After Astra’s exit Zentalis doubles down on Wee1

Things might be looking up in biotech but it is too early to declare the bear market over, and hard choices still have to be taken in prioritising R&D spending. So Zentalis should be congratulated for pulling the plug on ZN-c5 and ZN-e4, respectively an oral Serd and EGFR inhibitor. Radius/Menarini’s elacestrant could soon become the first approved oral Serd, and pivotal data are expected from Astrazeneca and Lilly’s contenders. And the EGFR space is fiercely competitive, featuring Astra’s blockbuster Tagrisso and numerous advanced players. The question for Zentalis, fresh from a $200m equity raise and $25m share purchase by Pfizer, is whether in focusing on ZN-c3 and ZN-d5 it is backing the right horses. ZN-d5, a BCL-2 inhibitor, has marketed competition, though not in its selected niche of AL amyloidosis. ZN-c3 could be the big one: after Astra pulled adavosertib ZN-c3 is the industry’s most advanced Wee1 inhibitor – a mechanism that has promised much but delivered little. Zentalis will argue that ZN-c3 has better tolerability, and might not hit adavosertib’s problematic lack of a therapeutic window. Perhaps Astra’s decision encouraged Zentalis; a phase 2 ZN-c3 trial ending in December could reveal all.

Zentalis makes some hard decisions
What's in…
Project Mechanism Clinical trial 2028e sales ($m) Commercial position
ZN-c3 Wee1 inhibitor Ph2 in uterine serous carcinoma 244 Astra discontinued adavosertib in Jul 2022; ph1 projects from Debiopharm, Impact Therapeutics & Shouayo
ZN-d5 Bcl-2 inhibitor Ph1/2 in AL amyloidosis NA* Roche/Abbvie's Venclexta is marketed for blood cancers; clinical lead is Abbvie's navitoclax, in ph3 for myelofibrosis
…and what's out
ZN-c5 Oral Serd Ph1/2 in ER+/Her2- breast cancer 686 Radius/Menarini's elacestrant filed; Sanofi's amcenestrant & Roche's giredestrant failed in ph3; pivotal data from Astra's camizestrant in H1 2023, and from Lilly's imlunestrant in mid-2023 
ZN-e4 EGFR inhibitor Ph1/2 in EGFR+ve NSCLC NA* Marketed drugs include Astra's Tagrisso, Pfizer's Vizimpro & J&J's Rybrevant, plus 1st-gen products Tarceva, Iressa etc; pipeline includes J&J's lazertinib & Dizal's sunvozertinib; Black Diamond recently discontinued BDTX-189
Source: Evaluate Pharma sellside consensus; *no analyst consensus available.

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