Buntanetap: From Execution Poison to Potential Alzheimer’s Disease Drug

Deep in the forests of modern-day Nigeria and Cameroon, a vibrant ethnic group called the Efiks had a seed that could end a life in minutes. The pod of Physostigma venenosum, better known as the Calabar bean, determined whether a person accused of a crime was innocent or guilty, with innocence decided by survival. Crushed and mixed with water, the potion was given to the accused in this trial by ordeal, and those who vomited it walked free. The less fortunate ones would die after ingestion, proclaimed guilty as charged.

When Scottish physician Robert Christison obtained specimens of the Calabar bean in 1855, he tested it, as Victorian scientists sometimes did, on himself, chewing a piece, experiencing its effects, and then quickly washing his mouth with water to avoid a fatal dose. His observations helped launch a pharmacological investigation that would span the next century and a half.¹ In 1864, two chemists, Julius von Jobst and Oswald Hesse, isolated its active compound, physostigmine. Within decades, it was in clinical use for glaucoma. By the 1970s, researchers were wondering whether it might have more to offer.

Today, researchers are studying a molecular descendant of that poison in clinical trials for Alzheimer’s disease. Its modern name is buntanetap, and its long and winding journey may, at last, be nearing a finish line.

Reinventing a Poison

The pharmacological action of physostigmine, the active compound of the ancient Calabar bean, is now well understood: It inhibits acetylcholinesterase, the enzyme that breaks down the neurotransmitter acetylcholine at junctions between nerve cells, or synapses. The discovery of acetylcholine and chemical neurotransmission, derived from the investigation of physostigmine, had a profound scientific impact and earned its discoverers a Nobel Prize for Physiology or Medicine in 1936.

In high doses, which was the case in the Efik trials, inhibition of the acetylcholinesterase enzyme leads to a dangerous buildup of acetylcholine resulting in sweating, muscle paralysis, and respiratory failure. However, in controlled doses, the inhibition of the same enzyme is beneficial: Acetylcholine lingers longer, enhancing the cholinergic signaling, which is important for cognitive processes such as attention, learning, and memory. This matters because Alzheimer’s disease progressively destroys neurons that produce acetylcholine. The cholinergic hypothesis, which long dominated the Alzheimer’s disease field, stated that degeneration of such acetylcholine-producing neurons is behind cognitive decline. In that sense, blocking acetylcholinesterase and improving the impaired signaling should restore cognitive function, and physostigmine was a nature-ready candidate to take on that task.

Clinical trials followed, and the drug showed modest benefits, but its original form had disadvantages: It lasted a very short time in circulation and had multiple side effects such as nausea, vomiting, and diarrhea. That limitation sent scientists at the National Institutes of Health to search for more favorable chemical analogs. In the 1990s, chemists Arnold Brossi, Nigel Greig, and their colleagues of the National Institute on Aging discovered and characterized phenserine, which was the most successful alternative built on the backbone structure of physostigmine.^2,3 Phenserine offered selective inhibition of acetylcholinesterase, better brain permeability, longer circulation life, and reduced peripheral toxicity compared to its ancestor. In other words, phenserine was a “domesticated” version of physostigmine.

Phenserine entered rigorous laboratory testing, and researchers made a surprising discovery: The drug reduced the levels of amyloid precursor protein and amyloid beta (Aβ), primary hallmarks of Alzheimer’s disease, through a mechanism distinct from the acetylcholinesterase inhibition.^4–6 Mounting evidence of promising data for the use against dementia allowed phenserine to begin clinical testing in humans. However, more challenges arose.

In February 2005, a press release from Axonyx, a company behind a Phase 3 clinical trial of phenserine in Alzheimer’s disease, ended the clinical prospects for the drug. The randomized, placebo-controlled trial that enrolled almost 400 patients with mild-to-moderate Alzheimer’s disease failed to meet its primary endpoints.⁷ The study showed a trend in cognitive improvement after treatment with the drug, but a robust response in placebo patients obscured the significant difference the phenserine-treated patients could have had. Most scientists gave up, but a few refused to do so.

