Oral CKD-506 Lessens Symptoms, Demyelination in MS Mouse Model
Chong Kun Dang (CKD) Pharmaceutical’s experimental oral therapy CKD-506 suppressed inflammation, myelin loss (demyelination), and lessened symptoms in a mouse model of multiple sclerosis (MS), a study reported.
Notably, the therapy resulted in benefits generally comparable to those of Gilenya (fingolimod) in these mice. But it also eased depression-like symptoms and continued to delay symptom worsening after its use was stopped, the researchers noted.
These findings suggest that CKD-506, shown to be generally safe in Phase 1 trials, may be a potential therapy for MS.
The study, “CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis,” was published in the journal Scientific Reports.
A combination of genetic predisposition and environmental factors is thought to trigger the immune attacks on myelin — the protective sheath around nerve cell fibers that is key for proper neuronal communication — that characterize MS.
Environmental factors can influence genetics, via epigenetic mechanisms that control gene activity, without altering a person’s DNA sequence.
Notably, compounds blocking the activity of all histone deacetylases (HDACs), enzymes involved in these epigenetic mechanisms, were previously shown to lessen neurological symptoms, inflammation, and demyelination in MS animal models.
However, these pan-HDAC inhibitors were also associated with adverse side effects, and not considered suitable for clinical trials.
CKD-506 is an orally available small molecule that works by blocking the activity of the histone deacetylase 6 (HDAC6). Previous studies showed that HDAC6 suppression is associated with anti-inflammatory and neuroprotective effects, while not resulting in worrisome side effects.
Researchers at the University of Ulsan College of Medicine, in South Korea, and with CKD Pharmaceutical, based in that country, compared the effects of CKD-506 to those of Gilenya in a mouse model of MS.
Developed by Novartis, Gilenya is an approved second-line oral therapy for relapsing forms of MS. It works to retain immune cells within lymph nodes, preventing them from reaching the brain and spinal cord, where they promote inflammation and the damaging immune attacks against myelin.
Previous studies have shown that Gilenya, which has several generic versions now available, lowers patients’ relapse rates by 65% within one year after starting treatment.
CKD-506, when given before symptom onset to mice in the MS model, was seen to significantly delay the onset and reduce the severity of symptoms to degrees comparable to those observed with Gilenya. In addition, both therapies led to similar reductions in myelin loss and the number of immune cells in the spinal cord.
Further analysis revealed that CKD-506 suppressed spinal cord infiltration of two types of immune cells, T-cells and macrophages, as well as their immune responses, while Gilenya blocked only T-cell infiltration and immune responses.
This CKD-506-associated reduction in the number of immune cells infiltrating the spinal cord was associated with the preservation of the blood-brain barrier (BBB)’s integrity, which was weaker in untreated mice. Gilenya failed to prevent changes in BBB integrity.
The BBB is a highly selective membrane that tightly regulates what substances and cells in the bloodstream can access the brain and spinal cord. Loss of the barrier’s integrity is thought to contribute to MS by allowing disease-inducing immune cells and toxic molecules to reach the brain and spinal cord.
CKD-506 and Gilenya, when given after symptom onset, also resulted in a similar easing of symptoms in these mice. However, while stopping Gilenya led to rapid symptom worsening, stopping CKD-506 caused no significant change in the animals’ symptoms during a three-day observation period, suggesting at least a delay in symptom aggravation.
“It remains unclear as to why the efficacy of CKD-506 was maintained,” the researchers wrote.
Notably, switching from Gilenya to CKD-506 prevented the increase in the number of immune cells in the blood that followed Gilenya’s discontinuation.
Use of CKD-506 also lessened depression-like behavior in these mice before symptom onset.
These findings highlight that CKD-506 “exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity,” the researchers wrote, noting it may be “a potential therapeutic agent for MS.”