Idorsia Ltd (IDIA) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the cenerimod Phase 3 Initiation Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Andrew Weiss. Please go ahead.

Thank you, operator. Good afternoon, good morning to you all. My name is Andrew Weiss. I'm the Head of Investor Relations and Corporate Communications here at Idorsia. I want to welcome everyone to our webcast to discuss the initiation of the Phase 3 program investigating cenerimod for the treatment of systemic lupus erythematosus, which we announced this morning. With me on the call here in Allschwil are our Chief Scientific Officer, Martine Clozel; and Alberto Gimona, our Head of Global Clinical Development. Next slide, please. As customary to these calls, we will be making forward-looking statements. You have therefore been appropriately warned about the risks and opportunities of investing in Idorsia shares. With that said, I hand over to Martine for prepared remarks. Next slide.

Good morning, good afternoon. I'm happy to start this presentation about cenerimod by reminding you of why we are so excited by its potential in the treatment of SLE. Our research on S1P1 receptor modulator started more than 25 years ago before S1P1 was even called S1P1. It fitted our interest in GPCR research and in the role of endothelium in pathology. Our research team was the first to discover and publish that selective S1P1 receptor modulators were going to be a very effective and safe approach for blocking the aggression of lymphocytes, T and B lymphocytes from the lymph nodes to the circulation. Next slide. Cenerimod is the next-generation product of this research. When we created an S1P1 receptor modulator, which would not only be highly selective, but also devoid of the side effects of vasoconstriction and bronchoconstriction associated with all previous nonselective or selective S1P receptor modulator. We now understand that cenerimod was devoid of these side effect because it has a unique intracellular and endothelial signaling with around 500-fold reduced intracellular calcium increase, probably explaining its very good profile. We are developing cenerimod for the treatment of SLE, not only because there is still a major medical need, particularly for better oral drugs, but also because we understand more and more how well the mechanism of cenerimod fits the pathophysiology of SLE. Next slide. So let's look at SLE in more detail. Next slide, please. SLE is an autoimmune disease, which causes multi-organ inflammation. There are, of course, the frequent skin rashes and the facial erythema, which gives its name to the disease, but many more organs are affected, giving symptoms which affect the daily quality of life, including fatigue, alopecia, and touching organs affecting life expectancy, including the kidney. Next slide. I'm now at Slide 7. It is considered that around 5 million patients in the world are affected by SLE, the large majority of whom are young female with a much higher frequency and higher severity in people of Afro-Caribbean and Asian origin compared to Caucasian. Next slide. Lupus is a systemic disease, where basically all components of the immune system, the adaptive and the innate contribute to autoimmunity against nucleic acids and nucleic acid containing cellular elements. Genetic factors and probably other susceptibility elements make some people more likely to develop lupus than others. Upon a trigger, for example, a viral infection, an autoimmune mechanism begins a loss of tolerance. The adaptive immune system gets activated and the T-cell activation, T-cell infiltration into tissues and production of Interferon gamma and other cytokine. The T-cell activation is followed by B-cell activation, especially autoantigen specific B-cells leading to autoantibody production and formation of immune complexes, which will start consuming the complement factors in [indiscernible]. The autoantigens are transported by dendritic cells into lymph nodes, thus causing more lymphocyte activation. The innate immune system also becomes activated, stimulating production of type 1 interferon, which in turn stimulates endothelial cells in particular to produce chemokines and cytokines like Interleukin 6 and TNF alpha, causing vascular and systemic inflammation. These multiple pathogenic pathways together create a vicious circle. Mortality in SLE remains about twofold higher than the general population and renal and cardiovascular complications are the main reasons. This is also why we wanted to have a very safe molecule, in particular, regarding cardiovascular safety. Next slide. Now let's look at the compound we have created and the remarkable fit between its properties and effects. Next slide, please. As an S1P1 receptor modulator, cenerimod inhibits the egression of T and B lymphocytes from lymph nodes preventing their migration and their infiltration into the different organs. Next slide. We now understand that Cenerimod not only decreases the trafficking of T and B lymphocytes and the consequent production of pathogenic autoantibodies, but it also acts on the other key aspects of SLE indeed. Cenerimod inhibits the transport of autoantigen by the dendritic cells to the lymph nodes and Cenerimod also inhibits the Interferon-driven immunological responses and therefore decreases inflammation. As a result, Cenerimod will interrupt the vicious circle of SLE pathogenesis. Next slide. The potential of Cenerimod to improve the different facets of lupus were evidenced by a study in a mouse model of SLE called MRL/lpr. In this model, many features of the human SLE disease are represented. T-cell infiltration, inflammation, autoantibody production, progressive deterioration of kidney function and decreased survival. Next slide. In this model, Cenerimod reduced T-cell infiltration and markedly reduced plasma levels of anti-double-stranded DNA antibodies and of several biomarkers of inflammation. Next slide. As a consequence, after 11 weeks of treatment, Cenerimod improved renal histopathology and markedly decreased proteinuria, and ultimately, it improved survival. Next slide. Thus, in conclusion, as you can see, Cenerimod is effective on multiple aspects of lupus pathogenesis. It is unique in SLE in tackling T cells, B cells, autoantigen transfer and the Interferon-related inflammation. As you know, Interferon-related inflammation is by itself a validated therapeutic approach in lupus. Cenerimod does not cause a strong immunosuppression, in particular, it did not cause an increased risk in susceptibility to infection in preclinical models, nor as you will hear in our clinical experience so far. With that, I'm happy to give the floor to Alberto Gimona who will tell you how excited we are that Cenerimod 4 milligrams is now entering the Phase 3 confirmatory program in patients with SLE. Next slide, please.

