Zealand Pharma A/s · OMXCOP:ZEAL
Zealand Pharma A/s — Investor Day (December 2023)
68 slides from Zealand Pharma A/s's investor day presentation, Dec 5, 2023
Slide 1: Shaping the future management of obesity
Shaping the future management of obesity Zealand Pharma Obesity R&D Event December 5th, 2023
Slide 2: Forward-looking statements
Forward-looking statements These presentation slides (including any accompanying oral presentation, question and answer session and any other document or materials distributed at or in connection with this presentation (the “Presentation”), are provided on a confidential basis, are personal to the r
Slide 3: Agenda
Presenter(s) Time 1 Welcome and introduction to speakers Anna Krassowska 5 min 2 The obesity pandemic Adam Steensberg 15 min Targeting obesity and low-grade inflammation with GLP-1/GLP-2 Daniel Drucker 40 min 3 Agenda receptor agonists David Kendall including Q&A – dapiglutide 4 Break 20 min Decembe
Slide 4: Today’s Zealand Pharma speakers
Today’s Zealand Pharma speakers Adam Steensberg David Kendall President and Chief Medical Officer and Chief Executive Officer Head of Research & Development 4
Slide 5: Today’s external speakers
Today’s external speakers Dr. Daniel Drucker Dr. Louis Aronne Dr. Carel Le Roux Professor of Medicine Professor of Clinical Professor of Experimental at the University of Toronto Medicine at Weill Pathology at University Cornell Medicine College Dublin 5
Slide 6: Addressing one of the biggest health crises of our time
By embracing this historic opportunity, and rising to the challenge together, we can address one of the biggest health crises of our time.
Slide 7: Our mission
Our mission We are committed to changing lives with next generation peptide therapeutics.
Slide 8: Our ambition
Our ambition We strive to be the world’s best peptide drug discovery and development company.
Slide 9: Shift from maximizing weight loss towards quality of weight loss
We believe in a shift from maximizing weight loss towards quality of weight loss and effects on comorbidities… Segment characteristics and drivers 5% Intensive lifestyle therapy Payer-reimbursed segment (prescriber-driven) First-generation weight-loss Demand driven by health outcomes data 10% medica
Slide 10: Future weight-loss medications will be determined by differentiation on multiple fronts
…and that success of future weight-loss medications will be determined by differentiation on multiple fronts Examples of differentiation factors GLP-1 mono GLP-1 backbone GLP-1/GIP Effects on obesity-related comorbidities GLP-1/GCGa Improved tolerability by addressing GI side effects GLP-1/GIP/GCG G
Slide 11: Our research and development pipeline
Our research and development pipeline addresses unmet medical needs across several therapeutic areas Product candidatea Pre-clinical Phase 1 Phase 2 Phase 3 Registration , diseases Dasiglucagon: SC continuous infusion Congenital hyperinsulinism Rare Glepaglutide (GLP-2 analog) Short bowel syndrome S
Slide 12: Targeting obesity and low-grade inflammation with GLP-1/GLP-2 receptor agonists
Targeting obesity and low-grade inflammation with GLP-1/GLP-2 receptor agonists Dapiglutide December 5th, 2023
Slide 13: The discovery and development of glucagon-like peptides
GLP-1/GLP-2 Daniel Drucker The discovery and development of glucagon-like peptides GLP-1 Isolation of First First First First First positive First First positive stimulates exendin-4 twice-daily once-daily once-weekly once-daily CVOT for once-weekly CVOT for insulin GLP-1RA GLP-1RA GLP-1RA GLP-1RA G
Slide 14: GLP-1 reduces appetite, delays gastric emptying, and regulates glycemic control
