Sareum Holdings plc

usual disclaimer that goes with all of these presentations we will be talking about future forward-looking events within this presentation and in the discussion so please be aware of the disclaimer that goes with it so a quick overview of where we are you know about the company as being a clinical stage small molecule drug company with deep expertise in kinase inhibitors and uh most notably of course in the tick to check one field where we will spend most of the time today but uh happily uh we're now back involved in the check one side having uh regained control of sra737 uh shortly after the period we're discussing ended um we are well funded now uh we closed in the period with cash at 4.1 with a further 1.07 million raised in early March. So the pipeline now looks like this. This of course is different from recent years in that Check One is included within our pipeline for the first time in my living memory. And on please Tim. So highlights from the period. Most notably, of course, we completed and announced the completion of the phase one study for SDC 1801. John will discuss that, of course, in a little more detail. We've been able, because of the funds raised during this last year, to start looking more actively at 1802 again. and of course with the return of 737 we now have a cancer drug which has already been in the clinic for phase one two studies both as a single agent and in combination and during the period when it was last sub-licensed an IND was opened in the US so there is now for the first time the ability to to conduct trials in the States. The financials I've just summarized, although it's worth noting that in addition to the post-period end placing, we also had an R&D tax credit. So the total income during this first quarter has been 1.3 million approximately into the company. So moving on from there. and we'll start looking at the Proprietary Programme. So very briefly in summary, the phase one data have demonstrated that we do have a highly selective molecule in AT01, which is a differentiator against competitors. And one thing which leads us to believe that we do indeed have potential for a best-in-class molecule. We can see that there is potential for this in many autoimmune disorders. We've spoken previously about psoriasis, but that's one of several molecules in the autoimmune, conditions in the autoimmune field where we believe that AG01 could well be applicable. And the and the positive results from phase one has led us to believe that we have a very strong story and we are undertaking this extended top study to provide hopefully a licensee with a ready for phase two compound. With that, I'm going to pass over to John who will go into more detail through the program.

