Great siRNA Science Or Savvy Business Acumen? You Need Both
By Craig Tooman, president and chief executive officer, Silence Therapeutics
In the two years since I was appointed CEO, Silence has made remarkable strides, with two wholly owned short interfering RNA (siRNA) therapies now in clinical trials, where they are generating very exciting data: zerlasiran, a cardiovascular disease program in Phase 2 for elevated Lp(a), and divesiran, a Phase 1/2 program for the rare disease polycythemia vera (PV). We also have one partnered program under our AstraZeneca collaboration in the clinic and a pipeline of other siRNA programs in earlier stages of R&D.
Moving from research into clinical development was a huge transformation for Silence, as it is for any company. But at the same time we were transforming on this front, we were also transforming on another: delisting from the AIM exchange in London and focusing our efforts on our Nasdaq listing in New York.
It makes sense that these transformations occurred together, because clinical development is expensive and needs to be funded. But as we’ve navigated this doubly transformative period, we faced the challenges of evolving our scientific legacy and steering the company into the new areas of clinical development and potential commercialization. Here, I take a look back on this transformative period: the challenges we faced, how we met them, and the great place our efforts have brought us.
Juggling Multiple Challenges In an Emerging Biotech Company
I’ve always been part of transformation, even if I haven’t always signed up for it. For example, I was part of a team involved in merging Pharmacia and Upjohn — two massive companies on their own — and ensuring they operated efficiently. This is one of the greatest transformations I’ve been part of, and I observed all the elements that went into it. At ILEX Oncology, a cancer CRO, my first project was transforming the company from a contract development organization, responsible for developing products for other companies, to focusing on developing our own drugs. This took ILEX from a 20%-25% margin to a 90% margin business, while instilling the creative spark that comes with developing an internal pipeline. I always look for a company’s innovation and the points of differentiation, then figure out how best to leverage those for the benefit of the company and, ultimately, the patients we serve.
When I arrived at Silence (as CFO in 2021), the company had exciting assets, but they were underfunded and had yet to reach the clinic. Advancing the best assets into clinical development, and the manufacturing and CMC side that comes with it, requires the skillset to execute the clinical development programs and to find funding opportunities. Transformation almost always comes back to the funding.
We were dually traded on AIM and Nasdaq, but as we gravitated toward the U.S. biotech funds, we delisted on AIM because the market was too illiquid, and we didn’t believe we were getting the right visibility and appreciation for our science. This brought with it certain challenges, including that of maintaining the stock’s value during and after delisting.
Successful financing required increasing awareness of the company’s science, assets, and platform technology. Our research has been conducted in Berlin for over two decades; it’s a great foundation but was relatively unknown, even in Europe. When I joined the company, I surveyed a large network of leading biotech investors and sell-side analysts to help inform me on how to raise awareness of our science so that we could finance the innovation.
We also faced the challenge of funding our clinical programs without neglecting our earlier pipeline. Data is the lifeblood of the biotech industry: it drives interest from the markets and it’s necessary to fund the pivots and the programs. But during this period, it was difficult to start (or buy) new programs because shareholders were not keen on diluting their investment. We had to be creative about building our early pipeline, such as retrieving preclinical assets from our Mallinckrodt partnership, while our clinical programs advanced.
All of this happened during one of the toughest funding environments I’ve ever encountered in my 30 years in biopharma. I had to work with my team to dial back the spending on some of our R&D programs. These prioritizations are not always easy for employees, and we were pleased we didn’t have to do any further restructuring.
Another challenge is that the gene silencing space is very competitive and very technical. That combination means spending the right amount of time finding the best people and working to keep those people engaged and inspired.1
Look, Learn, And Then Pick The Wins
One of my first bosses used to say, “No matter where you are, there you are.” I love this phrase because it reminds me that until I actually step into a new company — Silence is my eighth — I don’t really know what I have, what the growth opportunities are, and what the challenges will be.
As an analogy, I think about this as a vegetable cart: ultimately, my goal is to sell the best vegetables, by which I mean our therapies. Sometimes I inherit a full cart; sometimes I have to grow the seeds before I have vegetables. When I first arrive at a company, I spend a great deal of time — probably more time than a typical CEO — talking to the stakeholders, including shareholders, partners, board members, and employees, to understand what they think and need, and to assess the state of the vegetable cart, or company. What parts are in good shape? Where can we grow it out? Where are there gaps in skillsets, technology, board membership, employees, and elsewhere? Which ones need to be filled?
I don’t rush into making those decisions. I take time — but not too much time — to evaluate the situation and opportunities, and I study examples of what could and could not work. I want to be thoughtful about our next moves, because we can’t do it all. I want to set up a series of wins for the company.
Here are a few examples of these wins:
In my first week as CFO of Silence, the company was discussing financing for $90 million, the same amount as it had tried but failed to raise previously. I wasn’t interested in repeating past challenges. After talking to the stakeholders, I recommended raising $30 million, which surprised some people, but I wanted to start a series of successes that would energize the whole company. The financing round was so successful we upsized and raised $45 million. This opened a whole new dialogue around how we fund developments.
Another example is our AIM delisting: you might imagine our shareholders in the U.K. would dislike the idea because stock often loses value in this kind of transition, and in 2021 the U.S. markets were especially tough. We spent a lot of time with our U.K. shareholders to understand their needs and enlist their support. I also spent countless hours reviewing case studies on what other companies had done right (or wrong) and meeting with new institutional healthcare funds ahead of delisting. The result: we ended up maintaining, even increasing, the value of our stock as we delisted and had some top U.S. healthcare funds take positions in Silence within weeks afterward. This sparked interest from other funds and created momentum for our expanding global shareholder base.
