DNL201 / Denali Therap - LARVOL DELTA

TIGAR exacerbates obesity by triggering LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy in adipocytes. (PubMed, Autophagy) - "It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201...In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction."

Journal • Genetic Disorders • Metabolic Disorders • Obesity • Targeted Protein Degradation • LRRK2 • TIGAR • TP53

Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. (PubMed, Science) - "The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Recent advances in targeting leucine-rich repeat kinase 2 as a potential strategy for the treatment of Parkinson's disease. (PubMed, Bioorg Chem) - "Currently, five candidates, DNL201, DNL151, WXWH0226, NEU-723 and BIIB094, have advanced to clinical trials for PD treatment. In this review, we describe the structure, pathogenic mutations and the mechanism of LRRK2, and summarize the development of LRRK2 inhibitors in preclinical and clinical studies, trying to provide an insight into targeting LRRK2 for PD intervention in future."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

DNL151, DNL201 and BIIB094: experimental agents for the treatment of Parkinson's disease. (PubMed, Expert Opin Investig Drugs) - "Approval of Leucine-rich repeat kinase 2 inhibitors in case of positive clinical study outcomes will introduce personalized medicine for beneficial modification of progression as the most unmet need for treatment of patients with Parkinson's disease. In addition to the currently, preponderantly performed clinical rating with established scales, further clinical trial endpoints, such as dosing of dopamine substitution, may be considered in study designs to demonstrate therapeutic effects on the progression of Parkinson's disease."

Journal • Review • CNS Disorders • Inflammation • Metabolic Disorders • Movement Disorders • Parkinson's Disease • LRRK2

Unveiling the Selectivity Mechanism of Type-I LRRK2 Inhibitors by Computational Methods: Insights from Binding Thermodynamics and Kinetics Simulation. (PubMed, ACS Chem Neurosci) - "DNL201 is an LRRK2 kinase inhibitor entering phase I clinical studies...Our results suggest that the structural and kinetic differences between the proteins may play a key role in determining the activity of the selective small-molecule inhibitor. The selectivity mechanisms proposed in this work could be helpful for the rational design of novel selective LRRK2 kinase inhibitors against PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • JAK2

A New Experimental Drug Shows That It Has the Ability to Inhibit the Progression and Development of Parkinson's. [Google Translation] - "'It's exciting. The results are in line with the notion that inhibiting the work of LRRK2 could restore lysosomal function and block Parkinson's progression. It certainly gives us hope.' Tanya Simuni..."

Media quote

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease. (PubMed, Sci Transl Med) - "Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD."

Journal • Preclinical • CNS Disorders • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease

[VIRTUAL] Reduction of total LRRK2 in human CSF with LRRK2 inhibitor treatment demonstrates CNS target engagement and utility of total LRRK2 as a pharmacodynamics biomarker (MDS Congress 2021) - "LRRK2 inhibition in our Ph1 and 1b studies dose- and concentration- dependently reduced LRRK2 in CSF, demonstrating CNS target engagement with BIIB122/DNL151 and DNL201 at doses expected to be clinically relevant. tLRRK2 levels in CSF will continue to be evaluated in additional LRRK2 inhibitor studies to evaluate CNS pharmacodynamic effects relative to clinical benefit."

Biomarker • Late-breaking abstract • PK/PD data • CNS Disorders • Parkinson's Disease

[VIRTUAL] Safety, Tolerability, and Pharmacodynamic Profile of DNL201 at dose levels demonstrating LRRK2 inhibition in Parkinson’s Disease Patients with and without LRRK2 mutations (MDS Congress 2020) - "LRRK2 inhibition with two doses of DNL201 demonstrated substantial target and downstream pathway engagement, including effects on lysosomal biomarkers, at doses that were generally well tolerated. This first ever trial of LRRK2 inhibitors in PD patients with and without LRRK2 mutations supports further investigation of LRRK2 inhibition for the treatment of Parkinson’s disease."

