Novogen has synthesized over 350 analogues of the naturally-occurring isoflavone, genistein. These analogues embrace isoflavone, isoflavan, isoflavene and isoflavonone chemical skeletons, involving chemical substitution at various points, and involving both monomeric and dimeric steric structures.  In vitro screening of these compounds against a battery of human cancer cell lines has shown a number of compounds to have potent broad ranging cytotoxicity against cancer cells representative of a broad range of malignancies. Phenoxodiol was the first of these compounds selected for clinical development and is currently undergoing Phase III clinical trials.  All analogues developed are covered by a variety of patents.

Triphendiol is a derivative of phenoxodiol and was selected for further development based on superior anti-cancer activity against a range of cancers, especially pancreas and bile duct cancers and melanoma.  In non-clinical studies, triphendiol invoked cell cycle arrest leading to programmed cell death in cell lines representative of late stage pancreatic, and bile duct carcinoma.  Apoptosis induction was independent of p53 status and proceeded via the mitochondrial cell death pathway.  We have also demonstrated that triphendiol is able to sensitize cell lines representative of both pancreatic cancer and cholangiocarcinoma (bile duct cancer) to the standard of care drug, gemcitabine. Proof of concept studies in animal models of pancreatic cancer and cholangiocarcinoma, demonstrated that orally delivered triphendiol is effective at inhibiting tumour proliferation and limiting terminal tumour burden.  In further GLP compliant toxicology studies, triphendiol was shown to be non-clastogenic and non-mutagenic, and is well tolerated in rodent and non-rodent chronic repeat dose studies when delivered orally.  These data have indicated that clinical development of triphendiol as a biliary cancer therapeutic is warranted.  Two Phase Ia clinical studies have been completed investigating triphendiol pharmacokinetics and safety when delivered either orally or as an intravenous infusion.  No medication related adverse events were reported.  Triphendiol is a synthetic molecule.  A scaleable synthetic method has been developed as has a validated analytical method for the quantitation of API.  IND submission has been made to the US Food and Drug Administration to enable a Phase Ib efficacy study to be conducted.

 

A new drug cannot be marketed until it has been investigated in clinical trials and approved by the government regulatory authorities as being safe and effective for the intended use. Triphendiol is an investigational drug, and at this time it is not approved for sale or clinical use, except under controlled conditions of approved clinical trials.

NV-143 is a derivative of triphendiol and is a highly potent, pan acting ant-cancer.  It is active against every melanoma cell line tested to date and is able to sensitize melanoma cell lines to the standard of care drug, dacarbazine, and members of the platinum drug scaffold.  Proof of concept studies in animal models of melanoma have demonstrated that orally delivered NV-143 retards tumour proliferation.  The NV-143 mechanism of action in melanoma has not been fully elucidated.  NV-143 is non-clastogenic.

NV-128, an analogue of our lead anti-cancer agents triphendiol (triphendiol) and phenoxodiol (NV-06), has demonstrated efficacy as monotherapy and as a chemosensitizer against cancer cell lines representative of non-small cell lung carcinoma (NSCLC).  Proof of concept xenograft studies have confirmed that orally delivered NV-128 retards NSCLC tumour proliferation.  Efficacy studies are in progress in pre-clinical in vitro studies against late stage colorectal, breast, and gastric cancers and hepatocellular carcinoma, both as a monotherapy and in combination with current standard of care drugs.  Pharmacokinetic studies of NV-128 delivered orally and intraperitoneally have been conducted in rodents and demonstrated that the compound is bioavailable producing therapeutically significant plasma concentrations, and is completely excreted 24hr post administration.  Mechanistic studies have demonstrated that NV-128 induces cell death via a caspase-independent pathway involving endonuclease G translocation to the nucleus resulting in DNA degradation.  Further studies have demonstrated that markers of autophagy are upregulated and that morphologically, NV-128 treated cells appear to have autolysosomes, confirming that NV-128 induces autophagic cell death.  These data demonstrate that through minor modification of the parent isoflavene scaffold novel analogues can be generated which promote cell death via alternative mechanisms to those described for phenoxodiol and triphendiol opening up new opportunities for treatment of an even broader range of cancers.