LRRK2 AS THERAPEUTIC TARGET. Jan Egebjerg

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1 LRRK2 AS THERAPEUTIC TARGET Jan Egebjerg

2 Scientific and Medical Rationale(s) Scientific Strong genetic evidence causally associates LRRK2 to familial PD. Combined genetic and biochemical evidence supports a hypothesis in where the LRRK2 kinase function correlates with disease risk and that LRRK2 kinase inhibitors would be a new treatment paradigm for PD Expression of LRRK2 is highly enriched in brain, lung, kidney and blood. Successful LRRK2 inhibition would successfully dampen LRRK2 kinase activity in the brain with a sufficient TI Medical Rationale Current PD treatments treat symptoms and have no effect on disease progression and limited of effect at late stages of disease Large unmet need for effective treatments and in particular treatments that may alter the progression of the disease or even modifying the disease. 2 STRICTLY CONFIDENTIAL

3 How difficult can it be? Identify a selective LRRK2 kinase inhibitor Target engagement: Tools to determine target engagement in brain Pharmacological relevance: Disease relevant model for dose finding and time for intervention Patient selection and outcome measures for clinical trials 3

4 LRRK2 as a target for some PD patients? Disease hypothesis: Increased LRRK2 kinase activity causal for Parkinsons Disease Patient population? Target only G2019S carriers: develop a LRRK2;G2019 S selective compound Develop a selective pan-lrrk2 inhibitor and identify patients with increased risk or LRRK driven pathology Relative Disease Risk I2020T R1441C/G/H Y1699C N1437H G2019S A419V M1646T G2385R N551K, R1398H LRRK2 WT Very rare Rare Common Very common Minor Allelle Frequency (MAF)

5 Highly potent and selective LRRK2 kinase inhibitors have been identified. Challenging target (no approved CNS active kinase inhibitors) transition peripheral target properties to CNS drug properties High quality compounds have been shared with the community Patenting Activity Merck Sanofi Genentech Southern Research Institute Pfizer Arrien Pharmaceuticals GSK Elan Lundbeck Zenobia Origenisis Cellzome Ipsen Issue: PK properties for appropriate therapeutic index (TI) Pharmacodynamics: Dose finding based on a pathophysiological relevant readout 5

6 Tg rodent models 6

Dose finding based on a pathophysiological relevant readout: PD There is no validated preclinical in vivo model for disease progression in Parkinson s Disease Rodent animals models that carry G2019S

7 Dose finding based on a pathophysiological relevant readout: PD There is no validated preclinical in vivo model for disease progression in Parkinson s Disease Rodent animals models that carry G2019S or other pathogenic variants do not present with Parkinson s Disease i.e. a-syn aggregates Several tg models exhibit changes in locomotor activity and striatal dopaminergic tone Robustness of models an issue for drug testing Sloan et al 7

8 Basal ganglia circuitry in a PD-like state: STN burst firing and behaviour Rat asyn AAV model Cortex A-syn, AAV Striatum LRRK2 GPe Thal Cylinder test STN Coefficient of variation of the interspike interval (CV ISI). SNc SNr/GPi Single unit recording

9 Findings α-synuclein AAV rat model supportive of LRRK2 interaction- but still (several) inconsistencies LRRK2 KO studies Long Evans rat LRRK2 KO modulates a-synuclein mediated burst firing Effect on asyn-ps129 No significant effect on behavior although a partial reversal has been observed LRRK2 inhibitor studies Sprague Dawley rat Acute LRRK2 inhibition modulates a-synuclein mediated burst firing phenotype Chronic LRRK2 inhibition modulates a-synuclein mediated behavioral phenotype No significant chronic effect of LRRK2 inhibition on ephys No significant effects on asyn-ps129 after acute/chronic dosing No significant effect on behavior after acute/chronic dosing 9

PK/PD modeling PK/PD based on mechanistic readout Auto-phosphorylation correlates with occupancy and disease risk Direct P-1292 (not measurable in vivo) Indirect P-935 (correlates with occupancy) PD

