Alnylam: John Maraganore
“I’m blessed that my mother gave me a special power: optimism.”
The story of Alnylam is one of “second achievement” [T. Roosevelt 1910].
During the dark days of the ’08 financial crisis, clinical trial failures and waning investor sentiment in their RNAi technology, Alnylam remained firmly “in the arena.”
Their team learned from the many setbacks and continued striving towards their “great devotion” of making a new class of RNA-based therapies: “If you're running a company that's on the frontier of medicine, a lot of things won’t work out. But you must be optimistic about the next set of experiments and about trying again. That’s who I am,” says John Maraganore, founding CEO (2002-2021) of Alnylam.
Alnylam, like Genentech before it, now serves as a guidepost in biotech. How do you identify exciting science at its earliest stage, overcome inherent technical hurdles, and then develop transformative medicines? They have set a high bar. Founded in 2002 by a team of legendary scientists and investors (including Phil Sharp and Christoph Westphal), Alnylam was created to harness the principle of RNA interference [RNAi], to make a new class of drugs.
By using double stranded RNA molecules that could bind endogenous target mRNAs, scientists Andrew Fire and Craig Mello discovered that one could precisely degrade RNAs and “knockdown” gene products in a cell: “I knew that the science was important…I got excited about the potential of creating this whole new class of medicines. If we figured the technical hurdles, we could create something transformative,” reflects Maraganore.
Yet the technical challenges proved immense: how do you get these dsRNA molecules into cells? How do you deliver them to the right tissue, and produce a durable response? What targets and diseases are amenable to this type of approach? It was with these questions still unanswered that that founding CEO John Maraganore took the helm at Alnylam in 2002.
After earning his PhD in biochemistry at U.Chicago, Maraganore spent over a decade working in industry—at Upjohn, Zymogenetics and Biogen. He considers his work at Biogen (1987-1997) to be his formative training (or “post-doc”) in drug development: “[At Biogen] I invented a molecule, a peptide, that was a very potent inhibitor of the enzyme thrombin…and was ultimately sold as an anticoagulant [Hirulog]…it was an amazing early experience of literally inventing a drug and taking it to the clinic.”
Maraganore then spent several years at Millenium Pharma (1997-2001) working with the likes of Mark Levin and Kevin Starr. Though content at Millenium, Maraganore’s life changed after receiving a phone call from Alnylam co-founder Phil Sharp in 2001: “What really hit home for me is when I was driving to work, every morning to Millennium, I was really thinking about what Alnylam could become….It occurred to me that I had become infected with the desire to go do this thing,” he recounts.
Maraganore joined Alnylam as founding CEO in 2002 and embarked on a 20-year odyssey—one that has resulted in 5 FDA-approved medicines, a dozen pipeline programs, and the establishment of a new class of RNA-based therapeutics. Yet Maraganore predicts that it is just the beginning: “We're going to see RNA based medicines for a whole range of different diseases in tumors, muscle, CNS, heart, lung…this list goes on. It will just create a whole new wave of medicines that will ultimately make a big difference.” Though he moved on from Alnylam in 2021, John is still “striving to do the deeds” and helps several companies (Beam, Takeda, Agios, Kymera) develop novel drugs for patients.
He gives this advice to those just staring out in biotech: “If you're passionate about making medicines and helping patients…follow it. Be relentless in your desire to make a difference—be the person ‘in the arena,’ if you will, and just go for it.”
Below is an interview with Dr. John Maraganore from June 2023:
1. What was your first taste of science? Briefly, what about this initial experience drew you in, did you consider any other path?
I grew up with science all around me. My father was pathologist and had a clinical laboratory. I became excited about science and medicine as a child—I had the perfunctory chemistry, biology and geology sets. I'm not sure they still exist, but it was one of the Christmas toys I would get growing up. I loved experimentation. I used to do things like collect pond water and look under a microscope at all the organisms or keep saltwater aquariums and learn how to keep the conditions correct for the fish. Throughout my whole life, I've always been fascinated by science, biology, nature, and experimentation. It’s just who I am—I think this is true for a lot of people that get into the sciences, and it was definitely true for me. Of course, at some point in my youth, I wanted to be a fireman, policemen or astronaut. But science early in my life became a part of who I was and where I wanted to go.
2. Alnylam is a story of great science and resilience—to waning RNAi sentiment, market swings and trial setbacks. Any early experiences during your training that helped build this resilience?
I've said this a little bit on Luke Timmerman’s podcast [The Long Run], but my mother blessed me with a special power: optimism. So, I have always had a very glass half full view of the world.
I always had an optimistic view about the bench work I was doing--whether it was my PhD research in grad school, at Biogen or Millennium, and certainly at Alnylam. My mother gave me that gift and definitely she deserves a credit, just as much as my father who gave me the gift of passion for science and medicine. [These gifts] enabled me to live through the pains that many people experience when they're doing experimentation…because many experiments will never pan out. This is also true from a leadership standpoint—if you're running a company that's on the frontier of medicine, a lot of things won’t work out. But you have to be optimistic about the next set of experiments and about trying again. That’s who I am.
