microrna drug development - rna based …...confidential pg. 1 restoring biological harmony for...
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Pg. 1Confidential
Restoring Biological Harmony for Patients with Debilitating DiseaseRestoring Biological Harmony for Patients with Debilitating Disease
RNA Based Therapeutics as a Modality for the Effective Treatment of Multiple Fibrotic ConditionsCorrie Gallant-Behm, PhD, MQARSAnti-Fibrotic Drug Development Summit, November 14th, 2017, Boston, MA
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microRNA Therapeutics Regulate Systems Biology to Modify Disease
microRNA-targeted therapy is focused on disease modification by restoring homeostasis to dysregulated processes
microRNAs regulate complex biological systems
microRNA-targeted therapies are intrinsically focused on disease-relevant pathways
microRNA therapeutics particularly suited for complex, multigenic disorders
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miR-29 Pathways and Systems Control
Growth factors
Collagen transcription/translation
Post-translational modification& triple helix formation
N- and C-terminal cleavage& secretion
Fibril cross-linking
Mature collagen fibrils
miR-29
Inflammation
TGF-β + Diseased ECM
TGF-β2, TGF-β3, EGF, IGF2, IGFBP5, PDGFA, PDGFC
COL1A1, 1A2, 3A1, 5A1, 5A2, 5A3, 6A4, 6A5, 6A6, 8A1, 8A2, 9A1, 11A1, 12A1, 14A1, 22A1, 28A1
HSP47, P4HA2, P4HA3, PLOD2
PCOLCE2
LOXL2
in vivo Validated Targets
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miR-29 Pathways and Systems Control
MRG-201(promiR-29)
Growth factors
Collagen transcription/translation
Post-translational modification& triple helix formation
N- and C-terminal cleavage& secretion
Fibril cross-linking
Mature collagen fibrils
TGF-β2, TGF-β3, EGF, IGF2, IGFBP5, PDGFA, PDGFC
COL1A1, 1A2, 3A1, 5A1, 5A2, 5A3, 6A4, 6A5, 6A6, 8A1, 8A2, 9A1, 11A1, 12A1, 14A1, 22A1, 28A1
HSP47, P4HA2, P4HA3, PLOD2
PCOLCE2
LOXL2
in vivo Validated Targets
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A miR-29 Positive Feedback Loop in Fibrosis
Homeostasis
Matrix
TGFβ, PDGF EGFIGF
miR-29
Injury
Scar Formation
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Therapeutic Hypothesis
Homeostasis
Matrix
TGFβ, PDGF EGFIGF
promiR-29
MRG-201 restores homeostasis by modulating the positive feedback loops that maintain the fibrotic phenotype
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Fibrotic Diseases in Which Reduced miR-29 Has Been Implicated
Keloid scar.
Hypertrophic scar.
Scleroderma.
Cardiac fibrosis.
Pulmonary fibrosis – IPF, CTD-associated.
Liver fibrosis – cirrhosis, NASH, viral.
Kidney fibrosis – diabetic nephropathy, IgA.
Retinal fibrosis.
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Downregulation of miR-29 and Overexpression of miR-29 Target Genes in Keloids and Skin Scars
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miR-29 as a Therapeutic in Cutaneous Fibrosis
Preclinical models mPoC Human VolunteerWound Repair
Safety, PK,Target Engagement (PD)
PlaceboDrug Cutaneous Scleroderma
Keloids
Hypertrophic Scars
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Clinical Trial MRG201-30-001Part A: Establish Kinetics of PD Gene Expression
Incision
Day 1 Day 9 Day 16
Biopsy Biopsy RNA
miR-29qPCR
Nanostring
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miR-29 Expression Decreases and miR-29 Direct Target Expression Increases Following Incision
miR-29 QuantityGenes significantly regulated in
incised vs. intact skin (BH p-value <0.01)
Unincised Day 9Incision
Day 16Incision
0
2000
4000
6000
8000
10000m
iR-2
9 Co
py N
umbe
r Per
Cel
lns
0.002
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Parts B/C/D: Safety, Tolerability and PK in Intact Skin and Skin Incisions, PD target engagement Normal healthy volunteers Single and multiple ascending dose (N=3/cohort) 0.5-14 mg MRG-201 injected intradermally
Part B: Intact skin Safety/tolerability only, no biopsies
Part C: Incised skin, single administration Biopsy 24h after treatment for PD
Part D: Incised skin, multiple administration (6 doses over 2 weeks) Biopsy 24h after final administration for PD
