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Webcast with Type 1 Diabetes (T1D) Experts Investor and Analyst Event February 2025
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2 This presentation includes forward-looking statements regarding Nektar’s proprietary drug candidates, the timing of the start of and plans for ongoing or planned clinical trials with partners, the therapeutic potential of our drug candidates, the timing and outcome of regulatory decisions, and future availability of clinical trial data. Actual results could differ materially, and these statements are subject to important risks detailed in Nektar's filings with the SEC including the Form 10-Q filed on November 8, 2024. Nektar undertakes no obligation to update forward-looking statements as a result of new information or otherwise.
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Kevan C. Herold, MD TrialNet Chair and C.N.H. Long Professor of Immunobiology and Medicine at Yale University at Yale School of Medicine Daniel Moore, MD, PhD Associate Professor of Pediatrics and Pathology, Microbiology & Immunology at Vanderbilt University Medical Center 3 Today’s Speakers Jonathan Zalevsky, PhD Chief Research and Development Officer at Nektar Therapeutics Megan Levings, PhD Professor, Department of Surgery and School of Biomedical Engineering at The University Of British Columbia
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• Introduction • Jonathan Zalevsky, Ph.D., Nektar Therapeutics • Type 1 Diabetes (T1D), Epidemiology, Disease Pathology, and Treatment • Dan Moore, M.D., Ph.D., Associate Professor of Pathology, Microbiology & Immunology at Vanderbilt University Medical Center • The Role of Tregs in T1D • Megan Levings, Ph.D., Professor, Department of Surgery and School of Biomedical Engineering at The University Of British Columbia • About TrialNet and Rezpegaldesleukin Clinical Study • Kevan Herold, M.D., C.N.H Long Professor of Immunobiology and Medicine (Endocrinology) at Yale School of Medicine • Q&A Session 4 Agenda
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5 Type 1 Diabetes (T1D), Epidemiology, Disease Pathology, and Treatment Daniel Moore, PhD, MD, Associate Professor of Pediatrics and Pathology, Microbiology & Immunology at Vanderbilt University Medical Center Dr. Daniel Moore is an Associate Professor of Pathology, Microbiology and Immunology at Vanderbilt in the Department of Pediatrics in the Division of Endocrinology where he directs the T1D Immunotherapy Program. His research applies basic, clinical, and translational approaches to understand the processes that govern immune tolerance to prevent and reverse Type 1 Diabetes. As part of a comprehensive program to understand immune regulation, he also actively investigates the role of cell-cell interactions in the mechanism of action of regulatory T lymphocytes.
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What is Diabetes? • Diabetes is a collection of diverse disorders of excessive urine output • In diabetes mellitus, there is sugar detected in the urine • Diabetes mellitus results from an imbalance of insulin supply and demand • Type 1 diabetes results from adverse interactions between immune cells and beta cells, leading to loss of insulin production
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The Child with Type 1 Diabetes, 100 years ago Sub-acute and acute presentations of illness
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The Presentation of Type 1 Diabetes • Sub-Acute • fatigue, weight loss, either lack of appetite or hunger, nausea, polydypsia, polyuria, complaints may be vague • Glycosuria +/- ketonuria • FBS >125; 2hr post- prandial>199 • Acute • nauseated, vomiting, dry mucous membranes , abdominal pain, air hunger, rapid breathing, cyanosis, low grade temperature. These patients may appear to have gastroenteritis, appendicitis, or an acute asthmatic attack. • Low HCO3, low pH
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T1D Demographics • As of 2021, 8.4 million worldwide, 500,000 new cases • 2 million Americans, >300,000 children • By 2040, estimated to be nearly 17 million • Prevalence increases by about 0.3% each year • Disease driven by genetic, environmental, and stochastic factors • More rapid increases in several minority populations • Nearly equal number of new cases each year in children and adults • Risk increased ~15x in family members
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T1D Incidence is Rising 3-5% per year Incidence /100,000/ yr in children aged 0-14 Current Incidence 30–60/100,000/yr in Scandinavia and Sardinia* 10– 20/100,000/yr in South European countries and USA 1-3/100,000/yr in China, other Asia and S America Norris et al: Lancet Diabetes Endocrinol. 2020 March ; 8(3): 226–238. doi:10.1016/S2213-8587(19)30412-7.
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Treatment of T1D: 1970’s/1980’s
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Treatment of T1D: Today
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A Typical Pattern of Blood Sugars Shows Great Variation Even For Well Controlled
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Why Should We Control Diabetes and What is Control Today?
