In the UK, despite being licensed by the European Medicines Agency (EMA) the drug is not currently available for routine use on the NHS. In July 2012, the National Institute for Health and Clinical Excellence (NICE) issued final guidance that the drug will be made available on the NHS in England and Wales.
History
The drug was originally code named as CB 7598 for Abiraterone itself and CB7630 for Abiraterone Acetate. Rights for commercialisation of the drug were assigned to BTG plc, a UK company that manages commercialisation activity in pharmaceuticals. BTG then licenced the product initially to Boehringer Ingelheim who conducted Phase 1 clinical studies on dose escalation and safety. Later BTG licensed the package to Cougar Biotechnology which began development of the commercial product. In 2009, Cougar was acquired by Johnson & Johnson (J&J) which developed and sells the commercial product Zytiga, and is conducting ongoing clinical trials to expand its clinical uses in earlier stages of prostate cancer.
Mechanism of action
Abiraterone inhibits the enzyme CYP17, an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy derivatives by its 17 α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its C17,20 lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone to undetectable levels.
Pharmacokinetics
After oral administration, abiraterone acetate, the prodrug form present in the commercial preparation, is converted into the active form, abiraterone; this conversion is mediated by plasma esterases and occurs after absorption into the bloodstream. Administration with food increases absorption of the drug by up to 10 fold and thus has the potential to result in increased exposures; the drug should be consumed at a lower dose if taken with food. The drug is highly protein bound (>99%), and is metabolised in the liver by the cytochrome P450 enzyme CYP3A4 and the sulfotransferase enzyme SULT2A1 to inactive metabolites. The drug is excreted by faeces (~88%) and urine (~5%) with a terminal half life of 12 hours. This shows that only 12 % of abiraterone actetate is absorbed in the unfed state with 88% passing straight through the intestine and that this drug would be much better if taken shortly after eating to increase absorption.
Clinical studies
A phase 3 trial in subjects previously treated with docetaxel started in 2008 using a dose of 1000 mg daily in the unfed state to assist pharmacology studies. A placebo-controlled randomised phase III clinical trial in patients with castration-refractory prostate cancer who are chemotherapy-naive opened to accrual in April 2009.In September 2010, an independent panel found that the interim results of the phase III clinical trial in previously treated docetaxel patients were so successful that it would have been unethical to keep half the trial participants on placebo, and all patients began receiving the drug. Overall survival was increased by 3.9 months according to this trial. It was approved by the FDA in April 2011.
The first large scale clinical studies were run in 2004. A more recent study in patients who had not received chemotherapy reported in 2007 that abiraterone acetate induced decline in prostate specific antigen (PSA) in up to 70% of patients as well as radiological shrinkage of tumors, symptom improvement, and normalisation of lactate dehydrogenase.
Results of two phase 2 trials indicate that abiraterone may reduce prostate specific antigen (PSA) levels, as well as shrink tumors. Many of the 21 men in the Phase 2 trial reported significant improvements in their quality of life and several were able to stop taking morphine, used to control the pain caused after the cancer spread into their bones.On average, progression-free survival (PFS) was prolonged by 161 days in patients which had been treated with chemotherapy, and by 236 days in chemotherapy naive patients. Phase 2 clinical trials of abiraterone's effectiveness in patients who have not yet received treatment with chemotherapy found a median time to PSA progression of 48 weeks. Another phase 2 trial in patients who had failed prior treatment with docetaxel showed a median time to PSA progression of 24 weeks.
A phase 2 clinical trial evaluating abiraterone acetate in advanced breast cancer patients is also underway.
The results of a recent study showed that Zytiga cured prostate cancer in about one-third of men with early stage high risk prostate cancer.
