Mass General Brigham: Merit Cudkowicz
“We need to lower barriers for patient enrollment into trials in the US”
As any scientist knows, stumbling upon a good idea—the sudden flash of inspiration—is thrilling. Carrying this concept to fruition is another matter entirely. It can take years to assemble the proper reagents, techniques and pipelines to rigorously test a hypothesis.
Good ideas are commonplace—much rarer are the individuals who work for years to force them into reality. During the genomic renaissance of the 1990s and early 2000s disease-causing genes for conditions like Huntington’s, Parkinson’s and Alzheimer’s were identified. Many neurologists had the same great idea: leverage genetics to make novel drugs for their patients. How to evaluate these new therapies in humans was less clear: “When I was training in neurology, there was not a formal clinical trials program at MGH,” remembers Dr. Merit Cudkowicz, Professor of Neurology at Harvard Medical School and the inaugural Executive Director of the Mass General Brigham Neuroscience Institute, “I had to learn from other departments [like infectious disease] how to run and analyze trials.”
A clinical trial, like any good experiment, requires careful preparation. It takes years to draft protocols, identify appropriate biomarkers, perfect statistical plans, recruit patients and then generate the data. “In neurology we are often limited by a lack of relevant biomarkers or robust endpoints,” describes Cudkowicz, “those looking for quick wins are often disappointed.” Following the initial optimism of the genomics bubble, neuroscience drug development faltered. Complicated biology stymied therapeutic efforts, even for patients with clear genetic drivers of disease. An example is the SOD1 mutation in amyotrophic lateral sclerosis [ALS]: “When I was working with Dr. Bob Brown as a resident, we didn’t yet know that this was a toxic gain of function mutation,” says Cudkowicz, “we tried replacing SOD1,but this didn’t work.” In the early 2000s modalities like anti-sense oligonucleotides [ASO] and siRNA were in their infancy—it was often unclear how to durably hit targets in the brain or spinal cord. “Over thirty years after SOD1 mutations were identified as causing ALS, we are now seeing the approval of what we believe to be a truly effective drug [Tofersen],” she says.
Cudkowicz’s career has focused on developing the protocols and infrastructure to allow for evaluation of drugs like Tofersen. After being mentored by renowned neurologists like Bob Brown, Walter Koroshetz and Anne B. Young, she established the first formal clinical trials unit in neurology at MGH (NCRI) in 1994, and the national Northeast ALS consortium in 1995. “I was trying to replicate what had been done in oncology…and even conditions like multiple sclerosis, where there was robust collaboration and resources to run trials,” she remembers. Cudkowicz and her team at NCRI have streamlined protocols, innovated in trial design (HEALEY ALS Platform Trial), identified novel biomarkers and started global collaborations for ALS and other neurologic conditions. In her role as an ALS patient advocate, she has raised crucial funding for research and given patient voices a platform: “our success is only possible because patients make us better clinicians and researchers,” she states.
In 2025 there remains a lack of disease modifying therapies for most people with ALS, and for those suffering from conditions like Parkinson’s and Alzheimer’s. Yet the tide is beginning to turn: “with the emergence of new therapeutic modalities…there is more interest, excitement and novel agents to test than ever before,” states Cudkowicz, “our focus now is on removing the traditional barriers of clinical trials and fostering collaboration.” With Cudkowicz at the helm, the newly minted MGB Neuroscience Institute will bring together patients, basic scientists, trialists and industry: “My goal is that in five years, I want patients to feel like the MGB neuroscience institute is “the place” to go—with the best, novel diagnostics, coordinated care, clinical trials and basic research.”
Clinical trials in neurology—a good idea that is easier said than done. Yet Cudkowicz and the team at NCRI have been working for decades to put the pieces in place to formally test novel drugs. After such careful preparation, I am deeply excited to see what the next few years of work brings for patients with neurologic disease.
Below is an interview with Merit Cudkowicz MD MSc, Julieanne Dorn Professor of Neurology at Harvard Medical School, Director of the Healey & AMG Center for ALS and Director of the MGB Neuroscience Institute, from May 2025:
1. What got you interested in science and medicine initially? Who were some mentors that inspired you?
I wrote in my high school yearbook that I wanted to be a neurologist, believe it or not. I always had a fascination with the brain and medicine. My father was an immunologist at the University of Buffalo—he always had students in our home and was always working on papers. My mother had worked as a research technician…so we were a “science household.” I studied engineering in college but came back to medicine towards the end and enrolled in the HST program at Harvard Medical School. In HST, my mentor Michael Moskowitz taught our second-year neurology course—he is a fantastic headache neurologist and neuroscientists who inspired many physician scientists.. He was such a great teacher and got me even more excited about neurology