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The Average Teen is Living with 1970’s Diabetes Control
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Diabetes Control is the Primary Prevention for ALL Diabetes Complications
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You Can’t Have Good Glucose Control Without Low Blood Sugars
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T1DM patients with glycemia at target have increased risk for cardiovascular disease and death Norris et al: Lancet Diabetes Endocrinol. 2020 March ; 8(3): 226–238. doi:10.1016/S2213-8587(19)30412-7.
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1441 DCCT participants 855 with 1-5 year history of T1DM 412 assigned to intensive therapy 443 assigned to conventional therapy 138 Responders C-peptide 200- 500 pmol/L 274 Non- responders C-peptide < 200 pmol/L 586 outside 1–5- year T1DM duration Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med. 1998;128(7):517-23. Epub 1998/06/10. doi: 10.7326/0003-4819-128-7-199804010-00001. PubMed PMID: 9518395. Reviewed in: Latres E, Greenbaum CJ, Oyaski ML, Dayan CM, Colhoun HM, Lachin JM, Skyler JS, Rickels MR, Ahmed ST, Dutta S, Herold KC, Marinac M. Evidence for C-peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes. Diabetes. 2024. Epub 2024/02/13. doi: 10.2337/dbi23-0012. PubMed PMID: 38349844. Preservation of C-peptide decreases microvascular disease
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1441 DCCT participants 855 with 1-5 year history of T1DM 412 assigned to intensive therapy 443 assigned to conventional therapy 138 Responders C-peptide 200- 500 pmol/L 274 Non- responders C-peptide < 200 pmol/L 586 outside 1–5- year T1DM duration Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med. 1998;128(7):517-23. Epub 1998/06/10. doi: 10.7326/0003-4819-128-7-199804010-00001. PubMed PMID: 9518395. Reviewed in: Latres E, Greenbaum CJ, Oyaski ML, Dayan CM, Colhoun HM, Lachin JM, Skyler JS, Rickels MR, Ahmed ST, Dutta S, Herold KC, Marinac M. Evidence for C-peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes. Diabetes. 2024. Epub 2024/02/13. doi: 10.2337/dbi23-0012. PubMed PMID: 38349844. Preservation of C-peptide decreases severe hypoglycemia
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Challenges and Opportunities • Patients can be identified today prior to onset of symptomatic T1D • Preservation of insulin secretion (beta cell function, c-peptide response) is key to improving long-term health outcomes and quality of life • Immune-targeting therapy is likely to achieve this outcome but must be optimized and tailored.
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22 The Role of Tregs in T1D Megan Levings, Ph.D., Professor, Department of Surgery and School of Biomedical Engineering at The University Of British Columbia Dr. Megan Levings is a Professor in the Department of Surgery and School of Biomedical Engineering at the University of British Columbia and BC Children’s Hospital Research Institute. Her lab studies how a special kind of white blood cell, known as a T regulatory cell, could be used as a cellular therapy to stop harmful immune responses. She leads a vibrant group of trainees and staff who are researching how to use T regulatory cells to replace conventional immunosuppression in the context of transplantation and autoimmunity. She has won numerous awards, including the Canadian Society for Immunology Investigator Award and the YWCA Woman of Distinction, Science, Research & Technology. She is internationally recognized in the field of human immunology and currently chairs the Federation of Clinical Immunology Societies Centers' of Excellence.
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Regulatory T cells, IL-2 and type 1 diabetes Megan K. Levings mlevings@bcchr.ca
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CD4+FOXP3+ Regulatory T cells • ~5% of CD4+ T cells in peripheral blood • Express CD25 (IL-2Rα), FOXP3 (master transcription factor) and usually HELIOS (another lineage-defining transcription factor) • Produce no/low levels of pro-inflammatory cytokines • Regulate many different types of cells and immune responses Regulatory T cells Immune response
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Three phases of Treg suppression
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Adapted from Roep &Tree, Nat Rev Endocrin. 2014 Regulatory T cells in type 1 diabetes
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Are Tregs defective in T1D? Defective function Resistant effector cells Inadequate numbers Abnormal selection Decreased proliferation/survival Unstable phenotype Common, polygenic forms IPEX • FOXP3 mutations Rare, genetic cause Born with T1D
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Tregs rely on exogenous IL-2 IL-2
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Boosting the Treg/IL-2 axis in T1D High affinity IL-2R Kd ~10-11M Low affinity IL-2R Kd ~10-9M IL-2 Teff
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Delivering IL-2 specifically to Tregs Modified from Boardman & Levings, Nat. Biomedical Engineering, 2019 Ab-modified IL-2 βγ α Low-dose WT IL-2 βγ α βγ α α βγβγ α Pegylated WT IL-2 Orthogonal IL-2 + IL-2R IL-2 muteins
