Theresa Heggie, Freeline CEO

Free­line Ther­a­peu­tics slams the brakes on gene ther­a­py tri­al plans as FDA seeks more clar­i­ty on man­u­fac­tur­ing

Free­line Ther­a­peu­tics is join­ing a grow­ing line­up of com­pa­nies called to ac­count for CMC is­sues while walk­ing its gene ther­a­py can­di­date through clin­i­cal tri­als.

The UK-based biotech’s stock $FRLN slipped near­ly 2% on Mon­day morn­ing af­ter the com­pa­ny an­nounced it’s de­lay­ing plans for a piv­otal tri­al by two years in or­der to work on CMC feed­back from the FDA. The he­mo­phil­ia B pro­gram, dubbed FLT180a, was ini­tial­ly slat­ed to en­ter a piv­otal Phase IIb/III study in the sec­ond half of this year.

“The mod­i­fi­ca­tion to the FLT180a clin­i­cal de­vel­op­ment plan is in­tend­ed to ad­dress feed­back Free­line re­ceived from the (FDA) re­lat­ing to the char­ac­ter­i­za­tion and com­pa­ra­bil­i­ty of the in­ves­ti­ga­tion­al drug prod­uct used in its Phase 1/2 B-AMAZE tri­al that was pro­duced at small­er scale, as com­pared to its cur­rent in­ves­ti­ga­tion­al drug prod­uct that is pro­duced at com­mer­cial scale,” Free­line said in a state­ment.

De­spite the set­back, Free­line says it can re­main on track by con­duct­ing dose con­fir­ma­tion in an on­go­ing Phase I/II tri­al, in­stead of Phase IIb as orig­i­nal­ly planned. The dose-es­ca­la­tion por­tion is ex­pect­ed to launch by the end of 2021. It’ll be a six-month, sin­gle-dose safe­ty and ef­fi­ca­cy tri­al with a da­ta read­out by the end of 2022.

Free­line plans on ini­ti­at­ing a piv­otal Phase III tri­al by mid-2023, which would set it up to ap­proach reg­u­la­tors by the end of 2024 if the da­ta pan out. The late-stage study would be “near­ly iden­ti­cal” to the old Phase III por­tion of the pre­vi­ous­ly planned Phase IIb/III, ac­cord­ing to the com­pa­ny.

“We be­lieve con­duct­ing dose con­fir­ma­tion in a Phase 1/2 tri­al should al­low us to achieve sim­i­lar ob­jec­tives as our pre­vi­ous­ly planned tri­al, whilst al­so en­abling us to work with FDA on CMC pri­or to ini­ti­at­ing the Phase 3 piv­otal tri­al,” CEO There­sa Heg­gie said in a state­ment. “To stream­line the de­vel­op­ment path for our sub­se­quent pro­grams, we have de­vel­oped our en­tire pipeline from Phase 1 on­ward us­ing the same com­mer­cial-scale man­u­fac­tur­ing plat­form that we are now us­ing for FLT180a.”

He­mo­phil­ia is a ge­net­ic bleed­ing dis­or­der in which a pro­tein made by the body to help clot blood is ei­ther part­ly or com­plete­ly miss­ing (al­so known as a clot­ting fac­tor). In he­mo­phil­ia B, there is a de­fi­cien­cy of the clot­ting Fac­tor IX pro­tein.

Back in De­cem­ber, Free­line an­nounced that FLT180a showed “durable Fac­tor IX ac­tiv­i­ty” up to a pe­ri­od of near­ly three years, with no bleeds re­port­ed re­quir­ing FIX sup­ple­men­ta­tion in the Phase I/II B-AMAZE study. The com­pa­ny al­so said it had an “End of Phase II” meet­ing with the FDA in No­vem­ber, which sug­gest­ed it was on a “clear path” to be­gin the piv­otal Phase IIb/III by the end of this year.

Free­line isn’t the on­ly gene ther­a­py play­er to be ham­pered by CMC is­sues. Blue­bird bio, Bio­Marin and Voy­ager have al­so run in­to their own prob­lems. A cou­ple months ago, blue­bird pushed back the fil­ing for its gene ther­a­py in sick­le cell dis­ease by a year due to a new da­ta re­quire­ment from the FDA.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; 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.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.

Skin tu­mors in mice force Pro­tag­o­nist to halt lead pro­gram, crush­ing stock

Protagonist Therapeutics just can’t catch a break.

Six months after the Newark, CA-based biotech unveiled grand plans to launch its lead candidate for blood disorders into a Phase III trial, the FDA has slapped the program with a clinical hold. The halt — which applies to all trials involving the candidate, rusfertide — comes after skin tumors were discovered in mice treated with the drug, according to Protagonist.

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Take­da scores a win for a rare type of lung can­cer, gear­ing up for a show­down with J&J

Four months after J&J’s infused drug Rybrevant scored the industry’s first win in a rare type of non-small cell lung cancer (NSCLC), Takeda is following up with an oral option for the small but desperate patient population.

The FDA granted an accelerated approval to Takeda’s oral TKI inhibitor Exkivity (mobocertinib) in metastatic NSCLC patients with EGFR exon 20 gene mutations who had previously undergone platinum-based chemotherapy, the company announced on Wednesday.

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