Adrian Rawcliffe, Adaptimmune 🇬🇧 | Tecelra, TCR Cell Therapy | E22

We’re online with Adrian Rawcliffe, the CEO of Adaptimmune, the TCR cell therapy company behind the first engineered cell therapy for solid tumors that was approved for a rare form of sarcoma.

We talked about Tecelra’s commercial rollout. We also talked about what’s next in cell therapy, and Philly Cheesesteak vs Fish and Chips.

— — —

Thank you to today’s sponsor, Merck, who can support your antibody drug discovery. Learn more and claim a cool antibody pin here: https://bit.ly/48m9spf

The life science business ​of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. ​and Canada.

— — —

⭐️ ABOUT THE SPEAKER

Adrian Rawcliffe has been in the biopharma industry for over 20 years and has worked in high positions for companies such as GSK. Adrian has been with Adaptimmune for almost 10 years, serving as CFO before becoming the CEO in 2019. I didn’t know him personally but have heard and seen great things about him.

🔗 LINKS MENTIONED

Transcript

[00:00:00] Introducing Adrian Rawcliffe

Adrian Rawcliffe: The whole reason why TCR T cells and TCR therapies are going to be effective in the solid tumor space is because they can access these targets that are not cell surface proteins. Because it turns out there are very few cell surface proteins that are completely specific 

Philip Hemme: to cancer. I may be talking about the peak sales, it was like a 400 million dollars figure for the annual sales, and with pretty high gross margin as well.

But then I saw some figures from the analysts, and they were from Google and that their project is a bit lower. And with 80 million, what’s your take on this? Don’t comment on the analyst’s forecast for obvious reasons. I, I told you what 

Adrian Rawcliffe: we believe. 

Philip Hemme: Do you prefer Philly cheesecake or Oxford fish and chips?

Philly cheese steak. Oh, fine. Sorry. I guess. Bienvenue to a new episode. I’m yours, Philippe. And on this show, I’m interviewing the best Europeans in biotech. Help you grow. Cell therapy, especially CAR T, has changed how liquid tumors have been treated. But solid tumors were harder not to crack. In August this year, the first engineered cell therapy was approved for a rare form of sarcoma.

It’s a TCR based therapy developed by Oxford headquartered company Adaptimmune. So I talked online with the CEO, Adrian, who lives most of the time in Philadelphia. Adrian has been with the company for almost a decade. He joined as CFO before transitioning to CEO in 2019. I don’t know him personally, but I’ve followed Adaptive Immune since almost 10 years and knew some of the other C levels, and I’ve heard many great things about Adrian.

We talked about the commercial rollout of Adaptive Immune. We also talked about what’s next in self therapy as well as Philly cheesecake versus fish and chips. This is a conversation with Adrian and please hit the like and follow button if you’re enjoying it. Thank you to today’s sponsors Merck for accelerating the therapeutic antibody development.

Whether you are identifying your targets or optimizing your production, Merck has you covered. They have a comprehensive suite of tools from functional genetic screening to high throughput purification. With cutting edge advances in B cell loading and hybridoma development, you will both save time and resources.

Merck is also a proud partner of today’s guests at AppSimul. So, want to learn more how Merck can be your partner for therapeutics development? Click on the link below to download your brochure and get one of these cool antibody pens. Hi, it’s Aiden. Welcome to the show. Hi, great to be here.

[00:02:35] Commercial rollout of Tecelra, the first engineered cell therapy for solid tumors

Philip Hemme: I wanna, I wanna start with the commercial rollout.

Obviously you just, I mean, got Tessera approved for patients. It was in August. Great news. So yeah, how, how is it, how is it going with the patient rollout? So, 

Adrian Rawcliffe: so Ticellar approved very beginning of August and you know, that’s a, that’s a sort of fairly big transition for companies like us. But, but actually in terms of the relationships with the sites and the places that are going to be actually making Ticellar available to patients.

It’s really an extension of the relationships that we’ve had with them for, for the last decade or so, because, you know, we’ve been developing the cell therapies for sarcoma, synovial sarcoma specifically, and other soft tissue sarcomas. For for for that at least 10 years now and so so it’s more sort of like it’s an evolution of that But it’s a really important evolution and now for the first time we’ve got to Be using the commercial diagnostics to be able to test the patients.

We’ve got yet the treatment sites up and running We’ve got to get the patients flowing through those sites and all of that is sort of happened A pace they’ve been a big amount of enthusiasm from this from the from the sites because I mean This is this is the first therapy that the first new therapy that these physicians have had available for their patients for Over a decade.

And so so they’re really enthusiastic We’ve had a great uptake in terms of getting sites active Patients coming through the system. And, and, you know, we’ve, we’ve sort of said it’s going to take, it’s going to take three to four months to get the first patients all the way through that, that process, get them treated.

And we anticipate doing that by the end of the year. So we are. Deep in the bowels of it at the moment. 

Philip Hemme: I was up. Yeah I was about to ask how many patients are already Enrolled or already went through the process if that was this yeah 

Adrian Rawcliffe: We we haven’t disclosed that all that we’ve disclosed is the that we we we just want to make sure that everybody’s realistic about the time frame it takes to get here, I think there’s been a couple of launches in the cell therapy space where you know that that time frame has been A surprise to people But it take takes time to get patients, you know, tested to get the the reimbursement sorted out, then to get the patients released and then are then treated.

