US 20190160078A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0160078 A1 Masuoka et al. ( 43 ) Pub . Date: May 30 , 2019 ( 54 ) GANAXOLONE FOR USE IN TREATING A61K 47 / 38 (2006 .01 ) GENETIC EPILEPTIC DISORDERS A61K 47 34 ( 2006 .01 ) A61K 47 / 24 (2006 .01 ) ( 71 ) Applicant: Marinus Pharmaceuticals , Inc ., A61K 47 / 12 ( 2006 .01 ) Radnor, PA (US ) A61K 47 /26 ( 2006 . 01 ) A61P 25 / 08 (2006 . 01) ( 72 ) Inventors : Lorianne K . Masuoka , Chestnut Hill, (52 ) U . S . CI. MA (US ) ; Jaakko Lappalainen , CPC . A61K 31 /565 ( 2013 .01 ) ; A61K 9 /08 Wilmington , DE (US ) ( 2013 . 01 ) ; A61K 9 /4866 ( 2013 .01 ) ; A61K 9 /4858 (2013 .01 ) ; A61K 9 /485 ( 2013 .01 ) ; (73 ) Assignee : Marinus Pharmaceuticals , Inc . , A61P 25 / 08 (2018 .01 ) ; A61K 47 /34 ( 2013 .01 ) ; Radnor, PA (US ) A61K 47 /24 ( 2013 .01 ) ; A61K 47/ 12 ( 2013 .01 ) ; ( 21 ) Appl. No. : 16 /185 ,677 A61K 47 / 26 ( 2013 .01 ) ; A61K 47 / 38 ( 2013 .01 ) ( 22 ) Filed : Nov . 9 , 2018 (57 ) ABSTRACT Related U . S . Application Data The disclosure provides a method of treating a mammal having a genetic epileptic disorder , comprising chronically (60 ) Provisional application No . 62 /584 ,403 , filed on Nov. administering a pharmaceutically acceptable pregnenolone 10 , 2017 . neurosteroid to a mammal having a genetic epileptic disor der in an amount effective to reduce the seizure frequency in Publication Classification the mammal. In certain preferred embodiments , the mammal (51 ) Int . Cl. is a human patient who has a CDKL5 genetic mutation . In A61K 31/ 565 ( 2006 . 01 ) certain preferred embodiments, the patient has a low endog A61K 9 /08 ( 2006 .01 ) enous level of a neurosteroid ( s ) . In certain preferred embodi A61K 9 / 48 ( 2006 . 01 ) ments , the pregnenolone neurosteroid is ganaxolone . Patent Application Publication May 30 , 2019 Sheet 1 of 11 US 2019 /0160078 A1 Figure 1 . Figure 2 . Horios 14960 VS VA930 USO Particis Size . : . .: . Sinin : . iiiii . : .: . sinisis . : . : . : . : . : . : . : . : . : . : . :. : . .? .1 Patent Application Publication May 30 , 2019 Sheet 2 of 11 US 2019 /0160078 A1 Figure 3A Milling Slurry MAA 25 % ganaxolone Milling Dispersion 25 % ganaxolone Diluted Dispersion 20 % ganaxolone Stabilized Dispersion 19 . 9 % ganaxolone Intermediate Suspension Dilution Coating Feed Dispersion 8 % ganaxolone 10 . 9 % ganaxolone Final Suspension Dilution IR Coated Bead 4 . 9 % ganaxolone 45 % ganaxolone Filling & Bottling Encapsulation 225 mg capsule WA 50 mg/ ml Suspension Patent Application Publication May 30 , 2019 Sheet 3 of 11 US 2019 /0160078 A1 Figure 3B Vessel mixing of ganaxolone in aqueous stabilizer solution to form ganaxolone slurry Recirculation of ganaxolone slurry through NanoMill to reduce particle size of Milled Dispersion to approx . 150 nm Dilution ofMilled Dispersion Addition of stabilizing agents to stabilize particle size at approx. 300 nm Initial dilution of suspension to approx . 8 % ganaxolone Final dilution of suspension to 50 mg /ml Drug product packaging Patent Application Publication May 30 , 2019 Sheet 4 of 11 US 2019 /0160078 A1 Figure 3C Vessel mixing of ganaxolone in aqueous stabilizer solution to form ganaxolone slurry Recirculation of ganaxolone slurry through NanoMill to reduce particle size of Milled Dispersion to approx. 150 nm Dilution of Milled Dispersion Addition of stabilizing agents to stabilize particle size at vo approx . 300 nm Addition of coating excipients to form ganaxolone Coating Feed Dispersion Vio Fluid Bed Coating of ganaxolone Coating Feed Dispersion onto microcrystalline cellulose spheres to form Immediate W Release (IR ) Beads Encapsulation of ganaxolone immediate Release Beads into hard gelatin capsules Patent Application Publication May 30 , 2019 Sheet 5 of 11 US 2019 /0160078 A1 Figure 3D Particle Size Stability of Ganaxolone Nanomilled Suspension .. batch 16M - 144 bulk IR beads. batch 161M - 221, and encapsulated IR beads ( 161M - 345 ) , Horiba LA - 910 vs . LA - 960 , 703 . crrrrrrr . rrrrrrrrrr . (d50 . ,.mean . .. n = 3 ) . crrrrrrrrrrrrrrrrrrrrrrrrrrrr -* 2 W Figure 3B Curing Curve of Ganaxolone Particles Containing Parabens D50(nm) No sonication 1 min sonication 10 3040 Time (days ) Patent Application Publication May 30 , 2019 Sheet 6 of 11 US 2019 /0160078 A1 Figure 4 PC H19 ( N - } } } .. .. .. .. - 13 .. .. .. 3 - m o genown Patent Application Publication May 30 , 2019 Sheet 7 of 11 US 2019 /0160078 A1 Figure 5 . , , , , , , , , , , , , , , , , , , , , , , , . Figure 6 300 . -.- GanakoloneConcentrtion(nom.) . - * . * Patent Application Publication May 30 , 2019 Sheet 8 of 11 US 2019 /0160078 A1 Figure 7 . 009 . Ganaxoloneconcentrtion(ngml.) . - . - . - . 4. - . - . 2 . 