AXA-1665

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. 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 Covid. “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 Covid, 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.

As Axcella grapples with the abrupt resignation of R&D chief Alison D. Schecter and board member Shreeram Aradhye, the company is prioritizing its clinical development portfolio to focus on its investigative assets for COVID-19 and non-alcoholic steatohepatitis (NASH), while suspending a mid-stage rare disease study. In a filing with the U.S. Securities and Exchange Commission earlier this week, Axcella announced the departure of Schecter, president of research and development, as well as Aradhye. Schecter joined Axcella on March 2, 2021 and is leaving the company to pursue other opportunities, Axcella said in its filing. Aradhye also left for personal reasons. Axcella said his departure “was not the result of a disagreement with the company on any matter relating to the company’s operations, policies or practices.” Regarding its pipeline, Axcella said it is suspending its Phase II study in Overt Hepatic Encephalopathy that is assessing the efficacy and safety of AXA1665, an experimental oral candidate for the reduction in risk of recurrent forms of the disease. OHE is a common central nervous system disorder caused by chronic liver diseases that affect the brain and brain function. The liver is unable to clear toxin buildup from the body. Those toxins can travel to the brain and can cause confusion and other symptoms. The treatment is reversible. The only current drug approved for this indication is Salix Pharmaceuticals’ Xifaxan. Enrollment in the Axcella OHE trial began last year. Although the company noted investigator interest in this potential treatment for the rare disease, Axcella noted that “enrollment challenges and timelines to approval” are likely to be longer than expected and warranted a suspension of the program to focus on other developmental assets. “We continue to believe that AXA1665 is an effective therapy based upon two prior clinical trials, physician input, and AXA1665’s strong scientific support. We will explore partnerships and potentially other indications for AXA1665,” Bill Henshaw, president and chief executive officer of Axcella said in a statement. Two years ago, AXA1665 posted positive topline data from a study that saw clinically-relevant trends in certain measures of nitrogen/ammonia handling and physical function, the company said at the time. With the study of AXA1665 suspended, the company will aim its resources at its Long COVID and NASH studies. In Long COVID, Axcella is assessing AXA1125 in a Phase IIa study. This morning, the company noted that enrollment in the study is complete with 40 patients and topline data is expected in the third quarter of this year. AXA1125 is a multi-targeted endogenous metabolic modulator (EMM) composition that contains five amino acids and an amino acid derivative that works across multiple biological pathways. The company noted that preclinical and clinical data have shown that AXA1125 has the potential to increase fatty acid oxidation, ATP production, ketogenesis and mitochondrial bioenergetics, which can contribute to meaningful reductions in key markets of liver fat, insulin resistance, inflammation, and fibrosis. Henshaw said the execution of the Phase IIa Long COVID trial will advance the company’s pipeline and validate the effectiveness of EMMs to address multi-factorial diseases. “Achieving completion of enrollment is a significant milestone in the development path of AXA1125 as a potential treatment for Long COVID, a large and growing consequence of the global pandemic,” Margaret Koziel, chief medical officer of Axcella said in a statement. “We believe mitochondrial dysfunction is a key driver of Long COVID induced fatigue. Preclinical and clinical data indicate that AXA1125 may have an important impact.” AXA1125 is also being assessed in a Phase IIb study as a potential treatment for NASH, a condition in which excess fat is stored in the liver and is not caused by heavy alcohol use. There are no approved therapies for NASH other than lifestyle adjustments. Axcella expects data from the Phase IIb study in the third quarter of this year.