IL326537A - A method for treating seizures - Google Patents

Description

METHOD FOR TREATMENT OF SEIZURES PCT / US2024 / 0425 CROSS REFERENCE TO RELATED APPLICATIONS [ 0001 ] This application claims the benefit of priority under 35 U.S.C. $ 119 ( e ) of U.S. Provisional Patent Application Serial No. 63 / 533,059 filed on August 16 , 2023 , and of U.S. Provisional Patent Application Serial No. 63 / 548,345 filed on November 13 , 2023. The disclosure of the prior applications are considered part of and are herein incorporated by reference in the disclosure of this application in their entirety .

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION [ 0002 ] The present disclosure relates generally to compositions and methods for treating a seizure in a patient . [ 0003 ] BACKGROUND INFORMATION Absence epilepsy is a form of epileptic syndrome where patients show generalized non - convulsive seizures characterized by a brief unresponsiveness to environmental stimuli and cessation of activity . In human , typical absence seizures are associated with bilateral , synchronous and regular spike and wave discharges ( SWD ) . This type of epilepsy presents a specific pharmacology different from the one observed in other types of epilepsies . Therefore , careful evaluation of new antiepileptic drugs in development is needed , as there is a possibility of aggravation of SWD in idiopathic generalized epilepsies and particularly in absence epilepsy .

SUMMARY OF THE INVENTION [ 0004 ] The present invention is based , in part , upon the development of a method of providing anti - seizure effects in a subject by administering a compound BAER - 101 , which is a selective potentiator of a2 / 3 - containing GABAA receptors . BAER - 101 suppressed seizures in animal models of epilepsy , such as the GAERS animal model of absence seizures , without causing sedation or dizziness . [ 0005 ] In one embodiment , the present invention provides a method of providing anti- seizure effects in a subject including administering to the subject an anti - seizure effective amount of a compound of Formula ( 1 ) 1 NH , N N F F - 1 ! -- PCT / US2024 / 0425 Formula ( I ) ( 4 - amino - 8- ( 2 - fluoro - 6 - methoxy - phenyl ) -N - propyl - cinnoline - 3 - carboxamide ) ( also referred to herein as BAER - 101 or AZD7325 ) or a pharmaceutically acceptable salt thereof , in a pharmaceutically acceptable carrier . In one aspect , the techniques described herein relate to a method , wherein the subject has epilepsy . [ 0006 ] In one aspect , the epilepsy is idiopathic generalized epilepsy , photosensitive epilepsy . or genetic absence epilepsy . In another aspect , the idiopathic generalized epilepsy is childhood absence epilepsy , juvenile absence epilepsy , or Dravet syndrome . In various aspects , the seizures are absence seizures , focal seizures , complex partial seizures , tonic - clonic seizures , grand mal seizures , myoclonic seizures , atonic seizures , audiogenic seizures , or clonic seizures . [ 0007 ] In another aspect , the effective amount is from about 0.1 to 100 mg / kg . In an additional aspect , the effective amount is about 0.1 mg / kg , about 0.3 mg / kg , about 1.0 mg / kg . about 3.0 mg / kg , about 10 mg / kg , about 30 mg / kg , or about 100 mg / kg . [ 0008 ] In various aspects , the effective amount is administered by oral administration . In one aspect , the compound is administered once , twice , three or four times daily . In another aspect , the compound is administered at least 10 minutes before onset of a seizure episode . [ 0009 ] In one aspect , the method includes administering an additional compound . In an additional aspect , the additional compound is selected from brivaracetam , cannabidiol , carbamazepine , cenobamate , cenobamate , chlordiazepoxide , clobazam , clonazepam , diazepam , eslicarbazepine , ethosuximide , felbamate , fosphenytoin , gabapentin , ganaxolone , lacosamide , lamotrigine , levetiracetam , midazolam , oxcarbazepine , perampanel , phenobarbital , phenytoin , pregabalin , primidone , rufinamide , secobarbital , stiripentol , tiagabine , topiramate , valproate , vigabatrin , or zonisamide . 2 WO 2025/038882 PCT / US2024 / 0425 BRIEF DESCRTION OF THE DRAWINGS [ 0010 ] FIG . 1 is a graph showing a representative EEG tracing showing the well - defined spike - wave discharges that occur spontaneously in the GAERS model during the generalized absence seizure period in these rats . [ 0011 ] FIG . 2 is a graph showing the number of spike - and - wave discharges ( SWDs ) per min , in the vehicle condition ( top black line ) , diazepam at 2 mg / kg IP ( light grey ) , and BAER- 101 at 0.1 to 100 mg / kg PO ( other shades ) . The arrow indicates the time of compound administration . # , ## , ### , #### : p < 0.05 , 0.01 , 0.001 and 0.0001 as compared to vehicle ( n = to 12 as per Table 1 ) . [ 0012 ] FIG . 3 is a bar chart showing the number of SWD over the 80 min after administration , expressed in % of the baseline values , in all conditions . ## , #### : p < 0.01 and 0.0001 , as compared to vehicle . [ 0013 ] FIG . 4 is a graph showing average duration of remaining SWDs per 20 min , in the vehicle condition ( top black line ) , diazepam at 2 mg / kg IP ( light grey ) , and BAER - 101 at 0.to 3 mg / kg PO ( shades of grey ) . BAER - 101 at doses above 3 mg / kg were not considered , as few SWDs durations could be measured . The arrow indicates the administration time . # , ### , #### : p < 0.05 , 0.001 and 0.0001 as compared to vehicle ( n = 4 to 12 ) . [ 0014 ] FIG . 5 is a bar chart showing the average duration of SWDs remaining after administration , over the 80 min after administration , expressed in % of the baseline values . Vehicle , diazepam and BAER - 101 doses from 0.1 to 3 mg / kg were considered . Doses of BAER - 101 above 3 mg / kg were not considered , as few SWDs could be measured . ### , #### : p < 0.001 and 0.0001 , as compared to vehicle . [ 0015 ] FIG . 6 is a graph showing total time spent in SWDs per 20 min , in the vehicle condition ( black ) , diazepam at 2 mg / kg IP ( light grey ) , and BAER - 101 at 0.1 to 100 mg / kg PO ( other shades ) . The arrow indicates the administration . ## , ### , #### : p < 0.01 , 0.001 and 0.0001 as compared to vehicle ( n = 4 to 12 ) . [ 0016 ] FIG . 7 is a bar chart showing the number of SWDs over the 80 min after administration , expressed as a % of the baseline values , in all conditions . ### , #### : p < 0.0and 0.0001 , as compared to vehicle . [ 0017 ] FIG . 8 is a bar chart showing concentrations of BAER - 101 across the six EEG and blood sampling periods of the study . [ 0018 ] FIG . 9A is a bar chart showing concentrations of BAER - 101 from rat plasma as a function of dose . The bars are means ± S.D. 3 WO 2025/038882 PCT / US2024 / 0425 [ 0019 ] FIG . 9B is a graph showing the relationship of BAER - 101 concentration to suppression of SWD in the GAERS model . The points are means . [ 0020 ] FIG . 10 is a timeline for in vivo testing of concentrations of BAER - 101 and EEG tracings in the GAERS model as described herein ( see for example , EXAMPLE 1 ) . [ 0021 ] FIG . 11 is a graph showing the number of spike - and - wave discharges ( SWDs ) per min , in the vehicle condition ( top black line ) and diazepam at 2 mg / kg IP ( light grey . [ 0022 ] FIG . 12 is a graph showing the number of spike - and - wave discharges ( SWDs ) per min , in the vehicle condition ( top black line ) , diazepam at 2 mg / kg IP ( light grey ) , and BAER - 101 at 3 , 10 , 30 and 100 mg / kg PO ( other shades ; lower lines ) .

