The Antibody Drug Conjugate (ADC) stage just gets hotter and hotter!

Maybe I’m just a little biased, preoccupied and obsessed with ADCs but the last 2 weeks or so has seen really significant movements in the ADC world.  We already have had predictions that 2024 is going to be a ”hot year” for ADC but personally, I think 2024 is just the start and 2025, 2026 and 2027 might be even hotter for ADCs.  So, what’s kept me awake at night the last 2 weeks?  Let’s look at the dynamic duo of Daiichi Sankyo and Astra Zeneca, one of the ADC top performing dogs.  DS and AZ’s ADC armamentarium continues to demonstrate its impressive firepower.  Just last week on the 5th April 2024, DS & AZ notched their8th(!!!) FDA approval for Enhertu (or if you prefer the INN tongue-twister, fam-trastuzumab deruxtecan-nxki) , this time an accelerated approval for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. This approval was based on clinical data from 3 different trials from the DESTINY study series.  This approval is important as it allows another shot against a wide range of solid tumor cancers (CRC, lung, biliary, ovarian, pancreatic, etc, etc) all of which have to be HER2-positive but which have run out of treatment options.  In other words, these patients sadly are already in the last-chance saloon but now, as long as their cancer is HER2 positive (tumor-agnostic) they get a chance to have another crack against their old adversary.  Hope, determination and another weapon is what these patients need.

Notwithstanding a highly successful and durable collaboration with Astra Zeneca, Daiichi Sankyo isn’t done with their enthusiasm for more clinical partners.  On the 19th October 2023, Daiichi Sankyo formally entered into another ADC collaboration, this time with Merck. And this new double act will co-develop and commercialise yet another 3 ADCs (patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd)) all based on DS’s proprietary deruxtecan DXD platform technology.  And just last week on the 2nd April 2024, DS and Merck announced that the first patient has been dosed in the REJOICE-Ovarian01 phase 2/3 trial evaluating the efficacy and safety of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer.  There’s no stopping Daiichi Sankyo’s relentless march into ADC greatness and it seems, they are always on the lookout for partners.  Not content with the Daiichi Sankyo collaboration, Merck itself is doing some ADC fine tuning as well. Just last week on the 5th April 2024, Merck bought out the University of Buffalo spin-out Abceutics for a bargain $208m.  Merck clearly has its crosshairs on Abceutics’ “payload-binding selectivity enhancers” (PBSEs) to bind and neutralize stray payload molecules, thereby reducing the impact of these agents on otherwise healthy cells.  Meaning what?  Safety!  And this is going to be sweet music to regulators and indeed patients.  I’d be very keen to see how this relationship works out.

The rest of the pharma community isn’t just watching idly and impassively though.  This looks to be a golden opportunity to bring patient benefit and commercial success through ADCs. Everyone right now wants to get onto the ADC stage.  Look at Genmab!  On the 3rd April 2024, Genmab went public to say they will acquire the ADC company ProfoundBio in an $1.8b all-cash transactionPositive investor fundings and deals such as Torl Biotherapeutics $158m series B funding on the 10th April 2024 will only add more wild-eyed excitement on the ADC stage.  I personally am particularly excited by Torl’s offerings as their individual ADCs target Claudin 6 positive (CLDN 6+), Claudin 18.2 positive (CLDN 18.2+), Cadherin 17 positive (CDH17+) and DLK1 positive solid tumors.  As a Roche alumnus, I must confess I am particularly keen to know what chess moves Roche might take with ADCs.  To be fair, Roche has already got 2 approved ADCs.  But it’s been many, many years ago that I myself worked on trastuzumab emtasine that eventually got approved as Kadcyla and the ADC technology then isn’t as sophisticated as it is now, and it certainly can be better.  In January’s JPM 2024, Roche’s brilliant head of pharma partnering James Sabry wasn’t going to be pushed into spilling the beans on what Roche was going to do with ADCs.  We do have a nice clue though!  On the 2nd January 2024, China’s MediLinks Therapeutics announced it had entered into a worldwide collaboration and license agreement with Roche to develop a next-gen ADC targeting c-Met solid tumors, with their proprietary Tumor Microenvironment Activable LINker-payload (TMALIN®) ADC technology platform.  I’ll definitely be watching this space!

READ THE ARTICLEhttps://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

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