Annovis Bio: Against The Grain In Alzheimer's Disease
By Ben Comer, Chief Editor, Life Science Leader
What do Annovis Bio’s buntanetap, Pfizer’s Viagra, and Lilly’s GLP-1 drug Trulicity have in common? They could all end up being used together in combination as a new treatment focused on improving cognition in neurodegenerative diseases like Alzheimer’s and Parkinson’s, a project Annovis Bio founder and CEO Maria Maccecchini, Ph.D. is currently pursuing.
The rationale for such a project, explains Maccecchini, boils down to the human body’s need for glucose homeostasis, or the healthy regulation and circulation of sugar in the bloodstream. That combination work is in the earliest stages of development; Annovis Bio’s clinical programs with buntanetap as a single agent, in both Alzheimer’s and Parkinson’s diseases, have entered late-stage clinical trials.The company plans to initiate two pivotal Phase 3 studies, one in each disease. The pivotal Phase 3 study in Alzheimer’s disease will begin first, following a meeting with the FDA this month (October 2024).
In Maccecchini’s telling, she “ran into a guy at a neuroscience meeting that said his technology was dying, because he licensed it to a company that had died.” Maccecchini has a long-standing interest in neurology and was sitting on cash earned from her time as an angel investor, and the sale of her first company, Symphony Pharmaceuticals/Annovis, to Transgenomic in 2001. Posiphen (which later received the generic name buntanetap) had initially shown an ability to inhibit amyloid precursor protein, or APP.
But no one wanted to fund development of buntanetap, so Maccecchini put in the first $2 million, and then another $2 million, and “my salary for 10 years was $46,000,” she says. “I was lucky; I’d made money with my first company, and genomics had been good to me [as an investor].” Maccecchini ran a cerebrospinal (CFS) study, which was published in 2012. “What we found was that [in addition to inhibiting APP] buntanetap also inhibited tau and alpha-synuclein … that didn’t make sense to anybody, including me, but it did,” says Maccecchini. “So we kept going.” In January of 2020, weeks before COVID set in, Annovis Bio went public, and raised enough money to conduct two Phase 2 and two Phase 3 studies.
Amyloid Beta And Underpowered Clinical Studies
A few years ago, before the approval of Eisai/Biogen’s Leqembi and Lilly’s Kisunla, amyloid beta as the primary target for Alzheimer’s disease therapies seemed increasingly in question, due to clinical failures. Back then, “we were more honest,” says Maccecchini. “Now, there is desperation,” because Big Pharma put billions of dollars into developing and testing drugs targeting amyloid beta. “I actually think the overall understanding in the field hasn’t changed much … we still believe that there has to be something better.”
Five years ago, several companies had promising Alzheimer’s disease candidates in their pipelines, notes Maccecchini, including BioVie Pharma, T3D Therapeutics, Cassava Sciences, and Athira Pharma. “Those drugs might work, but [smaller companies] didn’t have the money” to do expansive, comprehensive clinical trials. “If I was Lilly, I would have done five studies in five populations, 500 patients each, at about $40 million each,” says Maccecchini. “Then, after discovering the population the drug worked in, I would have done a much larger study in that population.”
Smaller companies, including Annovis Bio, “don’t have that kind of money,” so “we do one study in a big population and say it only works in these patients, but we fail the primary endpoint.” It’s not that the drugs developed by BioVie Pharma or T3D Therapeutics, for example, don’t work, but that the studies were underpowered, says Maccecchini. “That’s just money, and Big Pharma doesn’t like us, because if they did, they would have to admit that maybe they’re doing something wrong.”
Maccecchini says Annovis Bio put together a KOL panel for its Alzheimer’s study, therapeutic area experts that will attend company meetings with the FDA (“at $650 an hour, which is ridiculous”) as well as KOL meetings before and after the FDA meeting. “These [KOLs hired by Annovis] are also in the Big Pharma groups, so I swallowed very hard and paid them whatever they want, and one of them attended the Eisai meeting, and [Annovis’s] buntanetap featured on Eisai’s list of molecules to watch,” says Maccecchini. “Another one said he was at the Lilly meeting, and buntanetap featured on the list of things to watch. So Big Pharma knows about us.”
Combination Therapy In Alzheimer’s And Parkinson’s Disease
The Annovis Bio thesis alluded to above — improving glucose homeostasis as a means of treating or preventing neurodegenerative disease — is supported by an increasing amount of research, with more on the way. And other companies, such as Intrinsic Medicine, are also taking a systems biology approach to neurodegeneration.
With a combination of buntanetap, Trulicity, and Viagra, Maccecchini hopes to improve glucose homeostasis, or in simpler terms, optimize sugar for the brain and other bodily functions. “We don’t have healthy diets, we eat too much sugar, and sometimes even if you are healthy, abnormal sugar levels can occur,” she says. “You need the right amounts of sugar and good circulation, which cleans out the brain, the liver, the kidneys, and you need happy nerve cells.”
In Parkinson’s disease, “alpha-synuclein deposits start in the gut, not the brain,” says Maccecchini. “They also start in the salivary glands and may start in the nose. This is why many Parkinson’s patients are constipated, and sometimes lose their senses of smell and taste.” The difference between Parkinson’s disease and Alzheimer’s disease, she says, is that Parkinson’s begins in the periphery — with aggregates that move to the brain, eventually causing dementia — whereas Alzheimer’s disease begins in the brain, and eventually moves out to the periphery.
The role of the gut-brain axis in neurodegenerative diseases, in terms of elucidating all of the specific mechanisms, remains mysterious. However, it is clear that microbiota play a role in disease. In China, Green Valley received approval in 2019 to market an Alzheimer’s disease “carbohydrate-based” drug called GV-971, or sodium oligomannate, which is a mixture of carbohydrates derived from brown algae. In April of 2020, just as COVID-19 closures were commencing, the FDA authorized an IND for a global Phase 3 study of GV-971. However, Green Valley halted the trial in May 2022, citing funding challenges and geopolitical instability; the drug remains available in China, and is listed on China’s National Reimbursement Drug List.
Keeping The Lights On
Asked about how she plans to keep pushing forward in such a difficult and expensive therapeutic area, Maccecchini says she will do whatever it takes. “I will pay my employees before I pay myself, and I will raise money at 30 cents with 100% warrant coverage if I have to,” she says. “I really don’t want to do that, of course, but I will do whatever I have to do” to make clinical progress.
As discussed above, funding drives clinical decision-making, and Annovis is pursuing symptomatic activity in Alzheimer’s and Parkinson’s disease first, because it’s a lot cheaper, says Maccecchini. “Then we’ll go after disease modifying … that would be the real cherry, if it works in symptomatic and disease modifying” therapeutic settings.
Smaller companies may have to carry the load, at least in the short term, when it comes to alternative treatment strategies for Alzheimer’s disease. Big Pharma is too invested to deviate away from amyloid beta, says Maccecchini. “If you have spent billions of dollars and built a whole plan to make antibodies, your bonus, and your whole group of 1000 people, depends on antibodies. Are you going to say, ‘I made a mistake?’”