The Business Benefits Of Revisiting Abandoned Therapies

By Gail Dutton, Contributing Writer
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There is an adage in the oncology community that if the cancer doesn’t kill the patient, the chemotherapy will. Serious side effects and the ability to develop more targeted therapies redirected oncology research from small molecules to immunotherapies, including immune system activators, checkpoint inhibitors, and CAR T-cells. Small molecules were largely forgotten.

DelMar Pharmaceuticals is helping to change that. Its small molecule oncology program began with a short list of compounds that advanced to Phase 2 at the NIH but were never commercialized. Those drugs had proven clinical activity and published data, which reduced the development risk. They were put on the shelf at the dawn of the genomics revolution, before the explosion of knowledge regarding tumor biology, underlying causes of disease, and mechanisms of action.

SMALL MOLECULES MAKE A COMEBACK
DelMar is focused on developing a treatment for glioblastoma (GBM), rare, malignant brain/spine tumors. Jeffrey Bacha, president and CEO of DelMar, says, “As the understanding of tumor biology evolved, it became clear there are different phenotypes [observable traits] driven by epigenetics [alterations to an organism caused by changes in gene expression] or drug resistance for which there is great unmet need.”

DelMar researchers found that a leading anti-cancer drug, Temodar (temozolomide), was ineffective if the targeted tumor overexpressed the MGMT enzyme. Basically, it prevented apoptosis — the programmed cell death that would kill the tumor cell. “Our lead compound, VAL-083, is just different enough from temozolomide that it works against the type of GBM found in two-thirds of patients who don’t respond to temozolomide and Avastin — an antivascular endothelial growth factor [VEGF] antibody used as a second-line treatment for recurrent GBM,” Bacha explains.

LEVERAGING HISTORICAL DATA REDUCES RISK
By developing drugs that were in Phase 2 trials many years ago rather than creating entirely new drugs, DelMar has the benefit of beginning a program with a large body of knowledge. “If there was clinical activity then, there will be clinical activity today,” he says. For example, safety and pharmacokinetic data from more than 1,000 patients using the original compound is in the National Cancer Institute’s (NCI’s) database. This reduces, but does not remove, developmental risk.

For example, with VAL-083, “The FDA raised concerns about the lack of safety data for patients exposed to VEGF inhibitors, which increase the risk of bleeding, and then to VAL-083, which depletes platelets,” Bacha says. The question was whether, despite allowing Avastin to clear the system, its effects on the blood vessels would remain. “There was still a lot of work to do,” Bacha says.

Also, while the old trials proved VAL-083 could be synthesized at scale, cGMP guidelines have changed in the 20 years since the drug was originally manufactured. For example, methods governing lot-to-lot variability have become more stringent.

Responding to those changes, however, also conferred benefits. “We had the opportunity to create new IP around the analytical methods to control variability and to detect the compound’s unique fingerprint,” Bacha says.

VAL-083 has orphan drug status in the U.S. for gliomas. This is possible because cancer is a subset of many divergent diseases, so each cancer is different. The types of cells from which tumors arise, their location in the patients’ bodies, the mutations that direct their formations, and other factors are all differentiators. “Gliomas, for example, are different from lung or breast cancer, even if those cancers eventually spread to the brain. Their treatments will be different, too.”

Such differences dovetail with the emerging personalized medicine approach, which lets researchers identify patients unlikely to respond to the current standard of care. “It’s well-known that overexpression of MGMT is correlated with poor outcomes, so we don’t have to prove that correlation,” Bacha says. “We don’t even have to develop a companion diagnostic, because pathology reports already measure the expression levels of the MGMT enzyme.”

PRIOR CHINESE APPROVAL WAS A SURPRISE
In a serendipitous twist, VAL-083 already is approved in China. DelMar didn’t realize that until it began searching for a CMO. When conducting due diligence, the company searched for new patent filings that would establish a modern IP position related to its compound. The older filing in China, therefore, wasn’t evident.

“We learned of a very good CMO in China that already was licensed by the Chinese FDA to manufacture this compound for chronic myeloid leukemia [CML] and lung cancer. That compound was an older drug, even in China, so there were concerns about the drug and the manufacturing process,” Bacha recalls. DelMar developed analytical methods and tested the Chinese version of the compound to modern standards, eventually using that compound (produced under DelMar’s specifications and labeling) for clinical trials in the U.S. “That saved us a lot of time and money.”

