The pan­dem­ic has posed a se­ri­ous chal­lenge to the way drug­mak­ers do busi­ness, which has made it an easy scape­goat for clin­i­cal tri­al duds. Once look­ing to solve Covid-19, Im­mu­nic’s lead drug has now flopped one study and failed to im­press in an­oth­er — is it fair to blame the pan­dem­ic for that?

On Wednes­day, the biotech re­vealed a study for its lead pro­gram in Covid-19 could not be eval­u­at­ed for its pri­ma­ry and sec­ondary end­points. Then on Thurs­day, Im­mu­nic said the same pro­gram hit sta­tis­ti­cal sig­nif­i­cance in pri­ma­ry scle­ros­ing cholan­gi­tis — though on­ly bare­ly — while not­ing the study pop­u­la­tion end­ed up much small­er than ex­pect­ed be­cause of pan­dem­ic re­stric­tions.

The Covid-19 news from Wednes­day sent Im­mu­nic $IMUX shares down about 20%, while Thurs­day’s PSC up­date left a more mut­ed im­pres­sion on Wall Street: in ear­ly morn­ing trad­ing, the com­pa­ny stock was flat.

The Im­mu­nic pro­gram in ques­tion is an oral treat­ment called IMU-838, which aims to block the en­zyme di­hy­drooro­tate de­hy­dro­ge­nase, or DHODH, and in­hib­it the in­tra­cel­lu­lar me­tab­o­lism of ac­ti­vat­ed T and B cells. DHODH in­hibitors can al­so pro­duce a host-based an­tivi­ral ef­fect re­gard­less of spe­cif­ic virus pro­teins and struc­ture, and Im­mu­nic is hope­ful this can lead to use as the treat­ment of sev­er­al dif­fer­ent virus­es.

Im­mu­nic large­ly pinned the Covid-19 tri­al miss on the way the treat­ment land­scape has changed through­out the pan­dem­ic. Re­searchers launched the study al­most a year ago — back in March, to be ex­act — when there was near­ly ze­ro sci­en­tif­ic con­sen­sus on how to treat the dis­ease.

As a re­sult, Im­mu­nic went af­ter ven­ti­la­tion in mod­er­ate Covid-19 cas­es. They sought to mea­sure how well its pro­gram could re­duce the need for in­va­sive ven­ti­la­tion af­ter four weeks in mod­er­ate cas­es. But over the course of the study, they found that less than 1% of hos­pi­tal­ized Covid-19 pa­tients with mod­er­ate cas­es need­ed ven­ti­la­tors at all, es­sen­tial­ly pre­vent­ing them from mea­sur­ing how ef­fec­tive their pro­gram is in this pop­u­la­tion.

Sim­i­lar mis­cal­cu­la­tions oc­curred in the sec­on­daries as well. Go­ing for 28-day mor­tal­i­ty, sur­vival with­out res­pi­ra­to­ry fail­ure and re­duc­ing ICU ad­mis­sions in mod­er­ate cas­es, Im­mu­nic again found in­ci­dence rates that were too low to con­duct analy­ses. Their study found mor­tal­i­ty to be un­der 2% and less than 4.5% of pa­tients re­quired an ICU stay.

Giv­en how lit­tle was known about the nov­el coro­n­avirus at the out­set of the pan­dem­ic, it’s cer­tain­ly pos­si­ble that Im­mu­nic is far from the on­ly biotech to shoot for these ag­gres­sive end­points and come up short. But they tried to pull a pos­i­tive out of the da­ta, high­light­ing that the pro­gram showed a nu­mer­ic ad­van­tage in time to re­cov­ery over place­bo: in pa­tients who were 90% like­ly to re­cov­er from Covid-19, those tak­ing IMU-838 felt bet­ter af­ter 18.9 days as op­posed to the 26.8 days need­ed in the place­bo arm.

Daniel Vitt

Im­mu­nic al­so pre­sent­ed da­ta that the ther­a­py could be help­ful against “long Covid,” where pa­tients who have suc­cess­ful­ly flushed the virus from their sys­tems con­tin­ue to suf­fer from symp­toms and an over­ac­tive im­mune sys­tem, some­times for months. A post-hoc analy­sis of 27 pa­tients saw low­er nu­mer­ic lev­els of long Covid-re­lat­ed fa­tigue in the drug arm.

CEO Daniel Vitt said in a con­fer­ence call Thurs­day morn­ing that the com­pa­ny ex­pects to speak with reg­u­la­tors about how to pro­ceed in Covid-19 and can hope­ful­ly plan a Phase III tri­al, but isn’t sure what that tri­al might look like yet.

The pan­dem­ic al­so af­fect­ed the pro­gram’s study in PSC, as much of the treat­ments were ad­min­is­tered at the Mayo Clin­ic in Min­neso­ta. Pa­tients had to trav­el to the site, which some­times proved chal­leng­ing over the last sev­er­al months, Vitt said. Orig­i­nal­ly plan­ning to en­roll 30 pa­tients, Im­mu­nic end­ed up on­ly be­ing able to ad­min­is­ter the ex­per­i­men­tal drug to 18 pa­tients while on­ly 11 fin­ished the 24-week treat­ment course. And in late 2020 the prin­ci­pal in­ves­ti­ga­tor de­ter­mined the tri­al need­ed to be stopped.

Look­ing to re­duce serum ALP in adults with PSC af­ter 24 weeks, re­searchers found IMU-838 de­creased lev­els by an av­er­age of 5.76 IU/L every 30 days in these 11 pa­tients. That was good for a p-val­ue of p=0.041, hit­ting sta­tis­ti­cal sig­nif­i­cance but com­ing close to the p=0.05 bor­der.

The pro­gram did not hit sta­tis­ti­cal sig­nif­i­cance in the 18-pa­tient pop­u­la­tion that in­clud­ed those who didn’t fin­ish the study, reg­is­ter­ing an av­er­age base­line change of -2.11 and hit­ting a p-val­ue of 0.578. Both stud­ies found the can­di­date to be safe and well-tol­er­at­ed, and Im­mu­nic is plan­ning to move for­ward with an­oth­er tri­al in PSC as well.

In ad­di­tion to Covid-19 and PSC, the can­di­date is al­so be­ing stud­ied to treat mul­ti­ple scle­ro­sis, ul­cer­a­tive col­i­tis and Crohn’s dis­ease. Last Au­gust, the com­pa­ny re­leased topline da­ta in re­laps­ing-re­mit­ting MS pa­tients, say­ing the ex­per­i­men­tal drug re­duced the cu­mu­la­tive num­ber of com­bined unique ac­tive MRI le­sions af­ter 24 weeks com­pared to place­bo.

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