Therapeutics

Rasagiline

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Overview

Name: Rasagiline
Synonyms: Rasagiline mesylate, Azilect, TVP-1012
Chemical Name: 1H-Inden-1-amine-2,3-dihydro-N-2-propynyl-(1R)-methanesulfonate
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Approved), Amyotrophic Lateral Sclerosis (Inactive)
Company: Teva

Background

Rasagiline is a selective monoamine oxidase B (MAOB) inhibitor widely used to treat symptoms of Parkinson’s disease. It works by blocking the breakdown of dopamine, thus increasing dopaminergic function in the brain. Rasagiline was approved for marketing in Europe in 2005 and in the United States in 2006.

MAOB activity was reported to be increased in Alzheimer’s disease brain, mainly in reactive astrocytes near amyloid plaques (Saura et al., 1994; Gulyás et al., 2011). Monoamine oxidase contributes to the generation of reactive oxygen species, leading to a suggestion that inhibiting this enzyme might delay progression of AD by reducing oxidative stress in the brain (Weinreb et al., 2010). Rasagiline has been reported to exhibit anti-apoptotic, neuroprotective activity, and to promote the non-amyloidogenic processing of APP (Youdim and Weinstock, 2001).

Findings

From 2004 to 2007, Teva Pharmaceuticals Industries and Eisai collaborated on a Phase 2, placebo-controlled trial of rasagiline versus placebo in people with mild to moderate AD who were taking Aricept. The multicenter trial enrolled 376 participants who were treated for one year with 1 or 2 mg rasagiline daily or placebo, and 10 mg Aricept. The primary endpoint was cognition. The companies ended their collaboration in July 2006, and no results or further information about the trial are available.

In May 2015, Cleveland Clinic researchers began a small, Phase 2 proof-of-concept study to gauge whether rasagiline might improve regional brain metabolism measured by FDG-PET in people with AD. The trial enrolled 50 volunteers clinically diagnosed with mild to moderate AD and FDG-PET findings consistent with AD; no Aβ- or tau-based markers were used to confirm their diagnoses. Participants received rasagiline titrated to 1 mg daily or placebo for 24 weeks, plus four weeks of follow-up. The primary endpoint was change in FDG-PET over 24 weeks. Results were presented at the 2019 CTAD conference, and published after peer review  (Dec 2019 conference news; Matthews et al., 2021). Forty-three people completed the trial. It met its primary endpoint, with glucose metabolism declining less in frontal, anterior cingulate, and striatal regions in the treated group compared with placebo. On exploratory clinical measures, the treated group significantly improved on the Quality of Life-AD (QOL-AD) test, and showed trends to better performance on six of seven other cognitive tests. Tau PET was also performed; higher tangle load at baseline correlated with more cognitive decline in the placebo group, and a larger effect of rasagiline in the treatment group.

In a trial of 170 people with Parkinson’s disease and mild cognitive impairment, 24 weeks of 1 mg rasagiline daily did not improve cognitive function (Weintraub et al., 2016). In several small studies, rasagiline improved sleep quality in PD (e.g. Panisett et al., 2016; Schettino et al., 2016; Schrempf et al., 2018; Mutti et al., 2022). There is debate about whether rasagiline modestly slows disease pogression in PD; a recent randomized controlled trial found no evidence for this (Arpin et al., 2022). Rasagiline appears to indirectly affect emotional well-being via its benefit on motor function (Hattori et al., 2022).

Rasagiline was also evaluated in ALS (Ludolph et al., 2018), schizophrenia (Buchanan et al., 2015), multiple-system atrophy (Poewe et al., 2015), PSP (Nuebling et al., 2016), serotonin syndrome, and retinal detachment. 

A different MAOB inhibitor, sembragiline, also posted negative results in an Alzheimer's disease trial (Jul 2015 news).

Rasagiline improved blood flow in a separate small study of 11 people with AD treated for a median of 1.7 years with 1 mg per day, along with donepezil. Compared to untreated age- and sex-matched controls, the treated group had increased perfusion, as measured by SPECT, in the cingulate gyrus and right inferior gyrus regions of the cortex. The study did not measure cognition (Song et al., 2020). 

For details on rasagiline trials in Alzheimer's, see clinicaltrials.gov.

