Audio SPC3649/New HCV Drug 2010

[Guest guest]

Audio SPC3649/New HCV Drug 2010

2 VIDEOS

Hitting Hepatitis C

Henrik Øren, Santaris Pharma- Also in the news this week, in the journal Science, there’s a paper which highlights a potential new treatment for hepatitis C. This new paper describes a molecule which will target hepatitis C by attacking a microRNA, a short piece of genetic material, which liver cells make and which seems to be absolutely critical for the virus to be able to replicate or grow. One of the people who’s helped to make this possible is Dr. Henrik Øren from Santaris Pharma. He's with us now. Hello, Henrik.

Henrik - Hi.- Welcome to The Naked Scientists.Henrik - Thank you. - So please tell us first of all, what is the problem with hepatitis C, actually treating it at the moment with existing therapy?

Henrik - Well, at this time, there’s probably about a couple of hundred million hepatitis C sufferers worldwide and the standard care is a combination of interferon and ribavirin which is effective in only about 50% of patients and associated with significant adverse effects.

- So what you're saying is that we can't do much about hepatitis C at this stage, so we have a strong need for better therapies.

Henrik - There’s absolutely a very strong need for new therapies.

- And what have you done?

Henrik - So what we’ve done is we’ve taken a non-traditional approach. Rather than trying to attack the virus directly, we’re attacking it indirectly by sequestering a host factor that the virus uses for its replication. It turns out that when we do it, we get a drug that is very potent in the chimpanzee model, which is the only other species (other than humans) that can contract HCV, so it packs a combination of very good potency and good safety, and a unique barrier to resistance.

- So first of all, tell us, what is the new drug and how does it work?

Henrik - It works by binding to and sequestering an endogenous microRNA called microRNA-122 that is specifically expressed in the liver and which the virus uses for its replicative cycle. And sequestering this basically removes it from the virus and hence stops the virus replicating.

- Why should the virus rely on a human cellular factor, this microRNA to grow at all? Why does it need that?

Henrik - Well, viruses depend on a lot of host factors. They do not encode all of the functions they need to complete their life cycles. So, when they enter cells, they do co-opt a lot of different host factors to complete that.

- And your new agent, how does it work? What does it do to that microRNA in the liver cells to make it so that the cells will no longer allow the hepatitis C to grow there?

Henrik - Well, the microRNA in the infected liver cell basically binds to two sites in the 5’ end of the HCV genome. And although the mechanism by which this binding facilitates replication is not entirely known in details at this point, it is known to be a direct binding event between the microRNA and the HCV genome.

- So in some way, that microRNA encourages the virus. It then enables the virus to copy its genetic material.

Henrik - Yes. So, what our drug does is it binds competitively to the microRNA and sequesters it in a form that it can no longer bind to the HCV genome.

- Where else in the body would your cells make microRNA-122, this particular linchpin, and does your drug therefore have the potential to inactivate a key component of cells in other bits of the body and therefore, cause side effects?

Henrik - All present data shows us that microRNA-122 is a liver-specific microRNA and it’s normal function is involved in the biosynthesis and metabolism of lipids and cholesterol. So, what we observed as the only other effect so far in extensive toxin pharmacology studies when we inhibit the microRNA-122 is the expected reduction in plasma levels of cholesterol.

- And so, when you inhibit this particular microRNA in the liver with your drug, what happens to the hepatitis C infected chimpanzees you were trying it on?