2. Early on in your academic career, how did you decide on neurology? Any memorable patients during your training?
I loved my neurology rotation in medical school. Back then everyone was always in the hospital—now I am not saying this is a “good thing,” but I remember seeing attendings rounding until nine or ten in the evening. There was constant teaching on the neurologic exam and in thinking through pathology. I had a lot of memorable patients—one who had a stroke flying in from London and presented with a transcortical aphasia: he was unable to produce language, but he couldunderstand communication. I spent a lot of time with this patient and even saw him recover, gradually. I felt that neurology is a field where you could spend a lot of time with patients and really think through pathology in a deep way. Part of this was that at the time, we didn’t have many treatments to offer, so the field emphasized a lot on thinking and teaching.
[How did you decide on clinical trials as a focus of research?]
At the time, there were not many formal neurology fellowships available. I decided to make my own in neurotherapeutics. In the 90s, the genes for Alzheimer’s and Huntington’s disease were cloned. The genomics boom had previously ushered in a new age in oncology, and there was hope that the same could be done for neuroscience. To be honest the thinking was a little naïve back then: we didn’t have the modalities or understanding we now have. Nonetheless, I wanted to develop a way to test treatments for these diseases. At MGH neurology every faculty member was a researcher with their own lab; so, there was a lot of enthusiasm for this type of idea. There was not a formal clinical trials program at MGH, so I looked around for a way to get training. I asked my residency director, Walter Koroshetz, what to do: he advised that I go to Rochester NY, where they had a clinical trials program run by Dr. Ira Shoulson, a movement disorder specialist focused on Parkinson’s. I went out to meet Ira—long story but he was actually good friends with Anne Young, the chair at MGH. When I was back in Boston, Anne called me into her office and “yelled” at me. She said she would be more than happy to support a program in experimental therapeutics at MGH, and hired me to build that program. Generally as a short piece of advice: when you try to do something new, always run it by the chair first! So, I ended up receiving mentorship from Ira, started working with Bob Brown on the genetics of ALS, and took courses in statistics at the school of public health. Initially our group started trials in a variety of neurodegenerative diseases—AD, HD and PD—but eventually I decided to focus on ALS.
3. Neurology drug development is hard. What are some of the biggest wins that you have witnessed in the field?
Multiple sclerosis has a lot of great examples of breakthrough therapies. Their breakthroughs came from a combination of planned research and good luck. The planning was in developing tools to measure the disease—T1 and T2 MRI techniques—that were predictive of functional outcome. Anytime there is a surrogate marker, gadolinium enhancing lesions in this case, it accelerates therapy development. The “chance” part was the discovery of beta interferon as a treatment, which was somewhat serendipitous. However, after this first big win in MS drug development, the MS community, academia and industry worked very well together to develop many follow-on therapies, which were even more effective. I would say that many fields in neurology have “MS envy,” because of how well drug development has gone for that indication. We have wanted to do a similar thing for patients with ALS—we want to have 10 to 15 therapeutic options. However, although we have neurofilament light as a marker of disease, it is not specific. Developing a sensitive and specific surrogate marker is one of the hardest parts of therapeutics research.
4. Briefly, what do you see as the biggest technical barriers to neuroscience drug development today?
One barrier is having biomarkers that reliably predict clinical response. In ALS, we are finding that neurofilament light [NfL] is good for genetic forms of the disease, like SOD1, but may not be as robust for sporadic cases. We will need to use a combination of fluid biomarkers for complex illnesses like ALS. We are also looking to combine fluid biomarkers with readouts like electrophysiology and advanced imaging. We are trying to learn from some of the good PET imaging studies done in Alzheimer’s, but these can be difficult to implement in large scale trials.
Diagnostic delay is another barrier across neurodegenerative disease: we diagnose people relatively late in disease course. In ALS, for example, it is on average one year from when patients notice their first symptom to when they're diagnosed—if the course is only on average three years, we are missing a huge chunk of prodromal and early disease: ideally we’d like to identify and one day treat patients before they are symptomatic. We need to learn from some of the biofluid and imaging studies being done in AD and PD, as well as other areas like heart disease—you want to modify risk and intervene before a heart attack occurs. In many neurologic conditions, another barrier is disease heterogeneity. In conditions like frontotemporal dementia and ALS, we often lump all patients into one bucket. In other conditions, like breast cancer for example, there are different tools to stratify patients based on hormone receptor and HER2 positivity. We don’t yet have those tools yet for most neurologic conditions. I worry that trials sometimes miss or discount small responder cohorts, because they are lost in the noise.
