Letter to the editor response for: “Schneider LS, Kennedy RE, Cutter G. Caution in interpreting disease‐modification claims with lecanemab: selective reporting and causal inference. Alzheimer's & Dementia. 2026”

1.

We thank the authors for their interest in our article ¹ and for providing their feedback. Our paper highlights results from an open‐label extension (OLE) study following completion of the randomized, placebo‐controlled phase 3 Clarity AD trial. OLE studies are used to collect long‐term safety and effectiveness data for the population in the primary study beyond the time needed to evaluate the primary efficacy outcome. These trials provide information on the long‐term use of new treatments and are generally required by regulatory health authorities, consistent with International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use guidelines. ² While OLE studies are not placebo controlled, the systematic and rigorous long‐term clinical and safety data they collect afford the opportunity to complement and extend the results of the double‐blind phase. As with countless other earlier OLE studies, we chose to publish these results to continue to advance the science and to provide the latest information for the Alzheimer's disease community.

Schneider and colleagues appear to focus their feedback and criticisms on the “claims” made from these OLE results, although they acknowledge that the proper limitations and caveats are stated in the paper. ³ We agree with them that randomized controlled trials are the preferred approach to answer key questions in clinical trial research. In our paper, we clearly describe the study design and associated methods, we state that all the analyses were descriptive, we provide a transparent accounting of the results, and we detail the several limitations of the study. Analyses that are not pre‐specified are so noted in the manuscript. The limitations section of our paper specifically states that “these analyses should be viewed as only hypothesis generating.” We avoid presenting results that the study was not powered or designed to assess, such as the suggested delayed‐start slope analyses. Understanding the limitations of results from such a study, we prospectively included a historical control group from the well‐established ADNI study for comparison. As is commonly understood, the use of a historical control group with an OLE is not meant to replace a randomized controlled study, but rather to provide context for the data and to optimize the legitimate hypothesis‐generating potential from such a trial.

As for some of the specific criticisms, we acknowledge that certain language could be interpreted as claiming more than the results allow scientifically. For example, we did use the term “significantly” in the opening of the discussion – the only place it appears in the manuscript; however, it was not meant to imply statistical significance. Although we avoided inferential statistics throughout the manuscript, we included a single hazard ratio with confidence intervals and p value for the risk comparison by 36 months of progressing to the next disease stage between the lecanemab and ADNI groups (figure 5). We recognize that our stated commitment to descriptive analyses would have been better served by omitting this statistic.

We must reject the authors’ criticism of the safety reporting, which has been thorough and transparent in Clarity AD. Safety data for lecanemab were more extensively published previously from the phase 2 study, the phase 3 study, and the OLE, which the authors fail to mention. ⁴ , ⁵ , ⁶ , ⁷ This includes the cumulative incidence rates for ARIA in the phase 3 Core study plus OLE. ⁷ These data have been assessed in publicly available regulatory reviews by the Food and Drug Administration and the European Medicines Agency. In addition, multiple post‐approval registries have been created across the globe, including the Alzheimer's Network for Treatment and Diagnostics (ALZ‐NET) registry, that will further add to our understanding of the lecanemab safety profile.

In summary, we agree with Schneider et al. that future studies with rigorous designs will be necessary to address specific questions. The present OLE results are also important to share with the Alzheimer's disease community. As the methods and associated limitations are clearly described, readers are well informed and able to evaluate the findings for what they represent. Taken together with the totality of the published data from Clarity AD, these results from the Clarity OLE study contribute to the overall safety and efficacy profile for lecanemab.

CONFLICT OF INTEREST STATEMENT

CHvD has been an advisor/consultant for Roche Pharmaceuticals, Eisai, Inc, Ono Pharmaceuticals, Cerevel, Bristol Myers Squibb, and UCB. CHvD and Yale University have received grant support from Eli Lilly, Janssen Pharmaceuticals, Biogen Idec, Eisai, Inc., Roche Pharmaceuticals, Genentech, Inc., Cerevel Therapeutics, UCB, and Merck. Author disclosures are available in the Supporting Information.

FUNDING INFORMATION

The author has no funding sources to report.

Supporting information

Supporting Information