Minoryx Therapeutics has revealed the findings from the first and largest international study to enroll adult male X-linked adrenoleukodystrophy patients.
The Phase II/III ADVANCE clinical trial of lead candidate, leriglitazone, published in The Lancet Neurology, did not meet the primary outcome for the six-minute walk test.
However, clinical measures of body sway (assessing balance) demonstrated clinically relevant differences and favourable trends were observed for Expanded Disability Status Scale (EDSS), Severity Score System for Progressive Myelopathy (SSPROM) and quality of life.
X-linked adrenoleukodystrophy (X-ALD) is an orphan inherited neurodegenerative disease. Adrenomyeloneuropathy (AMN) affects X-ALD patients when reaching adulthood and it is characterised by progressive deterioration of balance and sensory function, spastic paraparesis and development of incontinence.
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’s Phase II/III ADVANCE study is the first international and robust study providing evidence of drug effect in this population,” said Professor 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.”
X-ALD male patients (paediatric 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. In cALD patients, allogenic and autologous hematopoietic stem cell transplantation (HSCT) are the only treatment options available but are only possible in a limited number of patients.
The results of the trial also showed that leriglitazone reduces the progression of cerebral lesions and only placebo group patients developed clinically progressive cALD (six out of 39 patients).
“The finding that no patients treated with leriglitazone developed progressive cerebral ALD is very significant. The cerebral lesion stabilisation 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, Professor Fanny Mochel, Paris Brain Institute, Sorbonne University, Paris.
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 ADVANCE 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 be announced towards the end of 2023.
Moreover, a two-year paediatric 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) for the treatment of adult male patients with X-linked adrenoleukodystrophy (X-ALD).