Ironwood Pharmaceuticals, Inc. · NASDAQ:IRWD
Ironwood Pharmaceuticals — Cyclerion Therapeutics — 37th Annual J.P. Morgan Healthcare Conference (January 2019)
50 slides from Ironwood Pharmaceuticals's conference presentation, Jan 8, 2019
Slide 1: Creating breakthrough treatments for patients with serious and orphan diseases
Creating breakthrough treatments for patients with serious and orphan diseases by harnessing the power of sGC
Slide 2: Safe Harbor Statement
Safe Harbor Statement This overview contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, such as statements about the status, structure and timing of our separation from Ironwood; expected timing of clinical data and the filing
Slide 3: High-momentum company launch
5 programs: on track to deliver 4 clinical data readouts in 2019 including 3 Phase 2 studies, and 2 new drug candidates Distinctive pharmacology: differentiated, tissue- targeted compounds tailored for intended diseases Powerful pathway: nitric oxide-sGC pathway is clinically validated with signific
Slide 4: 2019 launch year expectations
2019 launch year expectations 5 Differentiated programs 4 Clinical studies ongoing 3 Phase 2 readouts 2 New tissue-tailored development candidates 1 Great company launch
Slide 5: 4 clinical data readouts in 2019 on differentiated compounds
4 clinical data readouts in 2019 on differentiated compounds Product* Discovery IND Enabling Phase 1 Phase 2 Phase 3 Status and Anticipated Next Milestones Vascular sGC Stimulator - Top line data expected in 2H2019 Olinciguat Sickle Cell Disease (SCD) - Granted Orphan Drug Designation by the US FDA
Slide 6: Tailoring proven, powerful pharmacology for treatment of serious diseases
Tailoring proven, powerful pharmacology for treatment of serious diseases A powerful pathway… …that Cyclerion is working to harness • Nitric oxide (NO) signaling plays a • Growing understanding of NO pathway role in central role in real-time physiologic health and disease regulation of diverse syste
Slide 7: sGC Stimulators Enhance NO-sGC-cGMP Signaling
sGC Stimulators Enhance NO-sGC-cGMP Signaling 7
Slide 8: NO-cGMP signaling regulates multiple aspects of physiology
NO-cGMP signaling regulates multiple aspects of physiology sGC stimulators: differentiated mechanism to modulate NO-cGMP pathway signaling: • Act synergistically with the NO signaling system: same time and same locations in body vs. acting independently of NO signaling • Increase overall pathway sig
Slide 9: sGC stimulators act synergistically with NO
sGC stimulators act synergistically with NO In vitro (HEK293 cells) In vivo (rat liver/retrodialysis) 800 30 Stimulator + NO donor **** 600 20 c G M P (n M ) c G M P (n M ) 400 EC50 ~ 100 nM Stimulator alone 10 *** * 200 EC50 ~ 3 µM 0 0 -1 1 -1 0 -9 -8 -7 -6 -5 -4 PBS NO donor S tim S tim + lo g [s
Slide 10: NO-sGC-cGMP signaling acts through multiple downstream pathways
NO-sGC-cGMP signaling acts through multiple downstream pathways to elicit pharmacological effects 10
Slide 11: Cyclerion is working to harness the power of sGC pharmacology in disease-relevant tissues
Cyclerion is working to harness the power of sGC pharmacology in disease-relevant tissues A pipeline of differentiated molecules Olinciguat Praliciguat IW-6463 Liver-targeted Lung-targeted 11
Slide 12: Each program offers the potential to create differentiated and meaningful clinical value
Significant unmet clinical need Nitric oxide connection Each program offers the potential to create differentiated and A targeted sGC stimulator meaningful clinical value for patients Preclinical evidence Clinical trials designed to enable decisions to halt or advance the program 12
Slide 13: Olinciguat: Significant potential in sickle cell disease (SCD)
OLINCIGUAT Olinciguat: Significant potential in sickle cell disease (SCD) SCD is an orphan Olinciguat is an oral, Potential to treat SCD Preclinically, Phase 2 STRONG SCD disease characterized once-daily sGC by reducing proportion olinciguat treatment study is ongoing to by a low NO state, stimulato
Slide 14: Sickle cell disease: the need
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Sickle cell disease: the need SCD results in severe complications that may include painful vaso-occlusive crises ( VOCs), daily symptoms such as chronic pain, fatigue High morbidity and shortness of breath, as well as and decreased progress