So yeah, we’re in that process. We will dose our first patients this year, we anticipate. That’s amazing. 

Philip Hemme: And on the, actually you mentioned reimbursement. I, I saw the pricing. I think per those, the listed, listed pricing is 720 K dollars, if it’s correct. Yeah. Yes. Like, I mean, just to put it into the context as well, it seemed, when I saw the figure, I was like, Oh, that seems pretty high, even compared to let’s say Cartier, which is already, I think more than 350 and already pretty high.

Can you like, why, like, what’s the, what’s the reasons behind it? 

Adrian Rawcliffe: Yeah. So, so the Carties now in the U S are priced here. Most of them are priced between five hundred and six hundred thousand. It’s a modest premium to the, to the CAR T therapies that are out there. And I think reflecting a couple of things.

One is the absolutely spectacular data that from the from the Spearhead 1 trial that was the basis of the approval which, you know, in this space, it’s, it’s, it’s. Difficult to overstate how transformational it is. 

Philip Hemme: I agree. I saw the data published in Bandset. I 

Adrian Rawcliffe: was like, wow, that’s amazing. Amazing, amazing data.

And, and, and, and for this patient population, that’s very small. I mean, this is a, this is a very, very small population. Targeted therapy you know, it’s targeted on patients who have the right HLA type, right, right tissue type and to have the right target. So it’s a discrete orphan, ultra orphan patient population with transformational therapy.

And, and that’s, that’s the basis of the pricing that that we rolled out and we anticipate the coming, coming years. 

Philip Hemme: It’s, it’s where there’s around a thousand patients per year. In the US alone. Yeah, so, so there’s about a thousand 

Adrian Rawcliffe: to 1300 patients who are likely to be diagnosed with synovial sarcoma each year.

So yeah, synovial sarcomas is about 10%, up to 10% of soft tissue sarcomas. So there’s about 13,000 soft tissue sarcos. About 1300 of those are. the synovial sarcomas. We, we talk, we target about a third of those. So maybe 400 patients a year in the United States. And, and, and then probably a similar number, maybe a bit more in Europe.

And and it’s, it’s tissue type is HLAO2 and it’s target type is MAJ4. So you’ve got to be, you’ve got to be biomarkers for both of those. So it’s very focused therapy. 

[00:07:35] The limits of TCR Cell Therapy

Philip Hemme: I think. Yeah, that’s also the, I think, one of the limits of TCR therapies in general. I remember talking with Baco and happy that at the, at thematic they were both on the show and they also had to exactly have the right HLA that is presenting the right peptide for the TCR r To recognize that has to be super specific.

Can you talk a bit if, first, if you agree and. expand a bit on that if that’s really a limit and how you like overcome it. 

Adrian Rawcliffe: Yes. So, so I, I think about this as actually as, as, as, as the potential of the opportunity, you know, the, the, the, the whole, the whole reason why TCR T cells and TCR therapies are going to be effective in the solid tumor space is because they can access these targets that are not cell surface proteins.

Because it turns out there are very few cell surface proteins that are completely specific to cancer. So even in the CAR T space, where the CAR Ts target cell surface proteins, they’re not targeting cell surface proteins specific to cancer. They’re just targeting lineage proteins for a B cell, on the grounds that if you have a B cell malignancy, I can clear out that lineage of B cells.

And cure your b cell malignancy because you don’t have any Is not No, it’s not specific cancer It says this is this type of b cell and that that therefore if I get rid of all of those I’ve got a pretty good chance of getting rid of your cancer, but I also get rid of all your b cells but Doesn’t work very well for and you can live without your b cells and you regrow your b cells and hopefully they grow back without cancer but But for for other cancers like if you take lung lung cancer, yeah If you said well i’m going to get rid of all your lung tissue in order to get rid of your lung cancer That’s unlikely to be an effective treatment strategy.

And that’s true Now there are there are places where you could say well that is an effective trade off prostate cancer For example, you could say that’s a could be an effective trade off There are some places like breast cancer, but but actually finding targets that are really specific to cancer Is is is quite difficult You And, and there are very few self surface proteins, and when you talk self therapy, you’ve got a different level of selectivity that is required, because for, for many types of, other types of therapies, including bispecifics like, like aminocores bispecific the, the bispecifics, you, You can tolerate a certain amount of off cancer, on target activity.

So you can have a certain amount of expression in normal tissue, and still have a therapeutic benefit, a therapeutic index. But with cells, that’s very different. Because, and the reason is that for most other therapies, when the therapy is most effective is immediately after it’s been given. And then it tails off you get sort of classic pkpd sort of you know The effectiveness of therapy tails off over hours if it’s a small molecule Days months if it’s a protein but with a cell therapy The when this therapy when the cells see target When they engage with target, the first thing they do is multiply.

So, 

Adrian Rawcliffe: so they, they, they kill what they, what they see, and then they divide and they multiply. So you get this expansion against whatever it’s seeing. But so sometimes, sometimes they become too active and once they become too active, and if, if you have even low levels of target expression in normal tissue and the T cells see them, they will attack that normal tissue.

So what that means is that you need very, very clean. targets to go after with a with a with a With a t cell and most of the things that you would normally target with cancer therapeutics Are not sufficiently clean and and very few of the cell surface proteins are sufficiently clean So you’ve got to go inside the cell now.

