Syntara Ltd Corporate Presentation Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Claire Harrison - Myeloproliferative neoplasms - Analyst : Sorry, slight delay with the audio there. So hello, everyone. So, I'm Claire Harrison. I'm a hematologist working in London. I've got 20 years experience as a consultant in this area, and this is my area special interest. I've been involved in many drug trials in myelofibrosis and have a lot of patients on my books, and I do a lot of work with patient advocacy. So that's led me to sort of understand quite a lot about the clinical spectrum, but also quite a lot about what the patient need is from the perspective of the patients as well. So where we are with myelofibrosis in 2024 heading into 2025 is in North America, at least, we have four different JAK inhibitors all with slightly different targets, but all broadly delivering some degree of spleen and symptom benefit for patients. Two of them also potentially targeting the ACVR pathway and delivering some benefit for patients in terms of hemoglobin. And they are, say, ruxolitinib is a first-in-class, fedratinib is a second and then pacritinib and momelotinib. But there's still a big area of unmet need for our patients. The average patient would stay on ruxolitinib for maybe three years. Their life will be prolonged by it. But ultimately, underneath their bone marrow still accumulating fibrotic tissue and their disease is still progressing. Many patients will have to stop the JAK inhibitor. And the reason that they often have to stop this because they have sort of on-target thrombocytopenia or low platelets and anemia and because the drug stops working for them. So for our patients, we really need something that's got a way of having traction on the basic biology of the disease. And one way of doing that is potentially by targeting the mutations. And we're a long way off a targeted mutational therapy, although there are some in development. Another way is to take a rational scientific approach like this one targeting LOXL. And so what I've seen here is impressive. And I like the fact that we've got monotherapy data. So there's a group of patients that have had PX-5505 on its own. So, we can only say for those patients, the changes that are seen here are just due to this drug. And for me, as a clinician, that gives me what I would call a reason to believe that this agent may well be effective for these patients. So that was data that was presented last year at ASH. It's a slightly more complete data set, I would say, and we saw the fibrosis change there. What we saw this afternoon in what was quite a busy session was this data that you've seen just now. And I just want to emphasize to you that these patients who are on ruxolitinib, who have often been on it for maybe up to five years. I think one of your patients was -- these patients are tough. They've got a heavy burden of disease. The disease has been progressing underneath. And they still got big spleen and they've still got symptom burden. So what we've seen presented is, one, reassuring from a safety perspective, this drug is well tolerated for patients. If they weren't tolerating it well, and they didn't feel some benefit, they would be stopping. Some patients are discontinuing, but I would say nothing more than the rate of discontinuation that we would expect and that we saw presented, for example, with navtemadlin, the MDM2 inhibitor this afternoon up to 60% of patients had withdrawn at the time of the analysis in that study. And so here, the data that we've seen, I think is impressive. I think what we've seen is that clearly, there is still one, a residual unmet need for spleen and symptoms. And the symptom data is particularly impressive. I do like the fact that it's progressively getting better. I think as the data was showing that's good. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies. DECEMBER 10, 2024 / 3:00AM, SNT.AX - Syntara Ltd Corporate Presentation I think with this agent, with this mode of action, we would expect to see slower changes in the spleen because one, the patient's already got some response from the ruxolitinib. And secondly, what we're expecting to see here is change in the bone marrow microenvironment, then also manifesting in a spleen change. So it's gratifying to see what we've seen today. A question I can see in the chart, but a question about what amount of spleen response would we expect to see on top of ruxolitinib. So just want to orientate you to the differences in the different data you may be looking at with different drugs and different companies. The data that's been shown today is for patients who have continued ruxolitinib. They haven't been washed out and then this agent added. So this is in addition to over and above. It demonstrates the unmet need and it's demonstrating what I believe is the activity of this drug. So often in the second-line setting, we are seeing more now something expressed, which is SVR 25%. In terms of the threshold for symptoms, Well, that's kind of a bit under discussion. We've seen some drugs failing in the frontline setting because they haven't significantly beaten ruxolitinib. But what I've seen today, would make me willing to recruit patients if we have the study open in the U.K., we don't at the moment. I think there's a strong biological rationale, toxicity looks good. And I'm really excited to see more data and understand what is the plan for next phase of development. It would seem to be logical to put it in combination, but I'm guessing you might come to that in questions. Thank you.

