Brenig Therapeutics Initiates First-in-Human Trial of LRRK2 Inhibitor BT-267 for Parkinson Disease

Author(s):

Key Takeaways

Brenig Therapeutics is testing BT-267, a potential best-in-class LRRK2 inhibitor, in a first-in-human trial for Parkinson's disease.
Preclinical data shows BT-267 has excellent safety and pharmacokinetics, with minimal lung or kidney changes at high doses.
A $65 million financing round supports Brenig's clinical program, with backing from NEA and other investors.
LRRK2 gene research has driven the development of kinase inhibitors, with BT-267 positioned as a promising therapy for PD.

To date, BT-267 shows strong potential as a best-in-class LRRK2 inhibitor for Parkinson disease, with a superior safety profile, excellent pharmacokinetics, and innovative development leveraging advanced technologies and biomarker modeling.

Iain Dukes, MA, DPhil, chairman at Brenig

According to a new announcement, Brenig Therapeutics has initiated a first-in-human trial to test the efficacy and safety of its investigational best-in-class LRRK2 inhibitor BT-267 as a potential therapy to treat Parkinson disease (PD). The study, which began this month, will test the effects of the therapeutic in a cohort of healthy volunteers, with proof-of-concept studies planned for patients with idiopathic PD.¹

Preclinical data highlights BT-267 as a potentially best-in-class LRRK2 inhibitor, demonstrating an excellent safety profile with minimal lung or kidney changes at the highest GLP toxicology doses and outstanding pharmacokinetics, including a high cerebrospinal fluid (CSF) to plasma unbound ratio. Leveraging advanced computer-aided drug design, AI/ML computational pharmacology, biomarker modeling, and structural biology expertise from Expert Systems Accelerator, Brenig aims to position BT-267 as a promising disease-modifying therapy for PD, including idiopathic cases without known genetic drivers.

Brenig Therapeutics is a small molecule drug development company that utilizes an AI/machine learning approach through a partnership with Expert Systems Inc. Advancement of the company’s clinical program was supported by a recent $65 million financing round. The financing, announced in July, was led by New Enterprise Associates (NEA), with support from an additional US-based healthcare investor as well as existing investors: OrbiMed, Torrey Pines Investments, and BioGeneration Ventures.²

At the time of the investment, Iain Dukes, MA, DPhil, chairman at Brenig, said in a statement, "With the financing, we advance our goal of addressing the needs of patients with Parkinson disease with our differentiated drugs."²

Earlier this year, at the ACS Spring 2024 Conference held in New Orleans, Louisianna, Brenig presented new safety data on BT-267. According to the company, the data highlighted the superior safety profile of the agent with an exceptional CSF to plasma ratio, in vivo efficacy of BT-267 in brain, as well as no visible lung and kidney morphological changes compared with other LRRK2 inhibitor candidates.³

The leucine-rich repeat kinase 2 (LRRK2) gene was first identified in 2004 as the gene responsible for the PARK8 locus that had itself previously been linked to PD in 2002. This gene is located on chromosome 12, contains 51 exons spanning 144 kb, and encodes for a large 286 kDa multidomain protein of the same name. As its name suggests, LRRK2 contains a leucine-rich repeat (LRR) domain and a kinase domain.⁴

In 2009, notable genome-wide association studies identified common genetic variance at and near the LRRK2 locus as a risk factor for PD, pointing to the possibility that LRRK2 dysfunction may be involved in PD pathomechanisms in patients who do not harbor a missense mutation. These findings of genetic evidence that LRRK2 is involved in PD and that the kinase hyperactivation may be a primary culprit became strong drivers of research programs in academia and industry to understand LRRK2 dysfunction and develop inhibitors of LRRK2 kinase activity.^5,6

REFERENCES
1. Brenig Therapeutics Announces the Initiation of First-in-Human Clinical Trial of BT-267, a Best-in-Class LRRK2 Inhibitor for Parkinson's Disease. News release. Brenig Therapeutics. November 26, 2024. Accessed November 27, 2024. https://www.prnewswire.com/news-releases/brenig-therapeutics-announces-the-initiation-of-first-in-human-clinical-trial-of-bt-267-a-best-in-class-lrrk2-inhibitor-for-parkinsons-disease-302315979.html
2. Brenig Therapeutics Announces $65 Million Series A Financing to Advance Leading Pre-Clinical Parkinson's Disease Pipeline. News release. Brenig Therapeutics. July 23, 2024. Accessed November 27, 2024. https://www.prnewswire.com/news-releases/brenig-therapeutics-announces-65-million-series-a-financing-to-advance-leading-pre-clinical-parkinsons-disease-pipeline-302202126.html
3. Brenig Therapeutics Presented New Data for the Best-in-Class LRRK2 Inhibitor Targeting Parkinson's Disease at the ACS Spring 2024 Conference. News release. Brenig Therapeutics. March 18, 2024. Accessed November 27, 2024. https://www.prnewswire.com/news-releases/brenig-therapeutics-presented-new-data-for-the-best-in-class-lrrk2-inhibitor-targeting-parkinsons-disease-at-the-acs-spring-2024-conference-302091628.html
4. Taymans JM, Fell M, Greenamyre T, et al. Perspective on the current state of the LRRK2 field. Npj Parkinson’s Disease. 2023;9(104). doi:10.1038/s41531-023-00544-7
5. Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet. 2009;41(12):1303-7. doi:10.1038/ng.485.
6. Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson disease. Nature Genetics. 2009;41:1308-1312. doi:10.1038/ng.487