Back in March 2023, Pfizer announced its intention to acquire the Antibody Drug Conjugate [ADC] powerhouse Seagen, with the deal completed in Dec 2023 for $43 billion. This “relatively-cheap” ADC powerhouse [based on the marketed and pipeline agents] is expected to reinvigorate Pfizer’s oncology portfolio, with five late-stage ADCs in their pipeline across solid and liquid tumours. While this marks one of the largest recent acquisitions, ADCs are becoming one of the most sought-after asset classes in the pharma space with 56 deals alone in 2023, and with financial opportunity linked to the broad multi-cancer potential [as well as a high price tag] making them hard to overlook. But key to their success is whether ADCs can really become the new Standard of Care (SoC) across a broad range of cancers, replacing the less targeted chemotherapy “gold-standard” in first line, or whether their price tag will limit uptake and their blockbuster potential.

Through this multi-part series we will take you through the ABC of ADCs, the future ups and downs, and what we think is next in the pan-tumour craze.

The ABC of ADCs

Since 2022, ADCs have taken centre stage across key oncology conferences, with not only pivotal readouts at key oncology conferences like ENHERTO at ASCO 2022 or Dato-DXs at ESMO 2023, but with education sessions and industry symposiums helping prescribers to understand effective treatment selection and sequencing for their patients. These well-attended sessions have helped interest engagement and enthusiasm ‘blow up’ in the oncology community, with HCPs now keener than ever to include these novel treatments in their practices and to see for themselves whether an ADC approach is better than “what we already have? And if so, at what cost?”

Chemotherapy has been the mainstay of cancer treatment, but as medical science has advanced, there has been a definitive movement to reduce its use in favour of more targeted therapies with a less toxic safety profile. ADCs sit in the middle, attempting to perfect the marriage of targeted treatment to chemotherapy in a single treatment. The technology combines a monoclonal antibody with a cytotoxic payload, via a specialized linker. The antibody portion enables selective targeting of a specific cancer biomarker/antigen, delivering the cytotoxic component to the relevant cancer cells. Not only can this decrease off-target effects and subsequent toxicities, but it can also allow for the use of more potent payloads that would be too toxic to administer systemically on their own. In short, “anything chemo can do, an ADC can do better” if the right “modules” are used. Indeed, the right antibody, the right target, the right linker, the right payload, as well as the right group of patients and tumour type, are all key for this Frankenstein-like agent to come alive and “do some good”.

 

Figure 1 – Number of ADCs launched in the US over time

This multi-variate balance may have affected the rate of clinical validation and development with the first ADC approval in 2000 (Pfizer/Wyeth’s Mylotarg in AML), followed by Adcetris and Kadcyla a decade later (2011 and 2013 respectively) and then an exponential wave of approvals from 2017 to 2022 [Fig 1]. As it stands, 11 ADCs are marketed in the US following FDA approvals [and discontinuations], albeit in later line settings, for a range of targets in solid and haematological tumours exemplifying the versatility of ADCs, with other drug platforms struggling to achieve this breadth of applicability.

This growth is assumed to be associated with the improvement in technology, particularly with the linker and conjugation methods enabling higher drug-antibody ratios, with target however also a key aspect. The most popular targets being looked at are HER2 and TROP2, accounting for the largest number of approved and investigational ADCs across tumour types [41 and 14, respectively]. This surge in development has resulted in some new life-changing options for patients but does beg the question of overcrowding and ‘marginal benefit gains’ for a new agent to launch in an established treatment segment, with for example ENHERTU and TRODELVY currently well ahead of the competition in HER2 and TROP2 respectively and with any novel therapies needing to be benchmarked against them. It also begs the question of whether we have already maxed out on the most viable targets, due to the other often less-validated mechanisms of action and with a plateau in launches potentially suggesting the  levelling of successful developments respectively.

While less-risky R&D might focus on ‘already-validated’ targets, crowding of the ADC landscape with agents rapidly becoming SoC may incentivise the development of next-wave drugs, potentially focusing on new targets or creating further Frankenstein-like agents, using the best parts of the current incumbents. The ability to mix and match ADC targets really underpins the “pipeline in a molecule” potential of the ADC approach and explains why numerous Big Pharma companies are jumping on the bandwagon.

With ADCs having now become SoC in later-line settings, to fully displace chemotherapy these agents will need to prove their value in earlier lines. Although ADCs are largely more tolerable than chemotherapy, they do still carry a notable adverse event burden linked to residual off-target effects, as well as a high direct cost to the healthcare system, given their high price tag. These considerations are particularly relevant in earlier treatment lines, where patients remain on the therapy for longer periods. Additionally, the ‘target market’ competitive risk-benefit analysis will not only focus on correct targeting and technology selection but also on the relative outcome benefit. The agent can be positioned either for a niche segment, becoming the go-to for that patient subgroup but risking a new all-comers challenge; or positioned for all-comers, presenting a larger commercial opportunity but risk missing the primary endpoint if efficacy is driven by a favored biomarker. There is also the question of whether a companion diagnostic is needed to identify eligible biomarker patients, and how readily this will be adopted into clinical practice.

While these important strategic considerations are critical to commercial success, it did not slow down deal-making across 2023  with at least 76 new ADC deals  showcasing the current market frenzy.

