The Commercialization Process of Immunotherapies:

An Interview with Olivier Lesueur and Rachel Laing, PhD

Olivier Lesueur

Interview with the Innovators

The field of immunotherapy has made great strides in recent years, culminating in the FDA approvals of 3 checkpoint inhibitors: Yervoy, Keytruda, and Opdivo. For Big Pharma, this means the race is under way to investigate the potential of immunotherapies in as many indications as possible. The potential for blockbuster products looms large as the dawn of targeted therapies and companion diagnostics changed the way we thought of cancer treatments from “one-size-fits-most” to highly specialized, personalized treatments inherently removing the possibility of traditional blockbuster status. Enter immunotherapies, which have been touted as a revolution in oncology comparable to the advent of chemotherapies in the 1970s. As a result, the commercialization of immunotherapies presents a challenge to pharmaceutical companies, prompting partnerships with strategy consultants such as Bionest Partners to drive competitive differentiation. Bionest Partners is a global strategic consulting firm serving the pharmaceutical, biotechnology, medical device, and diagnostic industries. Further information about this consulting service is available at www.bionest.com.

In their recent paper published in IN VIVO titled “Immunotherapy: Big Pharma’s Seductive Embrace,” Olivier Lesueur and Rachel Laing, PhD, from Bionest Partners, along with science writer Mark Ratner, explore the emerging field of immuno-oncology, the revolution of immune checkpoint targeting, and the strategies Big Pharma is using to expedite the clinical trial process. The publishers of ITO had the pleasure of speaking with Mr Lesueur and Dr Laing. What follows is their insightful exchange.

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ITO Thank you for taking the time to speak with us today. To begin, can you introduce us to Bionest Partners and your involvement in the field of immunotherapy?

Mr Lesueur Bionest is a strategy consulting firm based in New York and Paris with offices in San Diego, Tokyo, Munich, and London. For over a decade, we have specialized in providing consulting services to pharmaceutical, biotech, and diagnostic companies. In the immunotherapy space, we began work several years ago with a current leader in the field to look at their portfolio of checkpoint inhibitors because the science wasn’t providing obvious directions in terms of how to develop and prioritize the assets. At that stage, we felt the possibilities were wide open, much like the beginnings of chemotherapy. You could argue immunotherapies are somewhat like Avastin was; a ubiquitous asset that opened the field and raised many questions about the best path forward to commercialization—combination or monotherapy, what indication—without having a lot of mature scientific data directing that process. Since then, we have worked with several leaders in the field on a variety of topics, along with a number of companies looking to get into the immunotherapy field.

ITO Can you describe your observations of the progression of the immuno-oncology field?

Dr Laing It’s interesting when we think translationally and clinically about this field. If we go back in time, immunotherapy was traditionally thought to be prefaced on melanoma and renal cell carcinoma. Now we know it can be applicable to a number of different tumors beyond this.

From a clinical perspective, the types of responses we’re seeing are very different from what we’ve seen with targeted therapies. We have patients who were treated on the first Yervoy trial over 10 years ago, and they’re still in remission. That’s really transformational.

In contrast to targeted therapies, we haven’t seen much in the way of acquired resistance to immunotherapy. In many cases with targeted therapies, you see acquired treatment resistance after a certain period, and there’s a new pool of targeted therapies to address that resistance. That’s not to say that we won’t have an issue with resistance to immunotherapy at some point, but we haven’t seen it yet.

With immunotherapies, there are cases where we have been able to induce long-term responses even after treatment has stopped because of the nature of the immune system. It’s like resetting that system, and those responses seem to endure. To us, these factors change the clinical landscape and then calls into question how to develop and commercialize the therapies.

ITO The paper you authored, called “Immunotherapy: Big Pharma’s Seductive Embrace,” describes holding the tumor at bay as being the distinguishing characteristic of checkpoint inhibitors from other therapies. Can you elaborate on this?

Dr Laing If you take targeted therapies as an opposite example, you’re specifically targeting pathways within the cell that the cell requires to stay alive. If you can hit those relevant pathways, the tumor cells will die, and you’ll have tumor regression. But in many cases, you can’t achieve that in every single tumor cell, so there will be some cells left behind. Once you stop therapy, the cancer grows back with new mutations, and the treatment that originally produced a response is no longer an option.

By contrast, immune checkpoint inhibitors target the tumor-immune interactions and are not just focused on the tumor itself. The immune system has the ability to kill tumor cells in a perfect world, but the tumor is often able to inhibit that function.

Regarding holding the tumor at bay, immune checkpoint inhibitors act as sort of a reset button, priming the immune system to recognize those tumor cells as foreign. You may eradicate the majority of the tumor and achieve remission, and even if you still have some residual cancer cells, you may also have developed memory T cells that remain primed to trigger an antitumor response in case the residual cancer cells try to grow back.

In many patients who respond, it appears that not only do they respond but that the duration of response is still ongoing. To us, this seems like a drastic change from what we’ve seen with many of the targeted therapies today.

ITO That is remarkable. What are you observing in terms of its diffusion into practice?

Mr Lesueur There are several diseases, such as melanoma and lung cancer, in which immunotherapies have established value. It would also make sense to approach cancers where established, foundational treatments do not exist, with the intent to become the foundational treatment, like Revlimid in multiple myeloma, for example.

Currently, immune checkpoint inhibitors are mostly employed as monotherapy in later lines of treatment. The big question is how to become first-line and foundational across many different tumor types.

So the applicability is wider than a few immune-driven indications that we identified in the past. As a result, there’s a race to get trials set up in as many indications as possible.

