The clinical hold comes 2 days after an announcement from Denali Therapeutics detailing a partnership with Takeda Pharmaceutical Company to codevelop and cocommercialize the treatment.
The FDA has placed a clinical hold on the investigational new drug (IND) application for DNL919, an antibody transport vehicle (ATV) designed to activate the TREM2 protein and normalize microglial function in patients with Alzheimer disease (AD), Denali Therapeutics recently announced.1
An official clinical hold letter is expected to be provided by the FDA in approximately 30 days, though the agency notified the company about the hold on January 12, 2022, via email. Updates will be provided following a discussion with the FDA, Denali said in a statement.
The news follows Denali’s announcement from 2 days earlier, which stated that Takeda Pharmaceutical Company would be exercising its option to codevelop and cocommercialize the treatment for patients with AD.2 Takeda has also partnered with Denali on DNL593, a treatment for frontotemporal dementia granulin. In the same statement, Denali also announced plans to release the first clinical data on DNL919 to further validate its transport vehicle platform.
When compared with a non-ATV TREM2 antibody, DNL919 demonstrated enhanced brain uptake and improved pharmacodynamic response, according to animal model data. Prior to the clinical hold, Denali had planned to initiate first-in-human clinical trials in the first half of 2022, with human safety and biomarker data available in the second half of 2022. These results were also expected to include the effect of DNL919 on colony stimulating factor 1 receptor in cerebrospinal fluid (CSF), which is a key indicator of TREM2 pathway engagement.2
“We are looking forward to a high impact year in 2022, having accomplished several clinical and regulatory milestones in 2021 as well as further validation of our TV platform for delivery of biotherapeutics to the brain,” Ryan Watts, MD, CEO, Denali, said in a statement announcing program progress and expected milestones for 2022.2 “We are well positioned to deliver in 2022 with our dedicated team, our BBB [blood-brain barrier]-crossing platforms and our diversified portfolio of Denali owned and strategically partnered assets. We continue to build our clinical manufacturing and commercial capabilities as well as expand our global footprint. This is an exciting time at Denali as we make progress towards our goal of delivering life-changing medicines to people living with neurodegenerative diseases.”
In October 2021, at the 2021 Annual Northeast ALS (NEALS) meeting, Denali announced positive phase 1 clinical results, as well as regulatory process for 2 investigational small molecule therapies in amyotrophic lateral sclerosis. The receptor-interacting protein kinase 1 inhibitor SAR443820/DNL788 (Sanofi) was granted fast track designation from the FDA and plans for the phase 2 HIMALAYA study of the treatment were outlined at NEALS. Following positive results from a phase 1 trial of eukaryotic translation initiation factor 2B activator DNL343, which were also presented at the virtual conference, a phase 1b trial (NCT05006352) began in the third quarter of 2021.3 According to the company’s January 10 announcement, safety and biomarker data from the phase 1b trial is anticipated to be available in mid-2022, enabling the decision to advance to late-stage development.2
A phase 2/3 trial of DNL310, Denali’s proprietary enzyme transport vehicle for treatment of central nervous systema and peripheral manifestations of Hunter syndrome (also known as mucopolysaccharidosis II), is anticipated to begin dosing in the first half of 2022. This follows data from the ongoing phase 1/2 trial of the treatment, which demonstrated normalization of heparan sulfate levels in CSF, improvement in peripheral activity after switching from standard of care enzyme replacement therapy (ERT), and a safety profile consisted with ERT.2