Synonyms: Levetiracetam, Keppra
Chemical Name: (S)-α-Ethyl-2-oxo-1-pyrrolidineacetamide
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Other (timeline)
Condition(s): Mild Cognitive Impairment, Parkinson's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 3), Parkinson's Disease (Discontinued)
Company: AgeneBio, Inc.
Approved for: Epilepsy and Partial Seizures in U.S., European Union, plus about 20 other countries
AGB101 is a proprietary, once-daily, low-dose formulation of the atypical anti-convulsant medication levetiracetam, a modulator of the synaptic vesicle protein modulator SV2A. Levetiracetam itself was developed for the treatment of epilepsy but, as a pyrrolidone acetamide, is chemically unrelated to most other anticonvulsives. Levetiracetam is available as an oral syrup, an intravenous infusion, and immediate- and extended-release tablets. Generic equivalents of these formulations are on the market, as well, and the drug is widely used. Its side effects include sleepiness, headache, lack of energy, and others. AGB101 corresponds to roughly 1/15 of the dose typically prescribed for epilepsy, according to AGeneBio.
This compound's mechanism of action is not fully understood. It does not act on the GABAergic system and is inactive at classic receptor sites linked to epileptic seizures, such as amino acid-related receptors, adenosine receptors, and ion channels (Sills et al., 1997). Early on, inhibition of calcium signaling or depolarizing currents were proposed as possible mechanisms of action (Margineanu and Wülfert, 1997).
In recent years, both SV2A and levetiracetam have come to be of interest in Alzheimer's research. A human transcriptome study has implicated SV2A in mediating the effect of the ApoE4 risk allele on APP processing, and levetiracetam in reducing Aβ generation in cells cultured from ApoE4 carriers (Jul 2013 news). More broadly, a line of research has sprung up around Aβ-induced hyperactivation, aberrant network activity, and nonconvulsive seizures. These phenotypes are seen in the J20, APP23, APP/PS1, and certain strains of Tg2576 transgenic mouse models of AD (Sep 2007 news; Lalonde et al., 2005; Minkeviciene et al., 2009; Shi et al. 2013). In the J20 mice, levetiracetam was reported to quiet epileptiform activity in circuits of the medial temporal lobe network, as well as reverse hyperactivity in behavioral assays and deficits in spatial learning assays (Aug 2012 news). The drug was reported to reduce hippocampal hyperactivation and improve memory performance in an aging rat model (Koh et al., 2010).
In humans, observational research is ongoing on the nature and incidence of nonconvulsive seizures and their relationship to cognitive decline in the early stages of Alzheimer's disease, such as amnestic mild cognitive impairment (aMCI) (Sep 2007 news).
In a single-center, placebo-controlled Phase 2 trial in 17 people with aMCI and 17 age-matched controls, a two-week course of 50–500 mg of Levetiracetam twice a day reportedly reduced hippocampal activity as measured by fMRI and improved performance on a hippocampal memory task. Other tests in a neuropsychological test battery showed no response (May 2012 news).
A one-year study of levetiracetam in Alzheimer's patients who had seizures reported improved attention, verbal fluency, and good tolerability for its use in controlling seizures in AD (Cumbo and Ligori, 2010). It is unclear whether these benefits derived from reduced seizures or global cognitive benefits.
A 2010–2012 study at Johns Hopkins University Medical School in Baltimore conducted a within-subject crossover, dose-finding Phase 2 study of levetiracetam in people with amnestic mild cognitive impairment (aMCI) and a clinical dementia rating (CDR) of 0.5 at screening; controls had a CDR of zero. The trial compared 125, 250, and 500 mg/d of levetiracetam against placebo for their effect on neuronal activity in the hippocampus and entorhinal cortex as well as for performance on a memory task performed while in an MRI scanner. The study enrolled 69 aMCI patients and 24 controls, and analyzed data from 54 patients and 17 controls; 15 participants dropped out and seven moved in the scanner. At the two lower doses, levetiracetam was reported to have improved performance on the scanning memory task; the highest dose yielded no further improvement. The low doses were also reported to have reduced abnormal hyperactivity in the hippocampal dentate gyrus and CA3 regions, and to have boosted abnormal hypoactivation in the entorhinal cortex, both measured by fMRI. Full results were published in a peer-reviewed journal (for paper and Alzforum commentary, see Bakker et al., 2015).
