PRO­TAC® Pro­tein De­graders: How Arv­inas is Pi­o­neer­ing Po­ten­tial Next-Gen­er­a­tion Treat­ments for Neu­rode­gen­er­a­tive Dis­eases

The toll of neu­rode­gen­er­a­tive dis­eases in the U.S. is dev­as­tat­ing and, with an ag­ing pop­u­la­tion, is grow­ing worse by the day. For in­stance, an es­ti­mat­ed 6.7 mil­lion Amer­i­cans over 65 are liv­ing with Alzheimer’s dis­ease, the most com­mon form of de­men­tia, a fig­ure that could dou­ble by 2050, ac­cord­ing to the Alzheimer’s As­so­ci­a­tion.¹ Rates of oth­er neu­rode­gen­er­a­tive dis­or­ders, such as Parkin­son’s dis­ease, are al­so ris­ing.² Im­proved mol­e­c­u­lar test­ing and greater physi­cian aware­ness have led to mod­est in­creas­es in the preva­lence of a rar­er neu­rode­gen­er­a­tive con­di­tion, Hunt­ing­ton’s dis­ease.³

There is a pro­found un­met need, and new ther­a­pies are need­ed for these de­bil­i­tat­ing con­di­tions. Arv­inas is eval­u­at­ing a nov­el ap­proach called tar­get­ed pro­tein degra­da­tion that the com­pa­ny pi­o­neered, which may one day have the po­ten­tial to pro­vide new ther­a­pies for many of these dev­as­tat­ing dis­eases.⁴ Arv­inas’ PRO­TAC® (PRO­te­ol­y­sis TAr­get­ing Chimera) pro­tein de­graders, which work by ac­ti­vat­ing the cell’s nat­ur­al ma­chin­ery that de­grades ab­nor­mal pro­teins, are al­ready be­ing eval­u­at­ed in clin­i­cal tri­als for sev­er­al on­col­o­gy in­di­ca­tions. Now, we are ex­plor­ing the po­ten­tial for tar­get­ing pro­teins that are thought to cause a va­ri­ety of neu­rode­gen­er­a­tive dis­eases.⁵

These and many oth­er neu­rode­gen­er­a­tive dis­eases have large­ly de­fied ef­forts to dis­cov­er ef­fec­tive treat­ments for their de­bil­i­tat­ing symp­toms with many hav­ing cen­tral ner­vous sys­tem (CNS) tar­gets that have long been con­sid­ered “un­drug­gable.” Fur­ther­more, de­vel­op­ers have strug­gled to de­sign small-mol­e­cule ther­a­peu­tic agents ca­pa­ble of pass­ing through the blood-brain bar­ri­er to reach these tar­gets.⁶ Gene based ther­a­pies and mon­o­clon­al an­ti­bod­ies do not cross the blood-brain bar­ri­er, so small mol­e­cule PRO­TAC® de­graders may of­fer a sig­nif­i­cant ther­a­peu­tic op­por­tu­ni­ty as po­ten­tial treat­ments for neu­rode­gen­er­a­tive dis­eases.

PRO­TAC® pro­tein de­graders use a nov­el mech­a­nism to tar­get pro­teins im­pli­cat­ed in neu­ro­log­i­cal pathol­o­gy and dys­func­tion. Un­like typ­i­cal small mol­e­cule in­hibitors, they do not sim­ply block their tar­gets’ en­zy­mat­ic or sig­nal­ing ac­tiv­i­ty. In­stead, they har­ness a nat­ur­al path­way known as the ubiq­ui­tin-pro­tea­some sys­tem with­in cells to tar­get patho­log­ic pro­teins.⁶

Im­por­tant­ly, some PRO­TAC® pro­tein de­graders can cross the blood-brain bar­ri­er and can be en­gi­neered to tar­get on­ly dis­ease-caus­ing pro­teins and spare healthy pro­teins.⁷ Once in the brain, these agents can de­grade dis­eased pro­teins.⁸

Pre­clin­i­cal Stud­ies

Arv­inas is cur­rent­ly con­duct­ing pre­clin­i­cal stud­ies of sev­er­al PRO­TAC® pro­tein de­graders to ex­plore their phar­ma­co­log­i­cal po­ten­tial to re­move dis­ease-caus­ing pro­teins that have his­tor­i­cal­ly been high­ly chal­leng­ing to tar­get with con­ven­tion­al small mol­e­cules, in­clud­ing those that have his­tor­i­cal­ly been con­sid­ered “un­drug­gable” and thought to con­tribute to Parkin­son’s, Alzheimer’s, and Hunt­ing­ton’s dis­eases.

