Kip Harry: | Hello. My name is Kip Harry, Conference Director at Cambridge Healthtech Institute and so we have a special podcast for the upcoming Targeting Histone Methyltransferases and Demethylases conference, part of the 12th Annual Discovery on
Target event October 8-10 in Boston. Joining us from Spain via phone is one of our speakers during the meeting, Dr. Tamara Maes. She is the Co-Founder and CSO of Oryzon. Tamara, thanks for joining us. How are you today? |
Tamara Maes: | I am excellent. Thank you Kip. |
Kip Harry: | Great. Well thanks for joining us. Tamara, so Oryzon is one of the few developers and maybe in fact the first that’s really targeting the histone demethylase, LSD1. Can you explain your sort of initial rationale behind developing
inhibitors against this very novel class? |
Tamara Maes: | Okay, indeed, yes, we are very proud to say that Oryzon has been leading the way and we can confirm that we are the first company to move a specific LSD1 inhibitor to Phase I studies. More specifically for the treatment of refractory or
relapse acute leukemia. Our project for from LSD1 started in 2008, which is less than four years after [CNL 01:14] reported that the FAD-dependent amine oxidase was actually bonafide H3K4 demethylase. By the time that we had present to the field, it was known that LSD1 in fact was correct, that it formed part of transcription regulation complexes and has a role envisaged for help cancer science a little more. In 2006, there was [Liezel
01:36] who published that a non-selective MAOI inhibitor called TCP, tranylcypromine, inhibits LSD1 to some extent. We took this observation as a chemical starting point to develop our highly selective irreversible LSD1 inhibitor. This was not the only venue that was explored. There was the [Caseroa 02:01] at the John Hopkins who explored the potential
of [olive oil means 02:05] to inhibit LSD1 and actually there was an Australian company that was exploring the potential of a compound resulting from that program for a while. There have been additional players that have entered the field like [Solarias 02:18]. They claim to have a reversible LSD1 inhibitor in preclinical toxicology studies and more recent also GSK has presented preclinical data on both reversible
and an irreversible inhibitor. Finally, they chose to move an irreversible one forward into the clinic in a Phase I study in small cell cancer, which actually illustrates that the potential use of LSD1 inhibitor may not be limited
to hematological cancer. While most of the reports on LSD1 were and still are related to oncology, actually we did not decide to enter the field because of our interest in oncology. [Actually 02:58] while performing biomarker studies in their fields, neurodegeneration
we were studying, the brains of deceased patients from Alzheimer’s disease, Parkinson’s disease or dementia with Lewy bodies. In the collaboration with the group of Professor Isidro Ferrer. He is a very renowned Spanish
neuropathologist and they had identified … We have with them identified an interesting biomarker that was systematically down regulated in the effective areas of brains of these patients. Analyzing the mechanism of transcription control of these biomarker, they pointed out that the potential enrollment of the RAS complex could be efficacious of these changes. In Oryzon, with this knowledge, we then evaluated the components of this complex and we wanted to select potential drug targets from that. This complex contains targets like 8.1 and 2, but finally we focused on LSD1 because of its novelty
and because of its structural similarity to the MAOI enzymes, which classified this target as addressable targets. Our initial hypothesis was probably a little bit simplistic. We thought, well, if the RAS complex is involved in down
regulation of the expression of an important biomarker, maybe we can inhibit one of its components of the RAS complex and neutralize that down regulation. The literature since rapidly exploded with reports on the involvement of LSD1 in cancer and we also started to explore that angle. Through crucial publications on the role of LSD1 and AML and also in house validation data were deciding
our minds to move our thus selective LSD1 inhibitors forward in this indication. |
Kip Harry: | Tamara, let’s talk a little bit more about Oryzon and you’ve had some very exciting news. You recently formed a partnership with Roche and your lead compound has now been testing clinical [audit 04:56] trials, like you mentioned.
So it seems as if the therapeutic potential is certainly being validated at this point. What sort of therapeutic efficacy are you observing now in your early clinical studies? |
Tamara Maes: | To start with, we are extremely happy to have closed a deal with Roche as they are the number one partner in oncology and we have licensed them two of our patents which cover also ORY-2001, which is the compound we have in the Phase 1
studies for acute leukemia. We worked together with them and we remain still in charge of the Phase I study. They are providing of course invaluable feedback and advice and we are collaborating with Roche to profile further data. With respect to what kind of therapeutic efficacy are we observing from our early clinical studies, you must realize we are in a Phase I. The real convincing target validation takes time and I do not think we can make at this moment bold
statements about validation prior to the analysis of the data of a proper Phase II clinical proof of concept study. Anyway, in our Phase I study, our study has focused mainly on determining the PK/PD relationship and the toxicity limits
of the compound, although of course, we do hope to find the preliminary evidence of efficacy in select patients with specific genetic profiles. Of course, we will try to get the maximal data to support further clinical trials. In the preclinical studies, we showed that our compound was very focused on the leukemic stem cells as a population of leukemic cells with a capacity to reinitiate cancer even after regular cytotoxic treatment. This is the main problem
in acute leukemia especially in AML. The cytotoxic treatment initially tend to efficiencies that tend the cancer relapses and the cells are resistant, they are not responding to the treatment now. The ideal treatment we think may
consist and combining the two actions, emitting at the same time very rapidly [designing 06:55] cells and hitting the leukemic stem cells. Of course we’d also see reduction in the proliferation and cell life which translated in vivo models and reduced tumor cell growth and increased survival in [genographic 07:13] models. With respect to the challenges that we may encounter targeting LSD1, of course, if you ask this question generically with respect to the target, it will depend on the characteristics and the specificity of every compound in addition
