| (Jennings, 2022 #2068) | included both EOPD & LOPD, for LOPD stratified LRRK2 + vs -) no mention on genotype requirement, Screening DAT confirmation of PD • SOC therapy or Tx Naïve | LRRK2-PD) | placebo-controlled |
→ results: both doses achieved > 50 percent inhibition of LRRK2 and Rab10 phosphorylation in blood, and improved urine BMP (bis(monoacylglycero)-phosphate) by 20 percent and 60 percent at the low and high dose, respectively. | ||
|---|---|---|---|---|---|---|
| 2 | Plan | LRRK2-PD, standard Tx | DATScan/VMAT | |||
| 2/3 | Plan | LRRK2-PD, Tx naïve | Mds-updrs | |||
| 2/3 | Plan | iPD, Tx naïve | Mds-updrs |
v) Denali has announced a strategic collaboration with a gene diagnostic lab, Centogene, in order to globally identify and recruit LRRK2 mutation carriers, further characterizing this genetic subtype, and build a source for patient recruitment for future studies 58.
Preclinical
| [Jennigs 2022 #2283] | |||||
|---|---|---|---|---|---|
| Tx | ↓ pS935 LRRK2 | ↓ pT73 Rab10 | ↓ Cells with enlarged lysosome (%) | ↑ lysosomal protein degradation | |
| HEK293 cells (The potencies for DNL201 using these two LRRK2 phosphorylation sites were equivalent, with IC50 in HEK293 cells of 47nM for pS935 LRRK2 and 45nM for pS1292. | H4 cells expressing wild-type LRRK2 or mutant LRRK2G2019S | B) Primary astrocytes from wild-type LRRK2G2019S LRRK2 or mutant LRRK2 (AHA) labeling fibroblasts from healthy human controls and patients with Gaucher disease (GBA variant carriers) | |||
| Human PBMC (ex vivo) | |||||
| Human iPSC-derived microglia (ex vivo) | Human iPSC-derived microglia (ex vivo) | ||||
| In vitro? | G2019S : ↑ LAMP2 (IF), ↑ Lysosomal enlargement (drug restored this) |
| NHP |
(R&D Day slide) Comparable inhibition of LRRK2 in brain vs. PBMCs → LRRK2 INHIBITION IN PBMCs PREDICTS BRAIN LRRK2 INHIBITION Samples collected 24 hours postdose after 28 days of dosing (js: readout이 ratio니까 normal animal에서도 사용 용이한 가봄) B panel: pS935/LRRK2 (Normalized to Vehicle), x = Vehicle / 2 / 6 / 16 mg/kg DNL201 treatment, two groups (Brain orange, PBMCs grey). A panel: [DNL201] (µM) vs Time after dose (hours) — CSF (orange), Plasma unbound (grey); Comparable exposure of DNL201 in CSF & plasma (Inline slide; preserved as body_r02 evidence) |
| Mice | Cf) ETV:IDS (=DNL310)으로 Mouse brain BMP 감소 봤으나 DN;201로 본 건 없네. DNL151 (=BIIB122 , backup to DNL201, collaboration with BIOGEN)(small molecule) |
Clinical trials
| NCT | name | Target pt | status | number | design | Tx | Primary outcome m | Secondary |
|---|---|---|---|---|---|---|---|---|
| LIGHTHOUSE | Started 202209→ 20230611 Biogen is discontinuing the LIGHTHOUSE study due to its complexity and long timeline—which had an end date in 2031. |
LIGHTHOUSE Study: For PD patients with LRRK2 mutations
o o 10,000 participants were recruited and genetically tested by Mar May 2021, and the study was extended to include additional 2,500 PD patients o Patients enrolled in ROPAD study and identified with LRRK2 mutation are eligible for Phase 3 LIGHTHOUSE Study (if they meet the other inclusion criteria as well) • BMs: pRAB10 in PBMCs, urine BMP | ||||||
| LUMA | planned |
LUMA Study: For PD patients who do not carry LRRK2 mutations (idiopathic PD) → will amend the LUMA protocol to include eligible patients with a LRRK2 genetic mutation
| ||||||
| NCT04056689 | PD, H&Y 1-3 PD patients (30세이상) with or without LRRK2 mutation (JS: Included both EOPD & LOPD, for LOPD stratified LRRK2 + vs -) no mention on genotype requirement, MOCA 24이상 | Ongoing | 34 | 3 doses vs placebo, RCT DB | 42 days | (Target engagement) ↓ pS935 in whole blood was observed at the 90 mg/kg dose of DNL151/BIIB122 (... across all dose levels studied in PD patients (90 mg, 130 mg, and 300 mg given orally for 28 days). Primary & Secondary [Time Frame: Randomization to Day 28] | However, discussions with the regulators are ongoing, and there might be a requirement to conduct an additional study in this patient segment to support registration 20230112 → Target engagement and pathway engagement goals were met (pathway engagement) A dose-dependent reduction of phosphorylation of Rab10, a substrate of LRRK2, was observed across the HV cohorts, and a reduction of ≥ 50% was observed at all dose levels studied in PD patients After normalizing for total LRRK2 levels, pRab10 was elevated by ~ 2-fold in patients with sporadic Parkinson's disease as compared to LRRK2 mutation carriers compared with HV The levels of pRab10 reduction observed in the healthy volunteers are consistent with the magnitude required for normalization of pRab10 levels in patients with Parkinson's disease (pathway engagement) A dose-dependent reduction in urine lysosomal lipid BMP, a biomarker of peripheral lysosomal function, was achieved in both BIIB122/DNL151 studies The levels of pRab10 reduction observed in both studies | |
| Denali 151 program, an oral small molecule LRRK2 inhibitor. can work not just in patients with LRRK2 mutations, but also there is ample evidence of lysosomal hypofunction in other cases of PD, even patients that have LRRK2 mutations. And so, there potential is there that it could work in a broad range of Parkinson's patients, | ||||||||
| NCT04557800 | HV Healthy volunteers were treated with single or once-daily multiple doses ranging from 15 mg to 300 mg for up to 28 days or twice-daily doses of up to 400 mg for 14 days | ongoing | N=184 | |||||
Preclinical (BIIB094)
BIIB094 (=ION859) (IONIS-BIIB7Rx) (Biogen) (ASO)
| LRRK2 ASOs to the brains of mice reduced LRRK2 protein levels and Nlrp3-induced LRRK2 inclusions [67] |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| LRRK2 BMP outcome | improved urine BMP (bis(monoacylglycero)-phosphate) by 20 percent and 60 percent at the low and high dose, respectively. | Low/high dose direction may be flipped; the slide visual is small. |
| LIGHTHOUSE row | o o 10,000 participants | Double-bullet “o o” appears intentional in the source’s nested list. |
| BIIB094 row | Nlrp3-induced LRRK2 inclusions [67] | The wording is interpreted from a small footer paragraph; reference number [67] is faint. |