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113. Bull, Bear & Beyond – Oryzon Genomics: executive interview
2 Plays5 months ago
In this interview, we speak to Carlos Buesa, CEO of Oryzon Genomics, with a focus on the company’s lead programme targeting agitation and aggression in borderline personality disorder (BPD) patients. Oryzon recently submitted the Phase III protocol to the FDA to initiate the PORTICO-2 trial, and regulatory clearance is expected in September 2025. Carlos discusses the progress of the BPD programme, as well as the unmet needs in the space, since there are currently no FDA-approved drugs specifically for BPD. He also covers the expandable opportunity for vafidemstat into other neurological conditions characterised by agitation and aggression, such as autism spectrum disorder. The interview concludes with Carlos providing a summary of upcoming key catalysts and milestones for Oryzon, as well as an outlook for the sub-sector of neurological conditions as a whole.
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About ‘Bull, Bear & Beyond’
Bull, Bear & Beyond': features candid conversations with senior executives and from our own team of experts from across industries, exploring strategy, innovation, and the opportunities shaping their markets and 60-second pieces are a compressed summary of content designed to convey our message in a single, easily shareable hit.
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Original interview published on 31/07/2025 and reposted as a podcast
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Transcript
Introduction to Horizon Genomics and focus areas
00:00:07
Speaker
Hello and welcome to another Edison TV executive interview. I'm Aaron Atkar, healthcare care analyst here at Edison. Our guest today is Carlos Bueza, Chief Executive Officer at Horizon Genomics.
00:00:19
Speaker
Horizon is a publicly listed clinical stage biopharmaceutical company focused on the development of epigenetic based therapies with pipelines in both oncology and focused on CNS disorders.
00:00:29
Speaker
Welcome, Carlos. Thank you, Aaron.
CNS pipeline and Vafidemstat for BPD
00:00:34
Speaker
So we're going to keep the focus today on Horizon's CNS pipeline, which is led by the lead candidate, Vafidemstats, where the primary targeted indication is aggression slash agitation in borderline personality disorder, or BPD.
00:00:47
Speaker
So Carlos, Horizon's made headway in preparing for its phase three program in BPD. Can you provide an update on the current status of the program, including interactions with regulators and the choice of endpoints for phase three?
00:01:00
Speaker
Yeah, with pleasure, Aaron. No, yeah, it has been a ah very long journey till since we were publishing the the final results of our phase two data last year at the ECNMP conference in Milan.
00:01:15
Speaker
um We have um promising data for the audience ah to remind. I mean, we were missing the primaries in aggression um and and and overall um improvement, but we were getting very strong results in secondaries, also in aggression and overall improvement. That together with a number of other findings of the of the trial was really and sufficiently promising to go to the agency and we went to the agency, to the FDA in an end of phase two meeting.
FDA interactions and unmet needs in BPD
00:01:51
Speaker
where we discuss with them if the data were warranted or were having the merits to proceed proceed to a phase three.
00:02:01
Speaker
And the the truth is that they were very constructive. They are very aware that there is nothing approved in BPD, that there is a strong medical need. People are being treated with off-label antipsychotics. So they were very and very conscious that there is no gold standard in how you measure this patient. So they were examining the whole process. data package of the phase two, and they were agreeing with us that the the data was were deserving the shot to go for a phase three.
00:02:32
Speaker
So that was a very promising start. the Then the convention conversation continued. We wanted to carve out the indications to aggression because it's there where we see a strongest signal, and they agree with that as well.
00:02:47
Speaker
And finally, the of course, the the elephant in the room was and how we measure these patients, or in other words, what endpoints should we take for this phase three? Of course, um it looks like obvious that if you have got very promising results in a previous trial. You should repeat this endpoint in the next trial. But the agency cognizant of them recognizing this, still they said, well, it would be very convenient ah that you would complement this with um clinician rate endpoint that is also but providing additional confidence on your STACC to treat anger, which is a patient rated scale and was having um was giving us this strong result in the previous phase two.
