What has Antisense Therapeutics being doing in the last few months and can you give us a snapshot of what will be happening over the next six to 12 months?
Over the last six months most of the focus has been on our multiple sclerosis (MS) drug ATL1102. We have submitted an application to the ethics committee of a contract research organisation in the UK called Charterhouse who are going to conduct a Phase I study for us. In the last six months we have submitted that application and we have received approval from the institutional review board to start that study. Now we are in the process of preparing to start dosing patients.

You will be dosing healthy volunteers and looking at safety?
Yes. We will also be doing dose escalation. It will give us an indication of the dose we will be using in our follow up efficacy study in our Phase IIa trial. So most of our effort has been in accelerating the program for MS. At the same time we are working on our psoriasis program. We now have a lead compound which are we testing at the Murdoch (Murdoch Childrens Research Institute – MCRI) in some in vitro and in vivo experimental models. The next step will be toxicology studies, which we expect to start in 2004.

We are very excited by the progress we have made in our lead compound development. We have now received six new antisense lead inhibitors from Isis Pharmaceuticals for other disease indications, two of which we have taken into animal efficacy studies. We have concluded those two studies and we are looking forward to being able to announce the results of those studies once we have the appropriate intellectual property protection in place. Then we will be able to let the market know more specifically what we are doing with our pipeline development.

You recently spent some time overseas – what did you do?
The trip overseas focussed on visiting our major collaborator, Isis Pharmaceuticals, to follow up on a number of programs we are running in collaboration with them. We also attended an antisense conference in London. This was very informative. We got to meet with a number of the key players in the field, people who we have relationships with or with whom we are looking to develop relationships. It gave us a perspective on what is happening in the antisense field. It was a really important meeting for myself and Dr Christopher Wraight, our Research Director, to attend.

We also made investor presentations in Europe and in the US to keep them updated on Antisense Therapeutics. We visited them about seven months ago, so in a lot of cases it was following up with people who we had spoken with to let them know how we are progressing.

It is well known that Biogen has been developing an MS drug that is directed at the same target you are aiming at. You are using an antisense construct for the VLA-4 receptor, which is implicated fairly clearly in MS. I was wondering if you could comment on Biogen’s drug program and how it has taken risk away from what Antisense Therapeutics is doing?
It is a very important observation that the work Biogen is doing has direct influence on the risk associated with the development of our MS antisense compound. Essentially what Biogen has done is to spend many millions of dollars validating or proving the importance of VLA-4 as a target for the treatment of MS in humans.

Can you guess how much?
Probably to date, you would anticipate that having taken their compound into Phase II it would be tens of millions. With the very large Phase III program they have in place, as monotherapy and in combination with interferon, the cost would be hundreds of millions. So it’s a lot of money invested to confirm that if you suppress this target in patients with MS, you are able to stop progression of the disease. Their studies to date hint, they go further than hint, they show important benefits in treating patients with MS. Their Phase II study results were significantly improved over the current standard treatment of MS, interferon, where the Biogen compound demonstrated a reduction in relapse rates and also reduced the number of MS lesions versus interferon – very significant data. This led them to investing in this major Phase III program.

With MS, with that receptor, can you elaborate on how it is involved with MS?
The VLA-4 receptor is a receptor on the surface of lymphocytes. When the protein (ie the receptor) is over-expressed in the presence of another protein, VCAM-1, the combination of those two proteins leads to the attachment of these lymphocytes to blood vessel walls, allowing them to transport through the blood vessel wall and into the central nervous system. It’s thought that once these lymphocytes, which normally don’t find their way into the central nervous system or the brain, have appeared in the central nervous system, they attack the myelin sheath (the fatty insulation of nerve cells) that leads to the manifestation of MS.

Stopping VLA-4 with a monoclonal antibody or with antisense means you are stopping production of that protein?
Antisense specifically blocks the production of the disease causing protein, whereas the monoclonal antibody inhibits its activity once it is produced. Our antisense drug for MS will work by reducing, or normalising the amounts of that particular protein so that you don’t get inappropriate migration of cells into the central nervous system. We know this is important because of animal work we have completed. We have shown in animal models of MS that when you inject an antisense inhibitor for this particular protein you stop progression of MS.

Presumably you have dissected animals and found a cessation of lesions.
Importantly, when you monitor the symptoms associated with MS in these animal models, you see an improvement with application of the therapy. Interestingly, our animal studies virtually mirrored Biogen’s animal studies except of course they used a monoclonal antibody for the same target. Because the Biogen compound has been successful in stopping progression of the disease in humans, we are very confident about taking our compound into clinical development. Our goal is to develop a successful treatment, one that provides a significant reduction in risk, by selecting what is a highly validated, proven target for the treatment of MS.

What are some points of comparison between the Biogen/Elan drug, which is a monoclonal antibody, and your antisense compound?
I think that once we have an antisense compound on the market it will compete very successfully with a monoclonal antibody. We think we will have distinct advantages. This particular mab is not fully humanised, which does result in an immunogenic response, which causes the production of neutralising antibodies to the therapy. At the moment the long term implication of that is not known, but it may have an impact on the efficacy of the drug. Antisense medicines are not immunogenic. They do not cause the same immuno-stimulatory response of antibodies that neutralise the therapy. We think it is very important. We think its going to have implications for the efficacy of the drug.

