NEJM Letter to Editor 01.30.18 [not accepted for publication]

RE:  Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018;378:321-330. 

To the Editor:

Despite the careful selection of patients, despite evidence that the agent had activity, the EXPEDITION3 data led the authors to a disappointing conclusion.  They list possible reasons for the lack of benefit in cognitive performance, including the amyloid beta hypothesis itself. Hypotheses aside, one must ask: what was learned for moving forward, not just for solanezumab, but for Alzheimer’s therapy in general?

Once also frustrating, cancer therapy improved through clinical trials. Testing empiric therapy and combinations (over fifty years ago) gave us incremental progress (1). Recent effective immunotherapy does not even target the presumed malignant process;  CD20 and CD19 antigens were chosen more for feasibilty than for activity in leukemogenesis (2).

The Alzheimer’s Clinical Trials Consortium was recently funded, but no comprehensive therapeutic strategy planning was announced in budget documents (3,4 ).  Directive strategy helped pediatric oncology success.  In the meantime, did the solanezumab experience suggest any specific drug combinations, with other immunotherapy, or contrasting therapies, or synergies with “repurposed” drugs, that might lead to an effective treatment for those afflicted with dementia?

Ron Louie, MD

References:

  1. Hunger SP and Mulligan CG. Acute lymphoblastic leukemia in children. N Engl J Med 2015; 373:1541-1552.
  2. Jabbour E, O’Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood 2015; 125: 4010-4016.
  3. NIH Press Release: New NIH consortium award to enhance clinical trials for Alzheimer’s disease, related dementias, December 11, 2017 (https://www.nih.gov/news-events/news-releases/new-nih-consortium-award-enhance-clinical-trials-alzheimers-disease-related-dementias)
  4. NIH Bypass Budget Proposal 2019, Sustaining momentum: NIH takes aim at Alzheimer’s disease & related dementias, July 28, 2017. (https://www.nia.nih.gov/sites/default/files/2017-07/FY19-bypass-budget-report-508_0.pdf)

[Beta amyloid ribbon-stick model, public domain image: Crescenzi O, Tomaselli S, Guerrini R et al (November 2002),Eur. J. Biochem. 269 (22): 5642-8.]