Heidelberg Pharma AG (HPHA) Earnings Call Transcript

Hi, and very welcome, everybody, who joined our webinar today. My name is Andras Strassz. I'm the Chief Medical Officer of Heidelberg Pharma. And today, we want to share with you some exciting new news about our clinical development. As you might know, we are developing [indiscernible] asset, which has recently achieved a point and I think you will learn today about this new data in our clinical program. But first things first, on top of that, again, I'm thanking all of you who have joined this session. What is Heidelberg Pharma and what is our technology? Those who might not know that we are developing a new mode of action and novel ADCs and these ADCs has shown already really positive signs in the clinical, which means that it leads to definitely responses in a couple of myeloma -- in a few myeloma patients. But what is new about this ADC that this ADC has a new payload. And as of today, we are the single developer of this new type of ADCs and which is protected with our patent families. And we know that the payload makes the difference in ADCs. So if you change the ADC payload, if you optimize the ADC payload, you can achieve a wonderful results as we did in our clinical studies. On top of the new mode of action, which I will tell you a little bit more today, this ADC has a premise that it's specifically active on [ 7 typically ] patient population. As you know, this is a general issue in oncology, not just in multiple myeloma, but also in other solid tumors and hematological malignancies. But today, we will talk specifically about our lead compound, our flagship compound, which is the HDP-101. And what is HDP-101, is an ADC, which is designed by us. And the backbone antibody is targeted to BCMA. The B-cell maturation antigen, which is a well-known target in myeloma, which has superb results in other treatment mobilities, including ADCs, CAR-T cells and bispecific molecules. But what we did, we attached a new molecule and molecule, which was never before used in the clinic, which is Amanitin. And Amanitin is coming from the nature. It's come from the [indiscernible] mushroom and it's a well-known toxin in the nature. But so far, nobody was able to exploit this drug -- as a drug in clinic. What is completely new that the target of this payload. The target is the inhibition of RNA polymerase II. And RNA polymerase II is an essential cell cycle independent element, which is a eucretic function, it produces mRNA. And if we shut down RNA polymerase II, the cells cannot produce synthesized proteins and goes to apoptosis. Why I'm saying this is cell cycle independent. It has nothing to do with cell division. And therefore, this type of ADCs can kill dormant tumor cells, which is not true for other currently on the market or in development ADCs, which are using more like chemotherapy, classical chemotherapy, origin payloads. And because if it's a new mode of action, its circumstances -- and the currently known resistance mechanism and we can produce this payload synthetically. And we attach it to the ADC, because it's so powerful, we keep the drug antibody ratio exactly by 2, because we know that the rate limiting is really for each and every cycling, the rate limiting is the amount of RNA polymers II in the cells. so much about the introduction. And now I hand over this presentation to Professor Raab, who is one of our principal investigators and who was contributing a lot to this development and still contributing a lot to this development. But I think he's more capable to explain you and put into perspective our clinical results. After his talk, I will also give a short summary on our current achievements and development. But I think we should hear first Professor Raab's interpretation of our clinical data.

