CEO Blog 5th June

Explaining TRXE-009

Written by Dr Graham Kelly on 5th June 2015

This morning we announced some data that we have been sweating on for some time now, and that has the scientists excited. It represents a major step forward for Novogen.
Let me walk you through why we are excited.

Some background first.

Brain cancer is a tough cancer to treat. It ranks up there with pancreatic cancer and mesothelioma and malignant melanoma as poorly responsive to standard of care treatments such as radiotherapy and chemotherapy.

One main reason and one lesser reason for this. The main reason is that brain cancer cells are relatively insensitive to chemotherapy. This is not a question of where they are, because cancers such as pancreatic cancer that are outside of the brain are exactly as tough. It is just that different types of cancers vary enormously in how sensitive they are to the damaging effects of radiation and drugs, and brain cancer cells just happen to be among the least sensitive of all cancers.
The lesser reason is something called the blood-brain barrier. This is a filter within the blood vessels within the brain that stop chemicals moving from the bloodstream into the brain. It is an evolutionary protective mechanism. Brain tissue doesn’t repair itself all that well, so it is important that it doesn’t get exposed to chemicals that might damage it. The barrier is a mixture of an actual filter that keeps certain chemicals out, and a pump that throws back others that manage to sneak through. The result is that only about 2% of all drugs that humans take are able to cross this barrier and reach the brain. Hormones, anti-depressants, anti-epileptics, and of course, alcohol, are some of the few drugs that manage to get across.

The reason that the blood-brain barrier is a minor factor in the poor prognosis for brain cancer is that even if all the commonly used chemotherapy drugs could get across the blood-brain barrier, they probably wouldn’t do that much because of the relative resistance of the brain cancer cells to anti-cancer drugs.

That is the situation with what is known as primary brain cancer, or cancers that arise in brain cells. These cancers account for about 2% of all the life-threatening cancers that humans can get.
The other form of brain cancer is known as secondary brain cancer. These are cancers that arise outside of the brain, but spread there. These are far more common than primary brain cancers, with about 25% of all cancers having the ability to spread to the brain.

This is a different dynamic. Some of these cancers that spread to the brain (eg breast and lung cancers) might be able to respond to anti-cancer drugs, but now the main problem becomes the blood-brain barrier. Drugs that might help, simply cannot get there.
So here is what the world is looking for:

• a drug that kills both primary and secondary brain cancer cells. That is, a drug that works irrespective of where the tumor started;
• a drug that also kills the cancer stem (tumor-initiating) cells within the cancer in order to prevent it from recurring;
• a drug that does this without compromising healthy brain cells; and
• a drug that crosses the blood-brain barrier and reaches the cancer in sufficient quantities to work.

We think we know where the world might just have found such a drug.

It’s called TRXE-009.

It started life as one of a large number of molecules that Dr Andrew Heaton’s team had made for the initial testing at Cornell against their library of glioblastoma stem cells. TRXE-009 was a stand-out…it was a highly efficient killer of these tough cancer cells that resisted all common anti-cancer drugs.

As a follow-up, we also tested it against a pediatric form of brain cancer known as DIPG. This is a bad cancer that doesn’t respond to any drug. TRXE-009 was highly cytotoxic to these cells in the test-tube.
So we knew we had something special… a level of activity that no other experimental drug reportedly had shown.

Then we discovered that TRXE-009 wasn’t just active against brain cancer cells, but that it was highly active also against melanoma cells, neuroblastoma cells, and prostate cancer cells. In fact, it was a generally acting anti-cancer agent. But it was a case of showing particularly high activity against brain cancer.

This was all announced last year, and marked TRXE-009 as a prospective treatment for both brain cancer and melanoma. And there was a certain synergy there, with melanoma frequently metastasizing to the brain, thus marking TRXE-009 as a prospect for the treatment of both primary and secondary brain cancer.

But all of this was without hope unless we could get the molecule to cross the blood-brain barrier. And so the Novogen chemists went to work on designing different constructs that they thought might help carry the drug into the brain. We contracted a Boston-based company to help with this and different formulations were made up.

Those formulations then were injected intravenously into mice bearing human tumors and both the anti-tumor effects of the different formulations, as well as their ability to cross into the brain were measured.

One formulation was a stand-out, carrying TRXE-009 into the brain at levels that suggested an ability to deliver a cytotoxic effect on cancer cells. It also delivered a powerful anti-cancer effect on
the growth of the human cancer.

We thought that development worth reporting to the market.
Here is a molecule that:

• kills all forms of cancer cells in the test-tube;
• shows particularly high killing activity against brain cancer cells like DIPG that respond to nothing else;
• has little or no adverse effect on normal brain cells at therapeutic dose levels;
• is highly effective against brain cancer stem cells;
• AND CROSSES THE BLOOD-BRAIN BARRIER.

The next and final step is to show that it works in humans. Not an inconsiderable challenge, but so far TRXE-009 has met every challenge we have thrown at it. Importantly it has ticked more boxes than any other experimental drug candidate we know of in the brain cancer space.

That’s why we are excited