Spanish-headquartered Minoryx Therapeutics says the U.S. Food and Drug Administration (FDA) has approved its phase 3 clinical trial (CALYX) of lead candidate leriglitazone, to treat adult male X-linked adrenoleukodystrophy (X-ALD) patients with cerebral adrenoleukodystrophy (cALD).
X-ALD is an orphan neurodegenerative disease. The global incidence of X-ALD is approximately six to eight per 100,000 live births. ALD patients, boys and adult men, at any point in their lifetime can develop cALD, characterized by demyelinating brain lesions that rapidly progress, leading to acute neurological decline and death. These lesions can produce severe symptoms such as loss of voluntary movements, inability to swallow, loss of communication, cortical blindness and total incontinence and death with a mean survival of three to four years.
cALD occurs in 31-35% of ALD patients in childhood with onset typically between the age of two and 12. cALD ultimately affects two of every three male ALD patients (1/3 in pediatric age and another 1/3 in adulthood). All X-ALD patients reaching adulthood develop adrenomyeloneuropathy (AMN), characterized by progressive spastic paraparesis, as well as progressive deterioration of balance and sensory function, and development of incontinence.
This form progresses chronically with onset of symptoms typically in adulthood, affecting both men and women, and has poor prognosis. There is currently no pharmacological treatment available for X-ALD. In childhood, allogeneic hematopoietic stem cell transplantation (HSCT) and the FDA-approved ex-vivo gene therapy eli-cel can arrest the disease, however, it is an aggressive procedure and only available for a portion of patients. In adults, experience in HSCT is very limited and the intervention is often not recommended.
The CALYX protocol has received both FDA and central IRB approval. Preparations for the trial have been completed and patient recruitment is expected to start by the end of Q2 2023 with results anticipated by late 2025.
“Minoryx is focused on bringing therapeutic options to X-ALD patients and we now have an agreed route to the U.S. 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 the Series C financing together with proceeds from our European strategic collaboration with Neuraxpharm. We look forward to initiating this trial which could provide an important therapeutic option for patients suffering from this devastating orphan disease with a major unmet medical need.”
CALYX will enroll 40 adult male X-ALD patients with progressive cALD defined by the presence of gadolinium enhancing brain lesions. A pre-screening campaign will be initiated across participating sites in order to identify adult patients with brain lesions. The trial is placebo controlled with 1:1 randomization, and the primary endpoint is “time to death” or “bedridden with permanent ventilatory support.”
The design of CALYX builds upon the results from the ADVANCE and NEXUS trials. It also utilizes the ongoing compassionate use program where leriglitazone has demonstrated the ability to halt lesion progression. The NEXUS interim analysis (recently disclosed at the AAN conference) showed that after 24 weeks of treatment, all patients were clinically stable and, radiologically, demonstrated disease arrest or lesion growth stabilization. Radiological changes were similar to those attained with HSCT or ex-vivo gene therapy, hence it is expected that leriglitazone could provide a comparable clinical benefit to cALD patients.
CALYX will be conducted in the U.S. and South America and Minoryx has appointed Ali Fatemi at the Kennedy Krieger Institute in Baltimore, U.S. as the global principal investigator.
“There is a major unmet medical need for a treatment that can halt or slow the disease progression in cALD as the majority of patients, and particularly adults, do not have any treatment option,” Fatemi said.
“Leriglitazone results are so far very encouraging and with CALYX the objective is to confirm the clinical benefit of leriglitazone and provide cALD patients with a treatment that can arrest or slow-down their neurological decline and prolong their lives.”
Leriglitazone (MIN-102) is Minoryx’s novel orally bioavailable and selective PPARγ agonist with a potential first-in-class and best-in-class profile for CNS diseases. It has demonstrated brain penetration and a favorable safety profile. It showed robust preclinical proof-of-concept in animal models of multiple diseases by modulating pathways leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, demyelination and axonal degeneration.
In clinical trials, leriglitazone showed clinical benefit both for X-ALD and Friedreich’s ataxia patients. Leriglitazone has been granted orphan drug status for X-ALD from the FDA and the EMA, and fast track and rare pediatric disease designation from the FDA for the treatment of X-ALD.