Relationships with our partners are equally important to me, and I’ve spent a lot of time getting to know AstraZeneca, with whom we’re partnering on an undisclosed clinical program, and Hansoh, our partner in China. We also partnered with Mallinckrodt on complement-mediated diseases. When Mallinckrodt shifted their business model to focus on revenue-generating products, we reached out to Mallinckrodt, as a partner, and said we’d like to bring back two of the partnered preclinical assets and keep them as Silence opportunities. I counted this as a win-win for both parties; Mallinckrodt wasn’t focused on early-stage assets anymore and our research team was getting back two very promising and exciting preclinical programs, without having to pay an up-front fee and potentially dilute our stakeholders’ investments in our clinical programs. As I mentioned earlier, siRNA is a very competitive space — as a leader you need to be proactive and always think creatively for ways to keep your team engaged and feed your pipeline, particularly when resources are tight. This is a great example of how we were able to leverage a collaboration that was winding down to do both.
While my approach is often biased toward how to fund innovation, it’s also fueled by a keen love of science, because that’s the foundation of everything we do to bring products to patients. I love the time spent with my R&D team and on strategic discussions about the long-term possibilities for our science and where we can innovate internally. I often send ideas to my R&D team and others about the potential wins I envision and welcome their ideas on how to best develop our programs. All CEOs know the company’s technology and seek to expand. I aim to do this while keeping it well-funded, even when the environment is tough.
I also resist the pressure of disclosing data readouts prematurely. For example, shareholders had seen our positive data readouts on Lp(a) and so were equally excited about our PV program because this could position us as a true platform company. I had a lot of pressure to disclose the early data we were seeing from the ongoing Phase 1 open label study but at the time it was just a handful of patients with limited treatment time on study. I understood their excitement but said I didn’t want Silence to become an “anecdotal” company that shares data on a small number of patients without adequate follow-up. I’ve seen some of our predecessors do that, only to have subsequent data readouts that didn’t replicate the initial findings. Silence has worked too hard on the research and clinical execution of the program to risk that. So, I waited until we had data on closer to 20 patients with adequate follow-up, which put us on firmer scientific ground and helped people better understand the technical programs we have and the kind of partner we are.
It's An Evolving Transformation
Change is never easy. But Silence is a great example of what can be achieved when you have strong fundamentals, adequate funding, and the right team in place to execute.
We successfully navigated our AIM delisting while maintaining the value of our stock, as well as overcoming a challenging U.S. funding environment to raise $200 million over three financings. I give full credit to our employees who watched us navigate the tough financial waters and hung in there with us, because without their support it would have been much more difficult. The funds will allow us to advance our two proprietary clinical programs, which are already generating exciting data with more to come.
Awareness of our science and technology is increasing and is moving the company onto the global stage. Increasing awareness about Lp(a) over the past couple of years, thanks in part to some pre-marketing by the bigger pharma players in the space, has brought more attention to our zerlasiran program. People see Silence as an independent company with an innovative, exciting asset in a very large and competitive arena. This has enhanced the value of the program and contributed to the growth in the value of Silence.
Our second program, divesiran, is first-in-class, and thus best-in-class, for PV. It shows our technology is now working in three very different disease areas: cardiovascular, rare blood disorders, and an undisclosed area with AstraZeneca. The industry is now talking about us as a platform company, not an asset company, and I’m proud of the researchers and developers for getting us here.
Increased visibility brings up the importance of creating and maintaining a solid reputation with our investors and partners. We’ve de-risked our programs and enhanced their value for the company, and along the way demonstrated ourselves to be a scientifically rigorous company and partner.
As a leader of a fast-growing biotech company trying to compete in a highly competitive space, you need to make sure you understand your business inside and out, identify the areas of strength so you can pick the right wins, and most importantly, make sure you have the right people to execute and the funding to see you through. There will be moments (often many!) in between the data readouts when you’ll be under immense pressure to release news and get the stock price up. My advice: resist that temptation and keep your eye on the ball. Don’t jeopardize the integrity of your science and respect of your organization for a quick spike in the stock price. True, sustainable value creation is worth the wait. A key opinion leader recently commented to me that “siRNA is really revolutionary, not evolutionary.” I agree it is a modality that will continue to grow because it is proving to be safe, efficacious, and durable. We’ve been working on it for 20 years; now, many companies want this technology for their own pipelines. I look forward to being part of this exciting and rewarding future and seeing patients with genetic diseases experience the benefits of siRNA therapies.
References
- Lau, F. D., & Giugliano, R. P. (2022). Lipoprotein (a) and its significance in cardiovascular disease: a review. Jama Cardiology, 7(7), 760-769.
About The Author:
Craig Tooman joined Silence Therapeutics as chief financial officer in 2021 and was appointed president, CEO, and executive director in 2022. His experience in the biopharmaceutical industry spans more than 30 years, including 15 years as a public company CEO and CFO. Prior to joining Silence, he served as CFO and COO at Vyome Therapeutics. Prior to his tenure at Vyome, Tooman served as CFO, and then subsequently as CEO and board director, of Aratana Therapeutics, where he successfully negotiated a merger with Elanco. Before Aratana, he served as the CFO of Enzon Pharmaceuticals until its acquisition by Sigma Tau, and prior to that led the $1.1 billion M&A initiative and integration of ILEX Oncology and Genzyme. He has also held key positions at Pharmacia and Upjohn. Tooman currently serves on the Supervisory Board and the Audit and Remuneration Committees of CureVac. He also serves on the Board of Directors of Ondine Biomedical. He earned a BA degree in economics from Kalamazoo College and MBA in finance from the University of Chicago.