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Discovery & Development Drug Discovery, Small Molecules

The Catalan Connection

As we introduced ourselves, Marc Martinell was quick to stress that he is more than just the CEO of Minoryx – he’s also a chemist, with a PhD in molecular biochemistry from the University of Barcelona. The conversation that followed ranged from the surprising nuances of the leukodystrophy population all the way to the flourishing biotech scene of Catalonia. ¡Meravellós

Your company has just raised over €50 million – where will that money be invested?
 

The largest part of the investment will be dedicated to getting our drug through the review process in Europe. We are filing for a marketing authorization application in our lead indication, which is the chronic form of X-linked adrenoleukodystrophy (ALD). Should we succeed, our drug could be the first treatment on the market for the condition.

We’ll also be spending money on preparations for expanding use of the drug beyond the initial patient groups to other populations within the ALD space, including women with the chronic form of the disease, and also paediatric patients with the acute form of the disease. In the latter area, we are already conducting our first trial.

With the acute form of X-ALD, patients have an expected survival of three years. Overall, the medical need is huge. Besides all these preparatory activities in Europe, we are also thinking of taking it through the FDA and developing the drug globally. Part of the proceeds will be set aside for that. We are currently in discussions with the FDA on precisely what they need from us, and what we can do for them.

What causes X-ALD?
 

X-linked adrenoleukodystrophy is a neurodegenerative disease, and it is monogenic – meaning that it affects one single gene. It is hereditary and – as the name suggests – is linked to the X chromosome, but it does not only affect men, as can be the case in some X-linked diseases; however, the disease affects men and women in different ways.

For male patients, X-ALD manifests as a severe disease of the central nervous system (CNS) in two different ways. The first is a very acute form called cerebral ALD (CALD), which causes aggressive inflammation in the brain, including some lesions; for patients carrying the mutation, this can happen in either their early childhood or in adulthood.

In adult patients, X-ALD most commonly manifests as adrenomyeloneuropathy (AMM), which does not affect the brain but does affect the spinal cord. This has motor consequences for balance and sensory perception, and patients typically end up in a wheelchair with severe spastic paraparesis. The quality of life for the patient is terrible. Adult patients can also end up developing CALD on top of this chronic condition. Once CALD sets in, survival sits at three to four years. It is very rare for women to develop CALD, but AMM can affect women though typically at the age of 50 or 60.

One last point to mention is that ALD patients also face adrenal function problems, which can also prove lethal but can be treated with hormone replacement.

Is the condition invisible before symptoms appear?
 

There is a way to catch it in advance using a blood test. In the plasma, it shows up in very long chain fatty acids, but a genetic confirmation is also required. Cases are usually diagnosed via newborn screening (which all children in several US States and a few other territories now receive). In adult cases, symptoms typically arise before the physician will suspect that the patient may have ALD.

How about in the case of older female patients?
 

Interestingly enough, 20 years ago the literature stated that women should be treated as carriers only. But in 2022, the literature acknowledges that women are patients – the only major difference besides frequency is the age of onset 

The chronic form in women does not particularly affect survival, at least in a direct form. But chronic patients suffer frequent falls that may lead to injuries later on, and that carries significant complications when taken in context on top of all the other underlying problems. Quality of life is very poor and with years, the lack of movement due to spastic paraperesis and so on carries significant complications

Women have been very vocal at all the patient association meetings because most of the investigations to date were focused on men – where the form of the disease is better understood.

It almost goes without saying that, today, these drugs need to be developed with both men and women in mind, and that’s precisely our intention.

How did you come to set your sights on X-ALD?
 

Back when I founded the company, we were looking into problems that could be interesting in the area of inborn errors of metabolism affecting the CNS – a very specific space. We began collaborating with an academic group from Barcelona which was doing interesting research in the same area.

In time, we found that ALD was particularly interesting because there are no therapies – a space investing our time and energy made a great deal of sense. In short, a potential treatment for people in dire need alongside commercial viability.

How does the drug work?
 

Our drug, Leriglitazone, is a once-a-day oral suspension that acts on the key pathways that trigger or are involved in neurodegeneration. These elements are neuro-inflammatory processes, mitochondrial dysfunction, and demyelination, and all have important consequences at the level of the CNS.

These are the three key elements that the drug model addresses, and all three target peroxisome proliferator-activated receptor gamma (PPARgamma) agonism. Leriglitazone is able to engage in the CNS above the levels that are safe in other drugs, and it has already performed well in proof-of-concept animal studies.

Are any other companies using the same PPAR approach as you?
 

There is a great deal of data out there that suggests PPARgamma agonists can work for CNS ALD, and other indications too. What is lacking right now is a PPARgamma agonist able to achieve sufficient exposure in the human brains – and that’s precisely what we have in our hands! There are no other companies taking this specific approach.

Have you seen any other exciting developments in the leukodystrophy field in recent years?
 

There are two major strategies pushing developments. One involves trying to modulate the disease with a small molecule approach, which is what we have opted for. 

I don’t think we will see a single treatment that offers the definitive solution for everyone. What we’ll see is different treatments with different benefits for different patients – treated sequentially or even simultaneously. I’m convinced our treatment will sit among those options.

The other strategy involves treating patients with a stem cell transplant. This is actually the standard of care for the cerebral form of disease, but it only works if applied very early in the disease, and usually only for paediatric patients.

However, an ex vivo gene therapy from bluebird bio was recently approved and they are now in discussions with the FDA. It’s an interesting avenue but has the same limitations as the transplant; it works for paediatric patients early on, but would be far harder to apply to adults whose disease had progressed.

At the end of the day, I don’t think we will see a single treatment that offers the definitive solution for everyone. What we’ll see is different treatments with different benefits for different patients, treated sequentially or even simultaneously. I’m convinced our treatment will sit among those options.

Minoryx operates in Spain and Belgium. What is the ecosystem like in each of those locations?
 

Exciting, I would say! 

Spain’s biotechs are cohering around a few hotspots, and the strongest one is here in and around Barcelona. Around 15 years ago, there was nothing here, but now we are seeing young companies go through financing rounds you would expect to see in Europe’s wealthier countries, such as France, Germany, and the UK. The healthcare system in Spain is strong, and the presence of finance and law professionals has greatly helped to build up the auxiliary capabilities of the hub.

In Belgium, the sector is more advanced and there is a broader and deeper pool of experience in the later stages of the pipeline. Relative to its size, the country’s pharma companies really punch above their weight. I think that companies on the Catalonian scene can learn something there – and I think we can also benefit from being part of that ecosystem. And that’s also one of the reasons we have part of our team based there!

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About the Author
Angus Stewart

Associate Editor of The Medicine Maker

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