3. What have been some scientific high points? — What do you consider to be the most exhilarating set of discoveries you have been directly involved in throughout your career (as a bench scientist in academia and industry).
I got to Biogen in 1987. At the time, Biogen had a great culture where they encouraged scientists to spend up to 20% of their time on their own ideas. I'm a very curious scientist and I was at the bench [at Biogen]. I invented a molecule, a peptide, that became a very potent inhibitor of the enzyme thrombin, which could be used as an anticoagulant.
So, I discovered this peptide inhibitor [Hirulog] that was a sub-nanomolar inhibitor of thrombin. It became a program that we took into the clinic. Ultimately this work became a program that made it all the way to the market and was sold for many years as an anticoagulant to cardiologists.
In my life, it was an amazing early experience and taste of literally inventing a drug and taking it to the clinic. I was also responsible for running the program team that took the drug forwards, which was a great experience to learn [later stage] drug development.
While Biogen didn't commercialize it directly, we licensed the drug to a company called The Medicines Company that took it to market. Ultimately it was very successful and was used in millions of people around the world. Prior to Alnylam that was my biggest accomplishment. Of course, this has been eclipsed by what we ended up doing at Alnylam in terms of developing a whole new class of medicines.
[What were some lessons learned early on in your career?]
I'm a huge believer that recently minted PhDs—or MDs or MBAs for that matter—who want to go into biotechnology, should work at a more established biotech company…not necessarily pharma because they can be siloed.
If you work at a more established biotech company, like I did in Biogen or others have done at Alnylam or Vertex, you can learn so much from a group of really experienced people.
I think it's really important for an aspiring biotech CEO or leader to get that experience before they automatically plunge into their own entrepreneurial venture. Sometimes you don’t need that experience, and that's really cool. But there's something about getting some scars on your back, learning drug discovery, learning about business development, and doing it with people that are really good.
This experience can really equip future leaders to be better positioned and more successful. That’s the advice I always give to recently minted grads who are thinking about a career in biotech…and it [working at a larger company] doesn't have to be forever. It can be for just for a few years, whatever the case might be. Then you can go off and do your own startup, go to a venture group, or join a smaller company. But I think learning [about drug development] first is important.
4. While working at Millenium, but before joining Alnylam you had a summer (2001) of reflection. What were some things that got you excited about joining as the founding CEO of Alnylam?
Over that summer, I was also getting remarried. I was going through a lot of personal, exciting things. So, there was a lot to look forward to, and I really appreciated where life was going. Also at Millennium [now Takeda Oncology] it was an exciting time—we were basically getting our first drug through the FDA approval process [Velcade]. I loved working at Millennium with people like Mark Levin and Kevin Starr—they are just some of my favorite people in the whole world. But when I got introduced to the Alnylam opportunity, I wasn’t really looking for a job. Headhunters or VCs would typically call me up, and I would always say: “Nope, not interested, I'm busy.”
But after hearing about Alnylam, I knew that the science was important. I started doing more and more reading on RNA interference. I got excited about the potential of creating this whole new class of medicines, and I knew that if we figured the technical hurdles, we would create something transformative for patients.
What really hit home for me is when I was driving to work, every morning to Millennium, I was really thinking about Alnylam could become. I kept thinking about that instead of what was going on at Millennium. I was daydreaming about: could RNAi be used to go after this or that disease? I wonder if you could deliver these siRNA molecules with lipid-based or conjugate-based approaches? I was spending a lot of time thinking about all those things. It occurred to me, at one point, that I had become infected with the desire to go do this thing. I just couldn't pass it up. I was being approached as the founding CEO, but I was still a first time CEO. So, the investors would have ultimately found somebody else. I knew it wasn't going to be an opportunity that would stick around for another year or two. I really felt it was too good of an opportunity to walk away from it: it would be like walking away in the 70s from running a monoclonal antibody therapeutics company—one that had all the founders and IP consolidated. [Alnylam] was just too enticing.
[Did you have any specific insights, technical or otherwise, for being the founding CEO of Alnylam?]
I had some ideas. For example, I felt that targeting the liver might be an easy organ to start out with given some physiological reasons—for example [the liver] is where the predominant amount of blood flow gets distributed right away. In fact, the earliest project idea I had was around targeting APOB, for familial hypercholesterolemia, which is a key protein in LDL particles. That wouldn't be a great idea because you'd end up getting fatty liver, given how a APOB transports in the body. But it was an early idea. It is sort of cool that 20 years later, one of the five Alnylam marketed products is for the hypercholesterolemia indication—now we are targeting PCSK9, but this is an example of some of that early thinking materializing over time.
5. How should new modalities or “platforms” find product market fit? Using Alnylam as a case study: is this just empiric, or are there strategies you have developed over the years to identify what will be good shots on goal?
It starts with patient unmet need—if there is no need, there is no opportunity and you might as well just stop right there. But assuming there's patient unmet need, I'm a big believer in grounding your programs in human genetics.
