A Phase 1b, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Determine the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL201 in Subjects With Parkinson's Disease

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of DNL201 in subjects with Parkinson's disease.

Start Date04 Dec 2018

Sponsor / Collaborator

Denali Therapeutics, Inc.

NCT04551534

/ CompletedPhase 1

A First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of DNL201 in Healthy Subjects

This is a Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study conducted in three parts.

Start Date01 Jun 2017

Sponsor / Collaborator

Denali Therapeutics, Inc.

100 Clinical Results associated with DNL-201

100 Translational Medicine associated with DNL-201

100 Patents (Medical) associated with DNL-201

Literatures (Medical) associated with DNL-201

01 Feb 2026·BIOORGANIC CHEMISTRY

Unraveling the metabolic potential of Moringa oleifera derived metabolites in combating Parkinson's and Alzheimer's disease

Article

Author: Sun, Xinxiao ; Nawaz, Muhammad Zohaib ; Alghamdi, Huda Ahmed ; Zhu, Daochen ; Haider, Syed Zeeshan ; Iqbal, Muhammad Waleed ; Yuan, Qipeng

Moringa oleifera is a nutrient-rich medicinal plant recognized for its broad-spectrum therapeutic potential. However, the specific bioactive metabolites and their molecular mechanisms in curing and preventing these diseases remain inadequately explored. The present study unveiled how moringa metabolites interact with specific molecular targets linked to various diseases and explored their potential as natural therapeutic agents against these diseases. The study first constructed a metabolite library based on compounds identified through multiple analytical techniques, including GC-MS, LC-MS, HPLC, UFLC, and NMR, as reported in previous studies. Then utilized a comprehensive computational approach integrating virtual screening, ADMET analysis, molecular docking, and dynamics simulations, and MM-GBSA/MM-PBSA methods to predict and evaluate the binding affinities and stabilities of moringa-derived metabolites against disease-related proteins. In total, 72 metabolites derived from moringa were screened against the ten genes, the overexpression of which was reported in five related disease conditions, including Alzheimer's, Parkinson's, Kidney Stones, Multiple Sclerosis, and Asthma diseases. These metabolites demonstrated strong interactions with genes associated specifically with Alzheimer's and Parkinson's diseases. To enhance the reliability and translational relevance of the computational predictions, experimentally validated inhibitors lanabecestat (APP inhibitor), GNE0877 (LRRK2 inhibitor), and olaparib (PARP1 inhibitor) were included as positive controls to benchmark the binding affinity and interaction stability of moringa metabolites. Our findings revealed that metabolites delta-tocopherol and gamma-tocopherol exhibit potential to inhibit poly (ADP-ribose) polymerase 1 (PARP1), while 1-acetyl-4,4-bis[4-(3-bromopropoxy)-3,5-dimethoxyphenyl] piperidine and 9,9'-bianthracene showed potential in inhibiting leucine-rich repeat kinase 2 (LRRK2); overexpression of both genes is linked to Parkinson's disease. Additionally, the metabolite 1-acetyl-4,4-bis[4-(3-bromopropoxy)-3,5-dimethoxyphenyl] piperidine also demonstrated potential in inhibiting the amyloid precursor protein (APP) associated with Alzheimer's disease. The identified metabolites displayed strong binding affinities, favorable ADMET properties, and stable interactions during molecular dynamics simulations compared to their respective control compound, positioning them as promising natural therapeutic agents against Alzheimer's and Parkinson's diseases. The study underscores the relevance of integrating computational methodologies to explore the therapeutic potential of bioactive plant compounds.