Henrik - So we injected them once weekly every 12 weeks and during the whole dosage periods, we saw a steady decrease of virus titres, both in plasma and in the liver. And at the end of dosing, this effect lasted a couple of months post-dosing, consistent with the fairly long half-life of the drug. So, over a period of 5 months where we kept the microRNA fully suppressed in these chimps, they was a steady decline and very strong response on the virus that did not bounce back at any point in time. I think this combination of a good response in the virus and the safe treatment, combined with the apparent complete absence of a viral breakthrough through this extended period of time, that’s the combination that really creates excitement in the community. - And the next step is presumably now to try this in humans? Henrik - Yes. We’ve so far conducted the first study in healthy volunteers. It’s a single-dose study, single ascending dose study. We’re currently conducting a multiple ascending dose study to define the dose and the dosing schedules and we'll hopefully move to patients in the near future. We haven’t quite worked out the design and where those studies are going to be conducted, but we will setup a patient information centre on our homepage where patients interested in this new drug can get the relevant information.

- And you can get more relevant information in the journal Science this week and the drug that Henrik was talking about is SPC3649. That was Dr. Henrik Øren who is from Santaris Pharma.

References- Therapeutic Silencing of MicroRNA-122 in Primates with Chronic Hepatitis C Virus Infection; E. Lanford, beth S. Hildebrandt-sen, s Petri, Persson, Morten Lindow, E. Munk, Sakari Kauppinen, and Henrik Ørum (3 December 2009); Science [DOI: 10.1126/science.1178178]

Hepatitis C drug fights virus in new way Steenhuysen

Dec 09CHICAGO (Reuters) - A drug that targets hepatitis C in an entirely new way was highly effective at suppressing the virus in chimpanzees and kept working for several weeks after the treatment stopped, U.S. researchers said on Thursday.

The hope is that the drug -- made by Danish company Santaris Pharma AS under the experimental name SPC3649 -- could replace more toxic drugs as part of a cocktail to fight hepatitis C, said Lanford of the Southwest Foundation for Biomedical Research in San , Texas."As the study unfolded, just how well the drug worked became amazing to us," Lanford said in a telephone interview.

Lanford, who has no financial ties to Santaris, regularly tests new hepatitis C compounds in chimpanzees, which are the only animals besides humans that are susceptible to the virus.Hepatitis is blood-borne and damages the liver, causing chronic liver problems, liver cancer, cirrhosis and death.

It is the leading cause of liver disease worldwide, affecting an estimated 3.2 million people in the United States alone and 170 million worldwide.Typical treatment involves 48 weeks of interferon plus the antiviral drug ribavirin. The combination works in only about half of all patients, and some develop such taxing side effects that they have to stop.

Lanford said most current drugs and newer experimental compounds being tested in clinical trials take direct aim at the virus. But often the virus will mutate and develop resistance. "This can happen in a matter of days. The drug knocks down the virus and it comes right back," Lanford said.

The Santaris drug tries a new approach, Lanford's team reported in the journal Science. "Rather than targeting the virus, we are going to take something away from the virus that it needs," he said.

The drug targets a tiny stretch of genetic material called a microRNA, which works by directing the activity of genes.

ONGOING ACTIONIn hepatitis C, the virus uses microRNA 122, active in liver cells, to replicate. The Santaris drug is designed to block this process.Two chimpanzees given a higher dose of the drug had a 350 percent drop in levels of the virus in their blood and liver.

"That is a very good knock down of the virus. There are other drugs that can do that, but ... we did this for 12 weeks and there was no sign of resistance," he said."This molecule is so stable that even after we stopped delivering it, it continued to knock down the virus."

In chimps, it showed no toxic side effects. Lanford said the findings were so strong that the company has begun human clinical trials.

The drug also cut total cholesterol levels by 45 percent, but as it is delivered intravenously, it is unlikely to replace cholesterol-fighting pills known as statins.

For patients with hepatitis C, Lanford said the drug could become part of a cocktail that, when combined with newer agents now in clinical trials, may allow patients to avoid having to take interferon, a chief reason many people fail treatment.Lanford said the study also suggests that Santaris' new method of making genetic-based therapies shows promise.

Several drug companies have already signed partnership deals with the private company, including Enzon Pharmaceuticals, GlaxoKline, Wyeth Pharmaceuticals, part of Pfizer Inc, and Shire plc.

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