Novartis: Robert Baloh
“I found that I was most passionate about making new therapies for patients”
“Localize the lesion.” A universal challenge, issued from teacher to trainee on every neurology ward. How does the site of the pathology explain the patient’s symptoms? Considering the complexity of the nervous system—the question is enough to make a student (like me) start sweating.
Yet localization is not simply a didactic exercise, it is central to the history of neuroscience. A grisly construction accident damaging the frontal lobe of Phineas Gage, demonstrated this region’s role in personality and executive function. A misguided hippocampal lobotomy of “patient H.M.” set the stage for the study of memory formation.
Understanding “where” often points to “what” process (or pathology) may be the culprit. For example, weakness that localizes to both upper and lower motor neurons, with sparing of other pathways (like sensation), could suggest the terrible diagnosis of amyotrophic lateral sclerosis (ALS).
Yet the art of clinical localization has its limits: it does not explain why a particular pathology (like ALS) develops or suggest what to do about it. For this task, a subcellular localization is required. “When the Huntington disease gene was cloned, it was a turning point for me,” describes Dr. Robert Baloh, Head of Neuroscience at Novartis Biomedical Research: “molecular neuroscience had the potential to make drugs that could help patients.” A genetic localization can identify targets and pathways that if manipulated may alter disease progression.
As a budding academic neurologist in the early 2000s, Baloh appreciated the complexity and “uncertainty” of clinical neurology. Yet he yearned for a deeper understanding of molecular neuroscience. With mentors like Bob Brown, David Holtzman and Jeff Milbrandt for support, he started a research group investigating the genetics of neuromuscular conditions like ALS and Charcot Marie Tooth. Initially at Wash U in St. Louis (before moving to Cedars-Sinai with a joint appointment at UCLA), Baloh’s lab mapped how mutations in genes like TDP43 and C9ORF72 drive neuronal injury and neuroinflammation.
As Vice Chair of Neurology Research at Cedars-Sinai, he saw how genetic insights could be leveraged across different areas: “I was able to dive into Parkinson's, Alzheimer's, psychiatry and a bunch of other disease areas…I found it fascinating.” Around this time Baloh also witnessed drugs like Zolgensma, Spinraza and Risdiplam transform the lives of children with spinal muscular atrophy (SMA): “I took care of kids with SMA…but I did not think in my career I would see such an effective treatment…the sudden approval of these medicines had a huge influence on the course of my career.” Resolving to focus on drug development, Baloh accepted a position at Roche in 2020, and then at Novartis in 2021, as Global Head of Neuroscience: “I’m someone who loves delving into a variety of different areas of neuroscience, and thinking about where the science is closest to becoming a medicines and making a difference for patients.” At Novartis, Baloh takes a human-centered approach, relying on genetics and biomarkers to gain conviction about a particular program.
Today, “localization” in neurology goes beyond neuroanatomy, to include specific genes, pathways or processes within a cell that are disrupted. The challenge now is to deliver targeted therapies to the correct location, in sufficient quantities, at the right time: “for many conditions we have very good therapeutic targets…but we have only recently seen technologies that can address these targets in key areas, like behind the blood brain barrier and in the deep brain structures, which are much more difficult to access,” Baloh says.
With his team at Novartis, Baloh is laser focused on leveraging clinical neurology, genetics and emerging modalities (like gene and cell therapy) to hit the right targets in the right spots. “This is just the start,” Baloh emphasizes, “ultimately we will have assets that impact multiple nodes of disease biology and can provide tremendous benefit to patients.”
Below is an interview with Robert Baloh, MD PhD, Global Head of Neuroscience at Novartis Biomedical Research:
1. What got you interested in science and medicine initially? Who were some mentors that inspired you?
This is an easy one for me—my father is also an academic neurologist. He clearly had a huge impact on my career. I often tell people however that he did not directly encourage me to go into medicine—not because he wasn’t happy with it, but just because he didn’t want to “interfere” with my life. At the same time, I could see he was extremely passionate about the field; he continues to write about neurology and neuroscience even after he retired. Just seeing his excitement had a big impact on me.