Slide 15: Sickle cell disease: the nitric oxide connection
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Sickle cell disease: the nitric oxide connection Increased hemolysis Low NO bioavailability Reduced cGMP leads to These effects contribute leads to reduced NO results in reduced vasoconstriction, the symptoms and bioavailability and cGMP pr
Slide 16: Sickle cell disease: our solution
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Sickle cell disease: our solution 1 Reduce proportion of sickled RBCs 2 Decrease vascular inflammation 1 2 and cell adhesion XX 3 Improve NO- mediated vasodilation We believe olinciguat, by amplifying NO signaling, has the potential to impr
Slide 17: In preclinical models, olinciguat treatment was associated with positive effects on SCD pathology
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED In preclinical models, olinciguat treatment was associated with positive effects on SCD pathology • Preclinically olinciguat treatment was associated with: - Distribution to both the vasculature as well as key organs - Higher mRNA expressio
Slide 18: Greater normalized expression of the γ-globin subunit of fetal hemoglobin
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Greater normalized expression of the ɣ-globin subunit of fetal hemoglobin in cell culture treated with olinciguat Treatment of K562 cells with vehicle or olinciguat for 7 days in cell culture Increasing fetal hemoglobin is a clinically vali
Slide 19: Lower expression of cellular adhesion molecules with olinciguat in preclinical model
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Lower expression of cellular adhesion molecules associated with olinciguat treatment in preclinical model 1h predose olinciguat followed by treatment with TNFα in normal mice Reducing vascular inflammation via blockade of specific adhesion
Slide 20: Olinciguat is progressing through clinical development
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Olinciguat is progressing through clinical development • Completed Phase 1 studies in healthy subjects - Confirmed target engagement and proof of pharmacology - Dose-proportional pharmacokinetics with profile supportive of once-daily dosing
Slide 21: STRONG SCD: Phase 2 ongoing, topline data expected 2H 2019
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED STRONG SCD: Phase 2 ongoing, topline data expected 2H 2019 Ongoing Phase 2 Study Placebo Olinciguat Olinciguat Olinciguat Low dose Mid dose High dose QD, 12 WEEK TREATMENT PERIOD PATIENTS: ENDPOINTS: • Male and female patients with • Safety
Slide 22: Praliciguat has significant potential in cardio metabolic disease
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Praliciguat has significant potential in cardio metabolic disease DN and HFpEF are Oral, once-daily sGC Well suited for potential Positive effects on Phase 2 studies in HFpEF serious cardiometabolic stimulator with treatment of DN and metab
Slide 23: Diabetic nephropathy: the need
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Diabetic nephropathy: the need In patients with diabetes, nephropathy is a major risk factor for cardiovascular disease, Significant unmet the major driver of excess cardiovascular medical need mortality, and the single strongest predictor
Slide 24: Diabetic nephropathy: the nitric oxide connection
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Diabetic nephropathy: the nitric oxide connection Diabetes is NO signaling plays a associated with Defects in NO central role in renal endothelial signaling genetically physiology dysfunction and linked to diabetic reduced NO nephropathy2 s
Slide 25: Diabetic nephropathy: our solution
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Diabetic nephropathy: our solution We believe praliciguat will • Improve renal blood flow (autoregulation) XX function by preserve kidney • Reduce inflammation and fibrosis restoring and enhancing NO- • Improve insulin sensitivity and lipid
Slide 26: Preclinical and clinical data for praliciguat support potential utility in diabetic nephropathy
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Preclinical and clinical data for praliciguat support potential utility in diabetic nephropathy Praliciguat treatment preclinically was associated with: • Preservation of kidney function in multiple animal models*, including corresponding e
