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Atugen s Klaus Giese On the Company and its Foray into RNAi Therapeutics

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At A Glance

Name: Klaus Giese

Position: CSO, vice president of research, Atugen

Background: Postdoc, Howard Hughes Medical Institute, University of California, San Francisco — 1991-1994; Postdoc, Max Planck Institute for Molecular Genetics — 1989-1990; PhD, biochemistry, Free University of Berlin — 1989

After a four-year stint at Chiron, where he was group leader in functional genomics, Klaus Giese moved back to Germany to help Atugen advance its gene silencing contract services operations and, now, its RNAi-based therapeutics programs. Recently, Giese spoke with RNAi News about his work.

How did you get involved with RNA interference?

Atugen is a company that has worked in gene silencing [since 1998]. We started off using specific antisense molecules, which we call GeneBlocs, and we had a nice history of obtaining very specific knockdowns of target molecules. We created a [contract research] service business using gene silencing from 1999 on, and developed very potent delivery vehicles. When we saw the report by [Thomas] Tuschl in 2001 we realized that we had to immediately implement this technology … for our service [business], in which we have accumulated revenues of more than €18 million. [So as to] not lose our customers, we had to implement RNAi technology.

We also realized that if we are not better than what people can get by going to oligo shops, we will lose these companies [as customers]. So, we had to improve the technology beyond what is known in the literature.

Were you at Atugen when you first started working with RNAi, or had you been working with it prior to that?

Professionally, I got involved with it at Atugen.

As Atugen didn’t start out with RNA interference, could you describe how the company expanded into that field?

When we started looking at potency and specificity of what we call conventional RNAi molecules, we realized that these molecules, which are made up of normal RNA nucleotides, have very poor stability in serum. We always envisioned having to make the next steps, which are in vivo validation and maybe even therapeutic applications. So, we started in 2001 and 2002 to optimize the stability of these molecules to improve potency, to play around with modifications of the backbone, and to play around with the different lengths and structures. This is why we … had a molecule in our hands that had superior properties in terms of potency, specificity, and stability.

This is where we are right now, and why we had to reshape the company and move it into the therapeutic RNAi space. In addition, we had filed our own patent applications. If you put this all together, we had to move into this [part of] the RNAi field.

Can you comment in detail on the difference between conventional RNAi molecules and Atugen’s?

Conventional [RNAi molecules], I always say, are chimeric molecules composed of DNA overhangs and a core of ribonucleotides. Conventional molecules are 21 to 23 nucleotides in length, and they have no modified nucleotides — they are composed of DNA and RNA.

Our molecules differ in at least four features. The first feature is that we are working with blunt-end molecules — they have no overhangs. The second is that we are working with 19-nucleotide base pair RNA molecules. The third one is [that] our molecules consist of only RNA. The fourth one is that we have a modification at the 2’ position of the sugar backbone, which right now is a 2’ O-methyl modification. [This modification] belongs to what we call naturally occurring RNA because ribosomal RNA, which we all have in our bodies, also has this kind of modification.

The molecule we have is composed of naturally occurring modifications. We have no phosphorothioates — we only have phosphodiester bonds. The molecule is known to the cell, it’s shorter, but it’s stable. If you incubate this with serum, the molecule is stable up to a couple of days, but it is degradable. It is very important to have this in there — we don’t want to create something that survives for weeks or it’s not degradable like phosphorothioates, for example. We want to have something degradable over time, but [that] has enough stability to become a therapeutic molecule.

Our strength is a dual approach. One, we have identified these stabilized siRNA molecules, but what is even more important is the delivery. We have made major progress in delivering siRNA molecules across mammalian cells, [and] not only in tissue culture where we have an expertise.

We have a repertoire of liposomal formulations optimized for specific cell types and we have used this knowledge to move into animal models using the same formulations we have used over the years. This is what we believe is a big advantage. We at Atugen have not seen efficacy with naked delivery … We have high dosed repeatedly but not seen efficacy. However, we have seen very good efficacy when we used our liposomal formulations.

Are they delivered intravenously?

At the moment yes. It’s a very clinically relevant technology. There is no high pressure — low infusion, low volume.

As far as I know, your company is the only one out there that is doing both contract research and looking into RNAi therapeutics. Was there any concern when the decision was made to go into therapeutics that you might be trying to do too much?

