Re­vis­it­ing the 'cy­tokine stor­m' in ARDS; the painful wait for an­ti-in­flam­ma­to­ry drugs/tar­gets that solve Covid-19 deaths

Biotech Voices is a collection of exclusive opinion editorials from some of the leading voices in biopharma on the biggest industry questions today. Think you have a voice that should be heard? Reach out to senior editors Kyle Blankenship and Amber Tong.

I am a pul­monary and crit­i­cal care physi­cian-sci­en­tist with sub­stan­tial ex­per­tise in crit­i­cal care med­i­cine, par­tic­u­lar­ly in the in­flam­ma­to­ry path­ways in­volved in the acute res­pi­ra­to­ry dis­tress syn­drome (ARDS) and ven­ti­la­tor-in­duced lung in­jury (VILI).

As a re­sult, my lab­o­ra­to­ry has been pur­su­ing mech­a­nis­tic in­sights and ef­fec­tive ther­a­pies for ARDS and VILI for sev­er­al decades. Over this ex­pand­ed time hori­zon, there is abun­dant sup­port for the con­trib­u­to­ry role of the much dis­cussed “cy­tokine storm,” long as­so­ci­at­ed with fa­tal ARDS and now with Covid-19-as­so­ci­at­ed ARDS.

The es­sen­tial na­ture of the elab­o­rat­ed cy­tokines to Covid-19 ARDS out­comes has been ques­tioned in the me­dia and were ini­tial­ly voiced in an ed­i­to­r­i­al by UCSF ARDS ex­perts. It is ap­pro­pri­ate to con­sid­er this point of view; how­ev­er, it must be rec­og­nized that the pri­ma­ry ba­sis for this sen­ti­ment is re­lat­ed to ob­ser­va­tions cen­tered on the in­ter­leukin-6 (IL-6) path­way, well-rec­og­nized to be in­volved in ARDS patho­bi­ol­o­gy.

One ob­ser­va­tion is that me­di­an cir­cu­lat­ing IL-6 lev­els in five Covid-19 co­horts were low­er when com­pared to co­horts of non-Covid-19 ARDS, and the sec­ond ob­ser­va­tion is that sev­er­al high-pro­file tri­als tar­get­ing IL-6 re­cep­tor an­tag­o­nism in Covid ARDS failed to im­prove COVID-19 ARDS mor­tal­i­ty. Specif­i­cal­ly, the IL-6 re­cep­tor an­tag­o­nists tocilizum­ab (Roche/Sanofi) and sar­ilum­ab (Re­gen­eron/Sanofi), both failed to im­prove mor­tal­i­ty in Phase II/III clin­i­cal tri­als of Covid-19 pa­tients with se­vere dis­ease (“Cleanup on IL-6”).

In fact, tri­al ev­i­dence sug­gest­ed that drug re­cip­i­ents may be at in­creased risk for oth­er in­fec­tions, a par­tic­u­lar risk in re­gions where drug-re­sis­tant bac­te­ria are com­mon. The ac­cu­mu­lat­ed fail­ure of tar­get­ing the IL-6 path­way may re­flect sev­er­al fac­tors that are of spe­cif­ic rel­e­vance to IL-6, in­clud­ing the down­stream na­ture of this cy­tokine in the in­flam­ma­to­ry cas­cade, as well as the com­plex role of IL-6 in in­nate im­mu­ni­ty, i.e. ex­ert­ing both an­ti-in­flam­ma­to­ry and pro-in­flam­ma­to­ry ef­fects.

Over­all, I be­lieve there is wide ac­cep­tance that ARDS patho­bi­ol­o­gy is fun­da­men­tal­ly re­lat­ed to mas­sive ac­ti­va­tion of evo­lu­tion­ar­i­ly-con­served in­flam­ma­to­ry net­works by sep­sis (in­fec­tion in the blood), se­vere trau­ma, and se­vere bac­te­r­i­al or vi­ral pneu­mo­nias in­clud­ing SARS-CoV-2. This in­flam­ma­to­ry ac­ti­va­tion is sub­stan­tial­ly am­pli­fied when pa­tients are placed up­on me­chan­i­cal ven­ti­la­tion, a po­tent in­flam­ma­to­ry stim­u­lus and con­trib­u­tor to ARDS mor­tal­i­ty.

