Welcome to Partnology’s Biotech Leader Spotlight Series, where we highlight the remarkable accomplishments and visionary leadership of biotech industry pioneers. This series is about showcasing the groundbreaking strides made by exceptional leaders who have transformed scientific possibilities into tangible realities. Through insightful interviews, we invite you to join us in following the inspiring journeys of these executives who continue to shape the landscape of the biotech industry. This week we are recognizing:
Sam Jackson, Chief Medical Officer
Sam Jackson joined Neuron23 as Chief Medical Officer in 2022. A strategic leader and clinical development expert, Sam is a board-certified emergency physician with fellowship training in medical toxicology. He has a history of successful leadership roles in the biopharmaceutical industry. Before joining Neuron23, Sam served as Chief Medical Officer (Interim) at Alector, where he oversaw clinical development and operations while leading programs in Alzheimer’s Disease and Frontotemporal Dementia. Sam led the clinical due-diligence discussions that resulted in a transformational alliance with GlaxoSmithKline in one of the largest deals in the neurodegeneration space. Prior to Alector, Sam held the role of Chief Medical Officer at two other biotech companies after working in positions of increasing responsibility at Amgen, Genentech, and Dynavax. Sam graduated from Stanford University and received his MD and MBA degrees from the University of Pennsylvania.
Take me back to academia – it looks like you have a unique educational background. What made you want to study medicine?
I’m the first person in my family to graduate from high school so every educational opportunity was a significant leap forward for me. I came to Medicine on my own which distinguishes me from some of my colleagues who grew up in a culture of science or medicine. This has allowed me to add perspective in productive and unique ways.
There were a few steps before Medical School. Initially I worked as an analyst in the entertainment industry but felt I spent too much time making people who already watched television watch even more. At that time we thought of TV like we think of social media today – too much was clearly pernicious. I wanted something different from my work.
I went to the University of Pennsylvania for Medical and Business School. The joint MD-MBA program was very strong and I was privileged to get a full scholarship. I chose an MD-MBA program because I realized early on that healthcare was a business. Everyone in the healthcare industry has to consider how he/she creates value for patients and other stakeholders within the entire system, including society.
The joint-MBA program trains a few physicians each year (along with students from a wide variety of backgrounds) to use powerful analytical tools. Many graduates take a well-trodden path into banking or consulting; I was one of only a few in my class who pursued residency training. Maybe I didn’t understand my Finance classes very well because I worked long hours for low pay in the hospital as a trainee but I really enjoyed taking care of patients.
Walk me through your career, noting some of the most pivotal moments or decisions throughout, what are you most proud of?
I was a fellow in Medical Toxicology in Phoenix where I spent many hours taking care of sick patients. Medical Toxicologists specialize in the science of when drugs are destructive – when patients have been exposed to a high dose of a drug or bitten by a snake or exposed to a poison of some kind. During this period I became very interested in pharmacology and worked on a few clinical trials. I was fascinated by new therapeutic candidates that had never been tested in humans. How do we interpret preclinical data from animal models? How do we monitor for potential safety issues? I was fascinated by the trade-off between potential benefit and potential harm.
This interest led me to Amgen, where I joined their early development safety group that was led by a noted clinical pharmacologist who was a great mentor. Working there was almost like an industrial post-doc where I learned to apply all the principles I had learned in the clinic to industrial applications. From Amgen, I went to Genentech, where I learned more about leading teams of smart people who need to navigate the complex, multi-stakeholder process of drug development. Drug development is one of the most complex and complicated endeavors in which humans engage. It starts with science and medicine but quickly involves operations research, statistics, finance and other disciplines. How do you contend with risks, where you can describe the distribution of possible outcomes, and uncertainty, where you cannot?
Drug development is compelling because of its potential to magnify the impact of scientific and medical understanding. While being a clinician offers the satisfaction of one-on-one relationships with patients, getting a vaccine or therapeutic approved can benefit thousands. The prospect of creating benefit at scale fuels the long hours and gives me the resilience to pick myself up when programs fail.
After Genentech I joined Dynavax, a smaller biotech company with exciting biology. At Dynavax, I ran the last phase three trial for Heplisav, a more potent and safer Hepatitis B Vaccine. A particular challenge for developing vaccines is that the people who take them are primarily healthy. Vaccines always carry concerns about the potential for overstimulating the immune system that can lead to autoimmune reactions in rare circumstances. Vaccines are among the safest and most thoroughly tested products made by our industry, however.
