Advancing Tomorrow’s Cancer Medicines: Jacob Van Naarden Talks with Ken Herrmann and Johannes Czernin About Corporate Approaches to New Therapeutics Development

Jacob S. Van Naarden; Ken Herrmann; Johannes Czernin

doi:10.2967/jnumed.124.269354

Ken Herrmann, MD, MBA, from the Universitätsklinikum Essen (Germany), and Johannes Czernin, MD, from the David Geffen School of Medicine at the UCLA, talked with Jacob S. Van Naarden, executive vice president and president of Lilly Oncology for Eli Lilly and Company (Indianapolis, IN). In this role, Van Naarden oversees all aspects of oncology, from discovery through commercial development. He joined Lilly in 2019, when the company acquired Loxo Oncology, Inc. (Stamford, CT), where he was the chief operating officer. After the acquisition, he played a key role in establishing the oncology research and development program. He had previously worked in various biotechnology investing, operational, and advisory capacities, including positions with HealthCor Management, Aisling Capital, and Goldman Sachs (all in New York, NY). He received his undergraduate degree in molecular biology from Princeton University (NJ).

Dr. Herrmann: Thank you so much for taking the time to talk with us. Can you give us a bit of background about yourself, your career, and how you become the head of oncology at Lilly?

Mr. Van Naarden: I started out in the basic sciences in biology and genetics. I planned to get a PhD or go to medical school. I ultimately found the intersection between sciences and the corporate world very intriguing and wanted to learn more before deciding on a final career path. So, I started working on Wall Street right away at one of the big banks advising companies involved in life sciences, with a focus on small biotech but also some large pharma companies. I focused on buying and selling businesses, raising money, and learning the basic nuts and bolts of corporate finance and business concepts. I wanted to better understand the small company world. How does a small company raise money? How does a small company take innovation forward? One of the things I was observing was that so much innovation happens within small companies that are then purchased by larger companies.

I left the bank after a few years and went to a life sciences–focused venture capital firm, which was a formative experience. There I saw 250–300 company pitches per year. These were tough times, after the global financial crisis, and many companies were struggling to raise money. I gravitated toward cancer medicine, and it was from there that I joined a colleague who had started a company named Loxo Oncology. We built this company together. The idea was to create selectively designed small molecules. We raised money and went public, and we got our first medicine approved. We had a second medicine that was nearing approval and a third that was just entering the clinic when Lilly approached us and wanted to buy the company. I had a lot of pride in the drugs that we created and wanted to stick around to see their impact on patient care. And I encouraged our team to also hang around to find out whether there was more to do. Over the ensuing years, we took the culture and decision-making speed of a small company and married it with the culture and great people that had been at Lilly a long time.

Jacob S. Van Naarden

Dr. Herrmann: Was the first approved Loxo compound the neurotrophic tyrosine receptor kinase (NTRK) inhibitor?

Mr. Van Naarden: The NTRK inhibitor was first, the rearranged-during-transfection inhibitor was second, and the Bruton tyrosine kinase inhibitor was third. They’re now all approved medicines.

Dr. Czernin: How do you go about target discovery in cancer research? Also, do you believe the cellular surface has been mapped out; that is, are there many more targets to be discovered?

Mr. Van Naarden: If you think about targets as single-gene alterations that are very clearly drivers of cancer, you can often get high and durable response rates. But I do think that most if not all of these low-hanging fruits have been plucked.

Then think about synthetic lethality relationships. Some have been very difficult to drug; others have been more druggable. But the preclinical synthetic lethality hasn’t translated very well clinically. Then you get into the other target classes that rely a little bit less on biology. I would posit that, like the targets we have chosen for antibody–drug conjugate (ADC) and radioligand therapy (RLT) development, they don’t need to be cancer drivers. You just need them as mechanisms to get your payload to the place where it needs to be. Think trophoblast cell-surface antigen 2 (TROP-2) or B7-H3—these are not really cancer drivers. They just happen to be overexpressed on cancer cells. Even within the ADC world, you have substantial limitations. It has to be a cell surface cell receptor, it has to internalize, and you need enough tumor-to-normal ratio to optimize the therapeutic index. If you apply those filters, there aren’t that many good ideas, which is why there are several TROP-2 ADCs and several B7-H3 ADCs and a growing list of nectin-4 ADCs, including ones we’re working on.

With RLTs you suddenly have at your disposal intracellular targets, intracellular proteins, as well as cell surface receptors that don’t internalize. Now the aperture has widened considerably, and I think this is highly interesting. As we look at the portfolio of RLTs that we hope to build, we have programs against targets that have no implications in cancer biology at all. They just happen to be overexpressed in cancer cells for reasons that may be happenstance.

Dr. Herrmann: Lilly made a splash in 2023 when it acquired POINT Biopharma (Toronto, Canada). What prompted the decision to explore RLT?

