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Topline Result for First DIAN-TU Clinical Trial: Negative on Primary

DIAN participants and investigators today are grappling with difficult news. A topline analysis of the first Phase 2/3 clinical trial that the DIAN-TU trials platform mounted for carriers of dominantly inherited Alzheimer’s disease mutations showed that both of the trial’s investigational drugs missed the primary endpoint. That endpoint would have been a statistically significant difference between drug and placebo on the DIAN Multivariate Cognitive Endpoint (DIAN-MCE), a composite of four cognitive tests developed by DIAN for this stage and type of Alzheimer’s disease. The trial evaluated two investigational anti-amyloid drugs, Roche’s gantenerumab and Lilly’s solanezumab, against placebo and additional progression data drawn from the DIAN observational study.

“The initial negative results from the DIAN-TU trial regarding gantenerumab and solanezumab are terribly disappointing for the families and investigators who have committed so much time and effort to the trial over the past five years,” Catherine Mummery of University College London wrote to Alzforum (full comment below).

This negative result pertains to the entire study population taken together, i.e., recipients on all doses, and asymptomatic and symptomatic mutation carriers pulled into one. In other words, this topline analysis groups together asymptomatic participants who are some years away from the expected symptom onset for their respective family mutation with fellow participants who were already symptomatic at enrollment.

Additional analyses are ongoing. Given the small sample size and heterogeneity of disease stage in this trial, some of those analyses will focus on individual trajectories. Sometimes depicted as “spaghetti plots,” such analyses can relate a given participant’s drug exposure, or response to study drug, to where the person was in the 15-year pathogenesis of AD, for example.

“One big question is whether the high dose would have had an effect. My concern is we did not have the high dose up and running for long enough,” Randall Bateman of Washington University in St. Louis told Alzforum. Site investigators agreed that the trial may have been underdosed (see William Klunk and Lawrence Honig comments below).

The trial lasted for five to seven years. As planned in 2012, it started as a two-year biomarker target engagement trial, and later was upgraded into a registration trial that measured a cognitive endpoint after at least four years on treatment. But the investigators could not anticipate that between 2013 and 2017, the field at large would gain confidence about the safety of anti-amyloid antibodies. It did, hence sponsors started titrating participants to higher doses in several different trials of solanezumab, gantenerumab, and also Genentech/Roche’s antibody crenezumab.

The DIAN-TU trial increased the dose of solanezumab fourfold, and of gantenerumab fivefold, in summer 2017, midway through the trial. Alas, it may have been too little too late to meet the primary outcome.

The DIAN-TU trial results on the secondary outcomes are still being analyzed. Researchers do not know yet what the 19 other cognitive and clinical scales used in this trial showed. These include established instruments such as the CDR-SB and neuropsychiatric inventory, as well as many individual cognition tests such as maze learning, category fluency, pattern separation, and other tests. The DIAN-MCE comprises the Wechsler Memory Scale-Revised Logical Memory Delayed Recall, the Cogstate International Shopping List Test, the Wechsler Adult Intelligence Scale-Revised Digit Symbol Substitution Test, and the Mini-Mental State Examination

DIAN scientists have not yet seen any imaging or fluid-based biomarker data from the trial. “We still do not know what is really going on. In the next few weeks, we will get into that data, figure it out, and make headway,” Bateman told Alzforum.

Once the trial’s data is better understood, the sponsors will decide whether either antibody generated enough of a positive signal to warrant adding an open-label extension phase. “We do not know yet, based on how much target engagement and other findings we may have, whether we can offer an open-label extension,” Bateman said.

The current topline analysis compares data from 194 participants; 52 APP or presenilin carriers on gantenerumab, 50 mutation carriers on solanezumab, and 40 on placebo. To enlarge the placebo data set, the trial has FDA permission to also include natural history data from mutation carriers enrolled in the DIAN observational study, which is collecting the same type of progression data as does the DIAN-TU drug trial.

The data in this trial are being analyzed by three independent statistical teams, one at WashU, the sponsor DIAN-TU, and one at Roche and Lilly, the companies that develop the two respective antibodies and are partners in the DIAN-TU Pharma Consortium. The three teams met last week in St. Louis, cooped up together in a data analysis “cave” with security posted outside, and worked through the data. While most analyses are actively ongoing, the three teams quickly agreed on the topline result, Bateman said.

The investigators are legally bound to disclose topline data within two days of obtaining it, and Washington University, Roche, and Lilly each issued press releases. Letters to the participating sites have gone out, and the WashU team will hold a webinar with participating families as soon as they understand the data better, Bateman said.

Despite this setback, DIAN investigators are driving hard to start the next series of trials. An ongoing cognitive run-in to enroll people for the next drug arms will continue. DIAN-TU is on track to start testing a tau drug this year, as well as a primary prevention trial for young adult mutation carriers who do not yet have significant brain amyloid deposition. Roche’s two gantenerumab Phase 3 trials in late-onset AD are continuing, as is Lilly’s A4 solanezumab trial in presymptomatic LOAD.

Meanwhile, Bateman emphasized that today’s topline result reflects only the beginning, not the final conclusion of the trial result. He hopes participating families, and the field at large, will hold judgment until all data are in. “We were required to get this out on short notice, but I ask people to get the full story before you draw conclusions. We are still focused on this trial, on these drugs, and what can we do with them. There may be some next steps with these drugs. Please stay tuned,” Bateman said.—Gabrielle Strobel