I’ve read John Maraganore’s essay “Reflections on Alnylam” a few times and I recommend it to all my CEOs.
Here are 12 key lessons from building and leading an iconic biotech company.
1. Trust that voice.
If you can’t stop thinking about it, you have to do it…
“Driving into work each morning, I couldn’t stop thinking about the potential of RNAi as a new approach. Yet many friends and colleagues (including my two older children) thought I was making a mistake and cautioned against the move. After the ‘genomics bubble’ burst, the biotech sector was in a dark winter, and investment in novel science was highly disfavored. Millennium CEO Mark Levin who was a friend and a mentor, encouraged me to pursue what excited me most. What I kept coming back to was that if the technology hurdles could be conquered, RNAi therapeutics were too great of an opportunity to walk away from.”
2. Have a clear vision and mission.
Pay attention to the subtle distinction here: The vision is the dream, your true north. It inspires you and keeps you going. The mission is what the company does and how it’s going to achieve its vision.
“At my first board meeting as Alnylam CEO in December 2002, I presented my vision and mission to crystallize the company’s aspirations and direction. This was something Levin had taught me at Millennium. Our vision: Harness a revolution in biology for human health. Our mission: Build an independent, top-tier biopharmaceutical company founded on RNAi. Remarkably, those official words have not changed since.”
3. Always stay lean and hungry.
Constraints can spark creativity, resourcefulness and drive. The Alnylam team had no other option but to make it work—for patients and themselves! John’s focus on independence, urgency and impact all come together here:
“These remarkably different outcomes underscore the power of culture in biotech. At Alnylam, we were willing to take appropriate risks, advancing even ‘imperfect’ molecules into development to safely learn from early human studies. Furthermore, as a focused pure play, Alnylam had a ‘fear of mortality’ that made it essential for us to succeed in bringing RNAi therapeutics to market. But Sirna was part of a larger company, needing to fulfill certain criteria around drug candidates, and RNAi was very far from a ‘life or death’ proposition. The acclaimed management consultant Peter Drucker once claimed that “culture eats strategy for breakfast.” In the case of Alnylam’s story—and perhaps many biotechs—that was an understatement!”
4. In biotech, you IPO to build, Not to celebrate.
John: “I knew from the beginning that Alnylam would need to raise substantial capital from both investors and pharmaceutical partners to bring RNAi therapeutics to patients.”
The above explains the below:
“IPOs are often romanticized by company management and boards as a special ‘Kitty Hawk’ moment, but in reality they are simply financing events. To us, it was key that we would have sufficient news flow with science and pipeline progress, and partnerships to garner continued interest by public investors. We were confident that we would.”
5. Pharma, all I need is your money and your name.
This is what a pharma alliance is: Dear pharma, give me your money and your name, so I can get more money to get this thing to the patient and realise my vision. And don’t worry, this will be a win-win. I love you, Biotech.
Alnylam also benefited from partnerships with major pharmaceutical companies. Having watched Millennium’s remarkable deal-making over the prior decade, I recognized that pharma alliances were mostly about funding and external validation and, if structured correctly, could be associated with a minimal ‘tax’ on the company’s abilities to advance its own science and pipeline. Although there are notable exceptions, rarely do partnerships provide the ‘big brother’ benefits (such as drug discovery and development expertise) often advertised.
6. During your 15+ year journey many will lose faith in you.
Just soldier on and “keep a copy of that article by your desk”…
“The RNAi therapeutics downturn began in September 2010, when Novartis declined to exercise its $100 million option to acquire broad nonexclusive rights to Alnylam’s technology. After this, a combination of leadership changes and recession-driven profit-and-loss pressures at Roche led it to jettison its RNAi investment after just a three-year, toe-dipping sojourn. To say the least, the external sentiment about RNAi turned sharply sour. In early 2011, New York Times science reporter Andrew Pollack described it best in an article titled “Drugmakers’ Fever for the Power of RNA Interference Has Cooled.” I keep a paper copy of this article by my desk to this day.”
7. If you ever have to do the most painful thing in the world, do it with empathy and compassion.
It was not their fault. You know that. It was not your fault. They know that. All you have to do is take care of your most valuable asset: your people.
