Risk vs Reward
I have been meaning for some time now to write a general blog about drug development and to put the Veyonda(R) story into that context.
Drug development is potentially one of the most satisfying, exciting and rewarding investments an investor can make. Not only is success rewarding financially but it is self-affirming to know that you have had a role to play in expanding the boundaries of modern medicine and in helping fellow people to live longer, more fulfilling lives. However, it is not without risk.
The risk comes because almost every step in the process, no matter how well informed by research, carries uncertainty and involves stepping into the unknown. Unfortunately for many drug development stories, those unknowns culminate in the drug failing or being abandoned.
If the drug developer can’t be sure of what they are going to find, then how much harder for the investor who then has that extra layer of risk of the competence of the drug developer. It has always humbled me that the average shareholder without access to a team of analysts with PhDs in molecular biology or pharmacokinetics to review the data, would entrust someone like me with their hard-earned funds.
That trust comes with a cost attached, in that the drug developer has to live up to a lot of different expectations – some reasonable and some less so. A key job of running a drug development company then becomes managing those expectations. It helps if the investor has some in-depth understanding of the processes and timelines involved, but many understandably don’t, and this is where the challenge really gets interesting.
Understanding that there are a range of different expectations out there, over a series of blogs, I will try to explain what Noxopharm is aiming to achieve, the strategy that has been put into place to achieve those objectives, and some glimpse of our envisioned time-lines.
It’s a story with a lot of moving parts, so I am going to break it up into a number of bite-sized parts that I will post over the next 2 weeks.
To help frame the story, I am going to start with the background to idronoxil (IDX). My expectation is that IDX is about to become a major story, so its history is well worth chronicling.
The IDX backstory (1992-2008)
20 years ago, a group of eminent scientists and cancer surgeons at Yale University declared IDX a ‘breakthrough’ drug in the treatment of ovarian cancer. The basis of that was an international invitation they had made in the late-1990s to all large and small pharma/biotech companies, offering to test their new drugs against a panel of ovarian cancer cells they had established. At that time, this was a unique resource. It was a library of about 60 cancer cell lines sourced from women who had died from ovarian cancer. These cells were highly resistant to carboplatin and paclitaxel, the standard treatments for ovarian cancer, to the extent of growing in the test-tube in the presence of relatively high levels of these drugs. Yale saw this as a highly valuable resource in identifying promising new drugs for a cancer that then, and still now, has poor survival prospects.
I understand a significant number of companies submitted their experimental drugs to the Yale group for testing, including a number of well-known large pharma companies. Novogen submitted IDX. Some 3 months later, Yale came back with the news that IDX had killed all 60 cell lines, with the next best drug killing about 30 lines, and then daylight to the third-best drug.
So began a highly productive relationship with Yale, which along with Flinders University in South Australia, Purdue University in Indiana, and the John Wayne Cancer Research Institute in Los Angeles, led to some very elegant detective work in mapping out how IDX was killing cancer cells.
The IDX story had its roots in academic research at the University of Sydney Medical School, where a small band of scientists and chemists I was leading first discovered IDX. Mark Waring, who now works for Noxopharm in our U.S. office, was a key member of that team. IDX came to international attention because it showed an ability to kill all forms of cancer in the lab, while sparing healthy cells, an action profile that is still highly unusual today, but in the 1990s was rare to the point that we believed it to be unique.
That uniqueness turned out to be down to the way it worked. Instead of working like other chemotherapy drugs that are poisons, effectively killing cancer and healthy cells by inflicting overwhelming physical damage, IDX essentially suffocates cancer cells by shutting down a key source of energy that allows the cell to breathe (import oxygen).
- Purdue University. Purdue’s contribution was to identify the drug’s target – an enzyme with the impossibly long name ecto-nicotinamide adenine dinucleotide disulphide-thiol exchanger 2 (better known as ENOX2). This enzyme is a key regulator of energy production in the cell’s outer membrane which is where all the interaction between a cell and its environment takes place. Deprive the cell of that energy, and pretty much all internal functions of the cell either stop or are severely curtailed – including the ability to respire.
That explained how IDX was killing cancer cells, but it didn’t explain why it was killing only cancer cells and having no effect on healthy cells.
That explanation came again from work at Purdue showing that human cells have two forms of ENOX (known as ENOX1 and ENOX2) available to them. ENOX1 is the normal form found on all adult cells that have a normal rate of growth and a normal requirement for energy levels in their cell membrane. But once a cell increases its rate of growth and its energy requirements go up significantly, ENOX1 simply cannot meet that higher pace. That is when the cell needs to replace ENOX1 with ENOX2 if it wants to survive. The simple analogy is replacing a 4 HP pump with a 6 HP pump. All cancer cells rely on the 6HP pump (ENOX2); healthy cells happily survive with the 4 HP pump (ENOX1).
IDX inhibits ENOX2 but has no effect of ENOX1. Thus, the simple explanation for why IDX can attack all forms of cancer but have little or no effect on healthy cells.
- Flinders University. Flinders’ contribution was to show that another important effect of IDX was to shut down the action of another enzyme in the cell membrane called sphingosine kinase (SK). SK is known as the ‘master switch’ in a cell, effectively determining whether a cell lives or dies.
- John Wayne Cancer Institute. The JWCI’s contribution was to link those two effects together. They showed that a key consequence of shutting down ENOX2 function and the subsequent loss of energy being supplied to the cell membrane, was the shutting down of SK function. In essence, the cell’s ‘master switch’ was being turned OFF. They went on to show how the cancer cell died as a result of that switch being turned fully OFF.
- Yale University. Yale provided the final piece of the puzzle. In some cancer cells, IDX was only turning the ‘master switch’ half OFF, and they showed what the consequences of this were, effectively disabling the cancer cell without killing it and making it highly sensitive to further damage by chemotherapy or radiotherapy.
Decision time – how to use IDX
In the early-2000s, IDX was a novel-acting and potentially transformative anti-cancer drug. It seemed to work against all forms of cancer and seemed to spare healthy cells. It showed next to no toxicity in animals, so safety didn’t appear to be a looming problem. The key decision came down to how best to use the drug – on its own, with other drugs, what sort of patients?
One thing we did know was that IDX has a dose-response effect. At high enough doses in the test-tube, it will kill virtually all cancer cells. But at the sort of lower doses likely to be used in the clinic, it appears to turn the ‘master switch’ fully-OFF in only a minority of cancer cells; in most cancer cells it is switched only partially-OFF.
Hence, in agreement with Yale, it was decided that the best course of action was to use IDX in combination with standard therapy. The rationale was that in a cancer cell where the ‘master switch’ was partially-OFF, any additional damage inflicted by chemotherapy or radiotherapy should turn out to be lethal to the cell.
Yale went on to prove this rationale by showing that IDX had the capacity to make cancer cells that had become highly resistant to drugs like carboplatin, paclitaxel, gemcitabine and doxorubicin, suddenly responsive again, even to extraordinarily low dosages of these drugs.
And so was born the concept of using IDX in combination with carboplatin in women with late-stage ovarian cancer that had become resistant to carboplatin. A series of Phase 2 studies were conducted in Australia and the U.S. between 2000 and 2006 that showed evidence of this combination working, culminating in a multi-national Phase 3 study (known as OVATURE) commencing in 2008 in 340 women with carboplatin-refractory ovarian cancer.
In Part 2, I will look at 2009-2016 and the path to the creation of Noxopharm.