Another important aspect is dosing. At the moment, AntegrenTM (the Biogen/Elan drug) is administered as an intravenous injection, which requires patients to be hospitalised. That obviously adds a lot of costs to the health care system as well as the inconvenience to patients of having to go into hospital for their treatment. Our drug at the moment is being trialed with the use of a subcutaneous injection. The advantage of subcutaneous dosing is that patients can potentially self-administer their medicine. This lends itself to the use of the patient friendly devices such as needleless injection systems. Isis Pharmaceuticals has a relationship with a company called Weston Medical which is developing a needle free injection system for the delivery of antisense. One could anticipate then that we would be able to go to the market with a much more convenient device because of this administration route advantage.

We also know that antisense may be delivered orally. Isis has just concluded a Phase I study in which they showed significant oral bioavailability. They are very excited by the prospects of being able to take this forward as a platform for use with their second generation chemistries. Our MS drug is (also) based on second generation antisense chemistry. There is tremendous prospect for us to develop an orally available antisense treatment for MS which will be so much better accepted by patients and doctors as well, because of the convenience and compliance advantages.

We also know that with these second generation agents we can dose them as infrequently as once a week, and maybe – it is to be confirmed – that we may be able to dose as infrequently as once a month. So there are tremendous compliance advantages.

Another important observation to make is that antisense compounds are synthetic, not like the biologicals that have to be fermented and grown up, a tremendous cost impost on biologicals. We should be able to provide a much more cost-effective therapy.

So you don’t need to spend US$750 million to put in a plant that a biologics drug would require?
That’s right. It is interesting that when you talk to potential manufactures of oligonucleotides, they confirm that it is not a significant investment (to scale up). A lot of these companies have the ability to make oligonucleotides today. I think that is going to be a very important consideration for when these drugs are on the market and are competing against monoclonal antibodies, because we are talking about two similar therapies, both very targeted in their approach. There are a lot of features of antisense that will allow us to effectively compete with monoclonal antibodies.

One of the other striking things about this drug and the Antisense Therapeutics portfolio is that you have said that you can do things rapidly and cheaply. The anticipation is that in twelve months you could be in phase II studies. That would be quite an achievement.
We are excited at being able to take a drug quickly from discovery into clinical development. The success of our MS drug is evidence of that. We also know that it will be important for the development of our follow-up compounds. To be able to take a drug from pre-clinical development into Phase I human studies in 18 months, as we did for our MS drug, is a very rapid development.

From Phase II onwards you are probably looking at a more typical rate of development because you have to go through the standards assessments. The advantage we bring is that we know the characteristics of these drugs very well, so we don’t have to contemplate things like changing delivery aspects of the programs.

I heard you (David) recently refer to the concept of the ‘developability’ of drugs. This is an important distinguishing feature of antisense drug development. There is no new work that needs to be completed or knowledge gained to take this program forward except (to confirm) how well this drug is going to work in treating a disease. With the MS (antisense drug) we have a high degree of confidence because we know that things that inhibit VLA-4 work.

Several compounds that Isis were developing haven’t succeeded in clinical trials, although at the same time many other companies’ drug candidates haven’t succeeded as well. However Isis, or antisense drug technology, has a very different risk profile. Would you care to describe that risk profile?
I think that you are right to compare the technology to other companies developing medicines in the same area. When you do that you clearly see advantages to using a mature, well developed, well characterised medicinal platform. What I’d say about the drugs that haven’t succeeded for Isis, is that in late stage development it probably reflects the target risk. That’s the important aspect we were highlighting before. You really need to be contemplating the quality of your target early on to be able to reduce the long term risk associated with your project. (Isis recently had a Phase III drug failure although questions regarding the validity of the target for that drug surfaced half way into Phase III trials).

We know we are mitigating risk by working on highly validated targets such as our lead MS project and we are working with a very mature and well-developed technology platform. We think the technical risk is behind us. Now we are just contemplating how we are going to commercialise these drugs. There is some residual risk that these drugs may not show the requisite efficacy in these studies but when you compare it to nascent technologies that are going through adevelopment path for the first time, it’s a huge reduction in the technical risk!

Commercially we are reducing risk because we are working with a platform that is well-known. Big pharmaceutical companies who have licensed antisense compounds from Isis and Genta have done the due diligence on this technology. They are satisfied it meets their risk/return profile. So we feel it’s now just a matter of going through the necessary development steps and that we will succeed, in terms of developing an effective therapy, and we will able to commercialise these (drugs) through deals with pharmaceutical companies.

What is the upside for Isis Pharmaceuticals in its relationship with Antisense Therapeutics?
Isis is one of our major shareholders. It was the agreement struck with Isis that led to the foundation of the company. They benefit of course as a major shareholder and in the success of Antisense Therapeutics. Importantly one of the reasons why Isis was keen to undertake this kind of strategic collaboration was that the antisense technology as a platform provides a vast number of opportunities for commercial exploitation. For as many targets as we can identify, we have the prospect of being able to develop an antisense inhibitor to them. So Isis has more than enough opportunities to exploit themselves that they can fund. What they are very keen to do is to expand their technology platform, to be able to develop the technology beyond what they can finance themselves and work with people they can trust. (They wanted to be able to) put the technology in the hands of people they knew were experienced and could be successful in commercialising it.

The benefit they get in that regard is to see their technology presented globally as the lead antisense technology and expand the commercial opportunities beyond what they are able to achieve themselves.

Valid points. To finish off, can you sum up in a sentence what the risk/reward Antisense Therapeutics offers investors?
The way we are positioning the company is high-growth potential (with) lower R&D commercial risk because of the factors we have highlighted before. That’s contexted against companies locally and internationally. It can be encapsulated as simply as that.

Thank you for your time Mark.