When I went to college, at Brown University, I majored in neuroscience—which is pretty specific for an undergraduate major. I got to learn from Mark Bear who is a well-known synaptic physiologist and neuroscientist who since moved to MIT. Spending time with him pushed me even further towards studying the brain. How does the brain work? It was, and remains, the biggest question out there. As an undergrad I participated in some fMRI studies mapping movement representation in the cortex—and to be frank I was disappointed. I didn’t think studies like these were going to move the needle for patients back then [1990s]—now imaging has advanced considerably, and a lot of the fMRI studies today are quite remarkable in what they can demonstrate about the brain. But around the same time when I was an undergrad, the Huntington gene was cloned. This was a turning point for me…and I switched my focus to molecular neuroscience. Then I went to the MD-PhD program at WashU in St. Louis and joined Jeff Milbrandt’s lab—after that I was hooked. Jeff and his lab had so much energy, and it was such an exciting time to be a scientist.
Jeff [Milbrandt] was an interesting mentor, because at the time even though he was a somewhat young PI, he already had a “biotech” type of mindset. We were working on cloning genes before the genome was sequenced and were looking at the translational relevance of a variety of neurotrophic factors. We wanted to use these factors in neurodegenerative disease—Regeneron, Amgen and other companies were exploring this as well. I remember actually resenting some of these biotechs—because as a PhD student I was competing with them and had fewer resources. That said, I enjoyed the translational angle a lot. I even thought about going to Biogen to do a post-doc, because we had a collaborator there. I was lucky to get this early experience—both in academic science and in biotech. It definitely planted some seeds that led to my current role.
2. Early on in your academic career, how did you decide on neurology? Any memorable patients during your training?
I loved graduate school [PhD]…but I felt that I should still get clinical training. Part of that feeling was a curiosity about clinical medicine, and part was the security—research is risky and doesn’t always work out! It was a no-brainer for me to choose neurology given my interest in neuroscience, and I decided on the Mass General Brigham combined neurology program for residency—where you will be starting in a few weeks! I had an amazing experience. Marty Samuels was the chair of neurology at the time, and you could not ask for a better teacher or mentor. He knew everything and was one of the pillars of “old school” neurology: along with C.Miller Fisher, Raymond D. Adams, Rick Tyler, Lou Caplan and others. He [Samuels] was hilarious—his morning report or grand rounds would be like watching The Tonight Show, combined with a masterclass in clinical neurology. From him I learned what it was like to be brilliant at something—not to say I ever reached his level of clinical ability…but I saw what true excellence looked like. It is helpful to aspire to this level in whatever you do.
[On how clinical neurology is different than science]
Clinical medicine is not a deductive science. I think one of the things that being a clinician teaches you is to deal with uncertainty--it's very helpful for the rest of your life. In medicine you often have to make important decisions and communicate these decisions, without all of the data at hand. Even in biopharma, I observe physicians often have an easier time with this than others, making decisions on probabilities and accepting that we will often be wrong. One really has to embrace uncertainty in clinical medicine, and see that there is something intuitive about it that at times seems more akin to art than science —this is something that Marty [Samuels] was so brilliant at. Sometimes people are really good at both [science and clinical medicine], but more often being a good scientist does not directly translate to clinical ability, and vice versa. They end up being two separate skills.
3. How did you decide on neuromuscular medicine for your fellowship? What did you work on as a post-doc and early career faculty member at WashU?
I became interested in neuromuscular disease primarily from Bob Brown and Tony Amato, when I was a resident at Mass General Brigham. After residency though, I was looking for a fellowship where I could learn about neuromuscular disease and also do research, and at the time these types of opportunities were difficult to find. I chose WashU in St Louis—where I did my MD-PhD training.
