Investor Overview. January 2019

Transcription

1 Investor Overview January 219

2 Forward-Looking Statement These slides and the accompanying oral presentation contain forward-looking statements and information. The use of words such as may, might, will, should, expect, plan, anticipate, believe, estimate, project, intend, future, potential, or continue, and other similar expressions are intended to identify forward looking statements. For example, all statements we make regarding the initiation, timing, progress and results of our nonclinical and clinical studies and our research and development programs, our ability to advance product candidates into, and successfully complete, clinical studies, and the timing or likelihood of regulatory filings and approvals, our ability to successfully engage with the FDA concerning the clinical hold on a clinical trial of ZGN-161, our ability to successfully demonstrate the efficacy and safety of our product candidates and to differentiate our product candidates from first generation MetAP2 inhibitors, such as beloranib, and our expected cash, cash equivalents and marketable securities at year end and Zafgen s expectations regarding the length of its cash runway are forward looking. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that we expected. These statements are also subject to a number of material risks and uncertainties that are described in our most recent Quarterly Report on Form 1-Q filed with the Securities and Exchange Commission. Any forward-looking statement speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law. 2

3 Investment Highlights A rare disease focused clinical stage biopharmaceutical company with a pipeline of novel therapies that are intended to address unmet need in a variety of metabolic diseases ZGN-1258 for rare metabolic diseases; returning to Prader-Willi syndrome (PWS) first Prader-Willi syndrome is a rare, lethal disease emerging in childhood, with ~2, afflicted worldwide; no current therapeutic options First generation molecule demonstrated clinically important and highly statistically significant efficacy, but experienced safety issues in Phase 3 Second generation ZGN-1258 replicates efficacy of prior PWS molecule in a wide variety of nonclinical models, while demonstrating a differentiated safety profile PATH for PWS, a four year natural history trial in PWS, kicked off in 4Q 218; as of early 1Q 219, 3 of 5 participants are enrolled Next milestone: IND allowance to begin Phase 1, expected 1Q 219 ZGN-161 for type 2 diabetes with concomitant obesity and/or NASH; asset expected to be partnered before start of Phase 3 The diabetes market is evolving towards therapies that deliver significant A1C lowering and patient benefit beyond A1C (weight loss) Initial ZGN-161 Phase 2 proof-of-concept trial at low-to-mid range doses demonstrated significant A1C efficacy and a safety / tolerability profile generally comparable to placebo Add-on second cohort of trial evaluating full target engagement with 1.8 mg dose showed clinically significant A1C lowering and notable weight loss Nonclinical ZGN-161 studies have demonstrated significant NASH model efficacy, and complementary efficacy in combination with a GLP-1 Next milestone: Update on work with FDA to address clinical hold relating to first generation compound safety issues, update expected 2Q 219 September 3, 218 cash position of $128M; provides runway through 22 3

4 Prader-Willi Syndrome Approximately 2, patients worldwide (~1:4,) Most common genetic cause of life-threatening obesity Characterized by unrelenting pathologic hunger (hyperphagia), and a very low basal metabolic rate Hyperphagia dominates thought processes Individuals struggle with concentration, social interaction; impacts ability to attend school, work Overwhelming cravings set up potential lifelong conflict with family members, caregivers Food seeking behaviors can become dangerous Low metabolic rate (~8 calories / day) drives increasing, severe obesity Average life expectancy ~32 years; doctors have no clear therapeutic options 4

5 First Generation Experience in Prader-Willi Syndrome 1 st MetAP2i candidate demonstrated clinically important impact on co-primary endpoints in prior Phase 3 experience 2 nd generation ZGN-1258 appears to replicate efficacy, with a differentiated safety profile 6 4 Body Weight % Change HQ-CT Total Score * -2 Endpoint 1 st MetAP2i ZGN-1258 MetAP2 Enzyme IC 5, nm p = < Weeks Placebo Weeks 1 st MetAP2i p = <.3 DIO Mouse Efficacy (1 Day -.3mpk - % BW loss) ob/ob Mouse Efficacy (.3 mg/kg) DIO Rat Efficacy (1 Day -.3mpk - % BW loss) 15% 17% Robust weight loss, reduced food intake Robust weight loss, reduced food intake 6.5% 6.8% Endothelial Cell Trapping Yes No AE profile observed as generally equal to placebo CV safety issue arose halting progression Dog Thrombosis Model <5x margin >1x margin *HQ-CT Score assesses hyperphagia-related behaviors; developed by Zafgen, donated to Foundation for Prader-Willi Research (FPWR), broadly adopted by FDA and industry 5