RESULTS Dosing and follow-up complete All doses well tolerated up to the maximally deliverable dose No significant injection site reactions Low systemic exposure of full length MRG-201 for all subjects with many samples below limit of quantitation Treated skin biopsy biodistribution assessments (dual probe hybridization assay) showed concentrations ranging from 12 to 200 μg/g
tissue Pharmacodynamic biomarker data demonstrate target engagement with single and multiple administration of MRG-201
Line or Incision
Line orIncision
PlaceboDrug
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MRG-201 Mechanistic Proof-of-Concept in Human Incised SkinSingle Ascending Dose Cohorts C1-C3
Evidence of PD activity (mPoC) after single administration of MRG-201
Validation of preclinical PD biomarkers in human incised skin
SINGLE DOSE
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MRG-201 Treatment Significantly Blunts Fibroplasia in Human Incised SkinMultiple Ascending Dose Cohorts D1-D3
Dep
th/W
idth
(mm
) or A
rea
(mm
2 )
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MRG-201 Target Engagement Corresponds to Impact on FibroplasiaMultiple Ascending Dose Cohorts D1-D3
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miR-29 as a Therapeutic in Cutaneous Fibrosis
Preclinical models mPoC Human VolunteerWound Repair
Safety, PK,Target Engagement (PD)
PlaceboDrug Cutaneous Scleroderma
Keloids
Hypertrophic Scars
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MRG-201 Pharmacodyamic Biomarkers Translate to Multiple Fibrotic Indications
MRG-201 antimiR-29
Mouse skinvs. vehicle
Day 9 Day 16
Human skin incisionvs. unwounded
SSc skin SSc lung IPF lung
Human disease tissuevs. normal tissue
TGFB2Nedd4lPrickle1Faim2COL5A3Gimap7Cacna1gColec11ELNMfap2COL5A2COL1A1COL3A1COL11A1TGFB3Fstl1COL1A2Cytl1MMP2Sdc4Snx27Itga3NumbLbr
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MRG-201 Mimic Represses Collagen Expression in Human IPF Fibroblasts and Epithelial cells
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Day 4
125mpki.v.
Systemically Delivered MRG-201 Accumulates in the Lung
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Systemic Delivery of MRG-201 Blocks Bleomycin-induced Pulmonary Fibrosis
0 day
Bleo Takedown
10
miR-29 mimic (MRG-201)/control
3 14
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Aerosolized MRG-201 via Scireq Attenuates Fibrosis Induced by Bleomycin
Control
Saline
Hydr
oxyp
rolin
eµg
/rig
ht lu
ng
MRG-201 Saline
Bleomycin
0
50
100
150
200
250
ControlMRG-201 Saline
Performed at Yale w/ Naftali Kaminski
*
**
*p<0.05
0 day
Bleo Takedown
10
miR-29 mimic (MRG-201)/control
18
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Inhaled Pulmonary Delivery Assessed with Lovelace Respiratory Research Institute
Log2
(Fol
d Ch
ange
)
Col1a1Col1a2Col3a1ElnTgfb3Mfap2Igf1
Col
1a1
Col
1a2
Col
3a1
Eln
Tgfb
3M
fap2 Igf1
Saline/Saline Bleo/Saline0
2
4
6
Lung day 7
Col1a1Col1a2Col3a1ElnTgfb3Mfap2Igf1
0 day
Bleo Takedown
7
miR-29 mimic (MRG-201)/control
3
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Conclusions
MRG-201 represses expression of genes associated with extracellular matrix production
MRG-201 PD biomarker genes are conserved across species, tissues
Endogenous miR-29 and MRG-201 PD biomarker genes are inversely expressed in cutaneous incisions in normal healthy volunteers, indicating a role for miR-29 in fibrosis development/ progression
MRG-201 regulates PD biomarkers and reduces fibroplasia in skin incisions, demonstrating mechanistic proof-of-concept, and highlighting its therapeutic potential in reducing cutaneous fibrosis such as keloids, hypertrophic scars, cutaneous scleroderma
MRG-201 regulates PD biomarkers in multiple relevant lung cell types and in vivo in multiple IPF models following systemic and inhaled delivery, indicating therapeutic potential in additional fibrotic conditions such as IPF, SSC-ILD, RA-ILD
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Acknowledgements
miRagen: Aimee Jackson Rusty Montgomery Linda Pestano Christina Dalby Joe Piper Josh Lynch Paul Latimer Christianna Stack Kathryn Robinson
Yale: Guoying Yu Naftali Kaminski
Grants: NK and GY:
NIH Y01HL108642 NIH R01HL095397
NIH CADET II 1UH2HL123886-01
Contact: [email protected]