A Therapy for a Rare Neurodegenerative Disease Moves Towards Regulatory Review

X-linked adrenoleukodystrophy is a rare, inherited, neurodegenerative disease. It is a debilitating and chronic condition that is characterized by progressive weakness, stiffness, and muscle spasms, as well as sensory dysfunction, and incontinence. There is currently no approved treatment. Minoryx raised $51.4 million in May to support the application for marketing approval of its X-ALD therapy in Europe and to support launch preparations. We spoke Marc Martinell, co-founder and CEO of Minoryx, about X-ALD, the company’s experimental therapy leriglitizone, and why its being viewed as a potential treatment for other rare CNS diseases.

Daniel Levine: Mark, thanks for joining us.

Marc Martinell: A pleasure to be here.

Daniel Levine: We’re going talk about Minoryx, rare CNS diseases, and your experimental therapy, which is in development to treat multiple conditions. Let’s start though, with X-linked adrenoleukodystrophy or X-ALD. This is your lead indication. What is X-ALD?

Marc Martinell: Well, X-ALD is a terrible disease to task. It is a rare genetic and disease affecting the CNS where patients may well end up dying in three years’ time. But those that do not suffer this more acute version of disease end up in a wheelchair in 10, 20 years after onset of the disease.

Daniel Levine: This is a condition that typically has onset between ages 20 to 30. How does it manifest itself and progress?

Marc Martinell: Well, between 20 and 30 is the onset of this more, let’s say, chronic condition that manifests with problems on the walking, on the balance, on the incontinence. But patients end up in a wheelchair with a spastic paraparesis, which means with a lot of rigidity in the muscles, but that’s for the chronic form of disease. There’s also the acute one which can affect both adults, but also pediatric patients between two and 10 years old. And these patients develop a very aggressive inflammation in the brain and they die in three years’ time.

Daniel Levine: And how difficult a condition is this to diagnose? How is it usually diagnosed?

Marc Martinell: It is not difficult to diagnose provided that the right physician thinks about the right test, let’s say. The test is pretty simple, just a drop of blood. You can diagnose the disease. And that’s the reason why today in the U.S. newborn screening is in place in several states for the detection of ALD. The problem that happens in many countries and other U.S. states is that this is not a standard test that is regularly performed, and patients may be misdiagnosed because the physicians are not thinking that that may be the disease. And that’s the typical drama behind the rare diseases. It’s not just a problem of treatment, it’s also a problem of proper diagnosis.

Daniel Levine: And how is it generally treated today?

Marc Martinell: Well, there’s no treatment, unfortunately, for those patients with the chronic form of the disease, there’s no treatment at all, only supportive care. And actually, our drug is the most advanced one out there in development for this form of the disease. And then for those suffering the acute form, the cerebral form of the disease, the standard of care is a hemopoietic stem cell transplant, which is efficient to stop this acute process, but has no effect on the chronic component of disease and is a very aggressive process by itself. As you can imagine a bone marrow transplant is not a simple thing.

Daniel Levine: Your lead therapeutic candidate leriglitazone is a PPAR gamma agonist. What role does PPAR play in X-ALD?

Marc Martinell: Well, our molecule or drug is what we call a small molecule. It is an oral treatment, once a day. So, that’s very simple from the patient’s perspective. As an oral suspension, which is good for kids as well as for others with difficulties of swallowing, et cetera. What the mechanism of action has, this PPAR gamma agonism biology of the molecule, allows us to modulate simultaneously several pathways that are key for neurodegeneration. And this includes inflammation, which plays a central role in ALD but also in other CNS disorders. It also has a role in mitochondrial function. It has a role on myelination. So, all these three elements are central in ALD, also in other diseases. And that’s why PPAR gamma agonists have been proposed as a potential therapy for multiple CNS disorders. The issue was to have a PPAR agonist reaching the brain sufficient level. And that’s precisely what we have. That’s why our molecule allows us, now for the first time, to exploit this promising biology in CNS.

Daniel Levine: This is an oral therapy as I understood you just now. Is there any issue getting it to cross the blood brain barrier?