Good morning or good afternoon. I'm Marc Raab from the Heidelberg Myeloma Center and I'm happy to share the most updated data on the development of HDP-101 in multiple myeloma. Multiple myeloma is a bone marrow microenvironment disease originating from plasma cells that has around 180,000 patients currently worldwide and most of them still actually succumb to the disease at the end. The current tremendous progress in therapy and therapeutic options, namely with the T-cell redirecting therapies like bispecifics and CAR-T cells, are still considered not curative for almost all patients. So even the most advanced standard of care options largely lack curative potential. Furthermore, those just mentioned treatment options, the most advanced ones like T-cell redirecting therapies, are largely bound to large experienced centers like academic hospitals or huge specialized centers. For example, however, in the U.S. almost 85% of all patients are treated in a community setting like office-based physicians or small community centers. So in this regard, HDP-101 and ADCs in general address a high unmet need for this patient population. So briefly, what is HDP-101? It's an anti-BCMA antibody directed, as I said, against BCMA, a surface antigen on myeloma cells. And it has a payload with Alpha-Amanitin, which constitutes a toxin that is single first-in-class and has no known other resistance mechanism so far and the mechanism action is unique. ADCs in general are very suitable for administration in community hospitals, in outpatient settings and, for example, as well in patients who relapse after T-cell redirecting therapies. Other myeloma patient populations that are difficult to treat in general, even with T cell reducting therapies, are high-risk cytogenetic, high-risk myeloma in general, older age with comorbidities and frailty indexes, rapid progression, requiring off-the-shelf options, so not feasible for CAR-T cell therapy, for example, and as I mentioned, the broad availability and simple logistics in many parts of the world, even in advanced countries like U.S. or Europe. So ADCs in general and very specifically HDP-101 offer very convenient dosing regimens and safety aspects compared to the bispecifics and CAR-T cells. As I said, outpatient administration is very feasible for this class of agents. The off-the-shelf availability is much better than especially for CAR-T cell therapy. Non T cell approach is also, again, needed after the last exploration of the T cell redirecting their periodic approaches. And of course, the great opportunity to combine with the standard of care drugs and combination regimens is absolutely paramount in multiple myeloma as has been shown for many decades now with several combination regimens very successfully advancing therapies. And very specifically for HDP-101, there seems to be no ocular toxicity, which is very different from other ADCs, especially one ADC that is already approved, but with limited use, because of the side effects. So as we have published previously, HDP-101 is able to overcome quite some resistance mechanisms in multiple myeloma. So you can see on the left graph here, it is well able to address and to kill efficiently resting nondividing myeloma cells which is actually, especially in the remission setting and after induction therapy, for example, probably the most important population of myeloma cells in the patient, finally leading later to relapse. As well, it is very efficiently able to kill myeloma patient cells that are derived from myeloma patients who were resistant refractory to existing standard of care combinations. And it was also able to kill patient cells with very low expression of the target antigen on the surface, which is also important, because some T cell redirecting therapies might lead to some down-regulation on the surface of the antigen. So this is important to know. So the HDP-101 Phase I/II trial that is currently ongoing has, of course, the objective to explore safety, tolerability and to find the MTD and the RP2D doses. Up to now, we have solid data up to a Cohort 7, as you can see. In Cohort 6, we introduced a dosing regimen optimization strategy, which I will allude to a little bit later. And the key eligibility criteria, as you can see here, were that those patients had to have exposure to standard of care drugs that are available for multiple myeloma and largely did not have any other promising and efficacious alternative available. So far in the dose Cohorts 5 to 7 with the relevant doses between 90 and 112 mg per kg, you see with the green and red bars here in the swimmers plot, you see that we see already quite some remission, quite some durable remissions also in patients, again, in this very heavily pre-treated patient population with a patient here, for example, in the 100 mg per kilogram dose, reaching a complete remission, lasting more than 2 years. In other patients in this advanced patient population, achieving a partial response that is also durable for more than a year in some patients. So let me quickly introduce you to this patient -- to Cohort 5, as I alluded already in the previous slide, too. It was a 70-year-old lady, that already had the diagnosis of multiple myeloma in 2002. So up to enrollment, she had 9 prior lines of therapy. So basically, everything that was available, including BCMA CAR-T cell therapy and the GPRC5D bispecific antibody and iberdomide new CELMoDs class in combination with Dex, which she had immediately prior to enrollment. So almost all available therapies and all promising efficacious therapies have been applied in this patient. So in 2023, she was enrolled in HDP-101 -- in the HDP-101 trial, achieved a PR on partial remission already after 2 cycles. And by end of the first year, a stringent complete remission could be confirmed. Overall, the treatment was very well tolerated, mild adverse events. No keratopathies or no eye tox, no-liver damage or lung toxicities were found and no real toxicities were reported. There was only one transient thrombocytopenia in the first cycle, which recovered quickly. So actually in the same cohorts of the Cohort 5, but we found a channel phenomenon, obviously, that most patients had a very transient but quickly onsetting dip, so to say, in the platelets, so thrombocytopenia, around day 5. So