Glioblastoma Multiforme (GBM) is the most common and most lethal form of brain cancer. GBM affects an estimated 12,000 new patients each year in the US alone. The median survival in newly diagnosed patients with the best available treatments is 20.5 months.
After diagnosis, today’s standard treatment includes surgical resection of the tumor followed by radiotherapy and chemotherapy with temozolomide (TMZ). Nearly all GBM patients relapse following first-line treatment, and those patients have a one-year survival rate of approximately 25 percent. The average five-year survival rate is less than 3 percent.
Treating glioblastoma is very difficult due to several complicating factors: the tumor cells are very resistant to current approved treatments, the brain is susceptible to damage from conventional therapy, the brain has a very limited capacity to repair itself and, perhaps most important, many drugs cannot cross the blood–brain barrier to act on the tumor.
The brain is the only organ known to have its own defense system, a network of blood vessels that allows the entry of essential nutrients while blocking others. Ironically, this barrier effectively prevents life-saving drugs from being able to repair the injured or diseased brain.
DelMar Pharmaceuticals President and CEO Saiid Zarrabian believes its lead drug, VAL-083 can penetrate this barrier and deliver an effective treatment.
“VAL-083 has the potential to treat newly diagnosed patients as a ‘front-line’ treatment in conjunction with radiotherapy, as a ‘maintenance’ treatment after patients complete radiotherapy, and as ‘salvage’ therapy after treatment with temozolomide,” said Zarrabian.
“VAL-083 is a small molecule DNA targeting therapeutic that has been proven to cross the blood brain barrier, and to have tumor effecting properties in multiple PH1 and PH2 clinical studies. The biological and tumor effecting activity has been demonstrated in numerous clinical trials and in a prior glioma study has shown extension of median survival rates nearly double that of radiation alone,” he added.
WuXi AppTec Communications has begun a new series looking at novel and potentially breakthrough drugs which can make a difference in people lives, especially treating a disease as deadly as glioblastoma. We discussed with Zarrabian the challenges drug developers have had finding an effective therapy for this disease and why he believes the drug will become a successful treatment.
Zarrabian is an industry veteran who has served as San Diego based DelMar’s Chief Executive Officer since November 3, 2017, and President since January 1, 2018. Since October 2016, Zarrabian has served as an advisor to Redline Capital Partners, S.A., a Luxembourg based investment firm. From 2012 to 2014 he was Chairman and member of the Board of La Jolla Pharmaceutical Company. From 2012 to 2013 he was President of the Protein Production Division of Intrexon Corporation, a synthetic biology company. He has also been CEO and member of the Board of Cyntellect, Inc., President and COO of Senomyx, Inc., a company focused on discovery and commercialization of new flavor ingredients, and COO of Pharmacopeia, Inc.
WuXi AppTec: What are the challenges involved in diagnosing and treating brain cancers? How important is early detection?
Saiid Zarrabian: Diagnosis is not the major issue. This disease is hard to treat due to its rapid growth rate of 1.5 percent per day at peak growth, challenges with removing the tumor surgically, as well as the possibility of random cancer cells elsewhere in the brain. Unlike many other solid tumors where the tumor body and sufficient margin tissue can be removed without life threatening or debilitating results, it is not possible to remove the whole tumor mass in GBM both because it infiltrates micro capillaries in the brain and because of our inability to remove tissue surrounding the tumor given its location in the brain. All of this requires a systemic approach to GBM vs. a local solution, which creates the critical necessity of the drug’s ability to cross the blood brain barrier.
WuXi AppTec: Why has it been so difficult to find druggable targets for glioblastoma?
Saiid Zarrabian: Despite decades of effort to identify and develop novel drug candidates for GBM, most if not all have failed in clinical trials. There are many reasons for this including the impact of the blood brain barrier which limits the exposure of chemicals to protect the brain against toxicities. In addition, many potential biological targets and pathways identified for GBM are vulnerable to mutations that cause the tumors to become resistant to the potential anticancer effects of the therapy.
Recently, it has been confirmed that GBM is an immunologically “cold tumor” due to the lack of T cells infiltrating the tumor and as such is a challenging target for novel immunotherapy (I-O) treatments. This creates a much tougher challenge for many existing and new I-O treatment options as the human body’s immune defense mechanisms cannot be effectively exploited for successful brain tumor therapies.
WuXi AppTec: Has genomic analysis of glioblastoma improved drug discovery? If so, how?
Saiid Zarrabian: Yes, modern genomic analytical techniques have identified various gene expression patterns and mutations in GBM which have been the subject of drug development efforts. These include EGFR viii, IDH wild type versus mutations, and the identification of the expression of MGMT (methyl guanine methyl transferase) a critical DNA repair protein which limits the efficacy of temozolomide first-line therapy for GBM. VAL-083 is active for patients who have been identified through genomic diagnostics to have an unmethylated promoter for MGMT.