GLP-1/GLP-2 Daniel Drucker GLP-1 reduces appetite, delays gastric emptying, and regulates glycemic control Appetite Hepatic steatosis Insulin secretion Gastric emptying Food intake Lipid content GI motility Source: Figure adapted from Wang et al. Front Endocrinol (Lausanne) 2023;14:1085799, used und
Slide 15: GLP-2 enhances intestinal repair and potentially benefits other organs
GLP-1/GLP-2 Daniel Drucker GLP-2 enhances intestinal repair and potentially has beneficial effects on other organs as well Inflammation1 Epithelium apoptosis1 GI motility1 Gastric acid secretion1 Inflammation2 Inflammation1 Glucagon Gut permeability1 secretion1 Crypt cell proliferation1 GI motility1
Slide 16: Obesity increases low-grade inflammation driving comorbidities
GLP-1/GLP-2 Daniel Drucker People with obesity have increased low-grade inflammation, which drives several related comorbidities Excess fat storage can trigger low-grade systemic Obesity-related low-grade inflammation through reduced intestinal barrier integrity1 inflammation can result in: Obese ad
Slide 17: GLP-1 and GLP-2 reduce inflammation
GLP-1/GLP-2 Daniel Drucker GLP-1 and GLP-2 reduce inflammation • Bacterial proteins • Indole Ischemic injury GLP-1 • Bile acids • LPS Gut barrier dysfunction • Endotoxins • Short- & long-chain fatty acids • Ethanolamides • TLR ligands • Hydrogen sulfide GLP-23 Gut Gut lumen microbes Intestinal mucos
Slide 18: GLP-2RA reduced intestinal permeability and inflammation in obese mice
GLP-1/GLP-2 Daniel Drucker GLP-2RA reduced intestinal permeability and inflammation in obese mice Plasma LPSa and inflammatory tone (IL-1α, IL-10, and MIP-1α) 10 70 45 125 60 40 8 100 Plasma MIP-1α 35 Plasma IL-1α Plasma IL-10 Plasma LPS 50 * 30 (EU/mL) (pg/mL) (pg/mL) (pg/mL) 6 * 40 75 25 * 30 20 4
Slide 19: Contributory mechanisms for GLP-1/GLP-2 and effects on CV outcomes
GLP-1/GLP-2 Daniel Drucker Contributory mechanisms for GLP-1/GLP-2 and effects on CV outcomes in people with T2DM and/or obesity GLP-1 GLP-2 Blood pressure1 Systemic and hepatic inflammation4 Postprandial lipemia2 Blood flow to the GI tract5 Postprandial glucose2 Intestinal barrier function5 Body we
Slide 20: GLP-2 action in the liver
GLP-1/GLP-2 Daniel Drucker GLP-2 action in the liver Stellate cell activation1,2 Intestinal barrier function3 Inflammation1,2 Increased barrier function helps to restrict gut microbiota and inflammatory byproducts, which has a positive indirect effect on the liver4 Sources: 1. Fuchs et al. JCI Insig
Slide 21: GLP-1R/GLP-2R dual agonists may reduce liver steatosis, inflammation, and fibrosis
GLP-1/GLP-2 Daniel Drucker GLP-1R/GLP-2R dual agonists may reduce liver steatosis, inflammation, and fibrosis GLP-1/GLP-2 reduces hepatic GLP-2 reduces hepatic inflammation lipids in NASH mouse model1 and fibrosis in Mdr2-/- mice2 Mdr2-/- Mdr2-/- GLP-2 Hepatic triglycerides 150 H&E Mean (SEM) (mg/g
Slide 22: GLP-2 analog has shown neuroprotective effects in high-fat diet-fed mice
GLP-1/GLP-2 Daniel Drucker GLP-2 analog has shown neuroprotective effects in high-fat diet-fed mice Expression of pro-inflammatory mediators in the brain Expression of markers of oxidative stress 2 100 3 200 STD STD Mean (SEM) relative fluorescent intensity (%) Vehicle Vehicle Mean (SEM) interleukin
Slide 23: GLP-1R/GLP-2R dual agonist reduces body weight and improves body composition in DIO mice
GLP-1/GLP-2 Daniel Drucker GLP-1R/GLP-2R dual agonist reduces body weight and improves body composition in DIO mice Change in body weight Change in fat and lean mass Fat mass loss Lean mass loss 5 0 Mean (SEM) change in body weight (%) 0 -10 -8.4% -5 Control -15.2% -20 HFD vehicle Change (%) -10 GLP
Slide 24: Strong scientific rationale for GLP-1 and GLP-2 receptor agonists