Thus, tar­get­ing of the un­remit­ting in­flam­ma­tion re­mains a crit­i­cal com­po­nent to ad­dress­ing ARDS mor­tal­i­ty, al­beit un­like­ly as a sole ther­a­peu­tic strat­e­gy. This was sup­port­ed by the Unit­ed King­dom tri­als demon­strat­ing ben­e­fit of the po­tent, non-spe­cif­ic an­ti-in­flam­ma­to­ry steroid, dex­am­etha­some, in se­vere Covid-19 ARDS.

Clear­ly, ARDS is a vex­ing dis­or­der with­out FDA-ap­proved ther­a­pies and a stag­ger­ing un­met need in the cur­rent Covid-19 pan­dem­ic land­scape. The fail­ure of many promis­ing in­flam­ma­tion-fo­cused ARDS drugs in Phase II and III tri­als, such as IL-6 an­tag­o­nists and gam­ma in­ter­fer­on ana­logues, may re­flect is­sues in: 1) tar­get se­lec­tion, i.e. cy­tokines down­stream in the in­flam­ma­to­ry cas­cade; or 2) de­lays in ad­min­is­tra­tion of the an­ti-in­flam­ma­to­ry ther­a­peu­tic, there­by re­duc­ing its in­flu­ence on damp­en­ing in­flam­ma­to­ry ac­ti­va­tion is min­i­mal.

As a physi­cian-sci­en­tist and ICU care­giv­er, I have been long search­ing for nov­el ap­proach­es to re­duc­ing ARDS mor­tal­i­ty. When serv­ing as the Di­rec­tor of Pul­monary and Crit­i­cal Care Med­i­cine at Johns Hop­kins in 2005, I first re­port­ed the iden­ti­fi­ca­tion of eNAM­PT (ex­tra­cel­lu­lar nicoti­namide phos­pho­ri­bo­syl­trans­ferase) as a mas­ter reg­u­la­tor of in­nate im­mu­ni­ty-dri­ven in­flam­ma­tion that con­tributes to ARDS mor­tal­i­ty and is es­sen­tial­ly in­volved in VILI patho­bi­ol­o­gy.

Our sub­stan­tial pre­clin­i­cal da­ta sup­port the tar­get­ing of eNAM­PT with a hu­man­ized mon­o­clon­al an­ti­body (ALT-100 mAb) to sig­nif­i­cant­ly im­pact hu­man Covid-19- and non-Covid ARDS/VILI. We are mak­ing ex­cel­lent progress in mov­ing ALT-100 mAb down the drug de­vel­op­ment pipeline and to ARDS Clin­i­cal Tri­al eval­u­a­tion.

I am to­tal­ly con­vinced that the in­creas­ing avail­abil­i­ty of nov­el strate­gies (such as ALT-100 mAb) will ul­ti­mate­ly al­low for suc­cess­ful tri­als with drugs that re­duce ARDS sever­i­ty and mor­tal­i­ty, par­tic­u­lar­ly when we be­gin to em­ploy per­son­al­ized med­i­cine strate­gies in tri­al de­sign.

I do be­lieve, how­ev­er, sim­i­lar to the man­age­ment of many can­cers, that to dra­mat­i­cal­ly move the nee­dle on re­duc­ing ARDS/VILI mor­tal­i­ty, will re­quire a com­bi­na­tion of ther­a­peu­tic ap­proach­es (in­clud­ing an an­ti-in­flam­ma­to­ry drug). The wait for an FDA-ap­proved ARDS ther­a­py or ther­a­pies has been a frus­trat­ing re­al­i­ty. I am cer­tain many will agree that giv­en the cur­rent Covid pan­dem­ic and like­li­hood of fu­ture pan­demics, we sim­ply can­not af­ford to wait any longer.

Dr. Joe G.N. Gar­cia is an elect­ed mem­ber of the Na­tion­al Acad­e­my of Med­i­cine and CEO of Aqualung Ther­a­peu­tics, an ear­ly-stage biotech com­pa­ny de­vel­op­ing an im­mune-fo­cused, an­ti-in­flam­ma­to­ry plat­form cen­tered around nov­el ther­a­peu­tic hu­man­ized an­ti­bod­ies for ARDS/VILI pa­tients.

Biotech Voic­es is a con­tributed col­umn from se­lect End­pointsNews read­ers. Read pre­vi­ous pieces here. To in­quire about sub­mis­sions, con­tact Kyle Blanken­ship at kyle@end­pointsnews.com.

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