Drug Discovery
Average cost is > $1 billion & takes up to 15 years Prices are under constant pressure Regulatory is becoming very complex Patent landscapes are very sensitive Generics have attained ~ 50% of the market
R&D investments are becoming tough to make Only 3 in 10 drugs recover R&D costs Only 2 in 10 drugs are profitable to the owner Only 1 in 100 drugs are blockbusters
Figure 1: Drug discovery under siege. Several constraints against investments in R&D.
Entities (NCEs) were natural products, 299 NCEs were derived from a natural product with a semi- synthetic modification, 268 NCEs were natural product mimics and 55 NCEs were made by total synthesis but the pharmacophore may have a nat- ural product origin21.
According to Scannell and colleagues, the Figure 1
Drug discovery under siege. Several constraints against investments in R&D
if they can see them by their naked eyes. Through perseverance and technology advancements, the field has enabled the human race to go beyond the skies, the solar system and into deep space explo- ration using both manned and unmanned missions. The purpose of which is to unravel the mysteries of our universe, and to better understand our place in the cosmos. After several thousand years of research and a gigantic budget, have we explored or conquered space?
By comparison, have we successfully conquered the chemical space? The answer is not yet because we have only begun to explore its complexities. As disappointing as this may be, our ability to synthe- size complex chemical molecules is still rather primitive as compared to what nature can and has been doing over billions of years. As an example, bacteria can make a complex molecule in a few hours versus several years of hard work of a super creative synthetic chemist with an army of students and post-doctoral researchers resulting in one high profile publication with a gigantic authorship line- up 10 to 20 years later, and with a synthetic route of more than 60 steps; hardly amenable to conven- tional process chemistry for scale up. So, in essence, we can replicate or mimic what nature has already made given resources and time, but is it enough for conquering space and making novel drugs? Newman and Cragg would argue that we are at least making some progress, and suggest that natural product research should be expanded sig- nificantly, as assessed through their 30 years’ analysis of drug approvals: 64 New Chemical
76
world’s chemical libraries combined represent a very tiny miniscule fraction of the vast chemical space5, perhaps the best comparison would be the size of a rounded grain of salt versus the size of Earth; they further argue that these libraries con- tain redundant regions of the chemical space. Surprisingly, the CAS database counter registry contains ~68 million commercially available chemicals22. Based on the various suggestions as to the size of the chemical space23-24, I would propose that empirically it may contain 10180 possible organic and inorganic chemical struc- tures. I would also predict that up to 10% have evolved over billions of years to interact with liv- ing matter from bacteria, fungus, worms, scorpi- ons, frogs, dinosaurs, plants to humans. This would leave us with up to 1018 possible chemical structures to explore and synthesise, clearly an unattainable task. But if I would further empiri- cally predict that there are only 109 known chem- icals on Earth, it would then mean that we have covered only 7%, and leaving 93% or 930 mil- lion molecules up for chemical exploration. How realistic is it to engage in making these com- pounds over the next 30 years? That is 31 million compound per year or 2.59 million compounds per month or 86,111 compounds per day. Even with access to the most sophisticated high output chemical synthesis strategies and robotic enabled facilities in the world, simply put this task would also be unattainable. In a recent report, Reymond and Awale predict that by using their exploration strategies including improved compound enumer- ation, classification and virtual screening schemes, and implementation of chemical synthe- sis resources, we would have an opportunity to better explore the chemical space25. Thirty years of CC and chemical innovations have left us stag- nant at the same starting line for the race to pro- duce better drugs, and with only 387 NCEs dis- covered by random screening or modifications of existing molecules21.
Drug discovery under siege
1,073 drugs are considered unique NCEs approved over a 30-year period21,26. If these numbers truly hold, then the combined mighty of Pharma and biotech companies have only produced an average
Drug Discovery World Spring 2013
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80