DARPin-Delivered Radiotherapy With Molecular Partners And Orano Med

In this episode of In Combination, CEO Patrick Amstutz of Molecular Partners and CEO Arnaud Lesegretain of Orano Med join host Tom von Gunden in a discussion of using DARPins (Designed Ankyrin Repeat Proteins) as vector delivery platforms for high-affinity binding of radioisotopes to treat cancer. Using the example of small cell lung cancer. Patrick and Arnaud describe how DARPin-delivered radiotherapy can attack metastatic cancers while overcoming the targeting limitations of external beam radiation and of antibodies. 

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of In Combination. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for this series. And today, I have the pleasure of being joined for an In Combination conversation by representatives from two organizations that are partnering to deliver radioisotopes in the treatment of cancer. And those two organizations are Molecular Partners and Orano Med. And from Molecular Partners, I'm joined by CEO Patrick Amstutz.

Welcome, Patrick.

Patrick Amstutz, CEO, Molecular Partners:

Thanks, Tom. It's a real pleasure to be here and introduce you to the concept of Radio-DARPins. It's also a pleasure to be here with Arnaud, joining us from Orano Med.

Yes. And thank you for mentioning Arnaud. I was about to welcome him as well. So, in addition to Patrick joining me, I am also joined by Arnaud Lesegretain, who is CEO at Orano Med.

Welcome, Arnaud.

Arnaud Lesegretain, CEO, Orano Med:

Tom, Patrick, glad to be here and glad to be discussing this very exciting field together.

And we're going to obviously dive deep into the details of what you folks are working on. But before we get to that, I think it would be helpful for our audience to get some perspective on who you are, how you got to where you are in your careers, and how that might inform what we hear from you today.

So, Patrick, do you want to give us a little bit of a tracing of how it is that you arrived in the role of CEO at this place that we'll be talking about?

Amstutz: Sure, happy to do so. We started Molecular Partners 20 years ago when I was a founding scientist at the University of Zurich. And what we had worked on was DARPins. And DARPins are small proteins that can be selected to bind any given target, mostly a cancer target.

And back then — and this has not changed since the early days — we had one focus, one purpose, and that was to make drugs that matter. And to make drugs that matter, you have to have great science driving innovation, and that's what we're doing on the DARPin side.

And at the same time, you realize how challenging that is and that you don't do that alone. So, you need great people. And so, we have formed a group of scientists at Molecular Partners. We’re based in Zurich, in Switzerland, and we have around 150 coworkers here. And we realized that we cannot do everything, so we look for great partners. And, in our case, we have found, with Orano Med and with Arnaud and his team, a group that complements our technology that is ideal to target cancer with a warhead — in this case, radioisotopes. And it's been a fabulous journey.

We have also partnered with many others in the field, and we will come to that. But the most recent trick to DARPin is the radiotherapy trick that we are doing with Orano Med and Arnaud and his team.

Great. Well, thanks for the background, Patrick.

So, Arnaud, since you've been given some version of a flattering introduction, hopefully you can live up to it when you tell us about you.

Lesegretain: Thank you, and it's a pleasure collaborating with Molecular Partners on a very special collaboration and complementary skills between both companies. I joined Orano Med — I was fortunate to join Orano Med — nine months ago, and what attracted me to that company was really the exceptional science and technology. Orano Med is a pioneer and leader in the field of alpha radiotherapy; therefore, it was a unique opportunity to join a growing organization with leading science and a top team.

I was fortunate enough to have had a long career in large and mid-scale pharma and was fortunate enough to bring a couple of drugs to patients through registration and worldwide launch. And so, that experience really built the fundamental belief of, what we do matters. There's a burning obligation to bring drugs to patients with cancer. They’re waiting for us, they're counting on us, and I'm trying to bring that energy and passion to my colleagues at Orano Med.

Well great. I'm really looking forward to hearing more about that. So, let's just go ahead and turn to that patient population.

So, as you both look out over the landscape of patient needs and the therapeutic targets that you're focusing on in the area of cancer, can you tell us a little bit about what would traditionally, historically, or maybe even currently be available to the patients that you're targeting and to what effect and what would that experience be like? Because I'm going to then follow up by asking you: What are you working on to move that forward in a different and hopefully more effective way?

Lesegretain: I would start by saying that, at the end of the day, what patients with cancer really strive for is hope and progress. They want longer survival. They want less toxic regimens. They desire to preserve quality of life and a less burdensome experience with cancer.

And with chemotherapy, with targeted therapy, with immunotherapy, what we witnessed in the last couple of decades is tremendous progress in outcomes and prognosis. However, there are still significant and many needs in many, many different cancer progression, relapse, very complicated side effects, administrations. And, therefore, this gives us a very good framework in order to prioritize our R&D efforts around solving for those problems and truly trying to make leaps into advancing any or a combination of those parameters to change cancer outcomes and provide new hope for patients.

