N E W S & A N A LY S I S AN AUDIENCE WITH…
More than 45 million people worldwide are estimated to have Alzheimer’s disease (AD) or some type of dementia, and there are few therapeutics to help them. Although a handful of high-profile candidates are currently being tested in expensive large-scale clinical trials, the neurodegenerative space is particularly fraught with failure. As problematically, the early-stage pipeline for AD is running dry. So what happens if plan A fails again, as it has so many times in the past? Eric Karran, Director of Research at Alzheimer’s Research UK, hopes that the newly launched UK£30-million Drug Discovery Alliance can shore up the community. The former head of neuroscience research at Johnson & Johnson, Eli Lilly and Pfizer tells Asher Mullard about Alzheimer’s Research UK’s plan to embed drug discovery teams directly into academic centres. What are your aims with the Drug Discovery Alliance? There are relatively few targets that are being prosecuted by industry for AD at the moment. And if you take the example of γ‑secretase inhibitors, Eli Lilly had one in Phase III trials and when it failed a whole load of other γ‑secretase inhibitors in other companies instantly got withdrawn because everyone was following the same path. Yet we know that, just like for every chronic disease, more than one therapeutic approach is going to be required to help patients. What we want to do with the Drug Discovery Alliance is to populate the early-stage AD drug discovery space with novel targets and leads. We know that the academic community is driven by curiosity, but not necessarily by utility. We also know that replication of some academic studies has been challenging for a whole host of reasons. The Drug Discovery Alliance will therefore embed hard‑core drug discovery expertise and efficient use of resources directly within academic institutions. We hope that academic groups who maybe have 30 years of biological experience in a particular area will be able to take some of that knowledge and transfer it to our drug discovery teams. It’s been challenging for industry to have the time or resources to devote even 15 years to a particular area of biology. But for complex diseases like AD you probably need to devote that time to make astute selections of targets and also to have access to models, systems and reagents that enable you to probe that biology. By putting the academic researchers and drug discoverers together, I think we are going to be able to create something that doesn’t actually exist at the moment.
Are you building new facilities? We are not building new buildings. Instead, laboratory space is being made available to us at each of the three host universities: Oxford, Cambridge and University College London (UCL). At Oxford, the labs are equipped and we are in the process of recruiting staff. The labs there will be able to start functioning almost immediately. UCL has given us lab space that has already been used for drug discovery and that just needs a little more kitting out but is more or less good to go. Cambridge has given us a nice empty lab, and so the initial year’s funding there will probably go on purchasing the equipment we need to get the lab up and running. The funding we are providing will be sufficient for about 30 scientists, split between medicinal chemistry and biology, at each institute. I imagine that at steady state each institute will be working on one or two lead-optimization projects. Do you expect the project ideas to come primarily from these three universities? I think these universities will be the first port of call, because the drug discovery teams there will be able to have hallway discussions with the host academic researchers. But it is not written into the constitution that the drug discovery institutes have to select their targets from the host institutions. Alzheimer’s Research UK also has a network of 15 universities in the United Kingdom, and we are thinking of ways to get this whole network to feed novel ideas into the Drug Discovery Alliance.
230 | APRIL 2015 | VOLUME 14
Alzheimer’s Research UK
Eric Karran
How far will the teams take their drug discovery projects? We want to take novel ideas through to lead optimization. In some cases, the institutions would then partner with biotech or pharma. In others, they may go from lead optimization all the way through to a clinical candidate. But lead optimization is a reasonable exit point, because at that stage you probably have a 70% chance of delivering a clinical candidate. The European Lead Factory (ELF) and other initiatives are also working to translate academic ideas into drug leads. Why create a disease-specific lead-optimization effort? In my experience, getting novel molecules into the brain requires a particular type of knowledge and medicinal chemistry expertise. It is more challenging than developing drugs that just need peripheral exposure. So, given that we want to assemble the best possible team, I would like to have medicinal chemists who have experience in getting molecules into the brain. But that doesn’t mean we won’t also look at collaborating with the ELF. In fact, we will. What areas of science are ripe for AD target generation? There are several different areas that I’m interested in. I think basic homeostatic mechanisms could be an interesting area for novel targets. Autophagy and proteasome regulation are of interest, for example, because most neurodegenerative diseases involve misfolded proteins. The brain’s inflammatory system and microglial activation are also going to be rich areas for new biology and new targets. But I have not yet had a chance to get close to the science that is going on in the host academic institutions, and there is a lot of it. We are also going to be looking at fundamental mechanisms that may play a role in more than one neurodegenerative disease. Findings from a model system of a rare www.nature.com/reviews/drugdisc
© 2015 Macmillan Publishers Limited. All rights reserved
disease might be informative and valuable for a major or more prevalent neurodegenerative disease like AD. Will the Drug Discovery Alliance also work on imaging agents and biomarkers? There is probably scope for that, but it won’t be a major effort. In some cases of course, though, having a biomarker is also the way that you can assess drug efficacy. Leads and biomarkers may go hand in hand. You are also a partner on the Neurodegeneration Medicines Acceleration Programme (Neuro‑MAP). What’s your aim there? This is an initiative to see whether there are compounds within industry that companies started to develop for neurodegenerative disorders but then may have parked, and that we could take out of the company and put through clinical trials. We are still signing memoranda of understanding, and we don’t yet know what those compounds are or if they even exist. I think it is an interesting concept. But something we have to be cautious about is that there is probably a reason why those compounds were parked, and we need to be attentive to that.