this is days, not weeks, which recovered quickly in a few days later. However, that reached grade 3 or 4 toxicity level. And we had one patient with some short-term transaminase elevation in the first week after exposure. So that led to a strategy in Cohort 6, with adjusting the dosing regimen in 3 different ways: one with premedication; another so in RMB, so to say, with a weekly dosing instead of the Q3 weekly dosing; and RMC, a third regimen for dose optimization where we split the first dose only to once weekly, so day 1 and 2 and 8. And then after that, resume 3 weekly dosing thereafter. And that was set up to explore whether the thrombocytopenia, the early dip in platelets and maybe the liver enzyme elevation, which we saw in one patient only could be mitigated to using those regimens. And as you can see here, on the right side, Cohort 7, Cohort 5, you have seen this graph as a comparison before. Cohort 7, as you can see here, we didn't see any of the platelet dips in the early days after a first administration anymore, both in the weekly dosing as well as in the split dose for the first dose only and then the Q3 weekly -- Q3 dosing -- Q3 weekly dosing after it. So this adjustment in dosing regimen, which is actually a minor adjustment, if you have a split on the first dose and give some premedication successfully mitigated this thrombocytopenia phenomenon, we saw in Cohort 5, even in a higher dose. And very importantly, of course, it did not affect efficacy. You see that the Cohort 6 with the split dosing and dose adjusted regimens. 90 mg per kg, but also in the higher Cohort, the Cohort 7 that I just showed you, we continue to see responses despite having no split doses or Q weekly dosing in place. So that led us to focus in the Cohort 8 now in only 2 different scheduling regimens or dosing regimens. So one with a -- with a Q1 dosing and one with a split dose in the first dose only entry medication to be taken further in exploration. And the cycle Cohort 8 with 140, so still in dose escalation, 140 mg per kg. Now, and this is very up-to-date data as of 2 weeks ago, basically, we saw that we see in 4 out of those 7 patients, early responses, as you can see here in green, the partial responses and even early on in the first 3 cycles, 2 patients already achieved a stringent complete remission. So very rapid responses in the majority of patients, again, in a very heavily pretreated patient population that was basically devoid of other options -- therapeutic options available. And I would say, equally important to the great response rates that we seem to see in this cohort. There doesn't seem to be the platelet drop, the thrombocytopenia in the first few days to occur, as you can see here on the early data graphs here now on the platelets, some minor dips, but that recovered quickly and does not reach really like high-grade thrombocytopenia. Similar to the liver elevations -- liver enzyme elevations, we see in one patient a very minor slight elevation for a few days, but that is then mitigated later on and no higher grade liver enzyme elevations in terms of liver toxicity or something like this can be detected even in the 140 mg per kg dosing schedule. Overall, in terms of side effects, you see that if you concentrate on grade 3, 4 side effects across all cohorts so far, you see overall relatively few high-grade 3-4 toxicities, and those were mainly hematological in nature, mainly, of course, with thrombocytopenia as expected, that's what I have shown you just in that previous slides. And some anemia, which of course, very common as well in heavily pretreated patients, like myeloma fourth, fifth, sixth line. More importantly, although longer follow-up is here, certainly needed in Cohort 8 with 140 mg per kg dosing to the highest dosing so far, we didn't have any Grade 3, 4 side effects so far. So no early high-grade toxicity at all being found in this highest dose cohort with it, as I showed you, dosing regimen adjusted to split dosing. Importantly, again, no ocular or renal toxicity has been found so far and the dip in platelets has been mitigated by the adjusted dosing regimen. Also, interestingly and importantly, for those patients who have exceeded 12 months of therapy, we do not see any cumulative or delayed toxicity. So it's not going to have a long-term cumulative effect in terms of thrombocytopenia or any other damage we can see. No toxicity seems to occur so far. Again, summarizing across all cohorts response rates. So all cohorts taken together so far, we have a 38 overall response rate with a few patients reaching even complete remissions and very promising the highest Cohort now, the Cohort 8, with 140 mg per kg. We see 4 out of 7 patients with 57% of the patients responding and almost 30% or 2 out of 7 reaching a CR within the first 3 cycles. So clearly exceeding what we have ever seen with any ADC in myeloma in the single-agent advanced patient population setting. So let me summarize the unique features of HDP-101 and what those features might have in terms of potential benefits for patients. So as I have shown you, HDP-101 is highly effective against non-proliferating dormant myeloma cells, is highly effective against myeloma cells that have very low BCMA expression on the surface. It carries a novel mechanism of action with the Alpha-Amanitin to which all patients will be naive -- treatment naive. It has so far a very favorable safety profile, especially now after split dosing in the first cycle. And therefore, it's very prone to be very active and easy to combine with other standard of care therapies, which, as I said, has been very important in myeloma in the history so far of drug development. So all that might lead to really strong deep and long-lasting tumor responses, overcoming resistance acquired by previous lines of therapy. And therefore, especially in combination, leading to a best-in-class efficacy and tolerability profile in multiple myeloma, not only in the relapsed/refractory setting, but also in early relapses or potentially, of course, even in frontline later on in combination therapy. And this is all especially true if you compare it to already available ADCs in multiple myeloma that are now on the market and their specific features. With this, I thank you for your attention, and I'm happy to take questions.