Dave Holtzman at WashU is another major mentor of mine. When I was starting my PhD at WashU he was a junior faculty member, and he was on my thesis committee. By the time I ended up returning for fellowship, he was chair of the department and very supportive of my returning. He worked with me to find a creative way to design a fellowship where I could apply human genetics to neuromuscular medicine—at that time [early 2000’s] SOD1 was the only ALS gene that had been discovered. I was excited about neuromuscular disease because you can leverage genetics to make cellular and animal models—you can also biopsy tissue [peripheral nerve and muscle] and perform nerve conduction and EMG to assess function.
For my post-doctoral work, I was jointly mentored by Dave [Holtzman], Jeff [Milbrandt] and Alan Pestronk who ran the clinical neuromuscular program and was willing to let myself and another MD/PhD neurologist split the clinical work so we could get into the lab. I was lucky to have such strong support for fellowship. I ended up working on Charcot Marie Tooth disease initially, because the genetics were abundant, and the field was less crowded around one gene as in ALS. However, even back then I sensed that I didn’t want to study one disease or process for the rest of my life. I felt that all science was cool, and was a bit like a “dog chasing squirrels.” From an academic research perspective it is likely better to stick with one problem or area and become known as “the expert,” and really be the leader in that particular area. However, this ability to look step back from complete focus, and to learn both things outside my area of expertise and even neurology, is really what I embraced when I first went to industry, and in my current role at Novartis.
[What were some exciting stories you pursued in your lab?]
In ALS, we first explored TDP-43 pathophysiology, which was distinct from that of SOD1 and surprising in many ways. We later started working on C9ORF72 and in particular how loss of function in this protein drives neuroinflammation in glial cells—but of course can also produce toxic gain of function manifestations like dipeptide repeat proteins that damage neurons. I enjoyed this work a lot—but I also really enjoyed taking a leadership role in a department [at Cedars-Sinai]. As Vice Chair for research and in starting a basic research center, I was exposed to clinical and basic research across a range of areas—Alzheimer’s, Parkinson’s, multiple sclerosis and others—and learned how genetics and tools like imaging and biomarker analysis were being leveraged.
As a rule, I generally don’t have regrets when it comes to my career. Certain things may have been optimized, but of course I’m not sure I would have gotten to where I am if I had changed anything along the way, and I feel very fortunate to be here. I have learned that the way I like to do science—exploring a range of different topics—is more satisfied for me in industry than in academics. To make a successful career in academia you have to be somewhat more focused in your thinking and research activity—to publish papers and earn a reputation in a particular field. I learned that if you find that difficult, then there are other options [like industry], though admittedly somewhat later in my career.
4. What were some drug development stories that you were most excited about in neurology?
When I was a neuromuscular fellow at WashU, I did a camp for children with muscular dystrophy and related diseases like spinal muscular atrophy [SMA] every year. It was super fun. I took care of a bunch of kids with this disease, and learned a lot. At that time, we knew the genetics, but I did not necessarily think that in my career I would see an effective treatment for SMA. Years later as a faculty member, I followed the Nusinersen story closely as we had collaborators at Ionis—but to see it in action was astounding. The same goes for Zolgensma and Risdiplam, which followed shortly afterwards. The approval of these medicines changed the course of disease for those patients and had a huge influence on the course of my career. At the time [of the SMA approvals] I was building a research department at Cedars-Sinai and really enjoyed establishing the neuromuscular division as well. I had some great collaborators working on therapeutic development—Clive Svendsen for example—but we were not able to bring to bear the same resources as biopharma. I found that I was most passionate about making new therapies for patients. A lot of my mentors had run academic departments, but to me, the prospect of developing the next Zolgensma was too exciting to resist. Thinking back as I said, even during my PhD I had the urge to enter biopharma as a way to turn science into new medicines.
5. What do you see as the biggest technical barriers to neuroscience drug development today? [Briefly what are you doing at Novartis to address some of these barriers?
