Henrik Øren, Santaris Pharma
Chris - 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.
Chris - Welcome to The Naked Scientists.
Henrik - Thank you.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.
Chris - 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.