Ax­cel­la flunks long Covid PhII pri­ma­ry goal — but plots a path in­to PhI­II

As Covid-19 cas­es mount once again and mil­lions of peo­ple ex­pe­ri­ence lin­ger­ing symp­toms months af­ter di­ag­no­sis, Ax­cel­la Ther­a­peu­tics wants to treat long Covid, but like oth­ers in the past, it has failed to meet the pri­ma­ry goal of a mid-stage study.

The biotech isn’t giv­ing up on the pan­dem­ic dis­ease’s long-term ef­fects, a move that PureTech made af­ter miss­ing the beat in its own Phase II last month. Ax­cel­la will at­tempt to per­suade reg­u­la­tors in the US and UK with fa­tigue scores from the Phase IIa, rather than the missed pri­ma­ry goal, in dis­cus­sions about a po­ten­tial reg­is­tra­tional Phase III study fol­low­ing.

Ax­cel­la’s shares $AXLA rose about 15% be­fore the open­ing bell Tues­day, but the stock is still more than $1 be­low its price this time last year.

The main goal of phos­pho­cre­a­tine re­cov­ery rate (PCr) af­ter mod­er­ate ex­er­cise was not achieved in the rel­a­tive­ly small 41-pa­tient study. The biotech thinks clin­i­cal­ly and sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments in self-re­port­ed men­tal and phys­i­cal fa­tigue can get the drug to­ward the fin­ish line, as there are no cur­rent­ly ap­proved treat­ments for the pan­dem­ic dis­ease’s long-term im­pacts.

Con­duct­ed in the UK, the study looked at a va­ri­ety of mea­sures, in­clud­ing the PCr, fa­tigue scores, a six-minute walk test and serum lac­tate lev­els, which rep­re­sent a mea­sure of mus­cle health. The PCr is used to as­sess im­prove­ment of mi­to­chon­dr­i­al func­tion, which cre­ates most of the chem­i­cal en­er­gy, in the so-called pow­er­house of the cell in skele­tal mus­cle.

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来源: Endpts

Mar­garet Koziel

The me­di­an age of pa­tients was 43 years old and, to be en­rolled, the pa­tients had to have se­vere fa­tigue for at least three months, CMO Mar­garet Koziel told End­points News. No pa­tients in the tri­al had been on any oth­er Covid-19 ther­a­pies, she said.

For four weeks, re­searchers gave 21 pa­tients 67.8 grams of AXA1125 di­vid­ed in­to two dos­es per day, and gave a place­bo to 20 ran­dom­ized pa­tients. All 41 com­plet­ed the tri­al, which in­clud­ed a one-week safe­ty fol­low-up pe­ri­od.

Re­gard­ing the pri­ma­ry out­come, Ax­cel­la’s med­ical chief said the drug de­vel­op­er was ex­pect­ing base­line PCr to be around 50 sec­onds, but the fig­ure was “sky-high” in the pa­tients who ac­tu­al­ly took part in the study, con­duct­ed in con­junc­tion with the Uni­ver­si­ty of Ox­ford.

“In­stead, the base­line val­ue was 92 sec­onds, which is like peo­ple who have se­vere pe­riph­er­al ar­te­r­i­al dis­ease, like they are not get­ting blood flow to their low­er legs,” Koziel said.

“The re­al killer for us was that the stan­dard de­vi­a­tion was much high­er than we an­tic­i­pat­ed — it was 38%, not 15 to 20%, so with­in the sam­ple size, we couldn’t pos­si­bly demon­strate sta­tis­ti­cal­ly sig­nif­i­cant change in treat­ment groups,” she con­tin­ued. The abil­i­ty to walk and the ex­pect­ed high­er PCr lev­els of el­der­ly pa­tients are why the me­di­an age of the tri­al was op­ti­mized for mid­dle age, the med­ical chief said.

As long Covid im­pacts mil­lions of peo­ple, the bio­phar­ma in­dus­try has on­ly a dozen or so com­pa­nies look­ing at the con­di­tion. Tonix Phar­ma­ceu­ti­cals will be­gin a mid-stage test this quar­ter af­ter a few oth­er biotechs have flamed out in their at­tempts. Atea’s an­tivi­ral, AT-527, failed a mid-stage test last year, and the com­pa­ny sub­se­quent­ly ditched a six-month fol­low-on study look­ing at the drug’s im­pact on long Covid in up to 1,000 pa­tients. PureTech Health has al­so got­ten out of long Covid af­ter its drug LYT-100-COV did not pass muster in a Phase II study look­ing at res­pi­ra­to­ry com­pli­ca­tions.

