Exclusive Q&A with Dr Rakesh Dixit

I recently had the pleasure of talking with Dr Rakesh Dixit, President & CEO of Bionavigen LLC. Dr Dixit is a a key contributor to successful marketing approval of 10 different marketed biopharmaceuticals, and a key opinion leader in Safety Assessment with outstanding knowledge and proven experience in drug discovery, preclinical, and clinical development from IND/CTA through approval. I invited him to share some of the key learnings from successful and failed ADCs over the past years.

Mimi Langley: With the recently approved ADCs - PADCEV™ and Enhertu™ - over the past month, what is the current sentiment surrounding ADCs?

Rakesh Dixit: There is renewed enthusiasm in the ADC world with now seven approved oncolytic ADCs and one approved ADC-like recombinant anti-cancer immunotoxin. There is also a great likelihood of approval of at least four additional ADCs in the next two years.

ML: What are some of the key learnings from past ADCs – successes and failures?

RD: Some key learnings from successful ADCs include:

• a clinically meaningful therapeutic window between serious toxicities and efficacious dose that allows rapid oncolytic responses without serious dose and schedule limiting toxicities,
• rapid and sustained responses that provide meaningful survival benefits,
• manageable toxicities following repeated cycles of treatment.
• But the success in oncolytic ADCs has come with high failures in the last two decades raising doubts in the ADC-based magic bullets.

In contrast, clinically unsuccessful ADCs have also many features in common, including:

• lack of clinically meaningful therapeutic window,
• frequent severe dose-limiting toxicities that limit the administration of efficacious doses and repeated cycles of treatment,
• poor selection of right patients, right dose, and right dosing schedules.

A few additional shortcomings of failed ADCs include:

• short half-life with high normal tissue distribution,
• ADC formats that are not compatible with drug-like properties,
• use of highly potent and highly toxic warheads that are not compatible with antibody-based delivery.

ML: What are the implications for ADC design and development, and which ADC might see the most success?

RD: The key learnings from both successful and failed ADCs are being applied successfully to advance the cancer treatments. The next generations are being generated with better antibodies having a good half-life, more stable linkers and moderately potent warheads with a better selection of targeted patients.

Dr Dixit will be expanding on the above discussion during his Keynote Presentation on May 7, 2020 at the Clinical Progress of Antibody-Drug Conjugates (http://bit.ly/2uKczJn) program at PEGS Boston.