Mr. Van Naarden: We all had to join forces on this, because this isn’t like buying a small molecule. This requires a complicated and complex multidisciplinary effort. When I originally saw the randomized VISION trial data, I thought, “That’s cool, but I don’t know whether it will be transformative.” But then I talked to physicians who told me about a percentage of patients with very extensive disease and moving toward hospice care who, after 6 doses of the drug, have experienced incredible responses. It reminded me of the earliest days of PD-1 and melanoma. Those kinds of anecdotes are unusual in late-stage oncology care, and this raised our attention. So, we thought that maybe this was not only real but could apply to diseases beyond prostate cancer and gastroenteropancreatic neuroendocrine tumors. Then we started digging. “A lot of patients just don’t want the side effects that come with chemotherapy….I think that ADCs, despite being new technology, still create chemotherapylike toxicities. If we have a radioligand therapy that has similar benefit, there will be many patients who would prefer this.”

Novartis was showing that this wasn’t some niche idea that was going to be confined to a few places in the world. At Lilly we are in the business of making hard-to-manufacture medicines and doing it at scale. The complexities we’ve taken on in other parts of the manufacturing agenda at Lilly are different, but they’re complicated and they create a uniqueness to what we can do. I thought that the complexity was something that could actually be differentiating and that we could manage well. The other opportunity I saw was a marriage between our discovery capabilities for what I’ll call more traditional medicines and RLT discovery.

When we looked at the history of this space, including successful medicines such as Pluvicto (Novartis) and Lutathera (Novartis), most of these kinds of medicines have been academic projects, and there’s a limit to how much these can scale. On the flip side, we have a team of chemists and biologists who spend long periods of time discovering complicated medicines that require long half-lives, selectivity, and ADME (absorption, distribution, metabolism, and excretion) properties that allow for oral pharmacology—all of the variables that a lot of the small molecules that we have in clinical development took us 5–7 years to discover.

So, I thought, “What if we could take industrial drug discovery and apply that to ligand discovery for RLTs?” I’m not sure anyone’s ever really done that before. That could be an interesting thing to do and would also be differentiating. So, we made the decision that we wanted to be in this world. Then we canvassed the universe and said, “We’re not going to build this ourselves.” We believed over time we would need people, supply chain relationships, manufacturing, and products. We chose to prioritize the first three: people, supply chain, and manufacturing, realizing that once we have those we can do other things to get products, either by discovering them ourselves or by deal making. And that’s basically the strategy we’ve been executing.

Dr. Czernin: You indirectly talked about response rates in the context of the VISION and other trials. Is Lilly able to work on rational combination therapies with just traditional pharmacologic approaches? And what would that look like?

Mr. Van Naarden: The answer is yes, definitely. Here are a couple of thoughts on combination development in our portfolio. Number one, we don’t tend to make drug development decisions based on combining with other drugs we own. We ask whether there are backbone standard-of-care regimens that you don’t want to displace but you want to add to. In which case, you should try that and see if that can work. Second, are there biology-directed good ideas, maybe from other companies’ products or other investigational medicines? Or maybe we try to invent one that doesn’t exist. That’s admittedly a lot harder and a lot higher-risk, because the biology might not actually comply with the hypothesis. But we’ll do that.

Dr. Herrmann: Do you have any preferred ligand or any preferred kind of binder for RLT? Antibodies or small molecules? And how do you look at optimizing the radionuclides you are using?

Mr. Van Naarden: On the ligand side, there’s clearly a role for small molecules. I think small-antibody formats are interesting, and peptides are certainly an interesting format, too. There are enough clinical data that teach us that we should approach antibodies with caution. I’m not saying it’s a nonstarter in a binary way, but it’s certainly not our first choice. Their long half-lives and the potential bone marrow toxicity of an antibody are tricky.

We do care about the isotope. It is important to have isotope supply resilience. There is a lot of enthusiasm about actinium, and on some level, I understand the allure of the double-strand versus the single-strand break and what that can mean for efficacy for patients. But I don’t think that we know enough about the risks/benefits of actinium for patients—not to mention that the supply concerns are real. So, we are not betting the farm on actinium. It’s important to keep an open eye to all of the potential isotopes that can be used balancing supply and clinical risk/benefit, which incorporates things such as pathlengths and logistical ease or lack thereof for patients. And, of course, there’s some irony to the specific enthusiasm over actinium, because it’s the lutetium-based products that actually revitalized this entire field to begin with.

Dr. Herrmann: I want to get back to ADCs for a moment. Many targets are the same. How would you sequence RLT versus ADC, and what would be their ideal positioning?

Mr. Van Naarden: I think it really comes down to the risk/benefit ratio of these drug classes. If the benefit looks the same but one is better tolerated, I think that one will get used first. We will also need to explore the sequencing question empirically in patients, especially if it’s the same target. So, if you give an ADC first, does the target expression profile change at relapse such that an RLT may be less effective? What about vice versa? I think it’s impossible to answer those questions in the absence of clinical data.

A lot of patients just don’t want the side effects that come with chemotherapy. They don’t want to be perceived as getting chemotherapy. I think that ADCs, despite being new technology, still create chemotherapylike toxicities. If we have an RLT that has similar benefit, there will be many patients who would prefer this.

