Anthony Quinn, Aeglea CEO

Ae­glea's en­gi­neered en­zyme flops out­comes test in rare meta­bol­ic dis­ease. Is re­duc­ing a key bio­mark­er enough for an ap­proval?

Austin’s Ae­glea Bio­Ther­a­peu­tics is hop­ing to blaze a path re­duc­ing a key amino acid bio­mark­er for a rare wast­ing meta­bol­ic dis­ease with its en­gi­neered en­zyme ap­proach. But with a piv­otal out­comes read­out bod­ing poor­ly for the drug’s ben­e­fit, Ae­glea hopes it still has enough da­ta on hand to catch the FDA’s eyes.

Ae­glea’s pegzi­larginase, a re­com­bi­nant en­zyme de­signed to de­grade the amino acid argi­nine, hit its pri­ma­ry end­point re­duc­ing argi­nine lev­els in the blood over place­bo in pa­tients with the rare meta­bol­ic dis­ease arginase 1 de­fi­cien­cy (ARG1-D), the Austin-based biotech said Mon­day.

The 21 pa­tients dosed with pegzi­larginase post­ed an 80% re­duc­tion in mean plas­ma argi­nine over place­bo at six months, good for a sta­tis­ti­cal­ly sig­nif­i­cant p=<0.0001. Mean­while, 90.5% of pa­tients re­ceiv­ing the en­zyme reached nor­mal plas­ma argi­nine lev­els com­pared with no pa­tients in the con­trol arm.

The goal of the Phase III PEACE study was to demon­strate that sig­nif­i­cant­ly re­duc­ing el­e­vat­ed argi­nine lev­els — a ther­a­peu­tic route with no FDA-ap­proved treat­ments — would show a cor­re­la­tion with im­proved out­comes for pa­tients with ARG1-D, which typ­i­cal­ly presents in ear­ly child­hood with pa­tients ex­pe­ri­enc­ing spas­tic­i­ty, seizures, de­vel­op­men­tal de­lay, in­tel­lec­tu­al dis­abil­i­ty and ear­ly mor­tal­i­ty.

But those weren’t the re­sults Ae­glea turned up.

On two key sec­ondary end­points, in­clud­ing im­prove­ments in a two-minute walk test and a catch-all mo­bil­i­ty test known as GMFM-E, peglizarginase failed to best place­bo de­spite show­ing what Ae­glea called “pos­i­tive trends” on pa­tient out­comes.

For the two-minute walk test, pa­tients dosed with peglizarginase post­ed a mean in­crease in dis­tance walked from base­line of 7.4 me­ters com­pared with an in­crease of 1.9 me­ters in con­trol pa­tients. That came out to an ug­ly p=0.5961, far be­low the bar for sta­tis­ti­cal sig­nif­i­cance. On the GMFM-E test, pa­tients dosed with pegzi­larginase showed a 4.2-unit in­crease over base­line com­pared with a 0.4-unit de­cline for place­bo pa­tients (p=0.1087).

“We are dis­ap­point­ed this isn’t a sta­tis­ti­cal­ly sig­nif­i­cant re­sult,” Ae­glea Chief De­vel­op­ment Of­fi­cer Er­ic Brad­ford said on a call with an­a­lysts Mon­day. “It high­lights the chal­lenge of de­sign­ing a study where there’s no clin­i­cal prece­dent.”

Ae­glea said it didn’t flag any new safe­ty con­cerns in the study and no pa­tients drop­ping out due to dos­ing.

Even with no out­comes im­prove­ments to show, Ae­glea thinks it has enough da­ta in hand to go to the FDA for a rul­ing. The biotech said it plans to file a BLA in the first of the year and is plan­ning con­cur­rent mar­ket­ing fil­ings in the “cer­tain coun­tries in Eu­rope and the Mid­dle East” along­side part­ner Im­med­ica Phar­ma AB.

Some of that op­ti­mism is tied to re­sults from the open-la­bel ex­ten­sion por­tion of a sin­gle-arm Phase I/II study, in which 11 of 14 pa­tients showed im­prove­ments across a slate of three mo­bil­i­ty tests at 56 weeks. Those re­sults, of course, weren’t pow­ered for sig­nif­i­cance and weren’t con­trolled, cast­ing doubt on whether reg­u­la­tors will be con­vinced.

How­ev­er, it wouldn’t be the first time the agency has giv­en tac­it ap­proval to a sur­ro­gate end­point with­out the out­comes da­ta to back it up. From Bio­gen’s Aduhelm to Sarep­ta’s Ex­ondys 51, the agency has at times hand­ed out ac­cel­er­at­ed ap­provals based on a high de­gree of con­fi­dence a giv­en bio­mark­er will even­tu­al­ly lead to sig­nif­i­cant clin­i­cal ben­e­fit but with­out the ac­tu­al ben­e­fits shown in pa­tients.

In this case, Ae­glea’s out­comes re­sults are more ex­plic­it, like­ly lead­ing the biotech to pitch a “to­tal­i­ty of da­ta” ar­gu­ment to reg­u­la­tors based on in­cre­men­tal im­prove­ments and a dearth of ther­a­peu­tic op­tions — an ar­gu­ment CEO An­tho­ny Quinn high­light­ed dur­ing the team’s call with an­a­lysts.

Mean­while, Ae­glea has rolled the PEACE tri­al pa­tients in­to a long-term ex­ten­sion por­tion, where Ae­glea hopes to show sus­tained argi­nine re­duc­tion as well as im­prove­ments in clin­i­cal out­comes.