Last Updated: 08 Apr 2022

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References

News Citations

  1. At CTAD, Early Failures and Hints of Success, from Small Trials
  2. MAO-B Inhibitor Misses Primary Endpoint

Therapeutics Citations

  1. Donepezil

Paper Citations

  1. Matthews DC, Ritter A, Thomas RG, Andrews RD, Lukic AS, Revta C, Kinney JW, Tousi B, Leverenz JB, Fillit H, Zhong K, Feldman HH, Cummings J. Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia. Alzheimers Dement (N Y). 2021;7(1):e12106. Epub 2021 Feb 14 PubMed.
  2. Weintraub D, Hauser RA, Elm JJ, Pagan F, Davis MD, Choudhry A, MODERATO Investigators. Rasagiline for mild cognitive impairment in Parkinson's disease: A placebo-controlled trial. Mov Disord. 2016 May;31(5):709-14. Epub 2016 Mar 31 PubMed.
  3. Panisset M, Stril JL, Bélanger M, Lehoux G, Coffin D, Chouinard S. Open-Label Study of Sleep Disturbances in Patients with Parkinson's Disease Treated with Rasagiline. Can J Neurol Sci. 2016 Nov;43(6):809-814. PubMed.
  4. Schettino C, Dato C, Capaldo G, Sampaolo S, Di Iorio G, Melone MA. Rasagiline for sleep disorders in patients with Parkinson's disease: a prospective observational study. Neuropsychiatr Dis Treat. 2016;12:2497-2502. Epub 2016 Sep 29 PubMed.
  5. Schrempf W, Fauser M, Wienecke M, Brown S, Maaß A, Ossig C, Otto K, Brandt MD, Löhle M, Schwanebeck U, Graehlert X, Reichmann H, Storch A. Rasagiline improves polysomnographic sleep parameters in patients with Parkinson's disease: a double-blind, baseline-controlled trial. Eur J Neurol. 2018 Apr;25(4):672-679. Epub 2018 Feb 27 PubMed.
  6. Mutti C, Sarnataro RB, Beretta J, Enzo P, Negrotti A, Rausa F, Pizzarotti S, Parrino L. Rasagiline, sleep quality and well-being in Parkinson's disease: a pilot study. Neurol Sci. 2022 Aug;43(8):4791-4796. Epub 2022 Mar 25 PubMed.
  7. Arpin DJ, Mitchell T, Archer DB, Burciu RG, Chu WT, Gao H, Guttuso T, Hess CW, Lai S, Malaty IA, McFarland NR, Pasternak O, Price CC, Shukla AW, Wu SS, Okun MS, Vaillancourt DE. Diffusion Magnetic Resonance Imaging Detects Progression in Parkinson's Disease: A Placebo-Controlled Trial of Rasagiline. Mov Disord. 2022 Feb;37(2):325-333. Epub 2021 Nov 1 PubMed.
  8. Hattori N, Takeda A, Hanya Y, Kitagawa T, Arai M, Furusawa Y, Mochizuki H, Nagai M, Takahashi R. Effects of rasagiline on Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain in patients with Parkinson's disease: A post-hoc analysis of clinical trials in Japan. PLoS One. 2022;17(1):e0262796. Epub 2022 Jan 25 PubMed.
  9. Ludolph AC, Schuster J, Dorst J, Dupuis L, Dreyhaupt J, Weishaupt JH, Kassubek J, Weiland U, Petri S, Meyer T, Grosskreutz J, Schrank B, Boentert M, Emmer A, Hermann A, Zeller D, Prudlo J, Winkler AS, Grehl T, Heneka MT, Wollebæk Johannesen S, Göricke B, RAS-ALS Study Group. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol. 2018 Aug;17(8):681-688. Epub 2018 Jun 19 PubMed.
  10. Buchanan RW, Weiner E, Kelly DL, Gold JM, Keller WR, Waltz JA, McMahon RP, Gorelick DA. Rasagiline in the Treatment of the Persistent Negative Symptoms of Schizophrenia. Schizophr Bull. 2015 Jul;41(4):900-8. Epub 2014 Nov 2 PubMed.
  11. Poewe W, Seppi K, Fitzer-Attas CJ, Wenning GK, Gilman S, Low PA, Giladi N, Barone P, Sampaio C, Eyal E, Rascol O, Rasagiline-for-MSA investigators. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 2015 Feb;14(2):145-52. Epub 2014 Dec 8 PubMed.
