Slide 1: Dimerix presentation for 2018 Bioshares conference
For Immediate Release DIMERIX PRESENTATION FOR 2018 BIOSHARES CONFERENCE For personal use only MELBOURNE, Australia, 27th July 2018: Dimerix Limited (ASX: DXB), a clinical stage biotechnology company, is pleased to announce that Chief Medical Officer, Associate Professor David Packham will be presen
Slide 2: About Dimerix Bioscience and the DMX-200 program
About Dimerix Bioscience Pty Ltd Dimerix Limited’s (ASX: DXB) wholly owned subsidiary Dimerix Bioscience Pty Ltd is a clinical-stage pharmaceutical company committed to discovering and developing new therapeutic models identified using its proprietary assay, termed Receptor-Heteromer Investigation T
Slide 3: DMX-200 for Diabetic Kidney Disease
For personal use only DMX-200 for Diabetic Kidney Disease A/Prof David Packham MBBS(Hons), FRCP, FRACP, ARCP, MD Chief Medical Officer, Dimerix Nephrologist Bioshares Summit Queenstown, New Zealand 27 July 2018
Slide 4: Disclaimer
Disclaimer For personal use only Some of the information in this presentation may refer to Dimerix Limited (“Dimerix” or the “Company”) based on information available to it as at the date of this presentation. The information in this presentation is provided in summary form and does not contain all
Slide 5: Dimerix overview
Dimerix overview For personal use only Corporate snapshot Share price history ASX code: DXB Share price (16 July 18): $0.099 Market cap: $15.7m Cash (30 Mar 2018): $7.7m Shares on issue 158.8m Upcoming clinical milestones ü 18 July – Ethics approvals for both ACTION studies q CY18Q3 – Sites open and
Slide 6: Agenda
Agenda For personal use only • Prevalence of Type 2 diabetic kidney disease • Therapeutic options • Mechanisms of chronic kidney disease progression • DMX-200 • Discovery • Development plan • Concluding remarks 4
Slide 7: Diabetic Kidney Disease
Diabetic Kidney Disease For personal use only • There are 1-1.5 million type 2 diabetics in Australia • There are 30-84 million type 2 diabetics in the USA • 40% have or will develop diabetic kidney disease (DKD) • Increasing need for renal replacement therapy (dialysis or kidney transplant) • 25 ye
Slide 8: Increased development of DKD therapeutics
Increased development of DKD therapeutics For personal use only Year of approval for DKD In development (all are now generic) DMX-200 (AT1R & CCR2) Stem cells CCX-140 (CCR2) Sparsentan (AT1R & ETA) BI 685509 (sGC) Finerenone (MR) Dapagliflozin (SGLT2) Losartan (AT1R) BAY1142524 (chymase) TMX-049 (XO
Slide 9: Proteinuria & albuminuria
Proteinuria & albuminuria For personal use only • Correlates with severity and prognosis • Are drivers of progressive renal damage • FDA and EMA: 30% reduction in urinary albuminuria is one mechanism for Accelerated Approval of DKD 7
Slide 10: Mechanisms of DKD progression
Mechanisms of DKD progression For personal use only A. Hyperfiltration A B. Inflammation/Infiltration C. Podocyte damage/loss C B 8
Slide 11: A. Hyperfiltration
A. Hyperfiltration For personal use only • Glomerular hypertension • ACE/ARB blockade highly effective: efferent greater than afferent • Importance of hyperfiltration: IDNT (irbesartan) and REENAL (losartan) studies IDNT primary end point: 24% decrease in composite of a doubling of albuminuria in gr
Slide 12: B. Inflammation, infiltration and fibrosis
B. Inflammation, infiltration and fibrosis For personal use only • Correlates with severity and prognosis of DKD • Drivers of progressive renal damage • Therapeutic attempts to prevent, modify or halt progression • Recent studies in sulodexide, bardoxolone, atrasentan • Activation of chemokine recep
Slide 13: C. Podocyte loss
C. Podocyte loss For personal use only • Specialised cells unable to regenerate • Loss correlates with severity and prognosis • Loss drives progressive renal damage • Express both AT1R and CCR2 receptors 11
Slide 14: DMX-200 acts through GPCRs
DMX-200 acts through GPCRs For personal use only • G-Protein Coupled Receptors are the target of 30-40% of all known drugs • Robert Lefkowitz and Brian Kobilka won the 2012 Nobel Prize for chemistry for studies of G protein–coupled receptors 12
Slide 15: AT1R and CCR2 receptors
AT1R and CCR2 receptors For personal use only • AT1R and CCR2 are GPCRs expressed on podocytes and other kidney cells • Activation promotes kidney damage Receptor AT1R CCR2 Ligand Angiotensin II Monocyte chemoattractant protein-1 Membrane Key downstream signalling Efferent arteriole vasoconstriction
Slide 16: Heteromerisation of AT1R and CCR2
Heteromerisation of AT1R and CCR2 For personal use only • AT1R and CCR2 are GPCRs expressed on podocytes and other kidney cells • AT1R and CCR2 signal as monomers and heteromers • Synergy identified with DXB platform technology Receptor AT1R Heteromer CCR2 Ligand AngII AngII MCP-1 MCP-1 Membrane Syn
Slide 17: Inhibition AT1R & CCR2 heteromers
Inhibition AT1R & CCR2 heteromers For personal use only Block AT1R Block both Block CCR2 Ligand AngII MCP-1 AngII MCP-1 AngII MCP-1 Cell membrane Some signalling ALL Signalling blocked Some signalling continues continues 15
Slide 18: DMX-200 hypothesis
DMX-200 hypothesis For personal use only Simultaneous inhibition of AT1R & CCR2 will have a greater than additive renal benefit compared to inhibition of each receptor alone 16
Slide 19: What is DMX-200?
