Biogen and Denali Terminate Phase 3 LIGHTHOUSE Study of BIIB122 in LRRK2-related Parkinson Disease

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The companies have noted that the decision was not made because of safety or efficacy data, but to refocus efforts on the ongoing phase 2b LUMA trial of BIIB122.

Samantha B. Haeberlein, PhD, head of Neurodegeneration Development, Biogen

Samantha B. Haeberlein, PhD

Biogen and Denali have announced that they are discontinuing a portion of the clinical development program for BIIB122 (also known as DNL151), an investigational small molecule inhibitor of LRRK2 in development for the treatment of Parkinson disease (PD). As a result of this decision, the phase 3 LIGHTHOUSE study (NCT05418673), which was initiated in September 2022, will be terminated.1

The companies are choosing to refocus their efforts “to enable a timely readout on efficacy in early-stage idiopathic Parkinson's disease while gaining further clinical data in Parkinson’s disease with and without an LRRK2 mutation.” Those patients with PD related to LRRK2 mutations who were enrolled in the now discontinued program will be offered an opportunity to join the ongoing phase 2b LUMA study (NCT05348785), which began in May 2022.

No statement was issued by Biogen leadership/ Previously, in October 2022, Samantha B. Haeberlein, PhD, the head of Neurodegeneration Development at Biogen, said in a statement that "LRRK2 inhibition may be a promising therapeutic approach to the disease" and that LIGHTHOUSE would have "enabl[ed] us to test the genetic hypothesis and implicated lysosomal pathway." The LIGHTHOUSE study was the largest study ever undertaken in individuals with PD caused by an LRKK2 mutation.

The companies noted in the announcement that the decision was made “in consideration of the LIGHTHOUSE study’s complexity including the long timeline with anticipated study completion in 2031.” They added that the modifications were not because of safety or efficacy data from studies of the treatment and that they “remain committed to advancing the development of BIIB122.” Biogen and Denali noted that those patients who are currently enrolled and randomly assigned in the LIGHTHOUSE study should speak to their physician regarding participation in LUMA or other treatment options.

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LUMA is a double-blind, placebo-controlled study that aimed to include 640 participants between the ages of 30 and 80 years with early-stage PD. They are randomly assigned to either 225 mg of oral BIIB122 or placebo once daily for a minimum of 48 weeks and a maximum of 144 weeks. To understand whether BIIB122 slows the worsening of symptoms, investigators are evaluating patients on Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts 2 and 3.

Mutations in the LRRK2 gene are among of the most common genetic causes of PD, explaining an estimated 4% to 5% of familial and 1% to 2% of sporadic PD cases. Those of Ashkenazi Jewish or North American Arab Berber descent experience a higher frequency between 30% and 40% of cases.2 It has also been reported that dysfunction of LRRK2 may influence the accumulation of alpha-synuclein and its pathology to alter cellular functions and signal pathways by the kinase activation of LRRK2. The accumulation of α-synuclein is one of the main stimulants of microglial activation, which is believed to contribute to neuroinflammation and neuronal death in PD.3

There are challenges, though, with identifying candidates for clinical trials of PD with mutations such as these—genetic tests are typically not covered by health insurance, which may lead to a lack of understanding of the presence of possible mutations in genes relevant to the disease, such as LRRK2 or GBA. In May 2022, the Parkinson’s Foundation announced the expansion of its PD GENEration: Mapping the Future of Parkinson Disease program, which offers no-cost genetic testing for Parkinson-related genes and genetic counseling for participants to better understand their results.4

The program now includes more than 20 actively enrolling participant sites and an effort to expand the reach of new testing sites into historically excluded communities. The study has an enrollment goal of 15,000 participants—and in March 2023, hit a recruitment milestone of 7500 participants.5 Individuals have been enrolled from all 50 US states, Puerto Rico, and the Dominican Republic. The program seeks to help those with PD, with the results potentially identifying those who could be candidates for clinical trials.

REFERENCES
1. Statement: Biogen Provides Update on Parkinson’s Disease Clinical Development Program. News release. Biogen. June 5, 2023. Accessed June 6, 2023. https://investors.biogen.com/news-releases/news-release-details/statement-biogen-provides-update-parkinsons-disease-clinical
2. Bardien S, Marsberg A, Keyser R, et al. LRRK2 G2019S mutation: frequency and haplotype data in South African Parkinson disease patients. J Neural Transm (Vienna). 2010;117(7):847-853. doi:10.1007/s00702-010-0423-6.
3. Rui Q, Ni H, Li D, Gao R, Chen G. The role of LRRK2 in neurodegeneration of Parkinson disease. Curr Neuropharmacol. 2018;16(9):1348-1357. doi:10.2174/1570159X16666180222165418
4. Parkinson’s Foundation announces major expansion of PD GENEration study, increasing access to genetic testing and counseling across the US. News release. Parkinson’s Foundation. May 3, 2022. Accessed June 6, 2023. https://www.prnewswire.com/news-releases/parkinsons-foundation-announces-major-expansion-of-pd-generation-study-increasing-access-to-genetic-testing-and-counseling-across-the-us-301538402.html
5. Parkinson’s Foundation Global Genetics Study Hits Enrollment Milestone. News Release. Parkinson’ Foundation. Published January 24, 2023. Accessed June 6, 2023. https://www.parkinson.org/about-us/news/pdgene-enrollment-milestone
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