The hottest new oncology portfolio addition

Not only were ADCs a key disease-agnostic theme across all main oncology conferences, but they were also one of the most sought-after portfolio-additions. Of the 76 deals in 2023, the majority [37] were in licensing accounting for $27billion. Double that – ~$54billion – was spent on 10 acquisitions with $43 billion coming from the Pfizer acquisition of Seagen. The latter had held off for over three years rejecting large pharmaceutical advances from the likes of Merck, allowing ADCs to become more established, the overall hype to grow, and their valuation to skyrocket. Nevertheless, Merck scored the second largest deal of 2023 through the collaboration with Daiichi, valued at $16.5 billion, with the alliance covering three ADCs, all with first-in-class potential.

Another key deal was Abbvie’s acquisition of Immunogen and its already-marketed Elahere [Mirvetuximab soravtansine, Rα-directed] for $10.1 billion, making it the only agent for solid tumours in Abbvie’s portfolio. This follows Abbvie’s [at the time part of Abbott] rocky, and potentially premature, start with ADCs following the acquisition of Stemcentrix in 2014 and the failure of the associated Rova-T [Rovalpituzumab tesirine, DLL3-targeted] in NSCLC in 2019.

While 2023 could be considered the current peak of deal-making for ADCs, arguably the “per-asset” most expensive deal was in 2020, when Gilead acquired Immunomedics, with TRODELVY [sacituzumab govitecan] as the company’s only asset with one approved indication, for $21 billion. TRODELVY has since made good on Gilead’s vision [and investment], approaching block-buster status in triple-negative breast cancer, with a hefty pipeline to maintain that trajectory across tumour types and with peak sales of $4B annum. This is particularly true in NSCLC where it is going head-to-head with AZ/Daiichi’s TROP2-ADC, Dato-DXd, currently seen less favorably by analysts and KOLs due to ILD, but with the double primary endpoint having been met and presented as a presidential at ESMO 2023.

Smooth sailing ahead? Success is not guaranteed.

There is no argument ADCs have huge potential if all goes well, but it’s not all success stories, with some agents not having had the right component mix of antibody, linker and payload. Indeed, of the 267 ADCs tested over the past 25 years, about 35% have been discontinued [92 ADCs], with only 4% of the total currently marketed [11 ADCs]. While some of the latter are expected to reach blockbuster status, the remaining 60% representing ADCs in development, need some serious commercial consideration.

But if you can make it work, the modular platform opens pan-tumour potential, with Daiichi expecting to file for a tumour-agnostic designation in the US for 2L+ HER2+ solid tumours with ENHERTU in Q1 2024 and with broad spectrum of indications expected to support its best-seller position with $10.2bn worldwide sales in 2028.

However, the pan-tumour potential is equally a double-edged sword, putting all your eggs in one basket if the ADC platform doesn’t deliver. ADCs are also high-cost agents to manufacture, complicating supply chains whether or not you have sufficient expertise in-house, and facing pricing risk on the market if you can’t hit payers’ cost-benefit criteria vs current standard of care. GSK’s BLENREP [belantamab mafodotin] crumbled when data from the Ph3 DREAMM-3 in late-line patients with relapsed or refractory multiple myeloma [r/r MM] showed that the agent was worse than SoC, and with significant side effects. FDA Accelerated Approval was revoked and BLENREP withdrawn from the US market, with ongoing earlier line trials directly tinged by this and with several other competitor’s options available for patients. Most recently the EMA has also confirmed the recommendation of not renewing the marketing authorisation for BLENREP as “no longer outweighing its risk” with perceptions of this treatment deteriorating further. GSK remains confident in BLENREP’s potential with DREAMM-7 trial in combo with Bortezomib having met its primary endpoint of PFS ahead of schedule [data likely in H1 2024] and other trials potentially expected to readout in H2 2024. Nevertheless, repercussions could have been avoided by improved trial design, with a focus on potentially more favorable combo trials, as well as competitor awareness to assess the risk/benefit ratio needed to enter a crowded landscape.

With BLENREP’s technology having been validated previously, this is an example of how scaling up ADCs across different cancers may not be as low-risk as expected. Recent acquisition are not in calm waters yet, with marketed and pipeline ADCs yet to confirm their potential across tumour types. Additionally, with this overwhelming number of assets and deals developing, the efficacy bar will likely be raised at every approval and with ADC-vs-ADC trials becoming a requirement, as they become established as SoC; quality of life and improved toxicity profile is also likely to determine the winner if the benefit improvement is only marginal.

There is also the question of whether ADCs can remain scientifically relevant as more specialized and less toxic agents emerge such as novel biologics, and establish themselves in earlier settings potentially displacing or delaying chemotherapy further: can ADCs keep evolving and cement their place in the treatment algorithm, or will they too follow the same last-choice trajectory they have sent chemotherapy down? Additionally, increasing interest may lie in novel ADC combos to expand applicability [while trying not to impact tolerability], particularly with agents such as IOs which have traditionally been paired with chemotherapy.  What will these potential new agents [or agents’ combinations] need to achieve to displace ADCs like ENHERTU off the top spot? And is the risk associated to creating optimal Frankenstein-like ADCs, with understood technology, but unknown combinations’ efficacy and safety profile, worth it. These questions will be answered in the next blog posts.




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