A maddening syndrome has frustrated pharmaceutical companies for decades: the notion that most proteins in the human body are “undruggable.” But companies are challenging that idea now with a process called protein degradation.
Up to now, some diseases related to malfunctioning proteins — Alzheimer’s disease and several types of cancer, to name a few — can’t be treated with most pharmaceutical products.
Drug development in the works at a small biotech stock, plus a few Big Pharma companies such as
Pfizer (
PFE) and
Merck(
MRK), aims to change that. With protein degradation, drugs could hijack the body’s natural garbage disposal to rid patients of troublesome proteins.
One analyst calls protein degradation a multibillion-dollar opportunity that could even approach the $1 trillion mark. It could provide hope to countless patients with devastating diseases.
A small biotech company,
Arvinas, went public in September on the premise that it could make protein degradation work. And pharmaceutical companies back a number of protein degradation firms, including Arvinas.
Arvinas (
ARVN) has deals worth nearly $2 billion with Pfizer, Merck and
Roche(
RHHBY).
Celgene (
CELG),
Novartis (
NVS),
GlaxoSmithKline (
GSK) and
Biogen (
BIIB) have partnered with other companies.
The fact that big pharmaceutical companies have flocked to biotechs working in protein degradation says a lot, Aprilakis says.
“It’s incredibly telling for the promise of the technology and for just how exciting it is,” he said.
Pharmaceutical Companies Eye Protein Degradation
For decades, pharmaceutical companies have used drugs to inhibit problematic proteins.
A number of traditional drugs block excessive proteins. Researchers believe the buildup of amyloid or tau
proteins could cause Alzheimer’s disease. Another rare disease, amyloidosis, is a result of abnormal protein that builds up in the heart or nerves.
But the method only works when the protein has a “groove” for the drug to grab onto, JMP’s Aprilakis says. And that’s an ongoing frustration in drug development. Estimates vary, but some researchers say only 20%-25% of proteins have the necessary groove to be inhibited.
Enter protein degradation. It’s a natural process in the body. When a protein mutates or nears the end of its life cycle, the cell tags it with another protein called ubiquitin. Ubiquitin signals to the proteasome — the cell’s trash compactor — that the protein is ready for degradation.
The degraded protein is “chewed up” into its amino acid and peptide components, Andrew Benowitz, senior director for Glaxo’s protein degradation unit, told IBD in an interview. The cell can then reuse those components.
Benowitz calls the proteasome “the garbage disposal” of the cell.
Sending Proteins To The Garbage Disposal
In terms of drug development, protein-degrading drugs wouldn’t need to have a secure binding to a protein. These drugs only need to circulate near a bad actor protein. Then, the drug recruits ubiquitin to ensure the problematic protein heads to the cell’s trash compactor.
“This is a very transient interaction,” Arvinas Chief Executive John Houston told IBD. The protein degradation process allows the medicine to do its job multiple times in one dose. Eventually, the drug leaves the body. This is key to staving off permanent side effects, he says.
JMP’s Aprilakis says the technology has the potential to be “totally disruptive.” If viable in human tests, protein degradation could treat any disease caused by a faulty protein, he says. Due to the potential for side effects, he acknowledges researchers will need to be picky when selecting proteins to degrade.
Arvinas is targeting androgen receptors in metastatic castration-resistant prostate cancer and estrogen receptors in metastatic breast cancer. The biotech company plans to begin clinical studies in prostate cancer early this year. Breast cancer tests will follow in mid-2019.
Houston expects Arvinas to have early data from its prostate cancer test in the second half of 2019. That could include PSA levels after treatment with a protein degrader. High
levels of PSA, or prostate-specific antigens, are associated with prostate cancer. He expects to have breast-cancer data in mid-2020.
Piper Jaffray analyst Edward Tenthoff applauded Arvinas’ strategy in a recent research note. Scientists understand well the biology of prostate and breast cancers. He expects Arvinas to compare its breast-cancer drug against
AstraZeneca‘s (
AZN) rival drug Faslodex.
(Learn more about biotech companies’ plans to attack cancer and other diseases in 2019.)
Partnerships Abound In Protein Degradation
Arvinas will likely be the first company to test protein degradation in human studies. But others are likely to follow suit. The technology has pharmaceutical companies putting up big investments.
JMP’s Aprilakis notes the moves by large pharmaceutical companies are particularly interesting.
“I’ve noted Amgen, AstraZeneca, Glaxo, Novartis and Roche each have their own internal programs,” he said, “or are collaborating with other companies.”
Most pharmaceutical companies are mum on their specific targets. AstraZeneca is exploring protein degradation in oncology, cardiovascular, renal and metabolic and respiratory disease, a representative told IBD via email. But he wouldn’t say how far along the research is.
Glaxo’s Benowitz says the company doesn’t have a protein degrader in clinical studies yet. He wouldn’t comment on when Glaxo expects to enter clinical testing.
Areas Of Drug Development
Protein degradation is exciting because it’s “therapy-area agnostic,” Glaxo’s Benowitz said. The technology could work across multiple areas of drug development including oncology, cardiovascular, lung diseases, central nervous system disorders and more.
“I think what you would be looking for is diseases where the presence of a protein is what is causing disease,” he said. “You can ameliorate that by getting rid of the protein. In some diseases, you want more of the protein or to modify the function of the protein.”
JMP’s Aprilakis sees hope for protein degradation in oncology. For example, researchers agree a gene sequence known as KRAS provides codes for a protein with
ties to pancreatic cancer. But there’s a “graveyard” of failed experiments in drug development trying to inhibit KRAS.
“We can’t drug KRAS,” he said. “But if you can knock out KRAS, you could be looking at your first drug for pancreatic cancer. It’s difficult to drug, but we may crack it with protein degradation.”
If successful, these proteins would no longer be “undruggable.”
“Difficult to drug is a better term,” he said.