1 . Figure 8 - 009 NSW= OC Concentration(namL) Patent Application Publication May 30 , 2019 Sheet 9 of 11 US 2019 /0160078 A1 Figure 9 1000 100 Concentration(ng/mL) 1111111 0 2 4 6 8 10 12 14 16 18 Time (Day ) Figure 10 15, 000 10 .000 Responders Non -responders Patent Application Publication May 30 , 2019 Sheet 10 of 11 US 2019 /0160078 A1 Figure 11 20 , 000 Non - responder 15 , 000 10 , 000 [A110-9),pgmL 5 , 000 i m rker biomarker . 1 - 100 - 50 00 00 5 15 % A seizure frequency 1000 Figure 12 500 300 1.1460) plasmaAllopregnanolone 200 1 0 0 - 100 - 50 50 100 150 % A se izure frequency Patent Application Publication May 30 , 2019 Sheet 11 of 11 US 2019 /0160078 A1 Figure 13 50007 . Study 1042- 0403 ( 0 . 3 -x capsule ) Study 1042- 0404 ( 0 . 3 - 1 capsule ) 40001 AUC-2455)(ng*himL 800 1200 1600 Dose mg( / day ) US 2019 /0160078 A1 May 30 , 2019 GANAXOLONE FOR USE IN TREATING peutic agents ( e . g . , anticonvulsants ) are used together to GENETIC EPILEPTIC DISORDERS treat PCDH19 - related epilepsy, Dravet Syndrome, Lennox Gastaut syndrome (LGS ) , Continuous Sleep Wave in Sleep CROSS - REFERENCE TO RELATED (CSWS ) , Epileptic Status Epilepticus in Sleep (ESES ) , and APPLICATION other intractable epilepsy conditions and refractory genetic epilepsy conditions that clinically resemble PCDH19 - re [ 0001 ] This application claims priority from U . S . Provi lated epilepsy , CDKL5 Deficiency Disorder, Dravet Syn sional Application No . 62/ 584 , 403 , filed on Nov. 10 , 2017 , drome, LGS , CSWS , and ESES . the disclosure of which is hereby incorporated by reference [0007 ] There are also no approved or licensed therapies in in its entirety for all purposes. the United States for the treatment of patients with CDKL5 deficiency disorder . There is also no accepted standard of BACKGROUND OF THE INVENTION care , nor are there guidelines from authoritative scientific [ 0002 ] Infantile epileptic encephalopathies and rare pedi bodies regarding the treatment of these patients . However, atric epilepsies are conditions of significant unmet medical most antiepileptic drugs (“ AEDs” ) , including steroids /adre need . These conditions include PCDH19 - related epilepsy , nocorticotropic hormone (ACTH ) , ketogenic diet, vagal CDKL5 Deficiency Disorder ( CDD ) , Dravet Syndrome, nerve stimulation , and corpus callosotomy (to disrupt inter Lennox -Gastaut syndrome (LGS ) , Continuous Sleep Wave hemispheric connections for reduction of secondarily gen in Sleep (CSWS ) , Epileptic Status Epilepticus in Sleep eralized seizures) have been tried to treat this condition . ( ESES ), and other intractable and refractory genetic epilepsy [0008 ] Efficacy of multiple AEDs and ketogenic diet in conditions that clinically resemble PCDH19 - related epi patients with the CDKL5 mutation is very low . Newer drugs lepsy , CDKL5 Deficiency Disorder , Dravet Syndrome, LGS, tend to be less sedating , have fewer adverse effects on CSWS , and ESES . memory and learning , and are less likely to cause allergic [0003 ] PCDH19 - related epilepsy is a serious and rare reactions and serious side effects. However , some of the epileptic syndrome that predominantly affects females . The most commonly used AEDs to treat CDKL5 deficiency condition is caused by an inherited mutation of the proto disorder - associated seizures are associated with the follow cadherin 19 (PCDH19 ) gene , located on the X chromosome, ing severe adverse effects : and is characterized by early -onset and highly variable [ 0009 ] Cognitive side effects are a considerable concern cluster seizures, cognitive and sensory impairment, and with topiramate . behavioral disturbances . Currently , there are no approved [0010 ) Felbamate can cause aplastic anemia or liver therapies for PCDH19 -related epilepsy , nor is there any failure . effective standard of care therapy . [ 0011 ] Vigabatrin can permanently reduce a child ' s [0004 ] CDKL5 is a rare X linked genetic disorder that results in early onset, difficult to control seizures, and severe field of vision . neuro -developmental impairment. The most common fea [0012 ] Stevens - Johnson syndrome, a severe allergic ture of CDKL5 deficiency disorder is early drug - resistant drug reaction , remains a concern with lamotrigine. epilepsy, usually starting in the firstmonths of life . Seizures [ 0013 ] Compared to the pre - 1990 drugs , many of the are generally highly polymorphic . Complex partial seizures, newer drugs have a broader range of action , making them infantile spasms, myoclonic , generalized tonic - clonic , and more likely to work for generalized seizures . However, tonic seizures have all been reported . Many different seizure some , like gabapentin , pregabalin , oxcarbazepine , and types can also occur in the same patient, changing with time tiagabine, seem to