Potential new therapies for Alzheimer’s disease to look out for in 2022: anti-amyloid-β antibodies

The number of individuals worldwide with Alzheimer’s disease is growing at a rapid rate. Therefore, new treatments are urgently needed. In June 2021, the U.S. Food and Drug Administration (FDA) approved the first new drug for Alzheimer’s disease in 18 years. Although controversial, the approval of aducanumab marked a breakthrough moment for the field. The current pipeline of drugs in clinical trials and under the evaluation of regulatory agencies continues to grow. In this feature, we review three promising drugs for Alzheimer’s disease treatment to look out for in 2022.

Donanemab

 

The amyloid hypothesis of Alzheimer’s disease suggests that the build-up of amyloid-β in the brain is the main causative agent of neurodegeneration. Therefore, strategies developed to clear the peptide from the brain should stop or reverse disease progression.1

The efficacy of donanemab, a monoclonal antibody targeting amyloid-β, was evaluated in the Phase II TRAILBLAZER-ALZ trial (NCT03367403) in patients with early symptomatic Alzheimer’s disease who had detectable tau and amyloid-β deposition using positron-emission tomography (PET). A total of 257 participants were enrolled in the trial and assigned to receive donanemab or placebo intravenously every 4 weeks for up to 72 weeks. The change from baseline in the iADRS score at 76 weeks, which was the primary endpoint, was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% CI, 0.12 to 6.27; P=0.04). However, secondary endpoints, including the change in the amyloid and tau burden on PET, were not met.2

Based on the clinical data from the TRAILBLAZER-ALZ trial, in June 2021, the FDA granted donanemab Breakthrough Therapy Designation to speed development and review.

The ongoing randomized, placebo-controlled, double-blind, multi-center Phase III study TRAILBLAZER-ALZ 2 (NCT04437511) is evaluating the safety, tolerability, and efficacy of donanemab in 1500 participants with early symptomatic Alzheimer’s disease. The primary outcome will be iADRS; however, in this trial, efficacy will be analyzed using the Disease Progression Model, rather than looking only at the last timepoint. Results are due in the first half of 2023.3

 

Stephen Salloway, MD, MS, of Warren Alpert Medical School of Brown University, Providence, RI, highlights innovations in the conduction of the Phase III trial, including the use of tau PET and response-driven treatment discontinuation.

Additionally, a placebo-controlled Phase III trial (TRAILBLAZER-ALZ 3; NCT05026866) is recruiting 3300 participants with preclinical Alzheimer’s disease – cognitively normal people at high risk for Alzheimer’s disease based on elevated plasma ptau217 – to test whether the antibody can prevent the progression of Alzheimer’s disease. This trial will run until September 2027.4

Gantenerumab

 

Gantenerumab, an IgG1 antibody designed to bind to aggregated forms of amyloid-β and remove brain amyloid plaques, has recently been granted Breakthrough Therapy Designation by the FDA for the treatment of Alzheimer’s disease.5

The FDA’s decision was based on data from various studies, including early findings of two ongoing open-label extensions (OLEs) Phase III trials: Scarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) in patients with sporadic disease and the DIAN-TU-001 Phase II/III clinical trial (NCT01760005) in patients with dominantly inherited Alzheimer’s disease.

Previous findings from Scarlet RoAD and Marguerite RoAD OLEs have shown that high-dose gantenerumab administered subcutaneously once every 4 weeks resulted in significant amyloid-β plaque removal at 2 years (P<0.0001) in patients with prodromal to moderate Alzheimer’s disease, as shown by PET scans.6

In the DIAN-TU-001 study, designed to evaluate gantenerumab versus a placebo in people with inherited forms of early-onset Alzheimer’s disease irrespective of them showing symptoms, gantenerumab also led to a significant reduction of amyloid-β plaque formation in the brain compared with placebo at years 2 (P<0.001) and 4 (P<0.001). However, the trial missed its primary endpoint, a statistically significant difference between drug and placebo on the DIAN Multivariate Cognitive Endpoint (DIAN-MCE).7,8

Importantly, learnings from these studies have been combined into the design of the ongoing placebo-controlled Phase III GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973) trials.

 

These two pivotal studies are evaluating gantenerumab in over 2,000 participants with prodromal or mild Alzheimer’s disease, with results expected in the second half of 2022.5 Further, additional open-label studies are underway, the Phase III Open RoAD (NCT04374253) and the Phase II GRADUATION trial (NCT04592341). An exploratory OLE of DIAN-TU-001 is also being conducted.

In an interview with VJDementia, Prof. Salloway gave an overview of the major ongoing clinical trials in Alzheimer’s disease, including the GRADUATE 1 trial of gantenerumab.