WuXi AppTec: How did you choose to focus on glioblastoma?
Saiid Zarrabian: Although VAL-083 has been studied by the National Cancer Institute (NCI) in approximately 40 Phase 1 and Phase 2 studies in multiple indications the GBM program was the most advanced and the most likely to reach early success vs. other indications like ovarian cancer and non-small cell lung cancer.
WuXi AppTec: How did you develop your drug candidate?
Saiid Zarrabian: VAL-083 was originally developed at NCI, where close to 40 PH 1 and PH 2 trials in multiple indications were completed. DelMar’s founder and current CSO obtained the right to reference the IND for the drug, including all the preclinical and clinical study information that was developed prior to DelMar’s IND submission. DelMar has been advancing the drug since that time.
WuXi AppTec: What is the mechanism of action?
Saiid Zarrabian: VAL-083 is a DNA targeting agent that readily crosses the blood-brain barrier and has been shown to preferentially accumulate in brain tumor tissue. VAL-083 exhibits a unique bi-functional DNA crosslinking cytotoxic mechanism creating cross-links at the N7 guanine position. This mechanism is different from existing chemotherapeutic agents used in the treatment of GBM, such as temozolomide, and is not susceptible to the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair pathway. This results in the potential for VAL-083 to be more effective, initially in treating the approximately 60 percent of GBM patients whose tumors are MGMT unmethylated, and for whom the current treatment of temozolomide has limited clinical benefit. In the future, we hope to also include the remaining GBM patients without the MGMT unmethylated status as the drug is agnostic to this biomarker. The choice to go after this biomarker identified population is purely to help accelerate the process and get to the goal line of providing a better treatment option for this grossly underserved GBM patients first, before we extend the study for the remaining patients.
WuXi AppTec: What regulatory challenges do you face in clinical development?
Saiid Zarrabian: The typical challenges of making sure you have the right study design, the right efficacy endpoints, and are treating the right patient population. Fortunately, DelMar has fast track status with the FDA for VAL-083, so we can benefit from ongoing discussions with the agency on these types of issues.
WuXi AppTec: Have you worked with patients in developing your drug development strategy? If so, how?
Saiid Zarrabian: Our clinical studies involve extensive pharmacokinetics (PK) analysis. This is important to determine optimized patient dosing and scheduling. In addition, measurement of VAL-083 in the CSF (cerebrospinal fluid) which some patients have consented to, has helped determine the sufficient extent of drug penetration in the brain.
WuXi AppTec: What lessons have you learned during the drug development process?
Saiid Zarrabian: The importance of working with the right partners. From the manufacturing process where we work with STA Pharmaceutical Co., Ltd. (a WuXi AppTech company) and Italfarmaco, to conducting clinical trials with M.D. Anderson Cancer Center and Sun Yat-sen University Cancer Center, we have seen how important it is to work with the best possible collaborators.
WuXi AppTec: How soon will we have an effective treatment for glioblastoma? Will effective treatments require combinations of drugs?
Saiid Zarrabian: We expect the completion of both our current Phase 2 trials in approximately a year. The current trials are single agent trials with VAL-083. The Phase 3 registration study timeframe somewhat depends on the results from our current trials, but we are optimistic that we can initiate a trial in 2021, with a drug reaching the market as early as 2023.
WuXi AppTec: Can you comment on the specific progress or lack of progress in treating this disease in the last ten or 20 years?
Saiid Zarrabian: The development of new therapies for GBM has been extremely disappointing. Many promising approaches have not realized survival benefits for patients due to challenges in developing drugs that effectively cross the blood-brain-barrier, and the inherent aggressiveness of the tumor. There have been extensive clinical trials for drugs affecting unique cellular targets and biologics for immunotherapy that have not met the appropriate clinical trial efficacy outcomes for FDA approvals.
In addition, interest and investment by large pharmaceutical companies has been very limited. The creation of novel therapeutics with those unique attributes for brain tumors has not been a high priority.
WuXi AppTec: What are the top three impediments to delivery of better medicines faster and cheaper to patients?
Saiid Zarrabian: Access to capital, ability to enroll an adequate number of patients quickly into clinical trials, and necessary regulatory hurdles.
WuXi AppTec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure for cancer patients?
Saiid Zarrabian: Cancer prevention and early detection will probably provide the greatest impact to solve the cancer problem. The modern genomic screening tools and other diagnostics will continue to provide valuable support to identify patients at risk and potentially more effective therapeutics. Being able to target specific populations of patients, such as DelMar’s approach for MGMT unmethylated GBM patients, can lead to better outcomes.