Good day, and welcome to the Hansa Biopharma 12-month analysis results for HNSA-5487 conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing star, then zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on a touch-tone phone. To withdraw your question, please press star then two. Please note, this event is being recorded. I would now like to turn the conference over to Søren Tulstrup, CEO and President of Hansa Biopharma.
Thank you, operator. Good morning, good afternoon, and welcome to this call on the results of the first in-human trial of HNSA-5487, the lead candidate from our next generation NiceR program of IgG cleaving enzymes for repeat dosing. I'm Søren Tulstrup, President and CEO of Hansa Biopharma. With me today is Hitto Kaufmann, our Chief R&D Officer. This is an exciting time at Hansa. Our lead asset, the IgG cleaving enzyme, imlifidase, has received conditional approval by the European Medicines Agency for enabling kidney transplants in highly sensitized patients, and the launch is successfully underway, with market access now achieved for a majority of patients. Specific imlifidase protocols adopted by leading transplant centers across Europe, and growing uptake based on successful first outcomes. In the US, we completed randomization in the pivotal ConfIdeS trial before summer and look forward to readout and a potential BLA submission next year.
Imlifidase has also generated strong proof of concept in the autoimmune disease anti-GBM, and a pivotal phase three trial in this indication is currently moving forward at speed, with data readout expected next year. We are also very excited to see good traction with imlifidase within gene therapy, where our partner, Sarepta, has commenced a Phase 1b trial of imlifidase dosed ahead of their FDA-approved gene therapy, Elevidys, for Duchenne muscular dystrophy, with a view to enabling gene therapy in patients with high titers of neutralizing antibodies against the AAV vector used. Results from this trial are expected next year. While imlifidase, with its ability to reduce IgG to below detectable levels within a few hours from a single dose with favorable safety and tolerability, has a unique profile, very well suited for single administration scenarios such as monophasic autoimmune diseases, gene therapy, and transplantation.
Given its origin from a human pathogen, we've chosen to focus our efforts to develop drug candidates for chronic diseases and conditions requiring repeat dosing on second-generation IgG cleaving enzymes. Today, we're excited to share the very encouraging results from the first in-human trial of the lead candidate from this program, HNSA-5487. These results clearly demonstrate the potential to redose with efficacy, safety, and tolerability, mirroring imlifidase, opening a path to develop HNSA-5487 as a drug candidate for a broad range of serious diseases requiring repeat dosing, such as chronic autoimmune diseases. Before I hand over the call to Hitto to review the data and discuss prioritized first indications for the coming development efforts, let me briefly set the scene. Please move to the next slide.
If we look at the broader autoantibody treatment landscape, IgG cleaving enzymes such as HNSA-5487 clearly have the potential to transform this. More than 80 autoimmune diseases, which are chronic, unpredictable, and have debilitating recurring attacks and symptoms, have been identified, and IgG is a significant factor in many of these. Clinical guidelines call for fast and effective reduction of IgG in acute and recurring stages of the disease. While a range of IgG-reducing therapies and interventions are being used in an effort to achieve this goal, current approaches have significant side effects, are time-consuming, and may not be effective for all patients. For many conditions, there are no FDA-approved treatments available, and while we have recently seen an increased effort to develop newer and better therapies, results from preclinical models, including non-human primates, have yet to be replicated in clinical trials.
With this as a background and wider context, we're very encouraged by the results from the first in-human study of HNSA-5487, and to share these, I will now hand over to Hitto Kaufmann, our Chief R&D Officer. Hitto?
Thank you, Søren. Please move to the next slide. So at the start of our presentation today, this slide summarizes the therapeutic target profile of our novel compound, HNSA-5487, a next-generation molecule that can very rapidly and robustly reduce IgG with clear redosing potential, before taking you through the data and the target indications in a little bit more detail. So in summary, what we are aiming for is to developing compound HNSA-5487 as a next-generation IgG cleaving enzyme based on an animal pathogen, compared to imlifidase, that is a human pathogen, to face less pre-existing immunity in the patients we want to treat. This enzyme inactivates IgG by cleaving the heavy chain of IgG efficiently and eliminating the Fc-dependent effector function. It has been engineered for high potency, specificity, and safety, and we wanted to achieve an immunogenicity profile that supports redosing.
