Annovis Bio is developing an experimental drug called buntanetap for the treatment of Alzheimer’s disease and Parkinson’s disease.

Buntanetap, also known as posiphen, is characterized by a multimodal mechanism of action that targets neurotoxic proteins (amyloid beta, alpha-synuclein, and tau protein) thought to be responsible for pathophysiological processes in various neurodegenerative disorders.

Buntanetap therapy improves cognitive ability in Alzheimer’s disease and motor function in Parkinson’s disease.

The therapeutic benefits of buntanetap are claimed to be superior to those of other competing drugs, including aducanumab, masitinib, simufilam, and donanemab, in both potency and speed of action.

The success of the clinical evaluation of buntanetap will need to be confirmed by the phase 3 pivotal clinical trials that Annovis has already planned.


Buntanetap: Experimental Therapy for Alzheimer’s and Parkinson’s

The clinical trial NCT04524351 phase 1/2a (randomized, double-blind, placebo-controlled, multicenter) is testing experimental buntanetap in therapy for patients (age 45 and older) with early-stage (mild to moderate severity) Alzheimer’s disease or Parkinson’s disease.

  • Among the inclusion criteria for Alzheimer’s: a score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) scale of 0.5 or 1 and a score on the Mini-Mental State Exam (MMSE) scale ranging from 18–28. Cholinesterase inhibitors and/or memantine were allowed to be taken in a stable course for at least 12 weeks before screening.
  • For Parkinson’s: a score on the Hoehn and Yahr scale ≤ 4 and an MMSE score in the range of 18–30. Antiparkinsonian drugs, anticonvulsants, drugs for neuropathic pain, and mood-stabilizing psychotropic agents (e.g., lithium) were allowed to be taken in a stable course for at least 4 weeks before screening.

Participants received oral buntanetap in different doses or placebo daily.


Buntanetap for Alzheimer’s Disease

According to an interim analysis of Alzheimer’s patients in the first cohort (n=14), after 25 days of buntanetap therapy, there was an improvement in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) score, which measures cognitive ability and memory (word recall, following commands, orientation, praxis, etc.). The change in this score was 4.4 points, equivalent to a statistically significant 30% improvement from baseline (p=0.04). Relative to placebo, the improvement was 3.3 points, or 22% (p=0.13).

On the digit symbol substitution test (DSST) of the Wechsler Adult Intelligence Scale (WAIS), patients in buntanetap group showed a 23% improvement from baseline and a 16% improvement from placebo group (p<0.05). This test assesses speed of movement and speed of thinking.

Buntanetap has a favorable safety profile: the daily 80-mg dose of the drug does not cause any negative adverse events.

Just to get a better understanding of the efficacy of the treatment with buntanetap: according to a meta-analysis covering 52 clinical trials and nearly 20,000 patients with mild-to-moderate Alzheimer’s, the reduction in ADAS-Cog score in the placebo group averaged 5.5 points per year. In other words, buntanetap has come very close to curbing the progression of dementia in a clinically meaningful way.

According to Annovis, the clinical efficacy of buntanetap for treating Alzheimer’s is superior to that of all other approved and experimental drugs. And it appears to be true.

For instance, the monoclonal antibody aducanumab, backed by Biogen and Eisai (Japan), improved the ADAS-Cog13 score by only 1.4 points, and over a year and a half of continuous therapy involving monthly intravenous infusions of the drug.

French AB Science’s masitinib, administered twice daily for 24 weeks, improved the ADAS-Cog score by 1.46 points, or 1.04 points if a more rigorous analysis of the data is performed.

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Simufilam from Cassava Sciences, administered twice daily, improved the ADAS-Cog11 score by 1.6 points over 6 months.

Eli Lilly’s monoclonal antibody donanemab only slowed cognitive deterioration on the ADAS-Cog13 scale.


Donanemab: Possible Treatment for Alzheimer’s Disease

The amyloid hypothesis, being verified by Eli Lilly, is not about to go away. However, the therapeutic achievements are still quite modest.

