HCV Followup: Anadys Acquired for Active Antiviral
Oct24

HCV Followup: Anadys Acquired for Active Antiviral

It’s been a busy six months for new Hepatitis C (HCV) meds: first, Merck and Vertex have their drugs approved in May, and then Pharmasset leaks PSI-7977 clinical data. Now, Anadys Pharmaceuticals has just announced Phase IIb results for its clinical candidate setrobuvir (ANA-598). The pill lowered virus levels to undetectable limits in 78% of patients after 12 weeks of combination treatment with either ribavirin or pegylated interferon. Anadys notes only one major side effect, a rash occurring in 1/3 of the ‘598-treated patients. The therapy targets patients in tough-to-treat HCV genotype 1 (gen1), unlike PSI-7977, which targets gen2 and gen3. The data seems to have convinced Roche, which acquired Anadys last Monday in all-cash deal analysts say represented a 260% premium over Anadys’s Friday stock closing price. Roche, no stranger to the HCV battle, hopes to integrate setrobuvir into a potential oral drug cocktail with its current suite of polymerase and protease inhibitors. Setrobuvir interacts with N5SB polymerase at the allosteric “palm” binding site, located in the center of the baseball-mitt shaped enzyme. The drug’s sulfur-nitrogen heterocycle – a benzothiadiazine – is the key to virus inhibition; Anadys has installed the motif in all their HCV inhibitors, going back to their 2005 patents. Chemists have known about the virus-targeting properties of this heterocycle for a while, but most derivatives have been culled in pre-clinical testing (see J. Antimicrob. Chemoth. 2004, 54, 14-16 for a brief review). Interestingly, chemists initially prepared benzodiathiazines, such as those in Merck’s chlorothiazide (c. 1957, according to the Merck Index), as diuretics, which found use in diabetic treatment. Over the next 40 years, modified medicines treated conditions ranging from epilepsy and cognitive therapy to hypertension and transcriptase regulation. Tweaked benzodiathiazines first showed anti-HIV and anti-CMV activity in the mid-1990s. One final advantageous wrinkle in this structure: unlike PSI-7977, setrobuvir is not nucleoside-derived. This feature changes its binding behavior, pharmacokinetics, and even its intellectual property strategies, since many current antiviral therapies mimic the nucleosides found in RNA and DNA chains....

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The Race For the Next Big Thing in HCV
May03

The Race For the Next Big Thing in HCV

All spring, biotech watchers have been anxiously awaiting Phase III data for two new drugs to treat Hepatitis C, Vertex Pharmaceutical’s telaprevir and Merck’s boceprevir. Both drugs are expected to be approved next year, ushering in a new era in the treatment of HCV. This week’s cover story takes a look beyond that first wave of new drugs for HCV to assess the pipeline of second-generation compounds. After all, improving cure rates by adding a direct-acting antiviral like telaprevir or boceprevir to the current standard of care (PEG-interferon/ribavirn) will be great, but creating a cocktail of small molecules that work on their own would be even better. As the article notes, everybody wants to be the Gilead Sciences of the HCV market. Gilead has cornered the HIV market with a pill that combines three antivirals in one, and is hoping to unroll a four-in-one pill soon. Only there's a catch: unlike in HIV, where there is a steady stream of new infections each year, the rate of new infections in HCV has slowed considerably. As such, there will be a flood of patients seeking treatment--and ideally be cured of the disease--over the next decade, after which industry observers expect the patient pool to shrink. Industry observers expect to see more licensing and M&A activity in the HCV world as companies with antivirals in the late stages of development seek partners with compounds with complementary activity to their own drugs. "Larger companies cannot afford to wait five to six years for clinical development," says Decision Resources analyst Alexandra Makarova. "Its not even a choice of saving money—either you are late for the bus or not. You have to partner with someobody developing drugs in phase II or late phase I." Some deals have already been made, enabling the first studies of combinations of small molecules in the absence of interferon and ribavirin: -Roche, which has a vested interested in maintaining its leading position in the HCV market, partnered with Pharmasset in 2004 for PSI-6130, a nucleoside polymerase inhibitor that the companies later turned into the prodrug R-7128. Two years later, it snagged InterMune’s ITMN-191, for $60 million upfront and up to $470 million in milestones. The companies will split sales of ITMN-191 down the middle. Roche has already conducted a small clinical trial in New Zealand testing the efficacy of using a combination of R-7128 and ITMN-191 together. -Gilead has had mixed luck in its deal-making: the company entered into a HCV development with Achillion Pharmaceuticals in 2004, but later killed development of GS-9132 after it had unwanted side effects. In 2008, Gilead ended a four-year HCV collaboration with Genelabs....

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