The
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Phase 3 Trials of Solanezumab and Bapineuzumab for Alzheimer’s Disease To the Editor: Salloway et al. (Jan. 23 issue)1 report on two trials of bapineuzumab in mild-tomoderate Alzheimer’s disease, and in the same issue, Doody et al.2 report on two trials of solanezumab for this condition. The negative results of these phase 3 trials may be interpreted in two ways: either treatment was too late in the course of the disease or amyloid-beta (Aβ) alone is the wrong target for an effective treatment of Alz heimer’s disease. The first interpretation may be clarified when the results of ongoing treatment trials involving persons with preclinical Alzhei mer’s disease are available. These trials include the Dominantly Inherited Alzheimer Network Trial (DIAN-TU; ClinicalTrials.gov number, NCT01760005), Alzheimer’s Prevention Initiative (API; NCT01998841), and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease study (A4 Study; NCT02008357). The second interpretation has not yet been tested. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. Since the pathologic process of Alzheimer’s disease is characterized by the accumulation of both amyloid plaques and neurofibrillary tangles,3 it is reasonable to assume that a treatment strategy focusing on both targets may be more beneficial than a strategy focusing only on one. Christoph Laske, M.D. University Hospital of Tübingen Tübingen, Germany [email protected] No potential conflict of interest relevant to this letter was reported. 1. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:322-33. 2. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311-21. 3. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 2010;362:329-44.
To the Editor: In the editorial corresponding to the articles by Salloway et al. and Doody et al., it is curious that Karran and Hardy1 dismiss the overwhelming evidence gathered in the past few years showing that anti-Aβ therapy to rid the brain of Aβ deposits in patients with Alzheimer’s disease has been a clinical failure. Their comment that these recent trials of bapineuzumab and solanezumab “have provided valuable information” and that trials of anti-Aβ antibodies should continue is at odds with the facts. The question logically arises: when is a dead hypothesis really dead? Better pragmatic new principles need to be examined. The most important of these is prevention of risk factors for Alzheimer’s disease.2 Risk factors related to vascular disease3 include cerebrovascular disorders, hypertension, diabetes, cardiovascular disease, dyslipidemia, and atherosclerosis. Physicians should be aware that noninvasive, cost-effective tools can detect modifiable risk factors for Alzheimer’s disease. Detection of these risk factors in asymptomatic persons could lead to the initiation of preventive clinical measures aimed at treating or managing such risk factors. This approach has been missing from clinical practice, but if it is not begun this week’s letters 1459 Phase 3 Trials of Solanezumab and Bapineuzumab for Alzheimer’s Disease 1461 Surgery for Severe Ischemic Mitral Regurgitation 1463 Increase in LVAD T hrombosis 1466 Unexpected Abrupt Increase in LVAD Thrombosis 1467 Thrombosis and the HeartMate II
DOI: 10.1056/NEJMc1402193
n engl j med 370;15 nejm.org april 10, 2014
The New England Journal of Medicine Downloaded from nejm.org at US - Milwaukee on February 1, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1459
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
soon, clinicians will face an especially large in- Rachelle S. Doody, M.D., Ph.D. crease in new cases of Alzheimer’s disease in the Baylor College of Medicine United States; the number of new cases is ex- Houston, TX [email protected] pected to double by 2050, at a horrendous cost Martin Farlow, M.D. to society.4 Jack C. de la Torre, M.D., Ph.D.
Indiana University Indianapolis, IN
University of Texas, Austin Austin, TX [email protected]
Paul S. Aisen, M.D.
No potential conflict of interest relevant to this letter was reported.
for the Alzheimer’s Disease Cooperative Study Data Analysis and Publication Committee
University of California at San Diego San Diego, CA
1. Karran E, Hardy J. Antiamyloid therapy for Alzheimer’s dis-
ease — are we on the right road? N Engl J Med 2014;370:377-8. 2. de la Torre JC. Vascular risk factors: a ticking time bomb to Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2013; 28:551-9. 3. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311-21. 4. Hebert LE, Beckett LA, Scherr PA, Evans DA. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 2001;15: 169-73. DOI: 10.1056/NEJMc1402193
Since publication of their article, the authors report no further potential conflict of interest. DOI: 10.1056/NEJMc1402193
Dr. Salloway and Colleagues Reply: Alzhei mer’s disease is a complex, progressive disorder related to brain aging and neurodegeneration. We agree with Laske that we are most likely to slow progression of Alzheimer’s disease by intervening early with combination treatments targeting the accumulation of both amyloid and tau proteins and other facets of neurodegeneration. As de la Torre correctly points out, the clinical outcomes of amyloid-based treatments in Alzheimer’s disease have so far been disappointing. However, the effect of amyloid modification in earlier stages of Alzheimer’s disease, when amyloid deposition is likely to be exerting a major impact, has not yet been tested. The current DIAN, API, and A4 trials are designed to assess the role of amyloid modification in the treatment of preclinical Alzheimer’s disease. We agree with de la Torre that prospective trials should be developed to test whether modification of cardiovascular risk factors promotes brain health and lessens the overall burden of Alzheimer’s disease.