Amstutz: When we look at an indication, as Arnaud was just saying, we look for those indications where, today, there is no satisfactory treatment. And one indication the two of us are looking at very closely is small cell lung cancer. And in small cell lung cancer, the five-year survival rate is very low. So, if you're diagnosed and you're advanced, your five-year survival rate is low. And there are different reasons for that. And one is that, today, [with] this cancer, the treatment options are, first, chemo and then the cancer becomes very rapidly resistant to chemotherapy. So, the cancer finds ways to evade the current standard of care.

Then there is another drug that is approved, which is a T-cell engager. It harnesses the body's T-cells to attack cancer by targeting DLL3, which is the target on 85% of the small cell lung cancer cells or patients. And in this case DLL3 is the target. Now, the problem is, the response rate is only around 40%. So, if you're lucky you're one of those 40%. But, again, it will maybe prolong life a few months, but it won't cure you. And that is where we come in in this indication. That is obviously not the indication Arnaud was talking about where the treatment, in the last years, has sometimes transformed the deadly disease into a chronic disease with good treatments options. This is not true for small cell lung cancer.

Gotcha. So, I think we're ready to hear about the science and the technology that you're working on together.

Lesegretain: We are working with the Molecular Partners team on a very simple concept that we would generally call Radio-DARPin. So, we are using MP, Molecular Partners, technology called DARPin. And Patrick will be able to provide a lot more detail about what they're very good at. And we attach that to a very cytotoxic payload; in this case, a radioisotope emitting alpha emissions. In our case, this is lead-212, which is a very powerful alpha emitter with a short half-life of eleven hours. And that very powerful isotope will cause very complex double-strand DNA breaks — largely irreparable, therefore being extremely powerful in terms of cytotoxicity but also with no non-resistance mechanism.

So, in terms of the cancer escaping through traditional ways of either repairing itself or escaping through a compensatory pathway, with the lead-212 isotope, we believe — and we have strong reasons to believe — that we'll have a higher efficacy and less way for the cancer to evade and repair itself.

Safety is also very important in the whole patient experience. And right now, what we know from radioisotopes as an experience with radiotherapy is actually, largely acceptable and manageable and doesn't feel as burdensome as a traditional chemotherapy regimen that lasts for years and years that we know from the past. So, we believe we've got a very interesting concept, a very cytotoxic drug that will travel in very short paths into your tissues, hence preserving healthy tissue. So, cytotoxic to the cancer cells, preserving healthy tissues as much as possible, acceptable quality of life, manageable administration.

And then I will leave it to Patrick to tell us more about the targeting moiety, which is absolutely a very key piece of that.

Amstutz: Thanks, Arnaud. But maybe just to double down on what you said, I think everybody knows that radiation — external beamline radiation —has been used in cancer treatment very often and extremely successfully. So, if you have a non-metastasized tumor mass that you can radiate with beam line radiation — that's what cancer patients get — then do. The side effects are not so bad, and you can often really reach, even cure, if you get the cancer early on.

Now, the whole quest we're trying to do is, take that treatment success and bring it to patients that have metastasis, micro-metastasis, have a tumor where you cannot use external beamline radiation. So, that was the original idea: take a mode of action that has proven itself and bring it to situations where, today, that technology was limited. And for that, you need the isotope, the lead-212 that Arnaud was talking about. But you also need a delivery vector that brings the isotope to the tumor.

And the classical targeting moiety in the past was always an antibody. And antibodies are great, but they're also very large. They have a very long half-life, and, with that, they will also bind to a lot of blood cells and immune cells because of their Fc [fragment crystallizable region]. So, if you now attach lead-212 to an antibody, you will have side effects and not ideal tumor targeting. And that's where the DARPin technology comes in.

So, we develop DARPins to have no other effects than binding — be very small, go in fast, penetrate the tumor, and leave the body, also fast. So, this is a very different concept [compared] to a full antibody, and we have used that in different contexts. But we really like and have optimized [it] for radiotherapy, where we use a mono-DARPin for high-affinity binding of any given target. In our case, and going back to small cell lung cancer, it's DLL3 and optimizing a DARPin to bind to this target with high affinity.

And, as Arnaud said, it's important to spare the healthy body parts. So, you don't want [it] to accumulate in the liver, in the kidney, or in any other organ. And so, we put in years of research to finesse and optimize [so] that we deliver as much radio energy into the tumor and as little to the healthy organs as we can.

Gotcha. So, I'm curious as to what you would anticipate that the patient regimen and dosing would be like. How frequently would patients be going somewhere to receive this, and how do you envision that playing out?

Lesegretain: So, the treatment regimen will be between four and six infusions cycles, which, when you think about it, is a very different way to tackle cancer. If you compare treatment to progression with targeted therapies, like in the last years and years of immunotherapy, a very long cycle of chemotherapy or in combination, here we are potentially offering a very different way, a very different patient journey with experiencing four to six infusions, and then that's it. And that's a new line of treatment.