Dr. Herrmann: The toxicity profile is definitely the edge of RLT. We need to make sure we sustain it and not jeopardize it by being too aggressive. You said that when Loxo was acquired by Lilly you wanted to keep the spirit, efficacy, and speed of a biotech and bundle it with the resources of a big pharma company. What is the magic potion to do this culture merger successfully?

Mr. Van Naarden: Well, you should ask other people at Lilly whether we have succeeded or not. But first, we don’t have multiple units that all do oncology in different ways. There’s a single unit, and we all sit together. So, when my lead team meets (and we meet frequently), it covers the entire spectrum, from discovery all the way through to commercialized medicines. My discovery colleagues get to hear about pricing decisions, access situations, and distribution models, and the commercial people who manage our sales and our field personnel get to hear about synthetic lethality relationships that we’re exploring preclinically. It’s one team. As much as that just sounds like window dressing, it really does matter, because there are no handoffs. There are no silos. Another aspect about Lilly more broadly is that it’s a pretty flat company at the senior levels. It’s not just me bringing this small company ethos. The leadership of Lilly more broadly has bought into this idea for the whole company. If you look at Lilly’s behavior across all therapeutic areas over the last decade, the speed improvements that we’ve made in bringing medicines to patients have been pretty dramatic. That’s deliberate. It’s because the company has cultivated a team of leaders who think and act that way.

Dr. Czernin: Because you mentioned leaders, and this series is about discussions with leaders, how do you lead?

Mr. Van Naarden: I try to strike a delicate balance between knowing a lot of detail and challenging that detail when I feel like I need to but letting my capable people do their jobs. And I can’t say I’m always perfect at striking that balance, but I try to be.

Dr. Czernin: How do you select your people?

Mr. Van Naarden: I try to know them really well before truly selecting them. I try to have some experience with them before putting them in a bigger role. In general, when we (or any other company) interview people for jobs, especially if they’re coming from outside our current organization, we spend an hour with this person, barely get into any real substance, and then ask them for references. They give the names of people who are obviously going to say good things about them. And then we must decide whether we want to hire this person and work with them every single day. It’s no wonder that’s a pretty flawed process. I’ll admit I don’t have great ideas about how to make it better.

Dr. Herrmann: Play soccer with them? After 90 minutes you almost know everything about the person. You know if they are hard workers, if they are selfish, or if they are team players.

Mr. Van Naarden: I like that idea. I must work that into my process. I hire external people all the time. Sometimes you get them right, and sometimes you get them wrong. But I have found that when I’m hiring someone from within the company or from outside the company, if I’ve known them for a while it’s a much higher-probability situation.

Dr. Herrmann: Back to the process of target development. When do you decide to out-license versus collaborate with an outside partner versus in-house development?

Mr. Van Naarden: Usually what happens is we just start working on it. Then in parallel we start looking externally. If we find something externally that is the same product profile idea and is better than what we’re doing or will get us to the finish line more quickly, then we try to transact. Ultimately, none of us really care where these medicines come from. They just must be great.

Dr. Herrmann: One aspect is still missing, and that’s the last mile needed to make sure we get the medication to the patients and get the referral process going. Pluvicto sales were somewhere around $350 million in the last quarter. It’s okay but not what we really dream of. What needs to be done to make sure that patients who qualify for such a treatment really get it?

Mr. Van Naarden: Physicians, particularly in the United States, really don’t like referring their patients out. I think that reducing referrals and increasing the ability of practices to do this themselves is important. The second thing is just moving these medicines earlier in the course of therapy, and that’s happening literally in real time. So, I’m hopeful that Pluvicto gets its PSMAfore approval.

Dr. Czernin: I think patients will have a major voice in that, because of the combination of side effect profile and effectiveness. Pluvicto is so much better tolerated than chemotherapy. And that will solve the last-mile problem.

We are coming to the end of this discussion when we ask for career advice for the next generation, perhaps discussing the advantages of academia versus industry as a career path.

Mr. Van Naarden: I interact with a lot of younger people who think about their career on a very long time horizon: what they will be doing in 10, 15, 20 years and what decisions they need to make today to enable that. I tell them that it is an illusion to think that way, because you can’t imagine what will exist in 15–20 years. So, the best thing is to do a really good job at the thing that you’re doing right now and make sure it’s something that you like, because if it’s not something you like, you’re probably not going to do a very good job at it. And if you like it and do a really good job, you will be afforded future opportunities that you probably can’t even predict. I never thought I’d be doing what I’m doing now, never in a million years. I never said, “I want to run a unit of a large pharmaceutical company.” But you do one thing at a time and then reach forks in the road and have to make decisions. You make a series of those successive fork-in-the-road decisions, and hopefully that leads to a place where you have fulfillment and make an impact. However, you want to quantify impact on a personal level.

Dr. Czernin: Yogi Berra said, “When you come to a fork in the road, take it.”

Dr. Herrmann: That’s a good ending for this discussion. Thank you very much, Jacob, for spending this time with us. Our readers will appreciate your insights and knowledge.