If the FDA ultimately votes to approve Eli Lilly’s donanemab or Eisai’s lecanemab – both anti-amyloid beta (Aβ) antibodies – what impact will it make on Alzheimer’s disease?
If a tree falls in a forest and nobody is around to hear it, does it make a sound? Similarly, if the U.S. Food and Drug Administration ultimately votes to approve Eli Lilly’s donanemab or Eisai’s lecanemab – both anti-amyloid beta (Aβ) antibodies – will it make an impact on Alzheimer’s disease (AD)?
“The stupid question is: if I have Alzheimer’s disease and my plaque is gone, but I still have Alzheimer’s disease, do I care?” Maria Maccecchini, Ph.D., founder, president and CEO of Annovis Bio asked during an interview with BioSpace.
On Thursday, Maccecchini participated in a panel discussion, Integrative Systems Biology of Alzheimer’s Disease, at the Alzheimer’s Association International Conference (AAIC), addressing this very question. The panel, hosted by renowned AD researcher Dr. Jeffrey Cummings, M.D., and Krista Lanctôt, Ph.D. of Sunnybrook Research Institute, also looked at integrative approaches being taken to treat the disease.
The Battered Anti-Amyloid Theory
As anti-Aβ therapeutics continue to fail, allegations recently broke calling into question seminal research behind the hypothesis. While looking into claims of misconduct by AD drug developer Cassava Sciences, Vanderbilt neuroscientist and physician Matthew Schrag made a discovery: It appeared to Schrag that the pioneering research of Sylvain Lesné and Karen Ashe possibly contained tampered images of Western blots, a laboratory technique used to visualize proteins. This data formed the backbone of the argument that Aβ*56 - an oligomer of amyloid-β proteins - is responsible for the AD hallmark of memory loss. The 2006 paper has been cited by some 2,300 other studies over the past 16 years.
Despite the failure of these drugs (Biogen’s Aduhelm is a possible – though highly-scrutinized – exception), the pharmaceutical industry continues to cling to the theory. It’s no wonder why, given the astronomical resources that have been devoted to it. In 2021 alone, anti-amyloid research received nearly $300 million in support from the National Institutes of Health.
“I had thought that amyloid was dying 10 years ago,” Maccecchini said. “It does not die.” Maccecchini was perusing the booths at AAIC when she came across an Eli Lilly representative. She asked the individual why, with all of the failures in the space, she was still working in it. Her response? “Because Lilly is the only employer in town.”
“When you have put billions into something, unless that person resigns or dies, they’re not going to admit being wrong,” Maccecchini said.
She was unwavering in her position on anti-Aβ antibodies. “I would not use an antibody in an elderly person with an impaired brain if my life depended on it. It’s toxic. You’re killing these people earlier.” She also noted the perils of PET scans, which she said kills nerve cells.
The RNA-based Approach
Instead, Berwyn, PA-based Annovis is developing buntanetap, a small molecule that inhibits multiple neurotoxic proteins – tau, aSynuclein, TDP-43 and amyloid beta – at once. These proteins, she explained, are regulated by the same homologous region in messenger RNA (mRNA). This region, and only this region, binds to iron regulatory protein 1, a storage protein in the cytoplasm.
“When it’s bound, the mRNA is not translated; when it’s free, the mRNA is translated,” Maccecchini said. “When the mRNA gets over-translated, (leading to the aggregation of these proteins), our drug stops it because it keeps it bound.”
Buntanetap is currently being assessed in Phase III trials for Parkinson’s disease, and Annovis plans to kick off a Phase II/III trial in AD this Fall. The company also intends to file a grant to study the drug in Lewy body dementia, with potential grants for both Huntington’s disease and amyotrophic lateral sclerosis (ALS) also under consideration.
While Maccecchini believes buntanetap will be effective in stopping the progression of AD, she’s aiming higher.
“If you already have dementia, stopping it is nice, but you would like to get better, right?” she said. Eventually, while it is not possible today, Maccecchini envisions buntanetap being combined with stem cell therapy. “Even if we figure out how to make (stem cells) become neurons, they’ll die…because the brain has Alzheimer’s. But if our drug stops them from getting Alzheimer’s, then we can actually improve cognition.”
The HGF-MET Approach
In Bothell, Washington, Athira Pharma is developing fosgonimeton, a small molecule designed to enhance the activity of hepatocyte growth factor (HGF) and its receptor, Met, with the aim of impacting neurodegeneration and regenerating brain tissue.
