V600 mutation-positive advanced melanoma. COTELLIC is expected to be available within two weeks. Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and shares in the U.S. sales and marketing costs, including co-promoting COTELLIC in the U.S.

Corporate Highlights

Key Hires in Medical Affairs, Sales, and Marketing. In September 2015, the company announced three high-level appointments to support the commercialization of cabozantinib and cobimetinib: William Berg, M.D. joined the company as Senior Vice President of Medical Affairs, Jonathan Berndt as Vice President of Sales, and Gregg Bernier as Vice President of Marketing.

Public Offering of Stock Raises Net Proceeds of Approximately $145.6 Million. In late July 2015, Exelixis launched and completed a public offering of common stock. The company issued 28,750,000 shares, including 3,750,000 shares issued under the underwriters’ 30-day option to buy shares, at a price to the public of $5.40 per share, receiving approximately $145.6 million in net proceeds after deducting the underwriting discount and other estimated offering expenses payable by Exelixis. Exelixis currently expects to use the net proceeds from the offering for general corporate purposes, including for clinical trials, build-out of commercial infrastructure, research and development, capital expenditures and working capital.

"Over the last few months, we have made significant strides with our lead development program, cabozantinib in advanced RCC, including receiving Breakthrough Therapy Designation from the FDA, initiating our rolling NDA submission and obtaining accelerated assessment status from the European Medicines Agency’s CHMP," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "At the same time, we have significantly strengthened our organization’s capabilities, including the addition of high-level personnel in medical affairs, sales, and marketing in advance of the potential commercialization of cabozantinib in advanced RCC."

Dr. Morrissey continued: "Moreover, after the third quarter closed, Exelixis achieved a major milestone when COTELLIC became the second medicine to emerge from our research and development organization that has received FDA approval. We are excited to embark on the launch of COTELLIC in the U.S., working closely with our partners Genentech and Roche to commercialize the product, including fielding one quarter of the U.S. sales force."

2015 Financial Guidance. The company is refining its operating expense guidance for the second six months of 2015. We expect second half operating expenses to be at the upper end of the previously indicated $80 million to $90 million range including approximately $10 million of incremental non-cash stock-based compensation expense related to the vesting of performance stock options tied to the read-out of METEOR top-line results. As a result, we anticipate that our full year 2015 operating expenses will be near the upper end of the previously-indicated $150 million to $160 million range.

Third Quarter 2015 Financial Results

Net revenues for the quarter ended September 30, 2015 were $9.9 million, compared to $6.3 million for the comparable period in 2014. Net revenues for the third quarter of 2015 consisted of $6.9 million net product revenue related to the sale of COMETRIQ and $3.0 million of contract revenues for a milestone payment received from Merck related to their worldwide license of our PI3K-delta program.

Research and development expenses for the quarter ended September 30, 2015 were $26.1 million, compared to $43.6 million for the comparable period in 2014. The decrease was primarily related to a net decrease in clinical trial costs related to COMET and METEOR, the company’s phase 3 trials in metastatic castration-resistant prostate cancer and advanced RCC, and to a lesser degree, decreases in personnel related expenses resulting from an overall reduction in headcount. Those decreases were partially offset by an increase in stock-based compensation expense due to performance-based stock-options that vested as a result of the positive top-line data received from METEOR.

Selling, general and administrative expenses for the quarter ended September 30, 2015 were $17.8 million, compared to $9.9 million for the comparable period in 2014. The increase was primarily related to stock-based compensation expense due to the vesting of performance-based stock-options as a result of the positive top-line data received from the METEOR trial and higher marketing expenses, including expenses for cobimetinib under the company’s collaboration agreement with Genentech. Those increases were partially offset by a decrease in facilities costs and consulting and outside services.

Other income (expense), net for the quarter ended September 30, 2015 was a net expense of ($11.8) million compared to ($11.0) million for the comparable period in 2014. The net expense is comprised primarily of interest expense which includes $6.9 million of non-cash expense related to the accretion of the discounts on both the 4.25% Convertible Senior Subordinated Notes due 2019 and the company’s indebtedness under the Deerfield Notes for the quarter ended September 30, 2015, as compared to $7.5 million for the comparable period in 2014.