00:03:36
Speaker
So we assembled a group of very renowned scientists, secretaries in the US from Stanford, Yale, Albert Einstein and other
Development of Phase 3 trial protocol with FDA collaboration
00:03:48
Speaker
colleges. And these people and us, we were basically um examining all the FDA comments. We were going through and preparing um a draft of the protocol.
00:04:02
Speaker
So at the same time, we were having additional rounds of inter iterations of conversations with the FDA. They were um' requesting us to do some psychometrical studies. We did. They were request requesting us to do some qualitative research. We did. So we have been in strong close contact with the FDA.
00:04:23
Speaker
to try to accommodate all the requirements um to providing this protocol that we just submitted in June, um this last June, um and to accommodate all the and requirements that they did on this protocol. especially on the endpoints aspect. I mean, endpoints in terms of facial validity, psychometrical robustness, and so on and so forth, have to be convincing for the agency, for the doctors, and and for everyone. So I think that we have done um a thorough work on that.
00:05:01
Speaker
I think that the outcome is very satisfactory. What we have suggested, I mean, we have so submitted now to the agency is that we are going to complement the primary endpoint, Staxi-2-Trade Anger, which is ah ah patient rated, with a key secondary endpoint, which is the over-aggression scale and modified, which is this OESM is a scale that has been very well validated, is clinician rated, in other studies has has shown capacity of um measuring pharmacological effects on reducing aggression.
00:05:39
Speaker
And very recently, a number of members of the BPD community have started to use this scale as well. So we are, I think, in a very good position because the studies that were done in principle by
Phase 3 trial endpoints for BPD aggression
00:05:54
Speaker
Dr. Coccaro, who was the creator or designer of this scale, saw that um the psychometrical correlation between OASM and Staxi-2-Tritanger is 0.72. which is good because it's sufficiently high to indicate that they are measuring more or less the same things. And it's not that high to to say to say that you are repeating the same observation or the same ah and evaluation. So it's perfectly on the finest point to have this kind of complementarity. So that's where we are right now. We were submitting this trial to to the FDA, the protocol. We expect the the goal, obviously, in in due time, probably September, maybe October. And we are very hopeful that this is going to be a significant step forward for the for the BPD patient community because it has to be reminded that um that there is nothing approved, but there is nothing on the pipeline. So we are the only company right now
00:06:59
Speaker
um with an advanced asset in this disease, which is huge, is an enormous medical need and also a very substantial commercial opportunity.
00:07:11
Speaker
So, borderline personality disorder is a condition with no approved drugs.
Unmet need and Vafidemstat's potential impact in BPD
00:07:16
Speaker
Can you outline why you believe there is such a significant unmet need in this space and then how Bafidemstat's epigenetic mechanism of action aims to address this?
00:07:26
Speaker
Yeah, no, and you know, I mean, there are indications like chisophrenia that they have been there on the on the common on the common knowledge for more than 100 years, and they are part of our culture, so so to speak, you know? um There are other personality disorders or other syndromes which are much more recently described and characterized and therefore, I mean, they are relatively new.
00:07:53
Speaker
ah However, i mean, when you dig out on the data, you realize that 1.6% to 2.5%, depending on the sources of the of the population, general population develops BPD.
00:08:06
Speaker
Of course, not everybody is extreme. As as always, you have a Gaussian curve. You have very mild, moderate, meet severe and extremely severe people. But I mean, it's a disease which is causing lots of pain. I mean, these people are having lots of interpersonal relationship problems.
00:08:27
Speaker
I mean, there are people who are very suspicious that they are always feeling that they are going to be abandoned. They overreact. They basically ruin their romantic relations. There are people who are not able to get the job, to keep the jobs. to get and to keep the jobs. And there are also people who are very complicated for their families. And this is extremely complicated because additionally to that a condition which shows high levels of agitation and aggression.