There are different challenges facing different fields within neuroscience. For example, psychiatry is very different from say, genetic neuromuscular disease. In the case of conditions where we have strong genetics—like muscular dystrophies, SMA, Huntington’s, some types of ALS—the challenge is really biodistribution of the right modality, and when to treat. Getting the therapy to the right location at the right time is the key, because we have validated targets and biology. I believe that many past failures in this space were in part due to insufficient delivery mechanisms—AAV or ASO biodistribution to the muscle or nervous system is difficult, especially in adults. In SMA, where we have had great success with gene therapies like Zolgensma, it is likely that biodistribution to lower motor neurons and the rest of the central nervous system is better in an infants [than in adults]. Therefore on the AAV side, we have been very focused on looking at “evolved” capsids with improved CNS or muscle delivery: higher tissue transduction from a lower systemic dose, and de-targeting of peripheral organs. Naturally occurring viruses won’t have these properties—so we have spent a lot of energy thinking about engineered delivery mechanisms for neurologic and neuromuscular diseases.
6. At Novartis, you view the neuroscience portfolio on three levels—neuromuscular/genetics, neurodegeneration and neuroinflammation. Can you give some examples of how you are thinking about each category?
With genetically defined targets one has some sense of causality—for example you don’t need to understand the precise function of the SMN gene to know that its correction will greatly benefit SMA patients. With other conditions where we don’t have such clear genetics, we really look to human tissue, biofluids combined with natural history data to build conviction around a target. We believe multimodal data, including genetics whenever possible, is crucial for target selection.
I am less convinced that for a given [sporadic] neurologic disease there is a “perfect” target out there. Take Alzheimer’s disease for example: we have evidence that modulating pathways like TREM2, ApoE—along with amyloid and tau—could potentially impact disease progression. These are all core pathophysiologies that have been studied for a long time. Ultimately, combination approaches targeting multiple disease nodes is most likely to give patients benefit—rather than hitting just one “magic” target.
[Neuropsych appears to be limited by a lack of mechanistic understanding. Even once “clear cut” wins such as Karuna’s (BMS) and Cerevel’s (AbbVie) M1/4 agonists are now less compelling in the light of late-stage trials. At Novartis, how do you think about entering such a challenging area?]
Psychiatry has not been easily amenable to the approach of identifying genetic loci that influence disease progression and targeting these pathways. Historically [psych drug development] has essentially been phenotypic screening in humans and then rodents. I've gotten to work at two great neuroscience companies, Roche and Novartis—the companies that discovered benzodiazepines and LSD. The history of these discoveries involves medicinal chemists ingesting the compounds they synthesize and qualitatively describing their experience. Needless to say, this is not a scalable approach—for the safety of medicinal chemists alone!
We subsequently moved into model systems for psychiatry drug development—however these rodent models of depression or psychosis are very far from representative of human disease. So, what does one do? I think we [as a field] need to invest in biomarker development for “precision psychiatry” and move into human testing as early as possible. We need some way to measure target engagement, along with imaging or behavioral biomarkers that can give early signs of efficacy—like in other fields. Now if you look at the M1/M4 [Karuna/Cerevel] story, the discovery of that target in psychosis was still “by accident”, and is what I mean by human phenotypic screening. There was a theory that increasing acetylcholine signaling in Alzheimer’s disease would be beneficial for cognition; trials in the 1990s also showed that xanomeline decreased AD-associated psychosis. This observation led to trials in schizophrenia, and subsequent engineering of more specific M4 agonists and modulators to decrease peripheral side effects, in addition to combining with a peripheral blocker. It is very hard to reproduce this type of story for future therapeutics, given its serendipity.
Psychedelics are interesting--Albert Hofmann wanted to study LSD in psychiatric disease from early after discovery. There is a very long discussion to have here around these molecules and potential mechanisms. A fundamental question to me is whether one can separate the euphoric and dissociative effects from beneficial effects on depression, PTSD or other psychiatric diseases, or rather the two are intrinsically linked. However, given the lack of good preclinical psychiatry models and scarcity of precision biomarkers, clinical development continues to be challenging.
