'Very over sold': Biotech brags about PhII Alzheimer's data, but experts are underwhelmed
In a field now defined by Biogen’s Aduhelm — and the storm of controversy around it — what constitutes “industry-leading” data for an Alzheimer’s drug?
Alzheon, a little biotech developing an oral amyloid-clearing tablet, is taking a stab at it.
Reporting six-month data from a Phase II biomarker trial involving 84 patients, Alzheon announced that ALZ-801, or valiltramiprosate, spurred a 29% reduction in a biomarker called plasma p-tau181 — which it said is seven-fold greater than that triggered by other anti-amyloid antibodies. Paired with “significant improvement” in a memory test while not specifying how much, the numbers validate its approach and offer “a clear path forward with our molecules,” according to CEO Martin Tolar.
But a few experts who reviewed the press release at Endpoints News’ request dismiss the results as underwhelming and weak.
“Very over sold,” George Perry, the neurobiology chair at the University of Texas at San Antonio, wrote in an email.
The primary issue, he noted, is the lack of placebo controls in the study. Furthermore, Perry, a longtime skeptic of the amyloid hypothesis in Alzheimer’s, observed that Alzheon has constructed its argument using correlations that simply haven’t been proven.
Although companies have long tried to treat Alzheimer’s by getting rid of the amyloid plaques and tau protein tangles that build up in patients’ brains, most of those efforts have unsuccessful. In notable examples — such as Biogen’s controversial drug Aduhelm — companies have dramatically reduced patients’ amyloid levels, while showing inconsistent or negligible effects on cognition.
“There are NO studies that show reduction of any form of amyloid has cognitive benefit,” Perry said.
Tolar’s case is based on the premise that phosphorylated tau is produced in reaction to soluble amyloid oligomers, which are distinct from insoluble amyloid plaques. Thus, “the amount of damage of the brain that translates into clinical performance is actually linked to the levels of the p-tau. And also it dynamically correlates with the effective treatment.”
As a secondary outcome, Alzheon also measured patients’ performance on a learning and memory test called the Auditory Verbal Learning Test (RAVLT). Without disclosing the numerical improvement, the company said there is an improvement from baseline at week 26, with a p-value of 0.002.
When pressed, he declined to elaborate on the magnitude of benefit, choosing instead to talk about the burden Alzheimer’s patients face and the meaning of improvement.
“ADL is still the coin of the realm,” wrote Sam Gandy, the Mount Sinai professor of Alzheimer’s Disease Research, referring to a standard metric for activities of daily living. “If there is no meaningful functional benefit, I would be underwhelmed.”
Still, Alzheon does have its supporters. Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, called the results “impressive” and the trial “well designed, with a focus on patients with APOE4 — i.e., those at the highest risk.”
“I also want to note the mechanism of action is plausible and based on extensive science,” Fillit wrote in an email. “This approach has been in development for over 30 years, and was first tested by a biotech company based in Canada named Neurochem, which conducted a large Phase III trial of a related drug prior to the era of ‘modern’ biomarkers and clinical trial design.”
The NIH gave Alzheon a $47 million grant to run a Phase III trial, for which it’s enrolling patients. Tolar hopes the study, which will recruit around 1,000 patients and employ the gold-standard primary endpoint of ADAS-Cog 13, could serve as the basis for approval.
Reflecting on the controversy around Biogen’s Aduhelm, Tolar acknowledged the debate around the drug’s effectiveness and questioned the use of amyloid plaque removal as a surrogate endpoint.
“Yes, it’s been challenging, you know, because it’s been on the front page, and all over the media, these issues around Biogen and Aduhelm,” he said. “But, you know, again, I mean, I think we need to go and treat patients, you know, and have a very compelling evidence for efficacy.”