A 2012–2013 study at Beth Israel Deaconess Medical Center, Boston, compared single administration of 2.5 mg/kg and 7.5 mg/kg of levetiracetam to placebo. This trial was to enroll 20 patients with mild AD and seizures, and use perfusion MRI to evaluate whether levetiracetam normalizes blood flow in the course of controlling seizures. Memory and executive function tests were primary outcomes. A paper on this study did not report on the study's primary outcome; it did report that the higher dose had network effects, specifically changes in coherence of the delta, low beta, and high beta bands (Musaeus et al., 2017).
In June 2014, a Phase 2 study began at the University of California, San Francisco. It is enrolling 36 Alzheimer's disease patients for a 12-week evaluation of levetiracetam for its ability to improve executive function, reduce the frequency of epileptiform activity, as well as improve cognitive function and performance on a virtual navigation task.
For clinical trials on levetiracetam in MCI/AD, see clinicialtrials.gov.
In September 2015, AGeneBio received a $7.5 million grant from the National Institutes on Aging toward evaluating AGB101, and announced that it intended to begin a Phase 3 trial of this formulation in 2016 (see company website). Further NIA funds were received in September 2017, and a trial start announced for 2018 (see company press release).
In addition, levetiracetam has been tested in patients with Parkinson's disease. Prompted by preclinical data suggesting that levetiracetam reduces side effects of long-term levodopa therapy in nonhuman primates (Bezard et al., 2004), numerous small clinical trials were conducted in patients with Parkinson's disease who had levodopa treatment-induced dyskinesia. One small pilot trial reported improvements such as longer “on” time without dyskinesia and shorter “off” time with dyskinesia, but subsequent randomized controlled trials produced mixed results. Some studies indicated modest improvement, others did not, and yet others cautioned that PD patients did not tolerate levetiracetam well (see Wolz et al., 2010; Stathis et al., 2011; Wong et al., 2011; Lyons and Pahwa, 2006).
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
- Epilepsy Drug Calms the Hippocampus, Aids Memory
- A Genetic Approach to the ApoE4 Puzzle
- Do "Silent" Seizures Cause Network Dysfunction in AD?
- Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice
Research Models Citations
- Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer's disease. Epilepsy Behav. 2010 Apr;17(4):461-6. PubMed.
- Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688-98. Epub 2015 Feb 21 PubMed.
- Musaeus CS, Shafi MM, Santarnecchi E, Herman ST, Press DZ. Levetiracetam Alters Oscillatory Connectivity in Alzheimer's Disease. J Alzheimers Dis. 2017;58(4):1065-1076. PubMed.
- Bezard E, Hill MP, Crossman AR, Brotchie JM, Michel A, Grimée R, Klitgaard H. Levetiracetam improves choreic levodopa-induced dyskinesia in the MPTP-treated macaque. Eur J Pharmacol. 2004 Feb 6;485(1-3):159-64. PubMed.
- Wolz M, Löhle M, Strecker K, Schwanebeck U, Schneider C, Reichmann H, Grählert X, Schwarz J, Storch A. Levetiracetam for levodopa-induced dyskinesia in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. J Neural Transm. 2010 Nov;117(11):1279-86. Epub 2010 Aug 29 PubMed.
- Stathis P, Konitsiotis S, Tagaris G, Peterson D, VALID-PD Study Group. Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord. 2011 Feb 1;26(2):264-70. Epub 2010 Dec 13 PubMed.
