Sutro reads the farletuzumab tea leaves

Eight years after the 2013 blow-up of the folate receptor alpha (FRα)-targeting MAb farletuzumab Eisai managed to license its antibody-drug conjugate iteration to Bristol Myers Squibb for $200m, but now the latter, called farletuzumab ecteribulin, has had a serious knock-back of its own.

Today Eisai moved to conduct global development and commercialisation of the ADC on its own after revealing that Bristol had canned that 2021 deal, citing “portfolio prioritisation”. At a time when FRα-directed ADCs are enjoying a resurgence, courtesy of Elahere’s approval and of its maker, ImmunoGen, being sold to AbbVie, this is another worrying sign for Sutro.

That’s because Sutro’s luveltamab tazevibulin, the industry’s next-most advanced anti-FRα ADC after Elahere, bears significant structural similarities to Eisai’s farletu-e: both molecules use tubulin inhibitor payloads and cathepsin-cleavable linkers, and both employ a drug-to-antibody ratio (DAR) of 4.

Moreover, Sutro has already been passed over once, when in April Genmab bought ProfoundBio for $1.8bn – in preference to getting Sutro for a likely $500m or less. ProfoundBio was developing another anti-FRα ADC, rinatabart sesutecan, which employed a topoisomerase 1 inhibitor payload and DAR of 8; both attributes are more in line with current industry preference than those of luvelta-t or farletu-e.

However, it's worth noting that Elahere also employs a tubulin inhibitor, and has a DAR of 3.4.

Other reasons?

There might be other reasons why Bristol has given up on farletu-e, such as, for instance, fundamental problems with the MAb itself.

Such a possibility would be supported by farletuzumab’s 2013 failure in a phase 3 chemo combo study in 1,080 women with platinum-sensitive ovarian cancer, in which neither of two doses yielded a statistically significant PFS improvement versus standard of care alone. A post hoc analysis revealed some promise in undisclosed subsets, but immune-mediated adverse events were also seen.

If this were true Bristol would have to have failed to do its due diligence – unlikely given its standing as a big pharma oncology player. It’s unclear what Bristol might have seen in farletu-e that it didn’t like, as the only available data are from phase 1, where a high dose given to 21 FRα-positive ovarian cancer patients gave an ORR of 52%, as presented at ASCO in 2022.

Interstitial lung disease was reported at the time, but at grade 3 it was seen in zero low-dose patients and in 5% of those given a high farletu-e dose. Eisai said those results demonstrated its ability to minimise ILD while retaining a respectable ORR benefit thanks to body surface area-based dosing.

At Eisai farltuzumab and farletu-e both date back to the private biotech Morphotek, which the Japanese group bought for $325m all the way back in 2007. At the time the projects were coded MORAb-003 and MORAb-202 respectively, and Eisai intended the deal to help it build a US presence.

In the meantime targeting FRα endured the implosion of Endocyte’s vintafolide, followed by a resurgence of interest triggered by Elahere. Eisai still hopes to tap into the excitement, but as of today it’s on its own, even revealing that it's having to repay part of Bristol's $200m up-front fee.