Pharmaceutical Executive Europe - February 2008 - (Page 12) 12 R&D: Innovation February 2008 Pharmaceutical Executive Europe So now we are trying to understand how they do this. Just to give you an example, when they stop dividing and hide, they shut off a significant part of their metabolism. Most of the machinery being used for cell division, for instance, is turned off to save energy, which means that antibiotics don’t work anymore because they specifically address growth mechanisms. If you are interested in understanding how they hide, one thing to do is to map their genetic expression — which genes are turned off and which genes stay active during the latent phase — and try to derive targets. Now, for the first time ever, we are applying the same tools that we use to find cancer or Alzheimer’s or diabetes targets to these bugs. PE: Are these expression maps used often within the industry? PH: In the infective area, of course — the genomes of all of these pathogenic organisms are being published constantly. But there are very few people working in TB — four or five companies. Now another very interesting point is that most of the original antibiotics were natural compounds because—well, maybe I can ask you a little test question. Who invented antibiotics? PE: Was it Alexander Flemming? PH: Well, a lot of people think it’s Flemming, but actually that’s wrong. Penicillin was invented by bugs against bugs through millions of years of evolution. Antibiotics originally were secondary metabolites of bacteria, which they were using to kill each other. And Flemming learned relatively late that you can find within natural organisms compounds that can kill others. That was the origin of the human use of antibiotics. Now we try to synthesise them. Today we have our big libraries with a few million compounds. Whenever we select a new target out of the genome, we first test our library against it and see if we get hits, compounds that interact with that target. If we do, we take those as the starting point for a chemical-optimisation programme to transform the hits into what could be a drug. In the case of both TB and dengue, our compound libraries very often do not contain any drugs interacting with these targets. It seems that because nobody worked on these bugs for at least two generations, nobody made any compounds against them. And given that most antibiotics used to be natural compounds, made by bugs for bugs, the synthetic libraries do not contain any compounds that interact with these bacterial targets. What this means is now we have to apply the most sophisticated rational-chemistry mechanism, proteomics. We must determine the three-dimensional structure of those enzymes or signaling molecule pathways that we want to attack receptors, and then design a new compound or family of compounds that will interact with those. We always have to create new libraries. This is another way that the absolutely newest form of structural chemistry, rational chemistry, is being rolled out against neglected diseases, which was never the case before. At the Novartis Institute for Tropical Diseases, with our partners, we have solved the threedimensional structure of at least three dengue enzymes, which was essential because that was one of those areas where we didn’t find any lead compounds. The philosophy behind the NITD is to take sophisticated new drug-discovery mechanisms that are developed for our mainstream business and systematically apply them to the pathogens of neglected diseases. PE: Given that there are not a lot of therapies available and the unmet need for treatment is so urgent, are you implementing any new tactics to speed up the very long discovery and development time? PH: Well, if I did, I would apply it to the commercial part first, because it has the same problem. Anything to shorten the process for drug discovery and development and to reduce the attrition rate would have a monumental impact on the whole industry. Originally, we thought that developing treatments for TB and dengue might be faster, because it’s simpler to kill a bug straight off than to tweak a complex biological mechanism in the human body. But we realized that was a naïve illusion when we looked at how intimately the pathogen and the host are interconnected. I’ve spoken to other researchers about their drug-development innovations, and they’ve talked about doing Phase I/II or Phase II/III. That’s the one thing that Novartis was pioneering — with the proof of concept in man — for all our drugs going into the clinic. It is in contrast to what we were doing before — Phase I in normal volunteers and looking at the side effect profiles, Phase II doseescalation studies, and Phase III for efficacy. Because we understand the molecular mechanism of action in our drugs, the very first time we go into human beings, we try to see if the scientific hypothesis that we have made in preclinical
Table of Contents Feed for the Digital Edition of Pharmaceutical Executive Europe - February 2008 Pharmaceutical Executive Europe - February 2008 Contents From the Editor News and Analysis Brussels Report Calendar R&D: Innovation - Learning to Share Drug Launch - The Preparation Game Q&A - Getting a Head Start Regulatory Compliance - Credible Compliance Clinical Trials - Establishing Trials in China The Mix - Relevant ROI Comment - Taming the Trader Last Word - Under the Microscope Pharmaceutical Executive Europe - February 2008 Pharmaceutical Executive Europe - February 2008 - Pharmaceutical Executive Europe - February 2008 (Page 1) Pharmaceutical Executive Europe - February 2008 - Pharmaceutical Executive Europe - February 2008 (Page 2) Pharmaceutical Executive Europe - February 2008 - Contents (Page 3) Pharmaceutical Executive Europe - February 2008 - From the Editor (Page 4) Pharmaceutical Executive Europe - February 2008 - From the Editor (Page 5) Pharmaceutical Executive Europe - February 2008 - News and Analysis (Page 6) Pharmaceutical Executive Europe - February 2008 - News and Analysis (Page 7) Pharmaceutical Executive Europe - February 2008 - Brussels Report (Page 8) Pharmaceutical Executive Europe - February 2008 - Brussels Report (Page 9) Pharmaceutical Executive Europe - February 2008 - Calendar (Page 10) Pharmaceutical Executive Europe - February 2008 - R&D: Innovation - Learning to Share (Page 11) Pharmaceutical Executive Europe - February 2008 - R&D: Innovation - Learning to Share (Page 12) Pharmaceutical Executive Europe - February 2008 - R&D: Innovation - Learning to Share (Page 13) Pharmaceutical Executive Europe - February 2008 - R&D: Innovation - Learning to Share (Page 14) Pharmaceutical Executive Europe - February 2008 - R&D: Innovation - Learning to Share (Page 15) Pharmaceutical Executive Europe - February 2008 - Drug Launch - The Preparation Game (Page 16) Pharmaceutical Executive Europe - February 2008 - Drug Launch - The Preparation Game (Page 17) Pharmaceutical Executive Europe - February 2008 - Drug Launch - The Preparation Game (Page 18) Pharmaceutical Executive Europe - February 2008 - Drug Launch - The Preparation Game (Page 19) Pharmaceutical Executive Europe - February 2008 - Q&A - Getting a Head Start (Page 20) Pharmaceutical Executive Europe - February 2008 - Q&A - Getting a Head Start (Page 21) Pharmaceutical Executive Europe - February 2008 - Regulatory Compliance - Credible Compliance (Page 22) Pharmaceutical Executive Europe - February 2008 - Regulatory Compliance - Credible Compliance (Page 23) Pharmaceutical Executive Europe - February 2008 - Clinical Trials - Establishing Trials in China (Page 24) Pharmaceutical Executive Europe - February 2008 - Clinical Trials - Establishing Trials in China (Page 25) Pharmaceutical Executive Europe - February 2008 - Clinical Trials - Establishing Trials in China (Page 26) Pharmaceutical Executive Europe - February 2008 - Clinical Trials - Establishing Trials in China (Page 27) Pharmaceutical Executive Europe - February 2008 - The Mix - Relevant ROI (Page 28) Pharmaceutical Executive Europe - February 2008 - The Mix - Relevant ROI (Page 29) Pharmaceutical Executive Europe - February 2008 - The Mix - Relevant ROI (Page 30) Pharmaceutical Executive Europe - February 2008 - The Mix - Relevant ROI (Page 31) Pharmaceutical Executive Europe - February 2008 - Comment - Taming the Trader (Page 32) Pharmaceutical Executive Europe - February 2008 - Last Word - Under the Microscope (Page 33)
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