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33. Bull, Bear & Beyond – Oryzon Genomics: executive interview
9 Plays1 year ago
Oryzon Genomics is a Spanish biotechnology company focused on epigenetics. Its two lead assets, vafidemstat (central nervous system, CNS) and iadademstat (oncology), are in the clinical stages of development for various indications. Both are small molecule inhibitors of LSD1, a histone-modifying enzyme that forms part of complexes responsible for the regulation of genes implicated in CNS disorders and cancer.
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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 10/12/2024 and reposted as a podcast
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Transcript
Introduction to Edison TV and Horizon Genomics
00:00:07
Speaker
Hello everyone and welcome to Edison TV. My name is Aaron Atkar and I'm an analyst here at Edison. We're joined today by Carlos Bueza, who is CEO of Horizon Genomics, a Spanish-based biotechnology company and leader in the field of epigenetics.
00:00:21
Speaker
Welcome, Carlos. Hi, Aaron. Glad to be here today.
Vapodemstat and BPD: An Overview
00:00:25
Speaker
So we're going to focus today on Horizon's CNS pipeline and to get started, Vapodemstat is Horizon's lead CNS asset and it's being developed for Borderline Personality Disorder or BPD.
00:00:38
Speaker
So before we get into its track record in the clinic, can you give us an overview of BPD itself, including how the condition is currently managed and the potential opportunity in the space? Yeah, glad to.
00:00:50
Speaker
Borderline personality disorder is one of the well-defined, characterized ah personality disorder by the DSM-5 criteria. It's a very severe psychiatric disorder characterized by two basic components of the disease. One is the psychiatric components.
00:01:09
Speaker
by which these people have very complex and difficult interpersonal relationships. And the other one is characterized by a very strong impulsivity. This impulsivity is very often channeled through aggression and agitation that might be but maybe vocal aggression, maybe physical aggression. And this um very often it goes also in an autolytic component. So these people harm themselves, burn themselves, and and very often, sadly, they kill themselves. the The rate of suicide is basically the highest in any other
00:01:44
Speaker
and you either in any other psychiatric disorder. BPD is therefore a very severe disease and it's very prevalent as well. I mean, there are studies that ah basically calculated that there is 1.9% over the global population, meaning that we will have probably around 9 to 10 million people affected by this disease in the US and Europe.
00:02:06
Speaker
And um unfortunately, different to other psychiatric disorders, there is so far and no pharmacological treatment approved for this specific disease. That means that the patients are basically treated nowadays with off-label antipsychotics, off-label mood stabilizer, and also the some of them, they are following psychotherapy.
00:02:32
Speaker
which is helping in some cases and in some others it doesn't, but it's certainly not ah available for the majority of the patient population. So it's a very high unmet medical need and it's a very severe disease for which the industry has not been able so far to provide any kind of pharmacological treatments.
Phase 2b Trial Results and Implications
00:02:58
Speaker
So the candidate recently completed a phase 2b trial in BPD with the final analysis showing some encouraging and results. ah Could you discuss some of the key takeaways from the data? Yeah, I mean, as I said, in this ah ah trial, Portico was a a global phase two trial performed in the US and Europe, 211 patients, randomized one-one, and treated for 16 weeks.
00:03:24
Speaker
um These ah patients basically were tested for two main the two main components. One was the overall improvement of the disease. The other one was the agitation and the aggression.
00:03:35
Speaker
And as we and the FDA and the rest of the industry, we are cognizant that there is no and standard of care or a golden rule to measure the improvement of a patient of BPD under a pharmacological treatment. We um agree with the FDA to duplicate the scales for both measurements. So we were having two measurements of aggression, one as a primary, the other one as a secondary, and we were having two but two measurements of overall improvement, one as a primary and the other one as a secondary.
00:04:07
Speaker
So it was um it was very very intriguing because as we were seeing seeing a better performance of the patients treated with the the drug than the placebo in the primaries, we didn't achieve um ah a statistical significance.
00:04:26
Speaker
However, when we were measuring the and the aggression by the STACC2 trait anger as a secondary, we were getting a very strong signal with a very clear nominal statistical significance, which was also corresponding to a difference over the placebo group that was considered um to be clinically very meaningful for the KOLs.