Thank you, Martine. Hello, everybody. I'm really happy and proud to be here to introduce to you to the Phase 3 OPUS program, in which we have already screened the first subject just a few days after opening the first centers in the United States. I would like you to follow me on a journey that has brought Idorsia from the Phase 1 to where we stand today. But I will discuss particularly CARE and how this study has told us how to perform and how to ameliorate the design of the Phase 3 program. Next slide, Slide 18. From Phase 1, we have selected 4 doses that we then use in a Phase 2a early study, which showed that the compound does what it's supposed to do, decrease lymphocyte count as well as early indication of disease reduction is activity reduction at 3 months. Then we have performed a second Phase 2 study, one of the largest dose finding study in the field with efficacy after 6 months with 4 Cenerimod doses. With this learning, we designed the Phase 3 program, which has been discussed with the FDA. And I'm pleased to say again that as of yesterday, we have included the first patient. Next slide. Now I would like to share with you how the CARE study has helped us designing the OPUS program, basically to ensure 3 things: one, to identify the population in which the benefit risk of cenerimod will be optimized. Second, to select the dose, this is the role of the Phase 2 study, which unequivocally can give the best efficacy and safety profile. And third, which is really important in lupus is the choice of the endpoint. So we learn a lot from CARE, and you will see a bit of it over the next 15 to 20 minutes, how the choice of endpoint is important and how this endpoint will not only support regulatory approval, obviously, if the study is positive, but also allow market access. And for me, it's very important being innovative and provide more patient-oriented view on the efficacy of the drug in this population. Next slide, Slide 20. In this slide, you see the objective of the CARE study. But in just the sentence, I would say that, as I already mentioned, the main objective of the study was to identify the dose that is efficacious and safe at 6 months. But you see that the study also lasted up to 12 months. So why we did the study of 12 months? Next slide. On this slide, you see the design of the study. We added relatively long screening period with the aim of optimizing or reducing actually the corticosteroid dose. We did it that because to maximize the chance of showing a dose response, we wanted to keep the steroids stable during the first 6 months of the study. But why 6 months? And you see here that at 6 months, the Cenerimod 4 milligram patients were re-randomized to Cenerimod 2 milligram or placebo. This request came from the FDA based on preclinical findings in dog. And we were not allowed to go forward beyond 6 months. But we discussed and included in this study in the CARE study, a large echocardiographic study that will rule out the safety concern based on preclinical findings. So now I'm very pleased to say that the results of the echocardiography substudy are absolutely clean. And since the concern is lifted, we can go ahead with the dose of 4 milligrams in Phase 3. Next slide, Slide 22. On this slide, you see the baseline and disease characteristics of the population recruited. I put my finger on the high dose, the Cenerimod 4 milligram and the placebo that you see on the right of the slide. I would say that the population for many aspects is a typical SLE population. If you look at age 42 and sex, which is predominantly female subject as the epidemiology tells us. We had a predominantly wide population with approximately 8% of African Americans and 8% of Asians, which are maybe less than what we would have hoped, but it was driven by the allocation of the study. We will put in place a measure in Phase 3 to make sure that the racial representation will be appropriate, namely by increasing our footprint in the U.S. and in Asia. You will see that the patients were co-medicated with corticosteroids, immunosuppressive, antimalarials. The percentage is relatively high, actually high, but you can see that compared to some recently concluded studies, we had a little bit less patients with immunosuppressant or antimalarials and the dose of corticosteroids actually happened to be a bit lower than in other studies. Next slide, Slide 23. Nevertheless, these are the results of the primary endpoint, and we observed a change from baseline with the 4-milligram group. This is the red line, decreasing by 4 points compared to baseline. And you see also in the dark purple line, the placebo, which decreases as usual in these kind of studies. But we did observe a difference which is significant 1.2 versus placebo at 6 months. And the fact is establishing over time as we expect to such compound that takes time to get the full efficacy. And as you can see, probably the efficacy is not limited, is not completely achieved at 6 months. Next slide. As I mentioned above, we had the impression that because of the study design, and namely the fact that we wanted to reduce the steroids before entering to the study. And we didn't allow to change the steroid. We basically probably included