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

Sanofi head of development Dietmar Berger

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.

Sensor-based technology for clinical trial data collection represents the latest medical paradigm shift. There are more than 700 clinical studies involving wearable devices currently underway in the United States. A study from Intel IT projects their inclusion in clinical trials will surge to 70% by 2025.

Apps, biosensors and patient-centered technologies increase visibility of comprehensive patient data. Pharma leaders anticipate the benefits of wearables to include better data (58%), faster results (33%) and lower trial costs (10%).

When Bristol Myers Squibb celebrated the approval of ozanimod — branded Zeposia — in ulcerative colitis earlier this year, the company touted the first gastrointestinal indication for an S1P receptor modulator.

Now Pfizer wants to give the pharma rival a run for its money.

Pfizer is dropping $6.7 billion to acquire Arena Pharmaceuticals, whose lead drug, etrasimod, targets the sphingosine 1-phosphate receptor.

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As the investments in cell and gene therapy manufacturing continue to grow across the world, Cincinnati Children’s Hospital and CTI Clinical Trial & Consulting Services have entered a $100 million agreement to produce clinical material locally.

The joint venture enables the hospital to work on its Translational Core Laboratory, which manufactures and tests services for cell and gene therapy trials. This will help address the global gene and cell therapy shortage and prevent the lack of capacity from getting in the way of new development. About 15 C&G therapy products have been approved by regulatory agencies across the globe, and a study from the Alliance for Regenerative Medicine predicts another 10 to 20 per year by 2025.

Rob Califf, the famous cardiologist from Duke University, is likely to return to the top of the FDA, this time under the Biden administration.

At his confirmation hearing Tuesday, Democrats and Republicans on the Senate health committee offered their support for Califf, with Chair Patty Murray (D-WA) stressing the need for an experienced leader, like Califf, who can ensure that science comes first.

A Boston-based provider of lab space is tripling its footprint with the addition of a West Coast campus.

SmartLabs, a company with labs in three different neighborhoods in the Boston area, will open a new research and manufacturing center that will be located in the heart of the South San Francisco biotech corridor. The site will support end-to-end drug development and include 500L manufacturing bioreactors that can support allogeneic and autologous cell therapies.

Roche/Genentech CMO Levi Garraway

Breakthroughs in drug development have begun to unlock the potential of antibody-drug conjugates, therapies designed to better target proteins on tumor cells. Genentech’s Polivy has become an early winner in blood cancer, and now the drugmaker is revealing promising results in getting into patients even sooner.

A combination of Roche’s Polivy, an ADC targeting the CD79b protein on tumor cells, with Rituxan and the chemotherapy regimen R-CHOP cut the risk of disease progression or death over Rituxan-chemo alone by 27% in patients with first-line diffuse large B cell lymphoma, according to late-breaking data presented Tuesday at #ASH21.

Harpreet Singh, Immatics CEO (Credit: Allogeneic Cell Therapies Summit)

Just a few weeks after offering a positive readout on its first early clinical-stage offering, the transatlantic biotech Immatics is back with news that the research crowd around Rupert Vessey at Bristol Myers Squibb has anted up $150 million in cash to get on at the ground floor with one of their still-preclinical efforts.

This time the news is centered on IMA401, Immatics’ most advanced bispecific, which uses one binder to latch on to MAGEA4/8 while another is used to whip up T cell activity against tumor cells where that’s a common antigen. For now, that’s still a preclinical effort, with the first human trial set to launch in the first half of next year.

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The current generation of cell therapies has proven a game changer in terms of treating aggressive blood cancers, but the tech has its limitations. Novartis, one of the biggies in the current generation of these drugs, is now taking lessons learned from CAR-T Kymriah to supercharge a ‘second-generation’ of CAR-Ts putting superior cells into patients faster.

Novartis on Monday rolled out early Phase I data for a pair of autologous CAR-T cell therapies developed through the drugmaker’s T-Charge platform, a process designed to promote T cell ‘stemness’ — a measure of a cell’s ability to self-renew — by cutting manufacturing times and spurring cell proliferation primarily in patients’ lymph nodes.

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Aamir Malik, Pfizer chief business innovation officer

Pfizer made a big splash in the M&A space Monday, announcing a $6.7 billion buyout of Arena Pharmaceuticals to chase Bristol Myers Squibb in the S1P race. But company execs suggested the company isn’t finished bringing on new assets.

In an investor call outlining the Arena acquisition, chief business innovation officer Aamir Malik took a moment to discuss Pfizer’s growth plans going forward. The strategy was made up of three pillars: advancing the internal pipeline, continuing to pursue outside opportunities and exploring the combination of technology and data to ‘accelerate’ growth.

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https://endpts.com/ash-sanofi-uncorks-late-stage-data-for-rnai-drug-fitusiran-in-hemophilia-with-all-eyes-on-safety-profile/