The enemy within
AVANT Immunotherapeutics, Inc. uses novel applications of immunology to prevent and treat diseases caused by both the enemy within (autoimmune diseases, cardiovascular diseases, cancer and inflammation) and the enemy without (infectious diseases and organ transplant rejection). One of AVANT’s ‘anti-self’ approaches that has caused many eyebrows to raise across the industry is the development of a therapeutic vaccine against endogenous cholesteryl ester transfer protein (CETP), which may be useful in reducing risk factors for atherosclerosis. AVANT is developing a vaccine (CETi-1) to stimulate an immune response against CETP, which it believes may increase HDL (good cholesterol) and thus reduce the progression of atherosclerosis.
Dr Una Ryan is President & Chief Executive Officer of AVANT Immunotherapeutics and is also Research Professor of Medicine at the Whitaker Cardiovascular Institute of Boston University School of Medicine. She joined AVANT (Then T Cell Sciences) in May 1993. Formerly, Dr. Ryan held the position of Director of Health Sciences at Monsanto Company from 1990 to 1993 and was Research Professor of Surgery, Medicine and Cell Biology at Washington University School of Medicine from 1990 to 1993. Dr Ryan explained to Phacilitate why the concept of a vaccine for use in cholesterol management is so attractive, how the concept is becoming a reality and what challenges remain in the development of a safe, effective vaccine.
Phacilitate: ‘Anti-self’ vaccines are a major focal area for AVANT Immunotherapeutics. Could you explain what you mean by the term?
Ryan: We normally think of vaccines as a way of turning the immune system against a foreign invader, an infectious organism. And the immune system normally won’t attack self - T cells against self-proteins are actually deleted by the thymus when we are born. So in order to do this we had to trick the immune system. We wanted to target a protein in blood that regulates cholesterol balance (cholesteryl ester transfer protein, CETP), and we knew the epitope on CETP where cholesterol binds. So we knew that we needed to direct the vaccine against this epitope of CETP, but how did we make a vaccine against self? We tricked the immune system by coupling that epitope to an epitope from tetanus toxin that we know anyone’s immune system is reactive to. So we know we can make antibodies against tetanus toxin, and by linking up with that we made a vaccine against self. So instead of targeting some outside infectious organism, such as influenza virus, we are attacking something that in modern humans can be a problem, but which, in primitive man, was probably designed to keep a cholesterol balance on a rather low cholesterol diet.
Phacilitate: When we think of vaccines, cholesterol management is a very novel disease target. Has the community been surprised by your approach?
Ryan: Absolutely. In fact people were somewhat incredulous that this could be done. But if you think about it, vaccines against infectious disease have really shown us the way. We have eliminated many of the real scourges of the nineteenth and twentieth centuries. So what is the big epidemic of the twenty-first century? It is heart disease. And the incidence is set to rise as we all get older - and fatter. So we decided to try to use all of our experience in meeting that challenge. AVANT is an immunology company and we think about making vaccines that are useful, so we have used our experience to target a self-protein in the hope that we can control atherosclerosis.
The concept of CETi-1 originated within AVANT, driven by Chuck Rittershaus, a very clever scientist who has invented many things within the company. His background is closely linked with the real history of AVANT. Before AVANT, there was a company called T Cell Sciences where again we were making vaccines against self T cells - ones that we thought might cause autoimmune disease. That program did not turn out well in the clinic, but the concept was born in-house. Now we have joined forces with two vaccine companies - T Cell Sciences bought vaccine specialists Virus Research Institute (VRI). Then we bought Megan Health - a St Louis company specializing in animal vaccines.
So in many ways the concept reflects a natural evolution in our company - find a good target, then find a way for the immune system to address that. The immune system is very, very good to have on your side. It is very specific, so the risk of side effects is much less than it is for conventional drugs, which are often not very specific. It is a very powerful approach, we know again from vaccines against diseases such as smallpox that you can actually eliminate disease. It also has a memory, and it is very cheap - you are making each person’s body into a little factory for your drug, and all you have to do is immunize. There are many, many advantages in taking a molecular target that is clearly key in a process in which you are trying to intervene and then using the immune system to attack.
Phacilitate: What is the market potential for such a vaccine?
Ryan: Clearly, if this approach does work, it will be of blockbuster value. Increasingly, people realize that the story doesn’t just lie in LDL; there is a huge role to play for HDL. It is a difficult market. We know there are about 50 million people in the USA in whom HDL levels are too low. We also know that we cannot target every one of those without a major educational program. However, the statins represent a $12-14 billion market in the USA over the next few years. So what we can say is that there is a market of more than $2 billion that we can access - it is clear that we are talking billions not millions.