Not to be forgotten is the drug Oligomannate (sodium oligomannate) approved in China in November 2019 to treat mild-to-moderate Alzheimer’s disease. After 36 weeks of administration Oligomannate twice daily, the ADAS-Cog12 score improvement was 2.70 points.


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Buntanetap for Parkinson’s Disease

According to an analysis of the results of Parkinson’s disease patients (n=54), after 25 days of buntanetap therapy, there were motor improvements on the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), which assesses the severity and progression of this disease.

Thus, the subjects who received buntanetap in doses of 10 or 20 mg showed an improvement of 3.59 points, or 16.5%, from baseline (p<0.01).

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Buntanetap resulted in a 17.1% improvement on the DSST of the WAIS relative to baseline and a 27.1% improvement on placebo (p<0.01).

According to an analysis of inflammatory markers relevant in Parkinson’s and Alzheimer’s, administration of buntanetap resulted in a statistically significant decrease in their levels:

  • complement component 3 (C3): −24.9% (p=0.0072)
  • chitinase-3-like protein 1 (CHI3L1, YKL40): −22.9% (p=0.0213)
  • soluble triggering receptor expressed on myeloid cells 2 (sTREM2): −28.2% (p=0.0108)
  • glial fibrillary acidic protein (GFAP): −34.6% (p=0.000001).


Buntanetap: What’s Next

With the favorable results already collected, Annovis intends to launch two phase 3 pivotal clinical trials that will definitively establish the therapeutic efficacy of buntanetap. One trial will enroll patients with early-stage Parkinson’s who demonstrate symptoms but are not yet taking any antiparkinsonian medications. The second will involve patients with Down syndrome who are facing Alzheimer’s.

The idea is that Down syndrome is caused by trisomy on chromosome 21, and the amyloid precursor protein (APP) gene is encoded in it, and therefore the risk of developing Alzheimer’s disease in such people is multiplied. For example, in patients aged 40 years and older, Alzheimer’s develops in 15% of cases, and in those aged 60 years and older, it occurs in 50-70% of cases. The study of buntanetap in this orphan population will allow a significantly faster and deeper understanding of the specific pathophysiological processes in Alzheimer’s eventually scaling the conclusions to the general population with this neurodegenerative disease.

Annovis anticipates that by the end of 2024, it will be able to submit one or even two New Drug Applications (NDAs) to the U.S. Food and Drug Administration (FDA) for the approval of buntanetap.

Moving forward, if all goes well, buntanetap will be tested in patients with a more advanced form of Parkinson’s and in the general population of patients with Alzheimer’s and the task of preventing these neurodegenerative disorders.

In parallel, Annovis is evaluating ANVS405, an intravenous formulation of buntanetap, which could prove useful in the acute treatment of brain injury and stroke.

Annovis expects that buntanetap, which has a multimodal mechanism of action, could become a qualitatively new treatment option for various neurodegenerative diseases, chronic and acute.

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Buntanetap: Mechanism of Action in Neurodegenerative Diseases

Small-molecule buntanetap (ANVS401), also known as posiphen, is a chirally pure (+) enantiomer of phenserine. Both compounds, developed by TorreyPines Therapeutics, were licensed to QR Pharma in 2008, which changed its name to Annovis Bio in June 2019.

The basic idea behind buntanetap is to pharmacologically target neurotoxic proteins such as amyloid beta, alpha-synuclein, and tau protein, which disrupt axonal transport of neurotransmitters and neurotrophic factors and slow synaptic transmission, thereby impairing neural activity in general. Such disturbances lead to activation of the immune system, which attacks nerve cells leading to neuroinflammation, degeneration, and death of nerve cells. The result is impaired cognitive and motor performance.

A clear example of how posiphen works is that it restores the impaired retrograde axonal transport speed of brain-derived neurotrophic factor (BDNF).

