LRRK2 inhibitor lung findings

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Reina Fuji and 31 colleagues, at Genentech (Department of Safety Assessment), with Marco Baptista of the Michael J. Fox Foundation among the 32 authors (Science Translational Medicine 2015;7:273ra15). Marco Baptista of the Michael J. Fox Foundation and 32 collaborators from the foundation's LRRK2 Safety Initiative (Science Translational Medicine 2020;12:eaav0820).

What happened

• 2015. Two distinct selective brain-penetrating LRRK2 inhibitors caused abnormal build-up of lamellar bodies in type II pneumocytes (lung cells that make surfactant) in non-human primates. Rodents had no such change on the same drugs, and no kidney change appeared in monkeys. The picture matched LRRK2 knockout mice, so the authors judged it LRRK2-mediated rather than off-target. Urinary BMP (a lysosome marker) also fell. The authors said lung toxicity could be a critical safety limit.
• 2020. A 2-week study in macaques tested GNE-7915, MLi-2 (15 and 50 mg/kg) and PFE-360 (3 and 6 mg/kg). All caused mild vacuolation of type II cells without degeneration. At the low doses of PFE-360 and MLi-2, which gave about 50% and about 100% brain LRRK2 inhibition, lung changes were absent or minimal. The effect reversed after dosing stopped, and lung function tests (MLi-2 and GNE-7915) showed no deficit. The authors concluded the lung effects should not preclude clinical testing.

• The LRRK2 Safety Initiative. The 2020 study was the output of a consortium the Michael J. Fox Foundation convened in 2013, in which Genentech, Denali, Merck and Pfizer contributed inhibitors and Covance and Lovelace Respiratory Research Institute took part; MJFF's account says lung changes occurred with all compounds, on-target, reversible, with no loss of lung function (MJFF). A 2016 MJFF item reported the same finding from Genentech, Merck and Pfizer in late 2015, but the initiative's own start date is not given on MJFF's grant page.

Why it moved us toward a cure

This work removed a roadblock for first-in-human LRRK2 inhibitor trials (landmark 200) and later efficacy trials (landmark 145). It also matters as a rule: any LRRK2 drug needs lung monitoring.

Outcome

Advanced. The concern is on-target, reversible and clinically manageable in monkeys. Human lung data from long dosing are not covered here.

Sources

• Fuji et al., Sci Transl Med 2015;7:273ra15, DOI 10.1126/scitranslmed.aaa3634
• Baptista et al., Sci Transl Med 2020;12:eaav0820, DOI 10.1126/scitranslmed.aav0820
• No correction or retraction found for either paper (Crossref and Europe PMC, 20 Oct 2026).
• Not yet verified: animal numbers; human lung findings in LRRK2-inhibitor trials; kind "discovery" follows the original brief, though it is a safety study.