Parkin­son’s Dis­ease

Vari­ants of the LRRK2 (Leucine-rich re­peat ki­nase 2) gene are one of the most com­mon ge­net­ic risk fac­tors for Parkin­son’s dis­ease, hav­ing been as­so­ci­at­ed with both fa­mil­ial (in­her­it­ed) and spo­radic (no fam­i­ly his­to­ry) cas­es. Cer­tain LRRK2 vari­ants have been linked to in­creased ac­tiv­i­ty and ex­pres­sion of the en­zyme LRRK2 ki­nase, which has been re­port­ed in some Parkin­son’s dis­ease pa­tients and has been shown in pre­clin­i­cal stud­ies to con­tribute to patho­phys­i­ol­o­gy, fur­ther sug­gest­ing it may have a role in the ori­gin and de­vel­op­ment of the con­di­tion.⁹

Hu­man ge­net­ics and pre­clin­i­cal an­i­mal mod­el da­ta sug­gest that re­duc­ing the LRRK2 pro­tein by 50% may im­pact pathol­o­gy and dys­func­tion in Parkin­son’s dis­ease.⁵ There­fore, de­grad­ing LRRK2 in the brain may be ben­e­fi­cial for the treat­ment of this neu­rode­gen­er­a­tive con­di­tion. Arv­inas has de­vel­oped PRO­TAC® mol­e­cules that are high­ly se­lec­tive for degra­da­tion of the LRRK2 pro­tein.⁵ In pre­clin­i­cal stud­ies us­ing mice bred to ex­press the most com­mon fa­mil­ial mu­ta­tion of the gene, LRRK2 G2019S, these mol­e­cules have been po­tent de­graders of LRRK2 in the brain.^5,9

Alzheimer’s Dis­ease

Much re­search on the cause of Alzheimer’s dis­ease has fo­cused on tau, a pro­tein found in ax­ons, the neu­ronal com­po­nent that sends sig­nals to oth­er cells as elec­tro­chem­i­cal waves that are re­quired for healthy brain func­tion. Mu­tat­ed or path­o­gen­ic tau dis­so­ci­ates from mi­cro­tubules that nor­mal­ly sta­bi­lize the ax­on and neg­a­tive­ly im­pacts neu­rons as well as the sup­port­ing glia by form­ing patho­log­ic tau that ul­ti­mate­ly re­sults in cell dys­func­tion and death, in ad­di­tion to form­ing “neu­rofib­ril­lary tan­gles,” the hall­mark patho­log­ic fea­ture of Alzheimer’s dis­ease.⁵

In pre­clin­i­cal stud­ies, Arv­inas has shown that the form of tau as­so­ci­at­ed with neu­ronal tan­gles can be tar­get­ed with PRO­TAC® pro­tein de­graders. In a mouse mod­el of tauopa­thy, PRO­TAC® de­graders elim­i­nat­ed 95% of patho­log­ic tau.¹¹ In ad­di­tion to Alzheimer’s dis­ease, oth­er neu­rode­gen­er­a­tive con­di­tions char­ac­ter­ized by the ac­cu­mu­la­tion of tau, or tauopathies, could be can­di­dates for PRO­TAC® pro­tein de­graders, such as fron­totem­po­ral de­men­tia and pro­gres­sive supranu­clear pal­sy.⁹

Hunt­ing­ton’s Dis­ease

Hunt­ing­ton’s dis­ease is a rare but dev­as­tat­ing dis­or­der linked to a mu­ta­tion in the HTT (Hunt­ingtin) gene. This vari­ant re­sults in a mu­tat­ed ver­sion of a pro­tein known as mHTT that caus­es ag­gre­ga­tion, aber­rant cleav­age of the pro­tein and, ul­ti­mate­ly, the loss of stri­atal neu­rons, which are lo­cat­ed in a brain re­gion as­so­ci­at­ed with mo­tor con­trol.¹² Arv­inas has de­vel­oped PRO­TAC® mol­e­cules that tar­get and de­grade mHTT in cells, in­clud­ing neu­rons, while spar­ing healthy HTT.⁵ In on­go­ing pre­clin­i­cal stud­ies con­duct­ed in mouse mod­els of Hunt­ing­ton’s dis­ease, Arv­inas is study­ing the ef­fects of clear­ing patho­log­ic mHTT pro­tein.¹³

