Abstract
Uday Saxena was appointed Chief Scientific Officer at Dr Reddy’s Laboratories in 2000. In this role he provides the leadership and general strategy for the company’s drug discovery research into metabolic disorders, cardiovascular disorders, inflammation, cancer and anti-infectives. He is also a member of the company’s Senior Management Council. He gained his PhD at the Memorial University of Newfoundland, his thesis covering biochemical and functional characterisation of rat C-reactive protein with respect to lipid, lipoprotein metabolism, atherosclerosis and inflammation. On completing his postdoctoral fellowship at Colombia University, he went onto work on various drug discovery projects as Senior Scientist and Principal Research Scientist at Parke-Davis Warner-Lambert and as Director and Vice-President for preclinical research at AtheroGenics, Inc., before undertaking his current position. Uday Saxena has written over 50 peer-reviewed articles and invited reviews. He is currently on the Editorial Board of two international drug discovery-related journals including Expert Opinion on Therapeutic Targets.
1. What are you currently working on?
We are currently developing a candidate drug, RUS3108, for an orally deliverable pill for the treatment of atherosclerosis. Atherosclerosis is the process by which blood vessels get clogged and this can result in heart attacks (myocardial infarction), stroke and death.This drug candidate is currently at Phase I clinical trials.
The current treatment for atherosclerosis is to simply manage the risk factors, such as hypertension, diabetes, high blood cholesterol, lack of exercise and poor diet; by reducing these risk factors, the disease is controlled. However, there is still a significant unmet medical need as around 60% of people having their risk factors managed still experience cardiovascular events such as myocardial infarction or stroke. This risk reduction therapy is successful but only partially effective and, as heart disease is the number one killer in the world, this is not good enough and that is why we are trying to come up with something to tackle the disease directly.
2. How will it be used?
It will be given to patients with a history of heart disease and will be taken in combination with any of the risk reducing drugs that they are already on. It is an addition to the current treatment, not a replacement.
3. What is the target?
The target of the drug is a specific protein produced in the vessel wall called perlecan. The drug candidate increases the expression of perlecan, which has been shown to have a protective effect against the genesis of atherosclerosis.
There are three particular steps in the process of atherosclerosis: 1, uncontrolled proliferation of smooth muscle cells; 2, infiltration of inflammatory cells, such as monocytes; and 3, thrombosis. The combination of these three steps leads to the plaque formation. In vitro and in vivo work has shown that if we overexpress perlecan using the drug candidate, we are able to reduce inflammation and proliferation of smooth muscle cells and the end result is that we are able to show a marked reduction in atherosclerosis formation.
4. How did you identify the target?
We have been working on this now for five years. We recruited a leading scientist in this field who has done a lot of preliminary work in this area, which hinted that perlecan could be a target for treatment for atherosclerosis. Some work had been done in academia but no other company had actually used this to start a drug discovery process.
5. Is this target already being used in a similar type of therapy?
This target is currently also being explored in preclinical studies for use in treatment for restenosis induced by balloon angioplasty but, to our knowledge, no-one else has a drug candidate based on this.
6. What is the mechanism of action? What does the drug actually do to the target?
The drug causes the relevant gene to overexpress Perlecan.
7. How are you researching this?
Firstly, we had to do a lot of in vitro and in vivo validation to make sure perlecan was a suitable target, then we had to set up a screening strategy to identify compounds that might upregulate the expression of perlecan, then we had to optimise it to see if the candidate had drug-like properties and then test the candidate in animal models of disease and also test the safety in animal models.
8. What techniques are being used?
We are pretty much using the whole gambit. We have chemists making drug candidates for us to test; we have cell biologists who are testing the candidates first in cell-based models; we have animal pharmacologists who then test the candidate in animal models; then we have clinical development people who make sure that the candidate has appropriate features to make it to clinical trials (e.g., pharmacokinetics) and toxicologists looking at safety in a variety of animal models.
9. How will this drug candidate compare with other therapies currently available?
There is nothing available right now for direct disease modification for atherosclerosis, only risk reduction therapies such as statins that lower cholesterol, antidiabetics and antihypertensives.
