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Along with ominous drumbeats heralding the decline of the pharmaceutical industry, another recurring lament that we hear these days is about the decline of small molecules and the rise of biologics like antibodies and other proteins. The last decade has seen several successful antibody drugs, especially against cancer. Based on this success the prevailing wisdom (which does not tire of making its presence known) seems to suggest that traditional small molecule drugs are being shown the door even as biologics with their much higher specificities and lack of side effects are being welcomed in.
Not so fast. A rather refreshing opinion piece from a B. Meunier from CNRS in this week's Angewandte Chemie makes a strong case that rumors of small molecules' deaths are grossly exaggerated. Along the way Meunier also takes a swipe at what he considers to be Europe's stifling innovation culture; his point is that since the "new" model of pharmaceutical research is going to entail "Big" Pharma licensing compounds in from small companies, the model can only thrive in countries where a healthy startup culture already exists. And Meunier does not see European countries steering that boat. Of course he does not discuss the rather baleful VC funding environment in the US, but that's a tale of woe for another article.
Meunier points out some rather obvious but important problems with biologics that their upbeat proponents sometimes cheerfully dismiss. Foremost is the price tag, with the minimum cost of a monoclonal antibody being in the tens of thousands of dollars, and many costing hundreds of thousands. Secondly, antibodies have had their biggest success against cancer where the high cost has to be balanced against the terminal nature of the disease, the little time that patients have and the possibility of complete remission. Contrast that with chronic diseases like diabetes, heart disease and arthritis where people have to be on therapies for years. It would be prohibitively expensive to consider an antibody treatment in such cases unless there's some new revolutionary way to lower costs of production; needless to say such breakthroughs are not visible around the corner.
Thirdly, antibodies and protein therapeutics have obvious clinical limitations; they cannot cross the blood brain barrier and are therefore of little use against neurodegenerative disorders like Alzheimer's, and they can mostly attach only to extracellular targets and therefore may be useless for targeting intracellular proteins. There's also the perpetually inconvenient fact that they have to be injected, another stumbling block on the way to using them against chronic diseases. Finally, Meunier thinks that the whole economic basis for biologics, namely the belief that generics will take a very long time to hit the market because of the production challenges, may well be refuted sooner than we think. If there's one lesson we have learnt from the history of innovation, from the development of paper to the atomic bomb, it's that other countries don't lack smart innovators, and given enough time they will always come up with novel ideas to speed up production and lower costs. Putting all your eggs in the "It will be decades before India and China can come up with generic versions of biologics" basket is a dangerous strategy.
Ultimately small molecules have one thing going for them; they have worked ever since the dawn of drug discovery and they continue to be robust, versatile and easy to make. As Meunier points out, occasional competitors like oligonucleotide therapies have largely bit the dust. And of course the sheer number of ways in which you can combine six elements to build a drug is literally astronomical; we have barely scratched the surface of chemical diversity and there's still myriad scaffolds to plumb. Meunier's message is thus to keep up the good work with small molecules, employing the whole toolkit of chemistry comprising not just synthesis but analysis and modeling. Biologics may stridently stake out certain areas of the drug kingdom, but small molecules will continue to rule for the foreseeable future.
Not so fast. A rather refreshing opinion piece from a B. Meunier from CNRS in this week's Angewandte Chemie makes a strong case that rumors of small molecules' deaths are grossly exaggerated. Along the way Meunier also takes a swipe at what he considers to be Europe's stifling innovation culture; his point is that since the "new" model of pharmaceutical research is going to entail "Big" Pharma licensing compounds in from small companies, the model can only thrive in countries where a healthy startup culture already exists. And Meunier does not see European countries steering that boat. Of course he does not discuss the rather baleful VC funding environment in the US, but that's a tale of woe for another article.
Meunier points out some rather obvious but important problems with biologics that their upbeat proponents sometimes cheerfully dismiss. Foremost is the price tag, with the minimum cost of a monoclonal antibody being in the tens of thousands of dollars, and many costing hundreds of thousands. Secondly, antibodies have had their biggest success against cancer where the high cost has to be balanced against the terminal nature of the disease, the little time that patients have and the possibility of complete remission. Contrast that with chronic diseases like diabetes, heart disease and arthritis where people have to be on therapies for years. It would be prohibitively expensive to consider an antibody treatment in such cases unless there's some new revolutionary way to lower costs of production; needless to say such breakthroughs are not visible around the corner.
Thirdly, antibodies and protein therapeutics have obvious clinical limitations; they cannot cross the blood brain barrier and are therefore of little use against neurodegenerative disorders like Alzheimer's, and they can mostly attach only to extracellular targets and therefore may be useless for targeting intracellular proteins. There's also the perpetually inconvenient fact that they have to be injected, another stumbling block on the way to using them against chronic diseases. Finally, Meunier thinks that the whole economic basis for biologics, namely the belief that generics will take a very long time to hit the market because of the production challenges, may well be refuted sooner than we think. If there's one lesson we have learnt from the history of innovation, from the development of paper to the atomic bomb, it's that other countries don't lack smart innovators, and given enough time they will always come up with novel ideas to speed up production and lower costs. Putting all your eggs in the "It will be decades before India and China can come up with generic versions of biologics" basket is a dangerous strategy.
Ultimately small molecules have one thing going for them; they have worked ever since the dawn of drug discovery and they continue to be robust, versatile and easy to make. As Meunier points out, occasional competitors like oligonucleotide therapies have largely bit the dust. And of course the sheer number of ways in which you can combine six elements to build a drug is literally astronomical; we have barely scratched the surface of chemical diversity and there's still myriad scaffolds to plumb. Meunier's message is thus to keep up the good work with small molecules, employing the whole toolkit of chemistry comprising not just synthesis but analysis and modeling. Biologics may stridently stake out certain areas of the drug kingdom, but small molecules will continue to rule for the foreseeable future.
I personally can say that the bioinformatics job marker is 20 times larger then the cheminformatics job market.
ReplyDeleteThis article makes some excellent points but we would add to this a scientific point in favor of small molecules.
ReplyDeleteMost of the remaining unmet medical need relates to multi-factorial disease. Biology appears to work through a serious of complex protein interaction systems within cells which are interwoven. Complex systems science is showing that these complex systems require synergistic carefully analysed multiple target points of intervention for the system to be vulnerable. For efficacy against faults in such systems represented by the disease state then the mode of action will be diverse multiple targets to be bound to simultaneously.
The diverse spread of charge on proteins means that the chances of a single large molecule achieving this multiple binding task are very remote indeed.
Small molecules are less selective and the challenge therefore comes down to selecting the compounds that achieve the desired multi-target binding without excessive adverse side-effect. Professor Andrew Hopkins of Dundee University has published some compelling articles on network pharmacology and exactly this.
Large molecules may hold out the hope of delaying the tide of patent expiry but the future of new efficacy as created by the network pharmacology revolution looks set to be a fresh dawn for small molecules.
That's a good point. Polypharmacology is likely an area that can mostly be addressed by small molecules, once we figure out how to design selectively targeted inhibitors that hit a predefined subset of targets.
ReplyDeleteWhy is your blog called "The Curious Wavefunction". What Wave function were you refering to when you thought it was a curious one?
ReplyDelete