Many other experimental drugs against neurodegenerative diseases attack, as a rule, plaques, tangles, and other aggregates of neurotoxic proteins (and Lewy bodies in Parkinson’s) as the final stage of pathology. Buntanetap acts differently, as it prevents such neurotoxic cascades. No, buntanetap does not eliminate amyloid beta, alpha-synuclein, and tau — it reduces their levels, doing so in a clinically meaningful way, that is, before their concentrations acquire a toxic threshold.

When the brain is damaged, levels of neurotoxic proteins rise to fight the damage. When the damage is mild, these proteins eventually disappear, but when the damage is severe, their levels remain elevated, worsening the condition. Buntanetap tries to reverse the neurotoxic cascade. Since neurotoxic proteins are conserved (as they evolved and diverged, they retained one commonality), the action of buntanetap is very specific and does not affect normal proteins.

Posiphen and phenserine reduce amyloid precursor protein (APP) production by blocking its mRNA translation. Furthermore, while phenserine also inhibits acetylcholinesterase, posiphen does not. The molecules easily bypass the blood-brain barrier.

  • The proposed mechanism of action of buntanetap in inhibiting protein synthesis is related to the fact that it acts on the iron-response element (IRE) which is located in the 5′-untranslated region (UTR) of APP mRNA and which mediates the iron-dependent translational control of APP expression. For this purpose, buntanetap increases the affinity of iron regulatory protein 1 (IRP1) to IRE, and since IRP1 binding to IRE prevents mRNA release and its subsequent association with the ribosome, translation is inhibited.

Thus, buntanetap decreased APP and amyloid beta levels in neuronal cultures and brains of both wild-type and transgenic mice with Alzheimer’s disease model. [1] [2] Neuroprotective and neurotrophic properties of buntanetap, normalization of impaired memory, learning, and synaptic function have been shown in mouse models. [3] [4] [5]

Buntanetap similarly blocks translation of alpha-synuclein mRNA: in a transgenic mouse model with Parkinson’s disease, the molecule reduced alpha-synuclein expression in the brain and intestine and improved intestinal function. [6] [7] [8] [9]

Buntanetap reduces tau protein expression including phosphorylated one; this has been tested in a mouse model with Down syndrome. [10]

In a clinical trial of buntanetap among patients with mild cognitive impairment, it was found to significantly reduce levels of amyloid beta, alpha-synuclein, and tau protein, as well as inflammatory markers. [11]

Buntanetap also inhibits the expression of huntingtin (HTT) protein, mutations in the gene of which are responsible for the development of Huntington’s disease. [12]

In general, buntanetap can be referred to a new class of drugs called translational inhibitors of neurotoxic aggregating proteins (TINAPs).



Annovis Bio. Attacks Alzheimer’s disease and neurodegeneration by improving the information highway of the nerve cell axonal transport. Corporate presentation, January 2022. [PDF]

Annovis Bio. Positive biomarker data corroborate the positive efficacy data in two phase 2 studies with ANVS401 in Alzheimer’s and Parkinson’s patients. Biomarkers for Alzheimer’s disease. August 26, 2021. [PDF]

Annovis Bio. ANVS401. New Parkinson’s efficacy data. October 5, 2021. [PDF]

Annovis Bio. Phase 2 Alzheimer’s & Parkinson’s data. CTAD 2021. November 2021. [PDF]

Annovis Bio. Translational inhibition of neurotoxic aggregating proteins leads to efficacy in Alzheimer’s and Parkinson’s patients. CTAD 2021. November 2021. [PDF]

Annovis Bio. Attacks Alzheimer’s disease and neurodegeneration by improving the information highway of the nerve cell axonal transport. Corporate presentation, May 2021. [PDF]

Investigational drug brochure for posiphen. August 2019. [PDF]

Investigational drug brochure for posiphen. October 2015. [PDF]

Investigational drug brochure for posiphen. September 2009. [PDF]

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