CTAD 2022: Pivotal Anti-Amyloid Data and New Pathways (Updated)

Rachelle Doody_Roche

Roche Global Head of Neurodegeneration Rachelle Doody/courtesy of Roche 

The key narrative at the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference this week has been the anti-amyloid approach, specifically, the safety profile of Biogen and Eisai’s lecanemab and the fall of Roche’s gantenerumab.

Maybe the most meaningful aspect, though, is that these are Phase III clinical trial results.

“We've never really had a conference where there's been a lot of excitement about results from clinical trials, and I think it reflects progress in the field …,” Howard Fillit, M.D., co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF) told BioSpace in ahead of the conference.

On Tuesday, Eisai and Biogen presented full data from the Phase III Clarity AD trial of lecanemab amidst mounting concerns about the monoclonal antibody’s safety profile.

In October, a study investigator attributed the death of a patient to lecanemab, and on Monday, the journal Science linked a second patient death to the experimental drug.

During the CTAD session, Marwan Sabbagh, M.D., a behavioral neurologist at the Barrow Neurological Institute, said "there were no ARIA [amyloid-related imaging abnormalities]-related deaths” in the randomized, placebo-controlled analysis.

Sabbagh did concede that two deaths were associated with cerebral microhemorrhages in the open-label extension phase of the study. One of these occurred in the context of a tissue plasminogen activator, while the other patient was on medication for atrial fibrillation, and had previously had pneumonia and experienced many falls.

In the core study and subsequent open-label extension study, rates of deaths with concurrent cerebral macrohemorrhage were 0.1% in both the placebo group (1/897) and the lecanemab group (2/1608), said an Eisai spokesperson in an email statement to BioSpace.

“Both cases had significant comorbidities and risk factors including anticoagulation contributing to macrohemorrhage or death. Therefore, it is Eisai’s assessment that the deaths cannot be attributed to lecanemab,” the spokesperson said.

Gantenerumab Postmortem Begins

On the opposite side of the relative success spectrum, Roche presented topline findings of the GRADUATE I and II studies of gantenerumab. Both Phase III trials failed to meet the primary endpoint of slowing clinical decline in people with early Alzheimer’s disease.

Patients treated with the monoclonal antibody showed a slowing of clinical decline in GRADUATE I and GRADUATE II of -0.31 and -0.19 respectively from baseline score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) – a relative reduction of 6 and 8%. Neither was deemed to be statistically significant.

Dr. Howard Fillit_ADDFAdditionally, the level of beta-amyloid removal that could be attributed to gantenerumab was lower than researchers expected.

Fillit pointed to the subcutaneous administration of gantenerumab as a potential reason for the low efficacy. 

“A difference in the way it was administered could account for some of the reasons for this evidence of efficacy with [gantenerumab], in addition to differences in immunochemistry,” he said.

Speaking with BioSpace prior to Roche’s Wednesday presentation, Rachelle Doody, M.D., Ph.D., global head of neurodegeneration, said this shouldn’t have been an issue based on prior studies of gantenerumab.

In the SCarlet RoAD and Marguerite RoAD open-label extension trials, the antibody “significantly reduced brain amyloid plaque”, Roche reported.

Doody added that as Phase III studies were unblinded less than three weeks ago, pharmacokinetic data is not yet available. Roche rapidly moved to get these topline data into the field “so that investigators and companies making decisions have...some of really the best data that are out there,” she said. 

“Much of what we're learning is moving in the same direction. There are differences, but the field is moving forward. We want to contribute to that.”

In a statement Wednesday, Fillit said the phase III trial results for lecanemab and gantenerumab presented at CTAD "demonstrate why optimal treatment of Alzheimer’s will require drugs that do more than clear amyloid plaques."

More Shots on Goal

Consequently, the anti-amyloid hypothesis isn't the only star of this show.

“I think this time, we're going to hear a lot of positive results on novel targets,” Fillit said. In fact, he said that 75% of drugs in development for Alzheimer’s do not target either amyloid or tau.

“It's a very exciting time for the field because of the diversity in drug targets being explored in clinical trials," he said.  

Thursday morning, Fillit will hosted a focus session entitled Beyond Amyloid and Tau: Emerging Solutions.

Fillit said he was excited about an approach being presented by Mitzi Gonzales, Ph.D., neuropsychologist and associate professor of neurology at UT San Antonio. 

The Phase IIa trial is assessing a senolytic therapy made up of the cancer drug Dasatinib plus Quercetin, a plant flavonol, that aims to kill senescent cells in patients with early Alzheimer’s. The trial is being done in conjunction with Miranda Orr, Ph.D., assistant professor, gerontology and geriatric medicine at Wake Forest University School of Medicine in Winston-Salem, NC.

Senescent cells accumulate with age and secrete molecules that contribute to chronic tissue dysfunction and disease. Thus, cellular senescence has recently emerged as a promising potential target in Alzheimer’s disease.

“I think we need, so to speak, more shots on goal with novel and innovative targets based on our understanding of the biology of aging,” Fillit said.

“Right now, we're going after the pathology of the disease – plaques and tangles--but I think we need to start going after the biology and, as a result, the pharmacology that addresses the altered biology with aging that occurs in Alzheimer's disease.” 

These biological pathways include inflammation, epigenetic and metabolic disorders and vascular problems that represent abnormal biology with aging, he said.

Treeway, a neurodegenerative-focused Dutch biotech, is studying oral edaravone (Radicava), in a Phase II trial for Alzheimer’s funded by ADDF. One of only three therapies approved for ALS in the United States, Fillit said edaravone works as “a kind of antioxidant”.

Back at Roche, the company is studying brain shuttle gantenerumab (BS-gantenerumab, RG6102), which leverages brain shuttle technology to transfer gantenerumab across the blood-brain barrier in hopes of increasing antibody concentrations in the brain.

“It’s a completely different molecule because it’s a bi-specific antibody,” Doody said. “One of the problems with all monoclonal antibodies, whether you give them subcutaneously or intravenously, is that only about 0.1 - 0.2% of the peripherally circulating antibody gets into the brain."  

With RG6102, the gantenerumab molecule is attached to an antibody that binds to the transferrin receptor. Transferrins are glycoproteins that bind to and mediate the transport of iron through blood plasma.

“One of the benefits [of transferrins] is that they are very present on capillaries. The capillaries going into the brain will then shuttle  [gantenerumab] actively into the brain,” Doody said. 

RG6102 is currently in Phase Ib/IIa studies, and Roche anticipates data in early 2024.

“If you move enough amyloid, you start to get the clinical signal. We’re getting to that phase where we're honing in on what amyloid targeting can do, but…we do believe that number one, we can do better, and two, that we can combine drugs," Doody said.

"That's one reason for remaining involved with multiple mechanisms of action," she noted.

In another mechanism of action, Janssen (Johnson & Johnson) opted to move forward with one of two Alzheimer’s vaccine candidates (ACI-35.030) from its partnership with AC Immune.

The Swiss biopharma company presented interim Phase Ib/2a data at CTAD Wednesday showing that ACI-35.030, a potential first-in-class anti-phosphorylated-Tau (pTau) vaccine, “rapidly leads to the strong and durable induction of antibodies specific for pathological forms of Tau such as pTau and its aggregated form, ePHF.” 

BioSpace will have continuing coverage of the highlights from CTAD. 

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