VAL-083, or it’s chemical name dianhydrogalactitol (val-083), is a compound that came through the National Cancer Institute (NIC), which runs massive screens around the world looking for new cancer agents.
And the NCI (National Cancer Institute) still performs those duties, even though there's a large network of smaller and larger corporations now focused on oncology. So VAL-083 is a small molecule. And it's unique in the sense that it's a sugar that's derived with reactive epoxide groups. And this small molecule has the ability to cross the blood brain barrier, which is unfortunately very unique. Explained Dennis Brown, PhD.
There are only two other major cancer drugs for brain tumors that can cross the blood brain barrier and affect some kind of survival change. And those are temozolomide and the nitrosoureas like lomustine, and I'll be talking about them today. So this molecule came through the NCI screen and it met all its criteria, very active in the laboratory, both in invitro test tubes as well as in animal models and met all the decision networks to move on to clinical trials. And over the course of about 10 or 12 years, they studied the molecule. Not only in gliomas, like glioblastomas, but in other tumors like ovarian cancer and endometrial where it demonstrated activity, the drug may have an additional future for adult patients suffering from multiple indications (disease states).
VAL-083 is an innovative bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, resulting in DNA double-strand breaks and cell death.
VAL-083 circumvents MGMT-mediated chemoresistance and distinguishes itself from other cancer therapies used to treat GBM, such as temozolomide, according to in vitro and in vivo studies.
In vitro, VAL-083 functions as a radiosensitizer against GBM cancer stem cells. In a Phase 2 research, the safety and acceptability of VAL-083 delivered concurrently with radiation therapy (RT) in newly diagnosed MGMT-unmethylated GBM was evaluated.
Stage 1 consisted of a dose-escalation phase to determine the optimal VAL-083 dosage in this setting. Patients were administered VAL-083 at dosages of 20, 30, or 40 mg/m2/day x 3 days every 21 days in conjunction with standard radiation therapy (RT) (2 Gy/day, 5 days per week for 6 weeks).
Stage 2 was an expansion phase in which up to 20 additional patients at 30 mg/m2/day of VAL-083 with RT were enrolled. A total of 29 patients were enrolled and treated, with 25 receiving 30 mg/m2/day VAL-083.
Glioblastoma (GBM) also known as brain cancer, is the most deadly form of brain tumors. There are probably 10 to 15,000 new patients per year, and most patients are diagnosed depending on some other biomarker criteria.
Which like MGMT status and IDH status they may not live past the 15 to 30 months, so it's extremely deadly. There are two known compounds that have been approved, but the standard of care typically upon diagnosis, is surgery to debulk the tumor, get rid of most of it, and then radiotherapy for 6 weeks.
So that's daily for 6 weeks for a total of 60 Gry. And then there is the use of temozolomide, which is given daily during the radiotherapy treatment. After that, patients may go on to additional temozolomide, which they call in the adjuvant setting. And depending on some of their pathological characteristics or biomarkers their outcome of the length of time that the patients will survive or progress from those initial treatments may vary.
And typically, there's a biomarker called MGMT, and if patients are overexpressed in that enzyme, the use of temozolomide is limited, and those patients survive. A lot shorter period of time relative to if they don't have a high concentration of that enzyme. MGMT, which is where part of our focus of our molecule, is independent of that DNA repair enzyme MGMT. Said Dennis Brown, PhD.
So again, the NCI (National Cancer Institute) studied the VAL-083 molecule extensively, and demonstrated a survival benefit when the molecule was combined with radiotherapy. And this led us to really reactivate an interest in the VAL-083 molecule.
We went back to the laboratory and demonstrated that we were valuable, because patients being treated with temozolomide may not have a very good outcome. And we pursued clinical development work, went back into the clinic, and have been reporting on two major clinical trials that we call Phase 2 (VAL-083) at MD Anderson.
Where clinicians (principal investigator) study the VAL-083 molecule in the unmethylated setting, that means low MGMT DNA repair and enzyme concentration, and in a recurrent (GBM) setting where patients have recurred from standard of care. And we had an additional trial actually done in China, which we just reported on in an update at the SNO Meeting (Society for Neuro-Oncology), where patients who were newly diagnosed (GBM) brain cancer participated.
Instead of getting temozolomide, they were given our drug, VAL-083, if they were unmethylated, meaning they had a high concentration of this DNA repair enzyme. And the clinical data from that was very promising, so in conjunction with our clinician colleagues and advisors, we entered a trial called GBM AGILE for glioblastoma, which is a multi-centered trial that has an adaptive design that allows us to treat patients in over 40 clinical trial sites not only in the United States, but Europe and Canada and the adaptive design. A feature allows the use of our VAL-083 molecule with other companies' molecules, other sponsors, with only one sponsor. The need for only one arm to be a active positive control of the established chemotherapy, temozolomide for newly diagnosed patients or lomustine for the recurrence setting, and the VAL-083 trial is ongoing today. Explained Dennis Brown, PhD.
VAL-083 clinical trial has been a very successful design and it's been very modernized way of trying to get more agents studied in a, in an efficient fashion with the sort of the blessing of the food and drug administration or the statistical design.
There are two major settings for the VAL-083 trial. So the first setting, which is probably most important, is what they call recurrent (GBM) glioblastoma disease. So for patients who've had standard of care, surgery, radiation therapy, and temozolomide, if they progress and recur.
