Zytiga is a Blockbuster Drug

Zytiga the new drug for prostate cancer has now reached blockbuster status surpassing the billion dollar annual sales rate. Johnson & Johnson third quarter sales of Zytiga have now broken through the $ 250 M barrier reaching $ 265 M for this last quarter of a year.

These are remarkable sales figures that have been reached in a short space of time since the drug was only FDA approved in April last year. The rapid uptake of Zytiga reflects the medical oncologists confidence in its efficacy and safety profile. The drug is very well tolerated and the responses in many cases are phenomenal.

Over half the sales were accounted for from the United States alone and European sales are set to increase yet further. Zytiga is now on the national formulary in many European countries and has been approved for prescription use on the NHS in the UK which paves the way for more widespread usage.

Cabozantinib Effective Against Bone Mets

Cabozantinib is a VEGFR inhibitor that prevents blood supply to the tumour and combats bone metastases. Clinical trials have now shown that a low dose of 40 mg of Cabozantinib is still effective in combatting metastatic prostate cancer.

The ultimate combination of Cabozantinib with Zytiga offers a powerful approach to the treatment of metastatic prostate cancer.

Results have been released from a clinical trial of 51 patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases receiving a 40 mg daily dose of cabozantinib (XL-184). The data suggests that the 40 mg daily dose has similar clinical activity to the 100 mg daily dose previously reported from this trial. The key parameters used included measurement of reduction of metastatic bone disease and soft tissue disease, and reduction of bone-related pain and narcotic use, with apparent improvement in adverse event rates and tolerability at the lower dose.

Professor Johann de Bono, M.D., Ph.D., leader of the prostate cancer targeted therapy team at The Institute of Cancer Research, London, and honorary consultant at The Royal Marsden Hospital presented the data today in an oral presentation session on prostate cancer at the European Society for Medical Oncology (ESMO) 2012 Annual Meeting in Vienna, Austria.

"The results presented today at ESMO are consistent with interim data previously reported for the 40 mg cohort of an ongoing investigator-sponsored trial evaluating low-dose cabozantinib in men with CRPC and bone metastases," said Dr Michael Morrissey, Ph.D., president and chief executive officer of Exelixis. "The data suggest that the 40 mg daily dose has activity with respect to a number of key metrics, including bone and soft tissue responses, as well as changes in pain scores and narcotic use. Additionally, the 40 mg daily dose appears to be well-tolerated in patients with metastatic CRPC."

The interim results reported today include data from 51 men enrolled in the 40 mg cohort of an ongoing phase 2 randomized trial. All patients had bone metastases on bone scan and 41% had measurable soft tissue disease. All patients had received prior docetaxel, 67% had received prior abiraterone or enzalutamide (MDV3100), and 25% had received prior cabazitaxel. Seventy-one percent of patients had received at least 2 prior lines of therapy for CRPC. Bone Scan Response (BSR). Computer-assisted evaluation of bone scan lesion area (BSLA) was performed and response evaluated by an Independent Radiology Committee (IRC). An overall BSR rate of 49% was observed, with another 29% of patients having stable disease, and 14% having a best response of progressive disease.

Initial results from ongoing efforts focused on documenting the direct impact of cabozantinib on tumor lesions in the bone of prostate cancer patients were presented, and suggest that cabozantinib's effects on bone scan may be linked to induction of tumor necrosis in bone metastases. In a patient with complete resolution of pelvic metastatic lesions on bone scan, diffusion-weighted magnetic resonance imaging (MRI) findings were consistent with tumor necrosis occurring within the bone metastases. Additional evidence for the tumor selective effect of cabozantinib on bone scans was also presented, based on an analysis of a patient with concurrent osteoarthritis. In this patient, near complete resolution of bone scan tracer uptake at sites of metastatic tumor lesions was observed, while bone scan tracer uptake was maintained at sites of osteoarthritis. To gain further insights into the effects of cabozantinib on bone lesions, there are other ongoing clinical trials using MRI, other imaging techniques, and bone-metastatic tumor biopsies.
Soft Tissue Response. Twenty-one patients had measurable soft tissue or visceral lesions at baseline and 19 patients had at least one post-baseline assessment. Evidence of tumor regression was seen in 79% of the 19 patients with at least one post-baseline assessment. Overall response by RECIST among 21 patients with at least baseline data was partial response in 10%, stable disease in 71%, and progressive disease in 10%. Soft tissue responses were independent of prior therapy.