Of course, we want that molecule to be safe and well tolerated. What I will show you in the coming slides is that the data that we have in hand today show that this enzyme reduces IgG levels by more than 95% within hours, and that IgG levels will return to normal within a six-month range. And on top of it, it is efficacious as imlifidase in reducing total IgG levels across all classes of IgGs. More importantly, the other data that you're going to see in a minute support that the immunogenicity profile will allow redosing, especially at time points that we investigated six and 12 months after the first dose given to healthy volunteers.
At the end of the presentation today, we share an outlook on the indications that we intend to focus, where there's a clear role for autoantibodies as a driver of the disease, and there is a need for management of symptoms at the onset of the disease and during recurrent immune system attacks. Please move to the next slide. This slide summarizes the study outline as we have communicated it before. So the main purpose of this study in 36 healthy volunteers was to show a benign safety profile, which we have already communicated previously. We also generated PK and PD profiles, and we have seen no serious adverse effects, and also wanted to do some additional analysis on immunogenicity and the potential for redosing.
You see also on this slide, and I'm going to not walk through this in detail, the different dose levels investigated, and that the study was a placebo-controlled study with the exploratory endpoint that we have reached now after 12 months. Please move to the next slide. These data confirm that HNSA-5487 has an equal attractive profile in cleaving IgGs efficiency. So you see that in all relevant dose levels, we can show that more than 95% of IgGs are cleaved within hours after intravenous administration, and that the recovery of IgGs to a normal level occurs within six months. That was very encouraging because it showed us that our engineering steps ensured that HNSA-5487 has the same attractive pharmacodynamic profile as imlifidase.
On the next slide, you show the results of our analysis of the so-called total ADA response to HNSA-5487, compared to imlifidase. All of these data have been generated in healthy volunteers in older trials with imlifidase and now with the trial that we're reporting out today for HNSA-5487. Please note that the scale in this graph is a logarithmic scale, and you see, first of all, that according to our hypothesis, the original ADA levels were lower for healthy volunteers that would get HNSA-5487 compared to imlifidase. And more importantly, the ADA response was significantly lower and had a typical S-shaped curve, peaking at one to two months, and then going down further six to 12 months.
This was really exciting because the hypothesis that we started out with, that we can generate an efficient IgG cleaving enzyme with a much lower immunogenicity profile, could be demonstrated in those data from healthy volunteers. The next step is shown on slide number eight, where we then set out to take serum samples from patients at different dose levels, in different time points, up to 12 months after the first dose, and in an in vitro experiment, we assessed the cleaving potential of HNSA-5487, so what you can see here, that we have generated data that support two windows for repeated dosing of HNSA-5487. The first one, at the very beginning, after week one, which could significantly increase the duration of the initial low IgG window in patients when needed.
And the second one is the window that could be very relevant for retreating patients with chronic autoimmune diseases, six to 12 months. We could demonstrate with these data that in serum from patient, from healthy volunteers, six to 12 months after treatment, we can almost completely cleave IgGs in almost all healthy volunteers and subjects that have been investigated. If you compare that to the limited data that we have for imlifidase, you can show that we have a much higher cleavage efficiency. The data we have show us that in healthy subjects, after two months, we could not cleave healthy volunteers' serum samples for imlifidase. So a clear step forward into the space of repeated dosing.
Before we go into the indication spaces, the next slide shows and reminds us again about the profile of HNSA-5487 compared, for example, with FcRn inhibitors, and shows that the profile is very different. IgG reduction goes down to much lower levels and much faster, within hours. What you could also see from that graph here is that the pharmacodynamic profile of an FcRn inhibitor and the IgG reduction through our enzyme is very different. In the table to the right, we compared also the ability of imlifidase and HNSA-5487 to cleave, on one hand, intravascular IgGs, similar to FcRn inhibitors and PLEX, bringing down IgG levels intravascularly, but also as extravascularly, which is very efficient with imlifidase and HNSA fifty-four eighty-seven, and includes also the cleavage of those IgGs that are bound to the receptor of B cells.
