Ad­dress­ing Key Chal­lenges of Lipid-Me­di­at­ed De­liv­ery Sys­tems for mR­NA through In­no­va­tion

2020 is an­tic­i­pat­ed to be an ex­cit­ing year for the field of mes­sen­ger RNA (mR­NA) ther­a­peu­tics. Sys­temic de­liv­ery of lipid nanopar­ti­cle for­mu­lat­ed mR­NA (i.e. in­tra­venous, IV dos­ing) has been a sig­nif­i­cant chal­lenge for the field of mR­NA ther­a­peu­tics for about 25 years. Arc­turus, an emerg­ing leader in the field of lipid for­mu­lat­ed mR­NA med­i­cines, be­lieves it should be pos­si­ble to over­come this hur­dle by ad­dress­ing the fol­low­ing two key chal­lenges of lipid me­di­at­ed de­liv­ery sys­tems (LMDSs)–ac­cu­mu­la­tion of lipids in the liv­er and un­de­sired im­mune re­sponse to the mR­NA drug sub­stance.

Lipid Biodegrad­abil­i­ty

Through an it­er­a­tive process of ra­tio­nal de­sign and in vi­vo eval­u­a­tion, Arc­turus has iden­ti­fied var­i­ous struc­tur­al mo­tifs that fa­vor fast es­terase-cat­alyzed degra­da­tion and has lever­aged these learn­ings to gen­er­ate a li­brary of pro­pri­etary biodegrad­able lipids, ATX lipids. Arc­turus’ LU­NAR® tech­nol­o­gy, a LMDS, is com­prised of one or more of these ATX lipids. It is rea­son­able to ex­pect that the rapid clear­ance pro­file ob­served for ATX 2.0 in the liv­ers of mice (Fig­ure 1) will trans­late to both non-hu­man pri­mates and pa­tients.

Re­duc­ing Im­muno­genic­i­ty of mR­NA

Pro­duc­ing high pu­ri­ty mR­NA is im­por­tant for any mR­NA ther­a­peu­tic for which ac­ti­va­tion of the im­mune re­sponse would be un­de­sir­able. The Arc­turus pro­pri­etary mR­NA man­u­fac­tur­ing process en­sures that im­muno­genic im­pu­ri­ties; such as dsR­NA, un­capped 5’ mR­NA, resid­ual DNA and pro­tein used to pro­duce the mR­NA, are kept to a min­i­mum. Arc­turus has suc­cess­ful­ly pro­duced sev­er­al batch­es of mR­NA (up to the 12-gram scale) to sup­port tox­i­col­o­gy and ear­ly clin­i­cal tri­als.

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Arc­turus Pre­pares for First Clin­i­cal Tri­als with ARCT-810

Uti­liz­ing its core plat­form tech­nolo­gies, Arc­turus has been de­vel­op­ing a mR­NA ther­a­peu­tic, ARCT-810 (aka, LU­NAR®-OTC), for the treat­ment of or­nithine tran­scar­bamy­lase de­fi­cien­cy (OTCD). OTCD is the most com­mon urea cy­cle dis­or­der. Be­cause the func­tion of the urea cy­cle is to me­tab­o­lize am­mo­nia, a byprod­uct of pro­tein me­tab­o­lism, pa­tients with OTCD suf­fer from el­e­vat­ed am­mo­nia con­cen­tra­tions in the blood­stream (hy­per­am­mone­mia). Hy­per­am­mone­mia can re­sult in se­ri­ous meta­bol­ic cri­sis char­ac­ter­ized by vom­it­ing, re­fusal to eat, pro­gres­sive lethar­gy, po­ten­tial­ly lead­ing to co­ma, ir­re­versible neu­ro­log­i­cal dam­age, or death.

