The effectiveness of Genentech and Roche’s (RHHBY.OB) glioblastoma multiforme (GBM) treatment, Avastin, has recently been challenged raising concerns from physicians and patients alike that a huge void in patient care can develop if the FDA decides to revoke Avastin’s approval for treating GBM. GBM is one of the hardest indications of cancer to treat with a median survival of about 4.5 months without treatment and less than a year and a half with a combination of treatments currently available today. The big fear for GBM patients is that the FDA will pull the plug on Avastin in much the same manner as it did for breast cancer treatment two years ago and despite its issues with prolonging life, Avastin has proven to be effective at improving the quality of life of GBM patients.
Fears of any FDA action might be unwarranted, however, the FDA, oncology community and patients with GBM all have their sights set on any options that can not only replace Avastin, but be more effective at the same time. Hope for many of these patients could come from a drug that was originally studied against GBM by the United States National Cancer Institute 20 years ago and later approved in China as a cancer therapy for leukemia and lung cancer. Amid the fallout from the news regarding Avastin, Del Mar Pharmaceuticals (DMPI.OB) and their lead product candidate VAL-083 are poised to make a statement while most GBM treatment options continue to be insufficient with results that are far from being effective.
Glioblastoma multiforme is the most common and aggressive form of malignant brain tumor with an incidence of 2-3 cases for every 100,000 people in the US and Europe. Treatment of GBM is complicated due to the fact that tumor cells are very resistant to conventional therapies, the brain can be damaged rather easily upon receiving therapies while it is also limited in the capacity to heal itself. Complicating matters is that most available cancer drugs cannot cross the blood-brain barrier to target tumors. These limitations to treatment options combined with the aggressive nature of GBM tumor cells make this one of the most difficult indications to treat.
Avastin, or bevacizumab, has been used as a treatment for recurring GBM since its approval by the FDA in 2009. Following surgery, chemotherapy and radiation treatment, drugs like Avastin and Temodar (temozolomide) and older drugs such as the nitrosoureas are the only drugs currently approved for treating GBM following the more traditional approaches. Despite some successes, there are issues in the actions of both Avastin and Temodar preventing them from being more effective in treating GBM.
Avastin is a rather effective angiogenesis inhibitor that slows the growth of new blood vessels by inhibiting vascular endothelial growth factor A (VEGF-A). VDGF-Ais a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer. Avastin was the first clinically available angiogenesis inhibitor in the US used to treat cancer. The drug was initially approved for the treatment of colon cancer in 2004 and subsequently approved for breast cancer and GBM, but the FDA revoked the approval for breast cancer on November 18, 2011. The FDA breast cancer findings indicated that there was no evidence that Avastin extended or improved the quality of life and adverse side effects including high blood pressure and hemorrhaging occurred. Now the drug faces challenges with the treatment of GBM.
Results from two recent studies conducted by Genentech and the University of Texas (sponsored by NCI) have questioned the effectiveness of Avastin. Both studies found Avastin to be ineffective at extending the lives of GBM patients. In the University of Texas study, the placebo actually outperformed Avastin with a 16.1 month median survival versus 15.7 with Avastin while delaying tumor worsening by only three months. The Genentech study did prove the tumor worsening time frame of four months to be more significant, but this result does little to discount the median survival results. Despite these results, Avastin still appears to be effective at treating symptoms arising from GBM treatment like brain edema while also reducing the need for steroid use.
The troubles with Avastin leave Temodar (marketed by Merck (MRK)), approved in 2005 for the treatment of adults with newly diagnosed GBM, as the only viable treatment option currently available for treating GBM following surgery and/or radiation therapy. Temodar’s effectiveness, however, is limited by the resistance to the drug that builds quickly with the aggressive GBM tumor cells.
Temodar is an oral alkylating agent with the ability to alkylate/methylate tumor cell DNA. Temodar’s primary cancer-killing activity involves alkylating at the O-6 positions of guanine residues damaging the DNA and triggering the death of the tumor cells. The problem with Temodar or other drugs such as the nitrosoureas that work similarly is that GBM tumor cells can express proteins called O-6-methylguanine-DNA methyltransferase (MGMT) also known as O-6 alkylguanine-DNA alkyltransferase (AGT) which help repair this DNA damage. The presence of MGMT in brain tumors causes Temodar to be less effective even at maximum tolerated dose (MTD) levels. This is where VAL-083 comes into play.