So in terms of reduction of IgG levels, the current best option is using one of these enzymes, such as HNSA-5487, in terms of speed and totality of bringing down IgG levels. Let us spend some time on the indication space. What were our guiding principles? The guiding principles we used were, we would like to initially go after autoimmune diseases, where pathogenic IgGs have clearly been demonstrated to be the key driver of the disease. Number two, we want to go after indications where there's still a very high unmet medical need and where the condition overall becomes a chronic condition for patients. This is why we are now zooming in on those autoimmune diseases that have a very pronounced neurological phenotype. There are three indications that are in focus for us at the moment. The first one is described on this slide here.
It's called NMO for neuromyelitis optica. The symptoms are very much related to pain of the eye and vision loss, and the weakness or paralysis of arms and legs. The prevalence is about seven in 100,000 people in the U.S., and currently, there is about 22,000 people in the U.S. living with this condition. What you see in the graph.
Pardon me, it looks like we've lost connection with our speaker. Please hold while we reconnect. Ladies and gentlemen, thank you for your patience. We've reconnected with our speakers.
Thank you, operator. Unfortunately, we're cut off, so I'll hand back over to Hitto to continue with the presentation.
Thank you, Sir.
The last thing I was talking about was the first indication, NMO, and I would now like to continue with talking about the second exciting indication that we want to go after initially with our compound HNSA-5487. We're talking about myasthenia gravis, which is a rare chronic autoimmune neuromuscular disorder that is characterized by fluctuating weaknesses of the voluntary muscle groups. The biology of that disease is linked to autoantibodies that block the acetylcholine receptor, and that leads to disruption of the important signals at the neuromuscular junction. The symptoms resulting from that disruption are weakness in eye muscles, including double or blurred vision and drooping eyelids. They can develop widespread weakness in face, arms, or legs. Currently, there are some treatments available with acetylcholinesterase inhibitors and immunosuppressive therapy. In severe exacerbation, intravenous gamma globulin or plasma exchange is used.
However, currently, there is no approved treatment for severe exacerbations in myasthenic crisis, which is a condition that leads to the need for ventilation. It's very severe. The last indication on the next slide I'd like to briefly describe to you is called MOGAD. It is again characterized by attacking the myelin protection of the axons. In this case, antibodies have been described to be directed against a protein called MOG, and that protein is produced by oligodendrocytes, and again, it's very important to protect the nerve cells. Symptoms are similar in that regard that they affect the vision, weakness and numbness of the limbs, and paralysis caused by disruption of nerve signals. The prevalence is about 1.3-2.5 in every 100,000 people worldwide, and approximately 30% of all cases are observed in children.
The treatment for sudden onset and long-term symptom management may include steroids, plasma exchange, intravenous immunoglobulin, immunoglobulin, or immunosuppressants. Again, at the moment, there are no approved treatments in MOGAD. So hopefully, the three indications give you an idea of the high unmet medical need that we want to go after with our compound HNSA-5487, which in summary, has proven in our phase I trial in healthy volunteers to be equally efficacious in reducing IgG levels across all subclasses compared to imlifidase, which has been proven to have a lower ADA profile in response to intravenous administration, and which we could demonstrate in our exploratory endpoints, has clear redosing potential. With this, I would like to hand back to Søren.
Thank you very much, Hitto, for this overview, the data, and the intended path forward. Operator, let's begin the Q&A session.
We will now begin the question-and-answer session. To ask a question, you may press Star, then one on your touch tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press Star then two. At this time, we will pause momentarily to assemble our roster. The first question today comes from Douglas Tsao with H.C. Wainwright. Please go ahead.
Hi, good morning, and thanks for taking the questions and congrats on the progress and the data. I guess I'm just curious to get some initial thoughts in terms of the timelines and the development plans for the initial targeted indications, and then I have a follow-up. Thank you.