GLP-1/GLP-2 Daniel Drucker Strong scientific rationale for GLP-1 and GLP-2 receptor agonists to reduce weight and low-grade inflammation Obesity is associated with low-grade inflammation1 Established that GLP-1 and GLP-2 receptor agonists can help reduce weight and low-grade inflammation2,3 Data sup
Slide 25: Dapiglutide is a potential first-in-class GLP-1R/GLP-2R dual agonist
Dapiglutide David Kendall Dapiglutide is a potential first-in-class GLP-1R/GLP-2R dual agonist • Derived from a GLP-2 peptide backbone with amino acid substitutions to ‘dial in’ GLP-1R activity Design • Designed with higher potency towards the GLP-1R while retaining activity on the GLP-2R1 • Long-ac
Slide 26: Dapiglutide showed dose-dependent mean weight loss of up to 4.3% over 4 weeks
Dapiglutide David Kendall Dapiglutide showed dose-dependent mean weight loss of up to 4.3% over 4 weeks in healthy patients Phase 1 multiple ascending dose trial (n=40) Placebo Dapiglutide Dapiglutide Dapiglutide Dapiglutide (n=12) 1.0 mg (n=7) 2.25 mg (n=7) 3.5 mg (n=7) 3.5/6.0 mg (n=7) 2 Change in
Slide 27: In H1 2024, results expected from the investigator-led DREAM trial
Dapiglutide David Kendall In H1 2024, results for dapiglutide are expected from the investigator-led DREAM trial DREAM is evaluating the effects of dapiglutide on body weight, gut permeability, and inflammation1 N=54, men and women aged 18–75 years Population BMI ≥30 kg/m2 Duration 12 weeks Dose Sim
Slide 28: In H2 2024, results expected from the 13-week Phase 1b dose-titration trial
Dapiglutide David Kendall In H2 2024, results for dapiglutide are expected from the 13-week Phase 1b dose-titration trial The Phase 1b trial is evaluating higher doses of dapiglutide than the previous 4-week MAD trial and DREAM N=54, men and women aged 18–64 years Population BMI 27.0–39.9 kg/m2 Dura
Slide 29: Dapiglutide targeting obesity and low-grade inflammation
Dapiglutide David Kendall Dapiglutide is a potential first-in-class GLP-1R/GLP-2R dual agonist targeting obesity and low-grade inflammation Weight loss – pursuing ≥20% weight loss MoA – potential first-in-class GLP-1R/GLP-2R dual agonist Safety and tolerability – similar to other GLP-1RA-based weigh
Slide 30: Questions?
Questions? ZEALS&
Slide 31: Break
Break This meeting recommences in 20 minutes at 2:50 pm
Slide 32: Amylin: a next-generation weight-loss medication, an alternative to GLP-1 receptor agonists
Amylin: a next-generation weight-loss medication, representing an alternative to GLP-1 receptor agonists Petrelintide December 5th, 2023
Slide 33: GLP-1RA-based medications are effective but associated with tolerability issues
Amylin Louis Aronne GLP-1RA-based medications are effective at reducing weight but also associated with tolerability issues GLP-1RA-based medications are associated with GI side effects, including nausea and vomiting1 GLP-1RA-based medications Emerging modalities • Originally developed for T2DM but
Slide 34: Native amylin is a non-incretin peptide that increases satiety
Amylin Louis Aronne Native amylin is a non-incretin peptide that increases satiety in contrast to GLP-1, which reduces appetite Proposed physiological effects of amylin receptor activation1 Pancreas (indirect)a CNS Insulin secretion Leptin sensitivity2 Glucagon Satiety Mechanism of action secretion
Slide 35: Pramlintide showed weight-loss potential in people with obesity
Amylin Louis Aronne The short-acting amylin analog, pramlintide, showed weight-loss potential in people with obesity Phase 2b trial with pramlintide in people with obesity Double-blind study Single-blind extension ITT-LOCF 1 Placebo (n=36) 0 -1 Pramlintide 120 µg TID (n=38) -2 in body weight (kg) Me