00:08:59
Speaker
which many times this agitation and aggression goes autolytic. So they they they injured themselves, they cut themselves, they banged themselves, and also they killed themselves. So I mean, the the ratio of suicidal execution in this ah disease is the highest, is the highest in any other um psychiatric disorder.
00:09:24
Speaker
So the unmet need is there. These people are, and i mean I mean, populating the emergency rooms. There are people who are very vocal, very disruptive in the stream cases. and And as I said before, there is nothing approved. I mean, the the doctors basically try to to cope with these outbursts with this anti-psychotics, which have lots of side effects. They mitigated the outbursts for a short period, but people abandoned this medication because they get sleepy, they get rosy, they gain weight, they lost their libido. I mean, it' it's really not the way that you want to live as ah a full human being. So the medical need is there.
00:10:12
Speaker
And um and then the the reason why, and I mean, some farmers have been more reluctant to enter into this space was because it was a a sort of I will say a legend, urban legend that the this ah this um disease is particularly difficult or intractable or these patients are particularly difficult. And I must say that our experience do not agree with that. I mean, we have got, and we have performed a phase two B trial in the US and in Europe.
00:10:47
Speaker
We must say that these patients were normal and were not most more difficult than schizophrenia or ADHD or autistic patients. They are as difficult or as simple as you want to express that any other any other patients from other syndromes or diseases or disorders. So um yeah, all in all, we have right now a situation where there is and ah not only an enormous medical need, but I mean, there is also an emptiness on the pipeline.
00:11:21
Speaker
And this is placing us on our, as I said before, on now on a very comfortable, competitive landscape.
Key opinion leader insights on BPD challenges
00:11:29
Speaker
So, Horizon recently hosted a key opinion leader event which featured clinicians working sort of directly with BPD patients. So, could you briefly summarize some of the key takeaways from that event?
00:11:40
Speaker
Well, this this ah and this ah event that I invite the audience to hear by themselves, there is an hyperlink in the Horizon web page that you can basically click and um follow it. um It was ah basically an interesting, but um an important part of the discussion was about the de disease the disease itself.
00:12:04
Speaker
So talking about how more and more people are um being the diagnosed because this is a condition that is more and more well-known by the secretaries and the specialists, well described on the DSM-5 and also emphasizing how important was the mitigation of the agitation and aggression on the daily life. because um although this disease has these two components, the psychiatric component and the agitation and aggression component, it is true that the agitation and aggression component is also contaminating the psychiatric component component because of course, if you are having constant fights and constant clash with people around you,
00:12:49
Speaker
I mean, this is ah something that is going to um and worsen your perception of yourself. You think, well, I am a bad person because I'm having problems with everybody. On the contrary, if you enter in a sort of calm period, I mean, you are performing well, you are starting to feel better, your interactions with the other people are becoming less less stressful and so on and so forth. So there is a component in the aggression, which is a meta component.
00:13:16
Speaker
and that also spills over the psychiatric component. But what is true is that the the agitation and aggression components plays a very important role on the on the quality of life of these people, on the capacity of getting jobs, on the capacity of keeping the jobs, In fact, we did ah a qualitative research during the Portugal trial and when we were asking the patient what were the most significant, um in their words, what they were the most significant or more cumbersome or more impairing symptoms on their daily life.
00:13:55
Speaker
aggression, irritability, incapability to cope with frustration, outbursts were concepts that they were getting there. And the and the specialists and the k opinion leader were agreeing on that, were emphasizing this. And the other question is that they wanted to to see a drug for this patient that is a drug which has a tolerability profile, which is sufficiently good.
00:14:23
Speaker
And it is clear that Bafidenstat is having a very, and very good tolerability profile. We we have been and we have ah performed several phase one, two, and two-bit studies with almost 500 people dosed with this drug. And what we can see is that we don't see weight gain, we don't see loss of libido, we don't see drowsiness. So three of the main components that makes people to abandon their treatment is not there in Buffy. So I think that what it was also um a bit the message from the key opinion leaders was that with this, you would expect that in adherence to the treatment would be sufficiently good to let the drug to speak, now to let the drug speak.