Net loss for the quarter ended September 30, 2015 was ($47.6) million, or ($0.22) per share, basic, compared to ($62.6) million, or ($0.32) per share, basic, for the comparable period in 2014. The decreased net loss for the quarter was primarily due to decreases in research and development expenses and an increase in net revenues, partially offset by an increase in selling, general and administrative expenses.

Cash and cash equivalents, short- and long-term investments and short- and long-term restricted cash and investments totaled $282.1 million at September 30, 2015 compared to $242.8 million at December 31, 2014.

On November 10, 2015 The U.S. Food and Drug Administration reported that it approved Cotellic (cobimetinib) to be used in combination with vemurafenib to treat advanced melanoma that has spread to other parts of the body or can’t be removed by surgery, and that has a certain type of abnormal gene (BRAF V600E or V600K mutation) (Press release, , NOV 10, 2015, View Source [SID:1234508187]).
Melanoma is the most aggressive and dangerous form of skin cancer in the United States. It forms in the skin cells that develop the skin’s pigment and if not diagnosed early, the cancer is likely to spread to other parts of the body. The National Cancer Institute estimates that 73,870 Americans will be diagnosed with melanoma and 9,940 will die from the disease this year.

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"As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "Today’s approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma."

Cotellic works by blocking the activity of an enzyme known as MEK, which is part of a larger signaling pathway. Abnormal activity of signaling pathways can lead to cancer. Cotellic prevents or slows cancer cell growth. Vemurafenib, marketed in the U.S. as Zelboraf, is a BRAF inhibitor that affects a different part of the same pathway and was approved in 2011 to treat patients with melanoma that has spread to other parts of the body or cannot be removed by surgery, whose tumors express a gene mutation called BRAF V600E, as detected by an FDA approved test. Health care providers should confirm the presence of BRAF V600 E or V600K mutation in their patients’ tumor specimens using one of the available FDA approved tests prior to starting treatment with Cotellic in combination with vemurafenib.

The safety and efficacy of Cotellic taken in combination with vemurafenib were demonstrated in a randomized clinical study of 495 patients with previously untreated, BRAF V600 mutation-positive melanoma that is advanced or cannot be removed by surgery. All study participants received vemurafenib and were then randomly selected to also take either Cotellic or a placebo. On average, patients taking Cotellic plus vemurafenib experienced a delay in the amount of time it took for their disease to worsen (approximately 12.3 months after starting treatment) compared to approximately 7.2 months after starting treatment for those taking vemurafenib only. In addition, patients taking Cotellic plus vemurafenib lived longer, with approximately 65 percent of patients alive 17 months after starting treatment as compared to half of those taking vemurafenib only. Additionally, 70 percent of those taking Cotellic plus vemurafenib experienced complete or partial shrinkage of their tumors, compared to 50 percent among those taking vemurafenib plus placebo.

The most common side effects of treatment with Cotellic in combination with vemurafenib are diarrhea, sensitivity to ultraviolet (UV) light (photosensitivity reaction), nausea, fever (pyrexia) and vomiting.

Cotellic may cause severe side effects including damage to the heart muscle (cardiomyopathy) or to other muscles (rhabdomyolysis), new skin tumors (primary cutaneous malignancies), eye disease (retinal detachment), severe skin rash, liver damage (hepatotoxicity), hemorrhage and severe skin rash due to increased sensitivity to sunlight (photosensitivity). People taking Cotellic should avoid sun exposure, wear protective clothing, and a broad spectrum ultraviolet A/ultraviolet B sunscreen to protect against sunburn. Women taking Cotellic should use effective contraception, as the medication can cause harm to a developing fetus.

Cotellic was reviewed under the FDA’s priority review program that provides for an expedited six-month review of drugs that, at the time the application was submitted, have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Cotellic also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

Cotellic and Zelboraf are both marketed by Genentech of San Francisco, California.

On November 10, 2015 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on oncology with an emphasis on the treatment of primary and metastatic liver cancers, reported financial results for the three and nine months ended September 30, 2015 (Press release, Delcath Systems, NOV 10, 2015, View Source;p=RssLanding&cat=news&id=2110968 [SID:1234508184]).