Slide 36: Cagrilintide demonstrates weight-loss potential of long-acting amylin analogs
Amylin Louis Aronne Clinical data with cagrilintide demonstrate the weight-loss potential of long-acting amylin analogs Phase 2 trial of cagrilintide in people with obesity or overweighta without T2DM1 0 Placebo (n=101) Liraglutide 3.0 mg (n=99) -2 change in body weight (%) Cagrilintide 0.3 mg (n=10
Slide 37: Amylin agonism may facilitate weight loss in people with and without T2DM
Amylin Louis Aronne Amylin agonism has the potential to facilitate weight loss in people with and without T2DM Phase 2 trial in people with T2DM of CagriSema vs cagrilintide or semaglutide 0 Mean relative change at Week 32 -2 -4 Semaglutide 2.4 mg (n=31) -5.1% Mean (SE) change in body weight (%) -6
Slide 38: Amylin analogs have potential for better tolerability compared with GLP-1RAs
Amylin Louis Aronne Amylin analogs have the potential for better tolerability compared with GLP-1RAs Conceptually, increasing satiety could lead to a better patient experience during weight loss compared to reducing appetite Clinical data for the short-acting amylin analog, pramlintide, demonstrated
Slide 39: Cagrilintide reduced CV risk markers in people without T2DM
Amylin Louis Aronne In the Phase 2 trial in people with obesity/overweight without T2DM, cagrilintide reduced CV risk markers Absolute change in blood pressure at Week 26 Absolute change in lipid profile at Week 26 Systolic blood pressure Diastolic blood pressure Triglycerides HDL LDL VLDL Cagrilint
Slide 40: Cagrilintide also reduced CV risk markers in people with T2DM
Amylin Louis Aronne In the Phase 2 trial in people with T2DM, cagrilintide also reduced CV risk markers Absolute change in blood pressure at Week 32 Relative change in lipid profile at Week 321 Systolic blood pressure1 Diastolic blood pressure2 Triglycerides HDL LDL VLDL Cagrilintide Semaglutide Cag
Slide 41: Amylin agonism may facilitate fat mass loss and preserve lean mass
Amylin Louis Aronne Data suggest that amylin agonism may facilitate fat mass loss and relative preservation of lean mass Change in body weight in rats Change in body composition in rats 150 Fat mass Dry lean mass Vehicle Amylin baseline in body weight (g) Mean (SE) change from 6 100 4 baseline at We
Slide 42: Fat-specific weight loss demonstrated in pre-clinical studies
Amylin Louis Aronne This fat-specific weight loss has been demonstrated in a number of pre-clinical studies Change in body weight in DIO rats Change in body composition in DIO rats Fat mass baseline in fat mass (%) 20 Mean (SE) change from 0 10 Mean (SE) change in body weight 0 -10 (% vehicle-correc
Slide 43: Amylin analogs hold potential as stand-alone weight-loss medications
Amylin Louis Aronne Amylin analogs hold potential as future stand-alone weight-loss medications Potential for GLP-1RA-like weight loss1-3 Non-incretin MoA with potential for improved tolerability1,4,5 Potential to reduce CVD risk1,3 Sources: 1. Lau et al. Lancet 2021;398(10317):2160–2172; 2. Wilding
Slide 44: Petrelintide is a long-acting, potential best-in-class amylin analog
Petrelintide David Kendall Petrelintide is a long-acting, potential best-in-class amylin analog designed with stability at neutral pH Petrelintide (ZP8396) is a 36-amino-acid acylated peptide, based on the peptide sequence of human amylin Long-acting amylin analog (half-life of 10 days)1 due to acyl
Slide 45: Single dose of petrelintide 2.4 mg resulted in average weight loss of 4.2% at Day 7
Petrelintide David Kendall A single subcutaneous dose of petrelintide 2.4 mg resulted in average weight loss of 4.2% at Day 7 Change in body weight in Phase 1a SAD trial of petrelintide Placebo Petrelintide 0.7 mg Petrelintide 1.4 mg Petrelintide 2.4 mg (n=6) (n=6) (n=6) (n=6) 4 +0.6% Change in body
