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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

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Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

For those of you who attended #JPM22 in any shape or form, we hope you had a fruitful time. Regardless of how you spent the past hectic week, may your weekend be just what you need it to be.

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