DETAILED DESCRTION OF THE INVENTION [ 0023 ] The present invention is based on the seminal discovery that the compound AZD7325 / BAER - 101 , which is a selective potentiator of c2 / 3 - containing GABAA receptors , has potent anti - seizure effects . This discovery is supported by data showing that AZD7325 / BAER - 101 dose - dependently reduced the number , duration , and total time of spike- wave discharges ( SWDs ) . [ 0024 ] Before the present compositions and methods are described , it is to be understood that this invention is not limited to the particular compositions , methods , and experimental conditions described , as such compositions , methods , and conditions may vary . It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only , and is not intended to be limiting , since the scope of the present invention will be limited only in the appended claims . [ 0025 ] The present disclosure provides a method for treatment of seizures in a subject . BAER - 101 ( formerly AZD7325 ) is a selective partial potentiator of a2 / 3 - containing GABAA Receptors ( GABAARS ) and produces minimal sedation and dizziness . Antiseizure effects in models of Dravet and Fragile X Syndromes have been published . BAER - 101 has been administered to over 700 healthy human volunteers and patients where it was found to be safe and well tolerated . To test the extent of the anti - seizure activity of BAER - 101 , BAER - 101 was tested in the Genetic Absence Epilepsy Rats from Strasbourg ( GAERS ) model , a widely used and translationally relevant model . GAERS rats with recording electrodes over the frontal and parietal cortices bilaterally were used . Electroencephalography ( EEG ) signals in freely moving awake rats were analyzed for spike - wave discharges ( SWDs ) . BAER - 101 was administered orally at doses of 0.3 to 100 mg / kg and diazepam was used as a positive control using a cross- 4 WO 2025/038882 PCT / US2024 / 0425 over protocol with a wash - out period between treatments . The number of SWDs was dose- dependently reduced by BAER - 101 with 0.3 mg / kg being the minimally effective dose . The duration and total time in SWD were also reduced by BAER - 101 . Concentrations of drug in plasma achieved a minimally effective dose of 10.1 nM , exceeding the Ki for a2 or a3 , but times lower than the Ki for a5 - GABAARS . No adverse events were observed up to a dose 300x the minimally effective dose . The data support the possibility of antiseizure efficacy without the side effects associated with other GABAAR subtypes . This is the first report of an a2 / 3- selective GABA PAM suppressing seizures in the GAERS model . The data support the use of BAER - 101 in patients with epilepsy . [ 0026 ] As used in this specification and the appended claims , the singular forms " a " , " an " , and " the " include plural references unless the context clearly dictates otherwise . Thus , for example , references to " the method " includes one or more methods , and / or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth . [ 0027 ] As used herein , the term " and / or " includes any and all combinations of one or more of the associated listed items . [ 0028 ] BAER - 101 , formerly AZD7325 ( Formula ( I ) ) , is a positive allosteric modulator ( PAM ) of g - amino - butyric acid A receptors ( GABAARS ) . It is an N - substituted cinnoline structurally unrelated to the benzodiazepines . BAER - 101 has been reported to be potent ( ~ -I nM ) and selective for o2 and a3 over other GABAAR subtypes , where it functions as a partial agonist ( ~ 15-18 % of maximal diazepam response at a2 and a3 ; -8 % at a5 ) and a neutral antagonist at al subtypes . This compound has been studied in healthy human volunteers and in patients with generalized anxiety disorder where it displayed good tolerability and a relatively low level of sedation and dizziness , side - effects that are often seen with benzodiazepine structured GABAR PAMS like lorazepam . The compound is disclosed herein as a treatment for epilepsy , as well as for anxiety disorders . BAER - 101 ( AZD7325 or AZ12466186 ) , with the structure of Formula ( I ) , N Formula ( I ) WO 2025/038882 PCT / US2024 / 0425 is a non - benzodiazepine potentiator of a2 and a3 - containing GABAARS with molecular formula C19H19FN402 and molecular weight 354.38 . See also US 7,425,556 , which is incorporated herein by reference in its entirety . [ 0029 ] All publications , patents , and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication , patent , or patent application was specifically and individually indicated to be incorporated by reference . [ 0030 ] Unless defined otherwise , all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention , it will be understood that modifications and variations are encompassed within the spirit and scope of the instant disclosure . The preferred methods and materials are now described . [ 0031 ] GABAAR PAMS are anticonvulsant and include the recent addition of ganaxolone into clinical practice for the treatment of seizures in CDKL5 deficiency disorder . While ganaxolone is a neurosteroid which acts on both synaptic and extrasynaptic GABAARS , BAER - 101 preferentially potentiates a2- and 3α - containing GABAARS and is expected to suppress seizures . Darigabat and ENX - 101 are a2 / 3 / 5 - preferening GABAAR PAMs being developed for epilepsy . KRM - II - 81 , like BAER - 101 , is an a2 / 3 - selective GABAAR PAM , has robust effects in seizure models and appears to be under development for epilepsy and pain . Preclinical studies have reported antiseizure effects of BAER - 101 . The role of collybistin association to the a2 - subunit has been investigated using strategies that included specific loss of function mutations . Gabra2-1 mice had enhanced susceptibility to seizures and early mortality . AZD7325 reduced the anxiety and heightened electroencephalography ( EEG ) power of surviving mice . In a mouse model of Dravet syndrome using Scnlat mice , AZD73was protective against seizures without notable sedation . Fragile X Mental Retardation Protein ( FMRP ) is functionally lost in FXS . The potential protective effects of BAER 101 in FMRP- null mice have also been studied , and BAER - 101 reduced hyperexcitability in cortical circuits , partially corrected the increased frequency - specific baseline cortical EEG power , reduced susceptibility to audiogenic seizures , and improved novel object recognition memory . [ 0032 ] The rationale for the present study was to demonstrate that BAER - 101 reduces seizures in an animal model of generalized seizures where GABA has long been postulated to be a regulating mechanism . The Genetic Absence Epilepsy in Rats from Strasbourg ( GAERS ) model presents a well - characterized system accepted by those of skill in the art for evaluating 6 WO 2025/038882 PCT / US2024 / 0425 absence seizures in rats using defined electrophysiological readouts . This breeding - derived rat strain exhibits spontaneous generalized cortical seizures in the form of spike - wave discharges ( SWDs ) during an absence seizure in which there is behavioral arrest ( FIG . 1 ) . [ 0033 ] Effects of compounds in the GAERS model allow researchers to determine if their compounds are effective in suppressing these generalized seizures . The model has additional utility in predicting seizure exacerbating effects of compounds . Some antiseizure medications are contraindicated for generalized seizures - carbamazepine is one of these anticonvulsants , and also produces increases in SWDs in the GAERS model . The data have predictive validity in patients . [ 0034 ] As described in the present disclosure , BAER - 101 was given orally to GAERS animals in doses of 3 to 100 mg / kg . When all of these doses were found to suppress SWDs , an overlapping dose range of 0.1 to 3 mg / kg was subsequently explored . BAER - 101 suppressed SWDs in the GAERS model with a minimal effective dose of 0.3 mg / kg that resulted in plasma levels that were greater than the Ki for a2 , but less than the Ki for a5 GABAARs . When taken together with the antiseizure effects reported in the literature , these data combined with their human translational power , encourage investigation in patients . The GABA PAM , darigabat , suppressed SWDs in the GAERS model and also significantly suppressed seizures in patients with photosensitive epilepsy ) . The data with BAER - 101 provide the first data supporting the antiseizure efficacy of a GABA PAMS selective for the a2 and a3 subunit GABAAR constructs . [ 0035 ] The present disclosure shows that BAER - 101 suppresses SWDs in the GAERS model of absence seizure . BAER - 101 is a potent compound reported in this model ( see US 7,425,556 for reference compounds , the content of which is incorporated herein by reference in its entirety ) with a minimally effective dose of 0.3 mg / kg , PO . The data show that a GABA PAM is selective for the o2 and a3 - subtype GABAARS is active in this model . The pharmacology of BAER - 101 , which lacks activity at the al - subtype of GABAAR , may be the reason for the low incidence of dizziness and somnolence observed in both animal and human studies with the molecule . [ 0036 ] That potentiation of a2 and a3 - containting GABAARS demonstrates anti - absence effects in the GAERS model and is supported by its on - target engagement with these GABAAR subtypes . Drug exposures were dose - dependent for plasma and the concentration of BAER- 101 at the minimally effective dose for seizure suppression was 10.1 nM . Since the Ki of BAER - 101 at a2 and a3 - associated GABAARS of BAER - 101 is reported to be about 1 nM and 7 WO 2025/038882 PCT / US2024 / 0425 the Ki at a5 is 230 nM , plasma concentrations of BAER - 101 were about 10x the Ki for a2 and a3 but less than 23x the Ki at a5 - containing GABAARS . BAER - 101 is reported to be a neutral antagonist at al - subtype GABAARs . The selectivity of BAER - 10 in vitro and in vivo for 2α / 3- subtypes of GABAARS is consistent with its lack of sedation or other adverse events in the present GAERS study and is consistent with the pharmacological profile of KRM - II - 81 . In healthy human volunteers and anxiety , and FXS patients , BAER - 101 demonstrated the low sedative pharmacological effects reported in rats here and elsewhere . [ 0037 ] There are other molecules that have been designed to selectively potentiate a2 and a3 while avoiding activation of al with the goal of avoiding sedation and dizziness . Two compounds are currently being developed for epilepsy of this type , darigabat and ENV - 101 . Darigabat ( PF - 06372865 ) , an a2 / 3 / 5 - prefering GABA PAM was reported to partially suppress SWD in the GAERS model at a minimally effective dose of 1 mg / kg , and was also shown to translate into anti - seizure effects in humans in a photosensitive model of epilepsy in patients at a single dose of 17.5 mg . However , the aS GABAAR is thought to play a role in synaptic plasticity , cognition , and memory , suggesting that engagement of a5 risks anti - cognitive effects . BAER - 101 is the first clinical candidate which is selective for o2.3 and not for al or a5 , a pharmacology consistent with anti - seizure activity while avoiding side effects common to the GABAA PAM class . [ 0038 ] Absence epilepsy is not fully controlled by current drugs and has a high rate of drug resistance . Absence seizures have been characterized as being dependent on extrasynaptic GABA and antiseizure targets were hypothesized to be thalamic extrasynaptic or GABA transport mechanisms arising from data from a series of elegant studies . The present findings indicate that just an abbreviated subset on synaptic GABAARS is sufficient to suppress absence seizures . [ 0039 ] The GAERS model has pharmacological predictive validity and the efficacy of BAER - 101 in generalized seizures of the GAERS model , along with data from other epilepsy models , leads us to believe that BAER - 101 will have anti - seizure effects in patients . Darigabat suppressed SWDs in GAERS rats and also completely suppressed generalized seizures in a photosensitive model in patients at a single dose of 17.5 mg . The data in photosensitive epileptic patients appears to be predictive of antiseizure properties in a broad population of patients . [ 0040 ] Based on prior patient safety and tolerability data , coupled with the high potency and full efficacy in the GAERS model , BAER - 101 is considered to be a drug suitable for advancing WO 2025/038882 PCT / US2024 / 0425 into human clinical trials for epilepsy . In one embodiment , the present invention provides a method of providing anti - seizure effects in a subject including administering to the subject an N anti - seizure effective amount of a compound of Formula ( I ) Formula ( D ) ( 4 - amino - 8- ( 2 - fluoro - 6 - methoxy - phenyl ) -N - propyl - cinnoline - 3 - carboxamide ) or a pharmaceutically acceptable salt thereof , in a pharmaceutically acceptable carrier . In one aspect , the techniques described herein relate to a method , wherein the subject has epilepsy . [ 0041 ] In one aspect , the epilepsy