#409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles behind bringing new medicines to patients | Lloyd Klickstein, M.D., Ph.D.

Lloyd’s path from academic medicine to translational drug development [A: 3:15, V: 0:11];

Tell us a little about your background 

You’re a physician scientist, talk about how those 2 paths came together 

• Lloyd planned to follow the family business into medicine, but laboratory work at Brigham and Women’s Hospital between college and medical school showed him that he loved science and was good at it
• He completed an MD-PhD, trained in internal medicine and rheumatology
• He practiced rheumatology for about 10 years, and led an NIH-funded basic-science laboratory studying adhesion molecules in the immune system
• He remained at the Brigham for his entire academic career before moving to industry a little over 20 years ago

Was your medical training also at Brigham? Did you stay there after you finished your training?

• Yeah, he stayed there his whole academic career
  • Medical school, MD, PhD, PI (the whole thing)
• Lloyd shares, “I have a high activation energy for moving and doing other things.”
• He went to Novartis Institutes (founded by Mark Fishman) and was recruited by the then-CEO Daniel Vasella to reimagine how research and early clinical development done in industry

“They basically brought the whole concept of translational medicine to industry.”‒ Lloyd Klickstein 

• That term (translational medicine) was coined at Oxford or somewhere in the UK, and this was the first industry manifestation of it

The process by which a drug is discovered 

• There are lot of specific drugs and indications, pathways and targets that Peter wants to talk about today
• Before he goes there, there is a black box that exists in the world Lloyd occupies that is unknown by the public
  • It would be very insightful if people understood it
  • It is the process by which a drug is discovered
• The first person Peter ever read articulate this was Steve Rosenberg
  • He wrote one of Peter’s favorite books: The Transformed Cell 
  • He starts with the question: How do you discover new drugs for cancer?

Peter points out, “A very intelligent person can still have an enormous blind spot to what it is people like you do.”

• Lloyd starts from a very broad area of medicine, not just focus on cancer (because cancer is a special case, not a general concept)
• He personally starts with patients, clinical indications, and medical need
  • He looks for a drug or therapy that does not exist but is needed
• There are 2 broad categories: incremental improvements and quantum steps

“There are incremental improvements, and then there are quantum steps in the concept of drug discovery.”― Lloyd Klickstein

• 1 – Incremental improvements may mean
  • Taking a drug less frequently
  • Developing an oral drug instead of an injectable drug
  • Creating a drug in the same class that works better
• Examples of incremental improvements: Atorvastatin and rosuvastatin were enormous commercial successes in a Mevacor–Zocor world
• Drug-development infrastructure strongly favors these improvements because they are relatively low risk and carry less uncertainty
• 2 – A quantum step may involve an indication that has not been described, does not have an ICD-10 or ICD-11 code, and lacks a regulatory path
• It requires educating physicians, patients, payers, and others while creating that regulatory path
• It is a heavier lift, but Lloyd thinks this is where the greatest value to society and patients can come from

This is what he does, and there is a lot of failure involved 

• He can talk about:
  • How do you get a new regulatory pathway established?
  • How do you create new indications? (also a challenge)

How Lloyd and his team started something called “The New Indication Discovery Unit” at Novartis 

• Mark Fishman asked Lloyd and several colleagues to identify the most-needed medicines and determine what Novartis was not doing that it should be doing
• Lloyd started with patients and indications and medical need
• They began with a list of roughly 7,000 recognized clinical indications that were unmet
  • The list included only indications recognized at the time, but it gave the team a framework for thinking
• They separated indications Novartis was already studying from rare genetic and developmental conditions that would be difficult to approach
• The remainder fell into 7 or 8 opportunity areas
  • These included healthy aging, ear, nose, and throat conditions, renal disease, liver disease, and fibrotic diseases
• The unit grew to dozens of projects and eventually had to be narrowed
• One of them, bimagrumab for muscle disease emerged from the medical need Lloyd had seen among frail older adults
  • At the time, frail older adults who had to enter a nursing home had a 3-year mortality rate approaching 90%
  • So being a frail older person who had to enter a nursing home carried a prognosis worse than that of most cancers

Lloyd argues that serious diseases with outcomes worse than many cancers should be treated with comparable ambition 

• The aim was first to treat frailty and eventually to prevent it

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