|BioVie Announces Efficacy Data from Phase 3 Trial of NE3107 in Patients with Mild to Moderate Alzheimer’s Disease
|By: GlobeNewswire - 29 Nov 2023
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Positive Trending Data from 57 Per-Protocol Patients Suggest NE3107 is Biologically Active and May Have Impact on Cognitive, Functional, and Biomarker Endpoints
Sponsor Identified Issues Relating to Significant GCP Violations and Protocol Deviations, Which Allowed for Data from Only a Subset of Enrolled Patients to be Included in the Efficacy Analysis; Sites Suspected of Improprieties Have Been Referred to FDA
Due to Exclusions, the Primary Efficacy Endpoint Missed Statistical Significance; Adaptive Feature of Trial May Allow the Company to Continue Enrolling Patients to Reach Statistical Significance for Registrational Purposes
Management to Host Conference Call at 8:30 AM ET Today to Discuss Data
CARSON CITY, Nev., Nov. 29, 2023 (GLOBE NEWSWIRE) -- BioVie Inc., (NASDAQ: BIVI) (“BioVie” or the “Company”) a clinical-stage company developing innovative drug therapies for the treatment of neurological and neurodegenerative disorders and advanced liver disease, today announced positive analysis of unblinded, topline efficacy data from its Phase 3 clinical trial (NCT04669028) of NE3107 in the treatment of mild to moderate Alzheimer’s Disease (AD).
Data from evaluable patients show NE3107’s treatment advantage compared to placebo may be equal to or greater than the benefit from approved AD monoclonal antibodies. NE3107-treated patients also experienced a 4.66-year advantage in age deceleration vs. placebo as measured by epigenetics/DNA methylation Skin Blood Clock.
The trial started during the COVID-19 pandemic when access to clinical sites was limited and enrolled a total of 439 patients through 39 sites. Upon trial completion, the Company found significant deviation from protocol and Good Clinical Practice (GCP) violations at 15 sites (virtually all of which were from one geographic area). This highly unusual level of suspected improprieties led the Company to exclude all patients from these sites and to refer them to the U.S. Food and Drug Administration (FDA) Office of Scientific Investigations (OSI) for further action. After these exclusions, 81 patients remained in our Modified Intent to Treat (MITT) population, 57 of whom were in the Per-Protocol population which included those who completed the trial and were verified to take study drug from pharmacokinetic (PK) data.
“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,” said Cuong Do, BioVie’s President and CEO. “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. 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. 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.”
“The unblinded topline efficacy data from 57 per-protocol participants 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 Dr. Joseph Palumbo, Executive Vice President, R&D and Chief Medical Officer. “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.”
“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. Patients from this demographic group in this trial reportedly experienced cognitive improvements that were improbable scientifically, and inconsistent with the pathology of this disease,” stated Suzanne Hendrix, Founder & CEO of Pentara, a specialized biostatistics consulting firm that has assisted dozens of AD clinical trials. “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.”
Conference Call & Webcast
The NCT04669028 Trial – Background & Corrective Actions
The NCT04669028 trial is a Phase 3, double-blind, randomized, placebo-controlled, parallel group, multicenter study of NE3107 in patients who have probable mild- to moderate-AD withs cores on CDR 1-2 and MMSE 14-24. The study has co-primary endpoints looking at cognition using the Alzheimer’s Disease Assessment Scale-Cognitive Scale (ADAS-Cog 12) and function using the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Patients went through two weeks each of 5 mg and 10 mg BID dose titration followed by 26 weeks of 20 mg twice daily vs. placebo, randomized 1:1.
Data Review and Audit
In parallel, some sites started to complete their patient-facing activities in early summer 2023, which created the first opportunity for BioVie to start the data verification and assessment process. The process surfaced unusual data patterns and deviations from expectations (missing data, suspected copied/pasted MRI results, etc.), which led the Company to retain two new CROs to conduct a multi-step process that entailed quality control (QC) visits at all sites, performing source data verification (SDV) on 100% of the documents used in the clinical sites to ensure what was notated on paper during patient visits was accurately reflected in the EDC, and auditing the sites. This extensive, multi-month process concluded when the Company received the final report identifying six sites that appeared to have a large number of deviations from the study protocol and Good Clinical Practices (GCP).
