Current and Next Generation ADCs: Successes and Failures
Alain Beck, PhD, Senior Biologics CMC & Developability Director, Pierre Fabre Group
Surge in Antibody-Drug Conjugate R&D Focused on Payloads, Targets, and Combo Therapies
Antibody-drug conjugates (ADCs) have encountered a bumpy ride, with failures significantly outnumbering approvals. However, development pipelines are healthy and technology is improving, according to Dr. Alain Beck, Senior Director, Biologics CMC & Developability, at Pierre Fabre Group.
Beck spoke about the ADC sector at Antibody Engineering & Therapeutics Europe in June, telling delegates that 97 candidate products have failed during clinical development during the past decade.
“Eighty-four of them failed after phase 1, which is quite a high attrition rate, which shows that it is complicated to develop ADCs. A further 12% failed in phase 2 and 4% in phase3,” Beck said.
“The main reason for failure was lack of efficacy, for one-third of them, followed by safety issues, which remain the main concern, and also portfolio prioritization of companies.”
Other ADCs have failed because of the “difficult” molecules they target, Beck said, citing CD70, EGFR and PSMA as particularly challenging examples.
Despite these setbacks and challenges, Beck expressed confidence that the ADC market will grow, adding “maybe new technology can help to solve these issues.”
Current Market
Beck also cited the diversity of products that have been approved to date as evidence of developers’ willingness to innovate, pointing to the range of different payload types to support the interpretation.
“For the products that have reached market, we have many DNA damaging agents and microbial inhibitors as payloads. More recently, topoisomerase 1 inhibitors have been used,” he said.
“We have currently 13 ADCs that have been approved – six in hematologic indications and seven in solid tumours. Three target HER2. Most of them are IgG1, 2 or 4. Most use the linker vedotin, and many are conjugated on a cysteine of the hinge of [the] region antibody.”
For approved ADCs, the drug to antibody ratio is between 2.5 and 8. Additionally, most of them have a cleavable linker with the bystander killing effect, according to Beck.
“In haematology, we have efficacious ADCs against lymphoma, leukaemia, and myeloma. And in the solid tumorous, we have ADCs against triple-negative breast cancer as well as gastric and non-small cell lung cancers,” he said.
Combination Therapies
Approved ADCs have also performed commercially, according to Beck.
“We have three blockbusters on the market with one more than $1 billion [in revenue], which are Adcetris (brentuximab vedotin), Kadcyla (Trastuzumab emtansine) and Enhertu (Trastuzumab deruxtecan),” he said.
The revenue generated by the approved products is likely to increase over the next few years, Beck noted, as developers test their products in conjunction with other therapies.
“All these companies are trying to find combinations with other therapies. Only one is approved currently, but this strategy helps [developers] to have better results,” he said.
“So of course, people are using chemotherapies in combinations or immunotherapies, and this works well for Adcetris and Kadcyla.”
Combination therapy science is advancing because of these development efforts, Beck said.
“Some of the key lessons to emerge so far are [the need] to carefully check the combined toxicity of this modality … and to select the right population of patients who are likely to see the best clinical benefit.”
Late-Stage Pipelines
Beck also cited the seven ADCs currently in late-stage clinical trials – four of them that would be first-in-class for their respective targets – as an indication that the market is poised for growth.
“Two of them could have their BLAs [biologics license application] filed this year,” he said.
Similarly, Beck said, there are 13 ADCs in phase 2 or phase 2/3 or phase 2-3. Of these, 10 are directed against solid tumours, and three target blood cancers.
