Solv­ing the chal­lenge of nu­cle­ic acid de­liv­ery in RNA med­i­cines

Cell and Gene Ther­a­py is shap­ing up to be the next ma­jor growth area for the Phar­ma­ceu­ti­cal In­dus­try. The US Food and Drug Ad­min­is­tra­tion plans to hire 50 new clin­i­cal re­view­ers to han­dle the 200 plus IND ap­pli­ca­tions per year the agency is ex­pect­ing to re­ceive by 2020 for new ther­a­pies to en­ter clin­i­cal tri­als. In a state­ment, FDA Com­mis­sion­er Scott Got­tlieb and the di­rec­tor of the Cen­ter for Bi­o­log­ics Eval­u­a­tion and Re­search, Pe­ter Marks pre­dict that the agency may be ap­prov­ing 10–20 new cell and gene ther­a­py prod­ucts a year by 2025.¹

The path how­ev­er is not with­out dif­fi­cul­ties. Un­mod­i­fied nu­cle­ic acids can cause a strong im­mune re­sponse and are quick­ly de­grad­ed by en­zymes in the blood­stream and the gut.  There­fore, RNA med­i­cines must be de­liv­ered to tar­get cells us­ing a vec­tor. Vi­ral vec­tors and lipid-me­di­at­ed de­liv­ery sys­tems are the two main ap­proach­es used to de­liv­er in­tact, bioac­tive RNA to tar­get cells in ther­a­peu­tic de­vel­op­ment.

These de­liv­ery sys­tems can cre­ate their own un­want­ed side ef­fects. Vi­ral vec­tors and ex­ist­ing lipid vec­tor tech­nol­o­gy can cause liv­er dam­age and ac­ti­vate an ad­verse im­mune re­sponse in hu­man pa­tients. Vi­ral vec­tors may cause ac­ci­den­tal mu­ta­tions in host DNA, which can lead to can­cer. Pa­tients treat­ed with vi­ral vec­tors can al­so de­vel­op an­ti­bod­ies against these vec­tors that make the treat­ment less ef­fec­tive over time. There is clear­ly a need for im­proved de­liv­ery ve­hi­cles be­fore RNA ther­a­pies can be­come main­stream.

Arc­turus’ has de­vel­oped a pro­pri­etary lipid nanopar­ti­cle de­liv­ery sys­tem which en­ables mul­ti­ple nu­cle­ic med­i­cines with a fo­cus on large RNA. The LU­NAR de­liv­ery sys­tem ef­fec­tive­ly ad­dress­es the is­sues that plague ex­ist­ing vi­ral and lipid vec­tor de­liv­ery sys­tems. As well as its own in-house de­vel­op­ment pro­grams Arc­turus is ap­ply­ing the LU­NAR plat­form through es­tab­lished part­ner­ships with a num­ber of promi­nent Phar­ma­ceu­ti­cal com­pa­nies in­clud­ing Janssen, Take­da, and Ul­traGenyx amongst oth­ers.

LU­NAR®

The LU­NAR tech­nol­o­gy can ef­fec­tive­ly and safe­ly de­liv­er large RNA mol­e­cules in­to tar­get­ed cells with­in a pa­tient’s body. LU­NAR® lipid-me­di­at­ed de­liv­ery tech­nol­o­gy in­cludes a di­verse, grow­ing li­brary of over 160 pro­pri­etary lipids that were ra­tio­nal­ly de­signed to be ver­sa­tile, max­i­miz­ing ef­fi­ca­cy and in­creas­ing tol­er­a­bil­i­ty of a di­verse se­lec­tion of nu­cle­ic acids, tar­get cell types and routes of ad­min­is­tra­tion. A key fea­ture of LU­NAR® lipids is their biodegrad­abil­i­ty, de­creas­ing the un­de­sired ef­fects caused by lipid ac­cu­mu­la­tion that are as­so­ci­at­ed with ex­ist­ing lipid-me­di­at­ed plat­forms, re­sult­ing in tol­er­a­bil­i­ty that can de­crease ef­fi­ca­cy of the ther­a­py or even cause treat­ment to be halt­ed.

