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The most innovative drugs from cancer expo

By Mike Nagle , 11-Jun-2007

This year's American Society for Clinical Oncology (ASCO) conference is over and as 45,000 scientists head home, DrugResearcher.com looks at some of the most innovative drugs that were on show.

The conference is one the biggest pharma gatherings of the year, with over 5,000 abstracts presented. However, in line with the industry in general, only a handful of the drugs discussed were truly innovative 'first-in-class' cancer drugs.

 

 

 

Perhaps the most keenly anticipated results were for Nexavar (sorafenib). Originally developed by Onyx Pharmaceuticals and later licensed to Bayer Healthcare, it has been a rollercoaster of a ride through development for the small molecule.

 

 

 

Originally approved to treat kidney cancer in 2005, last December the drug subsequently failed a Phase III melanoma trial - which sent Onyx shares through the floor . Then, in February of this year, the shares recovered - and then some - when a Phase III trial in advanced liver cancer was stopped early after very good data from a planned interim analysis.

 

 

 

It was this data that was unveiled at ASCO, to baited breath. The drug extended overall survival by 44 per cent compared to placebo in patients with advanced hepatocellular carcinoma (HCC).

 

 

 

"There are currently no licensed therapies in the UK or Europe that significantly improve survival for the thousands of patients with advanced HCC, which makes these results incredibly exciting," said Dr Dan Palmer, Senior Lecturer in Medical Oncology at the University of Birmingham.

 

 

 

"For the first time, we have a potential treatment option that has clearly been shown to significantly improve the overall survival of these patients. Sorafenib could provide a new standard of care for first-line treatment of advanced HCC," he added.

 

 

 

Nexavar is the first compound to target both the RAF/MEK/ERK signalling pathway to inhibit cell proliferation and the VEGFR-2/PDGFR-beta signalling cascade to inhibit tumour angiogenesis.

 

 

 

It does this through inhibiting multiple kinases - tyrosine and serine/threonine - including RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.

 

 

 

Merck KGaA presented a whole bunch of new data on Erbitux (cetuximab). The monoclonal antibody (mAb) was originally developed by Imclone Systems, US and has already been approved for use in colorectal cancer and head and neck cancers. It is marketed jointly by Merck KGaA and Bristol-Myers Squibb. With these latest Phase III clinical trial results, the companies hope to establish Erbitux as a first-line therapy for both types of cancer.

 

 

 

The drug itself works by targeting the epidermal growth factor receptor (EGFR), often also called HER1. This binding prevents the receptor becoming activated, which normally helps tumours spread. The receptor is also thought to help tumour cells repair the damage caused by chemotherapy and radiotherapy and promote the formation of new blood vessels inside tumours.

 

 

 

Wyeth also took the opportunity to present results from a Phase III trial of the small molecule drug, Torisel (temsirolimus). The results showed that the kidney cancer drug improves overall survival rates and also quality of life, compared to patients treated with interferon-alpha.

 

 

 

Torisel was approved by the US Food and Drug Administration (FDA) just before the conference and is the first marketed therapy that inhibits mammalian target of rapamycin (mTOR), a key protein in cells that regulates cell proliferation, cell growth and cell survival. Detailed results from the trial were reported by DrugResearcher.com last week .

 

 

 

As well as treating cancer, this class of molecule is also used as an immunosuppressant to prevent organ transplant rejection and to reduce tissue proliferation in blood vessels as a treatment for coronary heart disease. Abbott recently applied for FDA approval for Xience, a coronary stent that secretes everolimus, which has a similar structure to Torisel. The device was approved for use in Europe last year.

 

 

 

Keryx Biopharmaceuticals was also present in ASCO, where it presented the results from Phase I and II trials for its own small molecule therapy perifosine (KRX-0401), developed in conjunction with AEterna Zentaris. The alkylphospholipid targets the PI3K pathway upstream from mTOR by inhibiting the phosphorylation of Akt. The drug also inhibits other signal transduction pathways, including MAPK and JNK that have been shown to be critical for the survival of cancer cells. Perifosine is currently being studied as a single agent and in combination with several forms of anti-cancer treatments for various forms of cancer.

 

 

 

The drug has been through seven trials to treat sarcomas and the company claim its clinical benefit compares favourably with mTOR inhibitors.

 

 

 

Immunogen, a biopharmaceutical company that develops targeted anticancer therapeutics using its Tumour-Activated Prodrug (TAP) technology, announced 'encouraging' clinical findings with TAP compounds for the treatment of solid tumours.

 

 

 

Clinical findings with three different TAP compounds - trastuzumab-DM1, huN901-DM1, and huC242-DM4 - were reported. Genentech developed the HER2-binding mAb Herceptin (trastuzumab), which Immunogen then added it to its own cell-killing agent called DM1 to produce an antibody-drug conjugate.