The problem is you can’t get t cells inside the set inside the cells so you’ve got to rely on the fact that The cell protein machinery is constantly breaking down proteins that are inside the cells, venting them up using HLA on the surface of the cells. And that’s what T cells actually see. They see this presentation, the context of HLA on the top of the cells.

So I think about HLA as the way in which we get access to the intracellular target, the intracellular proteome. And there are many more. Proteins that are specific to cancer inside the cell than there are on the cell surface. So actually I I whilst it is a restriction It’s a mechanistic restriction.

It’s down to the underlying biology of the And it’s actually the way in which you get access in a selective fashion to these these these cancer targets That are very difficult to target. Otherwise and and then the other thing that I would I would say is yeah Most of us most of us have been developing these Have been developing them in the context of hlao2 and that makes sense from a okay, that’s where the largest population is, 

okay, 

Adrian Rawcliffe: but there are other Hla’s and then they present That’s like different peptides and so you could you could expand the opportunity once you know that the target works and that Cell therapy is against that target work You can expand it to other hla types and overall if you had sort of three or four hlas for each target Then you would end up with 60 70 percent coverage Maybe up to 80 depending on the geography of the world population.

So it is it is viable to develop broad based therapies that could treat the vast majority of people with relatively small numbers of HLAs. Oh, that’s the thing, 

Philip Hemme: yeah. Yeah, I remember talking with Harpreet, he was making that point. I didn’t, it was not clear to me that the, they were, the TCRs were not recognizing the, I mean, they always talk about we target the intracellular targets, but it’s presented on the HLA and it’s very small.

piece of the peptide. So you need like ultra specific by specific or TCR engineered cells to recognize. Yeah. Now everything makes sense. Okay. That’s good. 

[00:13:54] Market access in Europe

Philip Hemme: And maybe to, to get back to, to patient access, how, how is it going in Europe? 

Adrian Rawcliffe: So, so we’ve had historically, we’ve had interactions with the regulatory authorities we conducted some of our clinical trials in Europe and we are, we’re, we’re consolidating the information from the Spearhead 1 trial, which had multiple cohorts, some of which is going to be required for confirmatory evidence in the United States.

And the totality of that we believe will be able to be submitted in Europe in the years to come. So it will come behind the United States but there in the population of patients in Europe. That I think is addressable by T Stellar and over time we will be able to address that. I think also got to think about this for a business context in the context of other things coming through and the infrastructure needed to support European launch.

We can do think about that ourselves or we could think about that in partnership as well. 

Philip Hemme: Okay, because you didn’t have a fast track mechanism for, for you, but you didn’t apply for it. 

Adrian Rawcliffe: So we have prime designation in Europe. We have prime designation in Europe. And, and the discussions with the agency were conducted under that, under that designation.

And so we, we believe we understand what will be needed to receive approval. I think, I think the commercialization of cell therapies is Is more challenging in Europe than it is in the United States, but all the car, the car Ts have showed that it is possible to do that. 

Philip Hemme: Okay. Yeah, no, that’s that’s good.

Yeah, I mean, I think it’s, it’s an amazing option for patients. So should be available also too more, more globally. Yeah. 

[00:15:36] Peak sales projections

Philip Hemme: Maybe talking about the, the peak sales. Like, I, I was curious. I, I, I heard you talk on, on the Zs show, podcasts interview. about the projections you had, which were, I think in the, you, you talked about the whole psychoma franchise, maybe not specifically to since et cetera, but I remember when I wrote it down, it was like a 400 million figure for the annual sales.

And it was pretty high gross margin as well. But then I saw that at least some figures from the other lists from Google and that they projected a bit lower, maybe 180 million or something. At least that’s the why, why, like, I mean, it seems like a one to two difference, like. What’s your take on this?

Yeah, 

Adrian Rawcliffe: I can’t comment on the analyst’s on this particular analyst’s forecast for obvious reasons. I talk about what we, what we believe. I mean, the, the, so there’s, there’s two products T Cellra, the first approved. And then behind that is, is, is a, is a product called Leticell at the moment. It’ll have a brand name in due course.

And letter cell. So Tcell targets MAJ for letter cell targets, N-Y-E-S-O. Tcell was for synovial sarcoma. Letter cell is for synovial plus and also for OID Sarco. And lettuce cell is, has completed its pivotal trial. The final data for that we anticipate at CTOs this year in mid-November.

We’ve already talked about the interim analysis, which is a little old but also showed that that that trial had met its primary endpoint even at the interim analysis So this is going to be a positive trial. And therefore we believe that we will be able to register that product and have that on the market in about two years time So you’ll have tesora and lettuce cell, coming side by side and the and the and the beautiful thing from our perspective is they go through exactly the same commercial channels and footprint So that so that the commercial channel that we’re building for tselra can just absorb treatment centers In crimson, okay same position.

Yeah, it’s same systems of supplying it. Although the manufacturing process is different Very slightly different. So so the the we think there there is a sarcoma franchise with massive leverage in From a business sense in the in the in the sort of commercial channel that we’re going through man the footprint We’re building and because of that we we’re looking at okay.

What what’s what’s the value of that to us? You And the 400 million number that we put out there was the value, I think it’s about, in the United States alone, of lettuce cell and T cell PKSL, in the launch indications alone. So we think that, that’s a, we, we, we made that available because if you go back to last year, I think people thought that the entire sarcoma business could be worth something like 80 million peak.

