• Significantly higher rate of improvement in ADAS-Cog 11 scores in each treatment dose relative to placebo for patients with mild AD
• Improvement in cognition measured by ADAS-Cog 11 at three months is 3.3 points as compared to 0.3 for placebo, consistent with our previous Phase II AD/PD and Discover studies
• Plasma Tau protein levels are reduced, consistent with our previous Phase II biomarker data
• Based on the findings of this symptomatic study, Annovis plans to conduct a pivotal disease-modifying Phase III trial in biomarker-positive early AD patients

MALVERN, Pa., April 29, 2024 (GLOBE NEWSWIRE) -- Annovis Bio, Inc. (NYSE:ANVS) ("Annovis" or the "Company"), a clinical-stage drug platform company developing novel therapies for neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD), today announced the data from its Phase II/III Alzheimer study of buntanetap in mild to moderate AD patients. Based on these data, the Company plans to conduct a pivotal Phase III trial in biomarker-positive early AD patients.

Buntanetap is an oral molecule that selectively binds to an iron-responsive element in the mRNA of amyloid precursor protein (APP) and other neurotoxic proteins and inhibits their translation. Through this mechanism, buntanetap was shown to decrease the production of amyloid beta (Aβ), tau, alpha-Synuclein (αSYN), and TDP43.

Phase II/III Study

The Phase II/III study was a randomized, double-blind, placebo-controlled trial investigating the efficacy, safety, and tolerability of buntanetap in patients with mild to moderate AD. This was a dose-ranging study where patients received either one of three doses of buntanetap (7.5mg, 15mg, or 30mg) or placebo on top of their standard of care for 12 weeks. In this study, over 700 patients were screened, a total of 353 patients were enrolled, and 325 patients completed the study across 54 sites in the US. The study included mild to moderate AD patients whose Mini Mental State Examination (MMSE) scores at baseline ranged from 14 to 24. More information on the trial can be found on www.clinicaltrials.gov (NCT05686044).

Beyond safety, the trial assessed the changes in two co-primary endpoints: Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) and Alzheimer's Disease Cooperative Study Clinician's Global Impression of Change (ADCS-CGIC), which assess cognition and activities of daily living. The study monitored for safety and collected plasma to measure several biomarkers to assess the disease state, potential disease progression, and treatment effects.

ADAS-Cog 11 (Co-primary Endpoint) Shows a 3.3 Statistically Significant Improvement

We observed a significantly higher improvement in ADAS-Cog 11 scores in each treatment dose relative to placebo for patients with mild AD. The analysis focused on biomarker-positive early AD patients (MMSE 21-24, pTau217/tTau≥4.2%) found that ADAS-Cog 11 was highly statistically significant at all 3 dose levels and in the combined dose levels compared to placebo as well as to baseline (Figure 1). This objective measure of cognitive function confirms our findings from the two small Phase II studies that showed improvement in cognition in mild AD patients (Fang et al. JPAD 2023). The treatment response in the current study was not related to a patient's age or sex.

Note 1: AD biomarker field has fast accelerated in the past few years. When we initiated the study in January 2023, the gold standard for measuring Alzheimer's-related amyloid and tau biomarkers were CSF and PET scans. Clinically validated plasma biomarkers became commercially available in 2024 and have been shown to be similar or superior to CSF biomarkers (Ashton et al. JAMA 2024, Barthelemy et al. Nat. Med 2024, Meyer Alzheimer's Dement 2024).

Note 2: Our initial recruitment did not prescreen patients for AD biomarkers in plasma. When we became aware of issues from other AD studies with sites recruiting non-AD patients, we fast-tracked biomarker measurements by collaborating with C2N Diagnostics. This enabled us, when we unblinded the data, to tell which patients had confirmed AD and which did not (Ashton et al. JAMA 2024, Barthelemy et al. Nat. Med 2024, Meyer Alzheimer's Dement 2024). Out of 325 patients who completed the Phase II/III trial, 202 had a ratio of pTau217/tTau≥4.2% that indicates AD. We further subdivided the patient population into moderate (MMSE 14-20; 112 patients) and mild (MMSE 21-24; 90 patients) AD patients. These two selections were not pre-specified analyses.

