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David Meeker, a physician by training from a critical care speciality, worked at the Cleveland Clinic during the first part of his career before joining industry through the company Genzyme in 1994. He held many roles at the biotech and after it was acquired by Sanofi, Meeker led Genzyme as a subsidiary business for six years. Now though, he is CEO of  KSQ Therapeutics, a biotech founded in 2015 with a focus on CRISPR-enabled functional genomics.

In an exclusive interview, Meeker talks more about 2015-founded KSQ, where the company is heading, and his hopes for and hang-ups about the biotech sector as it moves into 2019.

In Vivo: What attracted you to join KSQ?
David Meeker: There were two main reasons. One, our industry suffers from abysmal failure rates. It is amazing that people are willing to invest given the low probabilities of success here.  If you look back there are cases where we could have been better informed and done better. It is still a high-risk endeavor but there are things we could know with better knowledge going in. Currently, when you run an experiment you read the literature, you think you understand the biology, you test a hypothesis, you see some activity and it confirms your hypothesis, and then you carry on down that road. What you haven’t answered in that scenario is what you don’t know. The KSQ approach is to start with no bias. In our case we are looking for targets, gene targets, to develop drugs against. You experiment by saying, “We’re going to screen all 20,000 genes.” We’re not going to say, “We think this gene is important” and test that gene. We’re just going to do all 20,000 and then let the best candidate, the best target new gene, emerge from that complete data set.
 A: We are using a much later generation approach of CRISPR/Cas9 to enable this 20,000-gene screening approach. It has been quite powerful and has yielded some interesting findings. So, that was the first piece.
 A: Then the second attraction, as always, was the quality of the people and what the group had accomplished already. Frank Stegmeier, our CSO, led oncology drug discovery for Novartis prior to coming to KSQ. He had worked a lot on genomics there. With CFO John Trzupek, the two of them have really built a remarkable team and accomplished a huge amount in a short period of time.
Q: What were the biggest changes you felt when moving from a big pharma company to a younger, smaller biotech?
 A: For me, this industry is not about big versus small. We were a team of 35 when I joined just over a year ago, but we have doubled in size, which is rapid growth. Of course, we are still an incredibly small team; however, we have 150 full-time equivalents working on our projects through more than 30 different CROs. The point being, in today’s world, you can access almost everything you need as a small company through those kinds of networks. The advantage of a large company of having their own internal science resources has been largely neutralized. It’s one of those things that conceptually we all might understand but experiencing it is different – I have seen the nimbleness with which a small company, such as ours, can make decisions and move relative to just some of the inherent bureaucracy at larger firms. It’s not that Sanofi, or any large pharma, is necessarily overly administrative; there’s just a certain level of bureaucracy that is required to manage at scale. Sanofi was 110,000 people with hundreds of products in its portfolio; the ability of a large organization of that size to run efficiently is extremely challenging and with regard to drug discovery and innovation. I think big pharma is going to be increasingly challenged as the place where innovation occurs.
Those are some of the benefits; what are the challenges for biotechs like KSQ?
 A: You live or die with your funding; it’s as simple as that. In a large company, you are insulated from failure. You have revenue coming in, you have other resources you can tap into as needed to regroup if an unexpected failure occurs. In a small company, you are completely exposed. If you are successful you’re likely to continue to be able to raise money, but if you stumble, you don’t have that same insulation. You are working with much less room to maneuver.
Q: Having moved then from the Cleveland Clinic, into the big pharma environment, and now into the biotech sector, what do you think makes for a good leader of a drug development company?
 A: The basic qualities that we all admire in leaders hold true across both large and small businesses. The most valuable attribute of a leader is a high degree of self-awareness. It is difficult to lead others if you do not know yourself. I certainly try to be highly attentive to that in my own personal leadership approach.
A: The second thing is having a mission. There is no substitute for people who are motivated by the mission. Believing in what they do – that we could cure an individual, maybe a small segment of cancer – that is highly motivating. The leader’s challenge is to connect people with that mission.
A: For large companies, it is about managing at scale. You cannot run a 100,000-person organization in a highly centralized way. My personal belief, having witnessed it, is that you need to decentralize. You need to empower leaders who are managing smaller parts of the group, otherwise you just jam up at the top and you die. There are different challenges in a small organization. This is all about working with fragile resources, right? You are always trying to balance the piece that you have and the pieces you don’t have and how to meet timelines so that you can continue to raise money. The challenges are different but the qualities that succeed, in either case, are the same.
Q:  Along those lines, KSQ raised a substantial amount in a Series C financing round last year, why do you think the company was able to attract that level of interest from investors?
 A: It has been an interesting period; the market is open. There has clearly been a disproportionate willingness to fund innovative biotechnology companies and we have benefited from that.
 A: The two biggest recent breakthroughs in oncology, arguably, are the PD-1 class and cellular therapies. KSQ is now asking the question, when you knock out a gene in a T cell, what is the impact on that T cell’s ability to get into the tumor and proliferate? And then in subsequent validation experiments we are looking at how to kill the tumor. While PD-1 works quite well, we have found a number of targets that look like PD-1 and a small number of targets that actually look better than PD-1. Despite important medical breakthroughs of our generation, like PD-1, there is still a huge unmet medical need. PD-1 just opened the door to what was possible; but as we know only 20% to 30% of patients respond and the durability of the response is not uniform, and patients become refractory. We have seen a hint as to the potential in this space, but the unmet need remains massive and KSQ is looking to disrupt that space.
A: On the cellular side, the stories so far are amazing but there is a huge opportunity to do better, and then by far the biggest need is trying to get cell therapies to work in a solid tumor environment – particularly a PD-1 resistant solid tumor. Companies like Iovance are showing us a hint of efficacy, some early signs of efficacy; where you can target the tumor with your T cell, you have a chance of getting a response. We think we can disrupt here as well.
Q:  What key R&D goals have you set out for KSQ in 2019?
 A: We have nine programs in our preclinical pipeline. We have identified targets of interest and we are actively in the process of identifying drug compounds. In the next 18 months, the aim is to have at least one of those as a drug candidate. More immediately, our goal is to do an adoptive cell therapy experiment.
A: We will take two of our targets, which had superior efficacy to PD-1 in our models, and inhibit both simultaneously (a “dual edit”) in T cells obtained from the patient’s tumor (tumor infiltrating lymphocytes).  The editing will add one step to the expansion phase of the TIL process. Our goal is to be in the clinic with this adoptive T cell therapy approach treating the first patient in the first quarter of 2020. 