00:04:51
Speaker
similar similar situation in the other primary, the the BPVCL for the overall improvement where we saw that the patients treated with the drug were performing better.
00:05:01
Speaker
This improvement was insufficient to be clinically statistically significant. But when we were measuring the same then the and improvement by the other scale, the best, I mean, we were seeing ah again a very strong signal, which was both a statistically meaningful and clinically statistically significant and nominally statistically significant and clinically meaningful.
00:05:27
Speaker
So not only that, we also saw a trend in improvement in depression, which is a concomitant condition for most of these patients. We saw that the T-forest plot was kind consistently favoring all the primary and secondary endpoints to the Bafidem-Stat-treated group compared to placebo.
00:05:46
Speaker
And we were we when we did. um a global statistical test to to try to to see if this T-forest plot was really and meaningful in a global way. We saw that indeed the p-values of the global statistical test of all the primary and secondary were again statistically nominally statistically significant. so All that was ah very, very, very interesting, very intriguing in this in the in in terms of safety, as we have seen in others, previously in other clinical trials with our compound, which is very safe and very well tolerated.
00:06:24
Speaker
There was no, no, and any any if any red flag or any sign of intolerability or toxicity. And curiously, it was also worth noting that we saw a major tendency of um and not performing self-harming episodes on the patients treated and and with our drug than the patients treated with the placebo group.
00:06:54
Speaker
So, it was only one patient on the on the on the treated arm and six patients experiencing these self-injury episodes in the placebo group. So, all in
FDA Insights and Phase 3 Approval
00:07:06
Speaker
all, and it was really very informative.
00:07:09
Speaker
in an indication where there is nothing approved yet and where the, as I said, the industry, the regulators, we are all trying, the academy, we are all trying to figure out how is the best method or the best way to measure and and the the evolution of a patient under a pharmacological treatment in this condition.
00:07:33
Speaker
That's certainly some ah some very interesting results. and And we understand that this was followed by an end of phase two meeting with the US FDA, which endorsed your plans to progress to phase three.
00:07:43
Speaker
So could you tell us a bit more about this, including next steps for the program? Yeah, no, it has been a very intense period of conversation with the FDA by with by the way, we are very grateful because they have been exigent as always, but also very constructive and very supportive.
00:08:00
Speaker
And um so we we we basically had a number of questions. And we thought, we think that at the end of this ah and meeting with the FDA, we can say that we are um very, very satisfied with the outcome. First of all, we were asking the FDA, well, with this intriguing data, considering that we are hitting the primaries, sorry, of the aggression and the and the overall improvement in the secondaries, but not in the primaries, would you think that we should proceed or we could proceed to a phase three?
00:08:31
Speaker
And they say, yes, you can. So they could have perfectly say, well, I mean, it's intriguing, but why don't you repeat the phase two? And that was not the case. So second thing, we want now move to a phase three. They agree with that.
00:08:44
Speaker
And um we want to make a very powerful trial. So this, to to increase the power traditionally in a clinical trial, there is a a clear way with you. Basically, you increase the number of of subjects, obviously. But the second thing is is basically we restrict to a single primary.
00:09:03
Speaker
In the previous ah trial in Portico, in the phase two, we were having two primaries. One was aggression and agitation, and the other one was the overall improvement. Now we want to focus, and we we say to the FDA, we want to focus in ah agitation and aggression because is what we have seen on a stronger signal and where we think, and the sicker is also think that is ah one of probably the most disturbing symptom symptom of these patients.
00:09:32
Speaker
and the And the FDA says, yes, you can, I mean, basically carve out and and go to the agitation and aggression as a potential label for the treatment of BPD with your your molecule.
00:09:44
Speaker
And that was very, very, very, very positive on our view. And finally, and this is for us is a huge thing. um We were asking them, and would you agree that we proceed on this phase three on this aggression measurement with the scale that was secondary um and in the previous trial, considering that this scale is a patient rated scale.
00:10:10
Speaker
And they say, yes, you might pursue, um but you have to do some homework homework for us. um the the And the extra homework that they have required on our view is absolutely reasonable.
