Prostate cancer is already the most commonly diagnosed cancer in western men and the second leading cause of cancer death in men. The incidence of the disease is expected to soar as the baby boomer generation ages, with diagnoses and deaths more than doubling in the next 20 years. But for patients with advanced disease, standard therapies are ineffective.
It has long been known that vitamin D could be the answer to the big C. But no one seemed to know how to get around the fact that the high doses of the vitamin required to achieve an anti-cancer effect are toxic. Now one company Novacea, in the US, says it has a novel vitamin D - based cancer drug that is not toxic. Indeed, it works so well, the company says it will revolutionise the prostate cancer market. Not only is the new drug, Asentar (DN-101), not toxic, it increases survival and reduces the toxic effects of the chemotherapy drugs that patients with advanced disease have to take.
Business analysts would seem to agree that Asentar is potentially revolutionary. ‘This can be attributed to the innovative concept of pulsed drug dosing,’ said Sangeetha Prabaker, research analyst at Frost and Sullivan. ‘This is intermittent, intensive dosing at weekly intervals, an approach that gets around the problem of toxicity at high doses, a major hurdle that has not been addressed until now,’ she said. Although several companies are looking at the vitamin D problem, it looks like Novacea will get there first. ‘This is a multimillion dollar market,’ said Prabaker. ‘And there is additional potential to use these drugs as a preventive measure and as a therapy for other cancers, such as leukaemia and cancers of the skin, breast, colon, lung and GI tract,’ she said. Asentar is currently in Phase III trials and if all goes to plan, trial results will be available next year, and the drug could be approved as early as 2009.
Survival rate
When prostate cancer is detected early, the survival rate is very high. When the cancer becomes more advanced, most patients are given the chemotherapy drug taxotere, but over 50% of patients will die within two years of starting treatment. Prostate cancer kills one man every hour in the UK.
Previous studies have shown that combining chemotherapy drugs like taxotere with other drugs has a beneficial effect. So companies started to look for a drug to use in combination with taxotere in the treatment of prostate cancer. Vitamin D looked promising because scientists have long known that deficiency in this vitamin is linked to the development of certain tumours, including of the prostate. It has also been observed that vitamin D from sunlight can improve the prognosis of certain cancers (Cancer Causes and Control 2004, 15, 149).
But early-stage trials showed, that taking natural levels of the vitamin had no effect. And laboratory studies showed that when levels of vitamin D were sufficiently high to have an anti-cancer effect, it started to become toxic, causing excessive levels of calcium in the blood and creating kidney stones. This is one of the reasons why big pharma seems to have steered clear of vitamin D-based drugs. ‘Adverse effects at higher doses has been a major hurdle,’ said Prabaker.
Big blast
Novacea’s approach to the toxicity problem has been to give patients an occasional big blast of vitamin D, rather than a continual high dose. Levels of vitamin D 50-100 times higher than normal can be achieved without toxic effects by giving patients just one tablet of Novacea’s novel formulation Asentar. It provides 45µg of calcitrol, the most biologically active form of vitamin D. The tablet provides the same level of vitamin D as 90 tablets of conventional high-dose tablets like Rocaltrol (produced by Roche). Rocaltrol tablets contain 0.5µg of calcitriol. Patients with AIPC take one Asentar tablet once a week along with their weekly regime of taxotere for three weeks out of four.
Results from a 250-patient phase II trial showed that Asentar significantly improved survival rates, by nine months over patients on taxotere alone. Novacea ceo Brad Goodwin says this is a breakthrough. A spokesperson for the UK Prostate Cancer Charity (PCC) said although a few months may not seem like much, they can make all the difference to a person in the late stages of disease. ‘It can mean the difference between spending quality time with your loved one, or not,’ she said.
But the quality that really differentiates Asentar from other drugs is that it reduces toxic effects. And if the current phase III trials, which involve 900 patients, are a success, patients should have Asentar available to them in 2009.
If approved, Asentar would be the first in class as a vitamin D receptor agonist targeting cancer. Its anti-cancer activity is not fully understood, but it is thought that its ability to mitigate taxotere’s safety risks is due to its affect on the coagulation pathway. It up-regulates thromobulin expression (an anticoagulant) and down regulates tissue factor (a pro-coagulant), reducing clotting ability.
Market opportunity
Prostate cancer obviously offers a big market opportunity, given that incidences are expected to double in the next few years. Which is why most companies are, at least initially, looking at this area for their vitamin D drugs. AIPC alone represents a larger than $500m market in the US, according to US analysts Cowen and Company.
But according to the PCC spokesperson, although more cases of prostate cancer are being diagnosed, they are being diagnosed earlier. ‘This means that although more people have been identified as having the disease, the numbers of people reaching late stage disease (AIPC) and dying has not increased.’
A number of companies: Abbott, Leo, Aphios, Cytochroma, Bioxell Pharma, Roche and Chugas have drugs/drug candidates based on vitamin D. But their drugs are mainly in initial trial stages, all of which means that Novacea is well placed to be first on the market.
Being the pioneer will certainly give the company a leading edge. ‘It enhances the scope for partnerships and collaborations from leading industry experts and researchers and paves the wave for driving innovations, technology/product, licensing, research and development of novel drugs with better safety and tolerability profiles,’ said Prabakar.
Novacea is already in negotiations with potential partners. And there are plans to expand Asentar’s applications to lung cancer in 2007. Pancreatic cancer is also on the company´s short-term agenda.
Asentar may also prove applicable to preventative medicine. However, this is currently not something Novacea intends to pursue. A spokesperson said: ‘Preventative applications are intriguing, but due to the long trials needed to prove efficacy in this setting, we are unlikely to study it in the near term. However, we would be interested in working with cooperative clinical trial groups in this setting.’
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