5. When selecting a new agent to test in ALS, or more broadly in neurology trials, what are the key things you look for?
Number one is a solid mechanism: do we know how the drug works, and is it linked to ALS by genetics or biochemistry? We can get some of this information from preclinical models of disease: transgenic animal models and also iPSC derived motor neurons. We can also look for biochemical evidence in post-mortem tissue or patient blood. We set the bar high for pre-clinical work, before going into patients. We have a Northeast ALS Consortium, which has a science advisory board. We have most companies present to that board, and we give them advice on their pre-clinical models and the strength of the data. We also give them a sense as to if they are ready for human trials and help design early studies. We do this because we want folks to learn from prior experiencesand keep improving.
[What mistakes do you see investigators or companies often making in thinking about running and designing early Ph1/2 studies?]
Often there are many mistakes: especially when someone is new to the field, or they want the “quick win.” We frequently see underpowered studies with endpoints that are too short in duration. ALS is a condition with lots of variability, so that must be accounted for in study design. Small companies often do not have access to a lot of funding, so they have “one shot” to see if their drug works. These companies can be tempted to skip preliminary human work that verifies target engagement and dose finding; then they go to the “pivotal” study and the drug fails. In this scenario it is hard to tell if the mechanism is incorrect or the dose was simply not correct. We try hard to get companies to run the right target engagement studies, but acknowledge it is hard for them to access capital. Part of what I do as an ALS advocate is to raise money for these studies from foundations, the NIH, or other philanthropies.
6. Especially in the current environment, what challenges do companies face in getting drugs with new biology or mechanisms to patients? What can we as physicians do to help?
There is a lot we can do. We can try to lower the costs of clinical trials and make them easier to run. For example, a lot of the clinical trial assessments are done in the hospital presently. Are there ways to develop digital tools that can be used at home? I think running more distributed trials has a lot of promise, and we would like to pioneer that for ALS. I have also tried to get rid of the things that slow down progress. These can be simple changes like making sure we are all using the same IRB, so we don't have to duplicate unnecessary work. We have also started running platform trials that share a placebo group: this saves costs and lowers the number of patients that are started on placebo. We are also initiating earlier biomarker driven studies, in which data will be shared, and researchers or companies can learn from the collective experience.
I think we also need to lower barriers for patient enrollment into trials. I was just in China for an ALS meeting, and they move into patients sooner: albeit in small trials, dedicated solely to target engagement. I think we could do this more in the US and it would help both patients and drug developers.
7. The MGB neuroscience institute seems like an incredibly collaborative and exciting endeavor. What is the larger vision of this center?
Across the neurosciences we want to delivery seamless integrated care for patients. We want a patient—whether in the community or the MGH main campus—to have access to high quality care, clinical trials and have great communication with providers. Right now for example, a patient with Alzheimer’s can enter our system from many different ways—geriatrics, psychiatry, neurology, primary care—and there is not enoughcoordination of care between these disciplines. The idea of the institute is to create this center of excellence where patients can receive coordinated care and have immediate access to clinical trials or participating in research. I also want to eliminate the friction or silos between our scientists to enhance collaboration. Ultimately we want to connect basic scientists with clinical researchers to help translate their work. My goal is that in five years, I want patients to feel like the MGB neuroscience institute is “the place” to go—with the best diagnostics, coordinated care, clinical trials and basic research. It will also be a great place to train students and residents, as they will have a ton of exposure to the cutting edge. Hopefully we can also reduce some of the barriers for companies running trials that I mentioned, as well as promote the formation of new companies based on MGB research.
8. You have mentored many trainees over the course of your career, what advice would you give about establishing a successful academic career?
First—follow your passions and do the things you love. If you don’t know what exactly to focus on, talk to lots of people. Do not feel intimidated to approach people.
Another piece of advice I got from one of my mentors, Dr. Anne Young, is to work with people you like—who you feel are easy to get along with and are kind. I have always stuck to that notion, and it makes collaboration so much more fun. It is crucial to also create teams that work well together. Anne Young would also always say to not forget to have a personal life. She always made sure to have dinner with her family and leave work at the hospital or in the lab. I try to remember this because we all feel the pressure to work late, and there seem to be endless things to do. Spend some time with friends, family and on your hobbies. The last thing is to have many types of mentors. You should always have one primary mentor who is invested in your success: someone who is passionate about helping you. For me, Bob Brown was my primary mentor, even though he was a basic scientist. However, once I settled on running clinical trials, he connected me with others who became mentors as well. Go find the people that have what you need, and you can learn a lot from them…but don't forget to have one person who is your primary advocate.