I moved from Dynavax to Alkahest and my first Chief Medical Officer role. Alkahest was started by Stanford professor Tony Wyss-Coray. Researchers in Tony’s lab conducted an experiment using a 150-yr old technique called parabiosis in which the circulatory systems of an old mouse and a young mouse were connected. The researchers found that infusions of young blood could improve cognitive and other functions in older animals – an incredible result! The effect could bridge across species: old mice given young human plasma perform better at mazes and other tests. These early efforts to understand the underlying pathophysiology of aging, a hot topic today, led Alkahest toward Alzheimer’s Disease and other diseases where age is a primary risk factor.
Over the course of my career I’ve sought out areas of intense innovation, and although a plasma-based therapy for Alzheimer’s Disease may sound like a crazy idea, the biology behind how young plasma can influence biological processes is intriguing. Plasma contains thousands of components that vary with age. The challenge is distinguishing those factors that have positive effects from those that may be deleterious. To sort this out, Alkahest had a substantial proteomics effort that identified novel therapeutic targets.
After Alkahest, I did some consulting helping a wide variety of companies solve problems in drug development. The most interesting was Excision Biotherapeutics, a company based on the idea that CRISPR could be used to cure HIV by removing it from the human genome. While current HIV treatments are a remarkable scientific achievement they are not cures. The Company had a great team but they needed a part-time CMO; I was excited by the bold application of a new technology to solve a hard problem.
I was then recruited by Alector, an innovative company with great science where many former colleagues from Genentech were working. As the Senior VP of Clinical Development, I helped them scale the organization to better enable the conduct of late-phase clinical trials. This was difficult due to the Covid Pandemic but we found creative solutions that allowed patients to continue participating in clinical research. Eventually I took over the Chief Medical Officer role.
Could you expand more on the programs you’ve worked on, maybe highlighting those you are most proud of or passionate about?
Early in my career I was fortunate to work on Denosumab, a biologic intended for fracture prevention in patients with osteoporosis. It was initially approved for women with osteoporosis who are at high risk for fractures but the label has since expanded to include similar indications in men. It was novel biology; a highly effective injectable drug that could be administered every six months. Working on a phase three program that resulted in global approvals so early in my career was a rare opportunity, as anyone in our business must be prepared for a constant march of failed trials. I was very lucky to have participated in the later stages of a successful program that was the product of years of innovation and hard work at Amgen.
At Genentech, I led a program targeting the complement system which showed great promise for treating Geographic Atrophy (GA), the dry form of Macular Degeneration—a disease that plagued my mother. The phase two results were compelling but the molecule failed in phase three. This scenario, unfortunately, is more typical of our industry. That said, there is now an approved complement inhibitor called pegcetacoplan that does slow the growth of GA lesions on the retina and there is considerable promise that there will be more treatments for GA that target complement proteins.
It was very satisfying to work on Alector’s phase three trial of a drug intended to treat patients with Frontotemporal Dementia that results from a mutation in the progranulin gene, a terrible Gwith no current disease-modifying treatments. Alector’s Latozinemab program is a rational, targeted therapy that recently received Breakthrough Therapy Designation from the FDA – a status rarely awarded to development programs in neurodegeneration. The INFRONT-3 study has completed enrollment which means we aren’t too far from seeing these important data.
Tell me more about Neuron23 – what are you working on?
We are starting the most innovative clinical trial in Parkinson’s Disease drug development today. I can make this claim with confidence since Neuron23 is the only company using a companion diagnostic to identify patients who are more likely to respond to a LRRK2 inhibitor and the only company using a digital primary endpoint for a proof-of-concept study in patients with Parkinson’s Disease.
Terms like “precision medicine” or “personalized medicine” are used by many companies but with very few exceptions the only therapeutic area that regularly relies on these concepts to develop therapeutics today is oncology. The goal of precision medicine is to improve the benefit-risk ratio of therapy by identifying patients who are more likely to respond to a drug. Genentech pioneered the first drug and companion diagnostic combination in 1998 when Trastuzumab (Herceptin) and the HercepTest were approved for the treatment of Breast Cancer characterized by the over expression of the HER-2 receptor. If a tumor overexpressed HER2, Trastuzumab could offer potential benefit; if not, there was no reason to risk the side effects associated with the drug.