Covid-19 roundup: Eu­ro­pean gov­ern­ments push to rene­go­ti­ate vac­cine con­tracts — re­port; As PhII da­ta dis­ap­point, PureTech pulls long Covid pro­gram

For its part, Ax­cel­la will move for­ward with its long Covid pro­gram, look­ing to em­pha­size the clin­i­cal­ly and sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ments on men­tal and phys­i­cal fa­tigue seen in its study. The mean change in to­tal fa­tigue score ver­sus place­bo was -4.30, good for a p-val­ue of 0.0039. The fig­ures for phys­i­cal and men­tal scores were -2.94 (p=0.0097) and -1.32 (p=0.0097), re­spec­tive­ly.

Three pa­tients on the study drug nor­mal­ized their phys­i­cal fa­tigue scores, the CMO said, mean­ing their fa­tigue was sim­i­lar to be­fore get­ting in­fect­ed with SARS-CoV-2.

Fa­tigue is a ma­jor con­cern for pa­tients who ex­pe­ri­ence the lin­ger­ing ef­fects of Covid-19. Ax­cel­la not­ed its im­pact on the work­force, cit­ing re­cent con­gres­sion­al sub­com­mit­tee da­ta that say al­most one in five adults with Covid will go on to have long Covid, and that about one mil­lion Amer­i­cans are out of work be­cause of the con­di­tion. A Brook­ings In­sti­tu­tion re­port es­ti­mates four mil­lion full-time equiv­a­lent work­ers are out of work be­cause of the con­di­tion that can be a dis­abil­i­ty un­der fed­er­al law.

Giv­en the drug is al­ready be­ing test­ed in pa­tients with non-al­co­holic steato­hep­ati­tis, or NASH, and is in an on­go­ing glob­al Phase IIb clin­i­cal tri­al in that con­di­tion, Ax­cel­la thinks its his­tor­i­cal safe­ty da­ta on the oral ther­a­peu­tic can be a boon to its dis­cus­sions with reg­u­la­tors.

“The types of con­founders that of­ten lead to long Covid and Covid, in gen­er­al, are of­ten char­ac­ter­ized in the NASH pop­u­la­tion, so we al­ready know that it’s work­ing pre­clin­i­cal­ly and clin­i­cal­ly in that set­ting based on our pre­vi­ous da­ta, so this gives us a lot of op­ti­mism and con­fi­dence as we go for­ward,” CEO Bill Hin­shaw said in a joint in­ter­view.

While Omi­cron and oth­er vari­ants and sub­lin­eages of the coro­n­avirus have lim­it­ed the im­pact of vac­cines and ther­a­pies, Ax­cel­la doesn’t ex­pect that to be the case for AXA1125 in long CovidCovid.

“I don’t an­tic­i­pate that this is go­ing to be sen­si­tive to vari­ants. We’re not an an­tivi­ral where nu­cleotide sub­sti­tu­tion is re­al­ly go­ing to re­sult in re­sis­tance,” Koziel said.

The goal is to “take this for­ward as rapid­ly as pos­si­ble,” the med­ical chief said, with the CEO an­tic­i­pat­ing the reg­u­la­to­ry talks to be a “fa­vor­able dis­cus­sion.” While the end­points are yet to be hashed out, Koziel ex­pects gen­er­al qual­i­ty of life and im­prove­ments in phys­i­cal ac­tiv­i­ties to be stud­ied in the tri­al.

If the drug makes it in­to a Phase III study in long Covid, the biotech thinks it can be “ef­fi­cient” and will then “work with the right par­ties to help us de­vel­op and cap­i­tal­ize the com­pa­ny,” Hin­shaw said. The com­pa­ny tuned its pipeline in May by sus­pend­ing a glob­al Phase II tri­al of an­oth­er drug, AXA1665, in pa­tients with overt he­pat­ic en­cephalopa­thy.

UP­DAT­ED: Say­ing good­bye to R&D chief, Flag­ship-backed Ax­cel­la drops PhII pro­gram as it fo­cus­es on long CovidCovid, NASH

At the end of March, Ax­cel­la had about $63 mil­lion at its dis­pos­al. The com­pa­ny will re­port sec­ond quar­ter earn­ings in the com­ing weeks.

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