Phacilitate: What are the relative advantages over standard therapies?
Ryan: If there is a clear advantage, then people will use it. We believe that there are significant advantages over standard therapies, and our focus groups with cardiologists tell us that they are not happy with the options currently available for raising HDL. Statins raise HDL a little but not really very much, and some of the other drugs have side effect problems.
The advantages of a vaccine would be, first and foremost, compliance. Compliance is quite poor with cholesterol drugs, especially amongst the elderly. Once vaccinated, the patient will have complied - there is no need to remember to take a pill each day, and it is more convenient. Because of concerns about side effects, patients on statins visit their physician every six months to have liver enzyme and heart muscle tests. We would like to immunize every six months - provide a booster shot every six months. We believe that there is also an emotional component. Patients don’t like to feel condemned to take pills for the remainder of their life, when they don’t feel particularly ill. I believe that people would rather have an HDL shot and forget about it for six months.
Cost is another big issue, and this approach will be much cheaper for health care systems. From experience, we know that vaccines are the best way to provide the broadest population with the lowest cost health care, and that they are effective. We are now trying to direct that approach toward new disease targets - heart disease and atherosclerosis - because we believe that it is better for the health care system. We also believe that we may be able to access primary prevention, in that there are people who are not at great risk and who have not had cardiovascular events but in whom cholesterol balance could be improved.
Phacilitate: What is the current development status? Can you comment on the regulatory hurdles that you face?
Ryan: The vaccine is now in Phase II clinical evaluation. The Phase II study that we started in August 2001 has now finished enrolling. Now that may seem a long time, but we are talking about six monthly dosing, which we will do out in the field. This study has an initial immunization and two boosters - a six-month boost and a six-month follow up. So we would expect the trial to be complete in the second part of 2003.
Definitely there will be regulatory hurdles. What the world needs, and what the FDA says it wants, is novel drugs and not me-too drugs. We are essentially forging the way here - we are a company that is defining the processes required in taking a therapeutic vaccine like this to the market. However, I think that the requirements will in many ways be the same as for standard therapies. We don’t yet know whether we will be able to use HDL as a surrogate approval end point, whether we will have to undertake an outcomes trial or whether other more tried and proved parameters can be used. And it may be that our trials are longer because of our very favorable dosing system. However, I believe that the requirements for showing safety and efficacy will be similar to those for conventional drugs
We are very serious about our approach and we will do everything that we believe is necessary to do to gain approval and to market CETi-1. We will work with the FDA, and ultimately we will probably work with a larger partner. We plan to engage in a partnership following completion of the Phase II studies. Clearly we would like to retain as much of the value as possible, but the potential value is so huge we can afford to share it. Ultimately, the launch, marketing and the educational component will require the involvement of a company that is much stronger and more experienced than AVANT. There are several such companies out there, particularly among the statin companies.
Phacilitate: If all goes well, when can we expect to see a cholesterol management vaccine on the market?
Ryan: Well things are going well. I think we had more regulatory hurdles when we started than we have now. We have a very, very nice profile with no drug-related adverse events. So we believe the vaccine could be on the market in 2007. That said, none of us knows what is ahead, but I can say that all is going very well at the moment.
Phacilitate: What other potential targets in the anti-self field do you see as attractive?
Ryan: It is interesting to ask, ‘what will this vaccine teach us?’ Well, there are obviously some things still in the atherosclerosis area that we are already considering - lowering LDL, lowering oxidized LDL, lowering triglycerides and targeting other pivotal molecules. We believe we will be exploring in the same axis - putting cardiac disease at the forefront.
Elsewhere, there is a lot of interesting anti-self research, particularly in the cancer area. Now, whether cancer should be perceived as ‘foreign’ or ‘self’ can be debated, but for our purposes here I see it as ‘self’ because it is the whole human that we are trying to help. Contraception is another very interesting area, although it is an area that doesn’t fit within our company focus. We have seen pioneering work in this area in generating anti-self vaccines against human chorionic gonadotrophin (HCG).
In terms of AVANT, we are interested in other chronic diseases, such as Alzheimer’s disease. The Elan approach has given people a bad taste, but I’m not sure that the disease target is wrong. Rheumatoid arthritis is another huge scourge of the twenty-first century that has an extensive range of work directed toward it, and we would like to see if we could also target that kind of problem.