Tasquinimod Looks Promising in Trials

Tasquinimod is a small molecule with anti angiogenic activity that interupts blood vessel formation in tumours and cuts off their blood supply. Current Phase 2 clinical trials look promising and demonstrate that Tasquinimod has significant anticancer activity and showed antimetastatic activity. Tasquinimod is active at very low doses and a dose of 1 mg daily was the maximum used in the trials. It has dose limiting toxcity above 1 mg daily so this is the maximum that can be safely used.

Molecular structure of Tasquinimod which is a quinoline carboxamide.

Tasquinimod is an analogue of the drug Roquinimex also known as Linomide. Roquinimex has immunostimulant actvity as well as anti angiogenic activity. It also inhibits TNF alpha production. It is deactivated by metabolic 4-hydroxylation, a process that is blocked by a trifluoromethyl group in Tasquinimod.

Molecular Structure of Roquinimex

The precise mechanism of action of Tasquinimod is not known but it does have anti angiogenic activity and stops the development of new vasculature to the tumours.

Tasquinimod  phase II clinical trial  in men with minimally symptomatic metastatic castrate-resistant prostate cancer. A randomized, double-blind, placebo-controlled phase II trial  was conducted in men assigned (at a ratio of two to one) to either oral once-daily tasquinimod (TASQ) 0.25 mg/d escalating to 1.0 mg/d over 4 weeks or placebo. The primary end point was the proportion of patients without disease progression at 6 months, or pain criteria, excluding prostate-specific antigen. Two hundred one men (134 assigned to TASQ; 67 to placebo) were evaluable, and baseline characteristics were well balanced. Six-month progression-free proportions for TASQ and placebo groups were 69% and 37%, respectively, and median progression-free survival (PFS) was 7.6 versus 3.3 months. TASQ significantly slowed progression and improved PFS in patients with metastatic CRPC with an acceptable AE profile.

Docetaxel Therapy for Prostate Cancer

Docetaxel is a type of chemotherapy otherwise known as Taxotere. It is a derivative of Taxol (Paclitaxel) that has improved activity and is widely used in the treatment of advanced prostate cancer. Docetaxel is usually given in combination with prednisone which helps aleviate side effects.

The molecular structure of Docetaxel is shown below and it is an ester of Phenylpropanoic acid and Baccatinol. The raw material for the synthesis of Docetaxel is Baccatin which comes from the Yew tree needles.

Since Docetaxel is a form of chemotherapy it comes with all the side effects of chemotherapy such as nausea, hair loss, liver toxicity, etc so compared to Docetaxel, Zytiga has few side effects.

Zytiga represents the logical choice in patients that have relapsed on current androgen deprivation strategies since it can achieve total androgen blockade. Docetaxel should be seen as the second choice when Zytiga therapy has failed.

When both Zytiga and Docetaxel have failed then Jevtana (Cabazitaxel) can be considered which is a newer version of Docetaxel. It has been shown to have activity in post Docetaxel treated patients.

Molecular structure of the steroidal compound Abiraterone the key ingredient of Zytiga.

Fate of Zytiga in the Human Body

What is the fate of Zytiga when it enters the human body ? How is it processed by the human enzymes ? This all depends on metabolism and the drug metabolism of Zytiga has been thoroughly investigated. This takes place as part of the overall ADME process involving Absorption, Distribution, Metabolism, and Excretion.

For Zytiga (Abiraterone Acetate) only about 5 % is absorbed by the intestine in an unfed state. This means that for a 1000 mg (4 tablet) dose only about 50 mg is being absorbed. The absorption of Zytiga greatly increases when taken with food and a single tablet dose of 250 mg taken shortly after eating results in the absorption of 60 mg of drug which is higher than the full dose taken on an empty stomach.