00:15:13
Speaker
and i And I think that the the other aspect that was mentioned is that ah this epigenetic ah ah mechanism of action, which is controlling the expression of genes involved on the stress management on the prefrontal cortex,
00:15:31
Speaker
can work in not only in BPD, can work in other indications. And um they were also discussing the need in other indications like ah autistic spectrum disorder and and other things. So it was a very comprehensive view of the disease, a bit of the ah data that we have seen in in ah in the PORTICO trial, and Not too much discussion about the the protocol that we have submitted to the FDA, but it was very rich on on um on these other aspects.
00:16:07
Speaker
So you've touched upon it just there a little bit, but we understand that by targeting agitation and aggression, this may open the doors to address other neurological conditions.
Potential for Vafidemstat in other neurological conditions
00:16:15
Speaker
So can you talk to us just a little bit more about that?
00:16:18
Speaker
Yeah, no, indeed. I mean, as I was saying, yes, I mean, like well i mean it is something which is transversal to many, many indications. It's not only, not only neuropsychiatry. I mean, ah we we we know that it's very important. Aggression is very important in this schizophrenia, in ADHD, in autism, in borderline personality disorder, but also in in in Alzheimer's and also in Parkinson's disease.
00:16:45
Speaker
So, and again, this this aggression is many, many times triggered, not by an aggressive behavior, but by misjudgment of the stressful signals that the patient receives from the outer world, you know.
00:17:04
Speaker
So I think that on this in the sense that our mechanism of action is basically resetting the immediately genes on the prefrontal cortex to make up um more um a refreshed connection and between the prefrontal cortex and the amygdala and other aspects and other and regions involved on the stress reaction, stress response. I think that this ah is something that can certainly merit to to be tested. It has to be mentioned that we did um a very small preliminary phase two way trial with Alzheimer's and we saw some interesting signals there of reducing of aggression. So yeah, I mean, and indeed,
00:17:55
Speaker
Autism, aggression, and Alzheimer's aggression are fields where we could eventually continue the exploration of Bafidens in these domains.
00:18:08
Speaker
Fantastic. So before we wrap up, just for investors and prospective investors, could you briefly summarize the key catalysts and milestones to watch out for that are upcoming for Horizon?
Upcoming milestones and catalysts for Horizon
00:18:19
Speaker
Yeah, well, I mean, um I think that the the more important one is the FDA response that we expect by September, October to to get the goal for the phase three trial. um and I didn't mention, but we we were saying before that in previousview's ah in previous releases that ah we are also running a very interesting trial in schizophrenia. This trial was and initially constrained to Spain only because of financial constraints of the company. the company got 50 million dollars in the last month and because of that we have immediately expanded the trial to europe so we have also revisit with the biostatisticians we think that with 88 patients we will be having sufficiently alpha power
00:19:15
Speaker
to see differences on the and negative symptoms, which is the primary endpoint. But we are also going to measure, of course, positive symptoms. So it's going to be also very performative in this field. And this is a trial that we are accelerating, and we expect to be able to read in 2027, so um one ah one year and from now. We are right now already designing a phase two trial in aggression in autism with idiopathic autistic patients, but also enriched with Phelan-McDermid patients.
00:19:56
Speaker
um So we are very interested in seeing the overall and the overall response in the idiopathic population, but also on a specifically genetically defined populations. So these are the three basic pillars for for the CNS. But I would like to remind the audience that Horizon has another pillar, which is the oncology. It's a pillar, oncology and hematology is a pillar that we expect to our license at some time point or ah um and to monetize this to to get the the resources on the and the CNS. But we are going to present very promising, very positive data, um I think,
00:20:39
Speaker
um in the next ash from the several studies that we are performing either sponsored by the company or either through the grader uh greater agreement with the ncina in the us and some ah also some uh investigator initiated studies so we are um we are having also some good news there we have submitted to the emma um a new trial um in sickle cell disease, where we think that our other asset may play a fundamental role. I mean, it's well-described molecularly speaking that LFG1 inhibition basically and is able to disrupt the two main repressor complexes
00:21:30
Speaker
for the expression of fetal hemoglobin. and um And this is ah going to be very interesting as well. So yeah, plenty of ah plenty of catalysts coming in on the next month, so porters.