And so we thought, hang on, you know, you’re, you’re just thinking completely the wrong, you would collect one, but you got one product, whereas we’ve got two, two, you’re, you’re, the pricing is not where we now sort of landed on a three. We think you’re underestimating the patients et cetera. So there’s a, there’s a whole sort of set of stuff there.

It’s the why we wanted to rebase where we are. But I, but I, but we think about that as a, as a good, as a good start. Yeah. We can, we can address that. We can address that at a decent margin. And then we can, as we do that, we can also be thinking about how to expand that. Yeah. Once we’re commercially invested in this space, you know, are there other soft tissue sarcomas that express major A4 how do we go after those?

Could we think about use in earlier lines of therapy? Can we think about geographic expansion? And then how can we bring the rest of our pipeline through in sarcoma? So we really own this sarcoma space for cell therapy. 

Philip Hemme: That’s good. And I can imagine from a business strategy or corporate strategy, once you are first, now you’re commercial, once you are profitable and commercial, I mean, it’s a very different game.

And you can have much more flexibility, investments, expansion, et cetera, et cetera, et cetera. 

Adrian Rawcliffe: Fair, very much. And I also think there’s a difference. There’s a big difference between the investment in in the R and D to support the expansion of an existing franchise with existing products versus the investment in R and D In things that have yet to demonstrate that they are effective or can effectively generate sales and you know just the risk profile of that to say well, okay i’m in this space What does it take to expand the label into this space?

You know the the risk profile and the investment profile of that just looks very different and you You, there’s a, there’s a different return on investment approach to that. And, and once you’ve got products, you know, if you look at the history of, look at the history of successful biotech companies, and a lot of them have been successful by you finding something that works and then working out how to maximize the benefit that that product can provide to patients on a broadest possible front.

Yeah. 

Philip Hemme: Yeah. Yeah. I’m thinking about about Argenyx in Europe, which is. Built a massive franchise on the Yes, on basically a single product. Like it’s, it’s pretty . It’s not South , but it’s an amazing example. 

Adrian Rawcliffe: But it, but it, it is also true of some really big companies. I mean, take, take Keytruda. Take Merck and Keytruda, you know, when they initially had this, they didn’t really realize what they’ve got when they were first being developed.

They were like, well, I’m not really sure how big is, is the largest product in the world. Or take or take some of the some of the crazy on 

Philip Hemme: the single. Indeed. I mean, basically single indication almost, and that’s crazy. 

[00:21:34] Next steps into 2025

Philip Hemme: So I guess for the next step also, like 2025 would be a key year for, for you guys, I guess to show that you can reach the sales you have kind of predicted and that you have also profit, the profit margin that follows and that you’re on the right track for.

To solve the prediction that I can imagine. 

Adrian Rawcliffe: Yeah, absolutely. And the, I think it was, we said we anticipate to have our first patients treated and first commercial sales in 2024. The bulk, the real sales are 2025 onwards and we’ll, we’ll be, we’ll, that’s when we’ll see the patient flow through and and the, and the delivery.

And then the other piece of that is also moving that second product, lettuce cell forward as well and behind it so that we’ve got the confidence we can get to the other patients that we that are addressable, particularly in the myxoid sarcoma space. 

Philip Hemme: Yeah. 

Adrian Rawcliffe: That’s great.

[00:22:23] Rich History of Adaptimmune

Philip Hemme: Maybe, I mean, we talked about the current topics and the next step, maybe to, to zoom out a bit on the, on the history of adaptamine and, and your, where you joined into the, where you came in into the picture.

So I think that, I mean, the history of what I know for adaptamine is, is what do you like? It’s very interesting from where the science, there’s some science coming from Germany, from Medellin, baby cousin was the renal core when you split it. So therapy versus by specifics. It’s very like European led across cross continent, but with a very global development.

And you joined like almost 10 years ago. I guess you will celebrate your, your decade soon, I guess. 

Adrian Rawcliffe: Yes. 

Philip Hemme: Celebrated 

Adrian Rawcliffe: no. Early next year. I were day early next 

Philip Hemme: year. So, and you join I think A CFO first, then you transition to CE. And must. So can you Yeah. Maybe start with the, the history of Adam before you joined and how, how then it went on when, when you joined Until, until now.

Adrian Rawcliffe: Yeah, sure. So, so so Adaptimmune itself as a, as Adaptimmune has been around since 2008 when it spun out from gy. But the history goes back to about the year 2000 when. When technology was spun out from the University of Oxford or licensed from the University of Oxford into a company called Avidex back in, back in the history.

And, and, and that Avidex was really the precursor of both Adaptamine and Immunocore. So Avidex got acquired by Medigene and then separately Adaptamine and Immunocore spun out from from Medigene in 2008, about three months apart from each other. access to the same fundamental intellectual property, which is, is, is how to engineer the T cell receptors to fundamental tools to engineering for engineering T cell receptors.

And Obviously, Immunocore uses that for bispecifics, which requires a very different form of engineering to the engineering that you do for, for a cell, for a cell therapist. So from 2008 until 2014 Adaptavir was financed by high net worth individuals in, in, in the Oxford area and, and was researching how to incorporate T cell receptors into cells.

And moving forward into the clinic in very small trials in the United States in partnership with leading academic centers, including University of Pennsylvania.