- Wong KK, Alty JE, Goy AG, Raghav S, Reutens DC, Kempster PA. A randomized, double-blind, placebo-controlled trial of levetiracetam for dyskinesia in Parkinson's disease. Mov Disord. 2011 Jul;26(8):1552-5. Epub 2011 Apr 29 PubMed.
- Lyons KE, Pahwa R. Efficacy and tolerability of levetiracetam in Parkinson disease patients with levodopa-induced dyskinesia. Clin Neuropharmacol. 2006 May-Jun;29(3):148-53. PubMed.
- Sills GJ, Leach JP, Fraser CM, Forrest G, Patsalos PN, Brodie MJ. Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol. 1997 Apr 23;325(1):35-40. PubMed.
- Margineanu DG, Wülfert E. Inhibition by levetiracetam of a non-GABAA receptor-associated epileptiform effect of bicuculline in rat hippocampus. Br J Pharmacol. 1997 Nov;122(6):1146-50. PubMed.
- Lalonde R, Dumont M, Staufenbiel M, Strazielle C. Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen. Behav Brain Res. 2005 Feb 10;157(1):91-8. PubMed.
- Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fülöp L, Penke B, Zilberter Y, Harkany T, Pitkänen A, Tanila H. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci. 2009 Mar 18;29(11):3453-62. PubMed.
- Shi JQ, Wang BR, Tian YY, Xu J, Gao L, Zhao SL, Jiang T, Xie HG, Zhang YD. Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in APPswe/PS1dE9 Transgenic Mice. CNS Neurosci Ther. 2013 Nov;19(11):871-81. PubMed.
- Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016-25. PubMed.
- Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Seizures in patients with Alzheimer's disease or vascular dementia: A population-based nested case-control analysis. Epilepsia. 2012 Dec 6; PubMed.
- Lippa CF, Rosso A, Hepler M, Jenssen S, Pillai J, Irwin D. Levetiracetam: a practical option for seizure management in elderly patients with cognitive impairment. Am J Alzheimers Dis Other Demen. 2010 Mar;25(2):149-54. PubMed.
- Scharfman HE. "Untangling" Alzheimer's disease and epilepsy. Epilepsy Curr. 2012 Sep;12(5):178-83. PubMed.
- Mendez M, Lim G. Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging. 2003;20(11):791-803. PubMed.
- Devi L, Ohno M. Effects of levetiracetam, an antiepileptic drug, on memory impairments associated with aging and Alzheimer's disease in mice. Neurobiol Learn Mem. 2013 May;102:7-11. PubMed.
- Romanelli MF, Morris JC, Ashkin K, Coben LA. Advanced Alzheimer's disease is a risk factor for late-onset seizures. Arch Neurol. 1990 Aug;47(8):847-50. PubMed.
- Belcastro V, Costa C, Galletti F, Pisani F, Calabresi P, Parnetti L. Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur J Neurol. 2007 Oct;14(10):1176-8. PubMed.
- Weiner MF, Womack KB, Martin-Cook K, Svetlik DA, Hynan LS. Levetiracetam for agitated Alzheimer's disease patients. Int Psychogeriatr. 2005 Jun;17(2):327-8. PubMed.
- Zesiewicz TA, Sullivan KL, Maldonado JL, Tatum WO, Hauser RA. Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease. Mov Disord. 2005 Sep;20(9):1205-9. PubMed.
- Haberman RP, Branch A, Gallagher M. Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Neurotherapeutics. 2017 Jul;14(3):662-676. PubMed.
- Sanz-Blasco S, Piña-Crespo JC, Zhang X, McKercher SR, Lipton SA. Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes. Neuroreport. 2016 Jun 15;27(9):705-9. PubMed.
- Stockburger C, Miano D, Baeumlisberger M, Pallas T, Arrey TN, Karas M, Friedland K, Müller WE. A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. J Alzheimers Dis. 2015;50(1):201-15. PubMed.