It’s no secret that Denali Therapeutics is placing big bets on lysosomes as the X-factor behind a number of neurodegenerative diseases—the company’s pipeline targeting the cellular waste managers is currently 10 assets deep.
But which target to pinpoint and how to drug it have remained the (multi) billion-dollar questions. Now, Denali is pointing to preclinical and early phase 1 data of its med, DNL201, that suggest an answer. The latest results, published June 8 in Science Translational Medicine, found that using the drug to inhibit the leucine-rich repeat kinase 2 (LRRK2) gene was effective at regulating lysosomal function in both animals and humans.
The performance of lysosomes—cellular waste managers—has been tied to the onset of neurodegenerative diseases including Parkinson’s and Alzheimer’s. Mutations to LRRK2 have been identified as one of the most common risk factors for Parkinson’s specifically. While Denali’s data are merely a sample, the results suggest new therapeutic approaches to tackling Parkinson’s could be impactful.
The peer-reviewed paper, led by Denali Senior Medical Director Danna Jennings, M.D., laid out a multifaceted evaluation of the drug’s effect. First, using animal and ex vivo models, researchers found that the drug did, in fact, inhibit LRRK2, pointing to reductions in both pS935 LRRK2 and Rab10, two biomarkers of the gene. This also corresponded with restored lysosome size and morphology in addition to a reduction in lysosomal protein degradation.
One safety point the researchers specifically addressed was whether inhibiting LRRK2 negatively impacted lung function. After 39 weeks of treating monkeys at a dosing regimen meant to uncover toxicities, the results indicate the drug was safe and that on-target pulmonary changes are “nonadverse and reversible.”
But the crux of the study was the first inkling of data from the company’s two phase 1 trials, which, between both studies, included healthy volunteers, Parkinson’s patients with LRRK2 mutations and patients without the mutations.
In the trial with 122 healthy volunteers, DNL201 “exhibited strong LRRK2 inhibition,” measured by a median reduction in pS935 LRRK2. The same was seen in the second phase 1 trial of 28 patients with mild to moderate Parkinson’s disease. The analysis also found a median reduction in pT73 Rab10. Treatment with the drug corresponded to a reduction in urine bis (monoacylglycero) phosphate, a marker of lysosomal function. However, there were too few patients with the LRRK2 mutations included in this analysis to draw additional conclusions on the impact of the drug across all three groups of trial participants.
But the fact that the in-human findings mirror some of the preclinical work represents critical progress for Denali. The researchers concluded that “these results demonstrate that LRRK2 inhibition has potential as a disease-modifying treatment” for Parkinson’s and support more trials. Considering that these are Denali scientists writing about their own drug, the latter is a given. Critical questions remain, as was noted in a corresponding article from Patrick Lewis, Ph.D., a senior fellow at the Institute of Neurology in London.
“Despite considerable progress over the past decade, it is still not entirely clear how mutations in LRRK2 lead to neurodegeneration and thence to disease,” he wrote. As a result, it remains to be seen whether LRRK2 kinase inhibitors have a benefit for people with mutations outside of the gene’s kinase domain or those without disease-coding mutations. Lewis points to an antisense alternative developed by Biogen and Ionis that’s currently in phase 1.
Biogen is also interested in Denali’s inhibitors, though, having handed over more than $1 billion in upfront cash and investments as part of the 2020 deal to co-develop and co-commercialize the potential therapies. The agreement also involved more than $1 billion in potential milestone payments. However, DNL201 is not the asset that the companies are moving into the clinic. Instead, the deal surrounds DNL151, a distinct LRRK2 inhibitor from the one assessed in the Science study, although the mechanisms mirror each other. A spokesperson for Denali said that DNL151 has “pharmacokinetic properties” that allowed for more flexible dosing, specifically that it could be taken once a day.
“Denali and Biogen are partnering to jointly develop and advance BIIB122 (DNL151), and DNL201 remains a viable backup,” the spokesperson said.