Dr. Doody and Colleagues Reply: The two studies of solanezumab that we recently reported did not show efficacy for patients with mild-tomoderate Alzheimer’s disease as assessed by the principal outcome measures. However, as shown in Tables 3 and 4 of our article, there were some significant differences in secondary outcomes. Cognitive measures favored treatment in one study for the overall population, and differences in both cognitive and functional measures favored treatment in the subpopulation of patients with mild Alzheimer’s disease in the same study. Table S2 in the Supplementary Appendix, available with the full text of our article at NEJM.org, shows that this signal in the subpopulation of Stephen Salloway, M.D. patients with mild Alzheimer’s disease was pres- Warren Alpert Medical School of Brown University ent in both studies. These results provide support Providence, RI for the ongoing trials of solanezumab involving [email protected] patients who have genetic mutations associated Reisa Sperling, M.D. with Alzheimer’s disease and patients who are Harvard Medical School otherwise at greater risk for the development of Boston, MA this condition (DIAN-TU), healthy persons with H. Robert Brashear, M.D. elevated levels of brain amyloid (A4 Study), and Janssen Alzheimer Immunotherapy Research and Development patients with mild Alzheimer’s disease (Progress San Francisco, CA of Mild Alzheimer’s Disease in Participants on Since publication of their article, the authors report no furSolanezumab Versus Placebo [EXPEDITION 3; ther potential conflict of interest. NCT01900665]). DOI: 10.1056/NEJMc1402193
1460
n engl j med 370;15 nejm.org april 10, 2014
The New England Journal of Medicine Downloaded from nejm.org at US - Milwaukee on February 1, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
c or r e sp ondence
Phase 3 Trials of Solanezumab and Bapineuzumab for Alzheimer’s Disease To the Editor: Salloway et al. (Jan. 23 issue)1 report on two trials of bapineuzumab in mild-tomoderate Alzheimer’s disease, and in the same issue, Doody et al.2 report on two trials of solanezumab for this condition. The negative results of these phase 3 trials may be interpreted in two ways: either treatment was too late in the course of the disease or amyloid-beta (Aβ) alone is the wrong target for an effective treatment of Alz heimer’s disease. The first interpretation may be clarified when the results of ongoing treatment trials involving persons with preclinical Alzhei mer’s disease are available. These trials include the Dominantly Inherited Alzheimer Network Trial (DIAN-TU; ClinicalTrials.gov number, NCT01760005), Alzheimer’s Prevention Initiative (API; NCT01998841), and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease study (A4 Study; NCT02008357). The second interpretation has not yet been tested. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. Since the pathologic process of Alzheimer’s disease is characterized by the accumulation of both amyloid plaques and neurofibrillary tangles,3 it is reasonable to assume that a treatment strategy focusing on both targets may be more beneficial than a strategy focusing only on one. Christoph Laske, M.D. University Hospital of Tübingen Tübingen, Germany [email protected] No potential conflict of interest relevant to this letter was reported. 1. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:322-33. 2. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311-21. 3. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 2010;362:329-44.