Good morning, Doc, and thanks for this question. Right now, we are getting ready to engage in dialogues with the regulatory authorities, as well as continue our extensive discussions with the KOLs. Once that is done, we will of course communicate the specific timeline for this, but certainly we want to move ahead as quickly as possible. As I said, the first step right now is to commence, you know, dialogues with regulatory authorities to determine the specific path forward.
And then I guess for all these conditions, I guess I'm just curious, you know, in particular for like, say, MG, where you referenced, you know, an MG crisis, which, you know, can rapidly result in patients being intubated and an extensive ICU stay. I guess I'm just curious, at what point would you anticipate the product being used? Is that sort of immediately as you start to see a manifestation of symptoms? Presumably, a lot of these patients will be on FcRns, but as their sort of effect starts to wane? You know, just curious, and then as well as for the other ones as well, if you have some initial thoughts. Thank you.
Sure. So what we know is that actually intervening as quickly as possible and with maximum effect is critically important, right? So clearly, what we would want to do is to initiate therapy when you have a severe attack, whether it's upfront or it's a recurring attack. But maybe, Hitto, you want to comment on that as well?
Sure. So absolutely, I agree with what you said, Søren. I would say it, of course, in more detail, the intervention points for something like NMO and myasthenia gravis may not be exactly the same, which is what we are currently working out. And for this, it is really important that we work very closely with the experienced clinicians in the field, especially for myasthenia gravis. It could be that the initial intervention point is well before a myasthenia crisis actually is evident. But as S ø ren has said before, this is your question to the point of what we are currently trying to plan out in more detail.
Yeah.
Just one final one, if I may. Do you have a sense of limitations on lifetime dosing for an individual patient, and how many times they could potentially be treated with HNSA-5487? Thank you.
Hitto, I'll hand over to you, but I would say at this point, we don't clearly expect that these patients can be treated, you know, numerous times, right? But over to you.
Yeah. Thank you, Søren. Yeah. I mean, obviously, we have now shown that the ADA response we get in healthy volunteers can be cleared through in six and 12 months. A second dose will create another ADA response, which will probably have, at least in terms of the time course, a similar profile. We will have to demonstrate that in patients, and I'm confident we can. In patients, the ADA response may also depend on other treatments at the same time, which are often immunosuppressant. So you could look at our study in healthy volunteers a little bit like a worst-case scenario for this, and I think that's what makes us quite confident that we can treat repeatedly. Which would not necessarily be a chronic treatment, but would be a treatment whenever these acute phases or crisis phases occur.
Yeah. And maybe to add to that, I mean, there's also speculation that if you intervene effectively, you might actually reduce the frequency of attacks, right? So reducing the need to intervene subsequently, right, so.
Thanks.
Thanks, doc.
Great. Thank you so much, and congrats.
The next question comes from Matt Phipps with William Blair. Please go ahead. Matt Phipps, your line is open. You may ask your question.
Sorry. Thank you. Okay, hey, guys, congrats on this, nice proof of concept for the NiceR platform here, and thanks for taking a couple questions. I guess, first off, when you move into these indications, obviously, you showed a bit of a dose-dependent reduction on IgG, but are you going to aim for hitting that 95% reduction, or do you think there is some... I mean, is 80% enough? Just curious, what maybe will be the goal on initial IgG reductions in some of these indications?
Mm-hmm. Thanks, Matt. I'll hand this question over to you, Hitto.
Matt, great question. Obviously one of the aspects of our upcoming interaction with health authorities will be around dosing. It's a bit too early to conclude on this because all the data that we've shown so far are in healthy volunteers, and we will probably have to generate a greater body of evidence on dosing levels in patients. However, at the moment, our ambition is to go for almost complete removal of IgGs. The 95% bar is simply something we've used here to illustrate how our data for HNSA-5487 compared to imlifidase. That doesn't necessarily have to be a bar for future treatments. I think that will depend a lot on how much IgG reduction is needed to help those patients, so your question is a good one.
The answer is the 95% bar was, in a certain sense, an artificial bar we have set ourselves to be able to illustrate how the efficiency of our enzyme compares to what we have done with imlifidase.
