Effect of Age, Cognitive Impairment Severity, and Duration of Disease on Efficacy of Masupirdine in Moderate Alzheimer's Disease Patients: A Post Hoc Analysis of a Phase-2 Randomized Placebo Controlled Study Results

Article Sidebar

PDF Download
Published Sep 20, 2022
DOI: https://doi.org/10.18103/mra.v10i9.3061

Downloads

Download data is not yet available.

Submit your own article

Register as an author to reserve your spot in the next issue of the Medical Research Archives.

Author Registration

Join the Society

The European Society of Medicine is more than a professional association. We are a community. Our members work in countries across the globe, yet are united by a common goal: to promote health and health equity, around the world.

Join Europe’s leading medical society and discover the many advantages of membership, including free article publication.

Membership

Main Article Content

Ramakrishna Nirogi, Ph.D.
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Vijay Benade
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Ramkumar .
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Subramanian .
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Satish Jetta
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Anil Shinde
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Vinod Kumar Goyal
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Santosh Kumar Pandey
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Pradeep Jayarajan
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.
Venkat Jasti
Suven Life Sciences Limited, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana - 500034, India.

Abstract

Alzheimer's disease (AD) is an age-related progressive neurodegenerative brain disorder with cognitive symptoms as a hallmark phenotype of the disease. Masupirdine, a pure serotonin 6 (5-HT6) receptor antagonist is being developed for the treatment of cognitive deficits in AD. The objective of the current study is the post hoc analysis of a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled phase-2 study (NCT02580305) that evaluated the effects of masupirdine on cognition in patients with moderate AD.


Methods: Masupirdine phase 2 study included AD patients of 50 to 85 years age, mini-mental state examination (MMSE) score of 12 to 20 and diagnosis of probable AD at least 1 year prior to the screening visit. The impact of age, cognitive impairment severity, and duration of disease since diagnosis on efficacy of masupirdine as assessed by 11-item version of the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog 11) was evaluated. Treatment effects were assessed by Cohen’s d effect size.


Results: Cohen’s d effect size for change in ADAS-Cog 11 scores from baseline to week 26 ranged between ~0.2 and 0.4 for the subgroup of population with age ≤ 70 years, MMSE range of 18 to 20, and duration of disease over 4 years (since diagnosis).


Conclusions: Considering the linear relationship between age and cognitive decline, masupirdine effects across the subgroups could be attributed to “slowing of cognitive decline”. The study provides important findings for design of future clinical trials. Further research is warranted to confirm the potential beneficial effects of masupirdine on cognition in AD patients.

Keywords: Masupirdine, SUVN-502, 5-HT6 receptor, Alzheimer’s disease, Age, Cognitive impairment severity, Disease duration

Article Details

How to Cite
NIROGI, Ramakrishna et al. Effect of Age, Cognitive Impairment Severity, and Duration of Disease on Efficacy of Masupirdine in Moderate Alzheimer's Disease Patients: A Post Hoc Analysis of a Phase-2 Randomized Placebo Controlled Study Results. Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3061>. Date accessed: 05 nov. 2024. doi: https://doi.org/10.18103/mra.v10i9.3061.
ABNT APA BibTeX CBE EndNote - EndNote format (Macintosh & Windows) MLA ProCite - RIS format (Macintosh & Windows) RefWorks Reference Manager - RIS format (Windows only) Turabian
Issue
Vol 10 No 9 (2022): Vol.10 Issue 9 September 2022
Section
Research Articles

The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.

 

