With big pharma exiting the neurology space in droves, biotech innovation might be the key to bring about a much-needed shift. At the Bio-Europe conference in Hamburg last month, experts weighed in on the challenges and future of neuroscience.
Over the last decade, big pharma has become disillusioned with neuroscience research. Eli Lilly, Amgen, Pfizer, GSK, AstraZeneca and Bristol-Myers Squibb are among the multiple major players that have shut down or reduced their research in this area in recent years.
The reason seems to be that the risk/reward ratio in neurology is significantly lower than in other fields. Drugs targeting the nervous system have a success rate of around 6%, less than half that of the already low figures for all other drugs.
Clinical trials in neuroscience, and particularly in neurodegenerative conditions such as Alzheimer’s and Parkinson’s, also tend to be large and complex. This means they usually take longer and are more expensive to run than clinical trials in other indications.
In the last couple of years, the field has been plagued with late-stage failures of Alzheimer’s disease drugs. This has made researchers realize we might not understand the disease as well as we thought.
“Internally, you have to have discussions with your non-neuroscience colleagues about why they should keep funding neuroscience,” said John Isaac, Senior Director of Neuroscience External Innovation at Johnson & Johnson Innovation. “You’re placing a big bet on something that potentially could be very valuable to the company and to patients, but it’s also a very high-risk activity.”
“If you’re the head of a big pharma organization, you’re looking at oncology as a great opportunity to get medicines launched and to fill the pipeline up. The clinical trials for an oncology program are not nearly as challenging as doing neurodegeneration clinical trials.”
However, there is a lot the neuroscience field could learn from oncology. In recent years, cancer research has significantly benefited from studying the underlying genetics of the disease and from stratifying patients with the same type of cancer into subgroups with common characteristics.
“The major difference is that if you just look at the sheer number of publications in oncology compared to neurodegeneration, it’s probably tenfold higher. That is a direct correlation with success – an increase in understanding,” said Jill Richardson, Senior Director of Discovery Research at MSD.
“A few years ago, oncology was also having a lot of failures. That breakthrough in terms of harvesting the immune system is what’s led the major successes. I think we will start to see some of that in the neurodegeneration field – harnessing the immune system.”
Breaking the pattern
There is a series of challenges that have been making neuroscience drug development particularly difficult. One of them is the lack of animal models that can accurately predict the effects of a drug on humans.
For example, when studying amyotrophic lateral sclerosis (ALS), all the animal models available are based on familial forms of ALS — those caused by genetic mutations. This is particularly worrying considering that only up to 10% of ALS cases are estimated to be familial.
Richardson noted that many researchers are now turning to human stem cells to test new therapies. “They have their critics, but at least it’s an insight into the human biology, which I think is what’s been very much lacking in the neurodegeneration area.”
“The challenge in neurodegeneration is how to get an early indication of efficacy,” said Isaac. “Every single thing needs to line up preclinically, because if it’s not lining up preclinically, it’s definitely not going to line up in the clinic. You do see a number of companies or academics who try and shortcut. They might not do a pharmacokinetics study, which I know is really boring, but it’s absolutely critical.”
It’s not just early-stage research that needs to improve. Clinical trial results have shown strong placebo effects and a failure to translate early clinical success into large late-stage trials.
Just measuring the effects of a drug objectively is a big challenge in neuroscience. Lesley Stolz, CBO of the biopharma company Annexon Biosciences, experienced this when preparing for a clinical trial for the rare neurological disorder Guillain-Barré syndrome.
“When we were trying to design the trial for Guillain-Barré syndrome, we were really struggling because the only approved endpoint was a disability scale, which was really not very helpful. It went from 0 to 6; from being perfectly healthy to being dead.”
In some indications, the availability of biomarkers that can be objectively measured and be correlated to the progression of a neurological condition has made a big difference. That is the case of multiple sclerosis, where magnetic resonance imaging has proven a powerful tool to diagnose the condition.