the population, which was less severe than what could have been done. That is why we look at subgroup in this slide, where we have a more active or a more severe population. On the top left, you see basically the data that we have just shown in the previous slide, in the overall population. But in the middle top and the right top, you see the results in the population more serologically active. On the bottom, you see the population more severe clinically, either because of SLEDAI or BILAG or because of higher corticosteroids for treatment. Amazingly, actually in each of these subgroups, you have an even better effect compared to the overall population. Just as an example, in the C4a complement for low levels, we have a difference versus placebo of 3.12 compared to 1.2 in the overall population or [indiscernible] double-stranded DNA, high level, minus 2.55. So we said, let's try to go into this subgroup to maximize the efficacy of the compound. On the other hand, we need to also take into consideration of 2 factors. The size of the subgroup because you don't want to restrict too much the population, otherwise, recruiting the patient will be more difficult and obviously look at the consequences in the label. And you see here, as an example, that the complement [ 4C ] group was only 15% of the patients, the anti-dsDNA high antibody population was 20%. While we were discussing these things, actually, we got the results of a preplanned biomarker analysis in which we look at interferon gene signature at baseline. Next slide. This is a complex slide, but we confirm that as in all other studies, by interferon gene signature, we select 2 population, distinct population. In our case, 50% of the patients had interferon high gene signature, half of the population had the low signature. It's clear stipulation again, is expected as shown in other compounds, for example, [indiscernible]. What on the other hand was a bit surprising to us that the 50%-50% split confirmed that we had probably a less severe population. As usually, you would expect an 80-20 split or 70-30 split. So indeed, we said, okay, we have maybe a less serologically active population. And let's look at the results in that particular subgroup to this 50% of the population with high interferon 1 signature. Next slide, Slide 26. Now I repeat here on the left, the results that you have seen. So the change from baseline at month 6 for Cenerimod 4 milligram, minus 4.4, placebo, 2.85, difference 1.2, what you have already seen. Next slide. But here, you see that interferon high signature, actually, the difference versus placebo is much bigger. We have a 2.79, 2.8 difference versus placebo at the 4 milligram dose. So it really seems that the effect is maximized with the Cenerimod in a more active population. Of note, in the high interferon population, no difference versus placebo at lower dose was observed. It confirmed us that the 4 milligram dose was really the dose to go, which is a good outcome from a Phase 2 study when you have only 1 dose coming up. But just to answer a question that you may have, I want to go to the next slide, which is Slide 28, to show the results on the SRI-4 response that from regulatory purposes is probably the most relevant one. In the overall population, you see a difference between the 2 groups, 4 milligrams and placebo with about 9 points absolute percentage point, which is okay, is in line with what has been observed with other previous medication. But I would actually to see in the next slide, which is Slide 29, where we did the same analysis in the population with interferon high signature. This is one high signature. And you really see here an amazing difference with 70% of patients responding to according to this criteria on month 6 versus 45%, 46% in the placebo, is a 24% difference. These are great results and is actually, you don't find if I'm not mistaken, but I think I'm not better results with any of the biologics that we have now. But then you want to see whether the effect on the biomarkers was also at par with these great results. Next slide, Slide 30. And actually did. Here, you see the anti-double-stranded DNA antibody in the change from baseline at 6 months on the left, interferon 1 high population with a decrease of 35% to 40% of this biomarker, which is again at least a part of the effect which is observed with all other biologics. Actually, with the last biologic, I mean from deucravacitinib. So based on these results at the end, we decided in Phase 3 to enrich the population to get at least 75% to 85% of subject with interferon high population in our study. But before going to the design of the Phase 3 study, 2 or 3 slides about obviously, the safety data. As Martine said, it's important that the compound in this population is safe. Next slide, Slide 31. In this complicated slide, again, you see the high-level summary of the safety data. But we were happy to see these results. Cenerimod was well tolerated in all treatment groups. Similar rates of adverse events were reported across treatment groups during these 6 months, these are the 6 months results. We did observe, as expected, an higher discontinuation due to predefined criteria due to the mode of action. If