The monoclonal antibody that preferentially targets Aß oligomers failed to meet either of its coprimary end points—despite favorable results over the placebo group—in individuals who were unimpaired but at risk for AD.
Identifying and developing effective treatments for Alzheimer disease (AD) has been an ongoing challenge for the clinical neurology community for many years. Despite a multitude of failed investigational treatments, though, the work has continued, with improvements in clinical trial design and adjustments to the timing and target of therapies paving the way for small progressive steps.
At the 2022 Alzheimer’s Association International Conference, held July 31 to August 4, in San Diego, California, data from studies of 3 different interventions were presented during a Focused Topic Session on August 2. The session includes presentation from Eric M. Reiman, MD; John Didsbury, PhD; and Laura Baker PhD; with the discussion moderated by Maria C. Carrillo, PhD, the Alzheimer Association’s chief science officer.
The first of the presentations was given by Reiman and detailed data from the phase 2 Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia trial (NCT01998841) of crenezumab.1 In late June, the therapy’s developer, Roche, announced that it had not demonstrated a statistically significant benefit in either of its coprimary end points assessing the rate of change in cognitive abilities or episodic memory function in cognitively unimpaired persons at risk for AD.2
Reiman, the executive director of the Banner Alzheimer’s Institute and colead investigator, explained that the therapy was safe and well-tolerated, but showed no significant clinical or biomarker effects. “[Gene mutation] carriers were younger and at an earlier preclinical AD stage than predicted, reducing our power to detect a statistically significant benefit,” he said, adding that with a limited number of individuals carrying the PSEN1 E280A autosomal dominant mutation and the unexpected nature of their status as having preclinical AD, coupled with the short treatment duration at the highest dose, “limited our ability to know whether treatment at the highest possible dose would have a clinical benefit.”
With recent news of possible research misconduct and falsified images leading to a resurfacing of questions about the amyloid-ß (Aß) theory’s validity for the treatment of AD, NeurologyLive® inquired with the panel about the potential of these Aß-targeted therapies to be used in combination with other targeted treatments. Carrillo alluded to the possibility of precision medicine being on the horizon for AD at the start of the presentation, and responded that, “It's important to understand how each contributor—each treatment that targets a specific protein—can slow clinical decline because, ultimately, then when we can aggregate them, and they become additive—that's how other diseases have treated successfully. You start with one and understand what that one does and its contribution. Then, we continue to add.”
“I agree that ultimately there will be opportunities to look at combination treatments are sequential treatments that target earlier and later stages of the disease and have a more profound effect,” Reiman said in response to NeurologyLive®’s inquiry. “The challenge we have, as [Carrillo] noted, is that the science needs to get there. We need to have ways to be able to understand the individual adverse and beneficial effects and be able to put these studies to the test. What is happening over the last few years are tremendous learnings in how to do these treatment and prevention trials, which is going to benefit all of these different approaches.”
Ultimately, the end points assessed with crenezumab treatment showed relative changes in annualized scores that, in all cases, favored crenezumab over placebo, but were not statistically significant. Those included cognitive test scores for the API-ADAD composite score, the Free and Cued Selective Reminding Test (FCSRT), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score. For those assessments, annual changes were 22.9% (P = .43), 19.9% (P = .16), and 43.8% (P = .55), respectively.3
Similarly, for assessments of clinical function, the time to mild cognitive impairment because of AD was changed by 20.8% (P = .48), time to non-zero in Clinical Dementia Rating Scale-Global Score (CDR-GS) by 8.1% (P = .76), and CDR Sum of Boxes by 8.8% (P = .64). Biomarker results, which also favored crenezumab, reported relative changes compared with placebo, were not statistically significant. The PET measures included Aß PET SUVR, with a change of 3.6% (P = .69); Tau-PET SUVR, with a change of 51.1% (P = .20); and FDG PET SUVR, with a change of 18.1% (P = .25). The cerebrospinal fluid assessments included total tau (28.7%; P = .53), phosphorylated tau (37.4%; P = .28), and neurofilament light (18.2%; P = .46).
Patients who carried the mutation in the treatment arm (n = 85) were treated with the investigational monoclonal antibody for approximately 2 years at the highest dose. They were compared with 2 placebo arms, those with the mutation (n = 84) and those without (n = 83). Those enrolled in the trial in Colombia are expected to continue to receive crenezumab treatment. Additional analyses and assays in the subgroups of individuals who are amyloid positive and negative, as well as those overall carrier groups, are expected to help inform the next trial design, Reiman said.
“The historical impact of this trial is that it has helped introduce ways to accelerate the evaluation and approval of prevention therapies in AD,” Reiman said. “This showed that license-enabling AD prevention trials were possible and has set the stage for the growing number of trials in this area. It also included a precedent-setting data and sample sharing agreement that will help inform the study of preclinical AD, optimize the design of secondary and primary prevention trials, and support the potential use of run-in data and increase the power and speed of the next trial in Colombia.”