Arv­inas rec­og­nizes the chal­lenges faced by pa­tients with these and re­lat­ed dis­or­ders, which is why we re­main com­mit­ted to de­vel­op­ing this ex­cit­ing new ap­proach to treat­ing neu­rode­gen­er­a­tive dis­eases. Arv­inas is mak­ing strides in that mis­sion and hopes to sub­mit an in­ves­ti­ga­tion­al new drug or clin­i­cal tri­al au­tho­riza­tion (IND/CTA) ap­pli­ca­tion for the first CNS-pen­e­trant PRO­TAC® to emerge from our neu­ro­science ther­a­peu­tic pipeline by the end of 2023.

SOURCES
1. 2023 Alzheimer’s Dis­ease Facts and Fig­ures, p. 26. alzheimers-facts-and-fig­ures.pdf. Ac­cessed Ju­ly 19, 2023.
2. GBD 2017 US Neu­ro­log­i­cal Dis­or­ders Col­lab­o­ra­tors. Bur­den of Neu­ro­log­i­cal Dis­or­ders Across the US From 1990-2017
A Glob­al Bur­den of Dis­ease Study. JA­MA Neu­rol. 2021;78(2):165-176.
3. Med­i­na, A, et al. Preva­lence and In­ci­dence of Hunt­ing­ton’s Dis­ease: An Up­dat­ed Sys­tem­at­ic Re­view and Meta-Analy­sis. Mov Dis­ord. 2022;37(12):2327-2335.
4. Bond, MJ, and Crews, CM. RSC Chem­i­cal Bi­ol­o­gy. 2021;2(3):725-742.
5. Arv­inas web­site: Neu­ro­science. Neu­ro­science | Arv­inas Ac­cessed Ju­ly 20, 2023.
6. Bekes, M, et al. Na­ture Re­views: Drug Dis­cov­ery. 2022;21(3):181-200.
7. Hen­dric­son, A. Dis­cov­ery & Op­ti­miza­tion of PRO­TAC® Mol­e­cules That Se­lec­tive­ly Re­duce Mu­tant Hunt­ingtin. Pre­sent­ed at: CH­DI An­nu­al Meet­ing; Dubrovnik, Croa­t­ia; April 24, 2023; Dis­cov­ery & Op­ti­miza­tion of PRO­TAC Mol­e­cules That Se­lec­tive­ly Re­duce Mu­tant Hunt­ingtin.pdf
8. Ca­cace, A. PRO­TAC Dis­cov­ery En­gine: Har­ness­ing the pow­er of oral blood brain bar­ri­er pen­e­trant de­graders and new E3 lig­as­es. Pre­sent­ed at the Pro­tein So­ci­ety Meet­ing; Ju­ly 14, 2021; vir­tu­al.
9. Zhao, Y and Dzamko N. Drugs. 2019;79:1037–1051.
10. Sil­va, MC, et al. eLife. 2019;8:e45457.
11. Ca­cace, A. Dis­cov­ery of Brain Pen­e­trant PRO­TAC De­grad­er Mol­e­cules That Tar­get Patho­log­ic Tau and al­pha-Synu­cle­in Pro­tein Species [1-22]. Pre­sent­ed at: Tar­get­ed Pro­tein Degra­da­tion Sum­mit; Boston, MA; Oc­to­ber 24, 2019. https://s3.us-east-1.ama­zon­aws.com/arv­inas-as­sets.in­vested­dig­i­tal.com/sci­en­tif­ic-pub­li­ca­tions/Ca­cace_TPD-10-24-2019_fi­nal.pdf
12. Jarosińs­ka, OD and Rüdi­ger, SGD. Fron­tiers of Mol­e­c­u­lar Bio­science. 2021 Nov 12;8:769184.
13. Ca­cace, A, et al. Oral­ly Ad­min­is­tered PRO­TAC® Mol­e­cules Se­lec­tive­ly Clear Patho­log­ic Pro­teins in CNS & Mus­cle. Pre­sent­ed at the So­ci­ety of Neu­ro­science 2022 Meet­ing; No­vem­ber 12-16. San Diego, CA. No­vem­ber.