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Financial and other highlights for the third quarter of 2015 and recent weeks included:

84% increase in total revenue compared with the third quarter of 2014
23% decrease in total operating expenses compared with the third quarter of 2014
Establishment of national reimbursement coverage for CHEMOSAT procedures in Germany
Treatment of first patient in the intrahepatic cholangiocarcinoma (ICC) cohort of the Global Phase 2 HCC/ICC trial program
Acceptance for publication of prior Melanoma Phase 3 trial results in the Annals of Surgical Oncology
Presentation of data supporting Delcath’s Hepatic CHEMOSAT Delivery System at the CIRSE, ECCO and EADO annual meetings
Appointment of Jennifer Simpson, Ph.D., MSN, CRNP, President and CEO of Delcath to the Company’s Board of Directors
"Our performance in the third quarter and recent weeks was strong, with significant achievements in all of our commercial and clinical priorities," said Dr. Simpson. "Highlighting the period was the establishment of ZE reimbursement for CHEMOSAT procedures in Germany beginning in 2016, which represents our first national reimbursement mechanism and an important step towards increasing commercialization of CHEMOSAT in Europe. We also continued to drive commercial adoption of CHEMOSAT in other European markets, as evidenced by a nearly 84% increase in third quarter revenue compared with last year. In fact, our year-to-date revenue has already exceeded full-year 2014 revenue. This performance was achieved while maintaining disciplined expense management, which allowed us to beat our operating expense guidance of $4-5 million per quarter."

"During the period we also continued to advance our clinical development program, with the first treatment performed in the ICC cohort of our Global Phase 2 HCC/ICC trial program in October and data supporting CHEMOSAT presented at three major medical conferences. Adding to this growing body of evidence will be data from our prior U.S. Phase 3 clinical trial, which will published in the Annals of Surgical Oncology in the coming weeks. Publication of these results will be an important tool that will enhance our efforts to expand reimbursement in certain European countries, and will also help increase awareness of the value of this therapy in Europe."

"We held a productive meeting with the U.S. Food and Drug Administration regarding our plans for a global pivotal Phase 3 clinical trial in patients with ocular melanoma (OM) that has metastasized to the liver, with overall survival as the primary endpoint. The dialogue was constructive and the FDA is working with Delcath to advance the initiation of this important trial."

"Our team is executing our plan and entirely focused on delivering value for shareholders. We look forward to continuing this momentum through to the end of 2015 and beyond," concluded Dr. Simpson.

Third Quarter Financial Results

Total revenue for the third quarter of 2015 of $0.4 million increased 83.9% from $0.2 million for the third quarter of 2014. Selling, general and administrative expenses during the third quarter were $2.3 million, a decrease of $2.2 million or 48.9% from $4.5 million for the same period in 2014.

Total operating expenses for the third quarter of 2015 decreased by 23.1% to $4.0 million from $5.2 million for the same period in 2014. This decrease reflects a reduction in severance and compensation-related expenses following significant workforce restructurings throughout 2014 and into 2015, as well as a reduction in facility expenses.

The Company recorded a net loss for the third quarter of 2015 of $2.4 million, or $0.12 per share, a decrease of $2.2 million or 47.8%, compared with a net loss of $4.6 million, or $0.48 per share, for the same period in 2014. This decrease is primarily due to a $1.2 million reduction in operating expenses, a $0.1 million improvement in gross profit and a $0.8 million change in the fair value of the warrant liability, a non-cash item.

Nine Month Financial Results

Total revenue for the first nine months of 2015 of $1.3 million increased 62.5% from $0.8 million for the first nine months of 2014. Selling, general and administrative expenses during the first nine months of 2015 were $7.8 million, a decrease of $5.2 million or 40.0% from $13.0 million for the same period in 2014.

Total operating expenses for the first nine months of 2015 decreased by 27.7% to $12.0 million from $16.6 million for the same period in 2014. This decrease reflects a reduction in severance and compensation-related expenses following significant workforce restructurings throughout 2014 and into 2015, as well as a reduction in facility expenses.

The Company recorded a net loss for the first nine months of 2015 of $9.6 million, or $0.67 per share, a decrease of $4.8 million or 33.3% compared with a net loss of $14.4 million, or $1.54 per share, for the same period in 2014. This decrease is primarily due to a $4.7 million reduction in operating expenses, a $0.4 million improvement in gross profit and a $0.2 million change in the fair value of the warrant liability, a non-cash item.

