Two of Roche Holding AG’s experimental drugs for Parkinson’s disease caused lung toxicity in monkeys, researchers said, delivering a setback to one of the most promising pathways to a new type of treatment.
The findings will be a disappointment to advocates of Parkinson’s research. The LRRK2 gene mutation gained attention after Sergey Brin, co-founder of Google Inc., disclosed in 2008 that his genetic code carries the flaw, which is associated with increased risk of Parkinson’s. Brin has donated more than $100 million to find a cure for the disease.
Inhibition of the LRRK2 protein resulted in abnormal accumulation of compounds in specific cells that play a key role in many lung functions, including helping the organs inflate and deflate during breathing, according to the study run by Roche’s Genentech unit and published Wednesday in the journal Science Translational Medicine. The compounds were trapped inside the cells instead of being released into the lining of the lungs.
“We’re in a big bind,” said Ryan Watts, director of neuroscience at Genentech. “We want to make sure in patient populations that you have a safe drug to go into studies.”
A link between mutations in the LRRK2 gene and Parkinson’s disease was found in 2004. The mutation is only found in 2 percent to 5 percent of patients, according to the Michael J. Fox Foundation for Parkinson’s Research, but it is one of the few direct causes that have been discovered for the disease, making it the focus of drugmakers’ efforts.
The foundation has poured at least $10 million a year for the past decade into research on the LRRK2 mutation, which it sees as “one of the most promising therapeutic targets,” said Chief Executive Officer Todd Sherer. He said Genentech’s finding was “unexpected.”
The LRRK2 inhibitors, which are also in development by drugmakers Pfizer Inc. and Merck & Co., are seen as the leading hope for a disease-modifying drug. About 50,000 to 60,000 new cases of Parkinson’s disease are diagnosed each year in the U.S., according to the National Parkinson’s Foundation. The drugs currently on the market only treat symptoms and don’t slow progression of the neurodegenerative brain disorder, which reduces a patient’s ability to regulate movements and emotions.
The Genentech scientists also saw liver toxicity in mice that were genetically engineered so they didn’t produce the LRRK2 protein at all. While the liver problems weren’t seen in the monkeys, Watts said it’s possible liver damage would appear with long-term use.
Scientists had hoped an LRRK2 inhibitor could be given to early-stage patients or even healthy people to prevent the progression or start of the disease, Watts said. Since patients could end up using the drugs for decades, it’s especially important not to have toxic side effects, he said.
Despite the disappointing findings, the foundation and Genentech are continuing with their research plans for LRRK2 mutations.
“There’s a couple immediate next questions: Is the effect reversible? Does it go away if you remove the compound? Just because you see changes in the lung, does it mean anything physiological for the primate?” said Sherer by telephone. The researchers found that the primates’ lung functions appeared unaffected despite the cellular level changes.
The Fox Foundation, named for the actor who has Parkinson’s, has convened a group of scientists from Merck, Pfizer and Genentech to discuss how this finding will impact future work, said Sherer.
“This is a critical finding as it changes the way we will design important studies in animals as we’re building towards future clinical trials,” he said. “It’s actually a positive because it gives real direction and clarity to the research.”
Genentech also continues to research genetic links to the disease. This year, it announced a deal with 23andMe Inc., which sells DNA saliva kits to consumers. Co-founded by Brin’s wife, Anne Wojcicki, the company has already recruited a community of Parkinson’s patients, gathering both genotypic data as well as clinical information about their experience with the disease.
Genentech aims to sequence the entire genome of about 3,000 patients to look for genetic causes of disease progression.