Founder Spotlight #46: Adam Margolin @ Flashpoint Therapeutics
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Flashpoint Therapeutics will bring to patients a new approach to designing potent cancer immunotherapies that transform therapeutic components from ineffective to curative through optimized nanoscale architecture.
Flashpoint nanostructures are all-in-one formulations that kinetically tune and co-deliver precise combinations of therapeutic components with nanoscale presentation optimized to induce powerful, coordinated anti-tumor immune response. This approach overcomes limitations of current technologies that rely on mixing therapeutic components with little control over their co-delivery or structural presentation.
Based on in vivo mouse studies, Flashpoint nanostructures yield 35 times increased co-delivery of therapeutic components to immune cells, 80 times stronger immune activation, and 6.5 times greater tumor killing.
Across 9 in vivo mouse studies performed to date, spanning different tumor types, Flashpoint immunotherapies have achieved near curative or curative efficacy using the same components that are ineffective in conventional formulations.
Flashpoint Therapeutics was created to bring this same benefit to cancer patients.
Adam Margolin is Co-founder & CEO @ Flashpoint Therapeutics
Adam was previously a Venture Partner @ Khosla Ventures, where he led efforts in therapeutic platform company creation, investment diligence, board level strategic guidance, and executive leadership of a cancer cell therapy company named NextVivo.
Over his 20-year academic career, Adam performed highly influential work in computational biology and cancer research and led some of the largest and most successful research organizations in these areas.
Adam was Chair and Professor of the Department of Genetics and Genomic Sciences, Director of the Icahn Institute for Data Science and Genomic Technology, and Senior Associate Dean of Precision Medicine at Mount Sinai. In these roles, he led an organization that rose to become the #3 ranked genetics department in the country, encompassing over 700 people and over $100M annual revenue. Concurrently, Adam served as Chief of Data Science of Sema4.
Prior to Mount Sinai, Adam was the Founding Director of the Computational Biology program at Oregon Health & Science University, where he was also promoted to the rank of Tenured Full Professor. Previously, Adam was Director of Computational Biology and co-Leader of Strategy at Sage Bionetworks.
Adam is an internationally recognized researcher in the fields of computational biology and cancer research and has developed widely used methods that have been ranked among the most influential algorithms in the field.
Adam performed his postdoctoral research at the Broad Institute of Harvard and MIT and obtained his PhD. from Columbia University. He also holds a bachelor’s degree from the Wharton School of Business and a master’s degree in Computer Science from the University of Pennsylvania.
Personal Spark
What prompted you to pursue a career in Life Sciences? Was there a specific moment in time or influence you can remember?
After High School, I went to Wharton Business School and worked on Wall Street, because that’s what a kid who likes math does. In the early 2000s breakthroughs in sequencing technologies began generating large amounts of molecular data profiling human disease. I was captivated by the potential of applying the same analytic tools used to predict bond performance to instead predict what drugs will be most effective for a cancer patient.
What drives you to work in this space?
My mother died of cancer when I was 3. For the past 20 years, my career decisions have been driven by a mission to best contribute to curing cancer.
I don’t remember my mom and can’t make a conscious link between her suffering and my driving passion to cure cancer. But when my mind chatter is quiet, I look to my north star, which is to advance a cure for cancer through approaches at the frontier of medicine. Following that north star is why I’m building Flashpoint.
How did you get your training to be able to build your company?
In academia, I had the opportunity to lead organizations up to a scale of 700 people focused on leveraging advanced technologies to accelerate drug discovery. A lot of this experience directly maps to starting a biotech company, particularly in terms of experience with organizational leadership and developing scientific and technical strategies yielding differentiated capabilities.
I dove into my first company prior to having experience with the nuts and bolts tactical side of biotech in terms of developing a pitch deck, IP strategy, or operational costs and milestones for drug development. I gained experience in these areas by actively focusing on learning them as quickly as possible while building a company.
For people interested in entrepreneurship, I think it’s OK to have deep experience in some aspects and expect to learn others on the job. Just be willing to embrace this learning actively.