Balance Sheet Highlights

Cash and cash equivalents as of September 30, 2015 were $16.7 million, compared with $20.5 million as of December 31, 2014. During the first nine months of 2015, net cash used in operating activities was $12.2 million.

On November 10, 2015 Tokai Pharmaceuticals Inc. (NASDAQ: TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, reported results for the quarter ended September 30, 2015 (Press release, Tokai Pharmaceuticals, NOV 10, 2015, View Source;p=RssLanding&cat=news&id=2110919 [SID:1234508183]).

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"This was an important quarter of progress for Tokai," said Jodie Morrison, President and Chief Executive Officer of Tokai. "Active screening of patients in our ARMOR3-SV pivotal trial is underway, and we expect to report top-line results by the end of 2016. In parallel, under the experienced leadership of Lisa Taylor, we are making substantial progress in shaping our go-to-market strategy and engaging with clinical leaders throughout the world who recognize the significant need for new treatment options for patients who are unresponsive to existing therapies."

Recent highlights include:

Pivotal ARMOR3-SV Trial Underway: During the quarter, Tokai began screening patients for participation in ARMOR3-SV, the company’s pivotal Phase 3 clinical trial of galeterone, the first Androgen Receptor Degrader in clinical testing. ARMOR3-SV, the first pivotal trial in prostate cancer employing a precision medicine approach for patient selection, is evaluating whether administration of galeterone results in a statistically significant increase in radiographic progression-free survival as compared to Xtandi (enzalutamide) in 148 treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients whose prostate tumor cells express the androgen receptor splice variant-7 (AR-V7). AR-V7 is a truncated form of the androgen receptor that has been associated with non-response to commonly used oral therapies for mCRPC. The design of ARMOR3-SV is aligned with feedback obtained from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, and top-line data for the trial are expected by the end of 2016.

Expanded the Executive Team’s Commercial Expertise: Tokai continued to prepare its growing commercial organization for the anticipated launch of galeterone. Lisa Taylor joined the company during the quarter as Senior Vice President, Commercial Development, a newly created role. Ms. Taylor brings over two decades of experience in biopharmaceutical marketing, and was a member of the launch team for Xtandi (enzalutamide) at Medivation Inc.

Financial Results:

Cash and investments at September 30, 2015 were $73.1 million, compared to $105.3 million at December 31, 2014. Tokai believes that its existing cash and investments will be sufficient to enable the company to conduct ARMOR3-SV, fund the development of a companion diagnostic test for use with galeterone, conduct other clinical trials and nonclinical studies necessary to support the submission of an initial NDA to the FDA for galeterone, as well as to continue funding its operating expenses and capital expenditure requirements into the first half of 2017.

Research and development expense was $8.5 million and $24.9 million for the three and nine months ended September 30, 2015, respectively, as compared to $2.8 million and $10.8 million for the corresponding periods in 2014. The increases in research and development expense in both periods were primarily attributable to start-up costs for the ARMOR3-SV clinical trial and the development of the AR-V7 clinical trial assay, and costs associated with other clinical trial and manufacturing activities to support the submission of a new drug application for galeterone.

General and administrative expense was $3.4 million and $9.3 million for the three and nine months ended September 30, 2015, respectively, as compared to $3.6 million and $6.4 million for the corresponding periods in 2014. The increase in general and administrative expense for the nine month period primarily relates to increased headcount in general and administrative functions, increased legal and patent expenses and costs associated with operating as a public company since September 2014.
Net loss was $11.9 million and $34.1 million for the three- and nine-month periods ended September 30, 2015, respectively, as compared to $6.4 million and $17.1 million for the corresponding periods in 2014.

On November 10, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported the presentation by its collaborators from the University of British Columbia (UBC) and Vancouver Prostate Centre (VPC) of additional data on the unique molecular signaling events responsible for VAL-083 (dianhydrogalactitol) activity against cancer (Press release, DelMar Pharmaceuticals, NOV 10, 2015, View Source [SID:1234508180]).

