Bill Hinshaw, Axcella CEO

UP­DAT­ED: 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, un­like the move that PureTech Health 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 and end­ed up clos­ing the day low­er, at an 8.5% hike over Mon­day, 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.

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.

SVB Se­cu­ri­ties an­a­lysts pegged AXA1125 with a 45% prob­a­bil­i­ty of suc­cess at get­ting ap­proved in long Covid. If green­lit, the an­a­lysts project about $500 mil­lion in peak sales for the con­di­tion.

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

Ed­i­tor’s note: This ar­ti­cle was up­dat­ed with in­for­ma­tion from an SVB Se­cu­ri­ties an­a­lyst note. 

UP­DAT­ED: In a fresh dis­ap­point­ment, Am­gen spot­lights a ma­jor safe­ty is­sue with KRAS com­bo

Amgen had hoped that its latest study matching its landmark KRAS G12C drug Lumakras with checkpoint inhibitors would open up its treatment horizons and expand its commercial potential. Instead, the combo spurred safety issues that blunted efficacy and forced the pharma giant to alter course on its treatment strategy, once again disappointing analysts who have been tracking the drug’s faltering sales and limited therapeutic reach.

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Ad­dress­ing the ‘Ca­pac­i­ty Crunch’ with a Scal­able Plat­form Process Ap­proach

The field of gene therapy has been diligently moving forward over the past several decades to bring potentially life-saving treatments to patients with genetic diseases. In addition to two approved adeno-associated viral (AAV) gene therapies, there are more than 250 AAV gene therapies in various clinical trial stages.1 AAV vectors remain the most frequently used vector for delivering therapeutic transgenes to target tissues due to their demonstrated and lasting clinical efficacy and extensive safety track record. As AAV therapies advance through clinical trials and into commercialization, many biotech companies are turning to contract development and manufacturing organizations (CDMOs) to prepare their programs for late-stage clinical and commercial scale manufacturing. Given the scope and scale of the manufacturing needs that will accompany regulatory approvals for these assets, CDMOs continue to expand their capacity to meet the needs of increasing prevalent patient populations. However, despite rapid growth, projected gene therapy manufacturing demands still outpace the collective capacity of the CDMO industry.

A $5B Pfiz­er buy­out? Am­gen, Gilead head­line M&A Thurs­day; Al­ny­lam's AT­TR sweep; An­drew Lo's rare dis­ease quest; and more

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.

One of the cool things about adding EndpointsPharma to the daily roster is that my colleagues can now dedicate time to tracking quarterly updates and tuning into calls with Big Pharma companies. Check out their dispatch from the Q2 earnings below.

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Bob Bradway, Amgen CEO (Justin Kase Conder/AP Images for Amgen)

UP­DAT­ED: Am­gen chief Brad­way nabs a rare dis­ease play­er in $4B buy­out as the M&A tem­po ac­cel­er­ates

Amgen CEO Bob Bradway is bellying up to the M&A table today, scooping up the newly anointed commercial biotech ChemoCentryx $CCXI and its recently approved rare disease drug for $3.7 billion out of the cash stockpile. The deal comes in at $52 a share — a hefty increase over the $24.11 close yesterday.

Bradway and the Amgen team get a drug called Tavneos (avacopan) in the deal, a complement factor C5a inhibitor OK’d to treat anti-neutrophil cytoplasmic autoantibody (ANCA)-vasculitis, an autoimmune disease which can be lethal.

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Albert Bourla, Pfizer CEO (Laurent Gillieron/Keystone via AP)

Break­ing: Pfiz­er in hot pur­suit of a $5B buy­out of Glob­al Blood Ther­a­peu­tics — re­port

Pfizer CEO Albert Bourla has vowed to leave no stone unturned in the search for new biotech deals, and the BD team is not letting him down.

The Wall Street Journal reported today that Pfizer is in the final stages of acquiring Global Blood Therapeutics for $5 billion. According to the Journal report, though, Pfizer is not the only buyer at the deal table and while the pharma giant may be close to clinching it, there are no guarantees it will continue.

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George Yancopoulos, Regeneron president and CSO (Brendan McDermid/Reuters/Alamy)

George Yan­copou­los says he's on the trail of the holy grail: ‘This could rep­re­sent the next break­through for im­munother­a­py’

Two of the most outspoken — and successful — drug developers in biotech say they’ve collected early-stage clinical data that are pointing them down the trail to the holy grail in cancer immunotherapy R&D.

While analysts largely busied themselves today with chronicling the ongoing success of Regeneron’s two big cash cows — Dupixent and Eylea — chief scientist George Yancopoulos and CEO Len Schleifer used the Q2 call to spotlight their early success with a combination of the “homegrown” PSMAxCD28 costimulatory bispecific antibody REGN5678 in combination with their PD-1 checkpoint Libtayo. The presentation comes just weeks after Regeneron completed a deal to gather all rights to the PD-1 that had been in Sanofi’s hands. And the two top execs are unstinting in their praise of the potential of a whole set of costimulatory pipeline projects which they say may finally deliver the long-awaited next-level approach to broadening the immunotherapy field of drugs.

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(AP Photo/Richard Vogel, File)

US de­clares mon­key­pox a na­tion­al health emer­gency, as new drug­mak­ers con­sid­er en­ter­ing vac­cine race

Rising monkeypox cases have put the US on high alert as it announces a national health emergency, which grants the government more power in its response.

The news comes as Bavarian Nordic continues to fill orders for its Jynneos vaccine and other companies – including Moderna – consider jumping into the vaccine race. Meanwhile, the New York Times reports that the US has allowed around 20 million doses of smallpox vaccine in its stockpile to expire.

Al Sandrock, Voyager Therapeutics CEO

Al San­drock prunes his post-Bio­gen voy­age with sim­i­lar fo­cus on ALS

Al Sandrock is narrowing the focus of Voyager Therapeutics, concentrating on CNS diseases that were the hallmark of his time leading R&D at Biogen, including an emphasis on a familial form of ALS for which his former employer is getting a speedy review at the FDA.

Less than six months into his journey as CEO at Voyager, Sandrock is focusing the preclinical pipeline on Alzheimer’s disease, GBA1 Parkinson’s disease and SOD1 amyotrophic lateral sclerosis, the rare form of ALS for which the FDA will decide whether to approve Biogen’s tofersen by Jan. 25, 2023.

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Pfiz­er ter­mi­nates PhI­II study of rare car­dio­vas­cu­lar drug picked up in $11.4B Ar­ray ac­qui­si­tion

While Pfizer’s $11.4 billion acquisition of Array BioPharma in the summer of 2019 was mainly focused on oncology, namely Braftovi and Mektovi, there were a few non-cancer assets, including a Phase III drug being tested in a rare cardiovascular disease.

The late-stage trial is now being axed, alongside any further development of the oral small molecule, the pharma giant disclosed after the closing bell on Wednesday. Based on an interim futility analysis of the global Phase III REALM-DCM trial, Pfizer determined a path forward was not in its best interest. Pfizer no longer expected the study would meet its primary goal.

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