Slide 46: Six once-weekly low doses of petrelintide resulted in average weight loss above 5%
Petrelintide David Kendall Six, once-weekly, low doses of petrelintide resulted in average weight loss above 5% Part 1 of the Phase 1b MAD trial of petrelintide Placebo (n=6) Petrelintide 0.6 mg (n=7) Petrelintide 1.2 mg (n=7) 5 Change in body weight (%) 0 -0.4% -5 -5.1% -5.3% -10 Dosing 0 1 2 3 4 5
Slide 47: Petrelintide was well-tolerated in Part 1 of the MAD trial
Petrelintide David Kendall In Part 1 of the MAD trial, petrelintide was well-tolerated with no serious or severe TEAEs and no withdrawals TEAEs in Part 1 of the Phase 1b MAD trial with petrelintide Placebo Petrelintide 0.6 mg Petrelintide 1.2 mg Number of participants (events) (n=6) (n=7) (n=7) Tota
Slide 48: Results from Part 2 of the trial expected in H1 2024
Petrelintide David Kendall Results from Part 2 of the trial, exploring higher doses of petrelintide over 16 weeks, are expected in H1 2024 We are investigating significantly higher doses of petrelintide… …over a longer duration of 16 weeks… …using a dose-escalation scheme… …in 48 people who are over
Slide 49: Petrelintide significantly reduced fat mass while preserving lean mass in DIO rats
Petrelintide David Kendall Petrelintide significantly reduced fat mass Unpublished while preserving lean mass in DIO rats data Change in body weight at Day 30 Change in body composition at Day 30 Fat mass 10 4 Mean (SEM) change in fat mass (% of Mean (SEM) change in body weight (%) body weight) 2 5
Slide 50: Petrelintide is a potential best-in-class amylin analog
Petrelintide David Kendall Petrelintide is a potential best-in-class amylin analog for GLP-1-like weight loss with better tolerability Weight loss – potential for ~15% reduction in body weight as monotherapy, with high-quality weight loss1-4 MoA – mechanism reduces food intake by restoring leptin se
Slide 51: Questions?
Questions?
Slide 52: Targeting obesity and NASH with glucagon/GLP-1 receptor agonists
Targeting obesity and NASH with glucagon/GLP-1 receptor agonists Survodutide December 5th, 2023
Slide 53: Considering obesity as a neurological disease
Survodutide Carel Le Roux Considering obesity as a neurological disease Obesity is a set of diseases Our focus is not on ‘weight loss’ but ‘health gain’ Source: Painting from Joseph Wright of Derby (1790). 53
Slide 54: Oxyntomodulin represents the scientific foundation for survodutide
Survodutide Carel Le Roux Oxyntomodulin represents the scientific foundation for the investigation of survodutide • A hormone with dual agonism at GCG and GLP-1 receptors that reduces body weight by Oxyntomodulin increasing energy expenditure and regulating appetite1 (OM) • Clinical application is l
Slide 55: Survodutide activates GCGR and GLP-1R
Survodutide Carel Le Roux Survodutide activates GCGR and GLP-1R, which are critical in controlling metabolic functions GCG/GCGR GLP-1/GLP-1R4 Energy expenditure (metabolic rate) Insulin secretion Food intake Liver Adipose tissue (direct) (indirect) Pancreas GI tract Brain Fatty acid oxidation1 Lipol
Slide 56: Agonism of the GCGR by survodutide in mouse hepatocytes
Survodutide Carel Le Roux Agonism of the GCGR by survodutide in mouse hepatocytes is potentially relevant in humans mRNA sequence analysis from mouse hepatocytes suggests treatment with increasing doses of survodutide: Downregulates gene clusters upregulated in the Upregulates gene clusters downregu
Slide 57: 16-week Phase 2 trial in T2DM: reduced HbA1c and body weight