is idiopathic generalized epilepsy , photosensitive epilepsy , or genetic absence epilepsy . In another aspect , the idiopathic generalized epilepsy is childhood absence epilepsy , juvenile absence epilepsy , or Dravet syndrome . In various aspects , the seizures are absence seizures , focal seizures , complex partial seizures , tonic - clonic seizures , grand mal seizures , myoclonic seizures , atonic seizures , audiogenic seizures , or clonic seizures . [ 0042 ] The term " effective amount " refers to the amount of a compound , composition , or formulation that is sufficient to treat a condition or disease , to produce desirable effects or results , or to reduce , ease , or arrest symptoms of a condition or disease . " Effective amount " is used interchangeably with the term " therapeutically effective amount " . [ 0043 ] As used herein , the term " treatment " refers to an approach or regimen designed to improve or alleviate symptoms of a disease , sickness , or infirmity . Treatment provides anti- seizure effects . Treatment can lead to reduction in frequency or duration of seizures , improvement of quality of life , or decrease in number , duration , or total time of spike - wave discharges . Providing anti - seizure effects can also occur when symptoms or tests for seizures are nonexistent or improved , or when symptoms or tests for seizures do not worsen , or stabilize . [ 0044 ] In some aspects , the subject is a human . In other aspects , the method of the invention is for veterinary use , such as for non - human mammals , including canine and feline subjects . [ 0045 ] In some aspects , the effective amount is from about 0.1 to 100 mg / kg . In an additional aspect , the effective amount is about 0.1 mg / kg , about 0.2 mg / kg , about 0.3 mg / kg , about 0.mg / kg , about 0.5 mg / kg , about 0.6 mg / kg , about 0.7 mg / kg , about 0.8 mg / kg , about 0.9 mg / kg , about 1.0 mg / kg , about 2.0 mg / kg , about 3.0 mg / kg , about 4.0 mg / kg , about 5.0 mg / kg , about WO 2025/038882 PCT / US2024 / 0425 6.0 mg / kg , about 7.0 mg / kg , about 8.0 mg / kg , about 9.0 mg / kg , about 10 mg / kg , about mg / kg , about 12 mg / kg , about 13 mg / kg , about 14 mg / kg , about 15 mg / kg , about 16 mg / kg , about 17 mg / kg , about 18 mg / kg , about 19 mg / kg , about 20 mg / kg , about 21 mg / kg , about mg / kg , about 23 mg / kg , about 24 mg / kg , about 25 mg / kg , about 26 mg / kg , about 27 mg / kg , about 28 mg / kg , about 29 mg / kg , about 30 mg / kg , about 40 mg / kg , about 50 mg / kg , about mg / kg , about 70 mg / kg , about 80 mg / kg , about 90 mg / kg , or about 100 mg / kg . In one aspect , the effective amount is from about 0.1 mg / kg to about 1 mg / kg , about 1 mg / kg to about mg / kg , about 5 mg / kg to about 20 mg / kg , about 20 mg / kg to about 40 mg / kg , about 40 mg / kg to about 60 mg / kg , about 60 mg / kg to about 80 mg / kg , or about 80 mg / kg to 100 mg / kg . [ 0046 ] In various aspects , the effective amount is administered by oral , intravenous , intramuscular , subcutaneous , transdermal , or intranasal administration . In In another embodiment , the present invention relates to a pharmaceutical composition comprising a compound of the Formula ( 1 ) . The composition of the present invention is a pharmaceutical composition and comprises an excipient and / or carrier , wherein the excipient and / or carrier is selected from a solvent , diluent , bulking agent , filler , binder , coating , color , disintegrant , flavor , glidant , lubricant , preservative , sorbent , sweetener or vehicle . [ 0047 ] In some aspects , the solvent includes water , ethanol , propylene glycol , polyethylene glycol , glycerol , oil , medium - chain triglyceride , polyethylene glycol , ethyl acetate , triacetin , mineral oil , acetic acid , benzyl alcohol , cetyl alcohol , dimethyl sulfoxide , dimethylacetamide , and N - methyl - 2 - pyrrolidone . In one aspect , the diluent includes hydroxypropyl beta cyclodextrin ( HPbCD ) , water , saline , ethanol , glycerol , propylene glycol , sorbitol , and polyethylene glycol . In other aspects , the bulking agent or filler includes hydroxypropyl beta cyclodextrin ( HPbCD ) , lactose , microcrystalline cellulose , mannitol , cellulose , starch , sodium starch glycolate , pregelatinized starch , dicalcium phosphate , calcium sulphate , colloidal silicon dioxide , magnesium trisilicate , talc , magnesium carbonate , magnesium oxide , titanium dioxide , StarLac , croscarmellose sodium , crospovidone , citric acid , sodium bicarbonate , polysaccharides , lactose , glucose , galactose , starch , and sucrose In various aspects , the binder includes xanthan gum , tragacanth , acacia gum , alginate , pectin , methylcellulose , carboxymethylcellulose , hydroxyethyl cellulose . hydroxypropyl methylcellulose , polyvinylpyrrolidone , polyethylene glycol , poloxamer , sorbitol , glycerin , propylene glycol , gelatin , chitosan , bentonite , and magnesium aluminum silicate . In various aspects , the disintegrant includes croscarmellose sodium , sodium starch glycolate , crospovidone , calcium silicate , starch , starch derivatives , alginic acid , polacrilin potassium citric acid , WO 2025/038882 PCT / US2024 / 0425 microcrystalline cellulose , and silicon dioxide . In another aspect , the glidant includes polysorbate 80 , sodium lauryl sulfate , cetylpyridinium chloride , methylcellulose , hydroxyethylcellulose , bentonite , veegum , alginate , glycerin , propylene glycol , and polyethylene glycol . In some aspects , the lubricant includes dimethicone , simethicone , glyceryl monostearate , sorbitan esters , polyethylene glycol 400 , cetyl alcohol , stearyl alcohol , mineral oil , castor oil , glycerin , propylene glycol , polylsorbates , sodium lauryl sulfate , lecithin , wax , and stearic acid . [ 0048 ] In some aspects , the carriers include buffers such as phosphate , citrate , and other organic acids . In other aspects , the carriers include antioxidants such as ascorbic acid and methionine ; preservatives such as octadecyldimethylbenzyl ammonium chloride , hexamethonium chloride , benzalkonium chloride , benzethonium chloride , phenol , butyl or benzyl alcohol . [ 0049 ] In various aspects , the composition is formulated in crystalline , powder , granular , compacted solid , liquid , solution , tablet , capsule , granule , suspension , elixir , syrup , emulsion , cream , gel , droplet , mist , vapor or spray form . In various aspects , the compound is administered via intracutaneous , subcutaneous , intravenous , intralesional , intraperitoneal , intraarterial , intrathecal , intracapsular , intraorbital , intracardiac , intradermal , transdermal , transtracheal , subcuticular , intraarticular , subcapsular , subarachnoid , intraspinal and intrasternal , oral , sublingual buccal , rectal , vaginal , nasal ocular administrations , as well infusion , inhalation , and nebulization routes . [ 0050 ] In one aspect , the effective amount is administered by oral administration . In one aspect , compound is administered once , twice , three or four times daily . In another aspect , the compound is administered at least 10 minutes before onset of a seizure episode . In one aspect , the compound is administered from about 1 to about 120 minutes before onset of a seizure episode . In another aspect , the compound is administered from about 1 , about 5 , about 10 , about 20 , about 30 , about 40 , about 50 , about 60 , about 70 , about 80 , about 90 , about 100 , or about 120 minutes before onset of a seizure episode . In some aspects , the compound is administered from about 1 to about 10 minutes , about 10 to about 20 minutes , about 20 to about minutes , about 30 to about 40 minutes , about 40 to about 50 minutes , about 50 to about minutes , about 60 to about 70 minutes , about 70 to about 80 minutes , about 80 to about minutes , about 90 minutes to about 100 minutes , about 100 to about 110 minutes , or about 1to about 120 minutes before onset of a seizure episode . 11 WO 2025/038882 PCT / US2024 / 0425 [ 0051 ] In one aspect , the effective amount is administered for one week to 52 weeks or more . In another aspect , the effective amount is administered for at least one week , at least 2 weeks , at least 3 weeks , at least 4 weeks , at least 5 weeks , at least 6 weeks , at least 7 weeks or at least weeks . In further aspects , the effective amount is administered for at least 1 months , at least months , at least 3 months , at least 4 months , at least 5 months , at least 6 months , at least months , at least 8 months , at least 9 months , at least 10 months , at least 11 months , or at least months . " [ 0052 ] In one aspect , the method includes administering an additional compound . In an additional aspect , the additional compound is selected from brivaracetam , cannabidiol , carbamazepine , cenobamate , chlordiazepoxide , or another GABAAR potentiator . In some aspects , the additional compound is clobazam , clonazepam , diazepam , eslicarbazepine , ethosuximide , felbamate , fosphenytoin , gabapentin , ganaxolone , KRM - II - 81 , lacosamide , lamotrigine , levetiracetam , midazolam , oxcarbazepine , perampanel , phenobarbital , phenytoin , pregabalin , primidone , rufinamide , secobarbital , stiripentol , tiagabine , topiramate , valproate , vigabatrin , or zonisamide . [ 0053 ] Treatment with the claimed method provides an anti - seizure effect to the patient . An anti - seizure effect occurs when the number , duration , or total time of spike - wave discharges is reduced . In other aspects , the frequency , duration , or total time of spike - wave discharges , as measured in an EEG , are reduced , providing an anti - seizure effect to the patient . In one aspect , the frequency , duration , or total time of SWDs are reduced by about 5 to about 100 % , compared to the frequency , duration or total time of SWDs before treatment . In some aspects , the frequency , duration , or total time of SWDs are reduced by about 5 % to about 10 % , about 10 % to about 20 % , about 20 % to about 30 % , about 30 % to about 40 % , about 40 % to about 50 % , about 50 % to about 60 % , about 60 % to about 70 % , about 70 % to about 80 % , about 80 % to about 90 % , or about 90 % to about 100 % compared to the frequency , duration or total time of SWDs before treatment . [ 0054 ] In some aspects , frequency , intensity , length of seizures , or a combination thereof . are reduced after administration of the claimed method . In some aspects , frequency , intensity , length of seizures , or a combination thereof are reduced by about 5 to about 100 % compared to the frequency , intensity , length of seizures , or a combination thereof before treatment . In some aspects , the frequency , intensity , length of seizures , or a combination thereof are reduced by about 5 % to about 10 % , about 10 % to about 20 % , about 20 % to about 30 % , about 30 % to about 40 % , about 40 % to about 50 % , about 50 % to about 60 % , about 60 % to about 70 % , about 12 WO 2025/038882 PCT / US2024 / 0425 70 % to about 80 % , about 80 % to about 90 % , or about 90 % to about 100 % compared to the frequency , intensity , length of seizures , or a combination thereof before treatment . [ 0055 ] In some aspects , a change in the frequency of seizures experienced by a patient is quantified by maintaining a detailed seizure diary , where patients or caregivers record each seizure event . The data collected over a period , such as several months , are then compared to the baseline seizure frequency established prior to the initiation of treatment . A statistically significant reduction in the number of seizures per unit of time is indicative of a positive treatment outcome . A reduction in the length of time of a seizure is quantified by using a stopwatch or electronic timing device by an observer at the time of the seizure , or retrospectively estimated by the patient or caregiver immediately after the event . Providing an anti - seizure effect to the patient occurs when the severity of seizures is reduced . In one aspect , severity or duration of seizures is assessed using standardized scales such as the Chalfont Seizure Severity Scale , the National Hospital Seizure Severity Scale , the Liverpool Seizure Severity Scale , the Quality of Life in Epilepsy Inventory , the Seizure Frequency Scale , or other scales . These scales take into account factors such as the level of consciousness during the seizure , injuries sustained , and postictal symptoms . In some aspects , after administration of the claimed method , an anti - seizure effect is a reduction in the severity scale . [ 0056 ] Presented below are examples discussing methods of providing anti - seizure effects contemplated for the discussed applications . The following examples are provided to further illustrate the embodiments of the present invention but are not intended to limit the scope of the invention . While they are typical of those that might be used , other procedures , methodologies , or techniques known to those skilled in the art may alternatively be used .