References

1. NIH National Institute on Aging (NIA). How Is Alzheimer's Disease Treated? Accessed May 11, 2022. https://www.nia.nih.gov/health/how-alzheimers-disease-treated.
2. Cummings J, Reynders R, Zhong K. Globalization of Alzheimer's disease clinical trials. Alzheimers Res Ther. 2011; 3(4):24.
3. Liyanage SI, Santos C, Weaver DF. The hidden variables problem in Alzheimer's disease clinical trial design. Alzheimers Dement (N Y). 2018; 4: 628-635.
4. Skelly AC, Dettori JR, Brodt ED. Assessing bias: the importance of considering confounding. Evid Based Spine Care J. 2012; 3(1): 9-12.
5. Herrera AP, Snipes SA, King DW, et al. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010; 100 (Suppl 1):S105-S112.
6. Maher-Edwards G, Zvartau-Hind M, Hunter AJ, et al. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Curr Alzheimer Res. 2010; 7(5): 374-385.
7. Nirogi R, Abraham R, Benade V, et al. SUVN-502, a novel, potent, pure, and orally active 5-HT6 receptor antagonist: pharmacological, behavioral, and neurochemical characterization. Behav Pharmacol. 2019; 30(1):16-35.
8. Nirogi R, Mudigonda K, Bhyrapuneni G, et al. safety, tolerability and pharmacokinetics of the serotonin 5-HT6 receptor antagonist, SUVN-502, in healthy young adults and elderly subjects. Clin Drug Investig. 2018; 38(5): 401-415.
9. Nirogi R, Shinde A, Kambhampati RS, et al. Discovery and development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl] -1H-indole dimesylate monohydrate (SUVN-502): A novel, potent, selective and orally active serotonin 6 (5-HT6) receptor antagonist for potential treatment of Alzheimer's disease. J Med Chem. 2017; 60(5): 1843-1859.
10. Nirogi R, Ieni J, Goyal VK, et al. Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer's disease: A randomized, double-blind, phase 2, proof-of-concept study. Alzheimers Dement (N Y). 2022; 8(1): e12307. doi: 10.1002/trc2.12307.
11. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology.1984; 34(7): 939-944.
12. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984; 141(11):1356-1364.
13. Atri A, Frölich L, Ballard C, et al. Effect of Idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA. 2018 Jan 9;319(2):130-142.
14. Cohen, J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed. New York: Lawrence Erlbaum Associates; 1988.
15. Guerreiro R, Bras J. The age factor in Alzheimer's disease. Genome Med. 2015; 7: 106.
16. Herrup K. Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010; 30(50): 16755-16762.
17. Terry AV Jr, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003; 306(3): 821-827.
18. Mesulam MM, Asuncion Morán M. Cholinesterases within neurofibrillary tangles related to age and Alzheimer's disease. Ann Neurol. 1987; 22(2): 223-228.
19. Kumar A, Gupta V, Sharma S. Donepezil. In: StatPearls. Treasure Island (FL): StatPearls Publishing; December 22, 2021.
20. Burns A, Bernabei R, Bullock R, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009; 8(1): 39-47.
21. Khoury R, Rajamanickam J, Grossberg GT. An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine. Ther Adv Drug Saf. 2018; 9(3):171-178.
22. Budd-Haeberlein S, Von Hein C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Paper presented at Clinical Trials on Alzheimer’s Disease Conference; December 4-7, 2019; San Diego, CA.
23. Cummings J, Aisen P, Lemere C, et al. Aducanumab produced a clinically meaningful benefit in association with amyloid lowering. Alzheimers Res Ther. 2021; 13(1): 98.
24. Wattmo C, Minthon L, Wallin ÅK. Mild versus moderate stages of Alzheimer's disease: three-year outcomes in a routine clinical setting of cholinesterase inhibitor therapy. Alzheimers Res Ther. 2016;8:7.
25. Armstrong RA. Factors determining disease duration in Alzheimer's disease: a postmortem study of 103 cases using the Kaplan-Meier estimator and Cox regression. Biomed Res Int. 2014; 2014: 623487.
26. Friedman LG, McKeehan N, Hara Y, et al. Value-Generating Exploratory Trials in Neurodegenerative Dementias. Neurology. 2021; 96(20): 944-954.
27. Pradier C, Sakarovitch C, Le Duff F, et al. The mini mental state examination at the time of Alzheimer's disease and related disorders diagnosis, according to age, education, gender and place of residence: a cross-sectional study among the French National Alzheimer database. PLoS One. 2014; 9(8): e103630. doi: 10.1371/journal.pone.0103630.
28. Jack CR Jr, Wiste HJ, Weigand SD, et al. Age, Sex, and APOE ε4 effects on memory, brain structure, and β-amyloid across the adult life span. JAMA Neurol. 2015; 72(5): 511-519.
29. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015; 313(19):1924-1938.
30. Schneider LS, Kennedy RE, Wang G, et al. Differences in Alzheimer disease clinical trial outcomes based on age of the participants. Neurology. 2015; 84(11): 1121-1127.
31. Stanley K, Whitfield T, Kuchenbaecker K, et al. Rate of cognitive decline in Alzheimer's disease stratified by age. J Alzheimers Dis. 2019; 69(4): 1153-1160.
32. Rosselli MC, Ardila AC, Moreno SC, et al. Cognitive decline in patients with familial Alzheimer's disease associated with E280a presenilin-1 mutation: a longitudinal study. J Clin Exp Neuropsychol. 2000; 22(4): 483-495.