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New York, NY – October 1, 2024 – Alzheimer’s disease (AD) has become a focal point in the pharmaceutical industry as recent drugs such as Leqembi and Kisunla have received U.S. Food and Drug Administration (FDA) approval. However, while these treatments may slow cognitive decline in AD patients, they do not actually improve cognition, a critical target for the millions suffering from the progressive disease. In addition, GLP-1 (glucagon-like peptide-1) drugs, which were originally developed to manage type 2 diabetes and since have seen significant effectiveness in treating obesity, have also shown potential in the treatment of Alzheimer’s. However, there is no molecule or a combination of molecules that enhance cognitive functions. Thanks to innovative approaches by companies such as Annovis Bio Inc. (NYSE: ANVS) (profile), there is reason to be optimistic about potential future breakthroughs in the AD space. Annovis has completed early research with compelling results utilizing its lead drug, buntanetap, in combination with popular drugs approved for other indications Broadly speaking, there is ample reason to be bullish on new treatments for a variety of significant diseases, including AD and obesity, as companies such as Eli Lilly (NYSE: LLY), Pfizer Inc. (NYSE: PFE), Novo Nordisk (NYSE: NVO) and AbbVie Inc. (NASDAQ: ABBV) are making investments and progress on historically hard-to-treat diseases.

• Annovis is at the forefront, testing buntanetap in pivotal clinical trials as a therapy for Alzheimer’s and Parkinson’s diseases (PD).
• Company has filed three new patents protecting combinations of buntanetap with drugs such as Trulicity and Viagra, which work synergistically to improve cognition.
• Double combinations of buntanetap with Trulicity and Viagra, as well as a triple combination of all three drugs, are prepared to enter phase 3 clinical trials.

Click here to view the custom infographic of the Annovis Bio editorial.

Buntanetap vs. AD

Annovis Bio Inc. (NYSE: ANVS) is at the forefront of the movement to develop new safe and effective drugs for neurodegenerative diseases, including AD. The company has long pursued the goal to improve the health of nerve cells and, in the process, improve cognition in neurodegenerative disorders. The company’s lead drug candidate, buntanetap, has completed late-stage AD and PD clinical trials and was shown to be efficacious in both indications.

Earlier this year, Annovis announced promising results from its phase 2/3 clinical trial of buntanetap as an oral therapy for early AD. The study involved 353 patients and assessed buntanetap’s efficacy on top of standard of care medications as well as its safety. The trial demonstrated dose-dependent cognitive benefits in each treatment dose compared to placebo in patients with early Alzheimer’s, with the 30mg dose showing the most improvement, as measured by the AD Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11).

The data was consistent with previous phase 2 AD/PD (NCT04524351) and DISCOVER (NCT02925650) studies. Additionally, buntanetap was shown to reduce plasma biomarkers associated with the disease, including neurofilament light (NFL, axonal biomarker), glial fibrillary acidic protein (GFAP, inflammatory biomarker) and tau. Based on these findings, Annovis plans to conduct a confirmatory phase 3 trial in biomarker-positive early AD patients, the last step before filing a New Drug Application (NDA) for buntanetap as a symptomatic treatment.

Most recently, the company took an extra step by combining this drug with available treatments that treat the cognition issue more holistically. In particular, Annovis began to explore a combination of buntanetap with Trulicity(R) (dulaglutide) or Viagra(R) (sildenafil), or even a combination of all three. Each of these drugs brings its own set of cognitive benefits. Trulicity, a glucagon-like peptide-1 (GLP-1) agonist, helps restore glucose metabolism in the brain while Viagra improves cerebral blood flow. When complemented by buntanetap, which inhibits the production of neurotoxic proteins in the brain, such as amyloid beta, tau, alpha-synuclein and TDP-43, and improves the flow of information, these combinations enhance cognition beyond the levels seen in healthy mice and have the potential to enhance cognition in patients.

Buntanetap + Combinations vs. AD

Last month, Annovis released new preclinical data showing a synergistic effect between buntanetap and dulaglutide (Trulicity) in a mouse model of AD. Dulaglutide was selected due to its superior blood-brain barrier permeability, enhancing its ability to work with buntanetap. While buntanetap alone restored cognitive function to 100% and dulaglutide to 80%, the combination of the two compounds improved cognitive function beyond levels in healthy controls by an estimated 16%, reinforcing management’s contention that combining therapies can amplify treatment effects.

This data is the very first evidence of a treatment that not merely restores cognition back to normal levels but exceeds them.

“We are excited to see that buntanetap significantly amplifies the effects of dulaglutide on memory and learning, with a 6- to 10-fold increase in efficacy,” said Annovis Bio founder, president and CEO Maria Maccecchini, PhD, regarding the study results.

Amping up Nonconventional Approaches

GLP-1 agonists

GLP-1 drugs were originally developed to manage type 2 diabetes by mimicking a hormone that stimulates insulin release and regulates blood sugar levels. Drugs such as semaglutide and liraglutide have been highly successful in helping diabetic patients control glucose levels, as they improve insulin sensitivity and slow digestion, reducing blood sugar spikes after meals. However, during clinical trials, researchers noticed an additional benefit: significant weight loss. This discovery led to the approval of GLP-1 drugs such as Wegovy and others for obesity treatment, as they help suppress appetite and enhance the body’s ability to burn fat, offering new hope for millions struggling with weight management. Further, GLP-1 drugs are showing signs to reduce the risk of heart disease, kidney disease and stroke.

Recently, GLP-1 drugs have shown early promise in the treatment of AD. Studies suggest that these medications may protect the brain from damage related to Alzheimer’s by reducing inflammation, improving insulin signaling in the brain and enhancing neuroplasticity. According to phase 2b clinical trial data reported at the Alzheimer’s Association International Conference(R) 2024 in Philadelphia in July, the GLP-1 compound liraglutide (Victoza) was shown to minimize shrinking in specific parts of the brain responsible for memory, learning, language and decision-making by nearly 50% compared to placebo.

PDE5 inhibitors

PDE5 inhibitors represent another promising class of molecules with potential benefits for AD patients and individuals experiencing cognitive decline. Known for their potent anti-hypertensive effects, PDE5 inhibitors are commonly used to treat conditions such as erectile dysfunction (ED), where smooth muscle relaxation is beneficial. Currently, there are four oral PDE5 inhibitors available in the United States for the treatment of ED: sildenafil (Viagra, Pfizer), vardenafil (Levitra[R]/Staxyn[R]/, Bayer), tadalafil (Cialis[R], Eli Lilly), and avanafil (Stendra[R], Vivus).

Preclinical studies suggest that PDE5 inhibitors can enhance synaptic function and improve cognitive abilities, while real-world patient data suggest they can reduce the risk of dementia. One notable example is sildenafil (Viagra), which has shown encouraging results in improving cerebral blood flow, highlighting its potential therapeutic value in neurodegenerative diseases like Alzheimer’s.

A Cleveland Clinic study has supported sildenafil’s potential as an AD treatment. In the study, millions of de-identified insurance claims from two independent patient databases were analyzed, indicating a 30–54% reduced prevalence in AD diagnoses among patients who took sildenafil compared to those who did not.

“In brain cells from Alzheimer’s patients, researchers also showed that sildenafil lowers levels of neurotoxic tau proteins, which are known to be associated with AD when they build up,” stated the Cleveland Clinic report. “They also found that neurons treated with sildenafil expressed genes related to cell growth, improved brain function, reduced inflammation and other processes known to protect against the neural degeneration associated with Alzheimer’s disease.”

This potential neuroprotective effect of GLP-1 agonists and PDE5 inhibitors open new doors for attacking AD from multiple angles ensuring a more holistic approach to developing novel treatments.

Protected IP

Annovis has taken the requisite steps to extend its intellectual property. This week, the company filed three new patents for innovative combination therapies involving buntanetap. These patents cover the combination of buntanetap with Trulicity, Viagra or a combination of all three, creating a unique multifaceted approach to tackling neurodegeneration.

It’s a novel approach with unprecedented opportunity considering AD is one of the most common neurodegenerative diseases in the United States, impacting approximately 6.7 million Americans, with expectations that the number will reach 13.8 million by 2060 without any new medical breakthroughs.

Speaking to the importance of the patents and the company being successful in its mission, Maccecchini commented, “Our early data suggests a strong synergistic effect from combining these drugs, resulting in significant cognitive enhancement. The combination of buntanetap with Trulicity and Viagra not only has the potential to restore cognition to healthy levels, but also to improve it beyond normal, offering new hope in the fight against dementia. Since buntanetap has completed phase 3 studies as a standalone treatment, and both Trulicity and Viagra are FDA approved, these combinations are well positioned for phase 3 human trials.”

Key Players

There are certain diseases and health conditions that for decades have gone grossly underserved because of the extreme challenges related to developing new drugs. However, sometimes a breakthrough happens that moves the needle, and majors start seeing the potential return on investment as a development catalyst. Neurodegenerative diseases certainly fit into this category, as do GLP-1 and PDE5 drugs, with respect to the vast diversity they are showcasing in recent years.

Eli Lilly and Company (NYSE: LLY), which has a portfolio of neuroscience, GLP-1 and PDE5 drugs, including being the owner of Trulicity and tadalafil (Cialis), is also spearheading new approaches for Alzheimer’s. In July, the FDA approved Kisunla(TM) (donanemab-azbt, 350 mg/20 mL once-monthly injection for IV infusion), Lilly’s medicine for adults with early symptomatic AD, which includes people with mild cognitive impairment (MCI) as well as people with the mild dementia stage of AD, with confirmed amyloid pathology.

Pfizer Inc. (NYSE: PFE), the owner of sildenafil (Viagra), is also advancing a novel GLP-1 candidate, danuglipron, for the treatment of adults with obesity and without type 2 diabetes. The company has released topline data from its phase 2b clinical trial, which showed the study met its primary endpoint demonstrating statistically significant change in body weight from baseline. “We believe an improved once-daily formulation of danuglipron could play an important role in the obesity treatment paradigm, and we will focus our efforts on gathering the data to understand its potential profile,” said Pfizer R&D chief scientific officer and president Mikael Dolsten, MD, PhD.

Novo Nordisk (NYSE: NVO) is the owner of liraglutide (Victoza), the aforementioned drug candidate that showed some impressive data in a phase 2b clinical trial for AD. It is right on point to the diverse use of a medication with its roots in diabetes. Victoza is a once-daily noninsulin medicine that lowers blood sugar and A1C approved for adults and children 10 years of age and older with type 2 diabetes. It also is for adults with type 2 diabetes with known heart disease where it has been shown to reduce the risk of major cardiovascular events such as heart attack, stroke, or death.

AbbVie (NYSE: ABBV) recently announced positive topline results from its pivotal phase 3 TEMPO-1 trial for tavapadon as a monotherapy in early Parkinson’s disease. “The TEMPO-1 data, coupled with the previously reported TEMPO-3 adjunctive trial findings, further support the potential of tavapadon for people living with Parkinson’s disease,” said AbbVie SVP, immunology, neuroscience, eye care and specialty development, Primal Kaur, MD. “This marks a significant step forward in our commitment to enhancing our neuroscience portfolio following the strategic acquisition of Cerevel Therapeutics and further demonstrates our dedication to supporting patients at all stages of this challenging neurological condition.”

Annovis Bio and other leading pharmaceutical companies are driving progress in an array of serious disease treatments, with innovative combination therapies showing promising results for AD patients. As breakthroughs continue, there is growing hope for new treatments that not only slow disease progression but also improve cognitive function, offering renewed optimism for millions of patients.

For more information about Annovis Bio Inc. (NYSE: ANVS), please visit Annovis Bio Inc.

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