As the top-line efficacy data was unblinded and PK data became available, the pre-specified demographic subgroup analyses showed that patients in the identified demographic on placebo significantly improved cognitively without any intervention – a finding that cannot be explained scientifically. Furthermore, the pre-specified anomalous sites vs. others revealed a similar scientifically improbable and that these 9 sites are in the same single geographic area. It turned out that virtually all of the patients in the identified demographic group were associated with the 9 anomalous sites. Consistent with our pre-specified statistical plan, these 9 additional sites were also excluded to arrive at our Modified Intent to Treat population, which became underpowered with just 81 subjects. Out of an abundance of caution, we also referred these 9 additional sites to the FDA’s OSI. It should be noted that virtually all of the 15 sites referred to the FDA were in the same geographic area.
Adaptive Design & Next Steps
NE3107 is an oral, small molecule, blood-brain permeable anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase. BioVie’s Phase 3 trial is the largest study to date to evaluate the safety and efficacy of NE3107 in patients with AD. NE3107 is the only anti-inflammatory agent currently in phase 3 development for AD. Consistent with the proposed anti-inflammatory and insulin-sensitizing properties of NE3107, this phase 3 study was designed to confirm the efficacy and safety of NE3107 treatment in patients with probable AD.
BioVie Inc. (NASDAQ: BIVI) is a clinical-stage company developing innovative drug therapies for the treatment of neurological and neurodegenerative disorders and advanced liver disease. In neurodegenerative disease, the Company’s drug candidate NE3107 inhibits inflammatory activation of ERK and NFkB (e.g., TNF signaling) that leads to neuroinflammation and insulin resistance, but not their homeostatic functions (e.g., insulin signaling and neuron growth and survival). Both are drivers of Alzheimer’s and Parkinson’s diseases. The Company is conducting a Phase 3 randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate NE3107 in patients who have mild to moderate Alzheimer's disease (NCT04669028). Results of a Phase 2 investigator-initiated trial (NCT05227820) showing NE3107-treated patients experienced improved cognition and biomarker levels were presented at the Clinical Trial in Alzheimer’s Disease (CTAD) annual conference in December 2022. An estimated six million Americans suffer from Alzheimer’s. A Phase 2 study of NE3107 in Parkinson’s disease (NCT05083260) has completed, and data presented at the International Conference on Alzheimer's and Parkinson's Disease and Related Neurological Disorders conference in Gothenburg, Sweden in March 2023 showed significant improvements in “morning on” symptoms and clinically meaningful improvement in motor control in patients treated with a combination of NE3107 and levodopa vs. patients treated with levodopa alone, and no drug-related adverse events. In liver disease, the Company’s Orphan drug candidate BIV201 (continuous infusion terlipressin), with FDA Fast Track status, is being evaluated and discussed with guidance received from the FDA regarding the design of Phase 3 clinical testing of BIV201 for the treatment of ascites due to chronic liver cirrhosis. The active agent is approved in the U.S. and in about 40 countries for related complications of advanced liver cirrhosis. For more information, visit http://www.bioviepharma.com/.
This press release contains forward-looking statements, which may be identified by words such as "expect," "look forward to," "anticipate" "intend," "plan," "believe," "seek," "estimate," "will," "project" or words of similar meaning. Although BioVie Inc. believes such forward-looking statements are based on reasonable assumptions, it can give no assurance that its expectations will be attained. Actual results may vary materially from those expressed or implied by the statements herein due to the risk that unblinded data is not consistent with blinded data, the Company's ability to successfully raise sufficient capital on reasonable terms or at all, available cash on hand and contractual and statutory limitations that could impair our ability to pay future dividends, our ability to complete our pre-clinical or clinical studies and to obtain approval for our product candidates, our ability to successfully defend potential future litigation, changes in local or national economic conditions as well as various additional risks, many of which are now unknown and generally out of the Company's control, and which are detailed from time to time in reports filed by the Company with the SEC, including quarterly reports on Form 10-Q, reports on Form 8-K and annual reports on Form 10-K. BioVie Inc. does not undertake any duty to update any statements contained herein (including any forward-looking statements), except as required by law.
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1 CDR-SB = Clinical Dementia Rating-Sum of Boxes; ADAS-Cog12 = Alzheimer’s Disease Assessment Scale-Cognitive
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