At the end of 3 months of treatment, placebo group demonstrated slight improvement (LSM(SE), 0.26 (0.91)), but not significantly different from baseline. All three buntanetap treatment groups showed statistically significant improvement from their corresponding baseline (7.5mg improved 2.19 (0.87), p=0.013; 15mg improved 2.79 (0.81), p=0.001; 30mg improved 3.32 (0.82), P<0.001). Both 15mg and 30mg treatment groups also had a statistically significant improvement relative to placebo group (p=0.042 and 0.015 respectively). EOT- End of Treatment * P<0.05; ** P<0.01; ***P<0.001

Treatment Response is Highly Correlated to MMSE Score at Baseline

When we subdivided the baseline MMSE scores for patients positive for AD according to their pTau217/tTau >4.2% ratio, we observed a dose-dependent relationship to MMSE at baseline – the response to buntanetap treatment is more pronounced in mild AD patients than in those with more advanced AD. The response in the 30mg dose treatment group R2=0.17 (R² or the coefficient of determination), p<.001, indicates statistical significance of the MMSE score, which was not evident in the placebo group. Figure 2 confirms the efficacy of buntanetap as previously shown in Figure 1.

Three-Fold Increase in Number of Responders in Treatment Group vs. Placebo

A further look at responders versus non-responders showed a dose-dependent increase in the number of responders from placebo to 30mg. There was a three-fold difference in the proportion of participants who improved in the 30mg group relative to placebo (Table 1).

**Contrast with Placebo, p value < 0.01, *** Contrast with Placebo, p value < 0.001

Table 1. Distribution of responders and non-responders in placebo and 3 doses of buntanetap.

Data presented in Figures 1, 2 and Table 1 demonstrate the efficacy of buntanetap in early AD patients.

Other Study Endpoints

ADCS-CGIC

This study was designed to enroll 80 patients per group with minor expectations for a statistically significant outcome in ADCS-CGIC or ADCS-ADL. We measured both endpoints to assess a possible trend that could support a power analysis for the sample size in the next disease-modifying 18-month study.

During the trial, ADCS-CGIC in all groups of patients barely changed, with no statistically significant difference observed. The 15mg and 30mg buntanetap groups slightly improved in mild AD patients. The subjective nature of this assessment allowed for a greater placebo effect, particularly in the advanced Alzheimer's population, as patients and caregivers were likely hopeful for change.

ADCS-ADL

We observed a large placebo effect in ADCS-ADL, with 15mg and 30mg buntanetap groups showing similar improvements with no statistical difference between the groups. 

Biomarkers

In accordance with the mechanism of action of buntanetap, we observed a reduction in plasma tTau (total Tau) after treatment, providing further credence to buntanetap's efficacy and mechanism of action (Figure 3).
 

We plan to measure additional biomarkers for inflammation and axonal and synaptic functions.

Safety and Tolerability

Buntanetap was very well tolerated. The safety profile observed in this study was consistent with prior clinical trials, with comparable numbers of adverse events (AEs) between treatment and placebo groups. The majority of reported AEs were mild to moderate in severity. No serious AEs were related to buntanetap.

Summary

1. Buntanetap, a once-daily oral medicine with an exquisite safety profile, improves ADAS-Cog 11 score in a dose-dependent fashion to the mean of 3.3 points. The data is highly statistically significant in a subpopulation of early AD patients, confirmed by multiple data and biomarker analyses
2. Efficacy strongly correlates with disease stage at entry (as measured by MMSE)
3. Efficacy in the CGIC endpoint was not reached due to the limited number of patients and short trial duration
4. In accordance with the mechanism of action, buntanetap lowered tTau levels, suggesting a disease-modifying effect
5. As seen in all previous studies, buntanetap is safe and well tolerated.