Currently, there are trials focused on immunotherapies as monotherapy, and secondary trials testing immunotherapies in combination with other immunotherapies or targeted therapies sponsored either by a single company, companies in partnership, or investigators. Although proprietary combinations make the overall economics better for a pharmaceutical company, partnerships allow immunotherapy companies to rapidly penetrate a broad range of indications and across many lines.

ITO Please describe the drug commercialization process as one of the drivers of research in checkpoint targeting.

Mr Lesueur The many different stakeholders are pushing for broad acceptance of immunotherapy, including the investment community. The level of data required to get approved has changed over the past few years, with less and less being required of each subsequent approval. That changes the paradigm a bit from the development perspective and may convince more players to come into the immune checkpoint game.

From the commercial perspective, we see broad applicability across many indications, so mostly Big Pharma will be able to commercialize a PD-1 or PD-L1.

ITO How does the role of the pathologist play into the use of immunotherapies?

Mr Lesueur Pathologists certainly are a new consideration, and their role is changing. They will have to be educated in meeting the challenge of better qualifying patients who are more likely to respond. At some point, most likely when the competition among immunotherapy products is high, there will be some pushback from payers or the FDA to start requiring biomarkers as a predictor of response.

ITO Are there indicators of appropriate patients?

Dr Laing There’s ongoing investigation. Some looking at lifestyle cancer effects, especially in lung cancer, where we have seen improved responses in smokers versus nonsmokers. And there have been some looking more in-depth into the immune profile of a patient. PD-L1 is just 1 part of a very complex system. There are several companies that are looking more broadly outside of PD-L1 to determine if we should be looking at levels of different immune cells or other immune markers. Is it a question of patients’ immune system overall, is it localization of cells expressing PD-1 or PD-L1, or is it CD8+ T-cell levels? We have seen some movement on these, but I would say it’s still pretty early at this point.

Mr Lesueur We’re still very much in the infancy of the immunotherapy era. Once the competition starts becoming fiercer and we have multiple PD-1 or PD-L1 assets approved for the same patient, then there will be a very strong drive to have better PD-1, PD-L1 value propositions, and that would include having a better diagnostic for determining the likelihood of response. There is a PD-L1 expression biomarker today that many agree is not a great test. But still, it’s something that will probably be used in the market.

There will be a requirement for more and better enrichment, and that creates a drive for innovation, and a number of small companies are looking at this. There are deals that are happening between diagnostic companies and Big Pharma. And that creates innovation and a better value proposition from the price perspective.

ITO Would you say the search for the diagnostic qualifier test is essentially linked to and dependent on the complexity of the cancer being treated?

Dr Laing Most tumors are “smart,” meaning that they are not dependent on just 1 pathway, but they’re dependent on a whole host of different things. Sometimes you get lucky and identify the driver mutations or specific targets. But more often than not, the tumor is pretty intelligent and can evade different therapies.

So, yes, I think it’s partly the tumor complexity, but it’s also the fact that these immune checkpoint inhibitors are part of a very complex and broader immune system response. So the PD-1 or the CTLA-4 pathway is 1 of many checkpoint pathways in the body. The immune system is so dynamic that to rely on 1 marker may not be a realistic goal. You’d be quite lucky to find that 1 marker when in reality there are a hundred things going on in that interaction.

Mr Lesueur I would add another layer of complexity. It’s not just about the tumor but also about the state of each patient’s immune system. If the patient is immunocompromised, they may not receive the same benefit as the patient who is not.

ITO Can you describe side effects from therapy?

Dr Laing We’ve seen side effects, but they’re different from what we’re used to seeing with targeted therapies. Mainly, we see side effects such as pneumonitis because of the continued activation of the immune system. These can be well controlled in most cases.

Oncologists are traditionally used to managing the side effects from chemotherapy and targeted therapies, and that side effect profile is very different from what we see with immunotherapies, which is more akin to what an immunologist would feel comfortable managing. So, if they aren’t already, oncologists will need to get comfortable managing these new types of side effects.

ITO What do you think we can expect as a next step in the life cycle of immunotherapies?

Dr Laing The combination therapy strategy is the way things are headed. There are a number of combination trials across a number of different indications under way.

Mr Lesueur It’s a bit of a Wild West now, which is actually very good. Everybody wants to try their drug with an immunotherapy. The market is full of possibility because there’s relatively low scientific rationale as to what you cannot try in combination with an immunotherapy. You have to start with the basic science as to why a combination might be synergistic.
Another point to consider is that immunotherapies will come to a stage where they may compete one versus the other without a clear understanding of their differentiating factors or predictive indicators for response. Introducing a targeted agent in combination with an immunotherapy may bring differentiation and competitive advantage to one immunotherapy versus another.

We address this concept in our article; that for a period of time, combination with targeted agents will be the driving force of competitive differentiation and market segmentation of immunotherapies, because the introduction of a targeted therapy introduces the possibility of a biomarker that sets apart the immunotherapeutic agent in a certain segment of the treatment population.

ITO Thank you so much for your time today. We really appreciate your insights into this exciting field.

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Olivier Lesueur is Managing Director of Bionest Partners, having joined the firm in 2004 and relocating to the New York office in 2008 to develop US operations. Prior to Bionest, he was a consultant at Celerant Consulting.

Rachel Laing, PhD, is a Manager at Bionest Partners in the New York office. She received her doctorate in Medical Pharmacology from the University of California, Los Angeles, and has conducted translational research in the immunotherapy field.

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