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"We continue to demonstrate the therapeutic potential of VAL-083 both as a single-agent and in combination with other treatments," stated Jeffrey Bacha, DelMar’s president and CEO. "We have previously shown that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance. To further understand the unique anti-cancer mechanism of VAL-083, we collaborated with researchers from UBC and VPC to study VAL-083’s anti-cancer activity on a molecular level."

These new data were presented on November 9th by UBC and VPC researchers in a poster entitled, "Exploring the Molecular Mechanisms of Dianhydrogalactitol (VAL-083) in Cancer Treatment," at the 2015 Canadian Cancer Research Conference of the Canadian Cancer Research Alliance (CCRA).

"The study results show a pattern of durability in the DNA lesions caused by VAL-083 which indicate its unique mechanism and potential superiority versus other chemotherapeutic agents. This suggests that VAL-083 is effective at modifying tumor cells and may halt tumor progression by inhibiting natural cellular repair processes," added Mr. Bacha.

"VAL-083’s broad anti-cancer activity was established in prior clinical trials sponsored by the U.S. National Cancer Institutes (NCI). Employing modern biological tools to differentiate the mechanisms involved in VAL-083’s anti-cancer activity from other chemotherapies provides a basis for future combination treatments as well as guidance for our drug development efforts to concentrate on tumor-types representing significant unmet medical needs," Mr. Bacha stated.

VAL-083 is a bi-functional alkylating agent causing N7-guanine methylation and interstrand DNA crosslinks and is approved in China as a chemotherapeutic drug for the treatment of chronic myelogenous leukemia and lung cancer. Preclinical studies and clinical trial data suggest that VAL-083 may be active against a range of tumor types via a novel mechanism of action that could provide improved treatment options for patients.

The goal of this study was to further understand the detailed molecular mechanisms mediating VAL-083 sensitivity or resistance in cancer by investigating the signaling events responsible for VAL-083 activity against cancer. The study confirmed a four-fold hypotheses:

VAL-083 induces DNA double-strand breaks (DSBs).

VAL-083 cytotoxicity is due to cell cycle arrest and apoptosis resulting from DNA cross-linking lesions accumulating in S- and G2-phases of the cell cycle.
The antineoplastic effect of VAL-083 is dependent on cancer cells’ ability to repair the VAL-083-induced DNA damage.
Alterations in DNA damage repair signaling pathway lead to VAL-083 sensitivity or resistance in tumor cells.
Results indicate that treatment of cancer cells by VAL-083 induces phosphorylation of H2AX, a hallmark of double-strand DNA breaks. H2AX is a histone involved in the CHK2 checkpoint activation pathway, a key component of the body’s immune response to DNA damage resulting in down-stream signaling ultimately resulting in apoptosis.

"We will continue to explore the signaling pathways involved in VAL-083 for the treatment of cancer," added Mr. Bacha. "The further elucidation of these molecular mechanisms will help to focus our drug development efforts on patients with cancer who would most benefit from VAL-083 treatment. This ‘personalized-medicine’ approach leverages significant historical clinical data from prior NCI-sponsored studies; which, when juxtaposed against new understanding of VAL-083’s biological mechanism, provides an opportunity to accelerate the development of VAL-083 as a new therapy for cancer patients with limited treatment options."

The research presented at the 2015 Cancer Research Conference was funded in part by financial contributions from Canada’s National Research Council’s Industrial Research Assistance Program (NRC-IRAP) and Mitacs, a Canadian Network of Centres of Excellence, dedicated to supporting scientific and industrial research.

The poster on the molecular mechanisms of VAL-083 may be found on DelMar’s website under View Source

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar recently announced the completion of enrollment in a Phase II clinical trial of VAL-083 in refractory GBM. Patients have been enrolled at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO).

In the Phase I dose-escalation portion of the study, VAL-083 was well tolerated at doses up to 40mg/m2 using a regimen of daily x 3 every 21 days. Adverse events were typically mild to moderate; no treatment-related serious adverse events reported at doses up to 40 mg/m2. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed in two of six (33%) of patients at 50 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment, although one patient who presented with hemorrhoids received a platelet transfusion as a precautionary measure.

Sub-group analysis of data from the Phase I dose-escalation portion of the study suggested a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083 in GBM patients whose tumors had progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Patients in a low dose (≤5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.