Triphendiol
Triphendiol is the second anti-cancer drug from the Novogen isoflavonoid drug pipeline to enter the clinic. Triphendiol (previously known as NV-196) is a modification of the phenoxodiol skeleton.
Phenoxodiol
Triphendiol
Being closely related structurally, the two drugs not surprisingly display many features in common. Like phenoxodiol, triphendiol displays the following characteristics:
- it is orally available
- it is conjugated in the bloodstream to glucuronide and sulphate
- it is highly selective for cancer cells
- it has no detectable toxicity in animals and humans
- it displays broad anti-cancer activity against a wide range of human cancer cells
- it is both cytostatic (blocks cell division) and is cytotoxic (kills cancer cells)
- it synergises the anti-cancer effect of standard chemotoxic drugs and restores sensitivity to those drugs in chemo-resistant cells
- it induces apoptosis via the caspase-dependent pathway by inhibiting the production of anti-apoptotic proteins.
What distinguishes triphenodiol however, is its considerably higher cytotoxicity against pancreatic carcinoma, cholangiocarcinoma (bile duct cancer) and melanoma cells.
There is no black-and-white explanation for this difference between the two drugs, but all the evidence points to a difference in the way that the two drugs activate cell death. In short, phenoxodiol kills cells predominantly through the Fas death receptor mechanism, while triphenodiol works predominantly through the TRAIL death receptor mechanism. [Go to the phenoxodiol musings to see a more detailed explanation of death receptor function].
The downstream signalling pathways beyond these two death receptors are essentially similar, which is why the two drugs show remarkable similarity in the way they block cancer cells from dividing and the way they then go on to kill those cells. The difference lies in their upstream targets that initiate thosetriphendiol signalling pathways.
TRAIL (Tumor Necrosis Factor-related apoptosis-inducing ligand), also called APO-2L, is a protein produced by neighbouring cells and even from the same cell, that interacts with TRAIL receptors present on all cells in the body. Five TRAIL receptors have been identified. Two of them (DR4 and DR5) can lead to apoptosis. The other three serve as “decoy” receptors and do not induce apoptosis.
One of the mechanisms that cancer cells employ to evade death is the loss of expression of the Fas or TRAIL (DR4 and DR5) death receptors.
Depending on which form of death receptor mechanism a particular form of cancer expresses, so it will be more sensitive to either phenoxodiol or triphendiol. In the case of pancreatic carcinoma, cholangiocarcinoma and melanoma, the growing body of research evidence is pointing to a loss of Fas expression in a sizeable proportion of these cancers, while TRAIL expression appears generally to be retained. Hence the greater ability of triphendiol to target these particular tumour types.
This does not mean that triphendiol (or phenoxodiol for that matter) is limited to the treatment of particular cancers. On the contrary, the ability to target both main groups of death receptor mechanisms offers a unique opportunity in cancer therapeutics given (a) that most cancers are almost certain to contain heterogenous populations of cells, some expressing predominantly Fas and others predominantlyTRAIL, and (b) most cancer cells almost certainly will express at least some of each type of receptor, meaning that a double-barrelled hit by a combination of phenoxodiol and triphendiol seems a logical path to pursue to ensure maximum anti-cancer effect.
Combinational therapy of both drugs, as logical a step that it might seem, will not be something that the Company is likely to take in the near future. The quickest path to market approval is through establishing the bona fides of each drug separately. Subsequent clinical experience then will determine the merits of combinations of isoflavonoid drugs.
To date, triphendiol has successfully passed its first clinical test in a Phase 1a pharmacokinetic and safety study. That study established that the drug could be given orally, that its resulting half-life and levels achieved in blood were appropriate to deliver a potential clinical benefit, and that it was without significant safety issues.
On the basis of that clinical experience, along with pre-clinical data showing the ability of the to drug reducing growth of human pancreatic carcinoma, cholangiocarcinoma and melanoma in athymic mice to an impressive extent, triphenodiol has been granted Orphan Drug status by the FDA for the treatment of pancreatic carcinoma, cholangiocarcinoma, and malignant melanoma (Stages IIb-IV). Orphan Drug status applies to experimental drugs being tested in cancers that affect fewer than 200,000 individuals per annum in the US. With the exception of cancers of the breast, prostate, lung and large bowel, virtually every other cancer qualifies for Orphan Drug status. There are approximately 40,000 new cases of pancreatic cancer diagnosed each year in the US, 5,000 new cases of cholangiocarcinoma, and 60,000 new cases of malignant melanoma.
Orphan Drug status will benefit the Company in the development of triphendiol by providing it with study design assistance from the FDA and making it eligible for grant funding from the FDA. Post-approval, it provides the Company with 7 years of market exclusivity for the approved indication, along with tax incentives.
In January 2009, the FDA approved an Investigational New Drug status for triphendiol for a clinical study to assess its effectiveness in combination with gemcitabine in the treatment of inoperable pancreatic carcinoma and cholangiocarcinoma.
Both cancers have a poor prognosis. Most (80%) are detected at a stage when they are inoperable, and the drug of choice, gemcitabine, has only limited effectiveness, and no drug has been shown to improve overall survival. Most pancreatic cancers show either no response to initial gemcitabine therapy, or fairly quickly develop chemo-resistance to the drug to the extent that the death rate with this cancer is 96%. Cholangiocarcinoma shows little or
no response to any chemotherapy, including gemcitabine.
There are a number of reasons to believe that the most appropriate way to use triphendiol is in combination with gemcitabine:
- the first is that animal studies have shown that combination of the two drugs has a significantly greater anti-cancer on human pancreatic cancer cells growing in athymic mice than either drug alone;
- triphendiol has been shown to promote apoptosis via the mitochondrial pathway (so-called intrinsic apoptosis), which is the method by which gemcitabine induces apoptosis but which is inactivated in gemcitabine-resistance. The ability of triphendiol to restore sensitivity to gemcitabine in this way provides another layer of anti-cancer effect beyond the primary effect of triphendiol on the cancer cell.
While triphendiol has shown equally impressive anti-cancer activity in pre-clinical studies against melanoma cells, it seems unlikely that the Company would pursue this indication in the foreseeable future given its focus on the pancreatic and bile duct cancer opportunities.
All-in-all, triphendiol is an exciting prospect. By focusing on two cancers where there is no approved, standard treatment for patients who show unresponsiveness to gemcitabine therapy, the way is clear to bring the drug fairly quickly through to a pivotal trial stage, where any clinical benefit would be highly regarded.