NE3107 does well in Phase 3 trial, despite protocol deviations

BioVie shares update about experimental therapy for mild-to-moderate Alzheimer's

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by Steve Bryson, PhD |

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NE3107, BioVie Pharma’s experimental oral therapy, was superior to a placebo at improving performance of adults with mild-to-moderate Alzheimer’s disease on all cognitive and functional assessments of a Phase 3 clinical trial, top-line efficacy data shows.

However, these differences failed to reach statistical significance due to a loss of the study’s statistical power associated with the exclusion of data from more than 80% of trial participants.

According to a BioVie press release announcing the six-month results, upon trial completion the company found “significant deviation from protocol and Good Clinical Practice violations at 15 sites,” with nearly all being located in one geographic area.

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“When multiple patients came in for an MRI scan on the same day, they ended up having the same result posted to their records,” Cuong Do, BioVie’s president and CEO, said in a recent webcast. “We saw evidence of copying and pasting clinical histories or medical records.”

Suzanne Hendrix, founder and CEO of Pentara, a biostatistics consulting firm that has supported many Alzheimer’s trials, said in the release that “patients in a particular demographic group … reportedly experienced cognitive improvements that were improbable scientifically, and inconsistent with the [course] of this disease.”

“We found ourselves victim of suspected coordinated improprieties at a level that none of us have seen in our careers. It’s just so unusual, there’s just no other way of describing it,” Do said in the webcast. “The company and the Alzheimer’s community at large are victim of this misbehavior that will delay us bringing this potentially valuable drug to patients,” he said.

These protocol deviations led BioVie to exclude from analyses all trial participants from these sites and “to refer them to the U.S. Food and Drug Administration (FDA) Office of Scientific Investigations (OSI) for further action,” the release stated.

While this profoundly reduced the number of evaluable patients, the company noted that NE3107’s cognitive and functional effects after six months resembled those reported in trials for the approved Alzheimer’s therapies Leqembi (lecanemab) and Aduhelm (aducanumab) after 18 months.

BioVie will work the FDA on adapting trial design

Based on the promising efficacy benefits, BioVie hopes to work with the FDA to use the trial’s adaptive design to allow the continued enrollment of patients to regain statistical power to detect significant differences between the NE3107 and placebo groups.

“The adaptive trial design gives us the flexibility to continue patient enrollment in the advancement of this potentially important treatment for AD [Alzheimer’s disease],” Do said.

People with Alzheimer’s accumulate toxic protein clumps called amyloid plaques and tau tangles in the brain, ultimately damaging and killing nerve cells. These aggregates are known to activate a pro-inflammatory molecule called NF-kappa-B, resulting in chronic neuroinflammation.

Neuroinflammation in Alzheimer’s also is thought to trigger insulin resistance, in which cells no longer respond to insulin. Problems in insulin responses affect the normal function of nerve cells, possibly contributing to Alzheimer’s dementia and progression.

How NE3107 works

NE3107 is an oral brain-penetrant molecule designed to block the activation of NF-kappa-B and ERK, another key regulator of inflammatory pathways. In animal studies and Phase 1 and 2 trials, the therapy safely lowered inflammation and insulin resistance and prevented neurodegeneration.

The Phase 3 trial, NM101 (NCT04669028), began enrolling adults with mild-to-moderate Alzheimer’s in 2021. Participants were assigned randomly to receive an oral capsule of either NE3107 or a placebo, twice a day for 30 weeks (about 7.5 months).

Anomalies observed at clinical trial sites

According to BioVie, analysis of trial data revealed anomalies at several clinical sites, such as inconsistent data patterns compared with historical data, missing data, large proportions of patients on a placebo showing improvement, and unusual data variability.

After excluding data from 358 of the total 439 participants, the researchers looked at the outcomes of the 57 of the remaining 81 patients who had completed the trial: 24 given NE3107 and 33 on a placebo.

Results showed there was a 68% improvement in cognitive abilities among NE3107-treated patients compared with those given a placebo, as assessed by the Clinical Dementia Rating-Sum of Boxes (CDR-SB). A 26% improvement with NE3107 was observed when cognition was measured with the Alzheimer’s Disease Assessment Scale-Cognitive Scale (ADAS-Cog 12). These two measures comprised the trial’s main goals.

The therapy’s superiority over a placebo also was seen in other measures of cognitive, functional, and behavioral performance.

When looking at 18-month data from Alzheimer’s trials of the approved antibody-based therapies Leqembi and Aduhelm, CDR-SB scores were improved by 22-27% and ADAS-Cog 12 scores by 25-27%.

NE3107 was generally safe and well tolerated, with headache being the most common treatment-related side effect (9.5% of patients). And, unlike the approved antibody therapies, NE3107 was not associated with brain swelling or bleeds.

NE3107 has ‘treatment advantage over placebo’

“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 [Alzheimer’s disease] without the associated safety concerns,” Do said.

CDR-SB scores among NE3107-treated patients correlated with changes in disease-related biomarkers, including the pro-inflammatory molecule TNF-alpha and damaging amyloid and tau protein forms. Biomarkers of neurodegeneration and cognitive decline also were reduced with treatment relative to a placebo.

Finally, NE3107-treated patients experienced a 4.66-year advantage in age deceleration relative to those on a placebo. Age deceleration refers to the difference between a patient’s chronological age and their biological age, as measured by DNA methylation. DNA methylation is a type of chemical modification to DNA that represents the most promising biological biomarker of age.

These findings meant that those who took NE3107 were, on average, nearly five years younger — biologically — than those in the placebo group.

“NE3107 is believed to be the first drug candidate to demonstrate this impact on DNA methylation and the aging process in a … placebo-controlled clinical,” BioVie stated.

The Phase 3 trial’s efficacy data “reaffirmed what has been seen in previous studies of NE3107 – which is that patients treated with this molecule appear to experience cognitive and functional improvements as measured by multiple assessment tools,” said Joseph Palumbo, MD, executive vice president of research and development and chief medical officer at BioVie.

“This data reinvigorates our ambition to further evaluate NE3107 and bring the Alzheimer’s community a differentiated treatment that is safe and has a meaningful impact on cognition,” he said.