“Multiple sclerosis has been maybe the most successful indication in neurology in general because we have such a powerful biomarker,” said Marie Trad, Vice President at the contract research organization IQVIA. “In phase II, you can see whether your drug works or not. That has helped put almost 18 drugs on the market, which is not the case in other indications.”
In recent years, new biomarkers have been proposed to measure the effects of neurodegenerative conditions. That is the case, for example, of the blood levels of a protein called neurofilament light, which seems to give an indication of the amount of damage neurons have suffered in a range of neurodegenerative conditions.
Overall, Trad believes that the whole industry needs to rethink the design of clinical trials and the choice of endpoints used to measure efficacy. “We’re moving away from those subjective endpoints. I think we need to go into the next stage where we’re not necessarily doing things like we’ve been doing them up until today, but trying to evolve into more creative designs.”
In this context, collaboration among the different stakeholders involved could prove essential to guide the modernization of clinical trials in neuroscience. Trad noted that patient advocacy groups are starting to get more and more involved in clinical trial design, giving their input about which endpoints they find most valuable.
Collaboration is key
While news about pharma backing away from neuroscience research have created a general feeling of defeat, the field is far from being abandoned. There is still a big medical need that is driving innovation in this area.
“I think the idea that neuroscience is withering and wilting is actually untrue,” said Isaac. “There are challenges in large pharma, that’s for sure, but I think in biotech, neuroscience is flourishing.”
Indeed, in recent years pharma seems to have shifted away from developing its own neurology pipeline, investing instead more aggressively into licensing promising drug candidates that have originated in biotech companies. A clear example is Pfizer, which stopped its drug discovery efforts in Alzheimer’s and Parkinson’s last year. However, soon after, it launched a neuroscience spinoff and a venture capital arm that will be funding startups working in the field.
The challenge for biotech companies is attracting enough funding to take their research forward and make it attractive to pharma. “If you put a lot of effort into an early discovery effort, ultimately you got to persuade something to write a large check to run a quite expensive clinical trial,” noted Isaac. “Coming up with the best evidence early on that this is likely to work in humans is what you need.”
“For the most part, the money is not going to come from the J&Js or the Mercks, but the expertise can,” pointed out Stolz. “If the small biotech that’s seed-funded goes and talks to pharma about what they’re doing, all of these concerns and ideas and risks will come forward.”
“That’s one of the things that I think is great about our environment today, specifically in neuroscience — some of the big companies aren’t ready to jump in at the really early stage, but they’ve certainly got an opinion. If you have those conversations early in the lifetime of your company, you will be able to raise money based on experiments that have been suggested to you by pharma.”
A brighter future ahead
Despite concerns about pharma’s shifting strategy in neuroscience, the field has come a long way in the past decades. “In my young internship days we had very few therapies and it was very frustrating for the young neurologist that I was at that time,” said Trad. “In the past 25 years, we’ve done a lot in drug development in neurology. There were a lot of failures, but at the same time there was a lot of progress.”
Trad believes there has been a shift in the field over the last decade that has advanced our knowledge of many neurological conditions. New therapeutic modalities, such as gene therapy or RNA interference are offering new ways to approach treatment.
“For example, there’s a genetic form of ALS that was described in 2010 and now there are gene therapies targeting that,” explained Trad. “Up to 2014, in Parkinson’s, we were targeting symptoms. Now, we’re developing disease-modifying treatments.”
Another indication that has seen a big change is spinal muscular atrophy. In 2016, the gene therapy Spinraza became the first FDA-approved therapy that can slow down the progression of the neurodegenerative disease and not just manage the symptoms.
As we move into the future, Richardson expects our knowledge of neurological disorders will keep growing as more and more funding becomes available. “So many governments now realize the social and economic impact. As we age, I think, inevitably, there’s going to be a lot more funding in this area and in every sector – biotech, academic labs, and pharma. I feel very positive about it going forward.”