EXAMPLES EXAMPLE A Phase 2- Ready Potentiator of o2 / 3 - Containing GABAA Receptors Potently and Fully Blocks Seizures in Rats with Genetic Absence Epilepsy [ 0057 ] Rationale . GABAA receptor potentiators are in various stages of development for the treatment of patients with epilepsy . BAER - 101 ( formerly AZD7325 ) is a selective potentiator of a2 / 3 - Containing GABAA Receptors ( GABAARS ) with a lower liability for sedation , dizziness , and ataxia than that of non - selective potentiators . Prior published data have confirmed antiseizure effects of BAER - 101 in genetic models of Dravet Syndrome and Fragile X Syndrome . The aim of the present study was to determine efficacy in a model of generalized 13 WO 2025/038882 PCT / US2024 / 0425 seizures . The Genetic Absence Epilepsy in Rats from Strasbourg ( GAERS ) model is widely accepted for evaluating novel antiseizure medications and is translatable to patients . [ 0058 ] Methods . Fourteen adult male GAERS were maintained and used in a facility approved and monitored by the animal care and use controls in France in accord with all ethical guidelines . Recording electrodes were implanted under general anesthesia using stereotaxic methods . Four active monopolar electrodes were positioned over the frontal and parietal cortices , on both sides of the brain . The approximate coordinates for the frontal cortex were : AP +2 mm , ML +/- 3 mm ( from bregma as reference ) . The approximate coordinates for the parietal cortex were : AP -7 mm , ML +/- 3 mm . A fifth electrode was placed on the cerebellum . as reference . EEG signals were analyzed to count spike - wave discharges ( SWDs ) . [ 0059 ] BAER - 101 was given orally in doses of 3-100 mg / kg and subsequently , in doses of 0.1-3.0 mg / kg . Diazepam was used as a positive control , administered intraperitoneally ( mg / kg , IP ) . A cross - over protocol was used for each rat and minimal wash - out period of 7 days occurred between treatments . EEG recordings were collected on freely moving and awake animals for 40 min pre - administration ( baseline period ) and 90 min post - administration using SYSTEMPLUS EVOLUTION ™ M ( ®DEMORCIM ) . EEG recordings were subsequently analyzed offline and quantified blindly by an expert on our proprietary platform ( ®EUC ) , to identify SWD [ 0060 ] Results . The number of SWDs was dose - dependently reduced in rats given BAER- 101. When the data were summarized over the observation period , 0.3 mg / kg was found to be the minimal effective dose . The duration and total time in SWD were also significantly reduced by BAER - 101 . [ 0061 ] BAER - 101 produced anti - seizure effects with a minimal effective dose of 0.3 mg / kg , PO in GAERS rats confirming the antiseizure effects of this compound . The data are expected to translate into patients with seizures . BAER - 101 has already been in over 700 patients with generalized anxiety disorders and Fragile X Syndrome where it was safe and tolerable . Overall , the data encourage clinical study in patients with epilepsy . [ 0062 ] This study aimed at evaluating test compound AZD7325 on spike - and - wave discharges ( SWD ) in the genetic absence epilepsy rat from Strasbourg ( GAERS ) . AZD73was evaluated at doses ranging from 0.1 to 100 mg . AZD7325 was evaluated in treatment of epilepsy in the GAERS model of absence epilepsy . The study used 14 adult male GAERS rats that were obtained from the breeding colony of INSERM , Grenoble Institute of Neurosciences , France . The rats were implanted with electrodes for SWD recording using EEG . The collected 14 WO 2025/038882 PCT / US2024 / 0425 data included spike - and - wave discharge ( SWD ) . AZD7325 was administered at 0.1 , 0.3 , 1 , 3 , , 30 and 100 mg / kg , PO , with diazepam at 2 mg / kg administered intraperitoneally as a reference compound . The study concluded that AZD7325 reduced the occurrence of SWD dose - dependently in the GAERS model . [ 0063 ] Genetic absence epilepsy rat from Strasbourg ( GAERS ) is a selectively inbred strain of Wistar rats displaying spontaneous SWD . For the last twenty years , the GAERS has become a reference model for absence epilepsy , since these rats were shown to present behavioral , electrophysiological and pharmacological features of absence seizures . Cortical EEG recording is characterized by SWD lasting 17-25 sec , with a recurrence of 45-60 seizures per hour . SWDs start and end abruptly and are associated with a behavioral arrest lasting the time of the discharge . As in human patients , SWD in rats are suppressed by antiepileptic drugs such as valproate , ethosuximide and levetiracetam , whereas other antiepileptic drugs have no efficacy or can even aggravate SWD , particularly carbamazepine , phenytoin , and pregabalin . [ 0064 ] This genetic model offers therefore a high predictivity for identifying anti - absence as well as pro - epileptic effect for AED in development or other compounds acting on the CNS . [ 0065 ] This study was performed following local Standard Operating Procedures .

