BioVie blames protocol errors at trial sites for phase 3 Alzheimer’s drug fail as stock craters

BioVie has blamed "protocol deviations" at a number of clinical trial sites for the failure of a potential Alzheimer’s disease drug while claiming that the evaluable data still shows the candidate improves cognitive function.

As part of a phase 3 study of an anti-inflammatory insulin sensitizer called NE3107, BioVie originally enrolled 439 patients with mild to moderate Alzheimer’s disease across 39 trial sites from August 2021, the company explained in a Nov. 29 release. However, the study was completed in September this year, BioVie “found significant deviation from protocol and Good Clinical Practice violations at 15 sites (virtually all of which were from one geographic area),” the company said in a Wednesday release.

As a result, the biotech excluded all patients from these sites and referred them to the FDA’s investigations unit. That left just 81 patients in the "modified intent to treat" population, of which 57 were in the per-protocol population that included those who completed the trial and were verified to take NE3107, the company said.

The exclusion of the 15 trial sites meant that the study failed to hit its co-primary endpoints that assessed cognition and function. Instead, the company pointed to a subgroup of patients it chose to evaluate.

Despite amounting to less than a seventh of the originally enrolled trial participants, BioVie claimed that data from these 57 patients showed that NE3107’s advantage over placebo was “potentially equal to or greater” than approved Alzheimer’s therapies—namely Biogen and Eisai’s Leqembi and Aduhelm—“without the associated safety concerns.”

It’s a bold claim to make on the back of a late-stage failure and investors don't appear to be buying it. The company’s stock was trading down 64% at $1.81 per share in the opening hour of trading Wednesday from a Tuesday closing price of $4.99.

Still, BioVie stuck to its guns in the release, arguing that “NE3107-treated patients experienced a treatment advantage after six months that was equal to or greater than results reported from clinical trials for the approved Aβ monoclonal antibody treatments after 18 months.”

For example, on the clinical dementia scale rating called CDR-SB—one of the trial’s primary endpoints—the 24 evaluable patients who received NE3107 saw deterioration of 0.44 compared to 1.39 among the 26 evaluable patients who got placebo. BioVie compared this to a 0.45 deterioration after 18 months on Leqembi and 0.39 on Aduhelm.

The company also argued that patients who received NE3107 demonstrated an average of -5.66 years in age deceleration as measured by DNA methylation compared to those on placebo.

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

“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,” BioVie’s Chief Medical Officer Joseph Palumbo, M.D., said in the release. “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 company also drew on comments from Suzanne Hendrix, CEO of biostatistics consulting firm Pentara, to back up its claims that something unusual had taken place at those 15 trial sites. Namely, that patients receiving placebo still saw their Alzheimer’s improve.

“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,” Hendrix said.

“Patients from this demographic group in this trial reportedly experienced cognitive improvements that were improbable scientifically, and inconsistent with the pathology of this disease,” she added. “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.”

After all that, BioVie’s CEO Cuong Do is holding out hope that today’s unusual report doesn’t mark the end of the road for NE3107, a synthetic derivative of androstenetriol designed to modulate neuroinflammation and insulin resistance.

“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,” he added in the release.

As part of this, the company has brought on board a new CRO for any future trials.