[Operator Instructions] So the first question is the presentation on the 8th Cohort shows that the responding patients are not from the post-BCMA population. Current plans target approval for use specifically in the post-BCMA patient population. However, the current data while admittedly very preliminary, do not appear particularly promising on this. Could you comment on that, please?

Yes. Thank you so much. First of all, I thank Professor Raab for this really excellent summary. And before I answer this specific question, I will also ask you to -- there is still time to ask your questions. So please do not hesitate to post your question into the webinar. We will try to address most of them. So regarding the specific questions, yes, our study currently is not limited to post-BCMA or preceding naive patients. We accept for the dose escalation, we accept both patient population. And it is true that for the monotherapy development, we will pursue most likely the post-BCMA field, but we're still considering and not considering actually planning to develop this drug in BCMA naive patient population in earlier lines of treatment in the combination treatment. So generating data in both population is important for us. And because we don't control, so we cannot control that how many patients we will have who has BCMA naive or post-BCMA in a particular cohort, it's just really as the patients are getting into the study. But still, in the BCMA naive patient population in the last cohort, I think 4 responders in such a small cohort is quite substantial, especially if you compare to the early results from other ADCs. This is really something that is outstanding and it gives us confidence to further develop this drug as a monotherapeutic agent in -- particularly in both BCMA naive and post-BCMA setting. Next question, please.

Is it correct that fast track status is generally applicable and does not refer specifically to a post-BCMA patient population?

Yes, this is correct. So we got the fast track designation just recently. And this does not specify the BCMA status. It is written as a fourth line plus patients who received the majority of the currently available myeloma treatment, not including BCMA-directed drugs.

Next question is to what extent should or could the positioning of HDP-101 and study planning be considered? Is it an option to aim directly for the third line of treatment and position HDP-101 as the first choice BCMA therapy? Would this significantly change the scope or schedule of the study?

This doesn't -- has a change or any impact on the current scope of the ongoing Phase I dose escalation, first-in-human study. But however, we already have, and I will demonstrate you after our Q&A session, I have some slides on our current development plan. And this development plan includes development in a post-BCMA field and also development in BCMA naive earlier lines, which is particularly second line of treatment. So those who have not received any prior BCMA drug. And we also -- because of the 17p deletion, sorry, I briefly mentioned in the beginning of our presentation, we also developing -- also plan to develop this drug in the high-risk patient population where we know that the number of 17p deleted patients are higher.

Next question is currently, as far as I can see, the 17p deletion population is no longer being mentioned to any great extent. Do you have any 17p deletion patients in the ongoing Phase I? And are you planning to integrate this patient cohort into clinical trial planning?

Yes. So currently, we do have 70 patients with 17p deletion. And as you know, that the definition that with 17p deletion has recently has been updated. So as our original plan, we still would like to enroll and further test all of our patients for 17p deletion with a [indiscernible] tumor biopsy. And -- but to report anything meaningful for that, we need a larger cohort of patients. And that's why we plan only to report this data after the Phase IIa part of the study is completed, and we want to do a subgroup analysis on, if possible, a subgroup analysis on this particular patient population in the Phase III setup. And as I said, we also plan to have studies, specifically studies, maybe already pivotal studies in the high-risk myeloma population, which we all know is quite there, we all -- that we see quite often 17p patients. Do we have any further questions?

Yes. So how many of the patients that were not reaching the stringent complete response status in the former cohorts have died shortly after stopping treatment?

As of today, we have not released this data, but as of today, it's a definition of what it's short. So as of today, we have no knowledge on any patients who passed away quickly after stopping the studies. Obviously, we're following up each and every patient for survival data. But again, this data will be reported at the end of the study, then we have more or more robust and more larger set of patients.

[Operator Instructions] So next question is Alpha-Amanitin payload on HDP-101 eventually will be released into the system after the affected cells go into apoptosis. As such, it is expected that it will be cleared in the liver and cause some hepatotoxicity. Is there a hypothesis why are there no liver associated side effects?

Yes. Excellent question. So yes, the assumption is right that Alpha-Amanitin after it does its job and kills the myeloma cell, it is released into the circulation. But as of today, if you saw our previous report and posters and presentations, we continuously reported that we have not measured free, we were not able to measure free payload. We measure actually 3 different kind of free payloads variants, but we're not able to measure any of them or then we were able to measure the amount of these payloads were really minimal. And which means that the free payload concentration even after the cycling is so minimal that it's not -- could not cause a significant liver damage to a human body. As you all know that -- or you might know that liver is really the only target organ for the fee payload, because only the liver cells has the specific transporter to pick up Alpha-Amanitin. But as I just said, the Alpha-Amanitin half-life is so short that it's washed away from the circulation really fast and goes to the [indiscernible] to that.

Next question is how many patients are in Cohort 9? How many of them are post-BCMA and how many show a 17p deletion?

Yes. Thank you so much. Unfortunately, because cohort 9 is still ongoing. We are not able to release any data as of today on Cohort 9. Stay tuned. We will release as soon as possible. We will release data on Cohort 9, hopefully really soon.