UP­DAT­ED: Ab­b­Vie adds to the Botox war chest with a 12th FDA ap­proval — but com­pe­ti­tion is fast ap­proach­ing

Com­pe­ti­tion is clos­ing in on Ab­b­Vie’s block­buster Botox fran­chise — de­spite the drug­mak­er’s best ef­forts to avoid it. In the mean­time, the Chica­go area drug gi­ant can take some so­lace in a new in­di­ca­tion that will add to the block­buster drug’s war chest.

The FDA on Wednes­day gave Botox the green light to treat de­tru­sor (blad­der mus­cle) over­ac­tiv­i­ty as­so­ci­at­ed with neu­ro­log­i­cal con­di­tions in chil­dren 5 and old­er who were in­tol­er­ant to or didn’t im­prove on an­ti­cholin­er­gic meds, Ab­b­Vie said in a state­ment. Botox is now the first neu­ro­tox­in ap­proved for such use, the drug­mak­er said.

“While al­ways sat­is­fy­ing to bring forth new in­di­ca­tions, it is par­tic­u­lar­ly re­ward­ing when we can help ad­vance care for pe­di­atric pa­tients,” Mitchell Brin, Ab­b­Vie’s se­nior VP and CSO of Botox and neu­ro­tox­ins, said in a state­ment.

Blad­der mus­cle over­ac­tiv­i­ty oc­curs when the spinal cord and blad­der can’t com­mu­ni­cate ef­fec­tive­ly, caus­ing the blad­der mus­cle to in­vol­un­tar­i­ly con­tract. This in­creas­es pres­sure in the blad­der and re­duces blad­der ca­pac­i­ty, which can cause pa­tients to leak urine and suf­fer blad­der and kid­ney dam­age over time. In chil­dren, the most com­mon neu­ro­log­i­cal cause is spina bi­fi­da, though it can al­so be spurred by con­di­tions like trans­verse myelitis and spinal cord in­jury.

“When car­ing for pe­di­atric pa­tients with neu­ro­genic de­tru­sor over­ac­tiv­i­ty, we strive to re­duce blad­der pres­sure and in­crease the blad­der’s ca­pac­i­ty. Pre­vi­ous­ly, treat­ment op­tions were lim­it­ed pri­mar­i­ly to an­ti­cholin­er­gic med­i­cines, where long-term use needs to be con­sid­ered care­ful­ly, in ad­di­tion to surgery,” said Paul Austin, chief of pe­di­atric urol­o­gy at Texas Chil­dren’s Hos­pi­tal and pro­fes­sor of urol­o­gy at Bay­lor Col­lege of Med­i­cine.

Ab­b­Vie sub­mit­ted a sup­ple­men­tal BLA for the con­di­tion back in June, and said it ex­pect­ed a de­ci­sion by Q1 2021. Right on time, the OK was based on a Phase III study with more than 100 chil­dren, which showed that Botox re­duced day­time uri­nary in­con­ti­nence episodes, low­ered max­i­mum blad­der pres­sure and in­creased blad­der ca­pac­i­ty af­ter six weeks.

The most com­mon ad­verse re­ac­tions were bac­teri­uria (20%), uri­nary tract in­fec­tion (7%), leuko­cy­turia (7%), and hema­turia (3%), ac­cord­ing to Ab­b­Vie.

Al­ler­gan snagged its first ap­proval for Botox back in 1989 for two rare eye mus­cle dis­or­ders — ble­pharospasm and stra­bis­mus — then stacked on a va­ri­ety of oth­er in­di­ca­tions, in­clud­ing chron­ic mi­graine, over­ac­tive blad­der, cer­vi­cal dys­to­nia, spas­tic­i­ty and se­vere un­der­arm sweat­ing.

The fran­chise be­came Ab­b­Vie’s in 2019 when it sealed a $63 bil­lion deal to buy out Al­ler­gan. Ab­b­Vie im­me­di­ate­ly carved off Botox’s cos­met­ic use and Al­ler­gans’ oth­er cos­met­ic port­fo­lio in­to an Al­ler­gan Aes­thet­ics sub­sidiary and kept the drug’s ther­a­peu­tic in­di­ca­tions un­der the larg­er com­pa­ny’s di­rect um­brel­la.

Al­ler­gan has put up a tough fight against Botox com­peti­tors, in­clud­ing Evo­lus, which Al­ler­gan took to court on al­le­ga­tions that its Jeu­veau was de­vel­oped us­ing a stolen trade se­cret. In De­cem­ber, Evo­lus was is­sued a 21-month ban on the im­por­ta­tion or sale of the wrin­kle treat­ment — which was re­duced from an ini­tial 10-year ban pro­posed by a judge, Bloomberg re­port­ed. 

Still, oth­er ri­vals are cir­cling in on Botox, in­clud­ing Re­vance, which read out pos­i­tive Phase III re­sults for its Dax­i­bot­u­linum­tox­i­nA in Oc­to­ber. The FDA de­ferred its de­ci­sion on Re­vance’s BLA in No­vem­ber due to Covid-re­lat­ed trav­el re­stric­tions that kept the agency from per­form­ing an in­spec­tion of the com­pa­ny’s man­u­fac­tur­ing fa­cil­i­ty. And In June, Re­vance and My­lan an­nounced plans to move for­ward with a sep­a­rate pro­gram for a Botox biosim­i­lar.

Botox raked in $991.3 mil­lion in net sales in 2019, a 9.3% in­crease from 2018.

This sto­ry has been up­dat­ed to add that the new in­di­ca­tion in­cludes chil­dren who are in­tol­er­ant to an­ti­cholin­er­gic meds. 

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

What lured Hal Bar­ron away?; Top FDA minds on ac­cel­er­at­ed ap­proval re­forms; ‘Dead wrong’ Aduhelm ad blitz; 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.

Nothing can really compete with Hal Barron’s departure from GlaxoSmithKline as the news of the week, but we do have plenty of original reporting and analysis from the Endpoints team in this edition. Enjoy and have a nice weekend.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Mer­ck wins le­gal bat­tle over in­sur­ance cov­er­age af­ter ran­somware at­tack

Merck has emerged victorious from a years-long legal battle with insurers over the coverage of more than a billion dollars in losses from the malware NotPetya, with a New Jersey Superior Court judge concluding that the responsibility is on insurers to clarify their policies around cyber attacks.

The pharma giant was one of several victims of a global cyber attack back in 2017 that also hit Danish shipping company Maersk, American food company Mondelēz, French construction giant Saint-Gobain and even the systems monitoring the Chernobyl nuclear power stations, Bloomberg reported back in 2019.

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Flori­da man con­vict­ed of fal­si­fy­ing clin­i­cal tri­al re­sults sen­tenced to over 2 years in prison

A Florida man who falsified medical records in connection to clinical trials was sentenced to 30 months in prison in federal court Thursday.

Daniel Tejeda, 35, of Clewiston, was also ordered to pay $2.1 million in restitution. Tejeda was a project manager and study manager for the CRO Tellus Clinical Research, and made it appear that subjects were participating in trials when they weren’t. Two other research workers from Florida were sentenced in the same case in August for 46 and 30 months, respectively.

Troy Wilson, Kura Oncology CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.