Overview — PAC-832

PAC-832 is the first drug of its kind — it works by selectively blocking a receptor called “galanin receptor 1,” or GalR1. The drug has sub-micromolar potency for GalR1 and >30x selectivity over GalR2/3. When administered to mice, it significantly improves their memory across multiple different memory tests. PAC-832 also has excellent manufacturability, low toxicity, and great pharmacokinetics, including passing the blood-brain barrier — all critical things needed for a neurological drug to succeed.

Motivation behind PAC-832

The primary symptom of Alzheimer’s disease (AD) — memory loss — has long been hypothesized to arise from the loss of neurons that produce the neurotransmitter acetylcholine (ACh) in certain important brain regions, primarily the basal forebrain. This is known as the “cholinergic hypothesis of AD,” which forms the basis for how the AD drug donepezil works. Donepezil increases the amount of ACh between neurons by blocking an enzyme called acetylcholinesterase (which is responsible for breaking down ACh). In doing so, it’s been shown to reverse memory loss in AD patients.

Acetylcholine (ACh)

Donepezil

Donepezil is far from perfect and was discovered way back in 1983, yet shockingly the entire AD drug development field has been unable to improve on it after 40+ years of effort. During this time, the AD field has mostly focused on developing drugs that target amyloid-beta plaques and other “disease-modifying” mechanisms. This effort produced several new FDA-approved drugs in recent years which reduce plaque levels (like lecanemab and donanemab), yet none of these drugs meaningfully slow AD disease progression or outperform donepezil for managing AD symptoms, and they carry significant new safety risks like increased incidence of brain hemorrhage/stroke. Because of this, doctors are unwilling to prescribe these new drugs. Almost nobody uses them. Meanwhile, donepezil has remained the most effective, safe, and widely-used AD drug from its discovery up to today.

Given the underwhelming performance of anti-amyloid drugs, it’s a good time to focus on alternative AD drug mechanisms. I believe that the optimal place to look is the cholinergic pathway, which unlike more contemporary AD targets has a large body of the best possible supporting evidence — decades of real, human clinical data from cholinesterase inhibitors.

This line of thinking led me to develop PAC-832. Like donepezil and related cholinesterase inhibitors (galantamine, rivastigmine), PAC-832 ultimately increases ACh levels in the brain. However, PAC-832 is not structurally related to any existing cholinesterase inhibitors, and it doesn’t directly target the cholinergic pathway. Instead, it works through a new mechanism revolving around this complex, underappreciated molecule called “galanin.”

A brief history of the galanin-AD hypothesis

Galanin is a 30-amino acid neuropeptide — a small protein that acts as a signaling molecule in the brain. It was discovered in 1978. Though less well known than dopamine or serotonin, galanin is widely produced by neurons throughout the central and peripheral nervous system. Galanin signaling has been shown to regulate pain, metabolism, mood, sleep, and memory. It lurks in the background, quietly influencing many of our physiological functions on a daily basis.

3D structure of human galanin

Galanin dysregulation was first tied to AD pathology in the 1980s, 10 years after galanin’s discovery. Chan-Palay, Beal et al., and others observed that the basal forebrain from deceased AD patients contained many more galanin-producing neurons and higher galanin expression than healthy brains.

Meanwhile, Fisone et al. and Dutar et al. observed that galanin treatment onto slices from rat and monkey brains prevented the neurons from releasing ACh.

At the behavioral level, impaired memory was observed by McDonald et al. in rodents with galanin injected into their brains. Steiner et al. observed similar results in rodents genetically engineered to overexpress galanin.

Along with other supporting studies, these observations outlined a mechanism where galanin contributed to memory loss in AD by preventing ACh release in the basal forebrain, though neither galanin’s molecular mechanism nor the cause of galanin overexpression was understood at the time. This in turn led people in the 90s to hypothesize that a drug that ‘blocked’ the action of galanin could increase ACh levels and improve cognitive function in AD patients, similar to how cholinesterase inhibitors like donepezil work.

Source: McDonald et al. 1998, J Neurosci

In the 2000s, the galanin-AD hypothesis was complicated by the emergence of data showing that galanin had neuroprotective effects in certain contexts. O’Meara et al. showed that galanin knock-out mice had significantly fewer cholinergic neurons in the basal...