Materials and methods Compound preparations [ 0066 ] Test compound AZD7325 was formulated at the appropriate concentrations , for a dose volume of 5 ml / kg . Diazepam was formulated for a dose volume of 10 ml / kg . AZD73[ 0067 ] AZD7325 was formulated at 0.02 to 20 mg / ml , for a dosing volume of 5 ml / kg , in a % hydroxypropyl beta cyclodextrin ( HPbCD ) in water . [ 0068 ] The vehicle was prepared in advance and kept at 4 ° C for a maximum of 4 weeks . HPbCD ( batch A0434679 , ref . 297561000 , FISCHER SCIENTIFIC ™ , France ) was weighed , and transferred in 50 % of the final volume of water for injection ( Cooper , France ) . The mixture was stirred until complete dissolution , then the volume was adjusted to the final volume . [ 0069 ] A first solution of AZD7325 was prepared at 20 mg / ml ( phase 1 ) or 0.6 mg / kg ( phase ) . AZD7325 material was weighed in a glass vial . Then the appropriate volume of vehicle was added little by little while stirring . The mixture was vortexed , then sonicated for 15 min . The resulting formulation was a clear solution . [ 0070 ] Lower concentrations for each phase were then prepared using serial dilutions from the initial concentrated solution described above . An appropriate volume of AZD7325 solution WO 2025/038882 PCT / US2024 / 0425 was measured , and then the appropriate volume of vehicle was added . The mixture was vortexed . [ 0071 ] All formulations were then aliquoted in appropriate volumes for one EEG recording . Aliquots were protected from light and stored at 4 ° C for a maximum duration of 10 days . One formulation was used for two EEG recordings . [ 0072 ] When formulations were stored at 4 ° C before use , they were left at room temperature for 10-15 minutes before use . Then they were placed in an ultrasound bath for 15 minutes . All formulations were still clear solutions .

