Slide 1

May 2019 Inflammasome Program Exhibit 99.1


Slide 2

Forward-looking Statements This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, prospective products, product approvals, research and development costs, timing and likelihood of success, plans and objectives of management for future operations, and future results of current and anticipated products are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These known risks and uncertainties are described in detail in our filings made with the Securities and Exchange Commission from time to time. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and we undertake no obligation to revise or update this presentation to reflect events or circumstances after the date hereof.


Slide 3

Highlights of Conatus Approach Like inflammasome intervention, caspase 1 inhibition is a small molecule strategy to block the formation of IL-1b Additional benefits include IL-18 inhibition, gasdermin D inhibition, and a decrease in inflammation driven cell death (pyroptosis) vs. IL-1b blocking agents Multiple routes of administration possible (oral, inhaled, topical, ophthalmic, etc.) Conatus has developed a portfolio of novel, potent, orally bioavailable, highly selective inhibitors of caspase 1 Demonstrated functional activity and selectivity in animal models Active in animal models of NLRP3 driven inflammation Potency similar to NLRP3 reference standard (MCC950) Lead compound CTS-2090 selected to advance toward clinical development IND-enabling studies in progress, projecting initial clinical trial 1H2020


Slide 4

IL-1β Blocking Agents: Set the Stage for Next Generation Products Multiple approved biologic agents that block IL-1β Canakinumab (Ilaris ®) monoclonal antibody targeted at IL-1β Anakinra (Kineret ®) interleukin-1 receptor antagonist Rilonacept (Arcalyst ®)  IL-1 Trap Global sales of over $700 million in 2018 Approved rare disease indications include Cryopyrin-Associated Periodic Syndromes, Familial Cold Autoinflammatory Syndrome, Muckle-Wells, Twin Anemia Polycythemia Sequence, Hyper-IgD Syndrome, Familial Mediterranean Fever


Slide 5

IL-1b: Driven by Multiple Inflammasomes Solberger G, et al. Innate Immun. 2014, p115-125.


Slide 6

Disease Areas Implicated in the Inflammasome Pathway Therapeutic areas Disease Conditions Autoinflammatory Cryopyrin-Associated Periodic Syndromes Muckle-Wells Syndrome Schnitzler’s Syndrome Familial Mediterranean Fever Macrophage Activation Syndrome Gastroenterology Crohn's Ulcerative Colitis IBD Rheumatology Osteoarthritis Rheumatoid Arthritis Psoriatic Arthritis Gout Oncology NSCLC Breast Cancer Melanoma Renal cell Pancreatic Hepatology NASH Autoimmune Hepatitis PSC (POLT) a-ATTD Alcoholic Hep Respiratory Steroid Resistant Asthma COPD IPF Acute Lung Injury Renal Polycystic Kidney Disease Lupus Nephritis Acute Kidney Injury Dermatology Behcet Disease Inflammatory Acne Plaque Psoriasis Dermatitis Ophthalmology Retinal Detachment Macular Degeneration Retinitis Pigmentosa CNS/neuroinflammatory Multiple Sclerosis Parkinson’s Disease Multiple System Atrophy Epilepsy Huntington’s Disease Cardiovascular/Metabolic Atherosclerosis Myocardial Infarction Type 2 Diabetes Audiology Age-related Hearing Loss Drug-induced Hearing Loss


Slide 7

IL-1b Blocking Agents: Development Pathway Defined* Wide scope of clinical indications and therapeutic validation All agents given by injection (not orally active) Most recent success – Novartis, Ilaris® 2017: Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) Confidential Kineret® Ilaris® Arcalyst® 2015 2018 anakinra in pancreatic cancer trial (Ph1) canakinumab + docetaxel canakinumab + pembrolizumab in NSCLC trials (Ph3) Canakinumab approved for TRAPS, HIDS, MKD, FMF anakinra in acute MI trial (Ph3) Gevokizumab** in colorectal, gastroesophageal, renal cell cancer trial (Ph1) Kineret in hemorrhagic stroke trial (Ph2) *Modified from Dinarello and van der Meer, Semin. Immunol, 2014. **NVS acquired gevokizumab from Xoma Aug 2017.