VAL-083 is a “first in class” small-molecule chemotherapeutic that is small enough to cross the blood brain barrier to directly target tumors. Much like Temodar, it is an alkylating agent that is understood to be a bi-functional, but the cross-linking action on the N-7 position of guanine residues is what differentiates it in its method of action. This ability to target the N-7 position enables VAL-083 to destroy DNA and be immune from the effects of the MGMT repair mechanisms that act of the O-6 position with Temodar. VAL-083 has demonstrated activity in cyclophosphamide, nitrosourea and phenylanine mustard resistant cell lines with no reported evidence of cross-resistance.
Since VAL-083 has already been approved for use in China for treating lung cancer and chronic myelogenous leukemia (CML) with a proven track record of safety and tolerance, approval in the US for treating GBM is much more likely. In order to speed up the FDA approval process and meet patient demand, Del Mar initiated phase I/II trials with patients who had been previously treated for GBM with surgery and/or radiation while also failing to respond to treatment with Temodar and Avastin. These trials were conducted in three patient cohorts of 1.5 mg, 3.0 mg and 5.0 mg per m2 dosage levels of VAL-083 which were much lower than the anticipated MTD. In the June 1st ASCO Annual Meeting, Del Mar Pharmaceuticals (Del Mar) presented results that indicated 25% of the GBM patients and 17% of the secondary-progression brain tumor patients showed stable disease or tumor regression in response to these low doses. There were no signs of side effects at these levels and dose escalation is planned.
Del Mar president and CEO, Jeff Bacha noted, “We anticipate even better results at a MTD above 25mg/m2 and should be able to present some results for the higher dosage levels by November of this year. We have treated patients at doses higher than this before for other indications of cancer and have had no significant hepatic, renal or pulmonary toxicity. The only issue appears to be myelosuppression which can be controlled.”
Del Mar also employs a proprietary ChemState bioinformatics tool used to screen and identify potential patients and additional target indications. This technology will be used in the development of VAL-083 and helps cut down the costs associated with preclinicals. ChemState, developed by one of the company’s founders Dr Dennis M. Brown, was used to help advance the profitable drug Synribo leading to not one, but two buyouts to obtain the rights to Synribo. At last count Teva Pharmaceuticals (TEVA) ended up paying $6.8 billion to acquire Cephalon and the rights to Synribo. Can this happen once again?
Typical of many small biotechs, Del Mar currently has very little revenue and a decision on purchasing stock will probably have little to do with the books and fundamentals. Proceeds from a private placement and reverse take-over transaction that led to the public listing of their shares provided the company with proceeds of $8.58 million earlier this year. The private placement ($10.5 million total) represented an oversubscribed offering including an overallotment option that was not only exercised but increased to accommodate investor interest. According to a statement by Jeff Bacha, Del Mar had cash and equivalents of $7.53 million at the close of the first quarter and enough cash to fund VAL-083’s development and corporate activities for at least 24 months.
Del Mar is also looking for a strategic partner in China to help generate royalty revenue for VAL-083. In a move to advance VAL-083 in China, Del Mar is collaborating with leading lung cancer researchers to demonstrate the ability of the drug to treat and lung cancer in patients who either do not respond to or cannot access modern treatments such as tyrosine kinase inhibitors. Positive data from these new studies could reposition VAL-083 to create more value for it in the Chinese marketplace and eventually the global market as well as leading to treatments in hematologic cancers and solid tumors.
Despite all the positives, Del Mar’s stock has been rather flat. The resistance level seems to be at $2 a share and one breakthrough on February 27th had the stock advancing to a high of $3.40 a share. The shares are currently trading at $2.00 (June 10th) and the current market cap is $44.8 million but considering many analysts anticipated Avastin’s brain cancer revenue to reach $650 million by 2016, there is plenty of opportunity for growth. Even Temodar currently generates about$950 million in revenue primarily from treating just brain cancer.
The door is open for Del Mar and despite a push by Peregrine Pharmaceuticals (PPHM) with Cotara there is little else for GBM patients to look forward to in the near future. Since Cotara has a completely different method of action, utilizing tumor necrosis therapy (TNT) that targets the tumor necrotic core to deliver radioactive isotopes, VAL-083 is probably better situated for a more timely FDA approval. Peregrine did get phase III trial protocol approved in February, but the scope of Peregrine’s trials offers no potential for results any time soon.
Despite its troubles, Avastin has produced over $6 billion in sales for Roche with $170 million of this amount from treating GBM alone. This represents a big potential marketplace for Del Mar with VAL-083 and does not even include considerations of using the drug to treat additional indications. Factor in ChemState and the commitment from the FDA to push for anything that can be somewhat effective for treating GBM and Del Mar Pharmaceuticals might just offer potential investors a future as bright as VAL-083’s appears to be.