Makes sense. Okay. And then, you know, I think, in the kidney transplant setting, you've shown, yes, the similar rapid reduction and maybe over time, actually reduced donor-specific antibodies or, like, they don't reach kind of the original level. And then also given the activity against kind of the B cell receptor on memory B cells, I guess, do you think there's potential for greater durability of efficacy, even beyond kind of the return of total IgG levels in patients?
Hitto.
Yeah, this is a great question again. I think it will be really interesting to see how the immediate intervention with such a powerful IgG-reducing technology would change the long-term outcome in those patients. We know that B cell intervention can reduce the relapse rate. This is much more rapid, it's more profound. So it's an excellent question, and we definitely would like to investigate what happens after IgG levels have rebound to the long-term outcome in those different indications. To be investigated.
... Great, and then maybe one last question, I guess. You know, how confident are you that if you re-treat a patient at, like, a six-month mark, you don't then see a higher ADA spike post that retreatment, kind of up to the level seen with imlifidase? And then I guess, are you going to explore different background therapy regimens that might further reduce an ADA response over the healthy volunteers?
Yeah. Two good points. First of all, yeah, up to now, we have demonstrated the redosing for one treatment after the initial treatment. As I said, in the patient setting, the situation may be completely different in terms of immunosuppression, so the ADA response may even be a little bit lower than what we've seen. I'm confident that with the dose levels that we have established in phase I, we can achieve repeated dosing efficiently.
All of that will have to be proven in patients, and onto your second question, absolutely. I think, if we look long-term into the best dose regimens for conditions such as myasthenia gravis, it could well be that a combination of a certain form of maintenance treatment and those powerful IgG-cleaving enzyme technologies could really change the outcome for this patient long term. That could also have an effect on the ease of redosing.
Great. Okay, congrats again, and thanks for taking my questions.
Thanks, Matt.
No, thanks, Matt.
The next question comes from Suzanne van Voorthuizen with Kempen. Please go ahead.
Hi, team, this is Suzanne from Kempen. Thanks for taking my questions. On the three chosen indications, you highlight the acute phase and how HNSA-5487 positioning there, how you would position the drug there with redosing potential. Would be great if you can elaborate a bit on the next clinical development thinking. For example, are you planning to do proof of concept studies in all three indications at the same time, or one by one? And what hypothesis are you going to test in these studies? Are you thinking more about measuring IgG reductions, the clinical benefits, or the evaluation of repeat doses? Thanks.
Certainly very relevant questions there, Suzanne. Thanks for those. As I said, initially, you know, we are currently planning to engage in dialogues with regulatory authorities, and before we've been through those, we're not going to speculate on specific trial designs or overall strategy here. But clearly, the intent is to move forward at speed into patients and demonstrate clear clinical outcomes, positive outcomes in these acute attacks. I don't know if you have any additional comments, Hitto?
I would say, like, Suzanne, this is your question is exactly what we're now sketching out in more detail. The two indications that could even be combined potentially in a trial would be NMO and MOGAD. Myasthenia gravis is clearly different. And in terms of outcomes, as you said, there's, there are two things that will be in focus. For sure, one is we want to really demonstrate that the specified antibodies, and I alluded to them, which structures they, they bind, and which is nice in these diseases, that you have good biomarkers, will be something we would look for. And the second thing is obviously patient outcome, and I described the symptoms, so it could give you a bit of an idea of what we would probably be looking at here.
Got it. Thanks for that. And maybe one follow-up regarding what you do see in terms of ADAs. The comparison to imlifidase is clear. Could you put some context to how these ADA levels with HNSA-5487 compare to, for example, anti-antibody-based treatments in chronic indications, chronic conditions?
I would be very hesitant to draw any comparison here, because especially with any other assay, it's really important to generate this data side by side in the same setting, with the same patient population and the same assay format. So I would be super hesitant to draw any conclusion. However, even with antibodies, the ADA levels that you can get between two different antibodies could be dramatically different. And that's another reason why a broad comparison is not really possible. What matters for us is really the biological outcome, and the outcome is: Can we cleave? Obviously, our enzyme is also cleaving the ADA, so in a certain sense, it's a titration experiment. And what we can nicely show in those serum samples is, at the doses we tested, we can efficiently, we can even very efficiently cleave.