Unless no, no, no, no, not not traditional vcs. 2014 they did their first vc round proper vc round led by nea and orbimed and that put us on course for an ipo in 2015 and this was when cell therapy was was sort of starting to become really super hot He just had the first car t data. Nabatis had had done this deal with with carl june 2015 a few years before and, and it was clear that CARTs were going to be huge and the proposition that CARTs were maybe not going to be the solution for all cancers and that TCRT cells would be another wing of that was sort of starting to become accepted.

And so first round of financing in 14, IPO in 15, I joined in between those two as CFO in order to help take the company public. Which we did very successfully in in, in 2015, in May, 2015. And, and the, what we did with that is we, we then sort of use the, use the proceeds and the, the momentum that we gained from those financing and from the belief in cell therapy.

To really invest in some of the core components that we believe are going to be critical for for cell therapy. Principally manufacturing and our manufacturing, internal manufacturing for our T cells. And, and so the history of that through then to, to the approval of T cell earlier this year is sort of a, Focus on moving from a technology platform company into a cell therapy company with the capabilities that you need to actually design, develop and deliver, as we say cell therapies, which are, which are, which we think are really specific, poorly understood by the, by the rest of the world.

And quite different to my experience with small molecules and biopharmaceuticals when I was my previous as a company GSK. 

Philip Hemme: Yep. Alright, that’s amazing. It’s, and then, and then between, between the IPO to now, like, And, and your transition to CO Hall, how did that go? Like, oh, tra tra 

Adrian Rawcliffe: transition. I, I, I think, I think, I think we’re, well so I transitioned in, in, in 2019.

At that point we were, we were we had seen the first signal in Sarco. With what is now T Cell, or what has been called a Famicel Leticell was being developed actually by our partner GSK at the time. And we were sort of moving the rest of our pipeline into, into the clinic to go 

Philip Hemme: bring So the company you got in via GSK, or you knew the company via GSK or there’s no connection?

Adrian Rawcliffe: I did, so I ran, I ran a business development for GSK for a number of years. But actually when they did the deal with, with adapt to read, I was, I was CFR of the North American business at the time. And so I, I, I had no understanding of adapt to read. I knew, I knew Avidex from, from from. Well, way, way, way back when I’ve interacted with them but I, I didn’t, did not know adaptamine at all.

And until I sort of got the call out of the blue about this small biotech company that was giant. 

Philip Hemme: It’s crazy sometimes in biotech, the biotech world is so small. But sometimes also you sit very next to something or an opportunity and you don’t see it. No idea. No idea that was 

Adrian Rawcliffe: happening. And you can imagine, you know, as the commercial organization of GSK you know, the, the focus is not on, well, Ooh, there’s a really interesting proof of concept in human study going on in this R& D or this actually is from the market.

You’re, you’re, you’re very focused on the respiratory franchise, the vaccines franchise, and the stuff that, that’s actually real time. So yeah, you can sit right next to it and not know what’s going on. That’s amazing. That’s cool. 

[00:28:47] GSK and transitioning to Biotech

Philip Hemme: And then maybe you talked a bit before about your, I mean, I’m curious of the skills or what you brought from your experience at GSK.

I mean, you said it’s it’s very different to expand the label. But at the same time, you have this commercial exposure and what it takes. So can you elaborate a bit on that of like, I don’t know what’s what was the most useful skills or most useful experience or some examples you had? 

Adrian Rawcliffe: Yeah, so so I, so I’m not a scientist by training.

My first degree was mostly molecular biology and biochemistry, but I’m not a scientist by training. And so But I had a number of roles at GSK and actually probably the most the most useful ones were the ones that sat with the ones that sit on the interface of science of the science and the business.

So I spent a lot of time in their business development organizations of various types ultimately leading. Worldwide business development for a number of years. I also ran their venture capital fund sr1. So, it is and the the beauty of those roles and is that you get to look at an awful lot of science and r& d projects.

Yeah, I probably did diligence on whilst I was running bd Maybe we did diligence on a couple of hundred companies, a couple of hundred programs over that period, you know, deep diligence. So you, so you get to look at, and when, when you do diligence on a, on a development program, it’s a fascinating thing because you get to see in one go the longitudinal history of all of the development decisions that were taken all the way back into research.

And you get that nicely packaged up and, and you get, I said, why, why did you take that decision? I didn’t do it. Why did you choose that trial and not that trial and that indication another indication? And and I think that that was incredibly instructive in in how Good r& d gets done. And and then also and then also the the overall what to pay attention to you know, I’m fond of talking about that.

I I didn’t I didn’t look when you’re when you’re running a business development organization you’ve got to trust that the experts in the company that are doing the diligence are doing a good job And so by and large I did not look at primary materials for most of The stuff that was coming through diligence.

Philip Hemme: But you have to understand, I mean, you have to, yeah, understand them and, I mean. 

Adrian Rawcliffe: Yes, yes you do. But you rely, to some extent, you do rely on the judgement of the people who are, who are doing it. There’s one exception, which I, I, we, we learnt, which is. When it comes to regulatory correspondence, that was the one piece of the, of the, of the due diligence report that I always tried to look at the primary correspondence with the agency.

Because it’s the one where you actually get a sense of the nuance of, of the program and what the, what the agency really thinks about the product. Quite different from the potential added value attached to it. Yeah. And, and so, and so there’s a, there’s a, And there’s a big difference, I found, I, I, I, I believe.