Question: Claire Harrison - Myeloproliferative neoplasms - Analyst : Sure. Thanks very much, Gary. So these changes in the marrow for these patients take sometimes many years to develop. And even if we use an incredibly aggressive therapy, which 90%, 95% of our patients are intelligible for, which is very risky bone marrow transplantation. By risky, I mean 20% to 30% chance of death. Even when we do that, the bone marrow doesn't really normalize for 12 to 18 months. Clearly, we would expect PX-550550 have an effect on the marrow, but it will probably be a slow and steady effect. We know it's difficult to reverse even with aggressive treatment. And therefore, I think these early signs that are being seen with regard to symptoms, probably are the type of thing that you would see early on, you might see some subtle changes in spleen. I just wanted to come back to that, actually, if you don't mind, and comment to say it's also important for these patients not to see worsening. So, these are patients whose spleen is gradually, probably early getting bigger over time and their symptom burden is getting worse over time. So, a stable spleen is also important here. So, I wouldn't expect the spleen to change substantially. So this is why I think the data is impressive. And then finally, to comment on these changes in the blood transfusion and their hematology aspect. That probably won't happen from this mode of action until we've got substantive changes in the marrow, I think. And to look at expecting a patient who's requiring very heavy burden of transfusions to suddenly require none, it is quite tricky. So, the subtle changes I might want to see early on would be for the non-transfused patients maybe a subtle drift up of the hemoglobin or the platelet count. But I think what I'm trying to say is bone marrow changes will be important because it's proof of concept. But we could expect it probably to take a while. So, I think the changes that we're seeing in the monotherapy again there are helpful for us.

Question: Claire Harrison - Myeloproliferative neoplasms - Analyst : Well, disease modifications is kind of the bus phrase in this field at the moment, but it's also a bit of a hated phrase. Because we know what we want to achieve for our patients, but it's a bit of a holy grail. So we want to achieve eradication of the claim that the bone marrow goes back to normal, that the spleen goes back to normal, that the patients have symptoms and they live. But so that's like reverting everything to normal. So that's actually quite tricky. So the way that benefit is measured in this disease at the moment is with these two measures SVR35 and TSS50 or this slightly modified endpoint, which is called absolute difference in symptom score. And there are really too few patients here to look at that in detail. And there's a good enough signal on TSS50, to be honest. But those are measures that are used to judge the benefit of ruxolitinib. So that means ruxolitinib is hard to beat. And it also doesn't totally speak to the activity of drugs such as PX-5505 where we would expect to see some on-target disease modification like reduction of fibrosis. So I think long answer to a short question, but I think this is evidence of benefit. Spleen reduction, we know is a measure that indicates survival advantage for patients. But I expect the field to pivot gradually over time such that spleen and indeed symptoms will remain very important. I think Ann Farrel is really convinced on symptoms being important for these patients. I've been to the FDA and myself with different companies a couple of times, and I've heard that from her. But I think over time, we're likely to want to see the changes in the bone marrow microenvironment like fibrosis grade reduction for our patients. But for now, the readouts on spleen and symptoms and ultimately perhaps hematological improvement will be important. JAK inhibitors get improved or just on spleen and symptoms without hematological improvement. Hopefully, that's addressed the point and maybe any few that we're looking around on that topic. Thanks.

Question: Claire Harrison - Myeloproliferative neoplasms - Analyst : I'm guessing that's one for Gary. We just need to do the fancy kind of muting and unmuting of the speakers because I won't have had the opportunity to talk to patients. But I can tell you while he's unmuting that, symptoms are a big issue for my patients. Their quality of life and how they live it is really, really important. Over to you, Gary.