7. Early drug development efforts (in any area) often start with testing in preclinical models. How do you evaluate internal preclinical data? Are there certain models that you find to be the most robust?
We internally debate this question often. Initially there was a lot of excitement about rodent transgenic models of neurologic disease—like the SOD1 mouse in ALS. What we realized was that these models don’t have good translatability in terms of discovering new targets or pathways. Similar genetic lesions often manifest differently in other species, so for target discover it is much better to use human data where possible. However transgenic models can be very useful to measure target engagement: to show that a drug is having its intended effect. We still rely on these models in ALS, AD and other conditions for pharmacokinetic and pharmacodynamics.
We do not try to do a 1:1 correlation between a mouse model and human disease for prediction of clinical benefit, rather we use preclinical models to gain confidence that we can alter biology in a predictable way in the right compartment of the target tissue, i.e. the CNS. From here, we try to move into humans as quickly as possible and leverage biomarkers to assess impact on neuroinflammation and neurologic function. Even this can be risky, because not all biomarkers are clinically validated or predictive of approvable clinical outcomes by the FDA.
8. Which biomarkers across neurology do you find most exciting? Besides neurofilament light [NfL], are there markers of neuronal injury or neuroinflammation that you feel are becoming more robust?
All biomarkers are very context dependent—even neurofilament light [NfL], which is among the most “validated” to date. For example, elevations in NfL just mean that there is axonal injury: it needs to be combined with imaging, CSF biomarkers or functional endpoints to truly have meaning. NfL is really just like a troponin or CK of the nervous system—it could be elevated for a variety of causes that are not directly relevant to disease pathology [trauma for example]. Similarly, neuroinflammatory and glial markers like GFAP need to be taken in context: we are trying to develop panels or a cadre of such markers that can accurately assess the functional astrocytic and microglial state in the brain. Looking at just a single biomarker will never be that useful.
Advanced imaging can also be very powerful—MRI revolutionized the relapsing MS field and has been incredibly impactful for therapeutic development. However, implementing imaging in large scale trials can be costly and complicated; fluid biomarkers are often more convenient from a trial perspective. For small early studies you can do more complicated imaging and biomarker collection—but you have to be much more focused as you bring this forward to a large phase 3.
[Are we limiting ourselves in neurology by testing single agents in isolation? Perhaps multiple nodes need to be impacted to show functional benefit]
One would love to be able to go directly into clinical development with multiple different nodes being targeted in a neurologic disease. It's just not realistic given the current way we conduct clinical trials, and the difficulty of dealing with multiple unknowns simultaneously in both efficacy and safety. We need to first show benefit from single agents, before we start combining mechanisms and modalities. I agree that perhaps it is the case that both amyloid and tau need to be targeted in Alzheimer’s—hopefully in 10 years neurologists will be able to combine multiple agents as disease progresses. However, for now we need to prove that just one therapy will be of benefit. My hope is that as soon as we show these agents to be effective in isolation, physicians will start to study them together to hit multiple nodes of disease pathology. First this will be done in small studies using biomarker profiling, and then in larger efforts. Ultimately, I think this type of work, done by enterprising physicians and scientists, will move the needle most for patients.
9. What advice do you have for trainees who want to play a role in drug development, and really deliver for patients? Is there any advice you wished you had received earlier in your career?
Throughout my early career I was always focused on getting to the next step as quickly as possible. I was always very driven…to learn, to get a job to pay my bills, to start a lab, to get the next grant. But rushing through isn’t necessarily the “right way” to approach this type of career—which is long and full of opportunity. What I would say is most important is to find mentors that can really give you support and help you through the tough times. I found that in Jeff Milbrandt and Dave Holtzman at Wash U, which was the best reason for me to go there for fellowship and stay as an early career faculty member. So, if I have a piece of advice for physician-scientist trainees it would be to really find these mentors that you can rely on…because you will really need that support as you start your independent career!