00:10:24
Speaker
is achievable, is not particularly expensive, and is not particularly ah lengthy in in time of execution. They were asking us, basically, you should but be provide us with ah additional literature data to confirm that the BPD patients are having a good conscience of self.
00:10:43
Speaker
Second, you will have to provide us the psychometric analysis of all the all the um the scales that you have done in Portico, we are working on that. This is mechanics and we don't expect any any any issue here. um Finally, they they also request us, and it would be absolutely important that you provide us qualitative research study on this particular population for this scale, the Stuxy2 trait anger.
00:11:15
Speaker
uh which is also feasible is something that the industry has done with a number of scales in other diseases so and we are not em inventing the wheel here um we have agreed with them because they they requested that that that we are going to present this qualitative research proposal at the same time or before that we propose the the the the final protocol.
00:11:38
Speaker
And we, of course, we will ah try to accommodate any of the suggestions that they might have to this qualitative research. But this is something again, that as I said, is going to be done in ah in a subset of patients and and is basically something that is being done almost routinely. So we don't expect here also any major drawback.
00:12:02
Speaker
So all in all, it was a very satisfactory outcome. The new trial, the phase three trial, according to the COHENS-D data that we got on the phase two, we'll have to recruit around 350 patients, which is something that is not particularly huge.
00:12:21
Speaker
and um And with this and restricting to a one single primary, we think that we will have the power and and the trial well well powered. So all in all, as you can say sometimes, or you might say sometimes, we we think that we have got a a home round here on our conversation with the FDA. So we are very, very satisfied.
00:12:43
Speaker
Fantastic.
Understanding LSD1 and CNS Applications
00:12:45
Speaker
Taking a step back now, Bafidemstat is an inhibitor of LSD1, which is an epigenetic target. Could you tell us a bit more about the role of LSD1 in conditions relating to the central nervous system?
00:12:57
Speaker
Yeah, LSD1 is one of the epigenetic chromatin modifiers. So it's one of these number of of proteins which are basically changing the shape of the chromosome, the scaffold, around which the the DNA fibers coiled and making areas of the chromosome open or close to the transcriptional machinery.
00:13:24
Speaker
We know that LSD1 is playing a fundamental role in neurogenesis during the the developmental period period and after birth in mammals is also playing a ah very important role in the maturation and final shaping of the of the of the central nervous system, including neuronal migration, axonal navigation, and the final shaping of the prefrontal cortex.
00:13:51
Speaker
um Different um works done by different groups in the academy and in different hospitals have demonstrated that in some particular neurodevelopmental syndromes, which have um a well-defined genetic cause, a well-defined genetic mutation, LSD1 inhibition is able to make a whole a whole phennotyqui phenotypic rescue on these animal models. So pointing out that the inhibition of LSD-1 is basically a mechanism downstream by which we can compensate some of the signaling but signaling pathways which are basically deficient on these neurodevelopmental syndromes.
00:14:34
Speaker
And this is also giving us a cue on how the mechanism of action might be acting on these large multifactorial and disorders. What is fascinating is that we and others, and using our LSG1 inhibitor, baffinensat, or other LSG1 inhibitors, we and others, we have seen that in different animal models at the high functional level produce basically three main three main and phenotypes. One is basically increased sociability in the animals. The second one, increase increase learning capabilities and and memory, short and long term memory.
00:15:14
Speaker
and Third, very important, and reduce or decrease or eliminate aggression. so This is basically what we are seeing in a plethora of animal models with different groups using different LLG1 inhibitors. Really, the rationale for the neurological effect is extraordinarily
Intellectual Property and Commercial Strategy
00:15:34
Speaker
strong.
00:15:34
Speaker
is very elegant and we have a molecule which is right now phase three ready after having treated almost 500 people, some of them for up to two years of exposure of the drug to the drug and i not seeing any particular particularly worrying side effect or untolerability effect.
00:15:58
Speaker
So we've seen a rise and share several updates recently on strengthening its intellectual property profile for academic stats. and Could you summarize some of these key achievements? Yeah, I mean, it is well known, we have to we have said before, that the composition of martyr is granted in all in all the jurisdictions where we have applied, which are obviously most the most important commercially speaking in the world. But what is also very gratifying is that that we have seen a number of metosophutes or different layers of new protection, particularly the use of Bafidin stat for the treatment of BPD, the use of Bafidin stat for the treatment of aggression and agitation, and the use of Bafidin stat for the treatment of other psychiatric disorders, which has been recently granted or we have been we have received very, very recently notice notice of allowance.