the patients had a decrease of lymphocyte below 200 cells per microliter, the patients had to be discontinued. There are 2 things that are important to note here. First, that there was not much of the difference between the 2 and the 4 milligram group. But actually, probably even more important is that we observe and we evaluate the incidence of infections in these patients with low lymphocyte count. And we didn't find any relationship between a decrease of this lymphocyte below 200 and in infections. Therefore, in the Phase 3, because now the study is ongoing, we have abandoned the criteria to make a bit more liberal and not exclude patients that may still continue to benefit from the drug. Finally, you see SAEs are very low, 2.4% with Cenerimod 4 milligram, 3.5% with placebo. But I'm sure you noticed also that there is on the adverse events greater than 5%, that is on hypertension, so actually 6% on 4 milligram, 4.7% on Cenerimod and lower in other groups. And I'm going to touch on that on the next slide. We are dealing with an S1P1 selective. So these are the, on board, you have the different effects that you would expect, nothing really to mention here. There is nothing, but 2 things, I would say. First of all, I will look at the low incidence of opportunistic infections that you see, 3.6% in 4 milligram versus 7% in placebo, which is a very good sign. Overall infections were up par 19% and 20%. And the blood pressure to answer the previous question, the question in the previous slide, you see that there is basically no difference versus placebo in the blood pressure. So as I put on the right, all lights are on green. But we have a 12-month study, therefore, just the next slide, Slide #33 to summarize the safety of 12 months and basically the same exactly findings as in the previous slide. Of note, the Cenerimod 4 milligram after 6 months, all the patients, as I mentioned earlier, were re-randomized to placebo or 2 milligram, and this is obviously altogether in this slide. Again, low incidence of serious adverse event in a 1-year study and low incidence of opportunistic infections. Next slide, Slide 34. So in a nutshell, CARE delivered to the promise. We really found extremely helpful looking at the Phase 2, a large Phase 2 study to inform the design of the Phase 3. And now let's go there. Next slide, Slide 35. Next slide. We call it the program OPUS. We will include 2 pivotal studies, which study adds 420 patients, 210 each. A long-term extension will be offered to all patients completing the 1-year study to increase the safety exposure to the 4 milligram. The treatment period is 1 year, as you can see. And we have been able to convince to bring only 1 dose to the Phase 3. Next slide, please. The target population doesn't change. It's the moderate to severe SLE population, but we target, as I mentioned earlier, a higher representation of patients with interferon-1 signature and a more balanced ratio representation. How we are going to do that? We have put in place different things to achieve this objective. First of all, we have adopted the inclusion criteria. Interestingly, we have performed with the help of so-called artificial intelligence and in-depth search on the baseline characteristic of patients in CARE to see which of those characteristics were more predictive of interferon high signature. And we adapted to the inclusion criteria accordingly. Then we also increased the population. We are going to increase the population coming from Asia because we have seen, and this is also described in the literature, the SLE patients in Asia are basically, let's say, 80% to 90% of high interferon signature. So with one move, having more Asian patients, we increased the racial diversity and we increased the interferon high signature. Although we are still excluding from the study, the patients with lupus nephritis, we have actually relaxed a bit the inclusion criteria for the kidney. So the patients with moderate kidney disease can enter into the study. And this, again, from this exercise was shown that patients with the renal disease are more likely to be interferon high. As I mentioned earlier, percentage of patients coming from the U.S., therefore, will increase automatically the African-American population. Finally, as I mentioned earlier, I think in CARE the fact that no corticosteroid reduction was allowed during the study was a bit going against the study because we selected the population, which was not as severe as we would have wished. Now in this study, we have included a forced titration of steroids in the middle of the 1-year study to allow patients with higher corticosteroid therapy at the beginning to enter the study because they will have the possibility to decrease their dose. Next slide, which is Slide 38. The primary endpoint remains the one that have been successfully used in the CARE study, but we have upgraded SRI-4 response as a key secondary endpoint to ensure regulatory acceptance of the study. And of course, this has been discussed with the FDA and the European authorities. Next slide, 39. As a secondary objective for which we adjust for multiplicity in order to add the data into the label, we introduced 2 innovative endpoints based on