12:00 AM
Feb 18, 2016
 |  BC Innovations  |  Product R&D

Crossing paths

Linking inflammation and oxidation in ALS

With its first foray into the brain, Catabasis Pharmaceuticals Inc. is using its linker technology to simultaneously target the inflammatory and oxidative stress pathways that drive neurodegeneration, starting with amyotrophic lateral sclerosis (ALS) and Friedreich's ataxia. While the two diseases affect different neurons, have different pathologies and cause different symptoms, the company believes there's enough common ground in the pathway biology to develop a single compound for both, and plans to complete IND-enabling studies by year-end.

The compound, CAT-4001, joins the NF-κB inhibitor docosahexaenoic acid (DHA), an anti-inflammatory, with the NRF2 agonist fumarate, which activates antioxidant pathways. (See Figure: Catabasis goes neuro)

It came about through Catabasis' strategy of finding independent pathways that drive disease, and linking together drugs that might produce better outcomes if they hit the same cell at the same time than if delivered independently. CAT-4001 is Catabasis' fourth disclosed candidate.

Andrew Nichols, SVP of research and non-clinical development, told BioCentury CAT-4001 evolved from its CAT-1004 program, which targets the NF-κB pathway by joining DHA with the anti-inflammatory compound salicylate.

CAT-1004 is in Phase I/II for Duchenne muscular dystrophy (DMD). The other two candidates, CAT-2054 and CAT-2003, are in Phase II for hypercholesterolemia and hypertriglyceridemia, respectively.

Nichols said as the company looked further into NF-κB signaling, it found evidence in the literature that the transcription factor is chronically activated in ALS and Friedreich's ataxia.

According to Nichols, genome-wide association studies have turned up multiple hits upstream of NF-κB. "In both genetic and sporadic cases of ALS, a variety of biological pathways are activated that converge on NF-κB" to trigger inflammation, he said. "A lot of the roads lead to NF-κB, and they can come from different directions."

Once activated, the pathway turns on transcription of a variety of factors including other inflammatory molecules, creating a self-propagating feedback loop. The chronic inflammation coupled with the oxidative damage also present in the disease eventually cause motor neurons to die, said Nichols.

He emphasized, "It's really a mash of emerging biology with these molecules, and what our platform can do, that has led us into these neurodegenerative diseases."

CEO Jill Milne noted that the approach used to create CAT-4001 is in keeping with the company's strategy of targeting downstream mechanisms driving disease rather than genetic causes. "We anticipate that CAT-4001's mechanism of action will be agnostic as to the underlying mutation."

Linking pathways

At the heart of Catabasis' platform is a set of linkers that can be used to covalently join pairs of small molecules to control at least four aspects of their biology.

First, the linkers force the two compounds to have identical tissue distributions and PK profiles.

Second, by connecting the bioactive regions of each compound to the linker, the molecules remain inactive while...

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