Why Tivozanib Deserves FDA Approval

Tivozanib is a new type of anticancer agent that selectively targets the VEGF receptors and has demonstrated useful clinical activity in Phase 3 trials against kidney cancer. Tivozanib is being developed by AVEO pharmaceuticals in partnership with Astellas, the company that partnered Medivation in the devlopment of Xtandi. What sets Tivozanib apart from other VEGFR inhibitors is that it targets all three isoforms providing complete receptor blockade. Targetting VEGF signalling has already led to successful anticancer therapies such as Avastin.

Since VEGF signalling is involved with the growth and spread of metastases VEGFR inhibitors have potential for treating all types of solid tumours that are prone to metastasis such as lung cancer, breast cancer, and prostate cancer. The potential utility of Tivozanib in treating prostate cancer has been somewhat overlooked and no clinical trials have been started yet, but this drug would make a good combination with Zytiga (i.e. Tivozanib Zytiga Combo) for treating metastatic prostate cancer, since both drugs are well tolerated and would combine well together. The VEGFR-2 inhibitor Cabozantinib in combination with Zytiga is currently in clinical trials and the results against resolution of bone mets look impressive.

Molecular structure of Tivozanib shows that it is a very well designed drug. The quinazoline group mimics adenosine and binds into the ATP binding site of the VEGF receptor with the chloroary side chain fitting into the hydrophobic binding pocket.

The next generation of potential blockbusters in oncology will come from the new "inibs", tyrosine kinase inhibitors that are targetted against specific kinases involved in cancer survival. This new generation of oncology drugs includes Ibrutinib (PCYC), Cabozantinib (EXEL), and Tivozanib (AVEO), all of which are showing exciting clinical activity. The first generation of "inibs" are already blockbusters such as Imatinib otherwise known as Glivec (NVS).

The Phase 3 clinical trials of Tivozanib are against kidney cancer, and compared this drug with the current VEGFR inhibitor Sorafenib. There was no increase in overall survival (OS) with patients treated with Tivozanib compared with Sorafenib, but there was a statistically significant increase in progression free survival (PFS) which was the primary goal of the trial. This trial also demonstrated the safety of Tivozanib which showed that it was a well tolerated drug with few side effects and importantly had an improved safety profile when compared to Sorafenib.

Taken together the improvement in progression free survival and good safety profile of Tivozanib make this a useful agent in oncology for treating kidney cancer and warrants regulatory approval.

10 Top Biotechs Advancing Oncology

There have been recent rapid advancements in the science of oncology with greater understanding of the biology of cancer and new therapeutic targets are being identified which hold the promise of targetted therapy for cancer. Behind the big pharma companies such as J&J and Novartis are the smaller biotech copmanies which are the originators of these new medications. So heres an insiders assessment of the biotechs developing exciting new drugs in oncology which are set to boom in 2013:

No.1 BTG (UK: BTG) - Zytiga (Abiraterone Acetate), licensed to J&J (JNJ)
                                      Varisolve

No. 2 Medivation (MDVN) - Xtandi (Enxalutamide), partnered with Astellas

No. 3 Exelixis (EXEL) - Cometriq (Cabozantinib) FDA approved for thyroid cancer.
                                      Potent anti-metastatic agent, set to be a blockbuster
                                      Clinical trials for prostate, breast, lung, kidney, and brain cancer

No. 4 Pharmacyclics (PCYC) - Ibrutinb for CLL and MCL, partnered with J&J, FDA breakthrough status.

No. 5 Astex (ASTX) - 6 Drugs in clinical trials, partnered Novartis and J&J.

No. 6 Array (ARRY) - 5 Drugs in clinical trials, several partners.

No. 7 Curis (CRIS) - Hedgehog Pathway Inhibitor, partnered Roche.

No.8 Aveo (AVEO) - Tivozanib for kidney cancer, FDA submitted, partnered Astellas.

No. 9 Cleveland Biolabs (CBLI) - Curaxins, apoptosis.