The paradigm introduced by Trastuzumab has been successfully repeated in oncology but Neuron23 is the first company to use a precision-medicine approach in a clinical trial for neurodegeneration. We have a genetic test that identifies patients with Parkinson’s Disease that is driven by the LRRK2 pathway and we will use it to identify patients who are more likely to respond to NEU-411, our LRRK2 inhibitor. The other aspect that makes our trial so innovative is the use of a digital primary endpoint. Clinical trials in patients with Parkinson’s Disease typically use clinical endpoints that are based on a subjective assessment of function developed decades ago to guide symptomatic therapy. Parkinson’s Disease is often slowly progressing with highly variable symptoms, making clinical trials large and long which is very expensive and challenging, especially for small companies. The use of an exquisitely sensitive digital endpoint allows researchers to measure how well patients are moving, thinking, or speaking with a much higher degree of precision and by collecting a much greater volume of data. Digital technology creates the possibility of detecting a signal in a smaller sample size, making clinical experiments better and more manageable.
Consider how measurement has become more precise over time. In the 16th century, “Hands” were used to measure the height of a horse, then a Hand was standardized at 4 inches. Later rulers and yardsticks were used to measure distance; now a laser can measure the length of a football field down to the millimeter. When conducting an experiment that measures the progress of two groups over time, such as a placebo-controlled clinical trial, more precise digital measurements will help researchers get closer to ground truth about whether a drug is exerting a treatment effect – as long as we are careful to measure what matters to patients.
What do you see as the most promising technologies in biotech over the next 5-10 years?
The confluence of tech and biotech, software and wetware, holds tremendous promise. Regardless of the outcome of our phase two trial, it is a model for future trials in Parkinson’s Disease. Because of its ability to increase the ratio of potential benefit to harm the precision-medicine approach informed by genetics or additional biomarkers is the future of drug development. And even if our digital endpoint doesn’t become a standard in clinical trials studying patients with Parkinson’s Disease, at some point in the future a digital technology will become the standard method to assess drug effects in these patients. The phone in your pocket contains an enormous quantity of data about how you move over time and there are millions of these devices in use today by patients.
Many biotech companies are excited about Machine Learning and Artificial Intelligence. These technologies offer great promise but they require large amounts of data on which to train and there aren’t many examples of successful clinical trials in neurodegeneration. In biotech, these technologies are unlikely to scale as they have in social media or large language models where it has been all about devouring open-source information and improving compute power. There are already use cases where AI and ML have improved the pace of research, however, especially in chemistry and genetics – domains where large and relatively clean datasets are available. For clinical applications, however, the data are complex and often full of confounding factors. For example, it’s acknowledged that adverse-event reporting for marketed drugs is inaccurate. If a drug actually causes stomach upset in a very small fraction of patients, for every report received there may be 2,3, or even 10 more that are missed and some reports will be misattributions. It’s difficult to use incomplete or dirty data to train a model.
CRISPR continues to be a very productive innovation. While it’s unlikely that many therapeutics that directly alter human DNA will be approved everyone eventually will be taking medications that were developed using CRISPR-based tools that allow us to gain insights into biology much more quickly than we did before. Testing hypotheses with CRISPR-based model systems will lead to a deeper understanding of fundamental biology which will translate to more successful programs in the clinic.
With the experience and insights you have gained, what advice would you give to young people aspiring to work in the biotech industry?
The best advice I’ve heard is to try to pick something at which you can excel – that’s important. In my career, I’ve become good at solving complicated problems, borrowing insights from different fields and applying them to domains where the application isn’t obvious. For example, what can we learn from the way Walmart stocks inventory on its shelves? Why can’t we use just-in-time patient selection to help our patients find the right clinical trials? How can we be more efficient and provide more opportunity?
If you’re very good at solving a general problem then you don’t need extraordinary insight into what specific problems will be important in the future. Nobody can do that! It’s great to have an advanced degree but it’s hard to predict how important immunology, genetics or biochemistry or oncology will be in the future. Consider what we can do in drug development with deep knowledge of genetics now that we can sequence the human genome for a few hundred dollars. But if that sequencing technology hadn’t been developed domain expertise in genetics might not be as applicable. There’s also value in a generalist perspective. I’ve cared for many kinds of patients with different diseases and this allows me to quickly form a basis of understanding for different therapeutic areas. In my role I don’t have to be the smartest person in the room; I just have to be the person who can bring the relevant expertise together to develop fit-for-purpose solutions. I try to improve every day. It’s critical to never stop learning.
