Ear­ly in 2019, Bris­tol-My­ers Squibb re­scind­ed an FDA ap­pli­ca­tion to mar­ket its check­point in­hibitor Op­di­vo in com­bi­na­tion with its CT­LA-4 ther­a­py Yer­voy for front­line use in pa­tients with the most com­mon form of lung can­cer. One year lat­er — the com­pa­ny is tak­ing the same step with the Eu­ro­pean reg­u­la­tor.

De­spite a head start, when Bris­tol-My­ers’ and its pi­o­neer­ing check­point in­hibitor Op­di­vo suf­fered a key lung can­cer set­back in 2016 — they found them­selves rel­e­gat­ed to the back­seat as Mer­ck’s Keytru­da seized the wheel on the road to im­munother­a­py star­dom. The drug­mak­er has since suf­fered a se­ries of blows in its quest to take a big slice of the lu­cra­tive mar­ket, pep­pered with some suc­cess­es.

This Op­di­vo/Yer­voy com­bo was meant to claw back some of that lost ground. Orig­i­nal­ly filed in 2018, the EU ap­pli­ca­tion was de­signed to al­low the use of the Op­di­vo/Yer­voy as a first-line reg­i­men in pa­tients with non-small cell lung can­cer (NSCLC) with high tu­mor mu­ta­tion­al bur­den (TMB) on the ba­sis of the Check­Mate-227 study.

In one arm of the tri­al, which com­pared the com­bo to chemother­a­py, re­searchers said they had ob­served a “high­ly” sig­nif­i­cant pro­gres­sion-free sur­vival rate in pa­tients with high TMB, re­gard­less of PD-L1 ex­pres­sion. The high TMB group ac­counts for 45% of all front­line pa­tients, the com­pa­ny es­ti­mat­ed at the time. Bris­tol-My­ers had re­designed the study to fo­cus on TMB af­ter stum­bling on a piv­otal tri­al that in­volved a broad­er pa­tient pop­u­la­tion.

Over­all sur­vival da­ta, post­ed months lat­er, showed that the haz­ard ra­tio in pa­tients get­ting the Op­di­vo/Yer­voy com­bo was com­pa­ra­ble whether they were high or low TMB pa­tients. How­ev­er, the me­di­an over­all sur­vival in pa­tients with high TMB was 23.03 months on the Op­di­vo/Yer­voy arm, ver­sus 16.72 months in the chemother­a­py group. In the low TMB group, the me­di­an OS was 16.20 months and was 12.42 months on the com­bi­na­tion and chemother­a­py arms, re­spec­tive­ly.

Since the OS da­ta came lat­er, the EU ap­pli­ca­tion was amend­ed ac­cord­ing­ly. A full as­sess­ment of the ap­pli­ca­tion by the EU reg­u­la­tor was not pos­si­ble fol­low­ing mul­ti­ple pro­to­col changes the com­pa­ny made, Bris­tol-My­ers’ said, cit­ing its re­sponse from the EU agency.

The com­pa­ny — which with­drew a sim­i­lar US ap­pli­ca­tion in Jan­u­ary 2019 af­ter it was un­able to con­vince the FDA of the con­nec­tion be­tween TMB and PD-L1 — has no plans to re­file this ap­pli­ca­tion in the EU, it said on Fri­day.

In­stead, Bris­tol-My­ers has tak­en a slight­ly dif­fer­ent ap­proach. Last month, the FDA grant­ed the com­pa­ny’s ap­pli­ca­tion for the Op­di­vo/Yer­voy com­bo for the first-line treat­ment of pa­tients with metasta­t­ic or re­cur­rent NSCLC with no EGFR or ALK ge­nom­ic tu­mor aber­ra­tions pri­or­i­ty re­view, on the ba­sis of the same Check­Mate-227 study.

In ad­di­tion, Bris­tol-My­ers plans to file ap­pli­ca­tions across the At­lantic fol­low­ing the re­sults of a Phase III open-la­bel study — Check­Mate -9LA — which eval­u­at­ed the im­pact of Op­di­vo/Yer­voy ad­min­is­tered con­comi­tant­ly with a lim­it­ed course of chemother­a­py for the first-line treat­ment of NSCLC.

Lung can­cer is the most lu­cra­tive on­col­o­gy mar­ket — and as such, check­point in­hibitors of all hues have been scram­bling to gain ground in the field. For now, Mer­ck’s Keytru­da re­mains way in front. Ac­cord­ing to 2024 pro­jec­tions com­piled by Cowen an­a­lysts, Op­di­vo is ex­pect­ed to gen­er­ate a meaty $12.4 bil­lion that year, while king Keytru­da is ex­pect­ed to reap a hefty $20.6 bil­lion.

Bris­tol-My­ers hunt for adop­tion in the small­er small cell lung can­cer (SCLC) mar­ket has al­so been punc­tu­at­ed with fail­ure. 2018 saw an Op­di­vo/Yer­voy com­bo miss the pri­ma­ry end­point for over­all sur­vival in the Check­Mate-451 study, where the Bris­tol-My­ers drugs were be­ing eval­u­at­ed as main­te­nance ther­a­py for SCLC, fol­low­ing an ini­tial round of chemother­a­py. The re­sults came just over a month af­ter the drug­mak­er un­veiled an Op­di­vo flop in the Check­Mate-331 study, which test­ed the im­munother­a­py against the sec­ond-line SCLC stan­dard-of-care.

Still, over the years, Op­di­vo has seen some lung can­cer suc­cess — in­clud­ing the ap­proval of the drug in squa­mous NSCLC pa­tients whose can­cer has pro­gressed de­spite plat­inum-based chemother­a­py as well as pa­tients with metasta­t­ic SCLC, whose can­cer has pro­gressed af­ter plat­inum-based chemother­a­py and at least one oth­er line of ther­a­py.

Cyclerion Therapeutics may have the design of a Phase IIb study ready to go, but it’s scrambling for a way to fund it.

The company said in a press release that it’s “actively evaluating the best combination of capital, capabilities, and transactions available to it to advance the development of zagociguat,” its lead candidate for a rare, genetic mitochondrial disease known as MELAS.

In a separate SEC filing, Cyclerion once again flagged “substantial doubt about (its) ability to continue as a going concern.” As of the end of 2022, it had cash and cash equivalents of only $13.4 million.

A small, Santa Ana-based biotech created in 2017 is looking to enter a SPAC deal as it lays out plans to begin trials in its lead cell therapy candidates and bring on new executives.

Graf Acquisition Corp. IV and NKGen Biotech announced Thursday, with few other details, that the two companies signed a non-binding letter of intent to “pursue a business combination.” Graf Acquisition II and III withdrew their IPOs last year.

The FDA has rejected Incyte’s extended-release formulation of ruxolitinib tablets, in a surprise setback for the company’s plans to build on its blockbuster Jakafi franchise.

The ruxolitinib XR tablets are designed to be taken once a day, whereas Jakafi is indicated for twice daily dosage (although some patients can take it once daily).

According to Incyte, the FDA acknowledged in its complete response letter that the study submitted in the NDA “met its objective of bioequivalence based on area under the curve (AUC) parameters but identified additional requirements for approval.”