Genetics is so powerful and it provides you with a level of validation around the disease target that is incomparable in drug development. There are so many data points that show that drug discovery programs that are grounded in genetics have an outsized likelihood of being successful at the end of the day. So, I personally like starting with human genetics, number one, number two, because development can be a long journey. I also like having early biomarkers that you can measure in clinical development, even as early as phase one trials.
You need signs to tell you that your drug is working in humans and that you're at the right dose, and have the right posology for the drug. These are things that are really important to get done early. And then of course it's a little bit of motherhood and apple pie, you want to have a tractable path from a regulatory approval perspective, and also from a value creation perspective for payers. To me these are the key elements—genetics, early biomarkers and a tractable path for approval and reimbursement.
6. How do you keep a team (or investor syndicate) motivated in the face of setbacks (both in the underlying science and capital markets?). Can you share some strategies with entrepreneurs wrestling with this at the moment?
It starts with following the science to give you confidence that you're heading in the right direction and are in a good place. I liken this to bread crumbs along the path—they can help you one step at a time, and tell you that you are on the path to making a medicine.
Even in the darkest days of Alnylam in 2010 or 2016, when we had challenges from an external market perspective [in 2010], or we had a phase three failure [2016]—there were always important scientific data points in front of us. Data points that gave us reason to believe. I think it starts with being grounded in the science, but it also requires the ability to inspire your team when things are tough.
How do you give your team that reason to believe and remain hopeful during the darkest days of a company or technology lifecycle. This is something you learn to do from a leadership perspective. This is a little bit of that optimism that I got from my mother, which allows me to do that reasonably well. I think it’s very important.
[What were some other leaders that you learned from as well?]
One of the greatest leaders in my life that I had the privilege of working with is Mark Levin, who was inspirational. Mark taught me to lead with vision. You need to communicate a vision and mission for your company to your team that's credible, exciting, disruptive and realistic as well. It can't be quixotic. This brand of leadership can be very powerful. To me, Mark was a person in my life who inspired me in so many ways.
7. Alnylam recently announced Ph1 data about durable and potent (90%) APP KD in the brain with C16-siRNA. Why is this so exciting (what factors have limited other modalities like ASOs), and what doors does it open for Alnylam and patients in the future?
We learned we learned back in 2010 and 2011 that when we “opened up” a new tissue, like the liver, we can open the floodgates for a series of medicines.
And so the benefit of being able to target the liver, was that Alnylam had its first approval in 2018, our second 2019, our third in 2020, our fourth in 2021 are fifth in 2022. For the foreseeable future, Alnylam should have regular new approvals targeting liver expressed disease genes. These aren't diseases of the liver, but these are disease targets expressed in the liver.
Now we've just opened up the CNS, which like the liver, is a treasure trove of disease targets. Many neurological disease are due to gain of function proteinopathies, which are just so ideally suited to a silencing-based approach with RNA interference. It's incredible that this conjugation approach opens up the brain.
But then beyond the CNS there is data from Alnylam and Arrowhead showing that the whole field of delivering small interfering RNAs using conjugate-based approaches is exploding. I think that my early dream of RNAi medicines rivaling what's been done with monoclonal antibodies is going to be achievable. I think we're going to see RNA based medicines for a whole range of different diseases in tumors, muscle, CNS, heart, lung…this list goes on. This will just create a whole new wave of medicines that will ultimately make a big difference for patients. The data for the CNS is just a harbinger of what is to come.
8. Which areas of science and medicine are you most excited about seeing develop in the next 10-20 years? How will these discoveries change medicine over the course of our lifetimes?
I'm a big believer in genetic medicines. In that category I include RNAi, of course, but also gene editing, gene therapy and cell-based therapies. I think all of those technologies have got great promise and will be used sometimes competitively against each other--maybe that's the reality of how drugs get developed. But I also think that they're just going to represent a continuum of powerful tools that we have to treat, prevent and cure disease. We often never used the word “cures” before because we thought it would create false hope for patients. We actually use that word now. Look at what happened with the COVID pandemic—RNA came to the rescue in the form of mRNA vaccines. I think there's a great future for RNA based medicines. There's a great future as well for gene therapy-based approaches with AAV. I think genetic medicines for the foreseeable future will be a major part of how we design the next frontiers of medicine.
9. What is one final piece of advice for a young scientist aspiring to have a career in the biotech industry? For a trainee (grad student) what should you be doing today, what things should you focus on for post-doc and then beyond.
Number one, follow your passion. If you're passionate about making medicines and helping patients with innovation, follow it and go for it. I just encourage somebody like that to be relentless in their desire to make a difference: be the person “in the arena,” if you will, and go for it. So that's number one. Number two: ground yourself. Start out with that “postdoctoral period” of your life and your career in a Biogen, Vertex or Alnylam or Takeda: that type of company can be a great foundation to get started. But ultimately, just go for it: whether it's starting a company, being an operator of a biotech, or whatever you choose.