No. 10 Spectrum Pharmaceuticals (SPPI) - Zevalin targetted radiotherapy

Zytiga Superior to Ketoconazole

Zytiga and Ketoconazole are both widely used in prostate cancer therapy and have a common mechanism of action both working by inhibiting the enzyme CYP17 which is responsible for androgen biosynthesis. Inhibiting this enzyme lowers testosterone levels which results in tumour regression. Ketoconazole is a non selective CYP inhibitor developed as an antifungal agent but was also found to inhibit a number of human CYP enzymes including CYP3A4 in the liver and CYP17 in the adrenals and testes. Zytiga is a specially designed inhibitor of CYP17 targetted specifically at this enzyme and is 10,000 times more potent as a CYP17 inhibitor than Ketoconazole.

The two drug have now been compared directly in clinical practice and as expected Zytiga showed superior overall survival results compared with Ketoconazole.

Comparison of Abiraterone Acetate (Zytiga) versus Ketoconazole in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to Docetaxel.

Background: Zytiga is standard treatment in patients with mCRPC refractory to docetaxel. Zytiga is a potent and selective CYP 17 inhibitor that blocks the synthesis of androgens in the testis, adrenal glands, and prostate tumour cells. However, in some countries where Zytiga has not been approved yet, Ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that Ketoconazole is much less specific and potent as an inhibitor of CYP 17, there is no clinical data comparing both agents. The present study aimed to compare the clinical effectiveness of Zytiga vs Ketoconazole in patients with mCRPC refractory to Docetaxel.

Methods: Records from 156 mCRPC patients treated with Ketoconazole 200 - 400 mg 3x day, in 4 centers across the US were reviewed retrospectively. 26 pts treated post Docetaxel were individually matched by clinicopathologic factors to patients treated with Zytiga. We compared the PSA response (decrease ≥50% from baseline), biochemical (bPFS) and radiological (rPFS) progression free survival, and overall survival (OS) between the groups. Progression free survival and overall survival were determined by Cox regression.

Results: The groups were matched by Gleason score and disease extent (limited-axial skeleton and/or nodal vs extensive- appendicular skeleton and/or visceral). Furthermore, they were balanced regarding median age, PSA response and time to progression on prior Docetaxel.
In the groups of Zytiga vs Ketoconazole,

PSA response was 46% for Zytiga vs 19% for Ketoconazole,

Median biochemical bPFS 7 months for Zytiga vs 2 months for Ketoconazole,

Median radiological rPFS 6 months for Zytiga vs 2.5 months for Ketoconazole,

Median overall survival (OS) 17 months for Zytiga vs 12 months for Ketoconazole

Therefore treatment with Zytiga increases overal survival by an extra 5 months compared to treatment with Ketoconazole.

Conclusions: In mCRPC refractory to Docetaxel chemotherapy, the outcome of patients treated with Zytiga was superior to Ketoconazole.

European Zytiga Sales Increase Whilst US Sales Decline

The latest sales figures for Zytiga show that sales appear to be remaining static going from $ 265 M in Q3 to $ 264 M in Q4, but these figures conceal two opposite trends that are affecting sales:

- A decrease in US sales down from $ 136 M in Q3 to $ 114M in Q4
= reduction of $ 22 M.

- An increase in the rest of the world (ROW) sales from $ 129 M in Q3 to $ 150 M in Q4
= increase of $ 21 M.

The ROW sales increase and US sales decrease cancel out to give no overall increase in Q4 sales.

The ROW sales figures are mainly contributed by an increase in European sales where Zytiga is now available on the National Health Services of a number of European countries such as the UK and Germany.

The decrease in US sales of Zytiga is largely due to competition from the newly licensed rival drug Xtandi. Without the market presence of Xtandi the US sales of Zytiga would have been expected to continue increasing as it has been doing, but this is the first time US Zytiga sales have declined representing market share taken by Xtandi. However this decrease will probably be short lived as Xtandi's shortfalls and lack of efficacy are revealed in clinical practise. There are already some oncologist who have tried Xtandi and are now switching thier patients back to Zytiga.

Further evidence for the impact of Xtandi comes from the fact that Xtandi is only FDA approved for use in the USA and has not yet received European approval which would explain why the European sales figures have been unaffected and continue to grow.