6 ZGN-1258 Efficacy Replicates Prior Compound In all tested models of hyperphagia/obesity, ZGN-1258 demonstrates robust efficacy and replicates responses seen with prior PWS compound 3 DIO ob/ob GTG Cumulative Food Intake 25 Cumulative Food Intake 4 Cumulative Food Intake During ZGN-1258 Treatment Hyperphagia Food Intake (g) 2 1 *** *** Food intake (g) * ** Food Intake (g) Vehicle.1 DIO.3 ZGN-1258 (mg/kg) 2 W T + V e hic le V e hic le.3 1. ob/ob ZGN-1258 (mg/kg) 15 W T + V e hic le G TG +.3 mg/kg ZGN-1258 GTG Weight Percent Change (%) Days V ehicle.1 mg/kg ZGN mg/kg ZGN % 4.% *** 9.4% *** Percent change (%) % % % *** % *** overnight fast Days W T + Vehicle.3 mg/kg ZGN-1258 Vehicle 1. mg/kg ZGN-1258 Percent Change (%) ZGN-1258 *** Recovery ** * Days WT + Vehicle GTG-induced obesity +.3 mg/kg ZGN-1258 *** *p<.5, **p<.1, ***p<.1 Abbreviations: DIO = Diet-induced obese mice: Mice become obese from eating a 6% kcal high-fat diet; ob/ob = Mice cannot produce leptin due to a genetic mutation and become profoundly hyperphagic and obese; GTG= Gold-thioglucose induced obese mice: Administration of GTG damages glucose-sensitive neurons in the hypothalamus, a critical brain region for energy balance regulation, leading to hyperphagia and obesity; WT= wild-type 6

7 ZGN-1258 Efficacy Addresses Additional Aspects of PWS People with PWS are extremely stress sensitive and live with high levels of anxiety and obsessive or compulsive behaviors In genetic models (Magel2-null and FMR1 knockout) that share these behavioral features with PWS, ZGN-1258 improved anxiety-driven and compulsive behaviors Open Field Test Nestlet Shredding Marble Burying Center Zone Entries Center Zone Total Distance Magel2-null Fm r1ko Fm r1ko Number of Entries Center Zone Entries (MageL2-null mice) * Distance (cm) Center Zone Distance (MageL2-null mice) % Nestlet shredded 8 * 6 Nestlet 4 shredding 2 (MageL2-null mice) % Nestlet shredded 15 ** 1 Nestlet shredding 5 (FMR1-KO) Number of marbles buried Marble Burying (FMR1-KO) * W T + V e hic le V e hic le.3 mg/kg ZGN-1258 Magel2-null W T + V e hic le V e hic le.3 mg/kg ZGN-1258 V e hic le.3 mg/kg ZGN-1258 Magel2-null V e hic le.3 mg/kg ZGN-1258 Fmr1KO W T + V e hicle V e hicle.3 mg/kg ZGN-1258 Fmr1KO 1 mg/kg S e rtra line Anxiety Anxiety / Compulsive Compulsive *p<.5, **p<.1 Abbreviations: Magel2-null mice a model of PWS: Mice lack the Magel2 gene which is typically inactivated in PWS, and exhibit some of the altered metabolic and behavioral phenotypes seen in PWS, such as increased adiposity in adulthood, reduced motor activity, and increased anxiety in response to novel environments; Fmr1KO = Fmr1 knockout mice a model of Fragile X syndrome: Mice lack the FMR1 gene, which is typically silenced in Fragile X syndrome, and exhibit some of the behavioral and cognitive phenotypes seen with Fragile X syndrome, such as altered anxiety/social behaviors and increased stereotypies 7

8 ZGN-1258 Safety Profile Differentiated Prior compound became trapped in endothelial cells, resulting in continuous inhibition of MetAP2 and tilting the biochemical pathway in endothelial cells towards a more pro-thrombotic state ZGN-1258 is cleared rapidly and does not impact this pathway at physiologically relevant concentrations P21 (% of Control) P-21 Levels PAI-1 Levels D-dimer Levels *** Control Beloranib (nm) P21 ZGN-1258 (nm) PAI-1 (% of Control) Plasminogen Activator PAI-1 Inhibitor ** Control Beloranib (nm) ZGN-1258 (nm) Dog Toxicology Model 1 st generation compound At 1-fold above projected clinical concentrations, D-dimer levels increased significantly and morbidity occurred in all animals ZGN-1258 At 1-fold above projected clinical concentrations, no effect on D- dimer levels At 1-fold above, only mild transient effects observed **p<.1, ***p<.1 PAI-1= plasminogen activator inhibitor 8

9 Natural History Study Collaboration Study being conducted in collaboration with the Foundation for Prader-Willi Research (FPWR) and National Organization for Rare Disorders (NORD) PATH for PWS designed as 4 year / 5 participant non-interventional natural history study Enrollment kicked off at FPWR annual conference in October; 3 enrolled as of early 219 Potential benefits of study for PWS community and Zafgen: Advances the collective community s knowledge of the medical history and medical events in people with PWS Provides context for potential benefits of treatment with ZGN-1258, as well as any adverse events Qualified participants may be referenceable as an extended clinical trial control group for ZGN-1258, potentially increasing study power and efficiency Participants in PATH for PWS will also be eligible to participate in future ZGN clinical trials; may accelerate enrollment/overall study time 9