At steady state each institute will be working on one or two leadoptimization projects.
What upcoming AD clinical trial read-out are you most excited about? I think it has to be Lilly’s solanezumab. The antibody is currently being trialled in patients with mild AD in the EXPEDITION 3 trial. In imaging studies it did not remove plaques, but it did seem to show cognitive benefit in the mild AD population in a pre-specified subanalysis. Moreover, it looked like the benefit got greater the longer the trial went on, which is what you would expect with a disease-modifying drug. If EXPEDITION 3 does show clinical benefit, it will be a fantastic achievement for the field. It will also tell us a lot about the disease process. Solanezumab does not bind amyloid-β plaques; it only binds the soluble monomer. I really hope solanezumab will work, but I find it difficult to understand how being able to reduce the amount of monomer in the brain in the absence of effect on deposited amyloid‑β could provide a therapeutic benefit. If it doesn’t work, we will all be very disheartened. But following close on solanezumab’s tracks are β‑secretase (BACE) inhibitors from Merck & Co. and others. I think Merck’s BACE inhibitor MK-8931 is a superlative molecule, both in terms of its potency and its smooth pharmacokinetics. I think that it is going to be a great test of targeting amyloid‑β production in mild to moderate AD.
NATURE REVIEWS | DRUG DISCOVERY © 2015 Macmillan Publishers Limited. All rights reserved
More than 45 million people worldwide are estimated to have Alzheimer’s disease (AD) or some type of dementia, and there are few therapeutics to help them. Although a handful of high-profile candidates are currently being tested in expensive large-scale clinical trials, the neurodegenerative space is particularly fraught with failure. As problematically, the early-stage pipeline for AD is running dry. So what happens if plan A fails again, as it has so many times in the past? Eric Karran, Director of Research at Alzheimer’s Research UK, hopes that the newly launched UK£30-million Drug Discovery Alliance can shore up the community. The former head of neuroscience research at Johnson & Johnson, Eli Lilly and Pfizer tells Asher Mullard about Alzheimer’s Research UK’s plan to embed drug discovery teams directly into academic centres. What are your aims with the Drug Discovery Alliance? There are relatively few targets that are being prosecuted by industry for AD at the moment. And if you take the example of γ‑secretase inhibitors, Eli Lilly had one in Phase III trials and when it failed a whole load of other γ‑secretase inhibitors in other companies instantly got withdrawn because everyone was following the same path. Yet we know that, just like for every chronic disease, more than one therapeutic approach is going to be required to help patients. What we want to do with the Drug Discovery Alliance is to populate the early-stage AD drug discovery space with novel targets and leads. We know that the academic community is driven by curiosity, but not necessarily by utility. We also know that replication of some academic studies has been challenging for a whole host of reasons. The Drug Discovery Alliance will therefore embed hard‑core drug discovery expertise and efficient use of resources directly within academic institutions. We hope that academic groups who maybe have 30 years of biological experience in a particular area will be able to take some of that knowledge and transfer it to our drug discovery teams. It’s been challenging for industry to have the time or resources to devote even 15 years to a particular area of biology. But for complex diseases like AD you probably need to devote that time to make astute selections of targets and also to have access to models, systems and reagents that enable you to probe that biology. By putting the academic researchers and drug discoverers together, I think we are going to be able to create something that doesn’t actually exist at the moment.
