Denali–Sanofi Partnership Dosing Alzheimer’s Patients in DNL747 Clinical Trial

Denali Therapeutics has begun dosing patients in its Phase 1b clinical trial of DNL747 as a treatment for Alzheimer’s disease.

“We are excited to advance DNL747 in a second neurodegeneration indication based on Phase 1 healthy volunteer data regarding DNL747’s safety profile, CNS [central nervous system] penetration, and target engagement, at the studied doses,” Carole Ho, MD, chief medical officer of Denali, said in a press release.

DNL747 is a small molecular that was specifically designed to cross the blood brain barrier and inhibit a protein known as RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which is involved in the tumor necrosis factor (TNF) receptor pathway that is implicated in inflammation, immunity, and cell death.

RIPK1 inhibition has been shown to have beneficial effects in preclinical models of Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Currently, DNL747 also is being evaluated in a clinical trial as a treatment for ALS (NCT03757351).

Still recruiting participants, the new study (NCT03757325), done in collaboration with Sanofi, is expected to enroll about 26 patients 55–85 years old who a have confirmed diagnosis of Alzheimer’s disease.

The study is being conducted at a single location in the Netherlands and was designed to explore the safety, tolerability, and overall stability and distribution in the body of DNL747 versus placebo for 29 days. During the trial, researchers also will look at specific biomarkers in patients’ cerebral spinal fluid and blood samples.

Participants will be assigned randomly to receive oral doses of DNL747 or placebo for 29 days, followed by 14 days of washout (no treatment). After that they will initiate treatment again, but in a crossover manner, meaning that those treated initially with placebo will switch to DNL747 and vice-versa.

Denali expects to announce results from this Phase 1b trial during the fourth quarter of 2019.

“Similar to our previously announced Phase 1b study in ALS, the primary purpose of this Phase 1b study is to gain additional safety and biomarker data in patients with Alzheimer’s disease to support dose selection,” Ho said. “The results from this study will inform our decisions on future clinical studies in Alzheimer’s disease.”

Results from a previous placebo-controlled Phase 1 trial conducted in 56 healthy volunteers demonstrated that DNL747 is generally well-tolerated, with only mild-to-moderate adverse reactions being reported.

The treatment did not induce any immune-related toxicity events or lead to clinically meaningful alterations of participants’ status. The most common adverse side effects reported after 14-day treatment with a single dose of DNL747 were diarrhea, headache, and nasopharyngitis (inflammation of the nose and throat mucosa).