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IC-Vec Executives Discuss the Company s RNAi Programs, Delivery Technology

Matthew Speers

At A Glance

Name: Matthew Speers

Position: CEO, IC-Vec

Background: Certified degree, accounting and finance - 1982

BA, modern history and politics/economics, University of Southampton - 1980



Michael Keller
Executive director, biochemistry

At A Glance

Name: Michael Keller

Position: Executive director, biochemistry, IC-Vec

Background: PhD, biochemistry, University of University of Lausanne - 1998

MSc, chemical research, Imperial College London - 1995

BS, natural sciences, ETH Zurich - 1994


In December 2001, IC-Vec was spun out from Imperial College London to develop gene therapies by four members of the Imperial College Genetic Therapies Center: Andrew Miller, now IC-Vec chairman; Michael Keller; Michael Jorgensen, IC-Vec's executive director of chemistry; and Eric Perouzel, the company's executive director of delivery systems.

In April 2004, CEO Matthew Speers joined the company, having held various corporate positions at Beecham (later SmithKline Beecham, then GlaxoSmithKline) and management consultancy firm Plexus Ventures. Since that time, the company has sharpened its focus onto RNAi-based therapeutics and delivery systems.

Speers and Keller spoke to RNAi News this week to discuss the firm and its projects.

Let's start with an overview of the company.

MS: The company now is very much focused on siRNA delivery and therapeutics. … IC-Vec was founded on the idea that gene therapy had some potential, and Mitsubishi [Chemical, the company's largest shareholder], was casting investment seeds on the water when the genomics revolution suddenly opened up in early 2000. This was the beginning of the company really.

As time has moved on, gene therapy has proven very difficult. We took a strategic decision last summer, after looking at what data we were able to generate and the kind of capabilities the company had, that … we would focus the company down onto siRNA and RNAi as a therapeutic area.

We have two core planks of the program. One is that we're trying to develop an siRNA therapeutic for hepatitis, particularly hepatitis C. … The other plank in the strategy was to develop the technology for delivery systemically - so not just to the liver [as with hepatitis], but to circulate [RNAi molecules] more freely and to attack other sorts of diseases. We are ourselves focused on siRNA in cancer applications.

So the two internal programs for you guys are hepatitis and cancer?

MS: Correct. Most of our resources are on the hepatitis programs because they're the most advanced, we're beginning to get good results, and it also gives us a therapeutic opportunity if the technology works. A lot of other companies are interested in our systemic delivery [technology], but we tend to do that work more in collaboration with other companies - so they're using our vector, they're providing their target genes and models, and we're formulating [while] they're doing most of the animal work.

MK: We have also got a number of important collaborations going on under the hepatitis project, especially with Imperial College Medical School … with a very eminent research group headed up by Howard Thomas. We are able to use their … models to evaluate our sequences and delivery technology, and we have recently had some good results.

On the delivery side of things, can you give an overview of the systemic delivery technology?

MK: Everything we do is liposomal based, so it's non-viral delivery technology. We have a very good patent background for a variety of different classes of lipids which are functionally and structurally very particular, and which we use to complex siRNA drugs and basically direct them towards the tissue of interest. … [It] requires two completely different technologies to make these vectors go to the right place - the liver or the cancer.

Which one of these programs uses [IC-Vec's] nanoparticle technology that was highlighted during the [RNAi Europe] conference in Amsterdam [late last month]?

MK: Both of them use the nanoparticle technology, but the nature of the nanoparticles is different because they need to go to a different site in the body.

Could you breakdown the nanoparticle technology and how you make it target different types of tissues?

MK: The technology which we use is introduced under the trade name ConzentRx. We also call it an onion-like technology because we build up gradually from the inside out.

Inside we would have what is called the A component, which is the active drug - in our case it's siRNA. Then we coat this active drug with the B layer, which is [liposomal], to pack them tightly into a nanoparticle. Then we've got the optional C and D layers - the C layer is what is called the stealth layer to protect the particle against attacks from nucleases and serum components in the blood. If we want to, we can add through a special chemistry reaction we have patented, a D layer that is an antibody or a targeting peptide to direct the particle towards a certain receptor family or receptor type in order to avoid it going to the wrong cells.

Is this C layer a PEG?

MK: That's correct. There's a family of polymers we can use. The chemistry is actually modular - we can use a whole variety [of things], either polyethylene glycols or polymers to attach the C layer to the nanoparticle.

This sounds a lot like another technology from a company called Protiva. Are you guys aware of this company?

MK: Absolutely. This is a very good company, and we have good contacts into that company. You are right, they use … a similar technology but with different lipids and different ways of assembling the lipids into nanoparticles. It's definitely a very serious competitor of ours.

On to the in-house therapeutics side of things. Can you talk a little bit about where the hepatitis and cancer programs are in terms of development?

MK: Let me start with the hepatitis program. We have gone through a variety of what I would call logical models, which you need to test with your vectors. The first one, of course, is in vitro. We selected from a pool of sequences we obtained from a Japanese partner company, RNAi Co., good sequences directed against HBV virus. We took the best sequences into a … hydrodynamic mouse model … and we had good success there. We moved on to a genetic animal model … and we again had encouraging success using our delivery technology.

Now we are planning to use a woodchuck model. This is going to be carried out either by the end of the year or in [the first quarter] next year. The woodchuck model is the gateway model for an IND filing for a new HBV drug. All the pharmaceutically relevant compounds, the nucleoside analogs, et cetera, have gone through this model because it is a chronic model [mirroring] HBV-infected humans. It's very similar in that the animals develop hepatocellular carcinoma, like humans, and this is actually the cause of death after HBV infection.

What's the timeline … on when you'd hope to have an IND filed?

MK: I can't give you a precise timeline.

What's the nature of the collaboration with RNAi Co.? Are they going to collaborate on development?

MS: They have provided the first round of sequences. They are not collaborating with us in the woodchuck study [or further development].

Do you have a partner on the hepatitis program?

MS: No. My intention is that if we can take it forward as far as we can ourselves, then we will. It depends on how much more funding we can attract to IC-Vec in its own right. At some point we will want to partner it, and we are kicking off a program this quarter to start contacting companies that we would want to partner with.

The problem is that IC-Vec has brilliant scientists, but in terms of developmental skills and other skills we need to go forward, we'd need to partner anyway. So we're starting those discussions.

What about the cancer program? What's happening there?

MK: The cancer program, in terms of pharmacodynamics, is a little bit behind in development. My colleague Eric [Perouzel, executive director of delivery systems at IC-Vec] has developed nanoparticles that circulate in the blood for about 20 hours, then passively accumulate in xenograft tumors, which we grow routinely in our animal house here at Imperial College. What he has shown is a very strong pharmacokinetics profile that shows the particles end up in the tumor. We managed to get about 5 percent of the total doses in the tumors, which is quite respectable if you compare it to the literature and drug delivery. We are looking into very good siRNA sequences in order to target a particular oncogene that is important for tumor development. We're now trying to establish pharmacodynamic profiles using these vectors.

MS: This program is heavily partnered. We have three collaborations running. One big pharma, one very sizable US biotech, and one US cancer research organization are collaborating with us on this. They're using our delivery vectors in their own models.

Are these collaborations proof-of-principle sorts of things?

MS: Yes.

Can you disclose who the collaborators are?

MS: No. We're under confidentiality.

Jumping back, do you have any partners [on the delivery technology]?

MS: Technology licenses to other companies? No. That would probably happen on the cancer program. We're trying to develop ourselves the in-house hepatitis program. But nobody's using [the technology] outside of what we've described.

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