What is DMX-200? For personal use only Co-administration of 2 drugs to achieve a synergistic renal effect • Irbesartan - angiotensin receptor blocker (ARB) Irbesartan Propagermanium • Small molecule • Global approval as anti-hypertensive, and FDA + (USA) approval for diabetic kidney disease • Propag
Slide 20: 5/6 nephrectomy model
5/6 nephrectomy model For personal use only Surgically remove 5/6th of the rodent kidney • Hyperfiltration • Glomerular hypertension • Interstitial inflammation • Fibrosis • Podocyte loss Pro • Proteinuria • Progressive renal failure 18
Slide 21: Simultaneous blockade of AT1R & CCR2
Simultaneous blockade of AT1R & CCR2 For personal use only Reduced proteinuria Sham Vehicle PPG IRB PPG+ IRB n=20 animals per group, p<0.05, #f p<0.01, Ayoub MA, et al. (2015) PLoS ONE 10(3): e0119803
Slide 22: Simultaneous blockade of AT1R & CCR2
Simultaneous blockade of AT1R & CCR2 For personal use only Decreased macrophage infiltration Preservation of podocyte numbers 200 Macrophage numbers/area 150 100 50 Sham Vehicle PPG IRB PPG+ Sham Vehicle PPG IRB PPG+ IRB IRB n=20 animals per group, p<0.05, #f p<0.01, Ayoub MA, et al. (2015) PLoS ONE
Slide 23: DMX-200 Intellectual property
DMX-200 Intellectual property For personal use only • Broad, class based claims granted in US and Australia (any CCR2 antagonist with any angiotensin receptor blocker) • Current clinical studies defining broader composition protection 21
Slide 24: DMX-200 Study design Phase 2a
DMX-200 Study design Phase 2a For personal use only Primary Endpoints Secondary Endpoints • Incidence and severity of Adverse Events • The proportion of responders, defined as those participants • Clinically significant changes in the safety profile of achieving normalization of proteinuria or a 50%
Slide 25: Phase 2a efficacy summary (N=27)
Phase 2a efficacy summary (N=27) For personal use only Responders 100 30% decrease in 13/24 patients 50 50% decrease in 6/24 patients Δ% PCR from baseline 0 -50 Patient subgroups Diabetic nephropathy IgA nephropathy Other proteinuric disease -100 P1 P2 P3 * P5 P6 P7 P8 * 0 1 2 3 4 5 6 7 8 9 0 1 2 3
Slide 26: ACR mean reduction
24 ACR mean reduction 35.6% n=10 For personal use only Δ% ACR from baseline (SD) 0 * p=0.0019 -50 30 60 90 150 240 240 240 Propagermanium mg mg mg mg mg mg mg dose -100 0 4 8 12 16 20 24 28 Weeks of treatment * Paired, 2-way t-test 24
Slide 27: New DMX-200 ACTION clinical studies
New DMX-200 ACTION clinical studies For personal use only Angiotensin II Type 1 Receptor (AT1R) & Chemokine Receptor 2 (CCR2) Targets for Inflammatory Nephrosis ACTION for DKD 25
Slide 28: Design of DMX-200 ACTION for DKD
Design of DMX-200 ACTION for DKD For personal use only 2-way crossover design allows: • Improved statistical power as each patient is their own control • All patients to receive therapy • Powered to detect a 30% reduction in proteinuria Weeks -2 -1 0 1 6 11 12 18 19 20 25 30 31 35 Visit 1 2 3 4 5 6
Slide 29: DMX-200 well positioned
DMX-200 well positioned For personal use only Hyperfiltration Inflammation DMX-200 (AT1R & CCR2) Podocytes 27