This is the first in a series of blog posts that will share how Lilly employees discover and develop innovative treatments for patients. We'll also highlight many of the passionate scientists and clinicians behind those cutting-edge discoveries.
The drug discovery process is not easy. Statistically speaking, there are more failures than successes. The overall probability of clinical success — the likelihood that a drug entering clinical testing will eventually be approved — is estimated to be less than 12 percent.1
Pharmaceutical companies must make critical decisions about which drug candidates to develop. The goal is to invest in molecules that have the greatest potential to help patients, the lowest risk of doing harm and a good return on investment that the company can invest in new discovery efforts.
There are two paths to drug discovery: indication first or drug first. Indication first is the most common approach taken. This happens when a drug is developed to specifically address an identified unmet need.
Drug development leads come from natural products — say, chemicals found in plants and microorganisms — or compounds similar to naturally occurring chemicals. "As a chemist at Lilly, I work in the lab making molecules I want to test," says Bruce Dressman, a Lilly senior research scientist in discovery chemistry. "I enjoy medicinal chemistry because you make something tangible. But there are days I do nothing but read [research] because there is something I need to understand thoroughly or I need a new direction for a project. You’ve heard the comment, 'You can spend a week in the lab or a day in the library.' That is a very true statement for chemists."
Out of thousands of molecules created, only a few will move forward as lead candidates. "There are so many molecules that fail," Dressman says. "When I first started here [at Lilly], it took me awhile to get used to that mentality. As I matured as a scientist, I started to look at it like 'You tested that and it didn’t work.' When you find the right molecule, it will show itself as the right one."
"When you have a molecule that is successful, the charge you get from that can keep you going for a very long time," says Mary Mader, Ph.D., a research fellow in medicinal chemistry at Lilly. "A common feature among scientists is persistence. I think that persistence comes from each day when you recognize that you made some sort of incremental progress. A colleague of mine says, 'How many more opportunities do I have to make something meaningful to patients?' You really do want this time to count, not only for you as a scientist but also for humanity."
The best drug candidates are identified based on an assessment of the relationship between the molecule’s structure and its biologic activity. This relationship serves as a starting point for further refinement during the lead optimization process. "Without both sides of this partnership [chemistry and biology], we’re going nowhere," says Dod Michael, Ph.D., a research fellow in biology at Lilly. "The chemists make the molecules, and the biologists test the molecules."
Using data from the biological tests of a molecule, the chemists modify drug candidates to enhance their activity. Testing often requires complex ex vivo analyses (using animal or human tissue) or in vivo analyses (using animals) to validate the biologic activity.
During exploratory work, "we’re incubating an idea, executing experiments, trying to gather enough data to see if the idea is worthy to move forward," says Michael. "Somewhere between 6 months and a year are allowed for this early discovery work. If the idea shows promise, then a team of biologists and chemists begin to move the project forward and come up with medicines to test."
What drives scientists to persevere through the complex, difficult and rarely successful drug discovery process?
"Being a scientist is more than a job," says Dressman. "At the core, scientists are people who like to solve problems."
"Every problem we try to solve is different from the last," adds Mader. "The evolution from antibiotics to neuroscience to diabetes and oncology shows the diversity. We are still learning how to best discover and test medicines. It’s an iterative cycle of learning."
"We are patients, and our loved ones are patients, too," says Michael. "We’re doing this because we have a passion
for discovery and for helping people."
1. PhRMA 2015 Biopharmaceutical Research and Development: The Process Behind New Medicines.
To read a version of this article in French, please visit LillyPad France.