It’s two-sided. The service business provides us with revenues, which support the R&D activities. This is important, and as long as the service [business] is very lucrative we will not stop it. The second [point is that] the service [business] provides us with an early entry to talk to big pharma because our clients are AstraZeneca, Schering AG [for example]. We also have Altana, [and] we now have Sankyo — the second biggest Japanese [drug] company — [as a customer]. [This] provides me an entry point to tell them where we are in terms of our activities. We hope this will trigger a research alliance with one of the big pharmas because we are already doing work with them on the service [side].

{Editor’s Note: Giese added in an e-mail after the interview that 20 percent of the company’s scientists work on the company’s contract research activities, and therefore the company feels the risk of “becoming defocused from [its] research activities [is] minimal.”}

How is that going, the process of striking collaborations?

We are in the process. We have visited [potential collaborators] now with recent data. We actually wanted to compile a [data] package, which we have now done. We have a nice package showing in vivo validation, a proof of concept using our delivery technology and our siRNA molecules. We have visited several large pharmas and some biotech [firms], and we are now starting talking to them in more detail [about] how we would envision a research alliance.

Are the discussions encouraging?

Yeah. We are expecting something in the next couple of months because every big pharma has implemented a task force — everyone is now, I feel, pushed to look into this field and not to miss out. It looks promising that we’re getting in.

Are you only seeking out collaborations, at this point, with big pharma? Are you looking at biotechs — some small players in the field?

We have one biotech [collaborator], which unfortunately I can’t name. Here we’re going into real animal experiments with monkeys very soon to look for proof of principle in a higher animal model.

This is a real collaboration where we’re providing IP and knowledge, our chemistry, and our delivery technology. The partner has provided the target. We’re actually going into GMP scale up right now.

This is for an RNAi-based drug?

Correct.

Are there any plans to announce the deal?

I expect that in the next two months we will have a press release.

You said that you have some proof-of-concept data put together. Are these the glucose-tolerance data [publicly highlighted by Atugen’s director of business development] Andre [Lochter]?

Correct. This is one set. We have chosen the glucose tolerance [test to show] quick optimization in a positive readout system because this is what you want to show customers or collaborators, that our molecules have no intrinsic toxicity.

Now, we moved on and have knocked down tumor growth in two different tumor types … We now have a nice [data] package for delivery and proof of concept in the liver, and we also have proof of concept [data for] inhibiting tumor growth.

What tumor targets?

One is a prostate cancer tumor model, [with] subcutaneous [administration]. We have targeted a specific molecule on which we’ve been working a long time. The other is an oncogenic-derived fibroblastic tumor, which we also used to show specificity and high-selectivity of our delivery [technology], and potency of our stabilized siRNA molecules.

The cancer field is the area the company is primarily focused on for its therapeutics, correct?

It’s based on where we all come from — the whole team is specialized in oncology. But, as you know, the technology is not restricted whatsoever, and in the collaboration with this biotech we are not going for a cancer target. We’re completely open if the collaborator brings expertise in terms of model systems, but our animal facility right now is focused on — and all the animal models are — in the oncology area. We also, clearly, have a small diabetic model system.

The collaboration — is Atugen part of it, or are you developing [the drug] for the collaborator?

We have an opportunity to make a 50-50 arrangement, and this is still under debate because it would require certain commitments in terms of money. This is why I said it might take another two months — we are right now in the process of negotiating the terms of how we would like to enter.

In terms of what is going on in house in the cancer field, would you expect to have selected a target soon? Is that what's going on?

We're planning to move on our own molecules [by] the end of 2005 or, the latest, 2006. Right now, in oncology, we have to test whether a single treatment against a single target is sufficient to ablate cancer growth. Right now, we have eight candidates where we have shown proof of concept in tissue culture [and] that these molecules are specific, that they can knock down a target gene in a dose-dependent manner. We are now looking for the right tumor models to prove that knocking down these targets … is sufficient to block tumor development or progression to a metastatic state.

What about Atugen's wound healing work?

It's a side project, which we are doing with [the Swiss Federal Institute of Technology (ETH)] in Zurich. It's a little bit opportunistic … Very low [priority].

Are there other disease areas being considered by the company?

[The one] in this collaboration, but I don't want to talk too much about it right now. Right now, Atugen is strongly focusing on showing the proof of concept in many different tumor models to attract a big partner and to start a research alliance.

Can you touch on, in general terms, what the collaboration is focused on?

It's growth, uncontrolled growth.

 

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