Gantenerumab is the first and only subcutaneous anti-amyloid antibody being investigated in late-stage trials. If approved, it may open the possibility of at-home administration of and antibody therapy for Alzheimer’s disease.5

Lecanemab

 

Based on encouraging preclinical findings, as well as Phase I and II trial results, multiple studies are currently investigating lecanemab, an anti-amyloid-β protofibril antibody, as a potential treatment for Alzheimer’s disease.1

In June 2021, the FDA designated lecanemab a breakthrough therapy based on the results of a large Phase II proof-of-concept study (BAN2401-G000-201; NCT01767311) in 856 patients with early Alzheimer’s disease with confirmed presence of amyloid pathology. The study explored the impact of lecanemab on reducing brain amyloid-β and clinical decline using multiple doses and dosing regimens. After 18 months of biweekly dosing of 10 mg/kg lecanemab, brain amyloid was reduced (least squares mean change from baseline: -0.306 SUVr units versus 0.004 for placebo). Additionally, a reduction in brain amyloid-β correlated with a reduction in clinical decline on ADCOMS (Alzheimer’s Disease Composite Score), CDR-SB (Clinical Dementia Rating-Sum-of-Boxes), and ADAS-cog (Alzheimer Disease Assessment Scale-Cognitive Subscale) compared with placebo. The most effective dose was determined to be 10 mg/kg biweekly, and an open-label extension (OLE) study has been initiated with this dose, which is ongoing.9

In a recent interview with VJNeurology, Chad Swanson, PhD, Eisai Inc., discussed the preliminary results from the ongoing OLE of the BAN2401-G000-201 study. Since the OLE commenced once the Phase II study was complete, subjects from the core study were brought back for treatment following a break, the average of which was 24 months. Interim data showed that lecanemab reduced amyloid PET SUVr from as early as three months compared with baseline, and more than 80% of participants achieved negative amyloid status by visual read on a scan. The amyloid reductions in those treated in the core study were maintained during the treatment break.10,11

 

In the OLE study, not only did clinical decline in subjects newly treated with lecanemab plateau relative to controls but also patients who had previously received lecanemab in the core Phase II study showed a reduction in clinical decline. Furthermore, changes in plasma Aβ42/40 ratio were shown for the first time to correlate with the response to lecanemab treatment – an observation seen in both the core and OLE studies.10,11

Further, lecanemab is being evaluated in two ongoing Phase III trials: AHEAD 3-45 (NCT04468659) in preclinical Alzheimer’s disease and Clarity AD (NCT03887455) in early Alzheimer’s disease. The trials are expected to run until 2027 and 2024, respectively.12

Written by Marta Palhas

References

  1. B Decourt, F Boumelhem, ED Pope 3rd, et al. Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. Jun 2021; 21(8), 39.
  2. MA Mintun, AC Lo, C Duggan Evans, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. May 2021;384(18):1691-1740.
  3. ClinicalTrials.gov. A Study of Donanemab (LY3002813) in Participants With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 2). Available from: https://www.clinicaltrials.gov/ct2/show/NCT04437511 Last accessed: 02/12/2021.
  4. Donanemab. Available from: https://www.alzforum.org/therapeutics/donanemab Last accessed: 02/12/2021.
  5. Genentech’s Anti-Amyloid Beta Antibody Gantenerumab Granted FDA Breakthrough Therapy Designation in Alzheimer’s Disease [Press Release]. Available from: https://www.gene.com/media/press-releases/14931/2021-10-08/ad-hoc-announcement-pursuant-to-art-53-lLast accessed: 02/12/2021
  6. G Klein, P Delmar, N Voyle , et al. Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. Dec 2019;11(1):101.
  7. ClinicalTrials.gov. Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer’s Disease Caused by a Genetic Mutation. Master Protocol DIAN-TU001 (DIAN-TU). Available from: https://www.clinicaltrials.gov/ct2/show/NCT01760005 Last accessed: 02/12/2021.
  8. S Salloway, M Farlow, E McDade, et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. Jun 2021;27, 1187–1196.
  9. CJ Swanson, Y Zhang, S Dhadda, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alz Res Therapy. Apr 2021;13, 80.
  10. Eisai initiates rolling submission to the U.S. FDA for biologics license application of lecanemab (BAN2401) for early Alzheimer’s disease under the accelerated approval pathway [Press Release]. Available from: https://www.eisai.com/news/2021/news202177.html Last accessed: 02/12/2021.
  11. CJ Swanson, S Dhadda, MC Irizarry, et al. Preliminary Assessment of the Clinical Effects of Lecanemab Following 18 Months of Treatment in the Open Label Extension of the Phase 2 Proof of Concept Study, BAN2401-G000-201, in Subjects With Early Alzheimer’s Disease. [Conference presentation abstract]. Alzheimer’s Association International Conference (AAIC) 2021, 26-30 Jul 2021.
  12. Lecanemab. Available from: https://www.alzforum.org/therapeutics/lecanemab Last accessed: 02/12/20021.