Are you building new facilities? We are not building new buildings. Instead, laboratory space is being made available to us at each of the three host universities: Oxford, Cambridge and University College London (UCL). At Oxford, the labs are equipped and we are in the process of recruiting staff. The labs there will be able to start functioning almost immediately. UCL has given us lab space that has already been used for drug discovery and that just needs a little more kitting out but is more or less good to go. Cambridge has given us a nice empty lab, and so the initial year’s funding there will probably go on purchasing the equipment we need to get the lab up and running. The funding we are providing will be sufficient for about 30 scientists, split between medicinal chemistry and biology, at each institute. I imagine that at steady state each institute will be working on one or two lead-optimization projects. Do you expect the project ideas to come primarily from these three universities? I think these universities will be the first port of call, because the drug discovery teams there will be able to have hallway discussions with the host academic researchers. But it is not written into the constitution that the drug discovery institutes have to select their targets from the host institutions. Alzheimer’s Research UK also has a network of 15 universities in the United Kingdom, and we are thinking of ways to get this whole network to feed novel ideas into the Drug Discovery Alliance.
230 | APRIL 2015 | VOLUME 14
Alzheimer’s Research UK
Eric Karran
How far will the teams take their drug discovery projects? We want to take novel ideas through to lead optimization. In some cases, the institutions would then partner with biotech or pharma. In others, they may go from lead optimization all the way through to a clinical candidate. But lead optimization is a reasonable exit point, because at that stage you probably have a 70% chance of delivering a clinical candidate. The European Lead Factory (ELF) and other initiatives are also working to translate academic ideas into drug leads. Why create a disease-specific lead-optimization effort? In my experience, getting novel molecules into the brain requires a particular type of knowledge and medicinal chemistry expertise. It is more challenging than developing drugs that just need peripheral exposure. So, given that we want to assemble the best possible team, I would like to have medicinal chemists who have experience in getting molecules into the brain. But that doesn’t mean we won’t also look at collaborating with the ELF. In fact, we will. What areas of science are ripe for AD target generation? There are several different areas that I’m interested in. I think basic homeostatic mechanisms could be an interesting area for novel targets. Autophagy and proteasome regulation are of interest, for example, because most neurodegenerative diseases involve misfolded proteins. The brain’s inflammatory system and microglial activation are also going to be rich areas for new biology and new targets. But I have not yet had a chance to get close to the science that is going on in the host academic institutions, and there is a lot of it. We are also going to be looking at fundamental mechanisms that may play a role in more than one neurodegenerative disease. Findings from a model system of a rare www.nature.com/reviews/drugdisc
© 2015 Macmillan Publishers Limited. All rights reserved
disease might be informative and valuable for a major or more prevalent neurodegenerative disease like AD. Will the Drug Discovery Alliance also work on imaging agents and biomarkers? There is probably scope for that, but it won’t be a major effort. In some cases of course, though, having a biomarker is also the way that you can assess drug efficacy. Leads and biomarkers may go hand in hand. You are also a partner on the Neurodegeneration Medicines Acceleration Programme (Neuro‑MAP). What’s your aim there? This is an initiative to see whether there are compounds within industry that companies started to develop for neurodegenerative disorders but then may have parked, and that we could take out of the company and put through clinical trials. We are still signing memoranda of understanding, and we don’t yet know what those compounds are or if they even exist. I think it is an interesting concept. But something we have to be cautious about is that there is probably a reason why those compounds were parked, and we need to be attentive to that.
At steady state each institute will be working on one or two leadoptimization projects.
What upcoming AD clinical trial read-out are you most excited about? I think it has to be Lilly’s solanezumab. The antibody is currently being trialled in patients with mild AD in the EXPEDITION 3 trial. In imaging studies it did not remove plaques, but it did seem to show cognitive benefit in the mild AD population in a pre-specified subanalysis. Moreover, it looked like the benefit got greater the longer the trial went on, which is what you would expect with a disease-modifying drug. If EXPEDITION 3 does show clinical benefit, it will be a fantastic achievement for the field. It will also tell us a lot about the disease process. Solanezumab does not bind amyloid-β plaques; it only binds the soluble monomer. I really hope solanezumab will work, but I find it difficult to understand how being able to reduce the amount of monomer in the brain in the absence of effect on deposited amyloid‑β could provide a therapeutic benefit. If it doesn’t work, we will all be very disheartened. But following close on solanezumab’s tracks are β‑secretase (BACE) inhibitors from Merck & Co. and others. I think Merck’s BACE inhibitor MK-8931 is a superlative molecule, both in terms of its potency and its smooth pharmacokinetics. I think that it is going to be a great test of targeting amyloid‑β production in mild to moderate AD.
NATURE REVIEWS | DRUG DISCOVERY © 2015 Macmillan Publishers Limited. All rights reserved