Q:  How are you preparing to grow the company in the years ahead?
A: We will remain incredibly focused on the drug discovery effort.  We have a powerful platform but unless we can translate the knowledge obtained from that platform into therapies we will not have realized its potential. Second, we will be extremely thoughtful about our management of capital.  Time is more valuable than money in the setting where you believe your approach can make a real difference to patients. We want to be aggressive in our discovery and development efforts and take calculated risks where it makes sense to accelerate our progress.  Finally, we do have a powerful platform and we will continue to invest in its potential expanding carefully into new areas.  For example, the logical next step where we have done a significant amount of work already is in the area of autoimmunity.
A: There is a more practical challenge in the industry… Manufacturing capacity for cell and gene therapies is tight. So, there are simple, practical issues about finding a CMO partner to work with that has capacity. That will be solved, industry is rapidly working to build capacity and it will catch up. But that is a practical near-term element.
A: Also, cutting-edge technologies are always at risk, not only for what happens within your own experiment but what happens to the field in general. For example, people were doing gene therapy experiments many years ago, but one bad outcome in a gene therapy trial put a deep freeze over gene therapy programs in general. There is always the risk that something could happen in a new area of development that could delay the field. Of course, delays when you are a small company can be devastating.
Q: As a smaller company, what is your approach to partnering?
A: There are two reasons you partner.. One, you partner out of desperation — you need money and therefore you sell the rights to your most valuable asset in order to survive. The second, the strategy everybody would like to pursue, is that you partner when it makes sense.
A: We clearly have more in our pipeline than we can take forward on our own, so we will partner at some point. My goal is to partner when it makes sense. In this case, that would mean taking what we have forward to proof-of-concept. Once we have defined whether we have a drug or not, it becomes much more straightforward to have a discussion with a potential partner about the value of a program and what a partner could bring to the equation. We would be looking for more in a partnership than money – funding can be raised in different ways – we would be looking for a partner who could bring in something we do not have such as capabilities, experience or reach.
Q: Aside from competition in the IO space, what are your greatest concerns when you look ahead to 2019?
A: The US health care system is challenged. We can get the best health care in the world in America, we just cannot get it consistently and universally. The ongoing debate around drug pricing has some areas of real concern. I worry that if price controls – structures or legislation – are imposed, it will have a chilling effect on innovation. What people lose sight of is the vast amount of money people are willing to put at risk in this environment, but this is possible because of the potential rewards. However, I am also concerned that we as industry do not universally take a responsible position in the pricing of our products. By that I do not mean pricing for innovative products; it is the year-on-year price increases, with no added value. This practice is not sustainable, and I think it will be damaging to us as an industry in the long term.

Q: What are you looking forward to this year and in the future?
A: More breakthroughs in gene therapy. I think we are on the cusp of seeing broad breakthroughs in gene therapy, which are going to transform treatment and the health care system. Also, in cancer, cures will come from immuno-oncology. So, despite immuno-oncology fatigue, it is the right scientific approach, and I think we will see the next wave of breakthroughs here and I believe that KSQ will be a part of that.

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