Absorption of Zytiga

Zytiga as Abiraterone Acetate is taken orally and enters the stomach where it is solubalised by bile acids which are released after eating a meal. The Zytiga tablets disintegrate in the stomach and the released Abiraterone Acetate passes along the small intestine where it is absorbed across the intestinal wall and enters the bloodstream.

Cleavage by Plasma Esterases

The intestinal bloodstream passes through the liver where Abiraterone Acetate escapes first pass metabolism and enters the bloodstream to the rest of the body. In the bloodstream plasma esterases cleave Abiraterone Acetate which is an ester to liberate free Abiraterone.

Binding of Abiraterone to CYP17

The free Abiraterone is then delivered by the bloodstream to the organs of the body including the prostate, the gonads, and the adrenal glands. Here Abiraterone binds tightly to the enzyme CYP17 preventing it from working. This enzyme CYP17 is responsible for making all of the androgens in the human body and so inhibiting CYP17 with Abiraterone causes all androgen production to stop and testosterone levels reduce to zero. This starves the prostate tumours of testosterone and they cease multiplying and start regressing.

Metabolism of Abiraterone by CYP3A4

CYP3A4 makes the inactive metabolite Abiraterone N-oxide. With its pyridyl nitrogen oxidised to the N-oxide Abiraterone is unable to block CYP17 and is rendered inactive.

Metabolsim of Abiraterone N-oxide by SULT2A1

The steroid sulfatase enzyme SULT2A1 puts a sulfate group onto the 3-hydroxy group of Abiraterone N-oxide to make the water soluble Abiraterone N-Oxide Sulfate which is excreted in the urine. About 4 % of Zytiga ends up in this way as the fully metabolised Abiraterone N-oxide Sulfate.

So the Zytiga that enters the human body is processed in a very precise way that allows Zytiga sufficient time to work and yet clears the drug safely from the system.

Molecular Structur of Abiraterone

Dasatinib Zytiga Combo

Dasatinib (Sprycel) is an inhibitor of the Src tyrosine kinase. This enzyme mediates signal transduction from the growth factor receptors to the downstream MAP kinase cascade. Blocking Src stops the meassage to grow that is sent from the growth factor to the cell nucleus. So the nuclear signals to grow are blocked by a Src inhibitor and this should have synergistic effects with total androgen ablation obtained with Zytiga.

The combination of Dasatinib and Zytiga represents a logical combination in the treatment of advanced prostate cancer and is currently undergoing clinical trials to test its safety and efficacy.

Molecular Structure of Dasatinib (Sprycel)

Molecular Structure of Abiraterone (Zytiga)

This looks like a good combination of drugs and we look forward to the results of the clinical trials.

Sunitinib Zytiga Combo

Sunitinib (Sutent) is a combined PDGFR and VEGFR inhibitor that is undergoing clinical trials in combination with Zytiga and Prednisone. VEGFR is inolved in metastatic tumour growth and so an inhibitor of this enzyme will be useful in stopping the spread of the cancer and reducing the growth of existing metastases.

Other VEGFR inhibitors that could be combined with Zytiga are:

Cabozantinib (Exelexis) VEGFR2 & Met Kinase

Sorafenib (Nexavar) VEGFR, PDGFR, Raf Kinase

Regorafenib (Stivarga) VEGFR, PDGFR, B-Raf

Vandetanib (Caprelsa, Astra Zeneca) VEGFR, EGFR, Ret Kinase

Cediranib (Recentin, Astra Zeneca) VEGFR

Pazopanib (Votrient, GSK) VEGFR, PDGFR, c-Kit Kinase

Linifanib (Abbot) VEGFR, PDGFR

Tivozanib (AV-951) VEGFR

Dovitinib (TKI-258) VEGFR, FGFR, c-Kit

Axitinib (Inlyta, Pfizer) VEGFR