 

 

 

In the Phase I study presented at ASCO, four of the ten breast cancer patients responded to the drug and Genentech has announced that it plans to initiate a Phase II clinical trial of trastuzumab-DM1 in HER2-positive breast cancer sufferers.

 

 

 

GlaxoSmithKline (GSK) also presented further data on Tykerb (lapatinib), as the pharma company strives to show that the small molecule inhibitor of the HER2 tyrosine kinase receptor can be used as a first-line breast cancer treatment.

 

 

 

GSK is also keen to evaluate Tykerb's usefulness as a therapy for brain metastasis as it will open up a whole new market for breast cancer sufferers that Herceptin cannot treat.

 

 

 

Another big pharma showing off its innovative drugs was AstraZeneca, in particular AZD0530 - a small molecule dual inhibitor of Src and the related protein Abl. Src was the first cancer-causing gene to be discovered in the 1970s and the Src kinases are a family of molecules that play an important role in cancer growth, spread, apoptosis and cell proliferation.

 

 

 

Currently in Phase II trials for colorectal cancer, AstraZeneca showed at ASCO, for the first time, how biomarkers were used to confirm that the drug inhibits its target in human cancers.

 

 

 

"AZD0530 offers a 'multi-mechanistic' approach to fighting cancer, meaning it not only delays tumour spread but has additional potential to treat tumours that have spread to patients' bones, enhance the efficacy of many standard cancer therapies and to treat leukaemia," said Dr Jose Baselga, the principal investigator on the study.

 

 

 

Bristol-Myers Squibb (BMS) also got in on the act when it presented new data from its Phase III trial of ixabepilone, a semi-synthetic analogue of epothilone B. It is the first drug in a new class of molecules that act on the tubulin molecular pathways which trigger cancer cell division. It is being tested against metastatic breast cancer and the results showed the patients on ixabepilone reported a 40 per cent increase in progression free survival.

 

 

 

By acting on tubulin pathways, BMS hopes the drug could stabilise microtubules - the network of proteins that contribute to cell structure. For tumour cells to divide, the microtubule structure must be broken down and so drugs that stabilise microtubules can prevent a cancer tumour from growing.

 

 

 

These good results have prompted the company to look at the drug in earlier stages of breast cancer and also as a potential treatment for lung, ovarian, prostate, pancreatic, and renal cancers.

 

 

 

Oxigene were also on the scene, reporting Phase II data of the combination therapy Zybrestat (combretastatin A4 phosphate/CA4P), which can significantly reduce blood flow in tumours.

 

 

 

Zybrestat is an investigative vascular disrupting agent (VDA) designed to prevent tumours receiving the blood they need to survive. Another small molecule VDA, at the same stage of development, as recently snapped up by Novartis from UK biopharmaceutical company Antisoma. AS1404 could potentially cost the pharma heavyweight up to $890m (€660m), depending on its success.

 

 

 

Zybrestat exerts its effect by homing in on immature endothelial cells in tumour-associated blood vessels and, via interacting with cytoskeletal proteins, disrupts the internal skeleton that gives these cells their characteristic flat shape. In response, the cells change to a rounded, bloated profile that effectively plugs the capillaries and obstructs the blood flow feeding the tumour.

 

 

 

Preliminary results from a Phase I study of MLN8054, a first- in-class, orally-administered, small molecule inhibitor of Aurora A kinase, were also outlined at ASCO. The drug was developed by Millennium, which hopes it will prove effective in blocking a target that cancer cells need to divide and create tumours.

 

 

 

"Building on our early experience with MLN8054 and our enhanced understanding of the biology and chemistry of the Aurora A kinase, we have engineered MLN8237, with

 

expectations for even better efficacy and tolerability," said Dr Nancy, chief medical officer at Millennium.

 

 

 

This second-generation drug has now been initiated into a Phase I clinical program.

 

 

 

Agennix were showing off talactoferrin, an immune system modulator to treat cancer and also, in its gel format, diabetic foot ulcers. The protein-based biopharmaceutical is a unique recombinant form of human lactoferrin. The protein binds to specific receptors on immune system cells and induces the production of certain chemokines and cytokines to enable the immune system to kill tumour cells.

 

 

 

The company gave data from a fourth Phase II trial, which showed the drug was effective in treating non-small cell lung cancer (NSCLC). Across all 100 patients in the trail, the average overall survival time was 62 per cent higher in the talactoferrin group than in the placebo group, 6 months versus 3.7 months respectively. That average was even higher with the 81 prospectively-defined evaluable patients: 7.6 months versus 4.4. months with placebo - a 73 per cent rise.

 

 

 

Summary

 

 

 

 

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