A New Therapeutic for ALD

X-linked adrenoleukodystrophy (ALD) is a life threatening rare genetic disorder caused by mutations in the ABCD1 gene, affecting the central nervous system (CNS) and adrenal cortex. Patients often experience irregular blood pressure and heart rate, as well as neurological problems, such as seizures, muscle spasms, and learning difficulties. In children, the disorder can lead to loss of vision, hearing, and an inability to speak.

In terms of CNS related phenotypes, ALD comes in two forms: adrenomyeloneuropathy (AMN) affecting the spinal cord, and cerebral ALD (cALD) characterized by brain lesions. When brain lesions are progressive, cALD results in rapid neurological decline and death, and standard of care treatment for these patients is a hematopoietic stem cell transplant, which can take months to arrange – all while brain lesions continue to progress.

Barcelona-based clinical stage biotech Minoryx’s lead program aims to tackle the brain lesions of cALD with a small molecule drug called leriglitazone, which demonstrated robust preclinical proof-of-concept in vivo. The company also completed a phase II/III trial in adults showing significant reduction of cerebral lesion progression and myelopathy symptoms, while a separate phase II/III study in children is underway. Also, a phase III study in adult male patients with progressive cALD is now recruiting in the US, Brazil, and Argentina while sites are being opened in the EU.

We spoke with Minoryx co-founder and CEO Marc Martinell to learn more.

How does leriglitazone help with cALD?
 

In the cerebral form of the disease, patients suffer inflammation-driven demyelinating brain lesions that can expand very rapidly, resulting in acute neurological decline and death in about three or four years. The ABCD1 gene actually has nothing to do with inflammation itself, but when it fails to function properly, there are numerous negative consequences in cells, rendering them prone to inflammation. Leriglitazone is a PPAR- gamma agonist that modulates inflammation, together with myelination and mitochondrial function. Treating these key pathways reduces the progression of brain lesions in patients with cALD.

In the clinical trial with leriglitazone, only the adult patients on placebo control continued to develop progressive brain lesions. Interim data in pediatric patients are also showing slower brain lesions progression than natural history of untreated patients.

Do you envision any major challenges in the commercial manufacturing and distribution of the drug?
 

No, there are few challenges in the manufacturing of leriglitazone – it’s all well under control. We work with well-established CDMOs whose partnership and expertise are invaluable. Distribution will come with issues, certainly – especially given that it is not yet approved. Our European distribution partner, Neuraxpharm, however, is a specialist in CNS diseases. The moment the drug is approved in Europe, they will be the ones commercializing and distributing it.

Do you anticipate any issues with regulatory approval?
 

Regulation is always difficult when developing drugs for a disease as rare and as complicated as cALD, and it’s extremely challenging to generate a perfect dataset with so few patients out there. These issues generate more complexity for regulators. We made an attempt at an early EMA approval that resulted in a negative opinion because the data were not yet sufficient. We are now finalizing ongoing studies and generating more data to support a new marketing authorization application.

What is the potential of leriglitazone if used in combination with advanced therapeutics?
 

What we’ve shown so far is the drug’s important effect on the progression of brain lesions. I could envisage treatment with leriglitazone alone, particularly if patients are treated prior to lesions becoming progressive. For patients with progressive lesions, the standard of care is a hematopoietic stem cell transplant, which also has a positive effect. Nonetheless, the majority of patients with progressive lesions are ineligible for transplant-based approaches, and if approved, leriglitazone would be the only source of hope for them. For those eligible for transplant, a combination treatment certainly looks possible at this stage. In the several months from diagnosis to the transplant procedure, lesions are progressing rapidly and are irreversible. If we can stabilize these patients until the right donor is found and a transplant can be performed, it could be very beneficial.

What does the ideal future look like for leriglitazone?
 

The ideal – and realistic – future, once more data is generated, is approval. I am confident that we will get that sooner or later. We know the drug works, but we need to generate a data package that is sufficient for regulators. We have an agreed pathway with the FDA, which – if successful – will lead to US approval. Through partnerships, we will also ensure that the drug becomes available outside Europe and the US.

The way this drug works is beneficial for cerebral ALD, but there are several other diseases affecting the central nervous system that leriglitazone may be able to help with, for example, Rett Syndrome. All those indications are equally dramatic and share a very high unmet medical need. ALD is just the first stage.