Is it possible that Noxopharm can do something meaningful for patients with brain cancer, where so many others have failed?
We believe so, with our recent announcement going some way to justifying that belief.
Yes, what we have just announced is laboratory data. And, yes, we have a long way to go before we can declare victory. But crucially we have ticked some boxes in the laboratory that we are not aware of anyone else ticking collectively, and until you tick all of these fundamental boxes, there’s little point in even thinking about starting a clinical program.
Our announcement concerns the cancer, glioblastoma multiforme (or GBM), which is the main form of aggressive brain cancer in adults, and which carries an average 15-month survival outcome.
To put our results into perspective, laboratory studies involving GBM typically use cancer cells collected by biopsy from patients after their cancer has failed to respond to therapy. In other words, these cells have a high degree of resistance to both radiotherapy and chemotherapy. The amount of radiation or chemotherapy drugs you would need to kill these cancer cells would be way too dangerous to use in the clinic.
In our case, we went one step beyond this. The university team who did these studies didn’t settle for cancer cells with the regular level of resistance …….they wanted ultra-resistant cells. They took GBM cancer cells and grew them in the lab in the presence of increasing dosages of the drug, temozolomide (TMZ). TMZ is the standard chemotherapy drug used to treat patients with GBM…not because it is the best drug, but because it is the only chemotherapy drug able to cross the blood-brain barrier to reach cancer tissue in the brain.
After 6 months, these cells were so resistant to TMZ, that dosages of TMZ (or any standard chemotherapy drug for that matter) required to kill them were off the scale. The purpose of this was to raise the bar so much, that if any new therapy was able to kill these ultra-resistant cells, then that made the prospect of that therapy working in the clinic so much more likely.
The summary of what we announced is:
- Idronoxil killed these ultra-resistant GBM cancer cells on its own, and did so at the same dosage levels that killed most other forms of cancer. (That is, idronoxil was able to kill these cancer cells where no other standard chemotherapy drugs worked and the potency of the idronoxil was unaffected by the ultra-resistant state).
- 60% of GBM cases express a gene that makes them poorly responsive to TMZ and possibly radiotherapy. The presence of this gene did not affect the ability of idronoxil to work. (That is, this points to idronoxil being able to work across the spectrum of GBM patients).
- Idronoxil made the ultra-resistant cancer cells more sensitive to TMZ. (That is, idronoxil was able to restore the killing effect of TMZ despite the high level of TMZ-resistance. If we can achieve that with these ultra-resistant cancer cells, then that provides hope that idronoxil will increase the response rate to TMZ in GBM cells with far less levels of resistance).
The boxes Noxopharm has ticked to date
- Able to cross the blood-brain barrier (in rats)
- Able to kill GBM cancer cells at levels believed achievable in the brain
- Able to kill GBM cancer cells despite very high levels of resistance to chemotherapy drugs
- Able to kill GBM cancer cells despite presence of gene responsible for 60% poor response rates to therapy
- Able to increase the killing effect of TMZ on GBM cancer cells.
The current poor outlook
Malignant brain cancer is one of those forms of cancer where there has been no meaningful improvement in patient survival over the past 40 years.
A diagnosis of GBM in an adult generally means a 2-year survival time at best, with only about 4% of patients still alive after 5 years. The median survival time is 15 months.
A diagnosis of diffuse intrinsic pontine glioma (DIPG) in a child, generally means only a 10% chance of surviving 2 years and <1% chance of surviving 5 years. The median survival time is 9 months.
Why such a poor outlook?
The 3 main tools of cancer therapy (surgery, radiotherapy, chemotherapy), where they might work for other cancers, are all severely limited when it comes to aggressive brain cancers.
- Surgery is difficult – wide resection of the cancer to ensure complete removal, as is possible in most tissues, is simply untenable in brain tissue.
- Radiotherapy is limited in use – healthy brain cells are highly sensitive to damage by radiation, and injured brain cells are not replaced (unlike in other tissues).
- Blood-brain barrier – this is a physical barrier that serves to protect the brain from foreign chemicals. 98% of all human drugs are excluded from entering the brain, including almost all chemotherapy drugs.
- Temozolomide (TMZ) – this is the only approved chemotherapy drug that crosses the blood-brain barrier, but it is a relatively weak anti-cancer drug. In fact, DIPG cells are completely resistant to TMZ.
- MGMT gene – this is a normal gene that helps keep our DNA healthy by detecting and repairing any damage. In cancer cells, this gene works against cancer therapies: the more active the gene = the more able the cancer cell is to repair DNA damage caused by chemotherapy and radiotherapy = treatment becomes less effective = poorer survival outlook. The MGMT gene is over-active in about 3/5 cases of GBM, meaning that these patients have lower rates of response to therapy.
Where to from here?
The neurosurgery group who conducted these studies is now proceeding to conduct studies in mice implanted with human GBM cells. These animals will be dosed with NOX66 with and without TMZ. Evidence of an anti-cancer effect in these animals will be the trigger to conduct a study in patients with GBM which has failed to respond to radiotherapy and TMZ. We anticipate these studies being complete by the end of this year, with a positive outcome leading to a Phase 1 study in 2018.
As encouraging as these chemotherapy studies have been to date, our expectation is that using NOX66 on its own or in combination with TMZ will offer a meaningful benefit.
- That benefit might be 90-100% patients with GBM responding to NOX66 + TMZ, where only 40% respond now to TMZ alone.
- It might be that NOX66 + TMZ might deliver a survival advantage beyond the 2-3 months that TMZ alone currently delivers.
And while either of those outcomes should be welcomed by regulators and the oncology community, we believe that we can go significantly further with long-term remission possible through a combination of NOX66 + TMZ + radiotherapy.
We have a parallel pre-clinical program running in collaboration with 2 Australian research institutions, that is looking at using NOX66 to sensitise brain cancers to radiotherapy, the rationale being that idronoxil will lead to effective killing of cancer cells in the brain using low (and well tolerated) dosages of radiotherapy. This program is looking at not just primary brain cancers (GBM and paediatric brain cancers such as DIPG), but at secondary brain cancers involving cancers such as lung, breast, prostate that spread to the brain and which account for the bulk of deaths from cancer of the brain.
The first round of these radiotherapy studies is due to be reported on within the next 3 months and will determine where our clinical efforts will be directed.