Results from the first two arms of the Dominantly Inherited Alzheimer’s Network trials unit (DIAN-TU) are now published. In the June 21 Nature Medicine, researchers led by Randall Bateman at Washington University in St. Louis fleshed out topline results initially presented at the AAT-AD/PD conference last year. Overall, the trial was negative, with neither solanezumab nor gantenerumab slowing cognitive decline in people who carried a familial Alzheimer’s mutation. However, gantenerumab moved numerous biomarkers in the desired direction, not only mopping up amyloid plaque, but also dropping total tau and p-tau181 in cerebrospinal fluid and slowing the rise of the neurodegeneration marker NfL (Apr 2020 conference news; Apr 2020 conference news).
Why did these biomarker changes not produce a cognitive benefit? Last year, the researchers noted that the heterogeneous trial population, which included people who were asymptomatic as well as those who already had mild cognitive problems, obscured the trial’s ability to discern a clinical effect. In brief, asymptomatic participants, whether on drug or placebo, did not decline on cognitive tests, while symptomatic participants declined before they reached full dosing with gantenerumab.
The new publication adds detail. Among the 52 participants taking gantenerumab, 31 people, i.e., 60 percent, were asymptomatic. Because they didn’t decline, the statistical power was low, with only an 8 percent chance of detecting a 30 percent slowing of decline in the gantenerumab cohort.
Meanwhile, symptomatic participants had worsened on the CDR-SB, from an average baseline score of 3.2 to 5.9, by the time they were receiving a high enough dose of gantenerumab. When the trial started in 2013, gantenerumab was being given at low doses to avoid ARIA, a vascular complication that results from displacement of Aβ from plaques to blood vessels in the brain. Doses were boosted fivefold in 2016, when the field at large realized that higher concentrations of antibodies were needed to move biomarkers, and that ARIA could be managed. This means the trial did not test the most effective doses until late in the study. This is similar to what happened in the Phase 3 trials for the anti-amyloid antibody aducanumab.
On biomarkers, too, symptomatic and asymptomatic DIAN participants diverged, with the latter reaping more benefit. The relative change in amyloid plaque compared to placebo was 33 percent for asymptomatic participants, and 19 percent for symptomatic ones. Asymptomatic participants started out with a much lower plaque burden. Improvements in CSF markers were also larger in asymptomatic than symptomatic participants, although the difference did not reach statistical significance.
The researchers noted that plaque reduction after two years on high-dose gantenerumab was less in DIAN-TU than in trials of late-onset AD, with most participants still above the threshold for amyloid positivity. This could be due to the high rate of Aβ production in people with a familial AD mutation, the researchers suggested. Possibly, this group will need higher doses or a longer duration of treatment to completely clear plaque.
The biomarker data led researchers to invite participants to join an open-label extension to further explore the long-term effects of gantenerumab treatment. The first results from this OLE will be evaluated soon, Bateman told Alzforum.—Madolyn Bowman Rogers
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- Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, Hitchcock JM, Mills SL, Santacruz AM, Aschenbrenner AJ, Hassenstab J, Benzinger TL, Gordon BA, Fagan AM, Coalier KA, Cruchaga C, Goate AA, Perrin RJ, Xiong C, Li Y, Morris JC, Snider BJ, Mummery C, Surti GM, Hannequin D, Wallon D, Berman SB, Lah JJ, Jimenez-Velazquez IZ, Roberson ED, van Dyck CH, Honig LS, Sánchez-Valle R, Brooks WS, Gauthier S, Galasko DR, Masters CL, Brosch JR, Hsiung GR, Jayadev S, Formaglio M, Masellis M, Clarnette R, Pariente J, Dubois B, Pasquier F, Jack CR Jr, Koeppe R, Snyder PJ, Aisen PS, Thomas RG, Berry SM, Wendelberger BA, Andersen SW, Holdridge KC, Mintun MA, Yaari R, Sims JR, Baudler M, Delmar P, Doody RS, Fontoura P, Giacobino C, Kerchner GA, Bateman RJ, Dominantly Inherited Alzheimer Network–Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 2021 Jul;27(7):1187-1196. Epub 2021 Jun 21 PubMed.