10 ZGN-1258 Next Steps IND-enabling studies completed IND allowance expected in 1Q 219 to initiate Phase 1 clinical trial Phase 1 start anticipated to be a single ascending dose trial in normal healthy volunteers focusing on PK, safety and tolerability 1

11 Type 2 Diabetes Requires Beyond A1C Approach Large market, multiple co-morbidities Evolving paradigm, high unmet need 415M people worldwide living with type 2 diabetes, and expected to grow to 642M by 24 1 In the US, every five minutes, two people die of diabetesrelated causes and 14 adults are newly diagnosed 2 High incidence of co-morbidities: >75% obese 3 >7% cardiovascular diseases 3 >22-7% NAFLD/NASH 4 >35% renal disease 5 New 218 ADA/EASD guidelines are patient-centric, driven by comorbidities, vs previous algorithms that prioritized generics regardless >5% type 2 diabetes patients with uncontrolled A1C despite multiple approved treatments available and combination therapies prescribed 6 High unmet need remains for sustained glucose control and beyond A1C benefits to address costly co-morbidities 1 Global Data, Type 2 Diabetes, March 218; 2 CDC, November 218; 3 Curr Med Res Opin. 216 Jul; 4 Williams et al. 211 and Bazick et al. 215; 5 Centers for Disease Control and Prevention. National Diabetes Statistics Report, 6 217; Lipska Diabetes Care Volume 4, April 217 Abbreviations: T2D=Type 2 Diabetes; NAFLD=Nonalcoholic Fatty Liver Disease; NASH=Nonalcoholic steatohepatitis; ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes 11

12 ZGN-161 Summary 2 nd generation MetAP2 inhibitor, with preferential distribution to peripheral adipose tissue and the liver Phase 1 SAD and MAD trials demonstrate favorable PK profile, safety and tolerability comparable to placebo at doses up to 4.8 mg Phase 2 proof-of-concept trial conducted in two parts; initial cohort evaluated low-to-mid range doses up to.9 mg for 12 weeks Results presented as late breaker at 218 American Diabetes Association meeting.9 mg dose demonstrated significant A1C lowering efficacy with a safety and tolerability profile generally comparable to placebo An add-on cohort evaluating full target engagement with 1.8 mg dosing was initiated 2Q 218 and completed dosing 4Q 218; top line results follow 12

13 ZGN-161 Proof-of-Concept Trial in Type 2 Diabetes Key Inclusion Criteria A1C 7. to 11.% Body mass index of 27 kg/m 2 Stable diabetes treatment regimen Primary Outcome Measures Glycemic control (change in A1C) Safety and tolerability Secondary Outcome Measures Change in body weight Other measures of glycemic control Biomarkers relevant to type 2 diabetes.5 mg (n=32).3 mg (n=34).9 mg (n=44) 1.8 mg (n=23) Placebo (n=42) A1C, % 8.6 ± ± ± ± ± 1.2 Fasting Plasma Glucose, mg/dl ± ± ± ± ± 49.8 Body Weight, kg 15.6 ± ± ± ± ± 15.2 BMI, kg/m ± ± ± ± ± 5. # of Existing Glucose-Lowering Medications None 3 (9.4) 1 (2.9) 1 (2.3) 1 (4.3) 5 (11.9) 1 12 (37.5) 16 (47.1) 21 (47.7) 8 (34.8) 14 (33.3) 2 11 (34.4) 12 (35.3) 16 (36.4) 8 (34.8) 18 (42.9) 3 6 (18.8) 5 (14.7) 6 (13.6) 6 (26.1) 5 (11.9) 52% female, 77% white and average duration of diabetes of 8 years. Data are mean +/- SD or n (%). 13

14 ZGN-161 A1C Lowering Efficacy.5 Progressive and statistically significant improvement in A1C for.9 mg and 1.8 mg vs placebo A1C continued to decline with no waning of effect for.9 mg and 1.8 mg doses through Week 12 Change in A1C (%) -.5 p=.2 p=.1 p=.3 LS mean difference: 1.1 ±.2% -1. p< Placebo (N=42) Weeks.9 mg (N=44).5 mg (N=32).3 mg (N=34) 1.8 mg (N=23) Data are LS mean ±SE for the ITT population (N=175). MMRM analysis 14