10. Who are your main competitors in this area, and how do their compounds compare with yours?
Drug companies have now realised there is the opportunity to modify the disease directly. Let me give you a couple of examples that are advancing in the clinic:
Atherogenics has a compound in Phase III clinical trials. Their compound, an antioxidant, is largely an anti-inflammatory compound whereas ours is anti-inflammatory, antiproliferative and antithrombotic. They have shown efficacy in a small population in Phase II studies and are currently in Phase III studies. GlaxoSmithKline also has a drug candidate which is an inhibitor of the inflammatory enzyme LPPLA2.
Both of these are targeting inflammation but no-one other than our group is specifically looking at perlecan and the strategy of combining anti-inflammatory, antiproleferative and antithrombotic properties.
It is a strong possibility that inflammation is a major component of this disease so I predict that the anti-inflammatory approach is the right direction to be going in. The main competition is from about five or six other companies working on direct disease modification. Hopefully we will all be successful as there is a huge unmet medical need. Heart disease is the major killer in developed and developing countries. As a scientist, it is very exciting that so much attention is being given to this problem, and that the various companies are all approaching it in different ways. This should give hope to the patient as it should mean that eventually something will be successful.
11. Is this drug candidate as safe and effective as other therapies?
It is really too early to talk about safety and efficacy in humans, but based on the preclinical science seen so far, it should be effective and safe. There are no glaring safety issues, but this is a ‘first in class’ drug so there is no precedent. The rewards of introducing a ‘first in class’ drug are huge but there are risks as a lot less is known.
12. Do you see this as the future of atherosclerosis therapy?
Absolutely. Direct disease modification is the future. From the perspective of the patient and the physician these are very exciting times. We have enough of an understanding of the disease to be able to try to directly modify it. Ten years ago we didn’t have the tools to be able to do this but we do now.
The tools for scoring how advanced the patient’s atherosclerosis is have also improved greatly in the last five years. Non-invasive imaging techniques can now be used and the progression of these tools means that clinical trials can be better designed to test an atherosclerosis drug. A protein circulating in the blood called C-reactive protein is an approved biomarker for heart disease.
I think the direct disease modification therapy will go hand in hand with the current risk reduction therapy. Drugs, such as statins, have been shown to be very successful and it would almost be unethical to take the patient off of these.
13. What are the current ‘hot topics’ in atherosclerosis research?
There are two major fields in this area in which there is a lot of interest at the moment:
atherosclerotic plaque regression and plaque rupture. Currently, balloon angioplasty is used to clear clogged blood vessels but is there a better way to use drugs to shrink the plaque? This is quite a hot topic at the moment.
People are trying to understand why the plaque becomes unstable and ruptures. This is not good as it can cause a heart attack. These two areas are being intensely studied both by industry and academia.
14. What are the implications of this drug candidate reaching the market?
The implications are huge. The risk reduction methods currently used are able to help about 40% of patients. What about the other 60%, who could have all of their risk factors controlled and still end up getting atherosclerosis and heart disease? With this drug, we would be able to help the people in that 60%, which, if you look at it from a worldwide perspective, is not a small number. If any of these approaches are successful then we can help those people who are not entirely being helped by the existing medicines.
15. Provide your Expert Opinion
The race is on. It is a very exciting time because, whichever approach is successful, hopefully it will mean that human life is saved and quality of life is improved.
If you consider males over the age of 45, 3 out of 4 will die from heart disease and the fact that there could be drugs developed that will save some of those lives; that is pretty profound. I find it very exciting that this breakthrough might be made in my lifetime. You must balance my excitement with the fact that our product is only in Phase I and the historical odds of a product making it through from Phase I is 1 in 10, Phase II around 30% and Phase III around 50%. The only way to find out if you have the right candidate is to put it in the clinic and be data-driven. I am pretty sure that in the next 10 years, at least one of these approaches will be successful. These will be the first generation. We just need one to get through the door and then a second generation will follow.