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Gantenerumab Affects Key Alzheimer’s Biomarkers: DIAN-TU

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New data from the phase 2/3 Dominantly Inherited Alzheimer’s Network-Trials Unit (DIAN-TU) trial shows notable improvements in key Alzheimer’s biomarkers with one of the study’s novel drugs, gantenerumab, despite the overall disappointing failure of the trial to meet its primary endpoint of slowing cognitive decline.

The new findings show decreases in key Alzheimer’s disease biomarkers with gantenerumab which, “compared to placebo groups, indicate removing plaques with gantenerumab causes downstream benefits in tau and neurodegeneration biology in the dominantly inherited Alzheimer’s disease population,” study coauthor Randall J. Bateman, MD, director of the DIAN-TU and professor of neurology at Washington University, St. Louis, Missouri, told Medscape Medical News.

Furthermore, the data suggest “gantenerumab is effective in removing amyloid plaques and has the potential to slow or stop Alzheimer’s disease if given to asymptomatic patients in this rare population,” he said.

The findings were presented as part of the American Neurological Association’s ANA2020 Virtual Annual Meeting, held online this year because of the pandemic.

The DIAN-TU trial, launched in 2012 at 24 sites in the US and around the world targeting Alzheimer’s disease prevention, included 194 patients who were at-risk for or with mild symptoms of dominantly-inherited Alzheimer’s disease (DIAD), a rare type of AD that, unlike sporadic Alzheimer’s, is highly predictive of disease onset, yet has close similarities to the more common sporadic form in many clinical aspects.

Patients were randomly assigned and treated for an average of 5 years in the 7-year, double-blind trial, with one of two novel anti-amyloid-beta monoclonal antibodies, gantenerumab (Roche) or solanezumab (Lilly), or placebo.

As reported by Medscape Medical News, the discouraging overall results from the trial, reported in early 2020, showed no significant differences in a composite measure of cognitive decline in either of the treatment groups, compared with placebo.

However, with gantenerumab showing some encouraging effects with a dose escalation halfway through the study, ongoing research in an exploratory open label extension of the DIAN-TU trial is focusing on that drug, while solanezumab is no longer being offered in the extension trial.

Biomarkers Show Favorable Effects  

In addition, a summary of results on key biomarkers shows some highly significant effects of gantenerumab at 4 years, compared with baseline.

They include a significant reduction in amyloid plaques on PiB PET imaging (-0.641; P < .001), and changes in cerebrospinal fluid (CSF) amyloid-beta 42 (change from baseline 207.50; P < .001), CSF neurofilament light (NfL; -0.153; P = .024); CSF tau (-104.22; P < .001) and CSF phosphorylated-tau181 (-31.55; P < .001).

There were no significant changes in the corresponding biomarkers in the solanezumab arm at 4 years, with the exception of CSF amyloid-beta 42, which significantly improved (1341.4; P < .001), and CSF NfL, which, of note, significantly worsened during the trial (189.65; P < .01), Bateman reported.

“Gantenerumab improved tau and neurodegeneration biomarkers CSF tau, phosphorylated-tau and NfL, indicating reduction in downstream disease activity,” Bateman said.

Comparisons of gantenerumab with placebo show significant reductions in amyloid, measured with PiB-PET, with the drug (-13.61), while there was a significant increase in amyloid accumulations in the placebo group at year 4 (12.46; P < .001), for a relative decrease of 209% in amyloid plaques in the gantenerumab group vs placebo, overall, Bateman said.

Notably, the reductions in amyloid with gantenerumab were observed in symptomatic as well as asymptomatic dominantly inherited Alzheimer’s disease patients, and the effects accelerated with the introduction of an increase in the gantenerumab dose at about year 2.

No Cognitive Decline in Asymptomatic Group

Additional findings showed that while patients who were symptomatic at baseline (n = 66) or became symptomatic (converters; n = 19) had steady cognitive decline on measures of the Clinical Dementia Rating (CDR) over 4 years, those who were asymptomatic at baseline (n = 57), remained stable and, in many cases, even improved.

