The market bottleneck with glioblastioma in particular has to do with the fact that the standard of care has not changed in decades. Temodar (temozolomide) is the first line chemotherapy for this disease after surgical resection, but its results are highly unsatisfactory. It’s not easy to introduce a new drug after so many decades, but VAL-083 has one more advantage in trying to widen the bottleneck. Its mechanism of action is relatively well understood.
The importance of understanding the mechanism of action is critical when it comes to clinical trials because it allows a company to tailor its patient-base with a fine-toothed comb. VAL-083 is known to bypass a DNA repair enzyme called MGMT that renders the first-line therapy temozolomide ineffective after a short period of time. VAL-083 operates independently of this enzyme, which allows DelMar to screen its patients specifically for high expression of MGMT. Selecting patients with high expression of that enzyme is expected to further differentiate VAL-083 from standard-of-care.
Consider the following hypothetical. If, for example, DelMar Pharmaceuticals Inc (NASDAQ:DMPI) did not know about the MGMT factor and patients with low or even zero MGMT expression were admitted for a pivotal trial, temozolomide would theoretically work decently on a control group, differentiating it much less from VAL-083. Admitting only patients with high MGMT will allow the FDA to see what is anticipated to be a stark difference between temozolomide patients versus VAL-083 patients, with the goal of showing a wide gap between the two therapies and making approval that much more likely.
From a market perspective, this is also quite helpful as it narrows down the patient base and increases the chances that the drug will work for its specific group, encouraging oncologists to prescribe it on an MGMT test.
Separating Two Knotted Strings
In terms of mechanism of action, the way the chemotherapy works is by causing cross links in the DNA structure, which when unraveled during DNA replication, cause both strands to break at the cross-link point. Think of pulling apart two delicate strings that are knotted at a particular point. The strings will separate until the point of the knot and then break.
The nature of glioblastoma cells is that they aren’t good at recognizing the knot or the resulting break for repair, one of the reasons the cancer is so abnormal and aggressive. The lack of repair causes the cancer cells to get stock, and eventually undergo apoptosis and die. Healthy cells on the other hand recognize the breaks and repair themselves, which explains why the side effect profile of VAL-083 is comparatively low according to the most recent data of the Phase II trial just completed.
Combination Possibilities
But there are other advantages to understanding the mechanism of action here. DelMar’s data so far provides evidence that glioblastoma cells get stuck in a particular phase of cell division when exposed to VAL-083, called the S-phase. There are other chemotherapies that are only active when cells reach this particular phase, which opens up the possibility of a combination therapy in any upcoming pivotal Phase III trial with these particular drugs.
The point here is not that the company will necessarily choose this path. It may not, or it may choose to use this kind of combination as one of the active arms in a future trial. The point is that DelMal, due to its deep understanding of its own candidate, has opened many options for itself as to how to ideally optimize a pivotal trial that would end up bringing this drug to market. Not only that, but it could even make finding a potential partner easier if DelMar can convince a partner that its own drug will be strengthened in this way. That is, if DelMar chooses to go the partnering route, which is not certain at this point. It may want to go it alone.
All of this together makes the chances of a successful Phase III much higher than a company that knows its drug works in some vague way, but is otherwise flying blind.