ABSTRACT
As a maturing field that continues to provide fundamental insights into cell physiology, autophagy is also beginning to attract considerable interest from the biotechnology/pharmaceutical sector. For this Editor’s corner, I thought it would be both useful and interesting to talk with somebody who has spent a lot of time in the commercial sphere, working on autophagy and related processes. I was fortunate that Dr. Leon Murphy, Chief Scientific Officer at Casma therapeutics, was willing and able to answer my questions. In addition to his insights on the commercial interest for autophagy, Dr. Murphy also shared his personal experience on the scientific life working in large and small pharmaceutical companies.
KEYWORDS: Autophagy activation, MTOR, CASMA, biotechnology, chemical tools
Introduction
Nicholas T. Ktistakis: Your company, Casma therapeutics, is one of the few biotech/pharma companies that has a strong focus on autophagy. Can you tell us what aspects of autophagy you find attractive from a commercial point of view?
Leon O. Murphy: After more than 30 years of fundamental research into autophagy it has become clear just how important this pathway is for normal physiology but also how it can be leveraged to treat a number of human diseases. I will add that in the last decade in particular, the field has become much more molecular – by which I mean that we now have a clearer picture of the mechanisms that are used in the cell to regulate each step in this pathway. Another exciting development has been the realization that some autophagy genes have important roles outside of autophagy. This type of information is critical to help shape a therapeutic strategy that will lead to the development of a selective autophagy modulator.
NTK: This is a very important point. You mean that we now understand both the signaling but also the structure of the proteins that are involved in this process.
LOM: Yes, the structural organization of autophagy proteins and complexes is a very active area of investigation and one that directly can guide the discovery and optimization of therapeutics. I would also add that from a commercial standpoint the opportunities are very significant. We have a strong conviction that autophagy enhancement will benefit patients with devastating forms of neurodegeneration and other chronic diseases. Across the industry, there is a big appetite (and a need) to bring novel approaches forward to treat patients with these types of disorders.
NTK: As a follow-up to this: a few years ago, during a Keystone meeting, there was a discussion session on autophagy as a pathway of commercial interest, and whether activating it or inhibiting it may provide the most straightforward route to a useful molecule. In that discussion, the majority of scientists opted for an activating molecule – do you have any thoughts on that?
LOM: I think I was present for that debate! At Casma we also agree that therapeutic enhancement of autophagy, either general enhancement or more selective, is the way to go. In contrast to this, there have been many important publications documenting the deleterious effects resulting from ablation of autophagy in mice. These reports indicate that any therapeutic approach to inhibit autophagy may have significant safety and health issues. With that said, it may be possible to develop a dosing schedule that permits the use of an autophagy inhibitor in humans but I still believe this will be challenging. Perhaps a tissue- or cell-type specific delivery approach is the way to go for autophagy inhibition, especially in a chronic dosing setting. Getting back to autophagy enhancement, there is strong evidence from model systems that this will be beneficial in many settings, so this is a promising direction to pursue.
NTK: Do you think that the investor community is sufficiently educated on autophagy as a potential pathway for drug discovery?
LOM: First of all, I believe that autophagy has now entered everyday lexicon. You go onto YouTube and find lectures on our pathway and many people touting the importance of intermittent fasting in order to capitalize on autophagy. The Nobel prize in 2016 was particularly important for putting our field on the radar of the general public and investors.
Getting back to the question: I have been in the fortunate position over the last 5-6 years to meet with many biotech fund managers who are interested in our work at Casma and autophagy in general. I want to point out that the vast majority of these investors have very strong backgrounds in biomedical research and drug development so these discussions are always enjoyable and I almost always learn something from such meetings. I recall that in the beginning, autophagy was quite new to some investors while others came with the impression it was a cell death pathway or even an extracellular process. Finally, some investors had been following the space for a number of years and were able to dive right into the mechanics of autophagy and ask the really tough questions! I believe that Casma and other biotech companies in this space have played a key role in creating an awareness of the therapeutic opportunity here for potential investors. It has been very rewarding. It goes without saying that early-stage companies like Casma are exposed to the ups and downs of the market and right now the biotech sector is in a particularly challenging time. With that said, strong teams and strong science always get recognition from investors, even in a difficult market. Casma has been very fortunate to be supported by high quality investors who understand what it takes to innovate in a relatively nascent area for drug development.
NTK: Another related question to touch upon is how big pharma views autophagy.My own feeling is that for most larger companies this is still not of immediate interest.
LOM: Everyone can see the future potential in autophagy as a treatment option for several diseases; however, most pharmaceutical companies still view entry into this space as risky. This is because some very fundamental questions around autophagy targets and indications remain to be answered. I expect that this situation will change now that significant funding has been dedicated to a number of autophagy biotechs attempting to answer these questions. Hopefully encouraging data will emerge that will illuminate a robust path to the clinic. We will then see renewed interest from larger companies in tapping into this potential.
NTK: From my academic experience, I would say that the commercially available tool molecules for autophagy research are not very plentiful or very specific, with the exception of the compounds that inhibit MTOR. First of all, do you think that this is true, and, second, if it is true, what are the reasons? Lack of effort, or difficult targets?
LOM: Generally, agree. It is easier to think about inhibiting a protein and therefore autophagy, than activating it so this is why several companies went in this direction to inhibit ULK, PIK3C3/VPS34 and ATG7 as a cancer treatment (~2006-2013). These inhibitors are now widely used in the field but we should always remember that their targets have important roles outside autophagy. So, the inhibitors will also affect the non-autophagy functions, which is something to keep in mind.