LU­NAR® tech­nol­o­gy can be ap­plied to all types of RNA med­i­cine, but it has most com­mer­cial op­por­tu­ni­ty and val­ue in de­liv­er­ing large RNA. These large RNA mol­e­cules show the great­est im­me­di­ate promise for RNA gene ther­a­py, but be­cause of their size and poor sta­bil­i­ty they have tra­di­tion­al­ly been the hard­est to ad­min­is­ter ther­a­peu­ti­cal­ly. The LU­NAR plat­form is al­so able to de­liv­er oth­er small­er ther­a­peu­tic RNA mol­e­cules in­clud­ing an­ti­sense RNA, RNAi, siR­NA, or mi­croR­NA.  Com­pa­nies us­ing small RN/small mol­e­cules can al­so ben­e­fit.

Ben­e­fits of LU­NAR®

• LU­NAR® de­liv­ery tech­nol­o­gy can be used with mul­ti­ple types of nu­cle­ic acid ther­a­peu­tics.
• LU­NAR® can be ad­min­is­tered by mul­ti­ple routes (IV, IM, neb­u­lized, sub­reti­nal, and in­trav­it­re­al).
• LU­NAR® can tar­get mul­ti­ple dif­fer­ent clin­i­cal­ly im­por­tant cells in­clud­ing stel­late cells, he­pa­to­cytes, lung ep­ithe­lial cells, eye cells, and my­ocytes.
• LU­NAR® can de­liv­er mix­tures of dif­fer­ent RNAs as one drug prod­uct.
• Pre­clin­i­cal stud­ies show that LU­NAR com­pounds, un­like oth­er LNP vec­tors, have a wide ther­a­peu­tic in­dex.
• LU­NAR® lipids are op­ti­mized for high RNA and DNA en­cap­su­la­tion ef­fi­cien­cy, which is im­por­tant for the cost of man­u­fac­tur­ing.

Arc­turus’ Pipeline of mR­NA Med­i­cines

Arc­turus aims to lever­age the pro­pri­etary and li­censed in­tel­lec­tu­al prop­er­ty re­lat­ing to LU­NAR® and the Nu­cle­ic acid tech­nolo­gies to de­vel­op a pipeline of mR­NA ther­a­peu­tics for in­fec­tious rare dis­eases and rare ge­net­ic dis­or­ders with sig­nif­i­cant un­met med­ical needs. The two flag­ship pro­grams; LU­NAR®-OTC and LU­NAR®-CF, are on track for IND sub­mis­sion in 1Q2020 and 2H2020 re­spec­tive­ly.

LU­NAR®-OTC

OTC de­fi­cien­cy is caused by mu­ta­tions in the OTC gene which leads to a non-func­tion­al or de­fi­cient OTC en­zyme. OTCD is the most com­mon urea cy­cle dis­or­der. Urea cy­cle dis­or­ders are a group of in­her­it­ed meta­bol­ic dis­or­ders that make it dif­fi­cult for af­flict­ed pa­tients to re­move tox­ic waste prod­ucts as pro­teins are di­gest­ed.

Pre­clin­i­cal proof-of-con­cept stud­ies have shown that LU­NAR®-de­liv­ered hu­man OTC mR­NA re­duces uri­nary orot­ic acid lev­els in a well-es­tab­lished mouse mod­el of OTC de­fi­cien­cy: OTC-spf ash mice. These mice have el­e­vat­ed uri­nary orot­ic acid. Be­cause they have a small amount of resid­ual OTC en­zyme ac­tiv­i­ty, they are not hy­per­am­mone­mic un­less chal­lenged with a high pro­tein di­et through in­hi­bi­tion of the resid­ual OTC en­zyme ac­tiv­i­ty. OTC-spf ash mice were treat­ed with in­duced hy­per­am­mone­mia re­sult­ing from a high pro­tein di­et, with one in­tra­venous dose of LU­NAR®-en­cap­su­lat­ed hu­man OTC mR­NA (can­di­date mR­NA se­quences test­ed at a low, mid­dle, and high dose lev­el)