Diazepam [ 0073 ] Diazepam ( Diazepam TVM , ®EHCOR , batch F0015-05 ) was diluted down to 0.mg / ml using saline ( 0.9 % NaCl ) , for a dose volume of 10 ml / kg . Diazepam was prepared immediately before administrations .

Animal model [ 0074 ] 14 adult male GAERS were obtained from INSERM , Grenoble Institute of Neurosciences , Grenoble , France and delivered to the laboratory at the age of ~ 3 months . Animals were first housed in groups in cages on wood litter with free access to food and water until surgery . Animal housing was maintained under artificial lighting between 7:30 am to 7:pm in a controlled ambient temperature ( 22 ± 2 ° C ) and relative humidity . [ 0075 ] At the time of experiments ( compound testing ) , animals were aged 4 to 5 months old . They were fully evïan and had not been submitted to any experimentations before the protocol described hereafter .

Electrode implantation [ 0076 ] Electrodes for SWD recording were implanted in all 14 rats , under general anesthesia ( isoflurane ; 2 % in oxygen ) using stereotaxic methods . [ 0077 ] Animals first received an injection of the antalgic drug buprenorphine ( 0.05 mg / kg ) , about 2 hours before induction of anesthesia . After anesthesia induction , rats were placed in the stereotaxic frame . The body temperature was monitored and maintained constant during the surgery . An ophthalmic gel was placed on the eyes to avoid the drying of the cornea . The depth of anesthesia was controlled before starting the surgery and the breathing rate and the cardiac rhythm were visually controlled during the surgery . The incision zone was first cleaned . and betadine was applied . The skin was incised , and the skull cleaned . Five monopolar electrodes were positioned over the frontal and parietal cortices , in both sides of the brain . The WO 2025/038882 PCT / US2024 / 0425 approximate coordinates for the frontal cortex were : AP +2 mm , ML +/- 3 mm ( from bregma as reference ) . The approximate coordinates for the parietal cortex were : AP -7 mm , ML +/- mun . The rats were equipped with a female connector fixed on the skull to allow chronic EEG recordings . A fifth electrode was placed on the cerebellum as reference . [ 0078 ] After surgery , animals were maintained in individual cages . Within 8 hours from surgery , animals received a second injection of buprenorphine ( 0.05 mg / kg ) . Animals were left in their home cage for at least one week of recovery .

Animal selection [ 0079 ] Two weeks after electrode implantation , a one - hour preliminary EEG was recorded . on all animals , in control conditions . EEG signals were analyzed , to count SWD . From the 14 implanted GAERS , all 14 animals were found valid for EEG experiments , according to quality criteria of signal - to - noise ratio and number of SWD per hour : they all presented a satisfying signal - to - noise ratio , and a sufficient number of SWD ( above 20 per hour ) . 12 animals were randomly selected for the pharmacological experiments . The remaining animals were kept in a reserve pool .

Compound testing in EEG recordings [ 0080 ] Acute doses of AZD7325 were administered and evaluated during EEG recordings grouped in 2 phases .

Compound administrations [ 0081 ] All compound conditions were administered PO , in a 5 ml / kg dose volume except diazepam which was administered intraperitoneally ( IP ) at 10 ml / kg dose volume .

Phase [ 0082 ] [ 0083 ] Vehicle ( 20 % HPbCD in water ) PO , intraperitoneal diazepam at 2 mg / kg , BAER- 101 at 100 mg / kg PO , BAER - 101 at 30 mg / kg PO , BAER - 101 at 10 mg / kg PO , and BAER- 101 at 3 mg / kg PO . Compound conditions were administered in a cross - over protocol , following the rules : each animal received each condition , in a random order and in separate recording sessions , two animals received each condition in each recording session , and a minimal wash - out period of 7 days was allowed between each administration .

The initial study plan with BAER - 101 included the following 6 conditions : 17 WO 2025/038882 PCT / US2024 / 0425 [ 0084 ] An intermediate check on study results after the second EEG of this cross - over protocol indicated that compound doses all produced substantial effects on EEG . The cross- over was interrupted , and doses were changed in phase 2 to a lower overlapping dose set . [ 0085 ] An intermediate check on study results after the second EEG of this cross - over protocol indicated that compound doses were too high and were adjusted . The cross - over was interrupted , and doses were changed in phase 2 .