Very often now, experts look at this radiotherapy as something intermediate between the classical lines of treatment. And I think that will completely change the way physicians plan their treatment sequence, inform patients about their options, and how patients actually leave their cancer treatment. [It] is a much more reduced-focus cycle than versus months and months and years and years of therapy and the burden associated with the emotional and sometimes physical burden of travel to hospitals or to infusion centers, [and of] side effects.

Patrick, anything to add to that?

Amstutz: I think Arnaud did a great job in explaining that. I think one part I would add is that, obviously, the line of treatment as we know it, it's an intervention. It is, as Arnaud said — it can be between two and six infusions of the Radio-DARPin. And that's where we will start. We will start by calling this a monotherapy.

I think there is an exciting evolution to that, when we didn't think, going from a monotherapy to a combination therapy. Because what radiotherapy does, we deliver a lot of energy into the tumor. This energy will kill tumor cells and cause massive inflammation and destruction. And this, again, would be an ideal starting point to be combined with classic immunotherapy — a PD-1, a T-cell engager —because this local inflammation will create T-cells, immune cells, and inflammation.

And in this case, I think we can even say you can turn a cold tumor into a hot tumor with [all the] energy we give in there. So, in this case, that's absolutely true. And given that the immunotherapies, the PD-1s with all their success, were always restricted to cold tumors. The combination with radiotherapy could really expand where such treatments are used. And that's when we believe we can go from treatment to possibly even cure because the immune system can then hump down the last tumor cells that maybe radio didn't kill and lead to a long-lasting treatment effect.

Lesegretain: The second piece of the promise of radio pharma: So, I have heard described the direct effect on the cell nucleus, which is the cell destruction. But then radio biology takes us to a lot more complex but also very potent effects. So, you have what we usually call a bystander effect, which are neighboring cells. Even if they are not irradiated, will receive some messaging and cell signaling that will tell them and then start a mechanism of apoptosis or [cell] death. And then you have the more distant, sometimes called abscopal effect that includes the immune system that will also allow [for] an immune response away from the local irradiation.

So, you can see it's really a very complex, promising field. And the combination strategy Patrick alluded to will certainly allow us to demonstrate that into the clinic and lift the survival curve in a way that really impacts more patients for longer versus the current tail of immunotherapy that is very profound but only for 20-25% of patients. And most of the patients do progress and do not benefit from those fantastic drugs.

So, tell us a little bit about the partnership itself between Molecular Partners and Orano Med. Basically, why these two organizations coming together? How did that come about and for what reason?

Amstutz:  I'll be happy to take that question. And actually, the idea of Radio-DARPins is not new. So, even 2007 — that was the first time we did a Radio-DARPin and tested that in a preclinical setting with quite some success. But that was ahead of the radiotherapy time as there were no real isotope providers, and there was also no commercial success.

So, it took Novartis to pioneer this field. They acquired different companies, including triple A. And, in prostate, they were successful with their drugs, foremost Pluvicto. That really is changing how prostate cancer is treated.

And in that wake, we said, let's have another go at Radio-DARPins. And we looked for what radioisotopes would make most sense to be coupled to a DARPin. And we had to choose between beta radiation and alpha radiation. And for us it was clear we prefer alpha. And in alpha, there's two: there’s actinium and there's lead. And from the profile, we said we like lead: short half-life, a lot of energy, in a short time. And also with that, not going to kill all incoming immune cells for the combination opportunity.

And then the next question was, so who has lead? And my team went out there, they went to a few congresses, and they came back and said there's really one company we should work with, and that is Orano Med.

And I think it's for Arnaud to tell you why my people were so supportive and excited when we met Orano Med.

Yeah, let's hear it.

Lesegretain: Yes, Patrick, it is a pleasure to work with you and your team. And what makes the collaboration so promising and successful is two things. So, what Orano Med brought to the table is two main aspects. The first one is 15 years of preclinical expertise into what it takes to develop a radiopharmaceutical company. So, Molecular Partners brought protein engineering, amazing skills in DARPins, some of the work based on how to tweak those DARPins.

We brought to the table what it actually takes to make a DARPin radio compatible for administration and connection with an isotope. So, that was the first thing we brought. The second piece we brought, and Patrick alluded to it, is a unique position in the field of radiotherapy because you have two things that are really hard to do in radio pharma. First is ownership of the isotope. Do you have enough? Is it under your control? Is it reliable? Is it affordable? And second, the manufacturing and the last mile, and Orano Med has cracked both aspects of those things. We have 22,000 drums of the starting materials under our control. So, it's a virtually limitless supply of thorium-232, the styling material. And we are developing and have finished developing a fully integrated vertical integrated supply chain to deliver, on-demand, lead-212 based therapy to cancer patients.

Well, great. It all sounds extremely promising. Patrick and Arnaud, I want to thank you for joining me and sharing your perspectives on the work that's being done in the partnership with Molecular Partners and Orano Med. And to our audience, I want to thank you for joining us for another episode of In Combination. We'll see you next time.