06 Aug 2025·ACS Chemical Neuroscience

Well-Tempered Metadynamics Simulations Combined with Free Energy Landscape Analysis Uncover the Conformational Transition Pathway of the DYG Motif in LRRK2

Article

Author: Tian, Yanan ; Liu, Huanxiang ; Yao, Xiaojun ; Tan, Shuoyan ; Gong, Xiaoqing ; Tong, Henry H.Y. ; Wang, Lingling ; Zhang, Qianqian

Leucine-rich repeat kinase 2 (LRRK2) is one of the most promising targets for the treatment of Parkinson's Disease. The activation of LRRK2 is regulated by the conserved Asp-Tyr-Gly (DYG) motif of the activation loop. Understanding the flipping process of the DYG motif from active to inactive is crucial for the regulation of LRRK2 kinase catalytic activity. Typically, type I inhibitors stabilize LRRK2 in the active conformation, while type II inhibitors favor the inactive state. To investigate the DYG-flipping mechanism, we performed well-tempered metadynamics simulations on LRRK2 in three distinct states: (1) the apo (ligand-free) state, (2) the type I inhibitor-bound state (DNL201), and (3) the type II inhibitor-bound state (rebastinib). The two-dimensional free energy landscape of DYG flipping in LRRK2 revealed transition pathways between the active ("DYG-in") and inactive ("DYG-out") states. Two distinct pathways were identified, which were differentiated by the orientation of Y2018. In the apo system, the DYG motif undergoes an upward flipping motion. Notably, type I inhibitor DNL201 stabilizes LRRK2 in the DYG-in active conformation, whereas type II inhibitor rebastinib promotes a downward flip into the DYG-out inactive state. These findings elucidate the conformational dynamics of LRRK2 in both unbound and ligand-regulated states as well as the mechanistic details of DYG motif flipping. Our study provides critical structural insights for targeted inhibition of LRRK2 kinase activity.

01 Mar 2025·Chemical Biology & Drug Design

Identification of Potent Leucine‐Rich Repeat Kinase 2 Inhibitors by Virtual Screening and Biological Evaluation

Article

Author: Shen, Hualiang ; Luo, Yanjuan ; Xiong, Yicheng ; Shang, Tianbo ; Cai, Tao ; Hu, Kai ; Zhu, Jiawei ; Shen, Runpu ; Yu, Guoqi ; Xi, Meiyang ; Bai, Xiaoxue

ABSTRACT:

Parkinson's disease (PD) is the second most common neurodegenerative disease but has limited medications. Targeting leucine‐rich repeat kinase 2 (LRRK2) has been identified as a potential strategy for the treatment of PD. The development of LRRK2 inhibitors has attracted much interest, and various compounds have been reported with significant improvement in preclinical and clinical models. Currently, no LRRK2 inhibitor has been approved for PD intervention. Herein, we reported a virtual screening (VS) workflow combining molecular docking and molecular dynamics (MD) simulations to achieve eight compounds for further enzymatic assay. The results indicated a potent LRRK2 inhibitor 2 with IC50 values of 2.396 and 5.996 μM against LRRK2 and LRRK2 G2019S, respectively, implying the reliability of this VS approach. Combined with predicted favorable drug‐like properties, this hit can be used as a starting point for further structural optimization, probably offering insight into targeting LRRK2 for PD treatment in the future.