Can you tell us a little bit about your background & career thus far? What were you doing before you started running a high potential venture backed startup?
I spent about 20 years in academia, gravitating towards a passion for leading interdisciplinary technology-driven programs. I became less interested in promoting my own ideas, and more interested in how we can integrate the best ideas to make a real impact on cancer.
During this time, I ran my own kind of experiment in studying, applying, and refining strategies for building high performing teams and organizations. I read every book I could find on the inner workings of silicon valley tech companies, dialogued with successful leaders in the industry, put these insights into practice, and refined my personal philosophy and style based on the most effective strategies.
I was recruited into 3 successive roles with increasing responsibility, ultimately entrusted with leadership over a 500-person organization at Mount Sinai as Chair of the Genetics Department, Director of the Technology Institute, and Senior Associate Dean for Precision Medicine. The leadership philosophy and values I had developed contributed to success at that scale as well, and over 3 years we grew the organization to 700 people, increased revenue by >$20M/year and became the #3 ranked Genetics Department in the US.
I loved my journey in academia, but ultimately felt I could more directly pursue my north star of working towards curing cancer from the biotech side of the fence. After working for 2 years as a Venture Partner at Khosla Ventures and CEO of a cell therapy company, I’ve indeed felt the opportunity to benefit cancer patients more directly than I could in academia.
Flashpoint is the most exciting opportunity I’ve seen to bring novel therapies to patients with breakthrough potential, which is why I decided to pursue this mission full-time.
In academia, I always said my goal was to cure cancer, but there was not really a direct path to do so. Now, I can say our mission in Flashpoint is to cure a cancer patient in 3 years. And I believe we will.
Anything else you’d like to share about your life, academic trajectory, etc.?
Innovation in the software industry has been enabled by “agile development.” Rather than planning the details of a project over multiple years, long-term objectives are defined at a high level, and the specifics are defined a month at a time.
I think the agile development concept also applies well to career choices. I’ve never really had a 5-year plan. In fact, it would be a pretty silly plan if I set out to work like crazy for 20 years in academia to achieve the end goals of tenure and large programmatic leadership roles, and then leave to build startups. But all of those choices were the right ones at each time and reflected where my excitement naturally gravitated.
I think the best companies are run this way as well. For Flashpoint, I have a clear vision of where we want to be in 2 years. I’ve laid out details of how to get there as well, but I think an effective leader should expect the details of any multi-year plan to change and improve as information is gathered during that time. Values and mission should be stable. Tactics should be flexible.
Company Overview
What problem is your company solving?
We know effective cancer therapy requires co-activating multiple pathways in the same cell. But current drugs just mix together components and cannot control how they work together.
Flashpoint solves this problem by integrating therapeutic components within nanostructures that control their co-delivery and coordinated activation of the multiple pathways required for the immune system to kill tumors.
We’ve cured mice with 9 different kinds of tumors using immunotherapies with the same components that are ineffective in conventional formulations. We are working to bring one of these candidates to the clinic.
How did you become motivated to tackle this particular problem?
The problem I’m motivated to tackle is curing cancer. I spent most of a year thinking about every possible way to pursue that, and converged on leveraging nanotechnology innovations. Most activity in cancer therapeutics centers around improving established modalities, such as cell therapy and antibody mediated immunotherapy. These are good, but they’re saturated, and innovations are incremental.
So what’s the next frontier? Nanotechnology enables delivery of the right combinations of therapeutic cargo into the right cells, which solves many major limitations of other therapeutics. I think the advantages of nanotechnology rival those of other major therapeutic modalities, but represent a small fraction of investment interest.
So I set out to build a company that would capitalize on the potential of nanotechnology tools to create more effective combination cancer therapies. The specifics of how to best do that crystalized through discussions with Chad Mirkin about the concept that became Flashpoint.
Quite simply, what does your company do?
