CPP‐115, a vigabatrin analogue, decreases spasms in the multiple‐hit rat model of infantile spasms

Abstract

SUMMARY Objective Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a GABA aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP-115, Catalyst Pharmaceutical Partners) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP-115 in reducing spasms and its tolerability in the multiple-hit rat model of IS, in which daily vigabatrin reduced spasms only for one day, but was not well tolerated. Methods Male rats were treated with the protocol of the multiple-hit model of IS at postnatal day 3 (PN3). Using a randomized, blinded, vehicle-controlled, dose-response study design, CPP-115 [0.1, 1, or 5 mg/kg intraperitoneally (i.p.)] or vehicle were given daily (PN4-12) or as single injection (PN7) after spasms onset. Intermittent video- or video-EEG monitoring was done. Secondary endpoints included: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3-20), horizontal bar (PN13-20), Barnes maze (PN16-19). Statistics used a linear mixed model of raw or normalized log-transformed data, taking into account the repeated observations on each animal. Results The lower CPP-115 doses (0.1–1 mg/kg/day, PN4-12) reduced spasms between PN6-7 without increasing mortality. CPP-115 at 5 mg/kg/day (PN4-12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP-115 injection (1mg/kg i.p.) decreased electroclinical spasms acutely but transiently. CPP-115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasms cessation. CPP-115 did not alter neurodevelopmental outcomes or visuospatial learning. Significance We provide proof-of-concept evidence that CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of IS at considerably lower and better tolerated doses than vigabatrin did in our previous studies. Further optimization of the treatment protocol is needed. CPP-115 may be a promising new candidate treatment for IS with better tolerability than vigabatrin.

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

“…Recently there has been an emergence of animal models of early life seizures and chronic models of early life epilepsies, genetic or induced, which have been used for therapy discovery 27. A few drugs emerging from such animal models have already acquired orphan drug status for pediatric epilepsy syndromes, like carisbamate and the vigabatrin analog CPP‐155 28, 29. Rapamycin's efficacy in epilepsy due to tuberous sclerosis was first demonstrated in animal models, before being tested in clinical trials 30.…”

Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

“…Similar to the clinical syndrome, the induction of cortical and subcortical lesions by doxorubicin and lipopolysaccharide in the multiple-hit model generates a chronic phenotype, including an early period of cluster of spasms, subsequent emergence of other seizures, and neurodevelopmental and cognitive deficits. Furthermore, the multiple-hit is currently the only tested model that exhibits relative pharmacoresistance to the available treatments by not responding to ACTH and only transiently responding to vigabatrin or a vigabatrin analogue (CPP-115) [111,134]. Ongoing studies are aimed at unraveling new therapy targets for treatment that could help control drug-resistant spasms and exhibit disease-modifying effects [105,135,136].…”

Recent Advances in the Pharmacotherapy of Infantile Spasms

“…No single model will replicate the human seizure exactly. CPP-115, a vigabatrin analogue with better tolerability than vigabatrin, has recently been shown to decrease spasms in the multiple-hit rat model of infantile spasms [114]. In a mouse model of TS, vigabatrin inhibits seizure activity and mTOR pathway activation [103].…”