“My hope is that within five years, we will be able to reverse more than 80% of early Alzheimer’s Disease, and that later, we will prevent it completely.”—Leroy Hood, MD, PhD, GEN, January 2021
Maria Maccecchini, PhD, is probably in the best position as anyone to understand Hood’s take on Alzheimer’s (AD). She once worked as a postdoc in Hood’s lab at Caltech. Maccecchini is also the president and CEO of Annovis Bio, which recently announced positive results from a double-blind, placebo-controlled, Phase II study of ANVS401, its lead oral drug candidate for the treatment of AD and Parkinson’s Disease (PD).
Patients treated for 25 days showed statistically significant cognitive improvement as measured by the Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11 (ADAS-Cog11). From baseline, ADAS-Cog11 improved by 4.4 points. Compared to a placebo group, ADAS-Cog 11 showed an improvement of 3.3 points.
The 11-part test is one of the most frequently used to measure impaired cognition in clinical trials for AD, according to Maccecchini.
“We previously reported that ANVS401 significantly increased speed, coordination, and motor function in PD patients in this trial,” she said. “We set up this study to measure the toxic cascade leading to nerve cell death and loss of function and its reversal in AD and PD. Since the study was powered to investigate changes in biomarker levels, not to demonstrate efficacy, we believe these results are that much more impactful.”
This is the first double-blind, placebo-controlled study that shows cognitive improvements in AD patients as measured by ADAS-Cog and functional improvements in PD patients as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS), added Maccecchini.
“The results from the first cohort of 14 AD and 14 PD patients, show that the drug is effective in both diseases,” she noted. “Seeing efficacy in both patient populations supports our hypothesis that the impairment of axonal transport, the information highway of the nerve cell, affects nerve cells in the same way in both diseases.
“The toxic cascade in neurodegeneration begins with high levels of neurotoxic proteins, which impair axonal transport, increase inflammation, and eventually lead to nerve cell death and permanent loss of cognition and function.”
Compared to other trials
Looking at other clinical trials, Biogen reported two years ago that aducanumab data from its EMERGE study, a double-blind, placebo-controlled large Phase III, showed an improvement of 1.4-points in ADAS-Cog13 over one year. And three months ago Cassava said its Simufilam showed a 1.6-point improvement in ADAS-Cog11 over six months in an open-label Phase II study.
The market responded to the Annovis Bio news by rewarding the company with a 127% rise (almost tripling) in share price to reach a record high of $60.00 and an increase of $230 million in value on the day of the announcement. Annovis Bio followed by reporting that it planned to raise $50 million by selling one million shares at $50 each.
GEN spoke to Maccecchini to discuss the clinical trial results along with the company’s future plans.
GEN: How would you rate the clinical trial results that were just reported?
Maccecchini: They are dramatic because of how we attack Alzheimer’s or Parkinson’s disease. The same approach is used whether we are dealing with frontotemporal dementia or PD. After 10 years of nobody really believing in what we were doing, we showed that a toxic cascade, including high levels of neurotoxic proteins, kills nerve cells. Amyloid-beta, tau, and alpha-synuclein are all toxic. If you just remove one, you still have the others. It so happens that the drug I licensed from the NIH, ANVS 401, has an extremely different mechanism of action compared to other approaches. It specifically inhibits the translation of all three neurotoxic aggregating proteins by targeting the conserved regions of each of their 5’ UTRs.
These neurotoxic proteins do their damage by inhibiting axonal transport from the brain to the periphery and other nerve cells. We have beautiful data that shows how ANVS 401 fully restores the speed of the transport of neuroinformation. So if you have sluggish cells, the information will move slower. Whatever you do will be slower. If the cells become normal, the information will move faster. That is the short-term effect. We knew from animals that the drug has a short- and a long-term effect. Short-term it improves axonal transport and long-term protects nerve cells from dying. In humans we observed that the drug improves cognition and motor skills after one month.
GEN: Where do you go from here? What are the next steps you plan to follow after these clinical trial results?
Maccecchini: So in one month we saw the first step, i.e., the improvement of axonal transport. In a year or two, when we do the longer-term studies in humans, we hope to see the second step—the drug will prevent nerve cell death. We have another 40 patients to go to finish the study. In addition, we were planning to measure 17 biomarkers per person covering the entire toxic cascade. I do not need 17 biomarkers because the current study showed us which ones provided the best data and information. Focusing on these select biomarkers will move the study along a little faster and at less expense.
We just applied for orphan drug indication for Alzheimer’s and Down Syndrome, and we are applying for breakthrough designation. In September, if we get approval to move into either Phase III or Phase II-B, we will start these trials later in the year.