That is really much more important for us than to compare our enzyme with, let's say, an antibody treatment.
Got it. Got it. Thank you. Maybe a last one from my side: Can you remind us what dose level is comparable to imlifidase?
In imlifidase, we have established those levels of 0.25 and 0.5 , and here we have gone up to one mg per kg dose levels in this phase I study. Which is, again, it's a dose study in healthy volunteers, and as I said in, I think, as a response to a previous question, the exact dose in patients will have to be established.
Got it. Thank you.
... Thanks, Suzanne.
The next question comes from Aksel Engebakken with ABG. Please go ahead.
Yes. Hello, good afternoon. I have a couple of questions, actually. The first question relates actually to the anti-drug antibodies cross study showed here, and as I understood it, it's a cross trial comparison, which means, you know, these samples, they haven't been run in the same experiment. Are you planning to do something like that? Like, maybe in the framework of a publication, that you could actually take the old serum samples that you have from the previous imlifidase phase I studies, and you just run them head-to-head in one experiment and in kind of one trial? I mean, it's kind of a simpler assay, that ADA experiment. That's my first question.
Okay, let's take that first question first. Yeah, Hitto.
Sure. Sorry if this may have caused a misunderstanding. The trials were separate trials. However, the serum samples were run in the same set of experiments.
Okay. But you're not planning to publish that full data set in some journal or like, are you planning something there?
At this point, it's too early to say. We don't know. Let's see.
Okay. Okay, good. Then I can continue with my next question, and it relates to immunosuppression, of course. I mean, if you did deplete like more than 95% of IgG, did you see some like safety signals that you have like an increase in infectious disease in your study, in your healthy participants, like especially in this six-month window, when you're really low in IgG?
Again, similar to imlifidase, but I'll hand over to you, Hitto, for this.
Obvious question. With regard to the 36 patients, at least for those who had the relevant dose and didn't have the placebo, the safety signals we saw were very comparable to imlifidase. For imlifidase, we have now more than 200 subjects being treated in our safety database. We are very, very confident here that this enzyme should end up having a very comparable safety profile, which from everything we know, from the many patients we've treated with imlifidase, is not leading to an infection risk that causes problems.
Okay, good. With that, I can come to my last question, and it's about a little bit more on a competitive landscape. I think, so today you talk about, you know, the FcRn, which maybe we know about, you know, argenx. There's a couple of other players that are also planning to go into, especially the MG, myasthenia gravis, disease area. I'm talking about Biohaven, Immunovant, they're expecting some data, like, how do you see HNSA-5487 position that they are in this market? Like, in terms of thinking about the different mechanisms of actions that are investigated in the field.
The way we look at it is, also after having had very extensive discussions with KOLs and specialists and so on, is that really knocking down pathogenic, you know, IgG fast and completely, you know, very robustly, is seen as something that is very important, right? So we have deliberately chosen to go after these acute attacks in serious diseases that can really be very, very debilitating for the patients. And so this is the response we get. You know, if you can replicate this in patients with... you should expect very good, you know, clinical outcomes in these acute attacks. Having said this, we don't actually consider imlifidase as broadly as, let's say, competitors.
We actually think, you know, and that even goes for IgG degraders, that there could be a very good case for combination therapy. So that's certainly something that we would look at, and we have reason to believe that would work. But Hitto, you may wanna add to this.
Sure. Since you mentioned Biohaven, I'm just gonna add a little bit more. We currently look at these classes of molecules as pretty different, even though the data for many of those you just mentioned are still yet to be shown, and some of that are based on pre-clinical data. but just using Biohaven as an example, it's a very different technology. It's a different approach to reduce IgG levels. and if you just look at that alone, an important difference is that imlifidase and HNSA-5487, they cleave IgG one, two, three, and four with similar efficiency. The Biohaven technology, to the data that we have available, doesn't touch IgG3 . and IgG3 are thought to be the key drivers of pathogenesis in many of those IgG-mediated autoimmunities.
