Headquartered in Spain, Minoryx Therapeutics said the US Food and Drug Administration (FDA) had approved a phase 3 clinical trial (CALYX), the lead candidate for leriglitazone, to treat adult male patients with X-linked adrenoleukodystrophy (X-ALD) with cerebral adrenoleukodystrophy (cALD). ).
X-ALD is an orphaned neurodegenerative disease. The global incidence of X-ALD is approximately six to eight per 100,000 live births. ALD patients, boys and men, can develop caLD at any time in their lives, characterized by rapidly progressing demyelinating brain lesions, leading to acute neurologic decline and death. These lesions can produce severe symptoms such as loss of voluntary movement, inability to swallow, loss of communication, cortical blindness and total incontinence and death with an average life expectancy of three to four years.
caLD occurs in 31-35% of ALD patients in childhood with onset usually between the ages of two and 12 years. caLD eventually affects two out of every three male ALD patients (1/3 in childhood and another 1/3 in adulthood). All X-ALD patients who reach adulthood develop adrenomyeloneuropathy (AMN), which is characterized by progressive spastic paraparesis, progressive loss of balance and sensory function, and development of incontinence.
This form develops chronically with onset of symptoms usually in adulthood, affects both males and females, and has a poor prognosis. There is currently no pharmacological treatment available for X-ALD. In childhood, allogeneic hematopoietic stem cell transplantation (HSCT) and FDA-approved ex-vivo eli-cell gene therapy can contain the disease, however, it is an aggressive procedure and only available for a subset of patients. In adults, HSCT experience is very limited and intervention is often discouraged.
the CALYX trial
The CALYX protocol has received central FDA and IRB approval. Trial preparations have been completed and patient recruitment is expected to start in late Q2 2023 with results expected in late 2025.
“Minoryx is focused on providing X-ALD patients with a therapeutic option and we now have an agreed route to the US market with a phase 3 trial designed to confirm the disease-modifying potential of leriglitazone,” said Marc Martinell, CEO, Minoryx.
“CALYX will be funded from a Series C financing together with the proceeds from our European strategic collaboration with Neuraxpharm. We look forward to starting this trial that may provide an important therapeutic option for patients suffering from this devastating orphan disease with major unmet medical needs.”
CALYX will enroll 40 adult male X-ALD patients with progressive caLD defined by the presence of a gadolinium-raising brain lesion. A pre-screening campaign will be initiated at all participating sites to identify adult patients with brain lesions. The trial was placebo-controlled with 1:1 randomization, and the primary end point was “time of death” or “bedridden on permanent ventilation support”.
The CALYX design was based on the results of the ADVANCE and NEXUS trials. It also takes advantage of an ongoing compassionate use program in which leriglitazone has demonstrated the ability to stop the progression of lesions. NEXUS interim analysis (recently disclosed at the AAN conference) showed that after 24 weeks of treatment, all patients were clinically stable and, radiologically, demonstrated either termination of disease or stabilization of lesion growth. Radiological changes are similar to those achieved with HSCT or ex-vivo gene therapy, therefore it is hoped that leriglitazone may provide comparable clinical benefit to caLD patients.
CALYX will be conducted in the US and South America and Minoryx has appointed Ali Fatemi at the Kennedy Krieger Institute in Baltimore, USA as the global principal investigator.
“There is a major unmet medical need for a treatment that can halt or slow disease progression in caLD because the majority of patients, and especially adults, do not have any treatment options,” said Fatemi.
“The results of Leriglitazone so far have been very encouraging and with CALYX the aim is to confirm the clinical benefit of leriglitazone and provide caLD patients with a treatment that can arrest or slow their neurological decline and prolong their life.”
Leriglitazone (MIN-102) is a novel bioavailable and selective PPARγ agonist Minoryx with first-class and best-in-class potency profiles for CNS disease. It has demonstrated brain penetration and a good safety profile. This provides strong preclinical proof of concept in animal models of various diseases by modulating pathways leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, demyelination and axonal degeneration.
In clinical trials, leriglitazone showed clinical benefit for both X-ALD and Friedreich’s ataxia patients. Leriglitazone has been granted orphan drug status for X-ALD from the FDA and EMA, and a rare and fast-track pediatric disease designation from the FDA for the treatment of X-ALD.