  12. Nuebling G, Hensler M, Paul S, Zwergal A, Crispin A, Lorenzl S. PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy. J Neurol. 2016 Aug;263(8):1565-74. Epub 2016 May 26 PubMed.
  13. Song IU, Im JJ, Jeong H, Na SH, Chung YA. Possible neuroprotective effects of rasagiline in Alzheimer's disease: a SPECT study. Acta Radiol. 2020 Jul 9;:284185120940264. PubMed.
  14. Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, Löffler J, Richards JG. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience. 1994 Sep;62(1):15-30. PubMed.
  15. Gulyás B, Pavlova E, Kása P, Gulya K, Bakota L, Várszegi S, Keller E, Horváth MC, Nag S, Hermecz I, Magyar K, Halldin C. Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int. 2011 Jan;58(1):60-8. PubMed.
  16. Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol. 2010 Nov;92(3):330-44. PubMed.
  17. Youdim MB, Weinstock M. Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. Cell Mol Neurobiol. 2001 Dec;21(6):555-73. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Mendzelevski B, Sprenger CR, Spiegelstein O, Rabinovich-Guilatt L. Cardiac safety of rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of Parkinson's disease: a thorough QT/QTc study. Int J Clin Pharmacol Ther. 2014 Mar;52(3):192-201. PubMed.
  2. Im JJ, Jeong H, Chung YA, Park JS, Heo Y, Oh JK, Song IU. Neuroprotective Effects of Rasagiline in Parkinson's Disease: A Regional Cerebral Blood Flow Study. J Neuroimaging. 2019 Nov;29(6):707-711. Epub 2019 Aug 28 PubMed.
  3. Nagai M, Hattori N. [Pharmacological properties and clinical efficacy of rasagiline mesylate (Azilect®)]. Nihon Yakurigaku Zasshi. 2020;155(3):187-194. PubMed.
  4. Guieu B, Lecoutey C, Legay R, Davis A, Sopkova de Oliveira Santos J, Altomare CD, Catto M, Rochais C, Dallemagne P. First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease. Molecules. 2020 Dec 27;26(1) PubMed.
  5. Xie SS, Liu J, Tang C, Pang C, Li Q, Qin Y, Nong X, Zhang Z, Guo J, Cheng M, Tang W, Liang N, Jiang N. Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-β aggregation against Alzheimer's disease. Eur J Med Chem. 2020 Sep 15;202:112475. Epub 2020 Jun 30 PubMed.
  6. Uddin MS, Kabir MT, Rahman MH, Alim MA, Rahman MM, Khatkar A, Al Mamun A, Rauf A, Mathew B, Ashraf GM. Exploring the Multifunctional Neuroprotective Promise of Rasagiline Derivatives for Multi-Dysfunctional Alzheimer's Disease. Curr Pharm Des. 2020 Apr 5; PubMed.
  7. Jost WH. A critical appraisal of MAO-B inhibitors in the treatment of Parkinson's disease. J Neural Transm (Vienna). 2022 Jun;129(5-6):723-736. Epub 2022 Feb 2 PubMed.
  8. Tan YY, Jenner P, Chen SD. Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease: Past, Present, and Future. J Parkinsons Dis. 2022;12(2):477-493. PubMed.
  9. Solla P, Ercoli T, Masala C, Orofino G, Fadda L, Corda DG, Zarbo IR, Meloni M, Sechi E, Bagella CF, Defazio G. Rasagiline Withdrawal Syndrome in Parkinson's Disease. Brain Sci. 2022 Feb 5;12(2) PubMed.
  10. Oka H, Sengoku R, Nakahara A, Yamazaki M. Rasagiline does not exacerbate autonomic blood pressure dysregulation in early or mild Parkinson's disease. Clin Park Relat Disord. 2022;6:100124. Epub 2021 Dec 13 PubMed.
  11. Hattori N, Takeda A, Hanya Y, Kitagawa T, Arai M, Furusawa Y, Mochizuki H, Nagai M, Takahashi R. Effects of rasagiline on Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain in patients with Parkinson's disease: A post-hoc analysis of clinical trials in Japan. PLoS One. 2022;17(1):e0262796. Epub 2022 Jan 25 PubMed.