Evicenter
P&T meetings

Aqneursa (levacetylleucine)

Ataxia-telangiectasia

Also known as IB1001
Manufacturer
IntraBio
Last updated
206 sources

Product information and disease descriptionProduct descriptionProduct informationPharmacology

Pharmacodynamics

14 evidence topics · 11 sources

Clinical pharmacodynamics: prescribing information

“Clinical pharmacodynamic studies have not been conducted for levacetylleucine.” (opens the prescribing information at this quote)

“A relationship was not observed between increasing levacetylleucine exposure and clinical efficacy.” (opens the prescribing information at this quote)

“The time course of pharmacodynamic response is unknown.” (opens the prescribing information at this quote)

Clinical pharmacology and exposure-response: European assessment

“The Applicant did not conduct clinical primary or secondary pharmacology studies.” (opens the source at this quote in a new tab)

“No phase I study in healthy volunteers has been conducted, and the primary pharmacology is primarily based on the non-clinical studies.” (opens the source at this quote in a new tab)

“The paucity of both the PK and PD data from study IB1001-301 cannot allow reliable conclusions from these analyses.” (opens the source at this quote in a new tab)

Cardiac electrophysiology

“With regards to hERG assay, it is understood that a single concentration (i.e., 525 µM) was tested and as this concentration did not inhibit 30% of the hERG tail current amplitude no dose-response curve was generated and the IC50 value was not estimated.” (opens the source at this quote in a new tab)

“According to the submitted clinical data, there is no signal or trend of pattern related to any TQT prolongation that could be due to levacetylleucine. Therefore, the Applicant request for a waiver for a thorough QT/QTC study with levacetylleucine is accepted.” (opens the source at this quote in a new tab)

Respiratory and central nervous system safety pharmacology

“In female Sprague-Dawley rats, respiratory function was not modified by a single dose of levacetylleucine administered orally up to 2500 mg/kg (maximum feasible dose level).” (opens the source at this quote in a new tab)

Active enantiomer: postural compensation and cerebellar glucose metabolism in the rat

“A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group).” (opens the source at this quote in a new tab)

“The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect.” (opens the source at this quote in a new tab)

“Measurements of the regional cerebral glucose metabolism (rCGM) by means of μPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7.” (opens the source at this quote in a new tab)

Active enantiomer: vestibular compensation in the cat

“Whatever the parameters tested, the behavioral recovery was strongly and significantly accelerated under pharmacological treatments with N-acetyl-dl-leucine and N-acetyl-L-leucine.” (opens the source at this quote in a new tab)

“In contrast, the N-acetyl-D-leucine isomer had no effect at all on the behavioral recovery, and animals of this group showed the same recovery profile as those receiving a placebo.” (opens the source at this quote in a new tab)

Neuronal membrane potential: central vestibular neurons of the guinea pig

“However, intracellular recordings from MVN neurons revealed that the nature of the response depended on the resting membrane potential.” (opens the source at this quote in a new tab)

“Altogether, our results suggest that acetyl-DL-leucine might act mainly on abnormally hyperpolarized and/or depolarized MVN neurons, by bringing back their membrane potential towards a mean value of -65 to -60 mV.” (opens the source at this quote in a new tab)

Disease progression, survival, and glucose metabolism in Npc1-deficient mice

“When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1−/− mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not.” (opens the source at this quote in a new tab)

“Relative to untreated Npc1−/− mice, the life span of animals treated from weaning was modestly but significantly increased by 8 days (9.1%) with ALL treatment (P = 0.0334), 4 days with ADLL (P = 0.0305) (4.5%) and was not changed with ADL (P = 0.6908) (Fig. 1G), therefore displaying l-enantiomer selectivity.” (opens the source at this quote in a new tab)

“Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1−/− mice.” (opens the source at this quote in a new tab)

“Individual enantiomers had distinct effects in NPC1 cerebellum; while ALL normalizes altered levels of PDH and LDH and mildly reduces SOD1 levels, ADL enhanced levels of the mitochondrial reactive oxygen species scavenger SOD2 (manganese dependent SOD2).” (opens the source at this quote in a new tab)

Regulatory appraisal of the nonclinical pharmacology package

“Most of the in vitro and in vivo primary pharmacological data came from publications by different authors.” (opens the source at this quote in a new tab)

“The Applicant affirms that levacetylleucine has been demonstrated to reduce lysosomal volume and glycosphingolipids levels (GSL) and normalize mitochondria numbers and mitochondrial superoxide levels.” (opens the source at this quote in a new tab)

“No data on secondary pharmacodynamics were performed.” (opens the source at this quote in a new tab)

Glucose and glutamate metabolism and autophagy in a Sandhoff disease mouse model

“ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2.” (opens the source at this quote in a new tab)

“ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1).” (opens the source at this quote in a new tab)

Autophagy flux and neuroinflammation after traumatic brain injury in mice

“We demonstrate that orally administered N-acetyl-l-leucine (NALL) significantly improved motor and cognitive outcomes in the injured mice, led to the attenuation of cell death, and reduced the expression of neuroinflammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice.” (opens the source at this quote in a new tab)

“Our data indicate that partial restoration of autophagy flux mediated by NALL may account for the positive effect of treatment in the injured mouse brain.” (opens the source at this quote in a new tab)

Lysosomal, mitochondrial, and synaptic proteins in human dopaminergic neurons

“Discovery-based proteomic analysis revealed that NALL treatment upregulated lysosomal, mitochondrial, and synaptic proteins without inducing cytotoxicity.” (opens the source at this quote in a new tab)

Glutathione synthesis enzyme in human induced neurons

“HiPNs from MS donors treated with NALL expressed higher levels of glutamate cysteine ligase (GCL), the ratelimiting enzyme in glutathione synthesis.” (opens the source at this quote in a new tab)

Cerebral glucose metabolism in patients with cerebellar ataxia treated with the racemate

“Retrospective analyses of [18F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B).” (opens the source at this quote in a new tab)

“With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group.” (opens the source at this quote in a new tab)

“The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms.” (opens the source at this quote in a new tab)