sustained response. The first one is basically a sustained SRI response as the reduction of [indiscernible] of SLEDAI-2K is the main driver of SRI response. And a sustained response you see that need to be maintained for 4 months at least. We also introduced a sustained response for the mucocutaneous manifestation of lupus for 2 reasons. One, because this is really one of the main concern of the patients with lupus because this is the visible part of the disease, which may affect more of the patients. And also because in the CARE, I didn't show the results, but we have a very nice effect on this parameter. Next slide, Slide 40. In here, actually, we use the data in the CARE study to see how the sustained SLEDAI-2K response would look like. These are real data. It's the 4 milligram versus placebo. Again, it's a 4 milligram, then placebo and 2 milligram. But this Kaplan-Meier show how this sustained response is observed much more frequently in the patients on Cenerimod than patients on placebo. At 6 and 12 months, we have basically 75% of patients who respond to treatment. So there is good encouragement to select this endpoint for Phase 3. Next slide. We have discussed with the patient association. And you see here 6 patient associations from different parts of the world, who actually were very, very useful in designing the study and make it in a world more patient friendly. As an example, we have every month visit for mSLEDAI. And we asked, does this bother you coming every month to the center? And they say actually no because it's for patients with SLE is important to get in touch with the caregiver. So they said what is important for us is that we are helped with the logistics of coming to the centers. And we put in place measures to help the patients to come to the site. But we ask actually about the endpoint, and we introduced a very innovative endpoint, which is really patient focused. Among the different areas of the mSLEDAI and among myositis, arthritis, rash, alopecia and mucosal ulcers, each patient will choose what is the symptoms that more affect the patients. So each patient may have his or actually her 95% or his 5%, chosen symptoms. And we will look at the end of the trial, whether these symptoms have disappeared. So this is really something that I like for because it takes what the patient needs. And I would like now to give you just close to the finish, a little anecdote about alopecia, which is among those symptoms. We got during the study, we received phone call from investigators who said, "Hey, guys, your treatment seems very, very effective in alopecia." Obviously, the study was blinded, so we couldn't say anything. So thanks for the comments. But this raised the interest to look at alopecia by itself. And actually, we look at these results, we started in the next slide is Slide 42. So interestingly, among the 70% of patients, remember, 95% are female who had a alopecia at baseline. And after only 6 months, basically, the symptoms disappeared, so alopecia was recovered in 1/3 of the patients on Cenerimod, while on placebo, only 10%. And this is an amazing result in my view, 3x more than placebo. And actually, this seems to be something which is important for the patients. But this, again, is just anecdotal finding now. Next slide, and actually, my last slide. So in conclusion, I really hope that I was able to share with you my enthusiasm or the company enthusiasm about this program, amazing program, which has really been crafted, I would say, on the learning from all previous studies, but in particular, for CARE study, which was just completed and presented at ACR a month ago. I would really like to thank the investigator again. I know I did it already, but I think it's important to thank the investigators and the patients who contributed to CARE and a special thank you to the first patient who is currently now as we speak, in the screening in the OPUS program. With that, I thank you for listening to me, and now I get back to Andrew to open the Q&A session. Andrew?

Thank you, Martine, and thank you, Alberto, for your prepared remarks. Now we have time to address your questions. But before, a few housekeeping rules. I'll ask for everyone to please limit yourself to one question only and jump back into the queue if you have more to ask. Second, this is a call on a clinical program and hence, we encourage you to use the occasion to ask questions to the experts on their findings in the field of expertise. We will not be answering questions on funding or finance in this call. And now without further ado, operator, please open the lines.

[Operator Instructions] Dear speakers, there are no questions at this time. Please continue.

Thank you, operator. All right. Well, it is the holiday season. And when sending out the e-mail this morning that was not coming as a surprise that there were a lot of out-of-office messages. So anyway, thank you for your attention. This concludes the call for today. We thank you for your ongoing interest in Idorsia and look forward to speaking to you again. Operator, please close down the lines.

Thank you. That does conclude our conference for today. Thank you for participating. You may now all disconnect. Have a nice day.