To the Editor: In the editorial corresponding to the articles by Salloway et al. and Doody et al., it is curious that Karran and Hardy1 dismiss the overwhelming evidence gathered in the past few years showing that anti-Aβ therapy to rid the brain of Aβ deposits in patients with Alzheimer’s disease has been a clinical failure. Their comment that these recent trials of bapineuzumab and solanezumab “have provided valuable information” and that trials of anti-Aβ antibodies should continue is at odds with the facts. The question logically arises: when is a dead hypothesis really dead? Better pragmatic new principles need to be examined. The most important of these is prevention of risk factors for Alzheimer’s disease.2 Risk factors related to vascular disease3 include cerebrovascular disorders, hypertension, diabetes, cardiovascular disease, dyslipidemia, and atherosclerosis. Physicians should be aware that noninvasive, cost-effective tools can detect modifiable risk factors for Alzheimer’s disease. Detection of these risk factors in asymptomatic persons could lead to the initiation of preventive clinical measures aimed at treating or managing such risk factors. This approach has been missing from clinical practice, but if it is not begun this week’s letters 1459 Phase 3 Trials of Solanezumab and Bapineuzumab for Alzheimer’s Disease 1461 Surgery for Severe Ischemic Mitral Regurgitation 1463 Increase in LVAD T hrombosis 1466 Unexpected Abrupt Increase in LVAD Thrombosis 1467 Thrombosis and the HeartMate II
DOI: 10.1056/NEJMc1402193
n engl j med 370;15 nejm.org april 10, 2014
The New England Journal of Medicine Downloaded from nejm.org at US - Milwaukee on February 1, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1459
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
soon, clinicians will face an especially large in- Rachelle S. Doody, M.D., Ph.D. crease in new cases of Alzheimer’s disease in the Baylor College of Medicine United States; the number of new cases is ex- Houston, TX [email protected] pected to double by 2050, at a horrendous cost Martin Farlow, M.D. to society.4 Jack C. de la Torre, M.D., Ph.D.
Indiana University Indianapolis, IN
University of Texas, Austin Austin, TX [email protected]
Paul S. Aisen, M.D.
No potential conflict of interest relevant to this letter was reported.
for the Alzheimer’s Disease Cooperative Study Data Analysis and Publication Committee
University of California at San Diego San Diego, CA
1. Karran E, Hardy J. Antiamyloid therapy for Alzheimer’s dis-
ease — are we on the right road? N Engl J Med 2014;370:377-8. 2. de la Torre JC. Vascular risk factors: a ticking time bomb to Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2013; 28:551-9. 3. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311-21. 4. Hebert LE, Beckett LA, Scherr PA, Evans DA. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 2001;15: 169-73. DOI: 10.1056/NEJMc1402193
Since publication of their article, the authors report no further potential conflict of interest. DOI: 10.1056/NEJMc1402193
Dr. Salloway and Colleagues Reply: Alzhei mer’s disease is a complex, progressive disorder related to brain aging and neurodegeneration. We agree with Laske that we are most likely to slow progression of Alzheimer’s disease by intervening early with combination treatments targeting the accumulation of both amyloid and tau proteins and other facets of neurodegeneration. As de la Torre correctly points out, the clinical outcomes of amyloid-based treatments in Alzheimer’s disease have so far been disappointing. However, the effect of amyloid modification in earlier stages of Alzheimer’s disease, when amyloid deposition is likely to be exerting a major impact, has not yet been tested. The current DIAN, API, and A4 trials are designed to assess the role of amyloid modification in the treatment of preclinical Alzheimer’s disease. We agree with de la Torre that prospective trials should be developed to test whether modification of cardiovascular risk factors promotes brain health and lessens the overall burden of Alzheimer’s disease.
Dr. Doody and Colleagues Reply: The two studies of solanezumab that we recently reported did not show efficacy for patients with mild-tomoderate Alzheimer’s disease as assessed by the principal outcome measures. However, as shown in Tables 3 and 4 of our article, there were some significant differences in secondary outcomes. Cognitive measures favored treatment in one study for the overall population, and differences in both cognitive and functional measures favored treatment in the subpopulation of patients with mild Alzheimer’s disease in the same study. Table S2 in the Supplementary Appendix, available with the full text of our article at NEJM.org, shows that this signal in the subpopulation of Stephen Salloway, M.D. patients with mild Alzheimer’s disease was pres- Warren Alpert Medical School of Brown University ent in both studies. These results provide support Providence, RI for the ongoing trials of solanezumab involving [email protected] patients who have genetic mutations associated Reisa Sperling, M.D. with Alzheimer’s disease and patients who are Harvard Medical School otherwise at greater risk for the development of Boston, MA this condition (DIAN-TU), healthy persons with H. Robert Brashear, M.D. elevated levels of brain amyloid (A4 Study), and Janssen Alzheimer Immunotherapy Research and Development patients with mild Alzheimer’s disease (Progress San Francisco, CA of Mild Alzheimer’s Disease in Participants on Since publication of their article, the authors report no furSolanezumab Versus Placebo [EXPEDITION 3; ther potential conflict of interest. NCT01900665]). DOI: 10.1056/NEJMc1402193
1460
n engl j med 370;15 nejm.org april 10, 2014
The New England Journal of Medicine Downloaded from nejm.org at US - Milwaukee on February 1, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