Slide 8

The Future of IL-1β Blocking May Be in Cancer


Slide 9

Inflammasome Companies: Investor and Pharma Interest IFM TRE raised a $31mm Series A in 2018 from Atlas, Abingworth, and BMS. Acquisition by Novartis announced April 2019 for $310M upfront (Phase 1) and up to $1.6B total. Jecure Therapeutics raised a $30mm Series A from Versant in 2017. Acquired by Genentech in 2018 (pre-clinical). Inflazome closed a $17mm Series A in 2016 from Novartis Venture Fund and others. Recently closed a $46mm Series B to move compounds to POC. Investors included Forbion, Longitude, Novartis Venture Fund, and Fountain Healthcare Partners. NodThera closed a $40mm Series A in 2018 from Sofinnova Partners, 5am Ventures, F-Prime, and Epidarex. Advanced lead candidate into IND testing in April 2019 targeting NLRP3.


Slide 10

(Novartis) (Amgen) (Regeneron) Caspase 1 Inhibitors Caspase 1 Inhibitors Target Inflammasome Pathway at Optimal Intervention Point We believe a caspase 1 selective small molecule inhibitor can be a safe and efficacious agent for intervention in the inflammasome pathway Modified from Mangan M et al. Nature Reviews Drug Discovery, 2018 p. 588-606.


Slide 11

Caspase 1 Inhibition Improves Survival Better than Blocking IL-1β, IL-18 or Both Constitutively active NLRP3 (FCAS model) results in chronic activation of caspase 1 Leads to production of IL-1β and IL-18 Leads to pyroptotic cell death via gasdermin D cleavage Caspase 1 KO showed improved survival over IL-1β KO, IL-18 KO or both Mimics a caspase 1 inhibitor Brydges SD, Broderick L, McGeough MD, Pena CA, Mueller JL, Hoffman HM. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J Clin Invest 2013;123:4695-4705.


Slide 12

Targeting IL-1b and Inflammation via Caspase 1 Inhibition IL-1b is a validated inflammatory target – high interest in the pathway NLRP3 Caspase 1 IL-1β Pro caspase 1 Pro IL-1β Inflammation NLRP3 companies Biologic products (Novartis) (Amgen) (Regeneron) “Detector” senses stress signal “Master” inflammatory molecule “Effector” critical for IL-1b


Slide 13

CTS-2090 Bridging the gap between “Detector” and “Master”


Slide 14

Conatus’ Caspase 1 Inhibitor Portfolio Designed highly selective caspase 1 inhibitors Incorporated novel chemistry to remove activity against apoptotic caspases Maintained sub-nanomolar activity against caspase 1 Inhibits downstream IL-1b (a clinically validated target) Demonstrated functional activity and selectivity in cellular models High potency in cell models of NLRP3 driven inflammation Not active in cellular models of apoptosis Demonstration of functional activity and selectivity in animal models Active in animal models of NLRP3 driven inflammation Potency similar to NLRP3 reference standard (MCC950) Not active in a standard animal model of apoptosis


Slide 15

Conatus’ Lead Caspase 1 Inhibitor: CTS-2090 Potency Sub-nanomolar IC50 against human caspase 1 Sub-micromolar IC50 in THP 1 cells Selectivity Broad panel of receptors and enzymes: >100,000 fold selectivity over caspase 1 No anti-apoptotic activity in cells at 10mM: enzyme selectivity reflected in cell-based functional assay No anti-apoptotic activity in vivo at 10mg/kg: cellular functional selectivity translates in vivo Oral Bioavailability Good oral bioavailability: ~10-fold higher than benchmark pan-caspase inhibitor in rodents1 Tissue Distribution Highest in the colon, AUC liver ~ AUC plasma. In vivo activity Pathway inhibition in multiple mouse models of inflammasome disease Potency similar to standard reference NLRP3 inhibitor, MCC950 1Hoglen NC. Discovery of a First in Class Apoptotic Caspase Inhibitor Emricasan PF 03491390 IDN 6556. CRC Press 2009:211-224.


Slide 16

CTS-2090: Enzymatic Potency and Selectivity CTS-2090 is a potent, selective and irreversible inhibitor of caspase 1 Additional analogs have similar potency Target: IDN-7314+ CTS-2090 Caspase 1 <5.08E-11 5.60E-11 Caspase 3 1.60E-09 *  Caspase 6 2.14E-08  * Caspase 7 4.63E-10  * CTS-2090: IC50 values against human caspases Dose response against human caspase 1: CTS-2090 and analogs + Reference pan-caspase inhibitor * No measurable inhibition at 1mM


Slide 17

CTS-2090: Potency and Selectivity Validated in Cell-based Functional Assays CTS-2090 is a potent inhibitor of LPS-stimulated NLRP3 driven IL-1b production in THP 1 cells IC50 value similar to that of the reference pan-caspase inhibitor, IDN-7314 CTS-2090 does not protect Jurkat cells from a-Fas – induced apoptosis (0% protection at 10mM) Pan-caspase inhibitor IDN-7314 is protective with IC50 ~50nM (greater than 200-fold window of selectivity) Cellular profile confirms mechanistic potency and functional selectivity of CTS-2090 CTS-2090: IC50 ~ 350nM in THP 1 cell assay IDN-7314: IC50 ~ 240nM in THP 1 cell assay CTS-2090 is inactive at 10mM in Jurkat cell assay IDN-7314: IC50 ~ 50nM in Jurkat cell assay


