After Pfizer launched Mylotarg, the first antibody drug conjugate (ADC) in 2000, it seemed to be the long-awaited “magic bullet” in cancer; it was a drug that would travel straight to tumors and drop a toxic payload inside of them. But despite the excitement and the promise, it took another 11 years for the next ADC (Seagen’s Adcetris) to arrive on the market.
Now, after two decades of trial and error in ADC development, the field is poised to deliver a plethora of targeted drugs to treat a wide range of tumor types. Mylotarg's initial approval was to treat acute myeloid leukemia, while Adcetris' was for two types of lymphoma. Now, there are 11 FDA-approved ADCs that are expected to be bringing in more than $20 billion a year in sales by 2030, Evercore ISI estimated in a June report.
In addition, there are more than 50 biopharma companies developing ADCs to treat blood cancers as well as a range of solid tumors, including gynecological, lung and bladder tumors.
“We’re starting to see activity across a number of different solid tumors,” said Maneka Mirchandaney, director of biotech equity research at Evercore ISI, in an interview. “That space has been hard to crack with other modalities, so that’s one of the big differentiating points of [ADC] technology.”
ADCs are constructed with four main elements: a monoclonal antibody designed to target a particular cancer-associated antigen; an anti-cancer medicine as a payload, like a chemotherapy drug; a “linker” that cleaves off that payload inside cancer cells; and the conjugation technology that attaches the linker and payload to the antibody.
But while it sounds relatively straightforward, the construction has been anything but simple for ADC developers. “You need the drug to have an incredible degree of stability as it gets into the tumor,” Mirchandaney said. “You need broad penetration across the tumor, and you need easy release of the payload. Those are really tough problems to solve.”
Mylotarg, in fact, was withdrawn from the market in 2010 after a post-marketing trial raised toxicity concerns. It was reintroduced in 2017 after the FDA cleared it at a lower dose for a subset of leukemia patients.
More recently, the ADC field took a major hit when Sesen Bio received a complete response letter from the FDA for what was expected to be its first product, the ADC Vicineum to treat bladder cancer. A subsequent news report revealed more than 2,000 violations in the company’s pivotal trial. With the future of Vicineum now uncertain, Sesen went from being a top-five contender on this list to being thrown off it altogether.
The Sesen soap opera is a stain on the ADC field, for sure, but it shouldn’t minimize the accomplishments of other companies that have labored for years to improve upon the technology.
“The linker and conjugation technologies especially have meaningfully improved over time,” Mirchandaney said. “With early generations, the drugs dropped off the payloads before they reached tumors, so you got toxicity. The conjugation technology created suboptimal drug properties. But now we have much better linkers and conjugation that can precisely attach the payload to the antibody.”
Advancements in ADC design are already paying off for companies tackling tough-to-treat cancers. Daiichi Sankyo, ranked second on this list, has enjoyed strong demand for its AstraZeneca-partnered ADC Enhertu to treat HER2-positive breast and gastric cancers. Now it’s poised for approval in HER2-mutant non-small cell lung cancer, while also setting out to unseat fourth place Roche and its blockbuster ADC for HER2-positive breast cancer, Kadcyla.
ADCs' complex design is something that in the long run could actually work to the benefit of their developers, Mirchandaney says. That’s because it will be challenging for biosimilar makers to copy such complex drugs. A lack of biosimilar rivals could translate into greater pricing freedom for ADC pioneers. “What are the prospects for biosimilar development in this space? That’s going to be an important dynamic to watch,” she says.
For this report, Fierce selected a mix of Big Pharma players with established, hit ADCs and startups with strong prospects in their pipelines. What they all have in common is that they’re expecting major milestones in the coming months that could greatly expand their presence in this growing market. Some, like Roche and GlaxoSmithKline, are developing one or two ADCs as part of a diverse oncology strategy. Others are ADC specialists with multiple shots on goal.
The latter group includes our top pick, Seagen. Not only did it nab two bladder cancer FDA approvals this summer for its second ADC, Padcev, but it has one of the deepest ADC pipelines in the industry. As it continues to work towards expanding the markets for Padcev and Adcetris, it’s developing six additional ADCs including disitamab vedotin, a HER2-targeted ADC it recently licensed from China’s RemeGen in a deal worth up to $2.6 billion.
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