Interview With Novartis’s Global Head Of Neuroscience Dr. Ricardo Dolmetsch

“At the Novartis Institutes for Biomedical Research we are developing new medicines to reduce human suffering and address serious unmet medical needs. For example, we are developing technologies that will allow us to diagnose and treat genetic diseases like autism and intellectual disability. We are also developing more precise ways of modifying neuronal circuits in the brain of patients with mental illness. Finally our pipeline includes potentially breakthrough treatments for Alzheimer’s disease and other neurodegenerative diseases. We aspire to generate the world’s best science and put it at the service of patients and families dealing with neuropsychiatric disease. 

My laboratory at Stanford studied the underlying cellular and molecular basis of autism spectrum disorders and other genetic neurodevelopmental disorders. We pioneered the use of induced pluripotent stem cells to study neurodevelopmental and psychiatric disease.”

 

The following has been paraphrased from an interview with Dr. Ricardo Dolmetsch on March 23rd, 2018.

(Click here for the full audio version)

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How much progress would you say neuroscience as a field has made in our understanding of brain disorders?

It is all relative, but I would say that we have made a lot of progress in the sense that we now know a lot about the genes that contribute to neuropsychiatric and neurodegenerative diseases. We are slowly moving in the direction of disease modifying therapies as opposed to purely symptomatic therapies, with a few amazing successes. There has been a huge step forward in multiple sclerosis, which went from being a death sentence to essentially a chronic disease. There has also been great success recently in treating migraines. We also have other areas where we think we have good ideas but we haven’t seen the fruits of our labor yet. That applies to neurodegenerative diseases broadly, but particularly in Alzheimer’s and Parkinson’s disease.

To quote you from a piece in Nature, “Neuroscience, in recent years, has started to look like a graveyard for drug development, with many large pharmaceutical companies either eliminating their brain disorder programs or cutting back heavily on such research.” Why is there so much pessimism in neuroscience from the pharmaceutical industry?

There has been a lot of pessimism because the trials have failed and they tend to be really large and really expensive. Even though everybody recognizes that there are enormous unmet needs, people have decided to invest in other areas. It’s a combination of people thinking that we really don’t understand the brain and therefore we shouldn’t work on it, which I disagree with, and people saying that the trials take too long.

Often in neuroscience you are trying to overcome three or four serious problems. One is that until recently we just haven’t had very good targets because, unlike in other disease areas, we don’t have access to biopsies. The second issue is that our pre-clinical models are pretty terrible, a lot of time is spent doing tests in mouse models, which very seldom accurately capitulate human brain diseases. The third problem is that we have to make drugs for people that allow them to be comparatively healthy for the rest of their lives, which means a lot of optimization has to happen for those drugs. Then the final issue is that the trials themselves have to be very long because the end-points are soft, we look at things like cognition or mood or depression, which are very difficult to measure. All of these elements have conspired against the field and driven a lot of companies out, such as, most recently, Pfizer.

Novartis, on the other hand, seems to be doubling down on neuroscience, why do you think you can succeed where so many have failed?

To be clear, it is not just us, there is still a small group of companies that remain committed to neuroscience. There are a few things driving us. One is just a recognition that there is a huge unmet medical need. Everywhere we look in neuroscience we have diseases that we treat inadequately or not at all, this robs millions of people from productive, healthy lives. The second is that there is value in being contrarian, we think that there have been developments in both clinical and basic neuroscience that provide opportunities. A final reason is that we have been successful in multiple sclerosis and that has made us optimistic that we will be successful in other difficult diseases.

Are there any surprising areas of the globe where you see innovation in neuroscience coming from?

I don’t know that it is necessarily surprising, but I think there have been huge strides in China, especially in basic neuroscience. They have made big investments in the field and have started to produce large amounts of high quality papers.

Human genetics is interesting because it is really about populations of people that have unusual mutations, and that can give us insights into common diseases. Some of those populations came from unusual places, for example, the early onset genes for Alzheimer’s came from populations in Columbia. There are populations in Turkey and Pakistan that have mutations in neurodevelopmental genes that are giving us some clues about Autism. That in a way is democratizing as physicians in those countries get to make those discoveries first.

In terms of scientific areas, one exciting field is the first antisense oligonucleotide therapies (synthetically produced strands of DNA or RNA that turn genes ‘off’), it shows that we are not just limited to small molecules. There is also some amazing early-stage human data using gene therapy that demonstrates that we may now be at a point where we can effectively deliver genes.