Slide 18

CTS-2090: Not Active in an Animal Model of Apoptosis In vivo activity is consistent with cellular and enzymatic selectivity profiles CTS-2090 does not protect against apoptosis induced by aFas in mice IDN-7314 is completely protective against aFas induced apoptosis in mice CTS-2090 (10 mg/Kg) and IDN-7314 (3 mg/Kg) were administered orally immediately prior to aFas Blood was collected 4.75h post-aFas and analyzed for levels of ALT (clinical marker of liver damage)


Slide 19

CTS-2090: Reduces IL-1b and IL-18 in an NLRP3 Driven Inflammasome Model CTS-2090 reduces IL-1b and IL-18 similar to MCC950 in an NLRP3 activation model of peritonitis CTS-2090 and MCC950 were administered i.p. 1 hour post-LPS injection At 2h post-LPS, ATP was administered and 30 min. later peritoneal lavage fluid was collected and analyzed for IL-1b and IL-18 (**** = p < 0.0001)


Slide 20

CTS-2090: Reduces IL-1b in the MSU Crystal-Induced Gout Model CTS-2090 (10mg/Kg) reduced IL-1b similar to MCC950 (40mg/Kg) CTS-2090 and MCC950 were administered i.p. 30 min. prior to MSU Peritoneal lavage fluid was collected 6h post-MSU injection and analyzed for IL-1b * * Percent reduction *


Slide 21

Intestine Liver tissue CTS-2090: Tissue Distribution and Metabolic Stability Good oral bioavailability: 45% in rodent Higher tissue distribution of parent molecule in colon than plasma or liver ~1:1 distribution plasma / liver Excellent metabolic stability in rodent tissue (liver and intestine)


Slide 22

CTS-2090: Reduces Disease Severity in the Rat TNBS Colitis Model CTS-2090 reduces TNBS-induced weight loss as effectively as prednisolone at day 7 Oral administration of CTS-2090 or Prednisolone initiated 1 day post-TNBS induced colitis and dosed for 6 days. Animal weights monitored daily


Slide 23

Autoinflammatory Diseases as Initial Clinical Target for CTS-2090 Single-gene mutations that activate inflammasomes and result in IL-1β production Spectrum of diseases with variable organ system involvement, severity and age of onset Cryopyrin-associated periodic syndromes (CAPS) Familial cold urticaria syndrome or familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome (MWS) Neonatal-onset multisystemic inflammatory disease (NOMID)/chronic infantile neurological cutaneous articular syndrome (CINCA) Familial Mediterranean Fever (FMF) Hyper-IgD syndrome TRAPS (TNF receptor-associated periodic syndrome) Canakinumab, rilonacept and anakinra (anti-IL-1β therapies) proven to be highly efficacious but are injectable, expensive and have differing durations of action


Slide 24

Overview of CTS-2090 Development Plan Phase 1, part A Single-dose PK Phase 1, part B Multiple-dose PK Phase 2a Multiple-dose/endotoxin challenge study in normal volunteers Phase 2 PoC Autoinflammatory Diseases Other Potential Indications IBD/Crohn’s Gout flares Oncology PK, Safety, Tolerability Dose-finding Proof of Concept


Slide 25

Intellectual Property Two new composition of matter provisional patent applications filed Applications describe two broad and distinct non-overlapping chemical series of inhibitors Additional novel chemical classes have been identified. New provisional applications planned.


Slide 26

Highlights of Conatus Approach Like inflammasome intervention, caspase 1 inhibition is a small molecule strategy to block the formation of IL-1b Additional benefits include IL-18 inhibition, gasdermin D inhibition, and a decrease in inflammation driven cell death (pyroptosis) vs. IL-1b blocking agents Multiple routes of administration possible (oral, inhaled, topical, ophthalmic, etc.) Conatus has developed a portfolio of novel, potent, orally bioavailable, highly selective inhibitors of caspase 1 Demonstrated functional activity and selectivity in animal models Active in animal models of NLRP3 driven inflammation Potency similar to NLRP3 reference standard (MCC950) Lead compound CTS-2090 selected to advance toward clinical development IND-enabling studies in progress, projecting initial clinical trial 1H2020


Slide 27