Episode 59: Bas van der Baan - President & CEO, Lixte Biotechnology

Join as we dive deep into the world of oncology drug development with Bas van der Baan of Lixte. Discover the inspiration behind Lixte's focus on PP2A inhibitors and how this innovative approach is poised to revolutionize cancer treatment by enhancing chemotherapy and immunotherapy responses. Bas shares insights into ongoing clinical trials, regulatory considerations, and Lixte's ambitious long-term goals in expanding their impact on cancer care. Tune in to explore the cutting-edge science and vision driving Lixte's journey in the fight against cancer.

First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder. Episodes launch weekly on Tuesdays. To view the full transcript of this episode, click here.

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Chapters

• 0:19 Innovative PP2A Inhibitor Enhances Cancer Treatment
• 12:35 Innovative Approaches in Cancer Treatment

Transcript

Speaker 1: 0:19

Thank you, featuring special guest host Amy DelMedico, vp of Ophthalmology, for this episode. We are joined by Bas van der Ban, ceo and President of LixD, to discuss their innovative approach to enhance cancer treatment efficacy with LB100, a PP2A inhibitor, in combination with chemotherapy and immunotherapy.

Speaker 2: 0:44

Hello everybody. I'm Amy Delmedico and I'm here today with Bas van der Baan from LixD. Bas, welcome. Would you like to give a brief introduction?

Speaker 3: 0:53

Sure, thank you very much and great to be here, amy. I joined the board of LixD in mid-2022, got a background in biotechnology mid-2022. Got a background in biotechnology, has been in the space for the last 20 years, co-founded two molecular diagnostic companies and two drug development companies and this is the first time I actually took over from a founder. In September last year I took over the position of CEO of the company and you know it's been a great ride so far.

Speaker 2: 1:24

Fantastic, thank you. So we've got some sort of broader questions as well as some more detailed questions about the IPLP with LB100. But first of all, more broadly, in your opinion, what are the biggest challenges and opportunities facing the oncology drug development landscape today?

Speaker 3: 1:40

So I think for me now the biggest challenge obviously is the amount of trials happening. You know it's become more difficult to enroll patients because there's just a lot of competing trials out there. But on the upside right, if you've got a really interesting biological rationale, like we do, you know you can trigger the interest of the PIs and make things happen. So the great thing is that I think the time between preclinical concepts and going into the clinic has substantially shortened and we clearly made use of that opportunity within LixD.

Speaker 2: 2:09

Okay, great. So what inspired LixD to focus on developing PP2A inhibitors and what potential advantages does your approach offer compared to traditional cancer therapies?

Speaker 3: 2:21

Yeah, so it's going to be a little longer answer. So it just got me short when you, when you've heard it all. But what triggered Lixity to take this path was also what really interested me to join as a CEO. So they weren't always on this path. As I just said, I co-founded two molecular diagnostic companies. One of them was actually a spinoff of the Netherlands Cancer Institute and I've always stayed in close contact with that research department. And the Netherlands Cancer Institute is an interesting institute because the research and the hospital are really close together and a lot of things that are happening in the research department spill over to the hospital and vice versa. So interesting setup.

Speaker 3: 3:02

And so one of the adventures there in those days was about breast cancer recurrence and the need of chemotherapy, and I've always stayed in touch and one of the founders, rene Bernard, always stayed an academic and moved on to drug combination right With the concept that you know in oncology it's probably not going to be a silver bullet that's going to solve it, right? What we see in cancer is that, especially with small molecules, they initially work really well and then some sort of resistance happens. And so at the NKI, independently, they were doing a lot of synthetic lethality screens, both with siRNA as well as CRISPR, to figure out. Okay, what are the mechanisms of resistance, right? How can I find that back door that a cancer cell is using to escape the therapy? And can I find that back door that a cancer cell is using to escape the therapy? And can I close the back door in parallel, in combination with the front door, so to speak?

Speaker 3: 3:50

So they found that the PP2A pathway was a really interesting pathway when they were looking at chemotherapy as well as immune therapy. So, independently of Lixity, they said, well, wouldn't it be great if we can inhibit that PP2A pathway? Let's have a look if there's any company around that's already working on it. And they found Lixity and Lixity was very receptive to their proposals of collaboration. And that's kind of how almost a restart of Lixity started, because Lixity originally was focused on monotherapy. They were focused on a few non-oncology indications and the sweet spot of this drug actually is in combination with either chemotherapy or immune therapy. And so we really changed the strategy, discontinued some trials outside the oncology space, discontinued the monotherapy approach and really focus now on the combination of chemotherapy and immune therapy based on, you know, independent research. And so that's where we are now.

Speaker 2: 4:52

That's really interesting. Thank you, and you touched on some of this in your answer, but can you elaborate further on the mechanism of action of LB100 and how it advances or even enhances chemotherapy and immunotherapy cancer treatment?