So I think we have to watch out in the future for how the profiles of these different classes of molecules fit into the needs, the therapeutic needs that we have. What it shows, I think, in general, is that the unmet medical need across many of those indications, and we only talked about three today, is still huge, and that's what's driving technology development. Our place will clearly be in a situation where a rather complete removal of IgGs under time pressure is essential.
Okay, very interesting.
Yeah, Alex. Thank you very much.
Thanks, Alex.
Thank you.
The next question comes from Johan Unnérus' with Redeye. Please go ahead.
Great. Thanks for taking some questions, and congratulations on promising robust results at this stage. Firstly, I presume that you will. It's a fair presumption that you will go forward with three different studies for three different indications that you pointed out. I mean, a combination portfolio study would be potentially very complicating, given that you would probably include different dosing intervals and perhaps doses as well.
Again, it's too early to be more precise here, right? But as Hitto talked about, there is you know potential to combine at least NMO and MOGAD, but that's something we need to further investigate through our dialogues with the regulatory authorities.
What about these discussions, then? Could you give us a flavor of the timelines with these discussions and results and protocols and so forth?
What I can say is that we want to engage as quickly as possible. Obviously some work has been done already, but as ever, it's impossible to predict the specific timeline here. But in general, we've had you know in past situations, we've had good dialogues and so on. So we expect to get a you know productive and effective dialogue going in the near future. As I said, you know, certainly we want to move into patients as quickly as possible.
Yes, and regarding the ADA levels, on the dose you have used at this stage in healthy volunteers, it seems robust. And what about the risks of accumulating ADA levels, when you give a second or perhaps a third dose?
Hitto, do you want to take this?
Yeah. So, I think that that's in line with what we said before. We are confident that the dose levels we have established can cleave to other responses efficiently. The data we show at the moment are data for a second cleavage, and we will investigate, of course, multiple cleavage as needed, depending on the indications that we're going after. But we are confident that that should work as well.
Also, there's a strong impression that you focused on the acute stage, which seems to be rational, given the efficacy you've shown so far. Is there a risk that this could reduce the risk of the need for a third and fourth dose in these indications?
A risk? I mean, obviously, a positive thing would be if the patient actually have less frequent attacks, right? That would be a major benefit that this therapy could provide. If you look at the various diseases here, the frequency of attacks varies a lot from patient to patient, but what most patients have, you know, several of these attacks, and they're very, very severe. As I said, actually, if you have a very efficacious, effective intervention up front, there is reason to believe that you might have a lower frequency of subsequent attacks, but that is something that needs to be established, but clearly, looking at the overall opportunity landscape, you just run the numbers, and you also factor in the high degree of unmet medical needs. This is a major, major opportunity.
Yes, of course, and it would be a very strong and positive if you can show an acute effect and perhaps even reduce the level of intervals and perhaps even less need of repeat dosing the second and the third time for each patient. So, being a very exciting, interesting journey ahead.
Absolutely.
I think.
Thanks, Johan.
I think that's all from us. Thank you.
Thank you.
As a reminder, if you would like to ask a question, please press star then one to enter the question queue. The next question comes from Christopher Uhde with SEB. Please go ahead.
Christopher Uhde from SEB, thanks for taking my questions. So, you know, looking at this graph of the ADA levels, a few questions come to mind. Maybe I missed some things. There were some technical difficulties where I kept getting kicked off by Chorus Call. But, have you said anything about what proportion of ADAs you detected that were actually neutralizing, first of all?
Yeah, sure. No, a good question. The data that we have generated and shared are total ADA data, so they don't differentiate between neutralizing and non-neutralizing. However, from all of our experience with those enzymes, the curve that you see will very likely be the same if you look at neutralizing ADAs only. But what we've shown here are total ADAs.
Got it. Okay, thanks. Then, so I can see there's, you know, more than an order of magnitude difference between the two curves, the imlifidase and the Hansa. But I didn't catch, did you actually define what cleavable levels are? Because clearly from the, I mean, the imlifidase is always at a higher level than the HNSA-5487, except perhaps in a tiny overlap in the confidence intervals at the beginning. So, are you, how confident are you that at, you know, initially it wouldn't be cleavable versus yeah, yeah.