News (Medical) associated with DNL-201

11 Apr 2019

·www.biospace.com

World Parkinson’s Day: How Science Is Battling the Disease

April 11 is World Parkinson’s Day, designed to raise awareness of Parkinson’s disease. Parkinson’s is a progressive disease of the nervous system that affects movement. April 11 is World Parkinson’s Day, designed to raise awareness of Parkinson’s disease. Parkinson’s is a progressive disease of the nervous system that affects movement. Symptoms start small, usually with a barely noticeable tremor or shaking in one hand. Over time, the tremors will become more pronounced, movements may slow, making everyday tasks more difficult. Muscle stiffness may occur, as well as impaired posture and balance, and changes to speech. Here’s a look at some of the advancements biopharma has made in treatments for Parkinson’s disease. The Michael J. Fox Foundation Grants $1 Million to Inflazome Recently, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) granted Dublin and Cambridge, UK-based Inflazome more than $1 million. The money will be used to fund the development of a NLRP3-specific Positron Emission Tomography (PET) tracer that allows non-invasive imaging of inflammasome-driven brain inflammation. Inflammasomes, the company indicates, create signals that stimulate immune cells to fight infections. Under normal circumstances, this is beneficial. But when the immune system is activated without control, the inflammation is linked to a broad range of disease, including Alzheimer’s, arthritis and various cardiovascular conditions. Inflazome focuses on developing ways of blocking inflammasome signaling to eliminate unwanted inflammation. The NLPR3 inflammasome is believed to drive chronic inflammation linked to many neurodegenerative diseases, including Parkinson’s Disease. The PET tracer is designed to determine what dosages are needed for clinical trials. Prana Biotechnology Becomes Alterity Therapeutics Late last week, Australian company PRANA Biotechnology changed its name to Alterity Therapeutics. Today, the company announced it was launching to Asian investors. Its lead drug candidate, PBT434, is a treatment for Parkinsonian disorders. It has received Orphan Drug designations for its first disease targets, Multiple System Atrophy. The drug targets key proteins associated with neurodegeneration of Parkinson’s and atypical parkinsonism. It is currently completing its first Phase I clinical trial. Impel Neuropharma’s INP103 Seattle-based Impel NeuroPharma is focused on diseases of the central nervous system, including Parkinson’s, bipolar disorder and schizophrenia, and acute migraine. In May 2018, the company initiated its Phase IIa trial of INP103 to evaluate the drug in Parkinson’s patients during an OFF episode compared to placebo. INP103 is a novel intranasal levodopa compound dosed using the company’s proprietary Precision Olfactory Delivery, or POD platform. Most Parkinson’s patients will eventually receive levodopa, which treats the symptoms. But as the disease progresses, more than half develop a frozen state, or OFF episode, which is related to fluctuating drug levels. Denali Therapeutics’ DNL201 In December 2018, South San Francisco-based Denali Therapeutics initiated dosing in a Phase Ib clinical trial of DNL201 in Parkinson’s. DNL201 is a small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2), a regulator of lysosomal function. This function is impaired in Parkinson’s disease and potentially can be restored by inhibiting LRRK2. Mutations in the LRRK2 gene are among the most frequent genetic causes of the disease. “Based on the positive outcome of our Phase I study in 122 healthy volunteer subjects, we are excited to evaluate DNL201 in Parkinson’s disease patients,” stated Carole Ho, Denali’s Chief Medical Officer, at the time. “This study will provide additional important safety and biomarker data in patients to support rational dose selection. The results from this study will inform decisions on further clinical testing of DNL201, including potential registrational trials.” Gene Therapy Eases Parkinson’s Movement Symptoms On April 4, The Michael J. Fox Foundation announced that a study it helped fund by researchers at the University of California, San Francisco (UCSF) was published in the Annals of Neurology . The Phase I trial involved 15 people ages 40 to 70 with moderate Parkinson’s disease. The researchers introduced an investigational gene that makes the AADC enzyme into the brains of the participants using a surgical procedure. AADC converts levodopa into dopamine, which helps control Parkinson’s movement symptoms. The study divided the patients into three groups that received different doses of the gene therapy in a single infusion. After six months, all groups saw an increase in AADC activity and a decrease in the amount of levodopa they were required to take. In fact, the cohort receiving the highest dosage required 42% less levodopa. Within one year, patients had more “ON” time without dyskinesia. They also appeared to be dose-dependent—the higher the dose, the more AADC activity, the greater the decrease in medication use. There are just a few stories of cutting-edge research being conducted to defeat Parkinson’s disease.