Marc Martinell: No, it’s certainly a neural therapy. Part of the molecule or a significant part of the molecule that is circulating in the plasma crosses the blood brain barrier. And essentially it crosses to an extent that sufficient levels reach the CNS and we achieve the required level of modulation of the target. So, the PPAR gamma, and that’s something that we demonstrated already in phase 1, and we confirm in the ongoing clinical exercise as well. So, that’s the advantage for the molecule essentially.

Daniel Levine: Is the expectation that this would slow disease progression, it would halt it, or is there any potential for it to actually reverse progression?

Marc Martinell: It’s a disease modifying treatment because we really stop the neurodegenerative process. We observed very impressive results on the progression of these cerebral brain lesions and how on treatment, this progression was significantly reduced compared with placebo. We also observed important impact on clinical outcomes related with the chronic component of the disease, such as the balance. And we think that the drug will stop progression or slow down significantly the progression in CNS disorders to see a recovery. It’s really difficult because when the there’s been a neurodegeneration, those cells that die, that’s unlikely to be recovered, but sometimes you can see some initial or some partial recovery and then stabilization, and we’ve seen that kind of thing in some patients. And that may come from the remyelinating capacity of the molecule.

Daniel Levine: What’s known about the safety or efficacy of the therapy from studies that have been done to date?

Marc Martinell: Well, what we’ve seen so far is that from the efficacy standpoint, we’ve seen pretty impressive results on the cerebral leision progression. We’ve seen that in different kind of outcomes that are radiological, using imaging outcomes that are more coming from the clinical angle, consistency with biochemical biomarkers that are going in the same direction, that’s for the cerebral progression. We also have data on the chronic component with objective measures that look into the balance. We also have data from clinical scales, all that consistently moving always in the same direction, which is showing a drug effect and all that with the safety profile that we think that is pretty good. Of course, it’s not innocuous as with any other drug. There are some, at best, [safety] events. So, we don’t want to minimize the relevance of the safety of a drug, but in our case, the most common findings are edema. We gain some increased lacrimation, which are already documented as adverse events for PPAR gamma agonists, but in general, these are moderate and manageable. So overall we think that we really have a very good benefit-risk profile for this molecule, particularly when we think about very severe conditions.

Daniel Levine: And what’s the development path forward?

Marc Martinell: Well, we are now in a very exciting moment, at least for a biotech that I founded 11 years ago, and now are preparing for filing a marketing authorization in Europe—that’s where we are. We are filing this summer and hopefully this will become the first approved treatment for this population in Europe. In the U.S., we are under discussions with FDA about the path forward and which additional activities FDA would like us to run. And we are in the process of agreeing on that. I’m confident that we will find the right path with FDA and we’ll offer it so to make sure that the drug becomes a reality, not just in Europe, but also in the U.S. and worldwide as soon as possible.

Daniel Levine: You are also developing this for the childhood version of ALD. Where are you in those development efforts?

Marc Martinell: Well, in this development, we are conducting a trial, a smaller study because in the childhood form it is a rarer form of the disease. And we are conducting an open label study. This study’s been conducted in Europe, and it’s part of what is called the pediatric investigational plan and is a registration enabling study in Europe. And we are going to have six months interim data for the study towards the end of this year. So far what we are seeing, we feel very encouraged with the results. Of course, with all caution in the world when I’m saying that we are in the middle of the study, but we think or we hope that this study will confirm this potential of the molecule on the treatment of the acute part of disease, the so-called cerebral progression.

Daniel Levine: You mentioned that this has implications in other CNS conditions. One of those is Friedreich’s ataxia. For our listeners not familiar with Friedreich’s ataxia, what is that?

Marc Martinell: Well, Friedreich’s ataxia is a completely different disease from ALD when we think on the genetic basis behind the disease. So the origin is completely different. One is the accumulation of something called very long chain fatty acids—that’s ALD, and Friedrich’s ataxia is the deficiency of Frataxin. But down the road, downstream of these genetic defects, these disease have very similar or very common aspects. And one is the mitochondrial dysfunction. In Friedrich’s ataxia disease, central in the disease progression, inflammation has been also recently proposed as another important factor for Friedrich’s ataxia and both inflammation and mitochondrial function are directly regulated by PPAR gamma. So with this agonist, we can counteract the dysfunctions that happen in Friedreich’s ataxia and thus potentially treat this disease as well.