Athira Chief Medical Officer Hans Moebius, M.D., Ph.D. explained that the origin of plaques is inside of neurons and that this is why anti-Aβ antibodies haven’t been effective to date.
“This is a lysosomal overload with amyloid fibrils and it originates inside neurons,” he told BioSpace. “These monoclonal antibodies…are entering the brain only to a minuscule fraction, about one percent. From this percent of monoclonal antibodies, I maintain that zero percent enter neurons. You cannot rescue neurons by hoping you can get your monoclonal antibody into the neuron.”
He shared that this “mechanistic consideration” has long led him to be critical of the amyloid hypothesis.
“It is amazing to me to see that we are following Einstein’s bon mot that repeating an experiment and hoping for a different outcome is the definition of stupidity,” he said. “At least what we should do is open our eyes a little bit and look with a different view on the disease.” In Moebius’ view, Alzheimer’s is “probably a family of diseases…and there are many pathophysiological processes ongoing.”
Moebius referred to HGF-Met as being “a key neurotrophic system to maintain homeostasis in the brain.” First discovered in the liver, HGF is now known to be ubiquitous.
“In Alzheimer’s disease, we know that in predilection areas like the frontal cortex and the hippocampus, we have a depletion of Met expression,” he said.
So, Athira is developing a pipeline of small molecules that aim to enter the brain and positively modulate the HGF-Met system. “Importantly, these small molecules are not agonists; they are modulators. We are not overruling the natural regulation; we can only boost the natural signal.” That, Moebius said, is a key point for safety.
Last week, Athira presented data from the Phase II proof-of-concept trial of fosgonimeton in mild-to-moderate AD. While the primary analysis did not meet statistical significance in the primary endpoint (event related potential (ERP) P300 latency), the company said the data gave meaningful insights into the drug’s potential effects. These include a statistically significant reduction in plasma levels of the validated neurodegeneration biomarker neurofilament light chain (NfL) in a pre-specified subgroup of monotherapy patients. This data will inform the larger LIFT-AD study, which has already enrolled 300 patients.
The Metabolic Hypothesis
For John Didsbury, Ph.D., president and CEO of T3D Therapeutics, amyloid could be part of the answer – but only part of it.
North Carolina-based T3D approaches AD as a brain-specific form of diabetes – type 3 diabetes –where aberrant metabolism is causing brain “starvation”, leading to loss of brain functions such as cognition. But, Didsbury said, “The metabolic hypothesis is not antithetical to the amyloid hypothesis. They’re highly interrelated and they perpetuate each other.”
Didsbury told BioSpace that three main causes of AD are interconnected in a “massive positive feedback loop”. These causes are metabolic changes, structural change (plaques and tangles) and stress.
Insulin, Didsbury said, is the single most important regulator of brain functions, including cognitive function. “Resistance to insulin precedes seeing Alzheimer’s symptoms,” he noted.
T3D set out to find a potential drug target that can bypass or correct the dysfunctional insulin signaling pathways causing this resistance. The company’s research culminated in T3D-959, which aims to break this positive feedback cycle by correcting these metabolic defects.
The drug acts to correct dysfunctional glucose energy metabolism and dysfunctional lipid metabolism found in the brains of Alzheimer’s patients. It targets multiple abnormalities, as opposed to just plaques and tangles. T3D-959 is currently being assessed in a Phase II clinical trial of mild-to-moderate AD patients.
While the company is currently blinded to the data, “We have encouraging results that are pointing to potential improvement, not just a slowing of decline, but potential improvement in cognitive performance and function and in executive function,” Didsbury shared. T3D anticipates reporting top-line results in early April 2023.
He added that these results seem to go against the “recently perpetuated mantra that you can never treat AD effectively if you’re at a mild-to-moderate stage.
“We vehemently disagree with that,” he continued. “Coming from large pharma, I believe that this new mantra that you have to go early before symptoms to treat…was brought on by large pharma as [a way of] rationalizing their failures.”
With anti-Aβ antibodies, Didsbury said, “at best, you are seeing just a slowing in decline.”
Is there still hope that anti-amyloid is the answer? Are we just targeting it the wrong way? More likely, it seems, Alzheimer’s is a complex disease process that requires an integrative approach.