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Boyman and Sprent, Nat Rev Imm 2021 Boosting the Treg/IL-2 axis in T1D in B6 mice Webster, Sprent et al, JEM 2009
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Boosting the Treg/IL-2 axis in T1D in NOD mice Khoryati, Campbell, Gavin et al, Science Immunology, 2020
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Low dose IL-2 monotherapy to boost Tregs in T1D Years/PIs/Refs Population Treatment Main Outcomes 2013, 2015 Klatzmann PMID: 32607749 PMID: 25634360 - 24 adults (18-55 years) - established T1D - Randomized, placebo controlled - 0.33, 1, or 3 MIU/day for 5 days - followed up for 60 days - dose-dependent Treg increase - no deleterious changes in glucose-metabolism - at the highest dose, suppressed Teff responses to beta-cell antigens 2016, 2018, 2022 Todd, Wicker, Waldron-Lynch, Ferreira PMID: 27727279 PMID: 30282826 PMID: 36443294 - 78 adults (18-70 years) - two trials - new onset T1D - open label, adaptive dose- finding IL-2 - doses from 0.09–1.5 MIU/m 2 - daily for 5 days then day 7, 9, 14 and 21; or every 2-3 days - followed up for 60 days - identified dosing regimen to establish a steady- state 20%-50% increase in Treg frequency: 0.26 MIU/m2 every 3 days - simultaneously reduced frequency of IL-21- producing CD4+ T cells - prolonged anti-inflammatory transcriptional changes 2020 Klatzmann PMID: 32607749 - 24 children (7-14 years) - new onset T1D - Randomized, placebo controlled - 0.125, 0.250 or 0.500 MIU/m 2 - Daily for 5 days, then fortnightly for 1 year - dose-dependent increase in Tregs - best response in people with lower baseline Tregs - improved maintenance of C-peptide at 1 year in seven Treg high responders
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Concept of IL-2 therapy to boost Tregs in T1D rezpegaldesleukin
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Source: 1. Fanton C, et al. Poster presented at the European Congress of Rheumatology (EULAR), 2020: THU0054.; 2. Dixit et al J Trans Autoimmun 2021; 3. Langowski J, et al. Poster presented at the American College of Rheumatology Annual Meeting, 2017: 2715.; 4. Fanton et al J Trans Autoimmun 2022; 5. Silverberg et al Nature Communications 2024 Compared with native IL-2, REZPEG has:1 Selectivity for the stimulation of regulatory T cells (Tregs) over conventional T cells (Tcons) via an attenuated receptor binding profile An increased half-life for extended dosing REZPEG has: Activity in animal models of systemic lupus erythematosus (SLE) 2 and cutaneous hypersensitivity3 Selective stimulation of Tregs observed with rezpegaldesleukin across multiple clinical studies (healthy volunteers, lupus, atopic dermatitis and psoriasis) 4,5 Clinical efficacy across multiple autoimmune indications • Islet autoreactive T cells REZPEG • Downregulate activity of conventional T cells • Suppress antigen presenting cells • Induce more Tregs REZPEG: IL-2 pathway agonist that selectively induces Tregs
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REZPEG Preferentially Expands Tregs in Mice A Single Dose of REZPEG is Superior to Repeat Doses of IL-2 36 • Selective induction of Tregs, Treg proliferation and activation markers by rezpegaldesleukin. • Increased Treg suppressive activity by rezpegaldesleukin in an in vivo/ex vivo Treg suppressor assay Single Administration 0 2 4 6 8 10 12 14 0 5 10 15 20 25 REZPEG* Time (Days) Fold change in Treg REZPEG, 0.03 mg/kg REZPEG, 0.1mg/kg REZPEG, 0.3 mg/kg Repeat Administration 0 2 4 6 8 10 12 14 0 5 10 15 20 25 IL-2* Time (Days) IL-2, 0.1mg/kg qdx5 IL-2, 0.3mg/kg qdx5 IL-2, 1mg/kg qdx5 dosing Fold change in Treg (mean ± SEM) Source: *13th Annual World Congress on Inflammation 2017, Langowski et. al.; 2017 American College of Rheumatology Annual Meeting; Dixit et al. J. Translational Autoimmunity 2021 Selective stimulation of Tregs observed with rezpegaldesleukin across multiple clinical studies (healthy volunteers, lupus, atopic dermatitis and psoriasis)
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37 About TrialNet and Rezpegaldesleukin Clinical Study TrialNet Chair and C.N.H. Long Professor of Immunobiology and Medicine at Yale University at Yale School of Medicine Dr. Kevan Herold is the C.N.H Long Professor of Immunobiology and Medicine (Endocrinology) at Yale School of Medicine. His background and research are in translational immunology, and his focus has largely been in the field of autoimmune Type 1 diabetes. Dr. Herold led the development of teplizumab, the first drug approved for delay of Type 1diabetes from preclinical studies in murine models through the clinical trials that led to its approval in 2022. His laboratory continues to investigate its mechanisms of operational tolerance. Most recently his lab has identified mechanisms involved in killing and protection of beta cells. He and his lab have also been studying the development of autoimmune diabetes in patients with cancers who are treated with checkpoint inhibitors. He is chair of NIDDK (National Institute of Diabetes and Digestive Diseases) TrialNet, an international network of type 1 diabetes researchers.