Flashpoint Therapeutics will bring to patients a new approach to designing potent cancer immunotherapies that transform therapeutic components from ineffective to curative through optimized nanoscale architecture. Flashpoint technology represents a key advance in the field of cancer immunotherapy, which requires co-activating multiple pathways to stimulate a coordinated immune response against tumors. Current immunotherapies focus on defining therapeutic components but cannot control how they work together. Flashpoint overcomes this limitation by precisely controlling the components that are co-delivered into single cells and their timing of target activation, enabling coordinated activation of the complex immune response required to kill tumor cells.
Now in more depth, what are the specifics of what your company does?
Traditional cancer combination immunotherapies are limited because they simply mix together therapeutic components and inject them into patients. These approaches offer little control over the structural presentation of components to immune cells, which is essential for driving anti-tumor efficacy. Structural consideration is also essential to ensure co-delivery of the right combination of molecules at the right time to trigger the multiple pathways that must be co-activated for an effective anti-tumor immune response.
Leveraging a novel approach, developed in Chad Mirkin’s laboratory over the past 10 years, Flashpoint immunotherapies are all-in-one formulations that kinetically tune and co-deliver multiple components via nanoscale presentation optimized to induce powerful, coordinated anti-tumor immune responses.
Many formulations we have tested to date combine the ability to induce more potent innate immune stimulation via structurally optimized presentation of oligonucleotides with the ability to direct adaptive immune response against specific tumor antigens co-delivered on our nanostructure surface.
We have extensively tested this approach in mice, and in all cases Flashpoint formulations transformed ineffective components to yield curative or near curatie efficacy. Flashpoint Therapeutics was created to bring this same benefit to cancer patients.
Why does your solution matter for the world when you get it right?
A long standing holy grail of cancer immunotherapy has been to induce potent activation of a patient’s own immune defenses against their specific tumor. Approaches to date have not achieved this goal, as approved therapies either induce non-specific immune activation (e.g. checkpoint inhibitors) or attempt to engineer tumor targeting cells outside of the body (e.g. cell therapies), whereas clinical trials attempting to stimulate tumor specific immune activation (e.g. cancer vaccines) have achieved only moderate efficacy.
We believe Flashpoint solves the missing link that has prevented these approaches from realizing their potential. The key is moving beyond just defining therapeutic components, and defining how they are co-delivered and structurally presented to induce a potent, coordinated anti-tumor immune response.
We’ve demonstrated this principle in mice — the same components delivered in traditional formulations are ineffective, and are transformed to curative when delivered as Flashpoint nanostructures. If the same advantage is replicated in humans, Flashpoint vaccines will enable highly efficacious treatments that can be delivered safely to patients, developed and manufactured efficiently, and customized to treat virtually any type of cancer.
Genesis
Tell us about the founding of your company — how did everything come together?
I knew I wanted to build a company in nanotechnology. I thought this was an area of untapped potential in cancer therapeutics. The ability to co-deliver diverse cargo through nanoscale constructs with improved cellular uptake solves many of the challenges that limit current therapeutics.
Beyond that concept, I needed to listen to the experts. I came in with lots of ideas around nanorobotics, energy activated multimodal theranostics, etc. Technically cool, but impractical. These conversations with experts converged on pursuing a well formulated focus on enabling better co-delivery of precise stoichiometric ratios of cargo into the right cells. Chad Mirkin had the most advanced technology in this arena, which he had been working on for over 10 years, and added key additional dimensions of optimizing the structural presentation of cargo and timing of target activation.
This rounded out the full picture — nanotechnology enabled therapeutics that precisely control cargo co-delivery and coordinated activation of multiple targets to optimize stimulating the complex immune response required to kill tumor cells.
How did you meet your co-founder?
I had met Chad peripherally during my academic career. When I was exploring ideas in the nanotech space, it’s hard to throw a stone without hitting Chad, so I reached out to him pretty quickly.
Chad shared a vision of building a company that could best capitalize on the potential of nanotechnology for cancer therapeutics and had been laying the groundwork to build such a company for the last decade. We were super aligned on vision as well as how to strategically build a platform therapeutics company.
The ultimate selling point to me was studying around 20 publications that lay the foundation of Flashpoint, and seeing how consistently the key technical advantages were replicated across studies spanning many years, people, tumor models, experimental variations, etc.