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Hope Through Phenserine’s Enantiomer: Posiphen

It turned out that phenserine had a mirror-image version, or enantiomer, that Greig and his team synthesized and named posiphen.⁸ Like the parent drug, posiphen was able to suppress levels of Aβ but had no effect on acetylcholinesterase inhibitory activity like phenserine did. This distinction offered a much better side effect profile, the ability to use the drug at higher doses, and the capacity to target exactly the pathological basis of Alzheimer’s disease.

In this sense, phenserine’s failure was not an ending, it was a clarification step that established exactly the right path for a future drug. What followed was a period of corporate turbulence: Axonyx merged with TorreyPines Therapeutics in 2006, which then licensed the drug rights to QR Pharma, later named Annovis Bio. For the next 17 years, scientists at Annovis Bio would dedicate themselves to a single question: Could this molecule finally crack the code of neurodegeneration?

Posiphen, it turned out, was capable of far more than initially thought. Extensive research showed that it could suppress the translation of Aβ and numerous other neurotoxic proteins that drive neurodegeneration.^5,9–14 A mechanistic picture took years to assemble, but it ultimately came together. The drug works via an RNA-targeting mechanism that underlies multiple neurotoxic proteins, including amyloid precursor protein and Aβ, alpha synuclein, tau, and more. These proteins share a similar region in their mRNA—a stem-loop structure called iron responsive element (IRE) that is recognized by and binds to a protein with a similar name, iron regulatory protein 1 (IRP1).^15–19 When the mRNA is bound by IRP1, translation is blocked, preventing the production of neurotoxic proteins.

In healthy cells, IRP1 regulates the normal production of these proteins, but in the conditions of high iron concentrations, which is also the case in an Alzheimer’s disease brain, the IRE is released from IRP1, and the proteins are overproduced. They ultimately aggregate and accumulate in the brain, leading to the formation of well-known amyloid plaques and tau tangles. What follows is a complex cascade of toxic neuropathological events: impaired communication between cells, neuroinflammation, and cell death. Posiphen helps hold IRP1 and IRE together, keeping the protein synthesis machine protected even in the harsh environment of the disease, and preventing the toxic cascade.

The Clinical Case for Buntanetap

Because of its advanced development stage, posiphen was given the generic name buntanetap by a US government agency. Under this new name, researchers studied the drug in a total of 12 clinical trials with two more currently underway. Studies conducted in patients with Alzheimer’s disease and Parkinson’s disease demonstrated that buntanetap improved cognitive functions as early as one month after daily treatment, with benefits sustained at three and six months.^13,20 The drug worked exceptionally well in patients with early stages of disease, who had amyloid and tau pathology in their brains. Based on the data derived from the analysis of biomarkers, buntanetap also reduced the toxic events that normally follow the overproduction of these harmful proteins: It improved cell-cell communication, decreased neuroinflammation, and restored neuronal health.

The 170-Year Journey to Buntanetap

The arc from the Calabar bean to buntanetap is not a straight line. From trials by ordeal to the discovery of acetylcholine signaling, failed trials of phenserine, and a stereochemical detour, this journey culminated in a mechanistic reframing that distinguishes buntanetap from its predecessors. At every stage, something was discarded: the toxicity, the wrong enantiomer, the “old” mechanism. What remained is a refined drug that might become the next therapeutic breakthrough.

Buntanetap is currently in a pivotal Phase 3 clinical trial for early stage of Alzheimer’s disease and is also being tested for Parkinson’s disease, both aimed at collecting sufficient data to help bring the drug to market. The Efik people who used Calabar beans were concerned with a verdict between guilt and innocence. The modern trials of the poison’s descendant will deliver a verdict of their own: between a disease that has gone unpunished for generations and the patients who have waited long enough for justice.