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TrialNet Kevan C Herold, MD, Chair, NIDDK/TrialNet February 24, 2025
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What is TrialNet? • TrialNet is a group of 18 Clinical Centers that are supported, by the NIH, to identify and test therapies that can delay or prevent the development of T1D in persons at risk. • TrialNet’s trials to stop ß-cell destruction and enhance ß-cell survival in persons with residual ß-cell function have clinical benefit for participants and also provide information relevant to more durable and effective prevention therapy. • In addition, using the knowledge gained through clinical research, our mission is build on our successes so therapies are clinically meaningful. • Our goal is to reach all patients at risk for T1D including individuals who, in the past, have not been engaged in this research mission
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What has TrialNet Accomplished • A trial that led to the first FDA-approved treatment (teplizumab) to delay the diagnosis of clinical (Stage 3) T1D • Increased understanding of the mechanisms of human T1D using clinical trials, studies, and laboratory investigations, building towards more effective and durable T1D prevention • Building collaborations with funders, industry, non-profits, others • New trials to build on our previous accomplishments, including trials of combination therapies, studies to enhance immune regulation, novel treatment modalities
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TrialNet Organization Other committees: Publications URM Psychosocial Emerging Leaders Collaborative Mechanistic Panel 18 Basic/translational scientists TrialNet Steering Committee 18 Clinical Center Directors Data Coordinating Center Clinical Network HUB Protocol committees TrialNet Executive Committee NIH: L Spain PhD, E Leschek MD Chair/VC: K Herold, MD, L DiMeglio MD TNCC: J Krischer PhD HUB: C Greenbaum MD
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Framework for Progression of T1D: A Chronic Autoimmune Disease
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Concept of rezpegaldesleukin to boost Tregs in T1D rezpegaldesleukin
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Study Objective: Determine the impact of rezpegaldesleukin on Treg expansion and Stage 3 T1D progression • Pegylated IL-2 will preserve C-peptide by specifically expanding Tregs. • Enroll 66 individuals in first 100 days treated at 12ug/kg every other week for 26 weeks • 2:1 tx:placebo • Assess C-peptide by MMTT at 0, 3, 6, and 12 months • First 18 subjects ages 18-45 with lower ages enrolled down to 12 or 8 after evaluation of initial data and safety signals • Assess additional immune and metabolic parameters
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Patient Enrollment Proposed Study Protocol Treatment Randomize (2:1) N=~66 Outcome Measures Part 1 Cohort: 18 Adult Subjects (18-45 yrs.) Part 2 Cohort: 17 Pediatric & Adult Subjects (12-45 yrs.) ENDPOINTS: Primary: C-peptide response to Mixed Meal Tolerance Test (MMTT) compared to placebo at 12 months Secondary/Exploratory: • Comparisons of MMTT- stimulated C-peptide and glucose AUCs at 3 and 6 months to placebo • Comparisons of MMTT- stimulated C-peptide at 3, 6, and 12 months to historical model- adjusted placebo controls • Glucose monitoring data and hypoglycemia events • Adverse Events Additional Assessments: • Metabolic Assessments (HbA1c, insulin usage, etc.) • Immunologic Assessments Key Inclusion: Ages starting at minimum of 18 and then decreasing to 12 and then 8 pending data review New onset T1D within 100 days Positive for ≥1 autoantibody (+AAB) Peak C-peptide >0.2pmol/mL Eligibility Part 3 Cohort: 31 Pediatric & Adult Subjects (8-45 yrs.) Safety Review at 6 months (DSMB/FDA) Safety Review at 6 months (DSMB/FDA) REZPEG Q2W regimen for 6 months Placebo Complete remaining 48 subjects in adults if data not supportive of 12 yrs. and up Complete remaining 31 subjects in pediatric and adults if data not supportive of 8 yrs. of and up
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Kevan C. Herold, MD TrialNet Chair and C.N.H. Long Professor of Immunobiology and Medicine at Yale University at Yale School of Medicine Daniel Moore, MD, PhD Associate Professor of Pediatrics and Pathology, Microbiology & Immunology at Vanderbilt University Medical Center 46 Q&A Session Jonathan Zalevsky, PhD Chief Research and Development Officer at Nektar Therapeutics Megan Levings, PhD Professor, Department of Surgery and School of Biomedical Engineering at The University Of British Columbia