15 ZGN-161 Weight Lowering Efficacy Seen with 1.8 mg Dose 1 Change in Body Weight (kg) -1-2 p=.39 p<.1 Progressive and statistically significant improvement in weight for 1.8 mg vs placebo Weight continued to decline with no waning of effect through Week 12 Weight loss competitive with bestin-class anti-diabetes therapies -3 p<.1 p= Placebo (N=42).9 mg (N=44) Weeks 1.8 mg (N=23) p=.2 Data are LS mean ±SE for the ITT population (N=175). MMRM analysis 15

16 ZGN-161 No Meaningful D-dimer Elevations or Other CV Safety Signals D-dimer (mg/l FEU) Placebo (N=42).5 mg (N=32).3 mg (N=34).9 mg (N=44) 1.8 mg (N=23) 2xULN Clinically relevant ULN No meaningful elevations in mean D-dimer concentrations across the dosing groups compared to baseline or placebo No notable changes in markers of coagulation or other CV safety signals 1.8 mg beloranib resulted in a population increase (approximately double) in D-dimer values in retrospective testing of Week 12 samples. Wk -4 Day 1 Wk 4 Wk 8 Wk 12 Wk -4 Wk 4 Wk 8 Day 1 Wk 12 Wk -4 Wk 4 Wk 8 Day 1 Wk 12 Wk -4 Wk 4 Wk 8 Day 1 Wk 12 Wk -4 D-dimer levels for all patients every 2 weeks through 12 week period Wk 4 Wk 8 Day 1 Wk 12 Data are mean ±SE for the safety population (N=175). Age-adjusted upper limit of normal (ULN=.54 mg/l FEU) indicated by dashed line. 2xULN=1.8 mg/l FEU. FEU=fibrinogen equivalent unit, ULN=upper limit of normal, VTE=venous thromboembolism; D-dimer is a fibrin degradation product that becomes markedly elevated during a VTE Plot excludes aberrant values from 2 timepoints due to blood processing issues (24-27 Week 1=7.14; Week 12=2.24); the plot excludes D-dimer elevations associated with confirmed AEs of: hand fracture (placebo), gout (.3 mg), synovial rupture (1.8 mg). Even with inclusion of these confounded values, the mean values are well below the ULN 16

17 ZGN-161 Highly Tolerable Safety Profile Adverse events primarily mild or moderate; no severe AEs with 1.8 mg Three patients (all.9 mg) reported SAEs (upper abdominal pain, skin ulcer, anaphylactic reaction to antibiotic); none deemed related to study drug Three patients (1.6%) withdrew early due to an adverse event (injection site urticaria, 1.8 mg; upper abdominal pain,.9 mg; sensory disturbance,.5 mg) No CV safety signals observed in trial Most Frequent Adverse Events (Incidence 5% in Total ZGN-161 Group) % of Patients.5 mg N=32.3 mg N=34.9 mg N= mg N=23 Total ZGN-161 N=133 Placebo N=42 Any AE Injection Site Bruising Upper Respiratory Tract Infection Diarrhea Contusion Headache Nasopharyngitis Pain In Extremity Arthralgia Data are the percent of patients. Safety Population (N=175) 17

18 ZGN-161 Next Steps Reviewing comprehensive data sets with diabetes/nash KOLs and potential partners Planning Phase 2 trial to evaluate 26 week A1C and weight lowering efficacy pending clinical hold MetAP2i has an insulin sensitizing effect; other diabetes clinical trials with insulin sensitizers (TZDs and prior MetAP2i) suggest that ZGN-161 s A1C lowering efficacy approximates 4-65% of full efficacy at 12 weeks Fasting plasma glucose lowering of 42 mg/dl (placebo adjusted) with 1.8 mg dosing in this current trial also supports the possibility of additional A1C lowering with longer duration of treatment However, the IND allowance for further clinical development is on hold pending resolution of US FDA-imposed clinical hold; working closely with the FDA on a path forward Expect to present full results of the Phase 2 clinical trial at an upcoming medical meeting in

19 ZGN-1345 Profile ZGN-1345 advanced to development candidate status in 4Q 218 Orally dosed MetAP2i; expected once daily dosing High concentrations in the liver; minimal to no detectable exposure systemically High MetAP2 levels strongly correlated with more severe outcomes in advanced liver disease like hepatocellular carcinoma Positive early data in multiple nonclinical liver disease models with high unmet medical need; further nonclinical trials ongoing 19

20 1H 219 Pipeline Milestones Program Milestones Timing ZGN-1258 for rare metabolic disease (Prader-Willi syndrome) IND allowance Phase 1 initiation 1Q 219 1Q 219 ZGN-161 for type 2 diabetes 1.8 mg cohort top-line data Update on FDA interactions Early 219 2Q 219 $128M cash position as of September 3, 218 Expected operating runway through 22 2

21 Advancing insight-driven MetAP2 therapeutics to transform the lives of patients with complex metabolic disorders