Phase [ 0086 ] Four EEG recordings were completed with the following set of compound conditions : Vehicle ( 20 % HPbCD in water ) PO , intraperitoneal diazepam 2 mg / kg , and BAER- 101 ( 0.1 , 0.3 , 1 , and 3 mg / kg , PO ) . Compound conditions were still administered in a cross- over protocol , following the rules : each animal received 4 different conditions from the indicated above , in a random order and in separate recording sessions , animals having received the vehicle , diazepam or BAER - 101 at 3 mg / kg during phase I were not ascribed again to these conditions , and a minimal wash - out period of 7 days was allowed between each administration . [ 0087 ] The final administration table after phases 1 and 2 are described in the Table 1 . [ 0088 ] Table 1 : Administration table during the 6 EEG recordings , indicating which compound condition was administered to which animal ( in line ) during which recording ( in columns ) . EEG 1 EEG 2 EEG comp . dose ( mg / kg ) comp . dose ( mg / kg ) comp . 23SC0623SC06vehicle N / A diazepam AZD73 dose ( mg / kg ) 0.AZD7325 } { } diazepam AZD7323SC0635 AZD7325 3 AZD7325 100 vehicle N / A 23SC0636 AZD7325 3 AZD7325 30 AZD73238C0637 vehicle N / A AZD7325 diazepam 23SC0638 AZD7325 30 AZD7325 1diazepam 23SC0639 AZD7325 100 AZD7325 30 AZD7325 0.23SC06diazepam AZD7325 3 AZD7325 0.23SC0643 AZD7325 100 AZD7325 10 AZD7325 23SC0644 AZD7325 3 { } vehicle N / A AZD7323SC0645 AZD7325 10 vehicle N / A 23SC0646 diazepam AZD73AZD73vehicle 0.N / A EEG 4 EEG S EEG comp . dose ( mg / kg ) comp . dose ( mg / kg ) comp . dose ( mg / kg ) 23SC0623SC06AZD73vehicle 0.3 AZD7325 N / A AZD7325 23SC0635 AZD7325 0.3 AZD7325 0.23SC0636 AZD7325 0.diazepam AZD73AZD73diazepam vehicle 0.N / A WO 2025/038882 PCT / US2024 / 0425 23SC0637 AZD7325 } AZD7325 0.3 AZD7325 23SC0638 AZD7325 3 vehicle N / A AZD7325 0 . 23SC0639 diazepam vehicle N / A AZD7325 23SC0641 AZD7325 1 AZD7325 0.1 vehicle N / A 23SC0643 vehicle N / A AZD7325 0.diazepam 23SC0644 AZD7325 diazepam AZD7325 0.23SC06diazepam AZD7325 3 AZD7323SC0646 AZD7325 0.1 AZD7325 AZD7325 0.

EEG recordings [ 0089 ] The day of the recording session , the 12 selected animals were placed in a recording chamber and connected to their cable . A habituation period ( -30 min ) was allowed before the EEG recording session . EEG recordings were collected on freely moving animals for minutes pre - administration ( baseline period ) and 90 minutes post - administration using SYSTEMPLUS EVOLUTIONTM ( ®DEMORCIM ) . Animals were maintained in quiet wakefulness state during the recording session . An experimenter was monitoring the animals and was maintaining wakefulness by gently stimulating the animals when needed .

Data analysis [ 0090 ] EEG recordings were subsequently analyzed offline and quantified blindly by an expert on the proprietary platform , to identify SWD ( Error ! Reference source not found . 1 ) . The SWD occurs spontaneously , with clear - cut start and stop well defined over the basal EEG activity [ 0091 ] SWD were analyzed during a 40 min baseline period ( immediately before compound administration ) , and for a period of 80 min between 10 and 90 min after compound administration . The first 10 min immediately after administration are not considered since the administration process disturbs strongly the occurrence of SWD . [ 0092 ] Data are expressed as mean ± SEM . For each animal and administration , data were computed for number , average duration and cumulated duration of SWD per 20 min periods . Post - treatment data were also pooled over the 80 min duration of the post - treatment period , and normalized in % for baseline values , providing a single data point measuring the percentage of inhibition for each animal and each dose . ED50 was calculated from these data , using a non- linear regression in GRAPHPAD PRISMTM v9.5 .

Statistics [ 0093 ] Statistical analyses were performed using GRAPHPAD PRISM ™ v9.5 . The significance level was set at p < 0.05 . 19 WO 2025/038882 PCT / US2024 / 0425 [ 0094 ] Absolute data measured per 20 min periods were analyzed using a two - way ANOVA with the compound condition and the time from administration as factors . As the crossover design was not fully completed , not all animals received all doses of AZD7325 . Consequently , measures were considered repeated within the time factor . When significant , ANOVA was followed by paired comparisons using a Dunnett test , with comparisons versus the second baseline period , versus vehicle , and versus diazepam . [ 0095 ] Pooled data over the whole post - treatment period were analyzed using a one - way ANOVA , with the compound condition as factor . When significant , the ANOVA was followed by paired comparisons using a Dunnett test , versus the vehicle condition .

Plasma Concentrations of BAER - 1[ 0096 ] Drug concentrations were determined for the purpose of correlating with pharmacodynamic effects .

Blood samples for PK measurements [ 0097 ] For the purpose of determining plasma drug concentrations , blood was sampled from each animal . Directly after each EEG recordings , blood was collected via tail sampling on each animal from the crossover for analysis and plasma collection .

Compound conditions [ 0098 ] A sample was collected at the end of each EEG from each phase . All animals included in EEG were sampled . The administration table is provided in Table 1 .

Sample collections [ 0099 ] Plasma samples were collected from each animal at the end of each recording sessions ( i.e. , 6 recordings in total ) about 2 hours after compound administration . The tail vein was punched with a needle , and blood was collected directly into a ®TDETSRAS ®ETTEVINIM POCT system . Blood samples were then transferred into a 0.2 ml PCR tube . All tubes were kept on ice for less than 30 min before centrifugation . The centrifugation was conducted at 3000 g , for 10 min , at 4 ° C . The resultant plasma , at least 25 lµ was collected and transferred into a labelled tube and stored at -80 ° C until shipment .

Bioanalytical Methods [ 0100 ] Plasma was analyzed for concentrations of BAER - 101 by ®VITONI ( West Lafayette , IN , USA ) by LC / MS . LC was a ®XEICS ®NOIXE . A ®XNEICS AD multiplate WO 2025/038882 PCT / US2024 / 0425 was employed . MS detection was by AB ®XEICS 5500 TRIPLE ®4_DAUQ , MS analysis for BAER - 101 ( Q1 / Q3 Masses : 355.000 / 296.100 Da ) used labetalol as an internal standard ( Q1 / Q3 Masses : 329.20 / 294.20 Da ) . [ 0101 ] The UPLC method made use of a WATERSTM HSS T3 column ( 2.7 x 50 mm ) . Elution was by gradient 0.6 mL / min with Mobile Phase A = 0.1 % formic acid in water and Mobile Phase B = 90:10 CAN : MeOH .

Bioanalytical Data Statistics [ 0102 ] Concentrations were evaluated for each experimental phase and at each dose level . The mean ± SEM concentration of BAER - 101 at each dose was determined and assessed for dose - dependence by ANOVA and Dunnett's test using the concentration of BAER - 101 at 0.mg / kg as the control . [ 0103 ] Although different doses of AZD7325 were evaluated in separate phases , all results from both phases were combined , to provide a better overview of the effects of AZD7325 on SWDs . Resulting from the dose change after interruption of phase , the number of data in each compound conditions were uneven ( Table 2 ) . [ 0104 ] the study . Table 3 : final number of animals having completed the compound conditions during Compound condition Vehicle PO Diazepam at 2 mg / kg IP AZD7325 at 0.1 mg / kg PO AZD7325 at 0.3 mg / kg PO AZD7325 at 1 mg / kg PO AZD7325 at 3 mg / kg PO AZD7325 at 10 mg / kg PO AZD7325 at 30 mg / kg PO AZD7325 at 100 mg / kg PO Number of Animals n n n = n n = } } n = n n = Vehicle [ 0105 ] Oral ( PO ) administration with the vehicle composed of 20 % HPbCD in water had no significant effect on the occurrence of SWD . The number and the duration of SWD remained unchanged after administration , as compared to baseline . For example , the number of SWD during the 80 min post - treatment period remained stable at 101.8 ± 7.5 % of the baseline value .