A LU­NAR®-en­cap­su­lat­ed Lu­ciferase mR­NA was in­clud­ed as a con­trol. As shown in the fig­ure be­low, this sin­gle treat­ment sig­nif­i­cant­ly re­duced uri­nary orot­ic acid lev­els for at least sev­en days post-treat­ment (n=4-6 an­i­mals per group).

LU­NAR®-CF

The LU­NAR®-CF pro­gram ad­dress­es cys­tic fi­bro­sis, a pro­gres­sive lung dis­ease caused by mu­ta­tions in the CFTR gene.

Arc­turus us­es LU­NAR® plat­form to de­liv­er op­ti­mized CFTR mR­NA in­to air­way ep­ithe­lial cells. This al­lows air­way cells to pro­duce func­tion­al CFTR pro­tein us­ing their na­tive trans­la­tion­al ma­chin­ery and pro­tein traf­fick­ing path­ways. This ap­proach has the po­ten­tial to treat the un­der­ly­ing de­fect that caus­es CF (dys­func­tion­al or ab­sent CFTR pro­tein) in all such pa­tients, re­gard­less of mu­ta­tion type. The po­ten­tial has been rec­og­nized by Cys­tic Fi­bro­sis Foun­da­tion Ther­a­peu­tics, Inc. (CFFT), with whom Arc­turus has part­nered with to de­vel­op this im­por­tant ther­a­py.

Arc­turus had com­plet­ed pre­clin­i­cal proof-of-con­cept stud­ies, demon­strat­ing that LU­NAR® ef­fi­cient­ly de­liv­ers a func­tion­al re­porter mR­NA ef­fi­cient­ly in­to mouse lung ep­ithe­lial cells in vi­vo (fig­ure be­low). Six hours fol­low­ing in­tra­tra­cheal de­liv­ery of 0.4 mg/kg of the LU­NAR®-en­cap­su­lat­ed re­porter green flu­o­res­cent pro­tein (GFP) mR­NA, GFP pro­tein ex­pres­sion (shown in brown) was ob­served in mouse lung ep­ithe­lial cells of the pri­ma­ry bronchus and in bron­chi­oles, im­por­tant lung struc­tures, lo­cat­ed in the up­per and low­er air­ways.

Arc­turus con­tin­ues to in­vest in the LU­NAR® lipid-me­di­at­ed de­liv­ery of mR­NA (en­cod­ing CRISPR, TAL­EN, zinc fin­ger pro­teins, and meganu­cle­as­es), siR­NA, DNA, mi­croR­NA, and an­ti­sense oligonu­cleotide tech­nol­o­gy plat­forms to im­prove their ef­fi­ca­cy and safe­ty pro­file, fur­ther ex­pand­ing their ap­pli­ca­tions. These in­vest­ments have led to key in­no­va­tions en­sur­ing op­ti­mal char­ac­ter­is­tics of LU­NAR® for­mu­lat­ed drug prod­ucts are at­tained, and this sets Arc­turus apart from oth­er nu­cle­ic acid ther­a­peu­tics and lipid-me­di­at­ed de­liv­ery plat­forms.

For more in­for­ma­tion on the LU­NAR plat­form, con­tact Ne­da Sa­farzadeh, Di­rec­tor, Head of In­vestor Re­la­tions/PR/Mar­ket­ing at 858.357.7894, or email at ne­da@arc­turus­rx.com.

Ref­er­ences

1. Cross R. FDA pre­pares for huge growth in cell and gene ther­a­py. Chem­i­cal and En­gi­neer­ing News. Jan­u­ary 16, 2019 | VOL 97, IS­SUE 3