Between looking at drugs that are sort of like transformational versus drugs that are, yeah, me too. And those look very different when viewed through a regulator’s eyes. 

Philip Hemme: I, I, yeah, it’s, it’s, I like that actually. I recently, I talked with a, with a friend and recently we were talking about the company evaluating and then he, you rapidly went, was approved drug, rapidly went to the, to see what the regulatory, what’s the, what’s the folder and what they really say and how they compare it to existing and what is their take.

And then you feel it’s very different. Message was a wash drug, but that’s very different from the wash commercial pitch. And it was very interesting to see actually, and very like detailed, but also they’re quite understandable from even like, not like super KOL level to read it. I mean, even for me, I could read it and pretty clearly understand the fight compares, which I Yes.

Very, very. Very good. Actually, I haven’t done it for that team. You know, I haven’t checked what the FDA says, but I guess for you, it’s, yeah, it, it, 

Adrian Rawcliffe: it, it, it, it’s interesting. There’s a whole lot of documentation that’s out there that shows the discussions that we had and, and yeah, there’s, there’s, there’s an interesting, interesting balancing act on this because it was actually a privilege going through that process because there’s two, and you look at it from two angles.

So, you know, we had the FD, we had to manufacture. See we have to manufacture these hours. So the fda inspected our manufacturing facility at the labor yard and we had We had an inspector there for eight days all of one week and then into the next week and They were exceptionally thorough with what they were asking and and and you’ve got this duality in your head going on because on one hand it’s like We’ve got this we know what we’re doing like There’s a sort of like okay.

We want to get through this. I want to provide you with everything But you know, like this is this is this is a lot and on the other hand There’s the view of the patient which is okay This is a regulatory agency that is going to give permission to a manufacturer to manufacture this product actually as a patient I can’t i walked away from that that process feeling Actually that regulator is doing their job.

They are going through that process and I was like, okay, if that’s the process the regulators are going through then actually I feel better as a patient Or a potential society that that regulator is actually regulating effectively even though it can be I don’t think it’s frustrated, it’s just like, it’s tense, if you’re, you’re going through this inspection for the first time, it’s a tense process.

But from a patient perspective, it’s what you anticipate 

Philip Hemme: the regulator should do. It’s, it talks also from a, even from an industry point of view, it brings trust to so many levels. And at the end of the day, that’s also what you want. Yeah, yeah. Global healthcare, bringing healthcare to patients, I mean You do.

And especially when it’s complicated and the patient cannot 

Adrian Rawcliffe: And, and, and for these therapies in particular, I think you know, because they’re manufactured on a patient by patient basis, the manufacturing is is different in terms of the The mechanics of it and then the overall the extent to which the product is the process is is so much more true for a cell therapy than it is for Yeah, a biopharmaceutical or yeah, you’re obviously for a small molecule because your ability to characterize that product and say you produce the same thing Is quite limited because this input cells are very different 

[00:35:54] Why Manufacturing is Crucial in Cell Therapy

Philip Hemme: I want to talk about manufacturing.

I wrote I wrote down here From from the previous thing you said that maybe to finish this on your first background You talked a lot about bd as well in your bd experience, but then at adaptimune On the BD, at least you didn’t, you went to the commercial on your own, you didn’t try to partner with someone.

So how, how intentional was that? 

Adrian Rawcliffe: Yeah, so, so I, and, and that’s not a, that’s not a discussion that says we will never, we will never partner on a global basis about, you know, we’ve, we’ve sort of been clear. We have some fundamental platforms. We have a pipeline, we have some product. Leveraging value of those on a global basis to the maximum extent is going to take partnerships.

And so, you know, very clear about that. Having said that Let’s get up, I go speak with, we can talk a 

Philip Hemme: bit after. 

Adrian Rawcliffe: Yeah, so, you know, that that’s a really good example. And then, you know, the what previous partnerships we’ve had with, for example, genetic and our allogeneic platform, other examples, how we can leverage the platforms that have broader utility than that we can provide, you know, if you got these fundamental platforms but at the same time I, I think that there is a, there is a desire or belief that in a new modality like cell therapy, The way that we’ve done everything up to this point in time has not been the same as it would be if We were developing a small molecule, you know And there’s lots of things that if you’re developing something that is well known and understood It’s easy to outsource or partner bits of the value creation chain, you know for us that’s that’s not apparent not as apparent in the in the In in in this new modality and so the way we go to market and the fact that so much of the commercial investment is actually on the supply chain is on actually how you deliver this product to patient Sort of meant that For this particular market, which is relatively small This is sort of perfectly sized for us and it’s something that we felt not only could we bite off But actually if you said who’s the best owner of this it would be us Because I think we are able to best extract dwelling from this.

Or for, for beer, deliver value, patience and extract value for our shareholder. 

Philip Hemme: Yeah. And I guess you had also access to capital as you mentioned. Yeah, you had the optionality to Yeah, to be able to of Pyrotech who don’t have the optionality. 

Adrian Rawcliffe: Well, it’s also, if you think about our commercial the actual true commercial investment, you know, ignore, ignore the, the sort of manufacturing investment, and just think about the commercial investment.

It’s a relatively small organization, you know, our commercial plus Med Affairs organization is about 30 people. We’re going to be targeting about 30 sites in the United States. And so yeah, it’s it’s it’s discreet and and but that’s what’s necessary. This is a this is a rare disease White glove model as opposed to a mass market And so I think I think it actually is perfectly suited to smaller smaller companies who are who are very specifically focused on delivery in this area.