Survodutide Carel Le Roux In a 16-week Phase 2 trial in T2DM, survodutide effectively reduced HbA1c and body weight Change in HbA1c Change body weight 0 0.0 0 -0.25% -1.20% -0.5 -0.5 -2 Mean (SE) absolute Mean (SE) relative change (%) change (%) -1.0 -1.0 -4 -1.47% -5.40% -1.5 -1.5 -6 -2.0 -2.0 -1.8
Slide 58: 46-week Phase 2 trial in obesity: body weight reduced by up to 18.7%
Survodutide Carel Le Roux In a 46-week Phase 2 trial in obesity, survodutide dose-dependently reduced body weight by up to 18.7% Phase 2 trial of survodutide in people who were overweight or had obesity Mean relative change at Week 46 (%) 0 -2 Placebo -2.0% (n=76) -4 change in body weight (%) Adjust
Slide 59: Phase 2 obesity trial showed no unexpected safety findings
Survodutide Carel Le Roux Treatment with survodutide in the Phase 2 obesity trial showed no unexpected safety findings • As expected, GI disorders were the most frequent drug-related AEs • Most treatment discontinuations occurred during the rapid dose escalation phase (up to Week 20) and may be miti
Slide 60: Survodutide reduced blood pressure at Week 46
Survodutide Carel Le Roux Survodutide reduced blood pressure by up to 8.6 mmHg (systolic) and up to 4.8 mmHg (diastolic) at Week 46 Systolic blood pressure Diastolic blood pressure 0 0 Adjusted mean (95% CI) absolute Adjusted mean (95% CI) absolute change from baseline (mmHg) change from baseline (m
Slide 61: Phase 3 program SYNCHRONIZE in obesity has been initiated
Survodutide Carel Le Roux The Phase 3 program with survodutide in obesity, SYNCHRONIZETM, has been initiated Inclusion criteria Study design Primary endpoint • HbA1c <6.5% (no history of diabetes) • N=600 • Percentage change in body weight SYNCHRONIZETM-11 • BMI ≥30 or BMI ≥27 with • 1:1:1 ratio (3.
Slide 62: Significant overlap between obesity and liver disease
Survodutide Carel Le Roux There is a significant overlap between obesity and liver disease Obesity is associated with severe comorbidities, for which there are significant unmet medical needs Mental illness Depression Anxiety People who are overweight or have obesity ~15–30%2,3 CVD Pulmonology Hyper
Slide 63: Phase 2 results from the NASH trial expected in H1 2024
Survodutide David Kendall Phase 2 results from the NASH trial with survodutide are expected in H1 2024 Survodutide dose group 1 QW Primary endpoint: Histological improvement of NASH without worsening of fibrosis after 48 weeks of treatment Survodutide dose group 2 QW N=295 R Secondary endpoints: • L
Slide 64: Survodutide holds potential as a leading GLP-1-containing medication
Survodutide David Kendall Survodutide holds potential as a leading GLP-1- containing weight-loss medication in the 2030s Weight loss – potential for ~20–25% weight loss,1 and improved glycemic control2 MoA – novel GCGR/GLP-1R dual agonist designed with bias towards GLP-1R3 Safety and tolerability –
Slide 65: Questions?
ZEML& ZEALAND PHARMA Questions?
Slide 66: Developing the keys to address the greatest healthcare challenge of our time
We are starting to develop the keys that could help address the greatest healthcare challenge of our time 300,000 years Dapiglutide 50 years1 Petrelintide 3 million deaths2 Survodutide Sources: 1. World Health Organization (WHO). Fact sheet. Obesity and overweight. 9 June 2021. https://www.who.int/n
Slide 67: Multiple catalysts across the obesity pipeline in 2024
Multiple catalysts across the obesity pipeline in 2024 H1 2024 H2 2024 Dapiglutide Dapiglutide Topline results from DREAM trial Topline results from 13-week dose-titration trial Petrelintide Petrelintide Topline results from MAD Part 2 Initiation of Phase 2b trial Survodutide Topline results from Ph
Slide 68: Thank you for attending
Thank you for attending