“People declined as expected if they were symptomatic, and there was no difference in the individual treatment groups,” Bateman said. “However, to our surprise, people did better or stayed stable on almost all of the measures if they were in the asymptomatic group.

“Asymptomatic nonconverters did not cognitively decline and unexpectedly improved, potentially due to practice effects,” he added.

Although the cognitive improvements were greater in the asymptomatic nonmutation carriers (n = 39), improvements were observed even in asymptomatic patients who were carriers of the mutation.

Importantly, the lack of a cognitive decline in the asymptomatic groups was seen across the gantenerumab as well as placebo groups, therefore the implications are unclear.

“We can’t interpret the cognitive effects of drug because there was no decline,” Bateman said.  

He noted that the ongoing DIAN-TU exploratory open label extension trial of gantenerumab may help to address the cognitive and clinical effects.

Dosing Increase Complicates Interpretation

Key limitations of the study include a small sample size, and a relatively short period to evaluate the effects of the drug dose increases — which could have made an important difference in the results, Bateman said.

“We up-titrated the target doses later in the trial, so the duration patients were on the target dose was relatively short and we therefore can’t say much about what would have been the effect if they had been on that dose for the duration of the trial,” he said.

Therefore, Bateman added that “although neither drug met the cognitive endpoint, that result is more of a null result than a negative result.”

Meanwhile, in the ongoing exploratory open label extension for gantenerumab, participants from the gantenerumab as well as solanezumab arms may be eligible for participation.

Roche has reported that it is continuing with two ongoing large phase 3 clinical trials of gantenerumab (GRADUATE 1 and 2) in people with sporadic Alzheimer’s disease.

Preparations are furthermore being made for the TAU NEXGEN trial to evaluate 3 different tau-based drugs with different mechanisms and targets for tau, Bateman said.

Another key encouraging finding from the DIAN-TU trial was the completion rate of nearly 100%, Bateman noted.

“This demonstrates the feasibility of comprehensive, long-duration prevention studies in this population,” he said.

Howard M. Fillit, MD, founding executive director and chief scientific officer at the Alzheimer’s Drug Discovery Foundation, commented that the biomarker effects, combined with the patterns seen with the increased dosing, are encouraging for gantenerumab.

“The findings give hope that in another trial, perhaps by using the highest dose possible, there will indeed be clinical effect,” he told Medscape Medical News.

“We see that there are encouraging effects on downstream biomarkers that are thought to be a result of amyloid beta toxicity…so you could say the drug ‘worked’ in the sense that it did hit its target,” he said.

Fillit added that, looking ahead, a key issue of interest will be the drug’s effects beyond dominantly inherited Alzheimer’s, in the much larger sporadic Alzheimer’s population.

“The hope would be that with the interesting results from this DIAN-TU population that a higher dose of gantenerumab, treated earlier in a sporadic Alzheimer’s disease population, might also work not only to further improve the biomarkers but also include clinical parameters like cognition and function,” he said.

Along with promising progress relating to the anti-amyloid antibody aducanumab, Fillit said research is making important headway.

“The bottom line is that by doing all of this really extensive human research, we’re refining and finding out how to go forward and we’re getting some consistency in the results that I think is pretty exciting,” he added.

The DIAN-TU trial received research funding from the National Institutes of Health (NIH), the Alzheimer’s Association, GHR Foundation, Anonymous Foundation, and the DIAN-TU Pharma Consortium. The trial’s pharmaceutical partners were Eli Lilly, Roche and Avid Radiopharmaceuticals. Bateman has relationships with Roche, AC Immune and Eisai. Fillit reports relationships with Alector, vTv Therapeutics, Lundbeck/Otsuka, Lilly, Biogen, Samus, and Pfizer.

American Neurological Association’s ANA2020 Virtual Annual Meeting. Presented October 8, 2020.

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