Daniel Levine: You recently completed a financing for, for a little more than $50 million. Part of those funds will be used for the commercial launch of leriglitazone. Where are you in terms of building a commercial team?

Marc Martinell: Well, now we are in the first steps of that path as we just closed the round quite recently. We are also in the dialogue with companies that have already the infrastructure and the expertise, as we are also evaluating this scenario of finding a good partner in Europe that has the capacity to successfully launch a new treatment in the orphan CNS space.

Daniel Levine: As you think about other indications that you would pursue how broadly applicable might the therapy be?

Marc Martinell: Well, we always like to say that this drug works for many different things, which is probably true, but at the end of the day you need to do a very specific analysis on the benefit profile and every single indication that we aim to pursue. Having said that, there are vast number of opportunities for this molecule because we do see that in multiple disorders, and you can have rare conditions such as Rett syndrome, which is a very interesting condition with a huge medical need. But even more prevalent conditions such as progressive multiple sclerosis. The pathways that are affected are very similar to those that are affected in ALD or Friedreich’s ataxia. Again, the genetic basis of the diseases is very different for all of them, but then when you go to those pathways that are really impacted in these patients, they are not that different. And now that we have data from clinical trials showing that all those aspects that were looking very promising in animal models and in cell-based models, now we are seeing that they translate into humans. That gives us a lot of reassurance that really the potential of the molecule is pretty broad, particularly in these others, where there’s a strong inflammatory component in the CNS, for instance.

Daniel Levine: Given that potential broad applicability, how do you go about prioritizing the indications you’ll pursue?

Marc Martinell: Well, it’s a multidimensional analysis. It’s not a quick answer, but we take multiple things into account. To start is the feasibility. I mean, can we really demonstrate that this drug may work in this condition? Meaning do we have a clinical endpoint? Do we have a path in the clinic that will be recognized by regulators, or it’s going to be a very long, long journey because there’s nothing. So that’s the first thing. Second is also availability of experts, people that we can collaborate with. This is essentially our model. We have a great team in the company, very specialized in drug development, particularly in the orphan space, but at the end, for every single condition, you really need to work with the real experts that are usually in academic groups [like] hospitals, research centers, and they have the real expertise of the disease, animal models, cell-based models, et cetera. And that’s also an important piece on the development, right? And then, these are more the scientific key elements together with the availability of, or the capacity to find the patients, the diagnoses, if there are reference centers, et cetera, that we can work with to run a clinical trial. But of course, we also need to take into account competition. Is this disease where there are already several other programs out there and more advanced and looking already good? If that’s the case then it is more questionable to move into that space because essentially if those treatments are doing well it may be very, very difficult to develop another treatment afterwards.

Daniel Levine: This is kind of a pipeline in a product.

Marc Martinell: Yes, exactly.

Daniel Levine: Is there an effort to look beyond this, to build a pipeline of other compounds as well?

Marc Martinell: Yes. That is also another of the possibilities that’s on the table for us. Certainly, this has not been our priority number one during the most recent time. So, because we are closing the financing and we are now priority 1, 2, 3, 4, and 5 is our lead indication, ALD in its chronic form and it’s acute form of the disease. But after that, we have all the other indications that we discussed, but certainly thinking more in the broader vision for the company, now that we have shown that we can develop drugs in this space efficiently, we will see if it’s successful or not at the end, because you never know, but at least we have been doing it quite efficiently. I think that one of the possibilities is to expand the pipeline into all the assets as well. That has not been our priority recently, but of course, that can be gaining more momentum as we move forward.

Daniel Levine: Mark Martinell, co-founder and CEO of Minoryx. Mark, thanks so much for your time today.

Marc Martinell: It’s been a pleasure.