Diazepam [ 0106 ] Diazepam was administered at 2 mg / kg intraperitoneally . 21 WO 2025/038882 PCT / US2024 / 0425 Number of SWD [ 0107 ] Diazepam induced a significant reduction of the number of SWD , immediately after administration . From an average frequency of SWD at 25.6 ± 1.1 SWD per 20 min during baseline , the epileptic activity was reduced down to 1.2 ± 1.1 SWD during the first 20 min period after treatment ( 10 to 30 min after administration ) . This reduction remained stable for the whole post - treatment period , up to 90 min after administration . The average effect of SWD over the 80 min after treatment was 93.1 ± 6.5 % inhibition from baseline .

Average duration of SWD [ 0108 ] The average duration of remaining SWD was not accurately measured , as two animals were still showing continuously epileptic events after treatment . In the other animals , SWD were totally inhibited for at least 70 min after administration . [ 0109 ] These effects of diazepam at 2 mg / kg IP are standard in the GAERS model , and match reference data .

AZD73[ 0110 ] AZD7325 was evaluated at doses ranging from 3 to 100 mg / kg PO during phase 1 . After evaluation of results from the first 2 recordings with these doses , a near complete inhibition of SWD was obtained with all doses . Doses were thus reassessed and reduced down to doses ranging from 0.1 to 30 mg / kg PO in 4 additional recordings . [ 0111 ] Of note , no gross behavioral modifications or adverse effects were observed after the administration of AZD7325 , at any dose included in this study .

Number of SWD [ 0112 ] AZD7325 induced a dose - dependent inhibition of SWD . When considering the number of SWD per 20 min periods after administrations ( Error ! Reference source not found . ) , AZD7325 induced a significant reduction of events at all doses above 1 mg / kg PO , as compared to both the baseline and the vehicle . The effect was immediate , as it was already significant during the first measurement time - point , 10 to 90 minutes after administration . And the effect remained stable over the whole post - treatment period , as it was still significant 70 to minutes after administration . [ 0113 ] When post - treatment data were pooled over the 80 minutes and expressed in percentage of baseline ( FIG . 3 ) , the SWD inhibition was significant for all doses above 0.mg / kg , as compared to the vehicle . The EDSO was estimated at 0.51 mg / kg ( 95 % CI : 0.47 to 0.56 ) .

WO 2025/038882 PCT / US2024 / 0425 [ 0114 ] The average duration of remaining SWD was measured with doses of AZD7325 up to 3 mg / kg . Above that dose , few animals have been tested , and almost no SWD remained , preventing any accurate measure of SWD duration . [ 0115 ] At 1 and 3 mg / kg , AZD7325 induced a significant reduction of the average duration of SWD , as compared to the vehicle ( FIG . 4 ) . For example , SWD lasted on average for 15.9 ± 0.8 s during the 80 min after vehicle administration , and they were reduced to 8.1 ± 0.8 s after treatment with AZD7325 at 3 mg / kg ( FIG . 5 ) . The effect was though less stable than the reduction of the number of SWD : at the end of recordings , 70 to 90 min after administrations , the average duration of SWD in all AZD7325 conditions were returned to values similar to the vehicle condition ( FIG . 4 ) .

Total time in SWD [ 0116 ] The total time spent in SWD is a combined parameter , affected by both the number of remaining SWD and their duration . As both measures were significantly reduced by AZD7325 , the total time in SWD was significantly reduced by AZD7325 . [ 0117 ] AZD7325 induced a significant reduction of the total time as compared to the vehicle , at all doses above 1 mg / kg ( Error ! Reference source not found . ) . The reduction was immediately obtained , 10 to 30 min after administration , with all these doses . And the reduction was still significant at the end of recordings , 70 to 90 min after administration . [ 0118 ] Pooled data over the 80 min post - treatment period showed a dose - dependent effect , with a significant reduction as compared to vehicle at all doses above 0.3 mg / kg ( FIG . 7 ) . At doses above 1 mg / kg , the effect of AZD7325 was not significantly different from the one of diazepam at 2 mg / kg IP . The ED50 for AZD7325 was calculated at 0.47 mg / kg ( 95 % CI : 0.to 0.55 ) . [ 0119 ] AZD7325 is effective at inhibiting SWD in the GAERS model of absence seizures . Doses above 0.3 mg / kg PO can significantly reduce the number and / or the duration of SWD , with an ED50 around 0.5 mg / kg . No adverse effects were observed at doses up to 100 mg / kg .

Drug Concentrations [ 0120 ] Concentrations of BAER - 101 in plasma of the rats were consistent across the EEG and blood sampling periods and showed dose - dependence ( FIG . 8 ) . The dose of orally administered BAER - 101 was proportionally related to the concentrations of BAER - 1achieved in rat plasma ( FIG . 9A ) - ( F6,17 ) = 732.5 , p < 0.0001 . The concentration of BAER- 101 in plasma was significantly associated with suppression of the number of SWD ( FIG . 9B ) . 23 WO 2025/038882 PCT / US2024 / 0425 [ 0121 ] FIG . 10-12 provide further data from our GAERS model investigation showing the surprising potency of BAER - 101 . In the model , dosing started out with 3 higher doses which showed efficacy . Accordingly , lower doses were used to provide a full a dose response .

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Claims (9)

WO 2025/038882 PCT / US2024 / 0425 We claim :

1. A method of providing anti - seizure effects in a subject comprising administering to the subject an anti - seizure effective amount of a compound of Formula ( 1 ) ₂HN N Formula ( I ) ( 4 - amino - 8- ( 2 - fluoro - 6 - methoxy - phenyl ) -N - propyl - cinnoline - 3 - carboxamide ) or a pharmaceutically acceptable salt thereof , in a pharmaceutically acceptable carrier .

2. The method of claim 1 , wherein the subject has epilepsy .

3. The method of claim 2 , wherein the epilepsy is idiopathic generalized epilepsy , photosensitive epilepsy , or genetic absence epilepsy .

4. The method of claim 3 , wherein the idiopathic generalized epilepsy is childhood absence epilepsy , juvenile absence epilepsy , or Dravet syndrome .

5. The method of claim 1 , wherein the seizures are absence seizures , focal seizures , complex partial seizures , tonic - clonic seizures , grand mal seizures , myoclonic seizures , atonic seizures , audiogenic seizures , or clonic seizures .

6. The method of claim 1 , wherein the effective amount is from about 0.1 to 100 mg / kg .

7. The method of claim 6 , wherein the effective amount is about 0.1 mg / kg , about 0.mg / kg , about 1.0 mg / kg , about 3.0 mg / kg , about 10 mg / kg , about 30 mg / kg , or about 100 mg / kg .

8. The method of claim 6 or 7 , wherein the effective amount is administered by oral administration .

9. The method of claim 1 , wherein the compound is administered once , twice , three or four times daily . For the Applicant,Naschitz, Brandes, Amir & .CoP-IL-50489/5