ALS therapy EKZ-102 on track to enter clinical testing in 2026
Experimental oral drug eased disease severity in mouse models, data show
EKZ-102, Eikonizo Therapeutics‘s experimental oral therapy for amyotrophic lateral sclerosis (ALS), is on track to enter early clinical testing in 2026, according to an announcement from the company.
EKZ-102 is designed to block the activity of a protein called HDAC6. A team led by scientists at Eikonizo has now shared new preclinical data showing that targeting HDAC6 can reduce several ALS-related biological processes and ease disease severity in mouse models of ALS.
The preclinical research was shared in the study, “A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia,” published in Brain.
Study focuses on predecessor to EKZ-102
ALS is caused by the degeneration of motor neurons, which are nerve cells that control muscle movement. Although the underlying causes of ALS are not fully understood, studies have suggested that problems with proteostasis and intracellular transport — that is, how cells regulate protein levels and shuttle molecular cargo between different cellular compartments — contribute to motor neuron degeneration in ALS.
The HDAC6 protein plays key roles in regulating these two processes, and it’s well established that blocking its activity can help cells clear out toxic protein buildups. Still, it’s been difficult to develop a drug that can efficiently block HDAC6 without also inadvertently blocking the activity of other proteins, which could lead to side effects.
Another major hurdle in the development of HDAC6 inhibitors for ALS is the blood-brain barrier, which is essentially a cellular wall that separates the brain and spinal cord from the rest of the body, helping to protect the nervous system from toxins and infections. To reach the motor neurons that are affected by ALS, an HDAC6-targeting medication would need to be able to efficiently cross this barrier.
In this study, researchers described the development of EKZ-438, a predecessor to Eikonizo’s lead candidate EKZ-102. The scientists showed that this molecule blocks HDAC6 with more than 8,000 times greater potency than other proteins and that it is able to cross the blood-brain barrier.
The scientists tested the compound in two mouse models of ALS — one reflecting familial ALS, where the disease is caused by mutations that are passed from parents to their biological children, and the other reflecting sporadic disease, where ALS develops in people with no family history of the disorder.
Collectively, the findings presented here support advancement of highly selective, potent, and [brain]-penetrant small molecule HDAC6 inhibitors for the treatment of ALS and FTD, specifically, and potentially for any neurodegenerative disease with defects in proteostasis and [intracellular] transport.
In the familial disease model, ALS is induced specifically by a mutation in the gene SOD1. In this model, EKZ-438 led to improvements in markers of intracellular transport and in motor function. Animals also had lower levels of nerve cell degeneration and slower disease progression.
In the sporadic ALS model, ALS is induced by engineering the mice to produce an abnormal TDP-43 protein, which builds up to toxic levels in most ALS patients and in about half of people with frontotemporal dementia (FTD), a disorder related to ALS that’s marked by cognitive problems. In this mouse model, EKZ-438Â reduced the abnormal buildup of TDP-43 and lowered markers of inflammation in the brain.
EKZ-438 was also shown to reduce abnormal protein buildups, improve the transport of molecular cargo, and improve motor neuron survival in cell models of ALS, including motor neurons derived from people with ALS.
“Collectively, the findings presented here support advancement of highly selective, potent, and [brain]-penetrant small molecule HDAC6 inhibitors for the treatment of ALS and FTD, specifically, and potentially for any neurodegenerative disease with defects in proteostasis and [intracellular] transport,” the scientists concluded.
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