Therapeutics

Leuprolide

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Overview

Name: Leuprolide
Synonyms: Leuprolide acetate , Lupron Depot, Eligard
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Tolmar Pharmaceuticals, Inc.
Approved for: Advanced prostate cancer

Background

Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). It acts as an agonist at pituitary GnRH receptors; however, by interrupting the normal pulsatile stimulation of the receptors, it indirectly downregulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Leuprolide is one of several androgen deprivation drugs used to treat prostate cancer. It is also used in fertility regimens, for severe endometriosis and uterine fibroids, and to prevent precocious puberty in children.

The rationale behind repurposing leuprolide for the treatment of Alzheimer’s disease is based on the hypothesis that LH, which becomes elevated later in life and in some people with Alzheimer's (Short et al., 2001), induces post-mitotic neurons to re-enter the cell cycle, leading to cell death and cognitive decline (Atwood and Bowen, 2015). Medicare hospitalization claims data were reported to support a protective effect on cognition (Smith et al., 2018). Other studies have linked androgen deprivation therapy used in men with prostate cancer to a higher risk of subsequent dementia (Jayadevappa et al., 2019).

In preclinical work, decreasing LH was reported to improve cognitive performance and decrease amyloid deposition and tau phosphorylation in animal models of aging and AD (for example, see Bryan et al., 2010; Casadesus et al., 2006). Other mouse studies did not replicate these findings (Rosario et al., 2012).

Findings

From 2003-2004, a Phase 2 study enrolled 109 women with mild to moderate AD to test the effect of leuprolide on cognition. Participants were randomized to 11.25 mg or 22.5 mg leuprolide acetate (Lupron Depot, AbbVie) or placebo, given by injection every 12 weeks for one year. This trial found no overall efficacy on the primary outcomes of ADAS-Cog or ADCS-Clinical Global Impression of Change. In a preplanned subgroup analysis, women treated with the higher dose who were already taking an acetylcholinesterase inhibitor declined significantly less on both endpoints. The mean decline in the ADASCog was 0.18 points in the high-dose group compared to 3.30 points in the placebo group and 4.21 points in the low-dose group (Bowen et al., 2015).

In November 2020, a new Phase 2 trial began. Called LUCINDA, the study plans to enroll 150 women with measurable cognitive decline and cortical amyloid on a PET scan. Participants must be taking donepezil. An additional 30 people who meet all inclusion criteria except amyloid positivity will be randomized into a separate sub-study. The drug regimen of 22.5 mg leuprolide (Eligard, Tolmar Pharmaceuticals), or placebo, is to be injected subcutaneously once every 12 weeks for 48 weeks. ADAS-Cog11 is the lone primary outcome; secondaries include ADCS-ADL, ADCS-CGIC+, and other measures of cognition, behavior, and pain. Fluid biomarkers of inflammation, hormonal changes, and AD will be measured, along with volumetric MRI and hippocampal perfusion by ASL. Sponsored by Weill Cornell Medical College, the study is taking place at three centers in the U.S., with completion slated for February 2026 (Butler et al., 2021).

For details on these trials, see clinicaltrials.gov.

Last Updated: 12 Oct 2021

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References

Paper Citations

  1. Bowen RL, Perry G, Xiong C, Smith MA, Atwood CS. A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. J Alzheimers Dis. 2015;44(2):549-60. PubMed.
  2. Butler T, Goldberg JD, Galvin JE, Maloney T, Ravdin L, Glodzik L, de Leon MJ, Hochman T, Bowen RL, Atwood CS. Rationale, study design and implementation of the LUCINDA Trial: Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer's. Contemp Clin Trials. 2021 Aug;107:106488. Epub 2021 Jun 22 PubMed.
  3. Short RA, Bowen RL, O'Brien PC, Graff-Radford NR. Elevated gonadotropin levels in patients with Alzheimer disease. Mayo Clin Proc. 2001 Sep;76(9):906-9. PubMed.
  4. Atwood CS, Bowen RL. The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease. Horm Behav. 2015 Nov;76:63-80. Epub 2015 Jul 16 PubMed.
  5. Smith MA, Bowen RL, Nguyen RQ, Perry G, Atwood CS, Rimm AA. Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. J Alzheimers Dis. 2018;63(4):1269-1277. PubMed.
  6. Jayadevappa R, Chhatre S, Malkowicz SB, Parikh RB, Guzzo T, Wein AJ. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. JAMA Netw Open. 2019 Jul 3;2(7):e196562. PubMed.
  7. Bryan KJ, Mudd JC, Richardson SL, Chang J, Lee HG, Zhu X, Smith MA, Casadesus G. Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits. J Neurochem. 2010 Feb;112(4):870-81. PubMed.
  8. Casadesus G, Webber KM, Atwood CS, Pappolla MA, Perry G, Bowen RL, Smith MA. Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice. Biochim Biophys Acta. 2006 Apr;1762(4):447-52. PubMed.
  9. Rosario ER, Carroll JC, Pike CJ. Evaluation of the effects of testosterone and luteinizing hormone on regulation of β-amyloid in male 3xTg-AD mice. Brain Res. 2012 Jul 23;1466:137-45. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Lehrer S, Rheinstein PH, Rosenzweig KE. No Relationship of Anti-Androgens to Alzheimer's Disease or Cognitive Disorder in the MedWatch Database. J Alzheimers Dis Rep. 2018 Jun 30;2(1):123-127. PubMed.
  2. Blair JA, Bhatta S, McGee H, Casadesus G. Luteinizing hormone: Evidence for direct action in the CNS. Horm Behav. 2015 Nov;76:57-62. Epub 2015 Jul 12 PubMed.

External Resources

  1. Spinning of negative result gives false hope on Alzheimer’s treatment