Speaker 3: 5:17

kinases, right, the on switch in signaling, because, you know, the general perception is there's too much signaling in a cancer cell, we have to shut the signaling down, and the difference between a cancer and a lung cancer cell often is that a cancer cell is way more active and then, using certain pathways to you know, grow and metastasize, and this is a phosphatase inhibitor. So essentially, we're now targeting the off switch, which is very counterintuitive. So not only, you know, is there too much signaling, we're taking away the off switch too. So what's happening? What we've seen now is that protein phosphatase 2a has a lot of targets, and so the initial concern was also toxicity, right, and that was great, because before I joined they've done all the tox studies, tox studies already on monotherapy, and it wasn't toxic, right, it was a potent inhibitor of PP2A and it wasn't toxic as monotherapy. So that fear was taken away. And so what it essentially does is because it has multiple targets, it has a multiple downstream effect. So one of the effects is that it pushes multiple targets. It has a multiple downstream effect. So one of the effects is that it pushes the cell into cell cycle. That's a great thing, because chemotherapy needs a cell while it's dividing, because then of course it can create all the damage in the DNA which leads to apoptosis. But on top of that, what we've seen that one of the other downstream targets of PPTOA inhibition is that it inhibits DNA repair. So not only does it lead chemotherapy to do its work in creating damage, it also inhibits the potential repair of the damage, which again makes it even more effective as a chemotherapy enhancer.

Speaker 3: 6:52

On the other hand, in the area of immune therapy it gets even more interesting because what we see it has three effects Two effects outside the cancer cell, actually on the immune system. So it actually enhances the release of cytokines. But it also enhances the proliferation of T-cells, so you get more soldiers to actually fight the tumor. But the effect on the tumor is interesting because it pushes the cell into cell cycle and it makes the replication a little chaotic. It creates the PP2A actually works on the RNA splicing and on the splice zone, creating new peptides or so-called neoantigens, and those are actually presented on the cell surface. So the cancer cell becomes more visible for the immune system. That we also enhance with PP2A by increasing the cytokines and increasing T-cell proliferation. So a lot of actions and they're all extremely well described in recent literature, because our collaboration with the Netherlands Cancer Institute led to two phenomenal publications that came out actually last week and one will come out tomorrow that precisely describe how this biology works and what the effects are of PP2A inhibition in combination with those therapies.

Speaker 2: 8:12

That sounds like a really exciting approach and good to hear that it's been well documented as well.

Speaker 3: 8:17

Yeah, I think it's one of the critical elements right For myself, I'd be like if you're going to spend your time and put your soul into a company you know, it's great if it has a big impact. And by enhancing chemo and immune therapy I mean most patients today are treated with either one or the other or both right, and we know that the effect can be better. Chemo response rates are 10 to 20%. Immune therapy spectacular in MSI, high colon cancer, in lung cancer, in melanoma, right Tumors with a very high mutation burden, but not so much in all those other tumors. So it can really use that boost. So I think this concept can have a very big impact. And then, secondly, I think in today's day and age you just got to understand the biology right to increase your chance of success.

Speaker 2: 9:04

Absolutely Everyone, as an industry is talking about precision medicine. I wondered is LixD able to tailor the therapies towards individual patients at this stage?

Speaker 3: 9:15

So that's interesting because, as I said right, I've got a lot of experience in molecular diagnostics. So that would have been another aspect that I would really like to see in drug development. But in this case it is actually pretty broad spectrum. So it is a general enhancer of chemo and a general enhancer of immunotherapy. But one of the trials we're conducting is at the MDN Cancer Center MD Anderson Cancer Center in Houston and they actually proactively approached us because they did a study on a failed immune therapy trial in ovarian cancer.

Speaker 3: 9:51

So in the unstratified population immune therapy didn't do much right, and I think to my knowledge there's no approval of immune therapy in ovarian cancer, but I might not be entirely up to date and so but in their trial at least immune therapy didn't do much in ovarian cancer.

Speaker 3: 10:08

And then, if they looked at a subset of ovarian cancer called ovarian clear cell carcinoma, they sequenced all the tumors and what they saw is that there's a small subgroup that did benefit of immune therapy and it turned out to be the patients that had a deletion in the PP2A gene. So patients with a PP2A mutation actually responded really well to immune therapy. And so what triggered that is like, okay, can we mimic that mutation and, of course, by inhibiting PP2A. That's how they found LixT, and they brought LixT and GlaxoSmithKline with their PD-1 inhibitor, drostarilumab, together and that's one of the trials we've currently opened. So it's not precision medicine as we know it. Theoretically you could leave the PP2A mutants out right, but it's such a small subset so that's not what we're doing. Currently we enroll all ovarian clear cell cancers. But it is a very nice indication of the concept that, looking back, you can make immune therapy work in PP2A mutant patients. There's only a few patients that actually have that mutation, so for the vast majority, inhibiting PP2A might be the solution to make immune therapy work.

Speaker 2: 11:19

Okay, thank you, and you've mentioned both breast and ovarian cancer. I wondered if there were any plans to expand LB100 syndications beyond what you're currently looking at, or if there are any other IPs in the pipeline that you're developing.

