Using outcomes such as the CDR-SB, ADAS-Cog12, MMSE, and ADCOMS, patients treated with NE3017 for 6 months demonstrated equal, if not greater, improvements than traditional antiamyloid therapies at 18 months.
Newly announced topline data from a phase 3 study (NCT04669028) of BioVie’s Alzheimer agent NE3107 showed beneficial treatment effects over placebo that were potentially equal to or greater than data reported from previously approved antiamyloid therapies. In addition, patients on the permeable anti-inflammatory insulin sensitizer saw an average of more than 5 years of age deceleration in comparison with placebo, becoming the first such agent to demonstrate this impact on DNA methylation, according to the company.1
The double-blind, parallel group, multicenter study began enrolling patients with mild to moderate Alzheimer disease (AD) in August 2021 during the COVID-19 pandemic when access to clinical sites was limited. After the trial was completed, BioVie identified significant deviation from protocol and Good Clinical Practice (GCP) violations at 15 sites, forcing the company to exclude these patients. The patients were referred to the FDA’s Office of Scientific Investigations and thus 81 patients remained in the modified-intent-to-treat (MITT) population.
In total, 57 patients of the MITT who completed the trial and were verified to take study drug from pharmacokinetic data made up the per-protocol population. Patients in the trial underwent 2 weeks of 5 mg and 10 mg BID dose titration followed by 26 weeks of 20 mg NE3017 twice daily vs placebo, randomized 1:1.
At the conclusion of the analysis, NE3017-treated patients demonstrated improved performance compared with placebo on several cognitive and functional assessments, which included the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog12), Mini-Mental State Examination (MMSE), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), ADCS-Clinical Global Impression of Change (GCIC), and AD Composite Score (ADCOMS). In contrast, those on placebo continually worsened on virtually all assessments as expected from the natural history of the disease.
"These data show NE3107’s treatment advantage over placebo to potentially be equal to or greater than data reported from clinical trials for the approved medications for AD without the associated safety concerns," Cuong Do, president and chief executive officer at BioVie, said in a statement.1 "The adaptive trial design gives us the flexibility to continue patient enrollment in the advancement of this potentially important treatment for AD, and we look forward to discussing our findings of NE3107’s magnitude of therapeutic impact with our potential partners."
Coming into the study, enrolled patients had CDR scores of 1-2 and MMSE scores between 14-24. After 6 months of treatment, those on NE3107 demonstrated a 68% improvement (difference, –0.95; P = .2278) in CDR-SB, 26% improvement in ADAS-Cog (difference, –0.94; P = .7212), 40% improvement in MMSE (difference, +1.02; P = .3181), 47% improvement in ADCS-ADL (difference, +3.08; P = .1620), 139% improvement in ADCS-GCIC (difference, –0.43; P = .2866), and 27% improvement in ADCOMS (difference, –0.03; P = .7063) in comparison with placebo. Notably, the betterment in CDR-SB among NE3017-treated patients appeared to correlate with change in tumor necrosis factor alpha, plasma phosphorylated tau, and the ratio of amyloid-ß42/40, all notable biomarkers in AD pathology.
To better understand NE3017’s treatment impact, investigators compared the 6-month results to 18-month data for previously approved antiamyloid therapies lecanemab (Leqembi; Eisai) and aducanumab (Aduhelm; Biogen). The comparator studies included were the phase 3 Clarity AD trial (NCT03887455) of lecanemab, the supportive data for its traditional approval, and the phase 3 EMERGE and ENGAGE trials (NCT02484547; NCT02477800) of aducanumab.
On CDR-SB, NE3017-treated patients at 6 months demonstrated a 27% and 22% greater improvement than lecanemab and aducanumab, respectively, at 18 months. Similarly, at the same time points, investigators observed a 25% and 27% greater progression on ADAS-Cog12 with NE3017 over lecanemab and aducanumab, respectively. MMSE data, available for NE3017 and aducanumab, favored NE3017 by 18%. On ADCS-ADL, the NE3017 group had a 36% better outcome at 6 months than lecanemab at 18 months. On ADCOMS, in comparison with lecanemab, NE3017 demonstrated a 23% greater improvement.
Age deceleration, assessed through the Horvath DNA methylation Skin Blood clock, showed that treated patients with NE3016 had an average of –5.66 years of age deceleration in comparison with placebo. BioVie noted it believes this is the first drug candidate to demonstrated this impact on DNA methylation and the aging process in a double-blinded, placebo-controlled trial.
"I am also very proud of the integrity our team displayed in taking immediate action to identify and report the potentially problematic sites to the FDA for independent investigation,” Do added.1 "Importantly, we recognize that along with the development of new and innovative therapeutics, our foremost responsibility in clinical testing is to protect the rights and well-being of study patients and the integrity of the clinical research process."
For more context, BioVie monitored blinded data over the course of the trial to track safety and ensure timely entry of data from the clinical site into the Electronic Data Capture (EDC), the official database submitted to the FDA for registrational purposes. Prior to the sites being frozen, the company completed several actions, including: modified the trial’s Statistical Analysis Plan to exclude the 6 sites with GCP and/or deviation from the analysis and notified the FDA’s Office of Scientific Investigation of the potential issues at the multiple sites with GCP and/or protocol deviation. Additionally, BioVie worked with the FDA to finalize CDR-SB and ADAS-Cog12 as the primary end points with an adaptive design that would allow to continue to enroll additional patients in the trial should statistical significance be missed because of the excluded patients from affected sites.
In a subgroup analysis, patients in the identified demographic on placebo significantly improved cognitively without any intervention, a finding that BioVie could not explain.
"The unblinding of topline efficacy data from the trial confirmed an unusual pattern we saw with the blinded data – that patients in a particular demographic group within the trial seemed to have a data pattern different from historical evidence for this demographic group," Suzanna Hendrix, founder and chief executive officer of Pentara, a specialized biostatistics firm that was used to review the blinded data, said in a statement.1 “Patients from this demographic group in this trial reportedly experienced cognitive improvements that were improbable scientifically, and inconsistent with the pathology of this disease. When sensitivity analyses were performed, we determined that the anomalous demographic data were associated with the previously identified anomalous sites located in the same geographic area."
The trial was originally to be 80% powered with 125 patients in each of the treatment and placebo arms; however, the unplanned exclusion of patients left the trial unpowered for the primary end points. Based on the efficacy signals observed, BioVie plans to work closely with the FDA to potentially employ the adaptive trial feature of the protocol to continue enrolling patients to achieve statistical significance.