Slide 27: Renal protective effects observed in praliciguat-treated animals
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED In a preclinical model of hypertension, renal protective effects were observed in praliciguat-treated animals Dahl salt-sensitive rat model * p<0.05, *** p<0.001; **** p<0.0001 vs High-salt control 27
Slide 28: Anti-fibrotic effects recapitulated in vitro and separated from hemodynamic effects
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Anti-fibrotic effects recapitulated in vitro and mechanistically separated from hemodynamic effects • Human renal proximal tubule epithelial cells in cell culture *** p<0.001; **** p<0.0001 vs TGFβ-vehicle 28
Slide 29: Exploratory Phase 2 study in T2DM with hypertension showed metabolic improvements
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED In an exploratory Phase 2 study, patients with T2DM with hypertension who received praliciguat on top of standard of care* for two weeks had improvements in multiple metabolic parameters *Patients on standard of care including anti-glycemic
Slide 30: Praliciguat is progressing through clinical development
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Praliciguat is progressing through clinical development • Completed Phase 1 studies in healthy subjects - Confirmed target engagement and proof of pharmacology - Dose-proportional pharmacokinetics with profile supportive of once-daily dosin
Slide 31: DN Phase 2 trial ongoing, topline data expected 2H 2019
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED DN Phase 2 trial ongoing, topline data expected 2H 2019 Ongoing Phase 2 Study Praliciguat Praliciguat Placebo Low dose High dose 12 WEEK TREATMENT PERIOD PATIENTS: ENDPOINTS: • Adult patients with type 2 diabetes and DN • Change in urine al
Slide 32: HFpEF: the need
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED HFpEF: the need Heart failure remains a rising global Large and epidemic with an estimated prevalence of growing ~38M individuals globally Five-year mortality prevalence rates for patients with HFpEF have been reported to range from 55% - 7
Slide 33: HFpEF: the nitric oxide connection
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED HFpEF: the nitric oxide connection Reduced cGMP Associated with Chronic signaling3 and Clinical endothelial microvascular titin precedence dysfunction1,2 inflammation phosphorylation4 Chronic microvascular inflammation and endothelial dysfu
Slide 34: HFpEF: our solution
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED HFpEF: our solution • Improve cardiac blood flow • Improve oxygen delivery and utilization by We believe that praliciguat skeletal muscle will improve symptoms of • Reduce microvascular inflammation and fibrosis HFpEF by enhancing XX NO-sGC
Slide 35: Preclinical data for praliciguat support potential utility in HFpEF
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Preclinical data for praliciguat support potential utility in HFpEF In a preclinical model of HFpEF, praliciguat treatment was associated with: • Preservation of cardiac function • Lower cardiac hypertrophy • Lower levels of biomarkers of i
Slide 36: Lower cardiac hypertrophy and inflammation markers in praliciguat-treated rats
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED In a preclinical model of heart failure, lower cardiac hypertrophy and markers of inflammation in praliciguat-treated rats **p<0.01; ****p<0.0001 vs High-salt Control; LV+S=left ventricular free wall plus ventricular septum 36
Slide 37: Phase 2 study ongoing; topline data expected 2H 2019
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Phase 2 study ongoing; topline data expected 2H 2019 Ongoing Phase 2 Study Placebo Praliciguat High dose 12 WEEK TREATMENT PERIOD PATIENTS: ENDPOINTS: • Adult patients with HFpEF (EF ≥ 40%) • CPET: change in peak VO2 – primary • Male and fe
Slide 38: IW-6463: first and only CNS penetrant sGC stimulator
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED IW-6463: first and only CNS penetrant sGC stimulator for treatment of neurodegenerative diseases Multidimensional IW-6463 is being developed Our translational trial We expect to initiate pharmacology of sGC as an oral sGC stimulator design
