The onset of one of the most devastating forms of dementia often comes with a misdiagnosis. Personality and behavioral changes in a patient can spark a hypothesis of depression or psychosis. Memory problems rouse suspicion of Alzheimer’s disease. By the time a physician determines frontotemporal dementia as the cause, the disease is well on its course. Patients typically live only six to seven years from the first symptoms, but even with a diagnosis there is no FDA-approved treatment for them.
Arkuda Therapeutics is developing a drug that it says could address the underlying cause of this form of dementia, potentially preventing the onset of the disease. The Cambridge, MA-based startup on Thursday unveiled $44 million in financing to advance its experimental treatment toward its first tests in humans.
Frontotemporal dementia (FTD) refers to a group of brain disorders characterized by the degeneration of the frontal and temporal lobes of the brain, regions that govern personality, behavior, and language. Arkuda is focused on a form of FTD rooted in the deficiency of a protein called progranulin (PGRN). This protein is produced by cells throughout the body but it’s particularly important in the brain, says Gerhard Koenig (pictured above), Arkuda’s co-founder, president, and CEO. Lysosomes, parts of cells containing digestive enzymes that dispose of waste and keep neurons healthy, depend upon PGRN to function properly.
“If you don’t have a high-functional lysosome, your cells will have an issue getting rid of the things they should get rid of,” Koenig says.
Low PGRN levels can be inherited. A mutation to one of the copies of the GRN gene, which provides instructions for making PGRN, leaves a person producing roughly half the usual amount of the protein. GRN-related FTD is rare, with tens of thousands of cases in the US annually compared to the millions with Alzheimer’s disease. Signs of the disease typically appear when patients are in their mid-40s to mid-60s.
Arkuda’s drug targets the remaining healthy copy of the gene, prodding it to produce more PGRN. Cranking out more PGRN is hoped to address the protein deficiency that leads to poorly functioning lysosomes, Koenig says. For competitive reasons, he won’t say exactly what his company’s experimental drug has been designed to target, nor would he specify how it works.
There are other companies trying to treat neurodegeneration by amping up PGRN production. Alector (NASDAQ: ALEC) aims to prevent deterioration of PGRN with a drug, AL001, that’s meant to stop the cellular process for breaking down PGRN. The antibody drug is given by intravenous infusion. In July, the South San Francisco biotech reported Phase 1b data showing that its drug increased PGRN levels in the blood and cerebrospinal fluid of healthy volunteers. A Phase 2 study in FTD patients started in September.
So far, Arkuda has data from animal studies. But Koenig says his company has the advantage of addressing PGRN deficiency with a small molecule drug that comes in the more patient-friendly pill form. Pills are “a tried and true approach for a chronic disease,” he says.
Koenig brings to Arkuda previous experience in neuroscience drug development. He was the former chief scientific officer of Forum Pharmaceuticals, a Waltham, MA, biotech that shuttered in 2016 following failures for Alzheimer’s disease and schizophrenia drugs. Despite the failures, Koenig says the Forum neuroscience research paved the way for his current work.
Arkuda has its own intellectual property separate from Forum’s research. Venture capital firm Atlas Venture co-founded Arkuda last year, providing seed financing for the startup and incubating it. Koenig says the company has identified small molecules that are “highly potent and selective,” meaning they hit drug targets they’re supposed to and leave everything else alone. After showing in animal studies that its drug can raise PGRN to levels that would benefit humans, the company started to look ahead to clinical testing.
Koenig notes that there is a growing body of research shows PGRN is important for fending off disease and that lyosomal dysfunction has been linked to neurodegenerative disorders, including Alzheimer’s and Parkinson’s. But the company will wait until it gets FTD clinical data developing the drug for other conditions, he says.
Arkuda’s latest financing, a Series A round, was co-led by Atlas and Pfizer Ventures. Tekla Capital Management and BioInnovation Capital also participated. Andy Hu, Arkuda’s chief business officer, says the company will use the capital to advance the drug through a Phase 1 test for safety, and then through a Phase 1b study to assess the drug’s ability to change PGRN levels in patients who have a mutation to the GRN gene. Koenig says the first human test could start in 2021.
Photo by Arkuda Therapeutics