It’s a typical Genzyme 

Philip Hemme: model. I read the how do you tell me your biography? Huh. Yes. But I can recommend that as a book. It sounds like that model. Yeah, that’s great. It’s good. And that’s perfect transition to to manufacturing it. I read quite a lot about this. And I heard that several times. In cell therapy, manufacturing was, I mean, is the product basically, and it was, it’s key.

I saw some examples in, even in CAR T where the manufacturing on the same CAR T can make a huge difference in the fitness of the cells, et cetera, et cetera. Can you, like, maybe explain a little for the audience of how important manufacturing is and maybe if you have some examples of adaptamine or not from adaptamine?

Well, 

Adrian Rawcliffe: I, I, I think it’s fundamental and I did not understand it when I joined the company. Although I think the people who have been deeply in health therapy for a long time have this this is this is what they live and breathe so, Everybody everybody talks about these things as if the primary differentiator for a therapy is the target, the thing it targets.

So we talk about CD19 CAR T’s and we talk about MAJ A4 targeting TCRs or PRANE targeting TCR. And, and that’s fine. You know, that, that’s the bit that we genetically edit into the cell. And, and therefore, you know, it is where a chunk of the IP comes. It is what gives it the ability to recognize a tumor that it previously wasn’t recognizing.

But the cell is doing, yeah, 150, 000 things all at the same time, and one of the, one of the beauties of cell therapy, there’s, there’s two things that differentiate cell, the cell therapy in my mind. One is, one is this, this one off therapy that gives permanent, Gain of function. Yeah, that’s the genetic editing part of the of the cells.

Yeah, you’ve been aspect of the gene therapy in a cell with cell in the form But another piece of the cell therapy and the differentiator from from gene therapy and from every other therapy Is that what you’re giving is a little engine and you can tell that little engine to do a whole load of other stuff So so you can take Cells that are previously in a particular state and you can change that state through your manufacturing process So you change it by editing, but you change it.

And I think it will be at least as much by the manufacturing process. And that’s, what’s being demonstrated in, in, in a variety, a variety of places, you know, Novartis is T charge where they, where they show fundamental differences in the fitness of cells that, that, that shorter manufacturing time seems to be seems to be.

Very significant and replicated across a range of different types of therapies. The, the, the one that we have is which we’ve talked about publicly, is that when we moved from our t-cell, previously a FMA cell to a product that’s now called user cell, which is a next generation version of of, of, of.

of T cell 1. We did two things, we did a number of things to it, but two of the things we did is, one, we used the same T cell receptor, but we added a a CD8 to make all of the cells killer cells and preserve, they preserve their T helper cell function, but they were all turned into killer cells.

So you get a much more potent product for a particular number of cells. But then the second thing that we did was we added we added an AKT inhibitor into the manufacturing process. And, and what that was designed to do, and what it seemed to do, was enable the cells to replicate, to, to, to expand without Growing older without differentiating as much.

So so you get you get a sim you get more cells You get similar dose of cells, but they they’re not as old. They’re not as then they’re not as exhausted They’re not as what’s terminally differentiated. So they’re not as far along their sort of program into into t killer cells as as or into terminally differentiated vector cells as you would expect and the advantage of that is that they are very easy to You going to you and they then expand more in you.

They then persist for longer and they have a more stem phenotype. They have a, an a, an earlier, an earlier phenotype, which means they, they are more capable of re of replicating. And they will do that in, in vivo as opposed to sitting in a, in a, in an incubator or ada. Okay. 

Philip Hemme: And this translate makes total sense and translate then to efficacy and.

Adrian Rawcliffe: Yeah, control completely different growth curve when they get into you. So theam cell grows very quickly, expands very quickly. You get any cytokine release, which we don’t see that much of with Aam cell quite quickly. With with user cell, it expands much more slowly. You know, PP Huntington takes, takes a few more days.

We get delayed cytokine release syndrome to the extent that we get it. etc. So it’s just a completely different phenotype of product behaves very differently, and actually is effective in a bunch of solid tumors that a FAMICEL T cell was not effective in. This T cell was very effective in sarcoma, outside of sarcoma, modestly effective.

User cell has been shown to be produce responses in a wide range of other solid tumors. 

Philip Hemme: Okay, that’s a very clear, very clear explanation. 

[00:44:47] The Future of Cell Therapy: When will Allogeneic and In Vivo Therapies be on the Market?

Philip Hemme: So is it, and it brings me also to another question, very similar, I mean, in a similar tone or category. I talked with a friend at J& E, obviously quite involved in, in CAR T as well and in self therapy.

And he was curious what’s your take on, let’s say, the next generation on the. Next wave of self therapy, especially when you’re talking about allogenic or in vivo yeah. InVivo self therapy. What, what’s your thoughts there? 

Adrian Rawcliffe: Yeah, so, so we have a, we have a allogeneic platform and we’re thinking about in vivo as well long term.

I, I think one of the amazing things about the biotech investment environment is it’s constantly looking for the next hot thing. And, and so, and I think as a tendency to. Underestimate the challenges and overestimate the speed at which those new next top things can be available. And I think it was very definitely true with allergen.

I think it was like, Oh, it 

Philip Hemme: took way longer than expected. Yeah. 