Thank you, Stephen. Yeah, so SDC 1801 is a, as you know, clinical stage dual TIK2 JAK1 inhibitor. The phase one trial dosing of the volunteers in Australia completed in June 24. We received the unblinded data in Q3 of 24 and the results were very positive. High blood exposure was achieved and there were no serious adverse events due to SDC 1801. In fact, the adverse event profile was very similar between treated and placebo groups. All adverse events that were noted were mild or moderate. There were no clinically significant effects on blood components or serum creatinine, and I'll come later to why we see that as being very significant. We also saw a significant dose dependent reduction in biomarkers of TIK2 and JAK1. So in our preclinical models, we had demonstrated the mechanistic proof of concept, seen dose-dependent efficacy in models of psoriasis and rheumatoid arthritis. We demonstrated that SDC1801 potently blocks TIK2 and JAK1 signaling in human whole blood assays with no measurable inhibition of JAK2. And the good safety pharmacology and toxicology that we observed in the preclinical studies translated into the clinic and we found that the human pharmacokinetics were suitable for once daily oral dosing so we really were very positive from the results that arose from that phase one trial this is a cartoon just to show you why we think dual tic-2-jac-1 inhibition is optimal for the suppression of a number of cytokines linked to several autoimmune diseases If you look at the cartoon, it's really demonstrating the cytokine receptors. When a molecule binds to the cytokine receptor, so to the interferon receptor, for example, interferon gamma binds to the interferon gamma receptor, it uses JAK1 and JAK2 to transmit the signal downstream. Now blocking some of these JAKs is beneficial because it blocks cytokines that are associated with autoimmune and inflammatory diseases. Blocking certain JAKs such as JAK2 you'll see on the left of this molecule has negative effects because JAK2 is very much involved in erythropoietin and thrombopoietin signaling and inhibiting JAK2 can lead to a number of haematology toxic side effects so we very much want to avoid JAK2 we see that in contrast to the selective TIK2 inhibitors so TIK2 and TAK279 by also inhibiting JAK1 another range of cytokines are inhibited which could have positive effects in diseases And just to demonstrate that, we've got some data here from clinical studies using a dual TIK2 JAK1 inhibitor, brecocitinib, versus single TIK2 or dual JAK1 inhibition in clinical studies. Slight caveat, you know, it's always somewhat, well, not dangerous, but you just need to be aware when you're comparing between clinical studies that these are different groups of patients. Different protocols are used in the clinic, for example. But I think this data does show quite nicely that brepacitinib gave the best readout in a psoriasis trial. We're looking at PASI 75, that's psoriasis area and severity index. So we're looking at reductions in psoriasis symptoms in patients. And the dual TIK2 JAK1 inhibitor appears to be more effective than the selective TIK2 inhibitors or the dual JAK1, JAK2 inhibitor baracitinib. so looking at the human pharmacokinetic profile of 1801 we saw a half-life of around 17 to 20 hours that confirms the suitability of the molecule for once daily oral dosing in MAD cohort D so this is the highest dose group in the MAD experiment we saw that plasma exposure of 1801 was equivalent to brepacitinib at 100 mgs so I'll come on to why that might be important later on. Just going back to our data, the exposure of 1801 exceeded the human whole blood interferon alpha and IL12 IC50s throughout the entire dosing period. So that means that we are achieving a concentration of drug in the blood that reduces interferon alpha and IL12 signaling by at least 50% for the entire dosing period. we didn't see any changes in haematology or serum creatinine after 10 days of dosing now in contrast brepacitinib that's the molecule i just described on the previous slide giving the best results in the psoriasis trial brepacitinib at 100 mgs caused increased serum creatinine and reductions in reticulocytes and neutrophils reticulocytes are in mature red blood cells and neutrophils are an important part of a white blood cell system so you don't really want to be reducing those those components of the of the blood cells so the data i showed you on the previous slide with prepositinib that was using prep over 30 milligrams going higher leads to these side effects and i think that's why prepositinib is limited to typical use of 30 to 45 milligrams in the clinic so switching back to 1801 we've got a very strong set of biomarker data ip10 interferon gamma induced protein 10 which is a marker of jack one and interferon gamma signaling we've seen dose dependent reductions in ip10 levels in the mad cohorts uh crp c reactive protein a general marker of inflammation and again downstream of jack one and in this case io6 signaling we saw dose dependent reductions in crp levels in the mad cohorts and then in an ex vivo challenge so this is where we're sampling blood from the volunteers in the clinical trial we're taking that blood and treating it with interferon alpha challenging it with interferon alpha and They remind me of these subjects have taken our molecule. We saw dose dependent reductions of phosphostat three and phosphostat five cells. So when interferon alpha binds to its receptor, it uses tick two and Jack one to phosphorylate stat 3 and stat 5 that's what the p on phosphostat 3 phosphostat 5 means so this is direct evidence that we have target engagement with our molecule on the targets that we wanted to hit and we observed that effect in two different cell types of the immune system t cells and monocytes so our differentiation versus prepositinib and this leads on to our theories around best-in-class potential for this molecule prepositinib is the most advanced dual tic-2-jap-1 inhibitor in the clinic it's currently undergoing phase three trials as i mentioned earlier it's typically used in the clinic at 30 to 45 mgs once daily qd is once daily going above 30 milligrams in their phase 1 trial they observed increased serum creatinine levels and that was due to the inhibition of OCT2 a renal transporter kidney transporter brepacitinib inhibits OCT2 1801 has much greater selectivity versus OCT2 so we don't see any effects on serum creatinine levels when we dose with 1801 giving exposures equivalent to 100 mg of brepacitinib. So greater than threefold the clinical dose of brepacitinib, we're not seeing this effect. Likewise, at greater than 30 mg of brepacitinib, reductions in neutrophils, those white blood cells and reticular sites, the immature red blood cells are observed with brepacitinib.

We saw no effect on neutrophils or reticular sites at doses equivalent to 100 mg of brepacitinib.