An immense amount of rigorous data supported the conclusions that therapeutics formulated as Flashpoint nanostructures exhibit marked increases in cellular update, immune activation, synchronization of innate and adaptive immunity, tumor killing by T cells, and improved efficacy in vivo.
As we continued to discuss the concept of Flashpoint, it was clear we had similar views on how to build a company, and this organically led to a mutual decision to dive in as partners in this endeavor.
Was there a specific moment when you knew you should pursue this as a business idea? If so, what was it?
For me, the decision point was when I was being pushed to explore ideas in other sectors, such as digital health, and my mind kept returning to the potential of building Flashpoint. I think there’s wisdom in where passions naturally direct themselves. So I followed them and took the leap.
Accomplishments
What are some of the notable milestones your company has achieved thus far?
In vivo mouse studies have demonstrated that the Flashpoint approach yields 35 times increased co-delivery of therapeutic components to immune cells, 80 times stronger immune activation, and 6.5 times greater tumor killing.
Across 9 in vivo mouse studies performed to date, spanning different tumor types, Flashpoint vaccines have achieved near curative or curative efficacy using the same components that are ineffective in conventional formulations.
A very good summary of our approach was covered in this TV news story. Since our launch, we were also fortunate to be covered in articles in endpoints, Crain’s, and Reuters and on WGN radio. Our technology was recognized by an award historically en route to the Nobel Prize.
We’ve secured broad IP rights reflected in 13 patents.
In addition to our founders, our team brings prior experience as the President of Takeda (Mark Booth) and winning lawyer in the CRISPR case (Ray Nimrod).
We’ve charted a strategy to move our first candidate down a clinical development path and to leverage the modularity of our platform to rapidly expand our pipeline through internal programs and partnerships. We are now raising our first institutional funding round to hit the ground running in these directions.
What are some of the biggest hurdles ahead? How do these create points of value inflection?
We’re laser focused on getting drugs to patients. It will be hard work, but there’s not much technical risk in getting to clinical stage. At that point, any clinical stage company faces risks associated with readouts from first-in-human studies. The data I have seen give me confidence that our initial trial has a high likelihood of demonstrating clinical efficacy, but this is always a risk until clinical readouts are obtained.
Strategically, one priority I have from the outset is to keep a long-term view of maximizing the potential of the platform, and to not turn a platform therapeutics company into a single asset company. We will need to keep this strategic focus while navigating immediate pressures to focus on short term priorities, which are important but not the full picture.
Beyond that, we need the essential nuts and bolts pieces of sufficient capital to execute towards our milestones, engaging the right strategic partnerships with pharma companies, recruiting top people at every level, and maintaining cultural and strategic alignment to execute on our mission.
Pay It Forward
Throughout the journey, what have been some of your biggest takeaways thus far? What advice/words of wisdom would you share from your story for other founders?
I mentioned that when my mind naturally kept returning to the idea of Flashpoint, I took that as a sign to follow that cue. There are times when your excitement just naturally directs itself in a certain direction. That’s the wisest guide to follow.
What are some of the must-haves for an early stage Life Sciences startup in your eyes? (Key critical components like team, academic papers, industry know-how, etc.)
Personally, I look for approaches that are technologically differentiated from the field and have robust data establishing their advantage in areas of importance. Such technology advantages are necessarily encoded in publications and patents, which are requirements, but I would dig into these with a view of establishing the differentiated aspects and market or clinical need.
Beyond that, the team is critical. It’s essential to engage people with the right experience, drive, shared values, and chemistry. How to do that can take various forms. If you can put this together from the outset, that’s great. If you’re a killer CEO with a killer founder, it’s often best to try to raise initial cash with a plan of recruiting a killer team from there.
What are some of the traits that make a great founder? What type of risk profile/archetype does someone need to have to be a founder in your opinion?
You have to be stupid.