10 PK/PD modeling PK/PD based on mechanistic readout Auto-phosphorylation correlates with occupancy and disease risk Direct P-1292 (not measurable in vivo) Indirect P-935 (correlates with occupancy) PD marker for PK/PD modeling? 0.02 Rab phosphorylation as measure for 0.01 pathophysiological pathway (link to α synuclein) Dose qualification based on in vitro Hypothesis: Revert kinase activity of LRRK2 G2019S to the level of the protective form: IC80 Catalytic efficiency (Kcat/Km) Relative Disease Risk N551K/R1398H (MAF ~8%) - protective variant WT M1646T (MAF ~2%) A419V (MAF ~3%) G2019S - Azkenazi G2019S - Arab G2019S 10

11 Target engagement: Translational tools to determine target engagement in human brain Markers for human studies mandatory! PET ligands- very challenging target low abundance protein, lipophilicity of high affinity compound compromise signal/noise P-LRRK2 levels in CSF exosomes (or brain specific exosomes isolated from blood) 11

12 Clinical progression of Parkinson s Disease (PD) FUNCTION PATHOLOGY Topics to resolve in preclinical models: Time for intervention: Is LRRK2 dysfunction critical at particular stages of the disease? What readout would be most sensitive to LRRK2 kinase inhibition?

13 Model for clinical trial based on PPMI data (idiopathic PD patients) Early idiopathic PD (Hoehn & Yahr 2 or less) Positive DAT SPECT Time from diagnosis < 18mts +/- different concomitant treatments Δ-DAT scan Δ-UDPRS 13

14 Modeling of change in disease progression DAT scan 1y Primary outcome at 1y: DAT imaging (change in striatum) Primary outcome at 2y: UPDRS Reduction (% mean striatum) Mean change (SD) 30% > (0.20) 50% > (0.18*) UPDRS - 2y Total sample size 80% power Difference (in Total Score) Mean change (SD) Total sample size 80% power 2 points (30%) 3.4 points (50%) > 4.81 (12.07) > 3.4 (10.86*)

G2019S A419V M1646T G2385R N551K, R1398H LRRK2 WT Very rare Rare Common Very common Minor Allelle Frequency

15 Segmentation strategies Exonic variants stratification LRRK2 G2019S + LRRK2 risk variant + PD minus LRRK protection carriers All PD patients Relative Disease Risk I2020T R1441C/G/H Y1699C N1437H G2019S A419V M1646T G2385R N551K, R1398H LRRK2 WT Very rare Rare Common Very common Minor Allelle Frequency (MAF) Biomarkers for elevated LRRK2 activity PBMC phosphorylation state Exosomes in urine Others Symptom differentiators 15

16 Focus area Increased focus on disease stratification Target/pathway specific markers for patient selection Biomarker approaches aiming at classifying patient heterogeneity Use ipscs as translational tool heterogeneity Patient disease pheno-/genotype defined ipscs Model disease heterogeneity Confidence in target for dose estimation Target identification Change in UPDRS Motor Score (OFF state) Change from Baseline in UPDRS Scores by Patient (OFF State) Progression/non-progression population defined at 2y and 3y post-baseline PATNO=3113 Progression 2y visit window 3y visit window 3113 Prog. criteria: Change in MS> Non-prog. criteria: Change in MS< Change in UPDRS I-III Score (OFF state) Change in UPDRS Motor Score (OFF state) Change from Baseline in UPDRS Scores by Patient (OFF State) Progression/non-progression population defined at 2y and 3y post-baseline PATNO=3808 Non-progression 2y visit window 3y visit window 3808 Prog. criteria: Change in MS>15 Non-prog. criteria: Change in MS< Change in UPDRS I-III Score (OFF state)

17 How difficult is it? Identify a selective LRRK2 kinase inhibitor Target engagement: Tools to determine target engagement in brain Pharmacological relevance: Disease relevant model for dose finding and time for intervention Patient selection and outcome measures for clinical trials 17

Novel Targets of disease modifying therapy for Parkinson disease. David G. Standaert, MD, PhD John N. Whitaker Professor and Chair of Neurology

Novel Targets of disease modifying therapy for Parkinson disease David G. Standaert, MD, PhD John N. Whitaker Professor and Chair of Neurology Disclosures Dr. Standaert has served as a paid consultant