There's very little opportunity to treat those patients or very few successful treatments, strategies for them. So part of the VAL-083 trial focuses on recurrent disease and another arm or arms of the study focus on newly diagnosed after diag newly diagnosed disease where patients might be, amenable to temozolomide, which works to some degree, but for the most part is not a very successful therapy.
And that subset it into patients which either have the high amount of the DNA repair enzyme, which they call unmethylated, which we think our compound is most suited for, are for those patients who might benefit well to some degree with temozolomide. And we're studying our VAL-083 in that setting as well. So we're studying both newly diagnosed as well as recurrent diseases. Explained Dennis Brown, PhD.
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So for glioblastoma in particular there are no surrogate endpoints that the FDA views as appropriate. So in other words, the only endpoint that we have to study in great depth is overall survival. There is data that we're collecting for progression free survival, which can be indicative of the potential for overall survival. And in addition, we're studying obviously the side effect profile and quality of life for patients.
There are some very significant side effects for the other drugs that are used. And we're gonna be studying our, demonstrated clinical activity of our drug and the safety relative to those other active agents.
So we're currently in a blinded study that's been ongoing for a couple years now with GCAR Edge and is blinded. So we're unaware, if you will, of the data. We understand how many patients we may have and how many clinical trials sites are involved, but in terms of understanding the sort of the clinical efficacy.
Of the molecule at this time, we're unaware of that. That will be a blind that gets broken, as is typical of a phase three type of design. We are aware of rare adverse events in which there is a side effect, an SAE (serious adverse event), that our clinicians are involved in reviewing. Sometimes it's related to the drug, and other times it's related to the progression of the disease.
We're a small company. We've been involved with the development of VAL-083 for over a decade now. The unfortunate situation for glioblastoma is that there are very few if any, good cancer therapies (novel therapies) for the disease.
Over the years, other types of strategies have been tried. Immuno-Oncology approaches precision targeted cancer therapies (novel therapies) like tyrosine kinase inhibitors (TKIs) and all have failed, unfortunately. So they now describe glioblastoma as a cold tumor immunologically, and there's no vulnerable achilles heel biological or molecular target that is single agent like a tyrosine kinase inhibitor (TKI).
Significantly affects to increase a patient's life expectancy. Our drug has been studied extensively for over 20 years. It's a long haul, but this molecule has shown good safety and clinical efficacy in our prior clinical trials and would be a valuable asset for clinicians to have when the drugs approved to have more options for their patients. Said Dennis Brown, PhD.
Since January 25, 2013, Dr. Dennis Brown, PhD, has served as our Chief Scientific Officer. Dr. Brown is one of our founders and has held the positions of Chief Scientific Officer and Director of Del Mar Pharmaceuticals (BC) Ltd. since the company's founding. Dr. Brown has over thirty years of experience in medication discovery and development. Since 2000, he has served as Chairman of the Board of Directors for Mountain View Pharmaceutical, and he is the President of Valent. He has served as a director of Rakovina Therapeutics, Inc., a Canadian public company, since March 2020. He launched ChemGenex Therapeutics in 1999, which combined with an Australian public business in 2004 to form ChemGenex Pharmaceuticals , where he served as President and Director until 2009. He was a co-founder of Matrix Pharmaceutical, Inc., where he held the positions of Vice President (VP) of Scientific Affairs from 1985 to 1995 and Vice President (VP) of Discovery Research from 1995 to 1999. Additionally, he has held the positions of Assistant Professor of Radiology at Harvard University Medical School and Research Associate in Radiology at Stanford University Medical School. New York University awarded him a Bachelor of Arts in Biology and Chemistry (1971), a Master of Science in Cell Biology (1975), and a Doctor of Philosophy in Radiation and Cancer Biology (1979). Dr. Brown is the creator of numerous issued U.S. patents and patent applications, many of which have overseas equivalents.
Kintara's internal research programs, located in San Diego develops innovative cancer therapeutics for unmet medical needs. Kintara, company's clinical trials sponsored, is developing two late-stage pivotal testing, Phase 3-ready medicines for unmet medical needs with low-risk development programs. VAL-083 treats GBM while REM-001 treats CMBC.
VAL-083 company's operation in this clinical trial, a "first-in-class" small-molecule chemotherapeutic with a new mechanism of action, has shown clinical activity against central nervous system, ovarian cancer, and other solid tumors (brain tumors) (e.g., NSCLC, bladder cancer, head and neck) in U.S. clinical studies sponsored by the National Cancer Institute (NCI). Based on Kintara internal research programs, company's clinical trials sponsored, and these prior NCI-sponsored clinical studies, Kintara is advancing VAL-083 in the Global Coalition for Adaptive Research registrational Phase 2/3 clinical trials titled Glioblastoma Adaptive Global Innovative Learning Environment (GBM AGILE) Study to support GBM (glioblastoma) development and commercialization.
Kintara company's ability in late-stage photodynamic therapy platform may treat localized cutaneous or visceral tumors and other indications. The laser light source, light delivery system, and REM-001 medicinal product were evaluated in four Phase 2/3 clinical studies in CMBC patients who had previously had chemotherapy and/or failed radiation therapy. REM-001 has 80% full responses of CMBC evaluable lesions and a strong safety database of 1,100 individuals across diverse indications. Kintara suspended the REM-001 CMBC initiative to conserve cash.
SNO 2022 - CTNI-32 - Phase 2 Study of VAL-083 and Radiotherapy in Newly Diagnosed MGMT-unmethylated GBM (brain cancer). SNO 2022, November 18, 2022