One approach Novartis is championing is the use of reprogrammed patient-derived stem cells (iPS cells) for drug discovery. Could you explain the relative benefits of using iPS cells as a model for drug discovery?

One of the big limitations of drug development in neuroscience has been the difficulty of getting human tissue from affected individuals. That meant we didn’t have many human neurons to work on, so we did most drug development using mouse models. We learned a lot from them, but many things were not translatable to humans.

IPS cells allow us to start with a skin or blood cell, convert them into a stem cell, and then differentiate them into almost any neuron we want. These days we can do even better than that by growing what we call ‘little brain organoids’, these are clusters of neurons that can act almost as mini-brains. The first advantage is that it is much easier to optimize compounds and anti-bodies in cells than in mice. We can also select the right cell type, which enables us to better study the receptor or the target we are interested in. For example, if you are trying to develop something in Parkinson’s, we now make neurons that have mutations in alpha-synuclein that causes the cell to die, and then run tests for compounds that can prevent that.

It also gives insight into differences between patients. Humans are very different from each other, we have some understanding of clinical and genetic differences, but not much understanding of the cellular differences. These new models will help shed light on some of that diversity, which is what you really want when developing treatments for a broad population. But iPS cells are just one tool that we need to integrate with our other tools to give us a better understanding of these diseases.

Do you believe we might one day be able to tailor drugs to an individual’s unique genetic makeup?

I think this will be practical in the near future in some diseases. We already do this in oncology, we don’t just treat breast cancer, we treat breast cancers that have specific mutations. In neurology I think we are starting to get a better sense for the different stages of a disease, as well as the different kinds of diseases that lead to the same set of symptoms. One of the issues in neuroscience is that diseases share a common set of symptoms but might have different underlying causes. Also, what works at one stage of a disease may not work at the next stage.

I’ve seen huge progress over the last five years in identifying biomarkers for PD and AD. To the point that in AD we are doing prevention trials for people who have a high likelihood of getting the disease because they have two copies of the APOE4 gene. If these treatments work in them we might try it in the broader population.

In PD we know there are some people who have mitochondrial dysfunction or lysosomal dysfunction or misfolded proteins in their brain, but we don’t know if everybody has all of those things. Trying to understand what problems people have allows us to tailor treatments. I personally believe this is going to happen much sooner than people think, the days when we had one treatment for all kinds of brain disorders are over.

Do you see any new biological or imaging tools on the horizon that will enable us to better understand what is happening inside a person’s brain?

Yes, there are three kinds of technologies that are progressing at a reasonable pace. One is just better PET ligands (a radioactive biochemical substance used for diagnosis or to study cell receptors), which will give us better ways of looking at misfolded proteins in the brain using molecules that have been labeled to emit positrons. We’ll have one soon for alpha-synuclein, one for synapses, and one that will enable us to better look at dopaminergic cells. Better imaging is key as it will help us understand what stage of the disease a person is at and will allow us to see effects of therapies before we see clinical changes.

We are also making huge strides in identifying biomarkers. We are part of a consortium with the Michael J. Fox Foundation and some other pharmaceutical companies to try and identify good blood and cerebral spinal fluid biomarkers so we can know what disease a person has and what stage of the disease they are at. The goal is to see whether we can use these as prognostic markers. A good analogy is in heart disease; when we started measuring people’s cholesterol that allowed for the development of a whole bunch of drugs that saved millions of lives. With good biomarkers you can do much smaller and shorter trials, that could be completely revolutionary as it will allow us to do much quicker and cheaper tests which will lead to more people investing in neuroscience.

Could you talk about any of the compounds Novartis is developing for Parkinson’s disease?

We have several projects ongoing that are focused on Parkinson’s disease. One trial we have under way is using a drug called Nilotinib. Anecdotally people have reported that it improves function in people with Parkinson’s and reduces the amount of L-dopa that people need to take. We are trying to develop a better version of this drug to make it more suitable, originally Nilotinib is a leukemia drug so it is not ideal for neuroscience. Other projects that are at a much earlier stage we typically don’t talk about until they are in people because they might not get there.

 

Click here for more on the work of Dr. Ricardo Dolmetsch and the team at Novartis or watch this video to learn how new drugs go from the lab to the clinic…