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. 

Big Phar­ma's Twit­ter ex­o­dus; Mer­ck wa­gers $1.35B on buy­out; $3.5M gene ther­a­py; and more

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Paul Perreault, CSL Behring CEO

CSL lands FDA ap­proval for he­mo­phil­ia B gene ther­a­py, sets $3.5M list price

The FDA has approved the world’s first gene therapy for hemophilia B, ushering into the market a treatment that’s historic in both what it promises to do and how much it will cost.

CSL will be marketing the drug, Hemgenix, at a list price of $3.5 million — which sets a new record for the most expensive single-use gene therapy in the US.

In a statement provided to Endpoints News, the Australian company noted that the current costs of treating people with moderate to severe hemophilia B can be significant over a lifetime. By some estimates, healthcare systems could spend more than $20 million per person.

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Image: Shutterstock

MIT re­searchers re­veal DNA "Paste" tech be­hind lat­est gene edit­ing start­up

MIT scientists have developed a tool that they say can insert large gene sequences where they want in the genome.

In a paper published Thursday in Nature Biotechnology, MIT fellows Omar Abudayyeh, Jonathan Gootenberg and colleagues detail a technology they call PASTE, which they say can potentially be used to insert long strands of DNA and treat genetic diseases caused by many different mutations, such as cystic fibrosis and Leber congenital amaurosis, a rare eye disorder that causes blindness.

Elon Musk (GDA via AP Images)

Biggest drug com­pa­nies halt­ed Twit­ter ad buys af­ter Lil­ly in­sulin spoof

Almost all of the drug industry’s biggest advertisers cut their spending on Twitter to zero or near-zero over the last two weeks amid worries about impersonation of their brands by pranksters and the future of the social media company.

Among 18 of the biggest pharmaceutical advertisers in the US market, 12 cut their Twitter ad spending to nothing for the week beginning Nov. 14, according to Pathmatics, which tracks data on prescription drug ad spending as well as general corporate advertising. The list of drugmakers cutting spending to zero includes Merck, AstraZeneca, Eli Lilly, Novartis, Pfizer and others.

Isao Teshirogi, Shionogi president and CEO (Kyodo via AP Images)

Sh­ionogi's Covid an­tivi­ral lands first ap­proval in Japan's new emer­gency ap­proval path­way

Japanese regulators on Tuesday signed off on Shionogi’s homegrown antiviral for Covid-19, known as Xocova (ensitrelvir), making it the first approval under Japan’s emergency regulatory approval system.

The emergency approval, following a back-and-forth with regulators since last February, is based on a safety profile with more than 2,000 patients who have accessed the pill, and clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors or vaccination status, and during the Omicron-dominant phase of the pandemic.

J&J's Spra­va­to pulls a PhI­II win against Sero­quel XR in treat­ment-re­sis­tant de­pres­sion

A day before Thanksgiving, J&J’s Janssen has a new cut of Phase III Spravato data to be grateful for.

The pharma giant announced on Wednesday that its nasal spray, also known as esketamine, beat extended-release quetiapine, previously sold by AstraZeneca as Seroquel XR, in treatment-resistant depression (TRD). Of 676 adults, a significantly higher number of patients on Spravato were able to achieve remission and avoid relapse after 32 weeks, according to J&J.

Rob Davis, Merck CEO

Up­dat­ed: No Seagen here: 'Do more' means a small $1.35B pur­chase of Ima­go for Mer­ck

Merck is making an acquisition, the Big Pharma announced before Monday’s opening bell. No, Seagen is not entering the fold, as had been speculated for quarters.

Folding under Merck’s wings will be Pfizer-backed Imago BioSciences. For nearly a year, Merck CEO Rob Davis has been saying the pharma giant needs to “do more” on the business development front after its 2021 $11.5 billion acquisition of Acceleron.

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Stanley Erck, Novavax CEO (Andrew Harnik/AP Images)

No­vavax pulls out of Covid-19 vac­cine al­liance with Gavi

Novavax is pulling out of its Covid-19 vaccine deal with Gavi, the Vaccine Alliance, a global partnership tasked with ensuring vaccine access in lower-income countries, following an alleged contract violation.

The Maryland-based company claimed on Friday that Gavi failed to purchase at least 350 million doses of its protein-based vaccine Nuvaxovid by the end of the year, per an advanced purchase agreement. Gavi, the World Health Organization and the Coalition for Epidemic Preparedness Innovations (CEPI) are co-leaders of COVAX, an effort to ensure that all participating countries, regardless of income levels, have access to vaccines.

Dermavant Sciences' first consumer TV ad for its Vtama psoriasis med shows people ready for a new topical treatment.

Roivant’s Der­ma­vant de­buts first-ever TV com­mer­cial for pso­ri­a­sis cream Vta­ma

Dermavant Sciences has been marketing its first product, psoriasis med Vtama, to dermatologists for months, but on Tuesday it rolled out its first consumer campaign. The debut DTC effort including a streaming TV commercial encourages patients to a “Topical Uprising” in a nod to Vtama being a topical cream.

In the new commercial, a swell of people discards scarves and jacket coverings, gathering in the street to converge on a pharmacy to demand a steroid-free prescription. A moment of levity follows when a pharmacist says, “You know you can just talk to your doctor, right?” The gathered crowds collectively says, “Oh.”

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