Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase 2 Randomized Placebo-Controlled Study

Ramakrishna Nirogi, Vinod Kumar Goyal, Vijay Benade, Ramkumar Subramanian, Jyothsna Ravula, Satish Jetta, Anil Shinde, Santosh Kumar Pandey, Pradeep Jayarajan, Venkat Jasti, Jeffrey Cummings, Ramakrishna Nirogi, Vinod Kumar Goyal, Vijay Benade, Ramkumar Subramanian, Jyothsna Ravula, Satish Jetta, Anil Shinde, Santosh Kumar Pandey, Pradeep Jayarajan, Venkat Jasti, Jeffrey Cummings

Abstract

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT6) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT6 receptor antagonist with pro-cognitive properties in animal models of cognition.

Methods: The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio. The study consisted of a 26-week double-blind treatment period. The primary efficacy outcome was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). In exploratory post hoc analyses, patients were subdivided based on the use of memantine dosage forms and memantine plasma concentrations, to evaluate the impact of memantine on the efficacy of masupirdine.

Results: In an exploratory post hoc analysis, less worsening in cognition (ADAS-Cog 11 scores) was observed with masupirdine treatment as compared with placebo in patients whose trough memantine plasma concentrations were ≤ 100 ng/mL.

Conclusions: Although prespecified study endpoints of the phase 2 study were not met, these exploratory post hoc subgroup observations are hypothesis-generating and suggest that the efficacy of masupirdine was adversely affected by concurrent therapy with memantine. Further assessment of masupirdine to determine its potential role as a treatment option for cognitive deficits associated with AD is warranted.

Trial registration: The study was registered at ClinicalTrials.gov (NCT02580305).

Keywords: 5-HT6 receptor; ADAS-Cog; Alzheimer’s disease; Clinical trials; Masupirdine; Memantine.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
ADAS-Cog 11 score: total population
Fig. 2
Fig. 2
ADAS-Cog 11 score: memantine 10 mg BID vs. Memantine 28 mg QD
Fig. 3
Fig. 3
ADAS-Cog 11 score: memantine concentrations ≤ 100 ng/mL vs. > 100 ng/mL
Fig. 4
Fig. 4
MMSE score: memantine concentrations ≤ 100 ng/mL vs. > 100 ng/mL

References

    1. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement 2021;17(3).
    1. Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States (2020–2060) Alzheimers Dement. 2021;17(12):1966–1975. doi: 10.1002/alz.12362.
    1. Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer's disease. Am J Med. 2007;120(5):388–397. doi: 10.1016/j.amjmed.2006.08.036.
    1. Alva G, Cummings JL. Relative tolerability of Alzheimer's disease treatments. Psychiatry (Edgmont) 2008;5(11):27–36.
    1. Budd Haeberlein S, Aisen P, Barkhof F, et al. Two randomized phase 3 studies of Aducanumab in early Alzheimer’s disease. Alzheimer's Disease J Prev Alzheimers Dis. 2022;9(2):197–210.
    1. Monsma FJ, Jr, Shen Y, Ward RP, Hamblin MW, Sibley DR. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 1993;43(3):320–327.
    1. Marazziti D, Baroni S, Borsini F, et al. Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology. Curr Med Chem. 2013;20(3):371–377.
    1. Helboe L, Egebjerg J, de Jong IE. Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: a double in situ hybridization study. Neuroscience. 2015;310:442–454. doi: 10.1016/j.neuroscience.2015.09.064.
    1. de Jong IEM, Mørk A. Antagonism of the 5-HT6 receptor: preclinical rationale for the treatment of Alzheimer’s disease. Neuropharmacology. 2017;125:50–63. doi: 10.1016/j.neuropharm.2017.07.010.
    1. Ferrero H, Solas M, Francis PT, Ramirez MJ. Serotonin 5-HT6 receptor antagonists in Alzheimer’s disease: therapeutic rationale and current development status. CNS Drugs. 2017;31:19–32. doi: 10.1007/s40263-016-0399-3.
    1. Lalut J, Karila D, Dallemagne P, Rochais C. Modulating 5-HT4 and 5-HT6 receptors in Alzheimer’s disease treatment. Future Med Chem. 2017;9:781–795. doi: 10.4155/fmc-2017-0031.
    1. Maher-Edwards G, Watson C, Ascher J, et al. Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease. Alzheimer's & Dementia Transl Res Clin Interv. 2015;1:23–36. doi: 10.1016/j.trci.2015.04.001.
    1. Wilkinson D, Windfeld K, Colding-Jørgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014;13(11):1092–1099. doi: 10.1016/S1474-4422(14)70198-X.
    1. Lang FM, Mo Y, Sabbagh M, et al. Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: a randomized, placebo-controlled, phase 3 clinical trial (MINDSET) Alzheimers Dement (N Y) 2021;7(1):e12136. doi: 10.1002/trc2.12136.
    1. 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;319(2):130–142. doi: 10.1001/jama.2017.20373.
    1. Fullerton T, Binneman B, David W, et al. A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. Alz Res Therapy. 2018;10:38. doi: 10.1186/s13195-018-0368-9.
    1. 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. doi: 10.1097/FBP.0000000000000414.
    1. 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.
    1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease Neurology. Neurology. 1984;34(7):939–944. doi: 10.1212/WNL.34.7.939.
    1. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198. doi: 10.1016/0022-3956(75)90026-6.
    1. Namenda XR (memantine hydrochloride) capsules label
    1. Friedman LG, McKeehan N, Hara Y, et al. Value-generating exploratory trials in neurodegenerative dementias. Neurology. 2021;96(20):944–954. doi: 10.1212/WNL.0000000000011774.
    1. Marcos B, Gil-Bea FJ, Hirst WD, et al. Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release. Eur J Neurosci. 2006;24(5):1299–1306. doi: 10.1111/j.1460-9568.2006.05003.x.
    1. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology. 1999;38:735–767. doi: 10.1016/S0028-3908(99)00019-2.
    1. Witt A, Macdonald N, Kirkpatrick P. Memantine hydrochloride. Nat Rev Drug Discov. 2004;3:109–110. doi: 10.1038/nrd1311.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi