DNL151, DNL201, and BIIB094: experimental agents for the treatment of Parkinson’s disease

ABSTRACT

Introduction

Pathogenic mutations of the abundant leucine-rich repeat kinase 2 gene support the onset of familial and sporadic forms of Parkinson’s disease. These genetic variants catalyze kinase activity by substrate phosphorylation. They promote the nigrostriatal neurodegenerative process, i.e. characterized by Lewy body formation.

Areas covered

This narrative review discusses leucine-rich repeat kinase 2 inhibitors as therapeutic concept for beneficial disease modification following a literature search.

Expert opinion

Leucine-rich repeat kinase 2 gene function contributes to the onset of microglia inflammation, cellular, and mitochondrial dysfunction. Leucine-rich repeat kinase 2 inhibition with oral application of DNL151, respectively DNL201, and intrathecal administration of the antisense oligonucleotide BIIB094 in a single and multiple ascending dose study was safe and well tolerated. 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.

Plain Language Summary

Certain mutations of the abundant leucine-rich repeat kinase 2 gene contribute to the onset of inherited and sporadic forms of idiopathic Parkinson’s disease. These genetic variants enhance the gene related kinase activity and promote nigrostriatal neurodegeneration with features like inflammation of microglia, cellular, and mitochondrial dysfunction. Inhibition of leucine-rich repeat kinase 2 activity was efficacious, safe, and well tolerated in experimental investigations and in the still ongoing clinical study program. Approval of this therapeutic concept after future positive clinical study outcomes is the introduction of personalized medicine based on molecular mechanisms and targets in Parkinson’s disease. Beneficial modification of progression is the most unmet need for the therapy of patients with Parkinson’s disease.

KEYWORDS:

• Parkinson’s disease
• LRRK2 inhibitors
• disease modification
• chronic neurodegeneration
• dopamine

Article highlights

• Disease modification and cure are essential unmet needs for the treatment of Parkinson’s disease.

• Pathogenic mutations of the LRRK2 gene and their related mechanisms are important risk factors for the onset of inherited and sporadic forms of idiopathic Parkinson’s disease.

• Extensive experimental and initial clinical research in healthy volunteers and patients with Parkinson’s disease demonstrated efficacy and safety of the inhibition of LRRK2 kinase activity.

• Future approval of LRRK2 inhibitors as disease modifying compounds will introduce precision medicine in the treatment of patients with Parkinson’s disease.

• Future long-term trials with clinically relevant endpoints, such as the need for levodopa equivalents, are important to demonstrate disease modifying effects of LRRK2 inhibition in Parkinson’s disease.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. There was no employment, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed they have been advising Denali in the past when the company was developing DNL201. Their center is involved in the LUMA and LIGHTHOUSE trials. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.