Phase 1Clinical ResultOrphan DrugPhase 2

02 Aug 2018

·www.biospace.com

Denali Shares Pop After Positive Parkinson’s Trial Data

Denali Therapeutics stock climbed 11 percent after the release of positive data from its Phase I clinical trial of DNL201 in Parkinson’s disease. Denali Therapeutics stock climbed 11 percent after the release of positive data from its Phase I clinical trial of DNL201 in Parkinson’s disease. Denali announced positive results from its dose-ranging Phase I clinical trial of DNL201 in Parkinson’s disease. It was a randomized, double-blind, placebo-controlled, oral dose trial in healthy patients. It met all safety, pharmacokinetic, and pharmacodynamic goals. The drug was generally well tolerated with no serious side effects. The drug is a small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2). LRRK2 gene mutations are the most observed genetic cause of Parkinson’s disease and a major cause of lysosomal dysfunction. This adds to the formation of Lewy body protein aggregates and neurodegeneration seen in the disease. LRRK2 regulates lysosomal genesis and function, which doesn’t function properly in Parkinson’s. It may be fixed by inhibiting LRRK2. In the trial, more than 100 healthy patients received either single or multiple ascending doses or a placebo. Based on the results, the company plans to advance the drug into a Phase Ib clinical trial in Parkinson’s disease patients with or without a genetic LRRK2 mutation. Denali expects to start the trial by the end of the year. “We conclude from this clinical trial that DNL201 was able to achieve the targeted level of LRRK2 inhibition at doses that were safe and well tolerated,” said Carole Ho, Denali’s chief medical officer, in a statement. “We are pleased that the trial was a success in all these key measures. The trial data give us confidence to proceed with further clinical testing in Parkinson’s patients and provide a solid basis for selection of the optimal dose for future clinical trials in patients.” The company also has a Phase I dose escalation trial ongoing in the Netherlands with another small molecule LRRK2 inhibitor, dubbed DNL151. “We are leading the way in testing LRRK2 inhibitors in humans with the goal of bringing a disease-modifying therapeutic to patients suffering from Parkinson’s disease,” said Ryan Watts, Denali’s chief executive officer, in a statement. “We are also encouraging to see mounting evidence supporting a role of LRRK2 inhibition in the broader sporadic Parkinson’s disease population, in addition to Parkinson’s disease genetically associated with a LRRK2 mutation.” On May 30, the company exercised its option to buy all outstanding shares in F-star Gamma. This was based on an Option Agreement it signed on August 24, 2016, that expanded its collaboration with F-star on Denali’s biologics Transport Vehicle blood-brain barrier platform technology. Denali decided to go ahead and acquire the company based on preclinical proof-of-concept data for the TV platform technology and the progress Denali’s lead program has made using the technology. “Our decision to exercise the option to buy F-star Gamma reflects the progress in our collaboration with F-star and the generation of preclinical data showing that our proprietary TV platform technology may enable us to deliver biologics across the BBB and into the brain,” said Watts, in a statement at the time. “Specifically, recent data demonstrated robust and sustained peripheral and brain activity for our ETV:IDS program for Hunter Syndrome and hence preclinical proof of concept. Furthermore, the expanded collaboration allows us to deepen and broaden our research efforts supporting our TV platform technology.”

Phase 1Clinical ResultLicense out/in

20 Dec 2017

·www.globenewswire.com

Denali Therapeutics Announces Advancement and Expansion of Its LRRK2 Inhibitor Clinical Program for Parkinson’s Disease