Speaker 3: 11:34

Yeah, so we currently have three trials open. So one is the ovarian cancer trial that I mentioned. A second one is a sarcoma trial, so it's advanced soft tissue sarcoma. That's a very difficult one, right? I mean I think chemotherapy has been the standard of care for the last 40 years and many have tried to get better outcomes in that disease. And here we're working with the European Consortium for Sarcoma called GEIS, out of Madrid, to combine LB100 with chemotherapy in advanced soft tissue sarcoma, called GEISS, out of Madrid, to combine LB100 with chemotherapy in advanced soft tissue sarcoma.

Speaker 3: 12:08

And then the third trial that we currently have open is in small cell lung cancer where the standard of care is chemotherapy with immune therapy. At least that's the standard in the US. Still those patients have a very poor prognosis in later stage of the disease. So there we're combining LB100 with chemo and immune therapy to see if we can give it a kind of a double boost. So those are the three that are currently in the works. And then we're looking and considering to do something in colon cancer, especially MSI. Low, because we know immune therapy is really effective in MSI. High colon cancer because of the high mutation burden, but there's hardly any benefit and no approval of immunotherapy in MSI low advanced or metastatic colon cancer and that's one based on that, you know, neoantigen production featuring capacity of PP2A inhibition. We think that we can make those cold tumors, we can make them immune hot, and so that's something that we are considering for the near future, based on recent publications.

Speaker 2: 13:13

Great, so a range of quite different indications.

Speaker 3: 13:16

Yeah.

Speaker 2: 13:17

So LB100, I believe, is a new class of therapy. I just wondered if you'd come across any particular hurdles from a regulatory perspective.

Speaker 3: 13:25

Well, not yet. So we have our IND approval in the US and our INPD approval in Europe and we're conducting trials both in Europe as well as in the US. It's definitely a first in class. Lixity is unique in their approach. There's nobody else taking this approach, which you know can be a little scary and taking such a new route. But I think also, you know, we've got to do new things and controversial things too, because in many cancers we do see a bit of a plateau in the survival. So to push for that extra survival benefit, we have to do things that we haven't done before, and one of the latest articles is calling it a paradoxical activation. Right, so taking the brakes off, but the preclinical data looks spectacular. And so now we're in a very interesting phase of having three trials open to see if that preclinical data actually translates to clinical benefit and to see if that preclinical data actually translates to clinical benefit.

Speaker 2: 14:25

Fantastic, thank you. So a more general question, and this is from more of a CRO perspective. I suppose we know clinical trials are complex and costly and time-consuming, and probably no more so than oncology clinical trials. I wondered what sort of role you feel that CROs will play in LICSTI's development process.

Speaker 3: 14:44

Yeah, so we're not just in the clinic because we did our safety trials right and the three trials were open our investigator initiated. So the roles of CROs at this point are more around monitoring and pharmacovigilance. But you know, I'd love to go to the next phase where we do the industry-sponsored trials and then I'd love to work with you, know, know, a good cro, to get those larger trials going that deliver the, the outcome and the quality necessary for for the approval process, both in the us and as in europe that's great good to hear, thank you.

Speaker 2: 15:16

Final question uh, just looking ahead, I wonder what the long-term goals are and the visions for LixD.

Speaker 3: 15:23

So, again, a very interesting company. It has one asset and some people sometimes say like well, you need to have a pipeline. What if your number one asset doesn't make it? Because, honestly, if you look at the approvals, I think currently there are almost 8,000 trials open in oncology, right. And how many first-in-class approvals do you have a year right? So that's maybe double-digit, but at best. So you know, you have to be realistic.

Speaker 3: 15:52

But I think for us it really works well, it gets our full attention, and so for us it's really about showing some first signals in humans and therefore we pick those three trials that we've currently opened to combine LB100 with only chemotherapy in soft tissue sarcoma, to combine it with chemo and immunotherapy in small cell lung cancer and with only immune therapy in ovarian.

Speaker 3: 16:17

So I think we've picked all the possible combination of where we think the sweet spot of our drug is. We pick three different cancer indications of which I think the sweet spot of our drug is. We pick three different cancer indications, of which I think the ovarian one is the most interesting because we have this mutation data that shows that patients with a mutation in PB2A actually do respond to immune therapy. But, as I said before, most patients will receive either chemo or immune therapy or both, and so we're really looking forward of expanding this indication within a much broader scale of cancers in the future. As I gave an indication already, we're looking at colon cancer at the MSI low colon cancer at the moment, but there's a number of other, I think, cold tumors that are not so immune responsive that hopefully we can make immune therapy more effective.

Speaker 2: 17:05

Bas, thank you very much for sharing your vision and also the science behind it. It's very interesting.

Speaker 3: 17:10

Thank you very much. Well, thanks a lot and great discussion, great questions. Thank you.

Speaker 1: 17:22

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