Minoryx Therapeutics announces X-linked adrenoleukodystrophy data

balance adrenoleukodystrophy

Minoryx Therapeutics has announced that data from its phase 2/3 ADVANCE clinical trial of lead candidate, leriglitazone, has been published in The Lancet Neurology.

The trial, assessing the efficacy and safety of leriglitazone in male patients with adrenomyeloneuropathy, is the first and largest international study to enroll adult male X-linked adrenoleukodystrophy patients. 

X-linked adrenoleukodystrophy (X-ALD) is an orphan inherited neurodegenerative disease. Adrenomyeloneuropathy (AMN) affects X-ALD patients when reaching adulthood and it is characterized by progressive deterioration of balance and sensory function, spastic paraparesis and development of incontinence. Mobility is significantly affected with progression and therefore maintaining sensorimotor balance in patients with AMN is very important.

X-ALD male patients (pediatric and adult) develop cerebral lesions that can evolve to progressive cerebral ALD (cALD), which is devastating and leads to death within two to four years. The potential of the development of cALD is a major concern to both patients and clinicians with regular MRI screening being recommended. In cALD patients, allogenic and autologous hematopoietic stem cell transplantation (HSCT) are the only treatment options available.

However, they are only possible in a limited number of patients. For AMN patients, only symptomatic supportive care is available. Therefore, a treatment is very much needed for X-ALD patients allowing early intervention to halt disease progression.

Minoryx Therapeutics’ trial details

Minoryx Therapeutics’ phase 2/3 ADVANCE clinical trial was a pivotal multicenter, double-blind and placebo-controlled study conducted in the U.S. and Europe in adult male X-ALD patients with AMN. 

In the trial, of 116 patients randomized, 77 received leriglitazone and 39 received placebo. The study did not meet the primary outcome for a six-minute walk test. However, clinical measures of body sway (assessing balance) demonstrated clinically relevant differences and favorable trends were observed for EDSS, SSPROM and quality of life. Leriglitazone was generally well tolerated.

In addition, the results also showed that leriglitazone reduces the progression of cerebral lesions and only placebo group patients developed clinically progressive cALD (six out of 39 patients). 

Plasma biomarker data showed that neurofilament light levels were significantly increased at week 96 in placebo patients with cerebral lesion progression, supportive of a drug effect on reducing axonal degeneration. Treatment with leriglitazone also significantly reduced plasma levels of MMP-9, a marker of blood-brain barrier integrity. Furthermore, while at baseline, both placebo and leriglitazone groups were well balanced in terms of number of patients with a Loes severity score greater than 0, an increase in this score at week 96 was significantly greater in the placebo group.

The study continues as an open label extension study for three further years with on-going monitoring of both myelopathy and cerebral lesion progression. The final five-year data will read out towards the end of 2023. Moreover, a two-year pediatric study in boys with progressive cALD, called NEXUS, is due to report six-month interim data in H1 2023.

The Committee for Medicinal Products for Human Use (CHMP) for the European Medicines Agency (EMA) is currently reviewing leriglitazone’s Marketing Authorization Application (MAA) that Minoryx submitted in August, 2022 for the treatment of adult male patients with X-linked adrenoleukodystrophy (X-ALD). 

Meaningful endpoints

“Minoryx’s phase 2/3 ADVANCE study is the first international and robust study providing evidence of drug effect in this population,” said Wolfgang Kohler, global co-ordinating investigator, University of Leipzig Medical Centre. 

“The ADVANCE study has consolidated clinically meaningful endpoints for AMN myelopathy with body sway assessments and also the need to treat early in the AMN time course with leriglitazone showing clinical utility in this disease with a significant unmet need.” 

“The finding that no patients treated with leriglitazone developed progressive cerebral ALD is very significant. The cerebral lesion stabilization seen with MRI in placebo patients who progressed in the blinded period and are now on leriglitazone is even more promising for patients with cerebral ALD,” said principal investigator, Fanny Mochel, Paris Brain Institute, Sorbonne University, Paris.

“The ADVANCE data are integral to Minoryx’s Marketing Authorization Application which is now under review by the EMA,” said Marc Martinell, CEO, Minoryx. 

“We are working together with our partner Neuraxpharm to ensure that leriglitazone reaches X-ALD patients as quickly as possible.”

Minoryx Therapeutics‘ 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.

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