Cur­rent Stan­dard of Care

Be­cause OTC is an in­tra­cel­lu­lar pro­tein lo­cal­ized in the mi­to­chon­dria, treat­ment of OTCD is not amenable to a tra­di­tion­al en­zyme re­place­ment ther­a­py ap­proach. Cur­rent front-line ther­a­py in­volves am­mo­nia scav­engers, a low pro­tein di­et, hy­dra­tion, and the use of sup­ple­ments such as argi­nine to re­duce symp­toms. He­modial­y­sis is some­times re­quired as an in­ter­ven­tion when blood am­mo­nia lev­els rise too high.

The Promise of a Func­tion­al Cure

ARCT-810 is de­signed to de­liv­er OTC mR­NA in­to liv­er (he­pa­to­cytes) where the urea cy­cle oc­curs. Up­on re­lease in­to the cy­tosol, the cells’ own trans­la­tion­al ma­chin­ery makes the OTC pro­tein and de­liv­ers the re­place­ment pro­tein to the mi­to­chon­dria where it may im­prove urea cy­cle ac­tiv­i­ty to re­in­state more nor­mal in­tra­cel­lu­lar phys­i­ol­o­gy and po­ten­tial­ly cor­rect the dis­ease. Thus, OTC mR­NA ther­a­py has the po­ten­tial to pro­vide a func­tion­al cure to pa­tients with OTCD.

Arc­turus has re­cent­ly com­plet­ed a com­pre­hen­sive non­clin­i­cal pro­gram of in vit­ro and in vi­vo phar­ma­col­o­gy, phar­ma­co­ki­net­ics, tis­sue dis­tri­b­u­tion, and tox­i­col­o­gy stud­ies, as well as, cGMP man­u­fac­ture of drug prod­uct and is on track to file an IND in Q1 2020 and sub­se­quent­ly ini­ti­ate first-in-hu­man clin­i­cal tri­als of ARCT-810.

Arc­turus Ther­a­peu­tics in 2020

2019 saw Arc­turus com­plete a num­ber of fi­nan­cial and col­lab­o­ra­tion mile­stones in­clud­ing ex­pan­sion of the Ul­tragenyx col­lab­o­ra­tion for an ad­di­tion­al $30M, in­creased com­mit­ment from the Cys­tic Fi­bro­sis Foun­da­tion to $15M, and a suc­cess­ful fund­ing round for $23M with in­sti­tu­tion­al in­vestors. Demon­strat­ing the con­fi­dence both of cor­po­rate in­vestors and of Phar­ma­ceu­ti­cal part­ners in the core LU­NAR® tech­nol­o­gy and leav­ing the com­pa­ny well-po­si­tioned to ex­e­cute its clin­i­cal and pre­clin­i­cal mile­stones for 2020. In ad­di­tion to fil­ing IND for its LU­NAR-OTC pro­gram, Arc­turus has two oth­er mR­NA ther­a­pies in ad­vanced stages of de­vel­op­ment and pre-clin­i­cal eval­u­a­tion both with key mile­stones in 2020.

• LU­NAR®-GSD3, a part­ner­ship pro­gram with Ul­tragenyx work­ing to de­vel­op mR­NA ther­a­pies for Glyco­gen Stor­age Dis­ease Type III, which con­tin­ues to progress to­wards a 2020+ IND sub­mis­sion. LU­NAR®-GSD3 uti­lizes mR­NA ther­a­peu­tics to re­place the de­fec­tive AGL gene prod­uct and al­low cells to break­down glyco­gen us­ing nor­mal path­ways.
• Arc­turus is al­so ini­ti­at­ing the de­vel­op­ment can­di­date se­lec­tion process for the LU­NAR®-CF Pro­gram. An mR­NA ther­a­peu­tic us­ing the LU­NAR® de­liv­ery plat­form to de­liv­er Cys­tic Fi­bro­sis Trans­mem­brane Re­cep­tor (CFTR) mR­NA in­to air­way ep­ithe­lial cells to treat Cys­tic Fi­bro­sis.

2020 is set up to be a wa­ter­shed year for Arc­turus and the field of mR­NA ther­a­py in gen­er­al, hope­ful­ly open­ing the door to a whole range of new ther­a­pies for pre­vi­ous­ly un­treat­ed ge­net­ic dis­or­ders.