00:21:46
Speaker
So I think that the investors should be so be tuned. Excellent. One more question, if I may, Carlos. We're seeing a resurgence of interest in the CNS space across the healthcare sector. Now, given that you're working at the forefront of the field, we'd love to hear from you.
00:22:02
Speaker
you know What are your thoughts on what's driving this current trend? Well, I think that the what is driving this current trend is the realization that was but particularly clear after COVID, that we are a society with loss of mental health issues, problems, um that the we need to, i mean, it's not to stigmatize anyone, of course, but we need to address those with new mechanism ah of action, with new drugs,
00:22:31
Speaker
and um And this is a clear need, and this is, of course, a very
Resurgence of interest in CNS treatments and mental health
00:22:36
Speaker
interesting market. We have seen transactions which have been triggering an interest, the acquisition of the cerebels by AbbVie. We saw the recent acquisition from BMS, from Karuna. um But basically, um also the the fact that we have seen approvals like Aplita for for him major depressive disorder, CIMBRAO for migraine-associated mood disruption,
00:23:05
Speaker
the postpartum depression molecule to survive. So we have seen some approvals and of of of course also in Alzheimer's. I think the big, um although it is clear that aducanomat and lekembi probably are not going to provide what the community is expecting, has been ah in a sparking, and a sparking,
00:23:29
Speaker
event to renew the mood and to to have a additional interest. I think that um it is interesting to see what happens with the Muscarini circuitry theory.
00:23:45
Speaker
I mean, to be fully fully candid, we were not expecting the failure of AB in that regard because the molecule and the mechanism of action was looking free really, really nice and solid. So it's interesting to see what going to happen with MAP lights, and the ML007, which is ah going to test, um is ah is a panagonist from the Muscaninic. So we'll see what happens with this, because I think that, um yeah, it is it was surprising. i mean, um um yeah there are other other aspects which are also promising no the orexin modulation is something that has been discussed to to to be able to control depression so so that that would be also very interesting and of course the the the psycho the psycho uh plastogen no the the the
00:24:45
Speaker
and This is another very complicated field, regulatory speaking, and and and in terms of dosage and in terms of, I mean, there are many, many things to be solved, but certainly it's a field which deserves to be continued.
00:25:00
Speaker
And I would like to ah end with the with the last word about epigenetics. So we we we think that we are right now um probably the only company developing an east an Eastern male is an is modifier. Okay. But there are also other um companies developing SDAQ5 selective inhibitors. So there are a number of attempts on coming back to epi epigenetics because as you and the audience for sure knows,
00:25:35
Speaker
Um, when there is a, uh, studies trying to look on the, on the more, uh, implicated genes in, in different neurodegenerative disorders and, and, uh, psychiatric disorders in all these GWAS studies, there is always a very strong epigenetic component. We know that the epigenetic component is on the basis of the, uh, of the etiology of these diseases. we still want to to find the the Holy Grail, which is going to be the ah the epigenetic ah leverage to um to modify some of these diseases. So I think it's a fantastic field. It's certainly a field to be in. And we have seen M&A, we have seen deals. So I think that, um yeah, we have up up and downs, of course, like ah any other field, because there are also failures, like the AB that they we commented, which was very unfortunate. But yeah, I think that we are in um in a very interesting moment on this on this on this s indication, on this field right now.
00:26:43
Speaker
Excellent. Thank you, Carlos, for sharing your thoughts and insights. It's certainly an exciting and time ahead for Horizon and the field. So if our audience would like to learn more about Horizon, please refer to edisongroup.com or the company's website. Carlos, thanks again for joining me today.
00:26:58
Speaker
Thank you. Thank you very much. It's been a pleasure as always.