Annovis Bio: Embracing Novel Approaches to Parkinson’s and Alzheimer’s Diseases

By Mark Terry
April 21, 2023

In a recent conference call and announcement, Berwyn, Penn.-based Annovis Bio discussed its progress in the clinic of its lead program, buntanetap, to treat Alzheimer’s disease (AD) and Parkinson’s disease (PD). It’s a bit unusual for a company to be testing the same drug for both those indications, but early studies are encouraging.

Part of the rationale is buntanetap inhibits the production of several neurotoxic brain proteins that are implicated in both diseases, specifically related to axonal transport, which leads to nerve cell death. The drug inhibits the synthesis of amyloid precursor protein (APP), Tau, and alpha-Synuclein. Many drugs in development and on the market for Alzheimer’s, such as Biogen’s Aduhelm (aducanumab) and Eisai and Biogen’s Leqembi (lecanemab), are antibodies against amyloid beta.

What makes buntanetap distinct is it is designed to inhibit the production of the toxic proteins before they form. As such, it inhibits all the major neurotoxic proteins associated with AD and PD.

“The reality is the latest data was interim data from a blind trial with only two months of data…. We are very encouraged by what we’ve seen and by the incredible recruitment in the Parkinson’s disease study,” Michael Hoffman, chair of Annovis Bio’s board of directors, said in a conference call.

Hoffman noted that the drug is very easy to take, which was responsible for a low recruitment failure rate. Buntanetap is an oral formulation.

“And we’re pleased we can finally share the Alzheimer’s data … which is completely supportive of the interim Phase II data.”

The patient recruitment for the Phase II/III trial of buntanetap for moderate AD now includes 27 activated sites with 38 patients having been screened. In addition, 13 patients have been randomized to receive one of three doses of buntanetap or placebo.

Maria L. Maccecchini, founder, president and CEO of Annovis, noted during the conference call that buntanetap has a “unique mechanism of action that works in both diseases. And we actually see an improvement in function.”

The drug inhibits translation of APP and AB in cultures. The drug doesn’t change mRNA levels but acts as a translation inhibitor. The company expects to publish research on its functionality and mechanism of action sometime this year.

Maccecchini also emphasized that earlier announcements of the company’s interim analyses were misunderstood, saying, “interim analysis gives probabilities, not data. It only gives a GO/NO GO determination. And it was GO.”

The ongoing Parkinson’s disease trial for the drug needs 450 patients. They have screened 540 patients with 385 accepted so far. There were complications with the study, with three times more patients treated in the U.S. than in Europe.

Maccecchini pointed out that this was complicated by too many bottles of the drug in Europe and not enough in the U.S. They have since been redistributed.

The drug focuses on four toxic proteins: beta amyloid, Tau, alpha-synuclein, and TDP43.

“All are toxic,” Maccecchini said. “We need to remove all four toxic proteins and that is what our drug does.”

To date, in animal studies and in earlier human trials, the drug has demonstrated increased axonal support, increased synaptic transport, reduced inflammation, healthy nerve cells, and improved cognition and motor function.

The results are slightly different from AD to PD. In early Alzheimer’s, there have been indications in people of increased cognition, memory and synaptic speed. In Parkinson’s, there was an improvement in motor function and coding speed. Coding speed refers to the results from Wechsler Adult Intelligence Scale IV (WAIS IV) Coding, which measures visual-motor dexterity, associative nonverbal learning, and nonverbal short-term memory.

The drug appears to protect nerve cells from dying. It also provides axonal transport. Axonal transport is responsible for neurotransporters, such as GABA (anxiety), Ach (cognition), dopamine (movement), serotonin (mood), and neurotropic factors such as NGF and BDNF.

Maccecchini said, “In Parkinson’s disease, there was a significant increase in both motor function and coding speed, which supports the ongoing Phase III trial. It is expected to recruit all its patients this trial and we hope to have data by Christmas.”

The company’s clinical development plans for the drug for Alzheimer’s disease include a symptomatic study with six weeks interim analysis expected in the third quarter. They are currently preparing a meeting request with the FDA to discuss full development for disease-modifying studies. The design would involve a basket study for advanced disease. “We want to test different groups of patients not currently in our studies,” Maccecchini said. “Our goal for the drug is to evaluate it for the whole symptomatic range.”

Their plans for PD are similar. Maccecchini said that in a very small study, the drug demonstrated a “highly statistically significant improvement in cognition against baseline, which gives us a lot of hope in a larger study.” In addition to a larger study, they hope to run a basket study in patients with a broader range of symptoms.

The Phase III PD study is already ongoing, as well as an ongoing Phase II/III trial in moderate AD.

Annovis Bio has a strong patent portfolio that runs to 2044. As of December 31, 2022, the company had a cash balance of $28 million with zero debt. The company raised an additional $8.7 million on April 11. Annovis recently brought on senior executives, “most with clinical experience,” Maccecchini noted. “We’re keeping our studies on track in a timely fashion.”

Buntanetap is also being developed for Lewy body dementia (LBD) and other diseases, such as glaucoma. Its ANVS405 is being developed for traumatic brain injury and stroke, and ANVS301 is being developed for advanced AD and dementia.

There are companies approaching both Parkinson’s Disease and Alzheimer’s Disease, typically focused on a single factor, such as Biogen and Eisai’s work on anti-beta-amyloid antibodies. Other companies, such as BioVie, focus on decreasing neuro-inflammation in Parkinson’s. Some companies, such as Syngle Therapeutics, target alpha-Synuclein.

Maccecchini said, “As far as I know, our focus on axonal transport is unique. It also affects inflammation, provides synaptic support, and affects alpha-synuclein. I am a strong believer that finally we have seven or eight companies that stand a chance. If a couple of us make it, it can open up the possibility of a combination. I’m happy to see the field has embraced novel approaches.”