That approval didn’t add immediately to the market, however. The manufacturer, Guangxi Wuzhou Pharmaceuticals, has the marketing rights in China for the older version of this compound for CML and lung cancer but had put very little effort into marketing the drug. DelMar’s new patents modernize the drug and should support sales growth under Guangxi’s current approval in China as well as for global approvals.

DelMar is working with Guangxi to determine how to jointly commercialize the product in China. “Guangxi could license rights to a company with an established oncology sales force in China, or it could establish a new sales force itself. In fact, it has very successfully built a new sales force for cardiovascular products,” Bacha says. Either way, it is the new data being developed by DelMar that will drive the global opportunity for new treatments and sales revenue with VAL-083.

Bacha says most Chinese physicians DelMar surveyed had never heard of the compound. Those who had heard of it were unsure where it fit into a treatment regimen that included platinum-based chemotherapy or tyrosine kinase inhibitors. DelMar’s preclinical work with researchers at the M.D. Anderson Cancer Center and the British Columbia Cancer Agency shows that VAL-083 has synergies with platinum-based therapies without overlapping toxicities and is active in tumors resistant to platinum-based chemotherapy regimens.

“NCI data shows a fair breadth of activity in multiple cancers, including non-small cell lung cancer,” Bacha says. “Our drug may have a niche in combatting solid tumors for patients whose cancer is resistant to treatment due to p53 mutations. That includes lung, ovarian, and cervical cancers. This would fill a big need.”

VAL-083 is in Phase 2 clinical trials at five U.S. sites, and DelMar plans to initiate a new postmarket Phase 4 trial for lung cancer in Shanghai in 2016.

A PARADIGM SHIFT IN CANCER THERAPY?
Bacha says VAL-083 could cause a paradigm shift in cancer therapy. Despite the enormous advances in cancer treatments during the past 20 years, very few applied to glioma. Median survival rates have not improved.

“At the 2011 meeting of the American Society of Clinical Oncology, physicians said they wished they had a new therapy that crossed the brain barrier and lacked MGMT-related resistance problems. That’s what our drug does,” Bacha says.

VAL-083 is relatively well-tolerated compared to other chemotherapies. The average life expectancy of patients entering one of DelMar’s trials is three months. The company’s data suggests that with VAL-083, median survival is nine months after only one to two cycles of therapy. Bacha says he expects the compound to allow much longer life expectancies for patients in the early stages of disease.

TWO-PRONGED COMMERCIALIZATION STRATEGY PLANNED
DelMar is planning a bifurcated commercialization strategy for academic medical centers and community oncologists. Patients treated today for refractory glioma tend to be treated in a few large academic medical centers that typically run Phase 2 and Phase 3 trials. “With only 69 NCI-designated cancer centers, we could market to them ourselves,” Bacha says.

Newly diagnosed glioma, lung, and breast cancer patients, however, tend to be treated by community oncologists. Their numbers are significantly larger. “The infrastructure required to serve this market is far beyond our scope today so, ideally, we would partner with a Big Pharma company that already has a strong foundation in place to reach community oncologists,” he says.

EXPLOIT SYNERGIES WITH IMMUNOTHERAPY
“Chemotherapy and immunotherapy go hand in hand,” Bacha says. “Both create an opportunity for added benefit in combinations.”

DelMar is watching advancements at immunotherapy developers to see which are most likely to be approved. As they advance, the company is considering which combinations would be most interesting. For example, there’s great anticipation surrounding Celldex Therapeutics rindopepimut. “Rindo may be the first new drug approved for GBM in many years that meaningfully improves survival,” Bacha says. That’s obviously good for patients, but it may be good for DelMar, too; the company would consider combinations or collaborations with any valuable immunotherapy.

Twenty years ago, the biotech revolution was just beginning. Many potentially viable compounds were shelved then because of problems that now can be resolved. DelMar’s experience with VAL-083 shows it’s possible to develop robust IP to make previously overlooked drugs commercially viable.

“By reinvigorating overlooked compounds, there are wonderful opportunities to benefit patients,” Bacha says. “The value of the modern understanding of tumor biology and mechanisms of action can’t be overstated. There are huge opportunities.”