Yeah, I think the answer to your question is the next slide. The next slide shows for HNSA-5487, the percentage of patient serum that we could cleave completely. And here you see that the six and 12 month , we reach those levels essentially across the board. And that's a nice correspondence to the curve shown in the previous slide. Obviously, we don't have the same data set for imlifidase historically, because that was something that simply wasn't investigated. So we only have some data points for imlifidase, not covering the entire time course. But the data points we have for imlifidase show that there's clearly an improvement through the different origin of the enzyme, because it's... Remember, it's not going, was not evolved against human as a host and because of the engineering that we have done.
So I think what we can take away from the phase I study is, using a different source in combination with engineering has worked to generate a significantly lower immunogenicity profile and to enable very efficient cleavage across many patient samples in the time frames, long-term and short-term redosing that we had envisioned for what we intend to do in patients.
Got it. Okay, thanks for your patience. I realize that, you know, I missed that part. So, my next question is, initially, you get an extremely rapid degradation, and really, certainly, as complete as anybody has ever shown. Now, you then start to produce ADAs, which are, to a large extent, IgG. So what I'm wondering is, knowing that tolerization, in general, can be helped with, you know, persistent exposure to the antigen, are you sure that there isn't scope for actually continuing to dose, considering that, you know, if you continue to dose, you're gonna have a continued elimination of the ADAs early on, right?
I mean, I guess, if there's a kinetics which would allow you to continue to cleave newly produced IgG, at least, you know. What can you comment about that? Are you sure that it's not worth exploring this, especially early on, to see whether or not you might be able to have a more frequent dose schedule than Q 6 months?
Good thought. At the moment, we are driven very much by the disease pathologies that we have in mind for initial clinical development. And I'm saying this because I think on one of our first slide, we're talking about there's about eighty autoimmune diseases that don't really have yet a good, are not well addressed, completely addressed, at least. Now, we want to initially start with indications where the role of IgG as a disease driver is clear. There are others that we may go after, that where the role of IgGs is not so clear yet. But our technology could actually be the best clinical proof for a role of IgG, like ANCA-associated vasculitis, Sjögren's syndrome, all these kind of disease pathologies.
We won't go after those that I described at the moment as starting indications, and because of the knowledge that we have or the medical community has on sort of the most likely timing of a relapse in an NMO or a MOGAD, we chose those data points, and we chose to initially evaluate those dosing regimes. That doesn't stop us from going after other dosing regimes when we gain more clinical knowledge about our compound in patients.
Yeah, absolutely. And I can see the rationale for those diseases that you're going for. I'm just still wondering, I mean, we also know that, for example, when you vaccinate, you're gonna have a higher antibody titer after you give a booster, right? And so there's a risk that with a redosing, you're gonna have a higher ADA titer here. Whereas if you, you know, try it early on, you might be able to nip that in the bud. And it also kind of then leads to another question, is whether or not you should be looking at using this for tolerization, for example, let's say with hemophilia, clotting factor concentrates, when ADAs appear. Thanks.
Yeah, sure. And of course, this is what we can do in a phase I study. We have to go into patients and generate more data. I also want to repeat that in all likelihood, those patients will be also on some form of maintenance treatment or immunosuppressant, which is telling us that maybe the healthy volunteer situation is a bit of a worst-case scenario. And then it will also all depend on how often do you need to treat those patients? What's the timeframe in between? And how much, I would say, with the doses that we are envisaging at the moment, how much more ADA can be cleaved through, will have to be demonstrated in clinical trials, of course.
Okay. Thank you very much.
And then there was Mike.
Okay.
Yeah.
Oops.
Yeah. Good. Good, good. Thanks, Christopher.
This concludes our question and answer session. I would like to turn the conference back over to Søren Tulstrup for any closing remarks.
Thank you very much, operator. And thanks, everyone, who's called in for this call. Clearly, we're very excited about these results. And as you heard, we have a clear path forward, and we look forward to updating you on progress here. Once again, thank you for calling in.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.