Late Fri­day ap­proval; Trio of biotechs wind down; Stem cell pi­o­neer finds new fron­tier; Biotech icon to re­tire; 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.

I hope your weekend is off to a nice start, wherever you are reading this email. As for me, I’m trying to catch the tail of the Lunar New Year festivities.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 157,500+ biopharma pros reading Endpoints daily — and it's free.

Pfiz­er lays off em­ploy­ees at Cal­i­for­nia and Con­necti­cut sites

Pfizer has laid off employees at its La Jolla, CA, and Groton, CT sites, according to multiple LinkedIn posts from former employees.

The Big Pharma confirmed to Endpoints News it has let go of some employees, but a spokesperson declined to specify how many workers were impacted and the exact locations affected. Earlier this month, the drug developer had confirmed to Endpoints it was sharpening its focus and doing away with some early research on areas such as rare disease, oncology and gene therapies.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Jake Van Naarden, Loxo@Lilly CEO

Lil­ly en­ters ripe BTK field with quick FDA nod in man­tle cell lym­phoma

Eli Lilly has succeeded in its attempt to get the first non-covalent version of Bruton’s tyrosine kinase, or BTK, inhibitors to market, pushing it past rival Merck.

The FDA gave an accelerated nod to Lilly’s daily oral med, to be sold as Jaypirca, for patients with relapsed or refractory mantle cell lymphoma.

The agency’s green light, disclosed by the Indianapolis Big Pharma on Friday afternoon, catapults Lilly into a field dominated by covalent BTK inhibitors, which includes AbbVie and Johnson & Johnson’s Imbruvica, AstraZeneca’s Calquence and BeiGene’s Brukinsa.

No­var­tis' ap­proved sick­le cell dis­ease drug fails to beat place­bo in PhI­II

Novartis’ sickle cell drug, approved in 2019 and branded as Adakveo, has failed an ongoing Phase III, according to preliminary results.

The Swiss pharma giant unveiled early data from the ongoing STAND Phase III study on Friday, saying that crizanlizumab showed no statistically significant difference between the drug at two different dose levels compared to placebo in annualized rates of vaso-occlusive crises that lead to a healthcare visit over the first year since being randomized into the trial.

Filip Dubovsky, Novavax CMO

No­vavax gets ready to take an­oth­er shot at Covid vac­cine mar­ket with next sea­son plans

While mRNA took center stage at yesterday’s FDA vaccine advisory committee meeting, Novavax announced its plans to deliver an updated protein-based vaccine based on new guidance.

Vaccines and Related Biological Products Advisory Committee (VRBPAC) members voted unanimously in favor of “harmonizing” Covid vaccine compositions, meaning all future vaccine recipients would receive a bivalent vaccine, regardless of whether they’ve gotten their primary series.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 157,500+ biopharma pros reading Endpoints daily — and it's free.

FDA ap­proves an­oth­er in­di­ca­tion for Keytru­da, this time in the ad­ju­vant NSCLC set­ting

Merck’s blockbuster cancer treatment Keytruda has been handed another indication by the FDA.

The US regulator announced on Thursday that it has approved Keytruda to serve as an adjuvant treatment for non-small cell lung cancer (NSCLC), which is its fifth indication in NSCLC and 34th indication overall.

According to a Merck release, the approval is based on data from a Phase III trial, dubbed Keynote-091, which measured disease-free survival in patients who received chemotherapy following surgery. The data from Merck displayed that Keytruda cut down on the risk of disease recurrence or death by 27% versus placebo.

Ying Huang, Legend CEO

J&J, Leg­end say Carvyk­ti beat stan­dard ther­a­py in ear­li­er-line blood can­cer

J&J and Legend Biotech’s next step in turning their CAR-T therapy Carvykti into a potential megablockbuster has succeeded, the companies said Friday.

Carvykti achieved the primary endpoint — progression-free survival — in an open-label Phase III study testing the treatment in second- to fourth-line multiple myeloma patients. The CARTITUDE-4 trial, for which there aren’t any hard data yet, represents the biggest development for Carvykti’s ability to compete with Bristol Myers Squibb’s Abecma since its approval last February.

Dutch biotech starts liq­ui­da­tion af­ter end­ing PhI­II in GVHD

A 13-year-old Dutch biotech is going through a liquidation process after an unexpected end to its Phase III trial testing whether its combination of two monoclonal antibodies was superior to Incyte’s Jakafi.

Xenikos had hoped to prove its investigational therapy, named T-Guard, was better than Jakafi at garnering a complete response in patients experiencing life-threatening complications in which new cells from a hematopoietic stem cell transplant begin to fight the body. Jakafi was approved for the indication, steroid-refractory acute graft-versus-host disease, in May 2019.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 157,500+ biopharma pros reading Endpoints daily — and it's free.

Eliot Forster, F-star CEO (Rachel Kiki for Endpoints News)

F-star gets down to the wire with $161M sale to Chi­nese buy­er as na­tion­al se­cu­ri­ty con­cerns linger

With the clock ticking on F-star Therapeutics’ takeover by a Chinese buyer, the companies are still scrambling to remove a hold on the deal from the US government’s Committee on Foreign Investment in the United States.

F-star and invoX Pharma said they are “actively negotiating” with CFIUS “about the terms of a mitigation agreement to address CFIUS’s concerns regarding potential national security risks posed by the transaction.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 157,500+ biopharma pros reading Endpoints daily — and it's free.