Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Approved for: Withdrawn from market
The NSAID rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. Its anti-inflammatory and analgesic effects appear to result from the inhibition of prostaglandin synthesis. In 2004, Merck voluntarily withdrew rofecoxib amid controversy over cardiovascular side effects (Sep 2004 news story).
In Alzheimer's research, interest in NSAIDs arose when epidemiological studies started reporting lower rates of Alzheimer's disease or protection of cognition among people who had been taking these drugs for chronic treatment of inflammatory conditions (e.g., Mar 1997 news story; in't Veld et al., 1998; Nov 2001 news story; Vlad et al., 2008; Obermann et al., 2013). Experimental studies supported the argument that inflammation plays a role in Alzheimer's pathogenesis, prompting a wave of clinical trials of various NSAIDs, such as ibuprofen, naproxen celecoxib, and R-flurbiprofen.
Three clinical trials of rofecoxib in Alzheimer's disease have been conducted. In 2000 and 2001, the Alzheimer's Disease Study Group conducted a 40-center trial that compared one year of treatment with 25 mg once daily of rofexocib or 220 mg twice daily of naproxen to placebo in 351 people with mild to moderate Alzheimer's disease. The trial assessed whether these drugs would slow cognitive decline, but found that neither showed any consistent benefit over placebo (Jul 2002 conference story; Aisen et al., 2003).
In 2004, Merck scientists published results of a larger, company-sponsored trial of of the same once-daily dose of 25 mg rofecoxib or placebo, given for one year, in 692 people with mild to moderate Alzheimer's disease. In this study, too, rofecoxib showed no effect on either cognitive or clinical/functional outcomes (Reines et al., 2004).
Similarly, a trial evaluating whether rofecoxib could delay a diagnosis of Alzheimer's disease in 725 people with mild cognitive impairment was negative, as well (see Thal et al., 2005; Aisen, 2005; and Aisen et al., 2008).
- Stockholm: Bad News Official: The Rofecoxib and Naproxen Clinical Trial Has Failed
- Merck Withdraws Vioxx®
- Ibuprofen Linked to Reduced Alzheimer's Risk
- Large Prospective Study Finds NSAIDs Reduce Risk of Developing AD
- Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ, . Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2819-26. PubMed.
- Reines SA, Block GA, Morris JC, Liu G, Nessly ML, Lines CR, Norman BA, Baranak CC, . Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study. Neurology. 2004 Jan 13;62(1):66-71. PubMed.
- Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, Assaid C, Nessly ML, Norman BA, Baranak CC, Reines SA, . A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology. 2005 Jun;30(6):1204-15. PubMed.
- Aisen PS. Can rofecoxib delay a diagnosis of Alzheimer's disease in patients with mild cognitive impairment?. Nat Clin Pract Neurol. 2005 Nov;1(1):20-1. PubMed.
- Aisen PS, Thal LJ, Ferris SH, Assaid C, Nessly ML, Giuliani MJ, Lines CR, Norman BA, Potter WZ. Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial. Curr Alzheimer Res. 2008 Feb;5(1):73-82. PubMed.
- in 't Veld BA, Launer LJ, Hoes AW, Ott A, Hofman A, Breteler MM, Stricker BH. NSAIDs and incident Alzheimer's disease. The Rotterdam Study. Neurobiol Aging. 1998 Nov-Dec;19(6):607-11. PubMed.
- Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008 May 6;70(19):1672-7. PubMed.
- Obermann KR, Morris JC, Roe CM. Exploration of 100 commonly used drugs and supplements on cognition in older adults. Alzheimers Dement. 2013 Aug 14; PubMed.
- Weir MR, Sperling RS, Reicin A, Gertz BJ. Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program. Am Heart J. 2003 Oct;146(4):591-604. PubMed.
- Graham DY, Jewell NP, Chan FK. Rofecoxib and clinically significant upper and lower gastrointestinal events revisited based on documents from recent litigation. Am J Med Sci. 2011 Nov;342(5):356-64. PubMed.
- Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA. 2008 Apr 16;299(15):1813-7. PubMed.