Adrian Rawcliffe: Way longer than expected, but, but, but that, and that doesn’t mean that it won’t. Happen, in fact, we still believe it very much will happen But it means that it will take longer because it’s not going to be the same product And so so our approach was look, you know, actually autologous cell therapies work and that because they work it’s worth trying to overcome the logistical and engineering challenges of making them available at volume at scale, which is not not not not in not Volume at scale Easy, but also not insurmountable and requires actually bringing in skills, engineering skills, logistic skills from other parts of the healthcare ecosystem that can be very useful to us.

So yeah, that, that is a problem that is being solved in real time and will continue to. And my view is the next, the next 10 to 15 years. Okay. Is autologous okay. So then I think you get to that, that point. Okay. I, I, I think it’s, we, we think it’s the next decade. Now in the hemo space, you might get to donor derived allogenetic before then.

But in the solid tumor space, nobody, nobody’s close. So I think the next 10, 10, 15 years is auto, auto. And then, you know, Aloe maybe gets overtaken by In Vivo. I don’t, I don’t know all of, all of that’s out there. In the meantime, there’s a lot of other renovation that can be done. And, and, and the thing is, There’s sort of a whole bunch of scientific innovation, I think multi targeting, multi edited, multi armored approaches and, and finding a way of developing these rapidly, iteratively, and in a regulatory environment that enables that is, is, is going to be critical to success beyond the first half dozen, ten products that people will get on the market, targeting prime, because the beauty of self therapy is you can iterate these things.

Yeah. 

Adrian Rawcliffe: And then the other piece I think is is just on the on the manufacturing when we understand all the parameters that actually define efficacy for our products over the long term And we’re sort of scratching the surface of that at the moment when we understand that then you’ll be able to design manufacturing processes that are Dramatically more efficient than the current manufacturing process and that’s the key to getting to this being a in any way a truly global widely available option.

Yeah. How’d, how’d you get out from the expensive medicines for the Western hemisphere and into, into a global solution for a large subset of cancer? Yeah, I think, I think that’s going to be key. That’s a great, 

Philip Hemme: that’s a great, great way to, to, yeah, it’s a great way to finish on the industry. 

[00:48:43] Quick fire with Adrian Rawcliffe

Philip Hemme: Before we have a, we have a, just a few minutes left or two minutes left.

Usually I finish with just rapid, a quick fire, just yes and no questions. Go for it. What? So yeah, go for it. And, and some are a bit more funny. The first one is funny. Do you prefer Philly cheesecake or Oxford fish and chips? Philly, Philly cheese, Philly cheesesteak, I’m afraid, 

Adrian Rawcliffe: sorry. 

Philip Hemme: Yes. 

Adrian Rawcliffe: What’s your favorite biotech book?

Emperor of All Maladies. Oh, I don’t know this one. Ah, yeah, there, it’s a, it’s a biography of, of cancer, a historical biography of cancer. It’s, it’s fascinating, amazing read. How much do you read actually? , I most, I mostly read, I read nonfiction and news. I’m not a huge fiction reader. No. So I’m, the answer is not as much as I should.

Yeah. , 

Philip Hemme: What’s your the, what’s your one of your biotech HEROs? 

Adrian Rawcliffe: Again, I, the risk of being stereotypical, ’cause I’m sure it’s, it’s on a bunch of, a bunch of people would say it’s John Margan CEO of founder, CEO of Alnylam. ’cause he, he, because he, he. Had an idea in a completely new modality and did absolutely what is what it takes to make that Our lion and the successful company it is today I saw you recently received the like a lifetime 

Philip Hemme: award or something.

Adrian Rawcliffe: Yeah It’s an amazing story. And there are, there are several of them, but but he’s, he’s, he’s particularly aspiring. 

Philip Hemme: Amazing. 

[00:50:20] Thanks for listening

Philip Hemme: That’s great. Let’s finish here and you’re perfectly on time for your next meeting. First, thanks. Thanks Adrian. It was amazing. Good. Great, great, great, great to speak with you. Take care.

Cheers. Bye bye. I’m impressed by the development of T Cellar and Adatimine and the benefits it will have for sarcoma patients. I’m also impressed by how clearly Adrian could articulate the big picture of TCRs, cell therapy, autologous versus allogenic versus in vivo, while having fun. If you also enjoyed this episode, please hit the like, follow, or review button.

Any of those actions would help us a lot to give more people access to the podcast. If you want to see similar videos, please check out our channel where we have many available. Also, I would be curious to hear what you think so I can further improve the content. If you could leave a comment wherever platform you are or shoot me an email at philip at float dot bio.

Alright, thanks for watching to the end and see you in the next episode.

SHARE

Further Episodes

Episode 26

Gunilla Osswald, BioArctic 🇸🇪 | Leqembi, Alzheimer’s disease | E26

Gunilla Osswald, BioArctic on the Flot.bio Show
View Episode
Episode 25

Sean Marett 🇩🇪 | BioNTech, Art of Dealmaking | E25

Sean Marett, BioNTech on the Flot.bio Show
View Episode
                           

Never miss a new episode 💌

                           

Trusted by 250+ professionals from top companies like Argenx, BioNTech, or Genmab. No spam, no noise.

                                           

Watch & Subscribe

Flot.bio on Youtube                 Flot.bio on Spotify                                    Flot.bio on Apple Podcasts