00:16:52
Speaker
which is basically extending the exclusivity period and and beyond the 2040 in the most important jurisdictions with and a number of additional years of um potential and ten extension term.
00:17:12
Speaker
and that we will have to to to see at the end. But yeah, this is very gratifying, as I said, because as you know, as everybody knows, to develop drugs, in and particularly in CNS, it's lengthy.
00:17:24
Speaker
And you want to be sure that at the end you get a commercial case, which is our case. We have a very clear and and strong commercial case, our our estimated estimate um only for BPD, um consider that we could achieve or our partner, the one the the day that we partnered this drug with one of the big pharma companies could achieve and almost three and a half, four billion on pixels only for the treatment of BPD.
00:17:54
Speaker
not including a potential label extension like schizophrenia or treatment of aggression in in in in Alzheimer's and others. So yeah, we are we are in this in this regard, we are in very safe grounds right now.
Future Directions: Trials, Partnerships, and Oncology
00:18:09
Speaker
Excellent. So it's looking to be an exciting and active period ahead for Horizon. Could you summarize or highlight some of the key events that investors should watch out for across the next 12 to 18 months?
00:18:21
Speaker
Well, I mean, of course, we are basically now um interacting with the FDA. So we expect to submit the the full protocol of the phase three around March, April. So around this time, end of first quarter, beginning of second quarter, we might get the they May proceed for the phase three, which will definitely set the um and the asset ready for starting the phase three. The company is already doing additional work to prepare this phase three.
00:18:55
Speaker
It's also well known that we have engaged an investment bank at Green Hill to help us on finding the right partner, the best partner to develop this molecule and to commercialize this molecule, where we think that we have an extraordinary commercial opportunity.
00:19:11
Speaker
an extraordinary and extraordinary commercial opportunity and um And this is not the reason ah today, but I mean, we are also having, as maybe some of the audience know, Horizon is also having a a program also around LSD1, also in epigenetics with a different and molecule, different composition of matter protection. in oncology where we are benefiting, we are having the immense honor to have um a a partnership with the National institute Institute of Health of the United States, with the National Cancer Institute. And through this CRADA-CREDA agreement,
00:19:51
Speaker
We are exploring now our molecule in first-line leukemia in triple combination with venetoclast and asacitidine in first-line and FIT patients.
00:20:02
Speaker
There are a number of patients which respond poorly to these standard of care, although in general, venetoclast and asacitidine is a quite effective first-line treatment. But for those particular sorts of patients, this combination adding Yadavnstat could be fundamental.
00:20:19
Speaker
We are having this ah program running in an investigator initiative trial at Oregon University with some encouraging preliminary data. and We are having also and NCI sponsor phase 1-2 trial in a small cell lung cancer first line in extended disease patients in combination with Durvalumab or atezolizumab, where again, the fundamentals, the the but the biology,
00:20:48
Speaker
and underlying biology of the mechanism of action, the synergism between our compound and the ICIs is really amazing.
00:21:00
Speaker
and um And this ah NCI i sponsored trial is including one of the most and there I mean, famous places, the more renowned places in the field, like the Memorial Sloan Katherin Center, the Dana-Farber, the MD Anderson, the Young Hopkins, Yale University, City of Hope. I mean, just to mention a few.
00:21:22
Speaker
So this is, ah as I said, a phase one, two randomized, um which expect to recruit 40 patients. And we are tremendously honored. I'm very eager to see how it goes, this trial. So for those in the audience interested on this other activity of the company, I also recommend to to him to to keep ah to keep us under the radar.
00:21:46
Speaker
Perfect. Well, thank you very much, Carlos, for the un insightful discussion. We look forward to following the progress of the company and including both of your assets. ah If our audience like to learn more about Horizon in Genomics, please refer to edisongroup.com.
00:21:59
Speaker
That's going to be your time today, Carlos. Thank you, Aaron. A pleasure.