Slide 39: IW-6463 has the potential to address four hallmarks of neurodegenerative diseases
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Increase Reduce IW-6463 has the potential to Cerebral Blood Flow Neuro- inflammation address four hallmarks of neurodegenerative diseases Improve Provide Neuronal Neuroprotective Function Effects Addressing these parameters may improve neur
Slide 40: Increased blood flow to brain areas in rats treated with IW-6463
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Increased blood flow to brain areas associated with memory and arousal in rats treated with IW-6463 Cerebral Blood Flow Neuroinflammation Neuroprotection Cognitive Function cortical transition areas thalamus ventral hippocampus Reticular ac
Slide 41: Anti-inflammatory neuroprotective effects in mice treated with IW-6463
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Anti-inflammatory neuroprotective effects in mice treated with IW-6463 Cerebral Blood Flow Neuroinflammation Neuroprotection Cognitive Function IW-6463 NO sGC cGMP GTP PKG pCREB Neuroinflammation - Increased cGMP and pCREB in rat brain 3D m
Slide 42: Neuroprotective effects in mice treated with IW-6463
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Neuroprotective effects in mice treated with IW-6463 Cerebral Blood Flow Neuroinflammation Neuroprotection Cognitive Function - Synaptic spine density in aged mice at same level observed in young mice - Note: data provided in this slide is
Slide 43: Improved cognitive function in rats treated with IW-6463
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Improved cognitive function in rats treated with IW-6463 Cerebral Blood Flow Neuroinflammation Neuroprotection Cognitive Function Thigmotaxis: tendency to stay close to walls when exploring open spaces, which is associated with cognitive dy
Slide 44: Cortical brain activity greater in rats treated with IW-6463
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Cortical brain activity greater in rats treated with IW-6463 - Opportunity for Early Clinical Proof of Pharmacologic Effects – - Pharmacological effects of IW-6463 can be assessed clinically using translational non-invasive methods includin
Slide 45: Expect to initiate first in human studies in Q1 2019
OLINCIGUAT PRALICIGUAT IW-6463 LIVER-TARGETED LUNG-TARGETED Expect to initiate first in human studies in Q1 2019 The IW-6463 Phase 1 trial is designed to provide early proof of pharmacology • Safety, tolerability and pharmacokinetic data on single and multiple ascending doses of IW-6463 will be eval
Slide 46: Liver-targeted sGC stimulator
LIVER-TARGETED Liver-targeted sGC stimulator to maximize the potential to treat serious liver diseases Chronic liver diseases We have designed sGC This provides the We expect to are serious diseases stimulators that opportunity to nominate a associated with specifically target the maximize hepatic d
Slide 47: Lung-targeted sGC stimulator
LUNG-TARGETED Lung-targeted sGC stimulator to maximize the potential to treat serious pulmonary diseases There is a clear role for We have designed This provides the We expect to nominate NO-sGC-cGMP signaling inhaled sGC opportunity to a development in serious pulmonary stimulators that are maximiz
Slide 48: Cyclerion Leadership
Cyclerion Leadership Brian Cali, PhD - Head of IR and Corp Comms • >20 years enterprise leadership—cofounder of Microbia/IRWD • Led preclinical R&D, R&D strategy, in licensing, program leadership and portfolio management Mark Currie, PhD - President • Extensive research in cGMP signaling pathways an
Slide 49: Separation: Cyclerion ready to launch 1H 2019
Separation: Cyclerion ready to launch 1H 2019 • Peter Hecht to be Cyclerion CEO effective upon separation Right leadership, • Experienced leadership team complemented with new skills right time • Expected to have a non-overlapping board with Ironwood • Board (including new Chair) expected to be anno
Slide 50: Sequence of the planned sponsored spin separation
Sequence of the planned sponsored spin separation Form 10 Distribute CYCN Build shares to IRWD Operating and Separation Design sponsor registration trading as statement shareholders and announcement financing investor receive equity independent book filed and companies effective investment from spon
Cyclerion Therapeutics — 37th Annual J.P. Morgan Healthcare Conference (January 2019) on 6ix