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.

Biotech in­vestors and CEOs see two paths to growth, but are they equal­ly vi­able?

The dynamic in the biotech market has been highly volatile in the last few years, from the high peaks immediately after the COVID vaccine in 2021, to the lowest downturns of the last 20 years in 2022. This uncertainty makes calling the exact timing of the market’s turn something of a fool’s errand, according to Dr. Chen Yu, Founder and Managing Partner of TCG Crossover (TCG X). He speaks with RBC’s Noël Brown, Head of US Biotechnology Investment Banking, about the market’s road ahead and two possible paths for growth.

Casey McPherson shows his daughters Rose (left) and Weston around Everlum Bio, a lab that he co-founded to spark a treatment for Rose and others with ultra-rare conditions. (Ilana Panich-Linsman)

Fa­ther starts lab af­ter in­tel­lec­tu­al prop­er­ty is­sues stymie rare dis­ease drug de­vel­op­ment

Under bright lab lights, Casey McPherson holds his 6-year-old daughter, Rose. His free hand directs Rose’s gaze toward a computer screen with potential clues in treating her one-of-a kind genetic condition.

Gray specks on the screen show her cells that scientists reprogrammed with the goal of zeroing in on a custom medicine. McPherson co-founded the lab, Everlum Bio, to spark a treatment for Rose — and others like her. A regarded singer-songwriter, McPherson never imagined going into drug development.

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Astel­las, Pan­th­er­na add or­gan to mR­NA tie-up; Rock­et launch­es sale of six fig­ures worth of stock

Astellas and Pantherna have expanded their November 2021 pact surrounding the latter’s mRNA platform to include a new target organ, the duo announced Tuesday morning, though they did not specify what that target is.

German biotech Pantherna is home to two platform technologies — one that designs mRNAs for non-vaccine therapies and another that designs LNPs. Astellas and Pantherna’s deal appears to mainly revolve around the first platform, which Astellas said it is using to research direct reprogramming, or turning cells from one kind into another without an intermediate stem cell phase.

Benjamine Liu, TrialSpark CEO

Paul Hud­son and Tri­alSpark's mu­tu­al de­sire to speed up de­vel­op­ment con­verges in three-year, six-drug goal

A unicorn startup that originally set out to hasten clinical studies for biopharma partners dug further into its revised path of internal drug development by linking arms with Sanofi in a pact that the biotech’s CEO said originated from the top.

TrialSpark and the Big Pharma on Tuesday committed to in-licensing and/or acquiring six Phase II/Phase III drugs within the next three years.

“I’ve known Paul Hudson for a while and we were discussing the opportunity to really re-imagine a lot of different parts of pharma,” TrialSpark CEO Benjamine Liu told Endpoints News, “and one of the things that we discussed was this opportunity to accelerate the development of new medicines in mutual areas of interest.”

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Andrew Crockett, KalVista CEO

KalVista ends a PhII study ear­ly af­ter pa­tients suf­fer se­vere and life-threat­en­ing side ef­fects

KalVista took a beating Tuesday after announcing it would scrap a Phase II trial for one of its experimental drugs.

The biotech said in an early morning press release that it is terminating the study for KVD824 after multiple patients in every treatment group saw unsafe, elevated levels of certain liver enzymes. By ending the trial now, KalVista hopes to save some money and funnel it toward another study for its lead program, CEO Andrew Crockett said in a statement.

Pen­ny stock play­er to re­view all op­tions to try stay­ing afloat af­ter clin­i­cal tri­al fail

Adamis Pharmaceuticals is slowly tumbling down, and the biotech is looking at all its options.

After a Phase II/III trial failure last month that sent the penny stock player down an additional 50% to just 15 cents a share, the company said Monday that it is examining options to get the best value for its investors. A statement from Adamis indicates that alternatives include anything from a partnership to a sale of Adamis’ two commercial products, Zimhi and Symjepi.

Dave Marek, Myovant CEO

My­ovant board balks as ma­jor­i­ty own­er Sum­it­o­mo swoops in with a $2.5B deal to buy them out

Three years after Sumitomo scooped up Roivant’s 46% stake in the publicly traded Myovant $MYOV as part of a 5-company, $3 billion deal, they’re coming back for the whole thing.

But these other investors at Myovant want more than what the Japanese pharma company is currently offering to pay at this stage.

Sumitomo is bidding $22.75 a share for the outstanding stock, which now represents 48% of the company after Sumitomo bumped its ownership since the original deal with Roivant. Myovant, however, created a special committee on the board, and they’re shaking their heads over the offer.

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Take­da to pull key hy­poparathy­roidism drug from the mar­ket en­tire­ly by end of 2024 af­ter years of man­u­fac­tur­ing woes

Takeda on Tuesday morning made an announcement that almost 3,000 people with the rare disease known as hypoparathyroidism were fearing.

Due to unresolved supply issues and manufacturing woes, Takeda said it will cut its losses and discontinue its hypoparathyroidism drug, known as Natpara (parathyroid hormone), halting all manufacturing of the drug by the end of 2024.

The decision to not re-commercialize Natpara will be a blow to not only the 2,400 people who were awaiting supplies of their reliable injection since 2019, but also the additional nearly 400 people who were accessing the drugs via the company’s Special Use Program as Takeda sought to resolve these manufacturing issues over the past five years.

Marc Dunoyer, Alexion CEO (AstraZeneca via YouTube)

Up­dat­ed: As­traZeneca nabs a small rare dis­ease gene ther­a­py play­er for 667% pre­mi­um

AstraZeneca is kicking off the fourth quarter with a little M&A Monday for a gene editing player recently overcoming a second clinical hold to its only program in human studies.

The Big Pharma and its subsidiary Alexion are buying out little LogicBio for $2.07 per share. That’s good for a massive 667% premium over its Friday closing price, when it headed into the weekend at 27 cents and just weeks after Nasdaq said LogicBio would have to delist, which has been put on hold as the biotech requests a hearing. It’s one of two biotech deals to commence October, alongside the news of Incyte buying a vitiligo-focused biotech.

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