Sanofi head of development Dietmar Berger

ASH: Sanofi un­corks late-stage da­ta for RNAi drug fi­tusir­an in he­mo­phil­ia, with all eyes on safe­ty pro­file

Sanofi’s fi­tusir­an has had a rough road in he­mo­phil­ia, weath­er­ing clin­i­cal holds and pro­gram halts tied to its lin­ger­ing safe­ty woes. Now, the drug is near­ing the fin­ish line with late-stage da­ta in hand, but will those same safe­ty con­cerns slam the brakes on the pro­gram de­spite its deliri­ous­ly ef­fec­tive re­sults?

Fi­tusir­an, an RNAi drug de­signed to si­lence the gene that over­pro­duces a pro­tein re­spon­si­ble for clot­ting sup­pres­sion, sig­nif­i­cant­ly re­duced the an­nu­al­ized rate of bleed­ing over on-de­mand fac­tor ther­a­py in he­mo­phil­ia A/B pa­tients with­out pre­ex­ist­ing fac­tor in­hibitors in the blood, ac­cord­ing to late-break­ing da­ta pre­sent­ed Tues­day at #ASH21.

Fi­tusir­an cut pa­tients’ ARB rate by 89% over con­trol, prov­ing a pow­er­ful pro­phy­lac­tic for bleed­ing episodes as a once-month­ly in­jec­tion. In this Phase III study, dubbed AT­LAS-A/B, 50.6% of pa­tients treat­ed with fi­tusir­an had ze­ro treat­ed bleeds dur­ing the study com­pared with just 5% of pa­tients in the on-de­mand arm.

These da­ta are a long­time com­ing for fi­tusir­an, orig­i­nal­ly an Al­ny­lam can­di­date that has pre­vi­ous­ly run in­to brick walls at the FDA due to its safe­ty pro­file, par­tic­u­lar­ly a trou­bling rate of throm­boem­bolism and in­creased lev­els of a pro­tein tied to liv­er dam­age.

In No­vem­ber of last year, Sanofi hit the brakes on its late-stage stud­ies of fi­tusir­an, which in­cludes AT­LAS-A/B and a late-stage test in pa­tients with pre­ex­ist­ing fac­tor in­hibitors dubbed AT­LAS-INH, af­ter a new case of throm­bo­sis cropped up. The pro­gram faced a clin­i­cal hold four years ago on ear­li­er safe­ty wor­ries.

On Tues­day, Sanofi re­vealed safe­ty da­ta from AT­LAS-A/B with 19% of pa­tients in the fi­tusir­an arm re­port­ing ab­nor­mal­ly high lev­els of the ALT and AST pro­teins. Mean­while, there were no re­port­ed cas­es of throm­bo­sis.

How­ev­er, in a sep­a­rate ple­nary ses­sion this week­end, Sanofi re­port­ed up­dat­ed re­sults from AT­LAS-INH show­ing 24.4% of pa­tients in the study had ab­nor­mal­ly high lev­els of ALT/AST and two pa­tients pre­sent­ed sus­pect­ed or con­firmed throm­bo­sis. In that study, fi­tusir­an al­so cut ARB by 89% com­pared with on-de­mand by­pass ther­a­py con­trol.

Sanofi has gone out of its way to por­tray those throm­bo­sis events as an ex­pect­ed if un­de­sired side ef­fect of fi­tusir­an’s use, with head of clin­i­cal de­vel­op­ment Di­et­mar Berg­er de­scrib­ing the drug­mak­er’s goal of hit­ting a sweet spot with dos­ing on an End­points News we­bi­nar Mon­day.

In­deed, Sanofi is flirt­ing with the pos­si­bil­i­ty of amend­ing its tri­al pro­to­col to in­clude low­er dos­es than the 80mg ad­min­is­tered in these stud­ies as well as po­ten­tial­ly try­ing out a once-every-two-month pro­phy­lac­tic sched­ule.

Fi­tusir­an is one of a group of next-gen ther­a­pies look­ing for break­throughs in he­mo­phil­ia, along­side in­ves­ti­ga­tion­al gene ther­a­pies from com­pa­nies like Bio­Marin, uniQure and blue­bird bio, as well as emerg­ing bis­pe­cif­ic an­ti­bod­ies among oth­er at­tempts.

Sev­er­al days ago, uniQure and part­ner CSL an­nounced they would file gene ther­a­py etranaco­gene deza­parvovec with the FDA af­ter a late-stage test com­pared fa­vor­ably with Fac­tor IX pro­phy­lax­is in he­mo­phil­ia B.

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.

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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.

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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.

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.

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.

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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.

Steve Harr, Sana Biotechnology CEO

Four years in, Sana gets first FDA go-ahead to bring can­cer treat­ment in­to the clin­ic

Sana Biotechnology is finally headed to the clinic.

Thursday afternoon, the biotech announced the FDA had cleared its application to start a clinical trial for its allogeneic, or “off-the-shelf,” CAR-T cell therapy targeting the antigen CD19 for patients with B-cell lymphomas and leukemias. Sana said its therapy, dubbed SC291, was designed to evade the immune system, which could help cell therapy produce a more durable response in patients, a concern that has followed such off-the-shelf therapies that use donor cells as opposed to a patient’s own cells.

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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.

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