In the nev­er-end­ing but hard­ly-chang­ing saga of the FDA and Aveo On­col­o­gy, the US reg­u­la­tor has once again spurned the com­pa­ny for fail­ing to prove that their drug helped re­nal cell car­ci­no­ma pa­tients live longer.

Aveo an­nounced this morn­ing that the FDA rec­om­mend­ed they not sub­mit an NDA ap­pli­ca­tion be­cause the lat­est Phase III tri­al da­ta don’t al­lay the agency’s con­cern that their drug, tivozanib, is hurt­ing pa­tients, as com­pared with the base­line treat­ment, Bay­er’s so­rafenib. Once again, the con­cern is about the over­all sur­vival rate.

“The FDA not­ed that the Com­pa­ny’s cur­rent in­ter­im OS re­sults do not ab­ro­gate the FDA’s con­cerns over detri­ment and that those re­sults may wors­en with fi­nal analy­sis at 263 events, and that the me­di­an OS for tivozanib is worse than that of so­rafenib,” Aveo wrote.

In re­sponse, Aveo said it will nar­row its pro­posed in­di­ca­tion to re­lapsed/re­frac­to­ry re­nal cell car­ci­no­ma, with plans to sub­mit an NDA in the first quar­ter of 2020. But they agreed with the agency that if in the fi­nal analy­sis, the over­all sur­vival haz­ard ra­tio is over 1.00 – if peo­ple are more like­ly to die in the tivozanib arm– they will with­draw their NDA. In Aveo’s telling, the reg­u­la­tors don’t sound op­ti­mistic about Aveo’s rec­om­men­da­tion.

Michael Bai­ley

“At the meet­ing, the FDA ac­knowl­edged AVEO’s re­spons­es and re­it­er­at­ed its con­cerns about the sur­vival in­for­ma­tion and the to­tal­i­ty of da­ta,” Aveo wrote. “The FDA not­ed that the choice to sub­mit the da­ta is the Com­pa­ny’s, and that a dis­cus­sion with the On­co­log­ic Drug Ad­vi­so­ry Com­mit­tee will like­ly be re­quired.”

The news sent Aveo’s stock plum­met­ing deep­er in­to pen­ny stock ter­ri­to­ry, down 30% to $0.62 per share.

The FDA first re­buffed Aveo in 2013 at the end of their first Phase III tri­al, af­ter the agency raised con­cerns about the sur­vival rate and ex­perts on the re­view pan­el ex­pressed out­rage at the tri­al de­sign and dis­ap­point­ment over the pro­posed la­bel.  Most no­tably, the agency said the drug im­proved dis­ease-free pro­gres­sion by 20%, but al­so in­creased the risk of death by 25%.

“If we ap­prove this drug based on this study how would we com­mu­ni­cate to pa­tients the po­ten­tial 25 per­cent in­crease in the risk of death?” Jonathan Jarow, then-med­ical of­fi­cer at the FDA, asked the pan­el, per Reuters. The pan­el vot­ed 13-1 against the drug, and the FDA re­ject­ed it.

The FDA had, in fact, al­ready rec­om­mend­ed a new tri­al, an SEC in­ves­ti­ga­tion would lat­er al­lege, and Aveo failed to no­ti­fy in­vestors of that fact – even­tu­al­ly lead­ing to ex­ec­u­tive res­ig­na­tions and a $4 mil­lion set­tle­ment.

Aveo is now near­ing the end of its sec­ond tri­al, ti­tled TI­VO-3, and still has not al­layed FDA con­cerns. They did man­age to con­vince the EMA in 2017 to ap­prove tivozanib for re­nal cell car­ci­no­ma but with the caveat that the Eu­ro­pean agency would re­view the TI­VO-3 re­sults as part of its post-mar­ket­ing re­quire­ments.

That ap­proval is al­so at risk. Af­ter Aveo’s first re­leased pre­lim­i­nary da­ta for Ti­vo-3 last No­vem­ber, re­veal­ing an OS HR of 1.12, the EMA warned “reg­u­la­to­ry ac­tion” was pos­si­ble if an Au­gust in­ter­im analy­sis didn’t yield a bet­ter over­all sur­vival rate. The Au­gust num­ber, HR 0.99, wasn’t enough for the FDA. It re­mains to be seen what the EMA thinks — and what the fi­nal re­sults will be.

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.”