For most scientists, a major drug discovery happens rarely, if ever, in a lifetime. However, for Northwestern’s Richard (Rick) B. Silverman, the Patrick G. Ryan/Aon Professor, lightning struck in a big way with pregabalin, a compound he discovered in his lab. Pregabalin went on to become the blockbuster drug Lyrica®, marketed by Pfizer for fibromyalgia, neuropathic pain, spinal cord injury pain, and epilepsy. As the world-renowned chemist and founding member of the Chemistry of Life Processes Institute approaches his 55th year in research (since undergraduate research), Silverman continues to beat the odds.
With the launch of his new company, Akava Therapeutics, Inc. in 2019, Silverman is working to bring more promising new compounds developed in his lab to the clinic. Akava’s lead compound, AKV9, is a protein aggregation inhibitor that improves the health of upper motor neurons that degenerate in motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and ALS/frontotemporal lobar degeneration (FTLD). The Investigational New Drug (IND) application (to request permission from the FDA for use in humans) for AKV9, the first-ever potential therapy to treat degenerating upper motor neurons that cause ALS, is currently being written.
When you first began working on the drug pregabalin in 1988 did you have any inkling of its enormous potential?
Rick: Of course not, but with all the work we scientists do, you have a goal in mind. When you write grants to the NIH, you have to rationalize why you’re making the compounds you propose. They want to see good science done and that’s my approach. I wanted to do new science and potentially make something that could be useful. When we made an unexpected finding and saw that maybe a compound we had synthesized had potential as a new drug, we gave it a shot at getting it licensed to a company for animal testing, but thought, “What’s the chance that it would go to market?” When we licensed it to Parke-Davis Pharmaceuticals, they moved it ahead, but there were many roadblocks. Once Pfizer bought Parke-Davis, I didn’t know what was happening for five years. I read about the approval in the paper with everybody else.
Lyrica® became a blockbuster drug (gross sales greater than $1B) in its first full year on the market, and in 2018, Lyrica® generated $5 billion for Pfizer. Silverman donated a portion of his royalties from the sales of Lyrica® to partially fund the construction of Silverman Hall, a state-of-the-art research building on Northwestern’s Evanston campus and home to Chemistry of Life Processes Institute.
What lessons did you learn from the experience?
Rick: You should stick with basic science and keep hope alive that it will lead to something promising—just keep trying. Science is mostly failure and a few successes.
When you started Akava Therapeutics in 2019, what was your aim?
Rick: I started Akava out of frustration from having drugs licensed through Northwestern to other companies and then having them get stalled because the company ran out of money or changed direction. These are drugs that could help people. In fact, one of the companies took a drug for epilepsy in newborns (infantile spasms) into Phase I clinical trials. A physician had a child with infantile spasms. He gave every drug he could give to the child and it had no effect on the convulsions. He then wrote an emergency use IND, just like the COVID vaccines were emergency use INDs, and he got approval to give the drug we developed, called CPP-115. This child has now been taking it for over seven years and it’s working. The company, however, ran out of money, so it never went through Phase II and III clinical trials to help other children with this disease. Northwestern eventually got the rights to the drug back, but in the interim, we discovered a variant of the drug that’s 10 times more effective that was licensed to another company six years ago. Finally, last month, it got into Phase I clinical trials.
That’s why I started Akava because then it’s in my control—as long as we can raise enough money to keep it that way. Akava is Hebrew for “inhibition.” The drug we’re developing now for ALS inhibits protein aggregation. We have other projects focused on the inhibition of cancer and/or inhibition of enzymes.
How are things progressing with other compounds in the Silverman Lab?
Rick: We are collaborating with Bill Klein’s lab in the Department of Neurobiology, using AKV9 in his Alzheimer’s model that was found to be effective in a preliminary study. Right now, we have a major preclinical study with this Alzheimer’s mouse model that is being carried out between the Evanston campus and the medical school to see if this preliminary result holds up. It started last March (2022) and should end this July. So far, it looks really good. If it shows the same promise, then we would start a clinical trial for Alzheimer’s disease.
We also are working on a molecule for melanoma. It has a new mechanism of action and is an oral drug that we hope to develop once the ALS clinical trials are underway.
We have another molecule for hepatocellular carcinoma that looks really good in preclinical trials. I have excellent postdocs in my lab and they have discovered four other molecules that are at least as good, if not better. I’ve run some pharmacokinetic and toxicology studies with those five compounds to see if we can differentiate them. Then, we still have to do the efficacy studies with all five compounds together and select the one we should move forward.
With regard to the drug for infantile spasms, we found that it also has a great effect on neuropathic pain. It would be like Lyrica® 2.0. My collaborator (Prof. Andrea Hohmann at Indiana University medical school) studies chemotherapy-induced peripheral neuropathy. Sixty percent of patients that are on chemotherapy start having tingling sensations, but then especially hands and feet become very sensitive to pain. It can be excruciatingly painful. In preclinical trials, my collaborator showed that our molecule reverses that pain, so patients could take their chemotherapy and this drug and not have neuropathy. My collaborator also does addiction studies and showed that this drug has no addictive effect, so it is a pain reliever without addiction.
You have been practicing chemistry for more than 50 years. What drives you to keep innovating and developing new compounds? You could be in Florida right now sipping pineapple cocktails.
Rick: My wife would like that [laughs], but she understands that this is my passion. This is what keeps me alive. What keeps me going is this hope that I’ll be able to help people that need help. There are so many diseases out there where there are no effective treatments. If I can have an effect, then that’s what keeps me going. I don’t like playing mahjong, so I would just rather be working on my own projects. I am trying to spend less time at research and more time with my family. You just have to find a balance.
What do you think has been the key to your success?
Rick: I’d say the students. We have amazing undergrads and grad students here and I’ve been fortunate to get great postdocs as well.
Are there any habits have you acquired over the years that help you stay focused and disciplined? Is it true that you come to work early every day and climb up three flights of stairs to your office?
Rick: I exercise (besides the 3 flights of stairs) and eat well. A little OCD doesn’t hurt. It’s this drive to succeed and to have new accomplishments.
You’ve written five books. Do you think you have another one in you?
Rick: Yes, it’s in production right now. It’s the 4th edition of The Organic Chemistry of Drug Design and Drug Action, published by Academic Press (Elsevier).
What advice would you give early career scientists coming up in the world?
Rick: Be passionate about your science. Don’t be frustrated. Get good students, keep working at it, and success will come.
Story and photo by Lisa La Vallee