Zytiga Q4 Sales 2012

The latest Q4 2012 sales figures for Zytiga of $264 M have been released today by Johnson & Johnson. The total sales for 2012 reached $ 961 M, just falling short of the billion dollar mark.

The 2012 sales figures for Zytiga are as follows:

Q1    $ 200 M
Q2    $ 232 M
Q3    $ 265 M
Q4    $ 264 M

Total $ 961 M

These figures show a levelling off of Zytiga sales with no significant growth over the last quarter. This may in part be due to the launch of Xtandi following its FDA approval in the post chemotherapy market. Xtandi is a competitor to Zytiga in the post chemotherapy space and some clinicians have opted to try this new treatment.

However Zytiga is now approved for the treatment of prostate cancer before chemotherapy and this is expected to double its market potential and 2013 sales may be as high as $ 2 billion.

Casodex Zytiga Combo

Casodex is a widely used antiandrogen and some oncologists are combining Casodex with Zytiga. This combination has promising potential by using an antiandrogen such as Casodex together with a hormone boisynthesis inhibitor Zytiga.

Zytiga blocks CYP17 and prevents all androgens including testosterone from being made. In the absence of testosterone caused by Zytiga the antiandrogen has a much better chance of working, since there is no testosterone to compete with its own binding to the androgen receptor (AR). So Casodex should bind better to the androgen receptor in the presence of Zytiga and so will inrease its activity as an antiandrogen.

There is also an added bonus of this combination as a result of drug meatbolism. Casodex inhibits the liver enzyme CYP3A4 which is the same enzyme that deactivates Zytiga to its inactive N-oxide metabolite. So Casodex will reduce the metabolism and clearance of Zytiga and increase its half life.

Co-administartion of Casodex with the drug Midazolam, which is a CYP3A4 substrate, showed that this increased the drug concentration 1.5 fold and doubled the half-life. This would be a useful effect when considered in context of the Casodex Zytiga combo. In practise this means that

a) The same dose of Zytiga (1000mg, i.e. 4 x 250 mg tablets) can be used for double the effect.

b) The dose of Zytiga could be reduced to 500mg (i.e. 2 x 250 mg tablets) with an equal effect.

The end result of combining Casodex with Zytiga is therefore to:

1) Increase Casodex antiandrogenic activity.

2) Increase Zytiga effects by 2-fold.

EMA Approves Zytiga Pre Chemo

The European Medicines Agency (EMA) has approved the use of Zytiga before chemotherapy throughout the EU including all member states. This follows shortly after the FDA approval of Zytiga pre chemo.

Just before Christmas the EMA advisory committee on new medications for human use made a recommendation to the EMA to approve Zytiga for use before chemotherapy which has now resulted in its European approval. This means that Zytiga is now available earlier in the key member states of France, Spain, Italy, Germany, Ireland and the UK.

Johnson & Johnson's (JNJ) Janssen-Cilag International announced it has received approval from the European Commission today that allows its cancer treatment Zytiga to be adopted in all of the European Union earlier in the treatment process.

The approved broader indication for this oral medication can now be used in combination with prednisone for the treatment of metastatic castration resistant prostate cancer (mCRPC) in men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy but before chemotherapy.

Until now, Zytiga with prednisone has only been approved to treat men with mCRPC whose disease has progressed on or after a docetaxel-based chemotherapy regimen.

Zytiga was discovered by Prof Gerry Potter in the UK at the ICR research labs of the Royal Marsden Hospital. "This EU approval means that Abiraterone is now approved in the UK for use before chemo. This was the intended design strategy to create a drug that replaces chemotherapy so this is very good news" Prof Potter said. 

Jane Griffiths, company group chairman for Janssen Europe said. "This decision by the European Commission is hugely welcomed news. Treating men with Zytiga before they undergo chemotherapy has been shown to improve outcomes in many patients, both in terms of extending survival and in bettering quality of life."

mCRPC occurs when cancer has spread beyond the prostate to other parts of the body and the disease progresses despite serum testosterone below castrate levels.

According to Janssen, Zytiga is the only approved therapy that inhibits production of androgen, which fuels prostate cancer growth, via inhibiting the CYP17 enzyme complex present at the testes, adrenals and the tumour itself.