to its capability to reach an inhibitor target. We know our compound is exceptionally clean and characterized by high selectivity for LSD1 and also by lack of inhibition of metabolic enzymes are essential all things which can
be related to toxicity. As for the rest, it’s not a secret that LSD1 is involved in hematopoiesis. If we retrial of this as we do expect to have an effect on this [prospect 07:58]. Our idea is that if genetic knockout studies teach you that your target has a role in a certain process, like hematopoiesis, which is true for many of the genetic targets, then you better believe this and take it [to themselves
08:11] and to the design of the recent scheme. Luckily for us, the doses that are required to achieve therapeutic effect in AML in different models of neurodegenerative disease need not provoke a full inhibition of the hematopoietic
stem cell proliferation and in addition, our compound does not kill normal hematopoietic stem cells nor affect their capacity to form colonies. It provokes a temporary half in the proliferation. Finally, the PK characteristics and the distribution pattern of the compound may also help to target specific indications. For example, in animals we have achieved pretty high levels in line with ORY-2001 and that’s knowing
that, for example, small cell lung cancer is an interesting target indication for LSD1 inhibitors of course is an interesting combination. |
Kip Harry: | Tamara, the question I have for you. You’ve already answered most of this was any concerns about toxicity of your small molecules or any sort of early clinical data that you can talk about regarding the tolerability of the compounds,
but I think you’ve already sort of mentioned. Anything else you would like to add? |
Tamara Maes: | Well, I think that generally when people thing about epigenetic drugs, they think that well, this is causing highly pleiotropic changes. What we observed surprises me and this is coming from our data on leukemic and neurological models
is that the inhibition of LSD1 does not affect such a very, very broad range of genes as well. In fact, complete inhibition of LSD1 by our compound ORY-2001 in for example, THP1 leukemia cells changes the gene expression level of about
150 genes by two fold, and that’s not so much. Although these changes are sufficient to provoke the differentiation of these cells from myeloblast into monocyte macrophages in genotypes. So another example is our compound ORY-1001, which we envisage for applications in neurodegenerative disease. The number of genes changed in the hippocampus characteristics doses of this compound get even lower. Only about 30 genes were
down regulated in the hippocampus, for example, by over 50%. LSD1 inhibition will only affect the expression of genes. If LSD1 is actually residing at the promoter or the regulatory control regions, and even then, the neutralization
of LSD1 may only have an effect if within that cell, other factors are present that can induce the transcription of the gene from which LSD1 is released let’s say. In most cells, LSD1 inhibition doesn’t seem to do much. In our preclinical toxicology study, actually the only toxic effect we ever saw was those high enough and we start to see the effect on the hematology, which is completely anticipated.
With respect to the toxicology in the Phase I study, we are in the dose escalation process. Going to the fifth cohort, we have not seen any treatment related tox effects yet. We are still going on with this process. |
Kip Harry: | Tamara, let’s talk a little bit about the upcoming lecture you’re giving. You’re giving a lecture at the upcoming targeting histone methyltransferase and demethylases meeting this coming October, just about a month, October
8-9 in Boston. You’ve given us a nice overview of the work you’re doing at Oryzon. What do you hope specifically to convey and share with attendees during that lecture? |
Tamara Maes: | Of course, we will present a resume of preclinical data, let’s say an update on … Update the public on our running Phase I study and finally, we also hope to convey the message that the [treatment of 11:57] of LSD1 inhibitors
need not be limited to oncological disease. We think if a genetic is involved in many biological processes and there is a great potential for the use of inhibitors [that look at 12:08] genetic targets also in inflammatory disease.
We think it may be particularly relevant for the treatment of neurodegenerative diseases. If you think of it, that makes sense. In the green, there are not too many cell divisions going on. The main mechanisms of change and function over time like ageing may be epigenetic rather than genetic. You know already that the inherited forms of Alzheimer and Parkinson’s represent only a small minority of cases and most forms
are not inherited and they are sporadic. I think that epigenetic will turn out to be an important factor in these diseases. |
Kip Harry: | Okay, Tamara, let’s go ahead and close out here. Before we do, I’ll like to ask your just general broad outlook of what do you think will be sort of the avenues with which epigenetic therapies take, particularly those sort
of modulating the histone methylomes? I’m going to ask this, but what are the anticipated challenges and roadblocks you may have to face before we actually see some of these drugs through in the U.S. and Europe? |
Tamara Maes: | There is no specific category for epigenetic drugs in the FDA or the EMA. In this sense, the challenges for the development of drugs modulating histone methylomes are no different than for any other drug. They must prove they are safe,
bring benefit to those patients. It’s true however that many of the epigenetic drugs address targets that are novel and that have not been characterized very extensively previously. However, I think that today we have, especially for studying epigenetics, we have incredibly potent tools that have to analyze epigenetic target functions and the actions of drugs developed to inhibit them, which on one hand provides us
with the means to better select target indication and population and also to foresee potential side effects. As a [rider 13:59], we believe that epigenetic drugs offer a possibility to shift extraction balances or programs in target cells on organs and that this may prove beneficial and different [for severe 14:11] diseases. |
Kip Harry: | Okay. With that, I think we’ll wrap up. It’s a great pleasure, Tamara, as always speaking with you and thanks for your time and joining us via phone all the way from Barcelona. I’m sure it’s beautiful right now.
We look forward to your upcoming presentation during the targeting histone methyltransferase and demethylase even this fall. For those of you listening, if you’d like more information, please visit discoveryontarget.com. Thank
you for tuning in and we look forward to seeing you at the conference. Good bye. |