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Interview: Mike Hutton, Lilly

Lilly’s chief scientific officer for neurodegenerative diseases talks about his hopes for Alzheimer’s research and making the move from academia to pharma
Dr Mike Hutton

Neuroscience research has seen some big advances over the last 20 years, but if your rear view vision doesn't stretch back that far you'd be forgiven for assuming the field has been drying up of late.

Senior pharma executives were last year wont to use phrases like “notoriously difficult” or “especially challenging” to describe the field, and there are few signs it's getting any easier.

Research into Alzheimer's disease, which accounts for over 60 per cent of all dementia cases, has been particularly problematic, with a number of costly, late-stage failures in recent years. Work on Pfizer, J&J and Elan's bapineuzumab, Lundbeck/Myriad Genetics' Flurizan, Pfizer and Medivation's Dimebon (latrepirdine), to name a few, has come to a halt in recent years.

Lilly has not been immune from such difficulties. Its BACE1 inhibitor LY 2886721 and amyloid-beta treatment semagacestat also failed, the latter in a large phase III clinical trial. Nevertheless, unlike some of its peers Lilly has been clear and unwavering in its long-term commitment to neuroscience research. 

At a time when many in the industry are either cutting their investments, almost to the bone, or exiting the area altogether, Lilly last year bucked the trend by adding additional neuroscience facilities to its Erl Wood campus in the UK. It's at this leafy, Surrey site that I met Lilly's chief scientific officer for neurodegenerative diseases Dr Mike Hutton to find out more about the climate for neuroscience research and his hopes for the future of Alzheimer's research.

“Historically we have really seen great advances in the treatment of depression, psychosis and schizophrenia,” he said. “People forget just what an amazing impact neuroscience drug discoveries, like the motor dysfunction treatments we see in Parkinson's disease and even the early cognitive treatments in Alzheimer's, had in terms of their effect on those particular diseases.”

But the former Mayo Clinic professor of neuroscience acknowledged recent years have seen his field become very difficult. “The translation of preclinical findings into clinical outcomes has proven very difficult. That's particularly true if you look in psychiatry, where we're increasingly seeing a focus more on the symptoms of the disease, rather than the disease itself.”

There have been similar issues with Alzheimer's, a therapy area in which Lilly this year marks a quarter of a century of research efforts.

Joining pharma from academia
Dr Hutton can claim almost as long a pedigree, having so far spent almost 20 years researching Alzheimer's, first in academia and latterly in pharma. 

Following the completion of a PhD from Cambridge in neuroscience in the early 90s, he joined the Mayo Clinic in Florida, eventually becoming a professor there and working largely on Alzheimer's and related dementias, particularly the genetics of Alzheimer's with a focus on the Tau protein. 

After 11 years at the Mayo Clinic he stepped outside academia. “In 2007 I decided that, interesting as our work on the genetics and models of the disease at the Mayo Clinic was, the next stage in terms of drug discovery was something that I really needed to do within industry, so I made the decision at that point to move into pharma.”

The first move took him to Merck & Co, where he spent two years until an opportunity “too exciting to turn down” came to head Lilly's pre-clinical drug discovery work for Alzheimer's.

The disease modification approach for Alzheimer's disease is an opportunity to hit this enormous unmet medical need

On joining the industry one of the things he noticed was the wider interactions that occur and are expected. “As an academic you're very focused on a very narrow area. You're working with your little team. Perhaps you have a few external collaborations, but much of the work gets done within a relatively focused group. In industry you're interacting with a whole bunch of other functions - chemistry, pharmacokinetics/pharmacodynamics, early-phase clinical, and that's one area that's very different, and makes this game really very exciting, particularly coming from an academic environment.

“I must say that the six years I've been in industry has been without question the most exciting period of my career. That's for sure.”

Alzheimer's, amyloid and Tau
During that time he has overseen work on two of the most interesting targets for Alzheimer's research, amyloid and Tau, the development of both has been driven by a deeper understanding of the genetic basis of the disease, and both of which Lilly is working to couple with diagnostic technology.

The deposition of amyloid beta in the brain in the form of plaques is one the hallmarks of Alzheimer's and the 'amyloid hypothesis' suggests that these plaques are the primary influence driving the neurodegeneration seen in the disease. But like all good hypotheses, it exists to be proven.

Lilly's amyloid beta drug semagacestat struck out in last-stage clinical trials in 2010, but the failure of this and other amyloid-based therapies didn't provide “a robust test of the amyloid hypothesis, making interpretation of these outcomes difficult”, according to Dr Hutton.

Lilly's great hope in amyloid beta is now solanezumab, a candidate with a chequered history. It failed to meet its primary endpoints in two late-stage trials, scotching hopes the data would be strong enough for the drug to be filed for FDA approval. But Lilly is pressing on with a third late-stage trial, and Dr Hutton was adamant solanezumab remains a priority project for Lilly. 

The new trial is focused on mild Alzheimer's, which is where previous studies have shown some effects, and this time it will incorporate Lilly's Amyvid amyloid tracer so only amyloid-positive patients are enrolled in the studies. “That's important, because roughly 25 per cent of patients enrolled into a mild Alzheimer's disease study turn out not to have amyloid-positive disease.”

However, the necessity of running a large, additional trial means the drug faces perhaps a three-year delay before it can be filed.

Another area Lilly is working on, and one that is close to Dr Hutton's heart, is the role of Tau proteins, tangles of which are thought to block the transport of molecules throughout the cell – leading to neurodegeneration.

“There is, and there should be, a lot of excitement about the potential for targeting Tau pathology as a second, complementary approach for disease modification.

“I think [Amyloid and Tau] are going to do somewhat different things. I suspect they both have tremendous potential to impact the disease process. I think Amyloid-beta will be a very powerful approach for early-stage disease, for delaying the onset of symptoms and their progression. Tau will be complementary in the sense that it will have an impact at later disease stages.

“Given my background, given the enormous bets the company has taken, the enormous investment the company has put in, I think the disease modification approach for Alzheimer's disease gives us an opportunity to hit this enormous unmet medical need of patients, caregivers, the cost to healthcare, and I think the potential of those therapeutics, be it amyloid or, indeed, Tau, is huge in terms of their ability to affect patient lives.”

Nearing a breakthrough?
Talking to Dr Hutton you get the sense that, despite some pretty hefty bumps in the road, significant progress is within the research community's grasp.

“We are on the cusp of something very, very exciting. I can't give you an exact timeframe, but if there was one thing I'd like to see over the next few years, it would be to see the Alzheimer's programme mature. I genuinely think it's got a great chance.”

But the next 10 years will be critical, not just for Lilly but for the industry as a whole, when it comes to Alzheimer's research. “I think what we've seen with solanezumab is very promising data that tells us we're on the right track, and as we start to see not only solanezumab continuing to mature, but also other compounds from us or from others, there is a real chance that we'll see robust efficacy in patients at an early stage of the disease, and by efficacy I mean a slowing of disease progression.

“What I hope we can get to over the next 10 years - and I think it's going to take us roughly that long to get to this sort of stage - is that we're able to slow progression in patients with mild Alzheimer's disease. But that we're also at the point where we can identify the disease very, very early on in its development. This is where Amyvid and other amyloid biomarkers will be so important.

“I'm really very optimistic … we're in this critical 10-year period where I think we'll really understand the potential of the amyloid therapies.”

Article by
Dominic Tyer

Editorial director - PMGroup

9th December 2013

From: Research



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