One time I was meditating in a Zen monastery during an intensive week-long retreat. When the master spoke on the last day, I expected he would praise how much progress we made for our effort. Instead, he gave a story of 2 frogs stuck in a vat of boiling milk. One frog was smart. He tried every possible way to escape. It was impossible. So he gave up and drowned. The other frog was stupid. He just kept kicking and kicking and kicking indefinitely, until he churned the milk into butter and jumped out.
I really hated that story. But a founder needs to be a stupid frog sometimes.
For folks coming out of academia, what advice would you share?
If I was an AI chatbot programmed to say the most rote answer, it would probably be “follow your passions”. But I’ll say that anyway. If you are drawn to focusing on hard core science, go do that — I did for 20 years. If you’re drawn towards the industry side, go do that. If you want a comfortable 9–5 job with well-defined parameters, go do that. Don’t worry as much about where these will lead in 10 years. Nobody knows. But if you enjoy it, any choice is more likely to lead somewhere good.
Not everyone knows everything. Often founders have to learn either the science or the business side better. What advice would you give for someone picking up a new skill set such as this?
I’m biased on this question. I spent my career in the deep rabbit holes of science and then picked up the industry side. The industry side is important, but my perspective is that a lot of this can be learned over the course of a few years, whereas science requires a substantially longer training period. I think it would be difficult to devote enough focus to the scientific side without an exclusively dedicated period of time. At least a PhD, advisably a postdoc, possibly additional time in academia. Maybe not staying in academia until tenure then jumping ship like I did — that’s a little silly.
I’ll hedge this perspective by noting that a foundational quality of a good leader is being able to engage the right people and really listen to them. A founder who’s really good at this, but lacks the scientific side, can certainly be successful.
Can you demystify the process of what it was like to raise VC funding? What were the highlights & low lights? Any advice or words of wisdom for future founders?
We’re actively in the process for Flashpoint, so may need to update this entry in a few months, though I can also share perspectives from my last fundraise.
First, prepare your materials, presentation, team, and plans as best as you can. As a mental model, when you get rejections, make sure you don’t have regrets that you left anything on the table in terms of being underprepared. There’s a lot you can’t control. Expect that until you’ve cured every cancer patient on the planet, investors will want more data, more derisking, etc. Don’t fake what you don’t have. But do everything you can with what you do have.
From there, it’s generally like being the stupid frog I described above. If you are expecting to email a few VCs and get a $10M check, this isn’t the right game. Prepare to take 6 months or a year and just persist in your vision and keep kicking the milk and not look down to see if any of it is turning into butter until then.
What advice for managing and hiring a great team can you share?
Focus as much on the human aspect as the technical aspect. You definitely need people who are well qualified, but don’t make that the full picture. I would sacrifice specific areas of experience for culture fit any day.
I have a specific set of values for organizational culture that are important to me, which I codify in my personal set of 6 core values. These are to always put the patient first, simplify, focus, share openly, value contributions over politics, work synergistically, and deliver results. I actively look for people who share these values. It’s good to have diverse opinions in pretty much everything, but not values. I would be clear on what values are important to you and build around those. The people I select for in terms of culture fit will be different from the people that fit with other organizational cultures. But I think it’s important to have a clear vision of the culture you want and select people who align with that vision.
Anything else you would like to add? Company, personal, etc.
To build successful companies, I think 2 things should be intransient from the outset — mission and culture.
Since this spotlight is being published at the very early stages of Flashpoint, I’d like to memorialize the mission and culture that will guide our journey over the next few years. In doing so, I invite anyone to hold us to these commitments and to call us out if we deviate from them.
Our mission is to demonstrate benefit to cancer patients. By 2026, I want to know the name of a cancer patient who is living because of a cancer drug we have made for them. By 2028, I want to scale the platform to benefit as many patients as we can.
Our culture will enable this mission by prioritizing what’s good for patients above all, and working as a synergistic, open, apolitical team focused on the goal of rapidly bringing to patients the most effective therapies enabled by our platform.
All of our tactics will change and evolve, but our core mission and culture will not change. That’s a commitment made in this document so anyone can hold us to it. If you share this vision and would be interested in participating in our mission please feel free to contact me at adam@flashpoint.bio.
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