Past efforts to discover autophagy enhancers focussed mainly on cellular phenotypic screens; however, the output from such efforts has been disappointing. During this early period, we also lacked a detailed biophysical understanding of the core machinery – specifically how things are organized in 3D and how dynamics can have an impact upon the spatial geometry of complexes – we are starting to see this level of detail which should help future efforts. The bottom line for me is that we need better pharmacological probes that act proximally to the core machinery – not multiple steps upstream in the cell. With this mind-set, superior tools will emerge that enable an even better understanding of the biology … as well as advancement of drug candidates.
NTK: Would you say that we are close to finding small molecules with the properties that you described above? They will be useful both commercially but also for academic labs.
LOM: I would say that the work required of setting up the assays to find those molecules is still hard, but the molecular understanding of the pathway and the machineries involved has encouraged several companies including Casma to work in this space.
NTK: I notice on your website that you have some positions open for what you call Casmaniacs!
Speaking in more general terms, and given your personal experience, how is the scientific life for those contemplating a move to industry?
LOM: There are similarities and differences between small and large companies. One similarity is that, depending on the company and the role that one pursues, the environment can be very scientific, intellectually challenging, data-driven and always aligned with developing treatments for human disease. A major difference is that in large companies there are many research programs, sometimes well over 100, so getting people interested in your data can be difficult at times. In small companies there are often only a few programs and there is more immediate pressure to get to data that will indicate a path forward or a No-Go decision. In such an environment one tends to feel success and disappointment more acutely and frequently! Therefore, it is important to think about which environment is right for you.
NTK: I also wanted to discuss very briefly publishing while working in the commercial sector. I know that you have always published very nice papers, but is this a luxury in some sense?
LOM: In some ways this is a philosophical thing. There are companies that are completely opposed to publishing, often for legal reasons, and others that actually encourage it. I tend to be in the second category, because I think that publishing is important for the visibility of the company and for the research team to be exposed to and integrated within the scientific community. With that being said, discovering and developing drugs is our priority and typically publications are only considered when efforts are sufficiently advanced into the drug discovery pipeline. While working in a company you do have to accept that despite being involved in some very amazing fundamental research, not all of this will end up in scientific publications.
NTK: For fresh graduates or young post-docs contemplating a move to industry and wondering about this question, what is the best way to broach it during interviews?
LOM: As a student or postdoc, developing and advancing your project to a publication is the goal. Before attending an interview with a company, you do need to reflect on what motivates you to pursue a career in industry. If your sole motivation is to publish then developing your career in industry could be challenging. During the interview, seeking insights on company publishing policy has to be done right. Top tip: this should not be your first question! Perhaps later in the interview one could ask the following: “I noticed that you have published some nice work in this area, how exactly did this happen”? Alternatively, when interviewing with a company that does not publish frequently you could ask “I see from your website that you are very active in this space, yet unlike other companies you have not published any of your work. Why is that?” The conversation should flow from there.
NTK: Please tell us a bit about yourself, your background, and your current role in the company.
LOM: I grew up in Northern Ireland and after completing my undergraduate degree in biochemistry decided to make the leap over to the US for graduate school and postdoctoral training. My training during this period was in cancer cell biology and signal transduction mechanisms. During the later stages of my postdoc at Harvard Medical School I was fortunate to be involved in a collaboration with a local pharmaceutical company which opened my eyes to things that I liked and did not like about potential roles in a company. In 2004, I joined Novartis in Cambridge Massachusetts at a time when they were building out a new site. It was an exciting time, very dynamic and innovative, almost like an early-stage biotech company. At this time the Novartis leadership were investing heavily in understanding fundamental mechanisms that underly human disease so this was a really perfect environment for me to get a formal training in drug discovery and development. I was particularly fortunate to have excellent mentors and role models – something that is very important for career development in any environment. Within a few months of joining Novartis, I became more and more convinced that autophagy modulation could be a new approach to treat disease and so this set me on my way.
In 2017, I had a unique opportunity to join Third Rock Ventures in Boston. Third Rock is a biotech fund focused 100% on company creation. There I was contributing to the seeding of Casma but also other companies. In 2018, as the second employee, I helped to launch Casma and then joined the company as Chief Scientific Officer. We are currently located steps away from MIT in Cambridge Massachusetts.
NTK: What is your typical day like at Casma?
LOM: It sounds cliché … but there is no typical day in an early-stage biotech company. We are very data- driven and unlike in much larger organizations we make decisions rapidly and then focus on the next series of studies with maximal alignment to get answers quickly. Like most scientists I live for moments where the team generates an amazing or surprising piece of data. The emotions associated with these events are quite special because there is so much more at stake in a small company compared to a larger and more established organization where “nice” data can get lost.
NTK: I am curious to also know how frequently you have to make big decisions, for example “this program needs to be stopped” or “let’s put a lot more effort into this work which looks promising”?
LOM: I would say that we make important micro-decisions almost daily, and I don’t always get involved in those since we have very experienced and capable scientists on the team. In terms of bigger strategic decisions on targets or molecules, this probably happens every few months, and although we do have to make hard decisions at times, we always try to be objective and data driven.
NTK: You commented that there are no typical days in a small biotech, but can you give us a sense of your daily schedule?
LOM: I usually start my day at Casma around 8 AM, catching up on some e-mails and meeting with scientists to review data and provide support. Often, I will join the CEO in meetings with potential investors and corporate partners. This can take up as much as 70% of my time. On some days we will also have larger format meetings where the leadership team or even the entire company comes together. For many years I used to remain in the office until well after 6 PM but now I aim to get home by that time so I can have dinner with my family. Most evenings I will spend 1-2 hours responding to e-mails, reviewing data, work on presentations or even present to investors and partners in Asia.
NTK: Thank you very much Leon, for this wide-ranging and very illuminating interview.