Clinical • PK/PD data • CNS Disorders • Pain • Parkinson's Disease

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL201 in Healthy Volunteers (clinicaltrials.gov) - P1; N=122; Completed; Sponsor: Denali Therapeutics Inc.

Clinical • New P1 trial

Denali Is Flush With Cash After Partnership With Biogen (SeekingAlpha) - "Denali has conducted both a Phase 1 trial and a Phase 1b trial of DNL201 and of DNL151 so far, although extended versions of the DNL151 trials remain open for enrollment at present to include higher dose cohorts....While Denali’s IND for DNL151 was just approved to move forward with human trials in July...Late stage studies aimed at demonstrating efficacy and enabling an eventual NDA filing should start in 2021."

Enrollment status • NDA • New trial • CNS Disorders • Parkinson's Disease

Denali Therapeutics Provides Pipeline and Business Update in Response to the COVID-19 Pandemic (GlobeNewswire, Denali Therapeutics Inc.) - "LRRK2 program for Parkinson’s disease:...For the ongoing DNL151 Phase 1 and Phase 1b trials, enrollment of additional healthy volunteers and patients at higher doses has been paused due to the COVID-19 pandemic. Denali is analyzing available data from these trials and is on track to select either DNL201 or DNL151 by mid-2020 to progress into Phase 2/3 trials; EIF2B program for ALS: the DNL343 Phase 1 trial in healthy volunteers is ongoing and dosing is completed for a portion of the study. Enrollment of additional subjects has been paused due to the COVID-19 pandemic and this could lead to a delay in the completion of the study."

Enrollment status • New P2/3 trial • Trial status

Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present). (PubMed, Expert Opin Ther Pat) - "DNL201 and DNL151 have entered early clinical trials to evaluate tolerability and target engagement biomarkers. This will pave the way for the development for future LRRK2 inhibitors."

Journal

Denali Therapeutics announces broad pipeline progress including positive results from its LRRK2 program for Parkinson’s disease (GlobeNewswire, Denali Therapeutics Inc.) - P1, N=34; NCT04056689; Sponsor: Denali Therapeutics; "Denali Therapeutics Inc....today announced the results of its Phase 1b clinical trial of LRRK2 inhibitor DNL201 in patients with Parkinson’s disease and its Phase 1 clinical trial of LRRK2 inhibitor DNL151 in healthy volunteers....Given these positive data, the DNL151 Phase 1 and Phase 1b clinical trials have been expanded to study higher doses. Denali intends to select either DNL201 or DNL151 in mid-2020 to advance into Phase 2/3 clinical trials in patients with Parkinson’s disease; RIPK1 inhibitor DNL747 Phase 1b trials in Alzheimer’s and ALS fully enrolled and open label extension in ALS ongoing with data readouts on track for mid-2020."

Enrollment closed • New P2/3 trial • P1 data

Study to Evaluate DNL201 in Subjects With Parkinson's Disease (clinicaltrials.gov) - P1b; N=30; Active, not recruiting; Sponsor: Denali Therapeutics Inc.; Recruiting ➔ Active, not recruiting; Trial completion date: Sep 2019 ➔ Dec 2020; Trial primary completion date: Sep 2019 ➔ Dec 2020

Clinical • Enrollment closed • Trial completion date • Trial primary completion date

Denali Therapeutics Announces First Patient Dosed in Phase 1b Study of DNL151 for Parkinson’s Disease and Launch of Its Engage Parkinson’s Website (GlobeNewswire, Denali Therapeutics Inc.) - "Phase 1b study of DNL151 includes Parkinson’s disease patients with and without a genetic LRRK2 mutation. Either DNL151 or DNL201 anticipated to be selected for potential registrational clinical trials in 2020. “We believe that this study will provide additional important safety and biomarker data in patients to inform the choice between either DNL151 or DNL201 for potential registrational trials.”."

Biomarker • Clinical • Enrollment status • Launch