FDA delays Biogen's ALS drug review by three months, decision to now come next April – Endpoints News

At­tempt­ing to push for­ward an ALS drug de­spite a failed Phase III study, Bio­gen saw its FDA re­view date de­layed Mon­day.
The big biotech an­nounced that the agency pushed back its de­ci­sion dead­line by three months to April 25, 2023 for tofersen, an an­ti­sense drug de­signed to treat a ge­net­ic sub­set of ALS. Bio­gen had pre­vi­ous­ly re­ceived pri­or­i­ty re­view for the ap­pli­ca­tion, which will fall un­der the ac­cel­er­at­ed ap­proval path­way.
In a press re­lease, Bio­gen said the FDA had re­quest­ed ad­di­tion­al in­for­ma­tion, but it’s not clear what they sought. A Bio­gen spokesper­son told End­points News, “We aren’t able to pro­vide fur­ther de­tail on our reg­u­la­to­ry in­ter­ac­tions, but in­for­ma­tion re­quests are a stan­dard part of the FDA re­view process.”
Bio­gen is try­ing to get tofersen ap­proved for ALS pa­tients with SOD1 ge­net­ic mu­ta­tions, a pop­u­la­tion that makes up rough­ly 2% of the glob­al pa­tient pop­u­la­tion. Though there are many genes known to be im­pli­cat­ed in ALS, SOD1 is the most com­mon. Cur­rent re­search es­ti­mates that all ge­net­ic mu­ta­tions ac­count for about 10% of ALS cas­es world­wide.
SOD1 falls un­der this um­brel­la, known as “fa­mil­ial ALS” due to its as­so­ci­a­tion with pa­tients’ fam­i­ly his­to­ries. The vast ma­jor­i­ty of oth­er ALS cas­es, called “spo­radic ALS,” make up the oth­er 90%, re­searchers be­lieve.
There have on­ly been three ALS drugs ap­proved by the FDA, all of which pro­vide on­ly mod­est ef­fects, and none are specif­i­cal­ly tar­get­ed to­ward fa­mil­ial cas­es. Tofersen at­tempts to slow SOD1-ALS pro­gres­sion by bind­ing to SOD1 mR­NA and re­duc­ing “syn­the­sis of SOD1 pro­tein pro­duc­tion,” the biotech says.
Us­ing a func­tion­al rat­ing scale mea­sur­ing pa­tient symp­toms as the pri­ma­ry goal, tofersen failed a Phase III test late last year. But Bio­gen is at­tempt­ing to win ac­cel­er­at­ed ap­proval based on the drug’s ef­fect on neu­ro­fil­a­ment light chain, an un­proven sur­ro­gate bio­mark­er that some re­searchers be­lieve can mea­sure neu­ronal cell death.
In pa­tients with neu­rode­gen­er­a­tive dis­eases, neu­ro­fil­a­ment lev­els can be el­e­vat­ed in blood and cere­brospinal flu­id. Bio­gen the­o­rizes that be­cause tofersen’s da­ta showed a low­er­ing of neu­ro­fil­a­ment dur­ing its clin­i­cal tri­als, the drug works, de­spite miss­ing the Phase III goals.
The FDA, how­ev­er, has nev­er ap­proved a drug based on its pur­port­ed neu­ro­fil­a­ment-low­er­ing ef­fect. Re­search show­ing neu­ro­fil­a­ment is im­pli­cat­ed in ALS is not con­clu­sive, though clin­i­cians note its promise. Oth­er bio­phar­ma com­pa­nies are like­ly watch­ing this case close­ly as well, to see if they can cen­ter their own new drug ap­pli­ca­tions around neu­ro­fil­a­ment.
Tofersen stands in con­trast to Re­lyvrio, the re­cent­ly ap­proved ALS drug from Amy­lyx Phar­ma­ceu­ti­cals, a Boston-area biotech. Where­as tofersen failed its Phase III while show­ing an ef­fect on neu­ro­fil­a­ment, Re­lyvrio earned a mod­est Phase II suc­cess — but showed no cor­re­la­tion to neu­ro­fil­a­ment lev­els.
That nu­ance has al­lowed Bio­gen to seek ac­cel­er­at­ed ap­proval while Amy­lyx was left search­ing for, and win­ning, a full green light. The ball is now in the FDA’s court, and if the path to ap­proval is any­thing like Amy­lyx’s, an ad­comm (or two) could be in Bio­gen’s fu­ture.
Key takeaways:
The data supporting regulatory approval alone are often insufficient for demonstrating the added benefit of a new therapy
Planning in advance to continuously deliver data that illustrate value and post-launch, to not only the regulator, but payers, healthcare professionals, and patients results in more clinically meaningful benefits
By working cross-functionally, biopharmaceutical teams can uncover evidence gaps and better shape registration trials to ensure the needs of as many stakeholders as possible are met
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