Scientists have been testing various ways to tackle neurodegenerative diseases—blocking the production of toxic proteins, regenerating functional neurons and restoring the brain’s waste-clearing system, among others.
One company says its drug candidate has the potential to address four of those important hallmarks, and it showed early promise in a phase 1 trial.
Ironwood Pharma spinout Cyclerion Therapeutics’ soluble guanylate cyclase (sGC) stimulator IW-6463 was well tolerated in healthy volunteers. “Pharmacokinetic data, obtained from both blood and cerebral spinal fluid, support once-daily dosing with or without food and demonstrate IW-6463 penetration across the blood-brain-barrier at levels expected to be pharmacologically active,” the company’s chief medical officer, Chris Wright, M.D., said in a recent statement.
IW-6463 is designed to work on the nitric oxide (NO)-sGC-cGMP signaling pathway, which modulates several physiological mechanisms such as arterial dilation, fibrosis and inflammation. In the central nervous system (CNS), the pathway is believed to be key for neuronal information transmission and synaptic plasticity, which is a foundation for learning and memory.
In preclinical tests in lab dishes and rodents, Cyclerion scientists have shown that IW-6463, by increasing cGMP production through stimulating the sGC enzyme, could tackle four important signs of neurodegenerative diseases.
First, they found that the drug enhanced blood flow in areas of rats’ brains associated with attention and memory. Disrupted cerebral blood flow is a feature of several neurological diseases and dementias. In rats whose brain blood flow had been reduced by NO inhibition, the drug increased it above baseline. A sister sGC stimulator that doesn’t penetrate the CNS showed minimal effects, according to Cyclerion.
The team further tested rats’ cognitive functions. Among healthy aged rats, those treated with IWP-247 had significant improvements in thigmotaxis—a measure of strategic thinking—compared to others treated with a vehicle in a water maze test by day four. And the treated animals’ thigmotaxis appeared on par with young rats.
In addition, in an LPS challenge—which is commonly used to test anti-inflammatory reagents—the drug reduced neuroinflammation in rat brain 3D microtissues. The drug also showed it could increase the density of dendritic spines—part of the architecture of the neuron responsible for transmitting electrical signals into the cell’s core—in the hippocampus and cortex. During normal aging, the number of spines is reduced, which correlates with decreased neuronal function. Their loss is also exacerbated in neurodegenerative disorders such as Alzheimer’s disease.
Because of sGC’s wide range of function, Cyclerion’s also developing other sGC stimulators for disorders such as sickle cell disease and liver and lung diseases. But not all of them are going as planned.
Last October, the company’s stock plummeted by nearly 80% at the news of a pair of phase 2 clinical trial failures for its praliciguat. In one, the drug couldn’t help patients with heart failure with preserved ejection fraction. In the second in diabetic nephropathy, the drug wasn’t able to significantly reduce albuminuria, a marker for kidney function, although the results got better in a post hoc analysis after excluding some patients at one trial site with undetectable or very low praliciguat blood concentrations.
At least the company is still hopeful that IW-6463 could be a first-in-class drug for neurodegenerative diseases. On top of the phase 1 on 110 people, Cyclerion is running a parallel translational pharmacology study in about 24 elderly people that will measure some biomarkers of CNS activity, including cerebral blood flow, with top-line data expected in mid-2020.
For the future, the company intends to further develop the drug in “high-value CNS indications.” During a Q&A session at the annual J.P. Morgan Healthcare Conference in San Francisco, Cyclerion Chief Innovation Officer Andy Busch, Ph.D., wouldn’t specify the indications, only saying the company will pursue both large and small diseases.
Jan 21, 2020