“We had no choice but to reduce our workforce so that we could ‘live another day’. In one of the most painful decisions of my career as CEO, we let ~25% of our workforce go in September 2010 and then another ~33% at the start of 2012. I learned the importance of dealing with a tough moment like this with empathy and compassion. Barry and I actively worked to find new roles for all our departing employees. We kept a list of affected employees and their new potential job prospects, and reviewed it weekly at our management board meeting. I personally reached out to many contacts across the industry to find homes for our departing people.”
8. Always trust your people’s judgement, especially when the world is on fire.
When you’re working on the frontiers of science, no manager has the answer. Or if someone does, that will be probably your amazing people who are working close to the problem.
“This showed some early promise, but we were again hampered by a lack of potency, and the longstanding investment in conjugates was wearing thin. In a memorable meeting in my office, Mano appealed for “one last experiment” to evaluate greater stabilization of the siRNA backbone as a way to achieve enhanced potency. Akshay was equally vocal about recognizing the potential for conjugates and having a healthy respect for the challenges of developing an intravenous LNP-based delivery platform. I had learned over the years to listen to my colleagues; after all, we were on the frontiers of science together, and no one had all the answers. I consented to continue the GalNAc effort and realize this last experiment’s conclusion. The bet paid off!”
9. Free up your people and let them play.
When your company’s vision is to “harness a revolution in human health”, you need innovation, i.e. kainotomia, i.e. “a new/fresh cutting”. Let your team cut away!
Aristophanes first used kainotomia, the Greek word for innovation, in 420 BCE in The Wasps. As a satirist, he mocked innovators as being unusual members of society. This resonated with Alnylam, especially in the early days, as many people questioned the likelihood of our succeeding with RNAi therapeutics. The spirit of kainotomia was our rallying cry to encourage creativity by our scientists and clinicians, but we also applied it across disciplines. We created a ‘20% time rule’ (something I had learned from my days at Biogen in the 1980s), encouraging our scientists to devote as much as one-fifth of their time to pursuing their own ideas. We explicitly discussed kainotomia as one of the key principles in our core value of ‘Innovation and Discovery’.
10. Empathise with stakeholders and win them over again.
Investors and partners have fears just like everyone else. If they’ve lost faith in you, do whatever you have to do to ease their fears.
“I convened members of my core team, including Barry, Akshay and Sara Nochur, our head of regulatory affairs, to discuss a shift of focus from platform to pipeline. I was convinced that the only way to restore confidence in RNAi was to demonstrate unassailable human POC results. Using the analogy of hearing jingle bells and believing in Santa Claus (from the children’s story The Polar Express), I reasoned that our external stakeholders needed to hear the ‘bells’ of human data.”
11. March your team with a clear and focused strategy.
The 5×15 strategy helped everyone push in the same direction during a critical time for the company. And it didn’t lack ambition. A 2×15 or 3×15 strategy would have sent the wrong signal: “we’re aiming for survival…”
“We discussed communicating a set of five-year goals at the upcoming January 2011 J.P. Morgan conference. I wanted to propose a new strategy called ‘Alnylam 5×15’, with a commitment to advance five RNAi therapeutic programs into clinical development by the end of 2015. […] The team pushed back on this. With only one liver-targeting program in development at that time (ALN-TTR01), and no human POC data in hand, the team suggested that ‘2×15’ or ‘3×15’ might be a more manageable goal to promote publicly. I disagreed, saying that a reduced number of targets would not excite our stakeholders nor motivate our team. And, so, Alnylam 5×15 it was! Our research organization rallied behind the new strategy.”
12. Always be transparent.
This is not just about protecting the trust of your partners. No, no, no. This follows directly from the vision. How can a patient-centric company, embarking on a journey to “harness a revolution in biology for human health”, not be transparent?
“While ENDEAVOR was enrolling, we heard reports of worsening neuropathy in the ongoing revusiran phase 2 open-label study […] Out of the abundance of caution, we asked the independent Data and Safety Monitoring Board (DSMB) of the ENDEAVOR study to conduct an unblinded assessment […] The DSMB had recommended that we stop ENDEAVOR, not due to a neuropathy finding, but due to an imbalance of mortality against the drug arm. We immediately moved to discontinue the study. Having just hired Yvonne Greenstreet out of big pharma as our COO, I asked her to coordinate our efforts in ensuring effective communication with our many stakeholders. […] We launched an internal investigation to learn more […] We achieved a remarkable level of transparency throughout this trying and uncertain period.”