SOUTH SAN FRANCISCO, Calif., Dec. 20, 2017 (GLOBE NEWSWIRE) -- Denali Therapeutics Inc. (NASDAQ:DNLI), a biopharmaceutical company developing a broad portfolio of therapeutic candidates for neurodegenerative diseases, today announced that its small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2), DNL201, achieved, on average, greater than 90% inhibition of LRRK2 kinase activity observed at peak and greater than 50% inhibition at trough drug levels at the highest multiple dose tested in a healthy volunteer Phase 1 study. Based on a full review of the clinical data from this ongoing study, and additional preclinical data, the FDA has removed the previously imposed partial clinical hold. LRRK2 inhibition was measured by two independent blood-based biomarker assays of LRRK2 activity: phosphorylation of LRRK2 at Serine 935 and phosphorylation of the LRRK2 substrate Rab10. Both markers reflect the function of LRRK2 kinase activity and Rab phosphorylation is linked to lysosomal dysfunction associated with Parkinson’s disease. In addition, robust central nervous system penetration of DNL201 has been achieved as demonstrated by measurement of DNL201 in the cerebrospinal fluid (CSF). These data, in combination with pharmacokinetics/pharmacodynamics (PK/PD) modeling, indicate robust and sustained target engagement of LRRK2 in brain. Denali also announced that it has commenced dosing of its second small molecule inhibitor of LRRK2, DNL151, in healthy volunteers in the Netherlands. Denali now has two distinct small molecules targeting LRRK2 inhibition in human clinical testing for Parkinson’s disease. Denali plans to select either DNL201 or DNL151 to move into studies in Parkinson’s disease patients carrying a LRRK2 mutation after completion of Phase 1 healthy volunteer studies for both molecules. In the ongoing studies in healthy volunteers, Denali is investigating safety and tolerability, PK and PD in blood and CSF, and characterizing a biomarker to estimate target engagement in brain. “Mutations in LRRK2 are a major risk factor for Parkinson’s disease. Targeting this degenogene represents a promising approach to develop disease modifying medicines for patients suffering from this terrible disease,” said Ryan Watts, Ph.D., CEO. “By restoring LRRK2 activity to normal levels, we believe we can reverse lysosomal dysfunction, which could potentially benefit both patients with LRRK2 mutations, as well as idiopathic Parkinson’s disease patients who exhibit lysosomal dysfunction,” said Dr. Watts. “Our robust biomarker assay allows us to establish and monitor LRRK2 target and pathway engagement, and assess the exposures required to reach desired target inhibition. We have demonstrated significant inhibition of LRRK2 kinase activity with DNL201, which gives us confidence to proceed with further clinical testing,” said Carole Ho, M.D., Chief Medical Officer. About Denali Denali is a biopharmaceutical company developing a broad portfolio of therapeutic candidates for neurodegenerative diseases. Denali is based in South San Francisco. For additional information, please visit www.denalitherapeutics.com . Cautionary Note Regarding Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements express or implied in this press release include, but are not limited to, plans to progress either DNL201 or DNL151 into studies in Parkinson’s disease patients following completion of Phase 1 healthy volunteer studies for both molecules, results of targeting mutations of LRRK2 to develop disease modifying medicines for Parkinson’s disease patients, the effects of restoring LRRK2 activity to normal levels and potential benefits to both patients with LRRK2 mutations and idiopathic Parkinson’s disease who exhibit lysosomal dysfunction, and Denali’s plans to conduct further clinical testing in this area. Actual results are subject to risks and uncertainties and may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to, risks related to: Denali’s early stages of clinical drug development; Denali’s ability to complete the development and, if approved, commercialization of its product candidates; Denali’s dependence on successful development of its BBB platform technology and product candidates currently in its core program; Denali’s ability to conduct or complete clinical trials on expected timelines; the uncertainty that any of Denali’s product candidates will receive regulatory approval necessary to be commercialized; Denali’s ability to continue to create a pipeline of product candidates or develop commercially successful products; and other risks, including those described in Denali’s Prospectus filed with the SEC on December 8, 2017. The forward-looking statements in this press release are based on information available to Denali as of the date hereof. Denali disclaims any obligation to update any forward-looking statements, except as required by law. Contacts: Lizzie Hyland (646) 495-2706 lhyland@gpg.com or Morgan Warners (202) 295-0124 mwarners@gpg.com

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 1	United States	Denali Therapeutics, Inc.	04 Dec 2018

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