Developing Novel Treatments for Autoimmune Diseases

Transcription

1 ACCELERATED PATH TO CURES Developing Novel Treatments for Autoimmune Diseases Dr. Josep Bassaganya-Riera Chairman & CEO

2 Landos BioPharma Summary 2 Scientific, Clinical and Business Leadership Expandable Oral Therapeutic Pipeline Financing Raised $10M Series A from Perceptive Advisors to advance Lead to Phase 1; Landos Biopharma is raising Crossover $60M Series B for Phase 2 CLINICAL STAGE TECHNOLOGY First-in-class oral therapeutics with a unique mechanism of action targeting immunometabolic pathways for autoimmune disease Advancing Lead Candidate in Crohn s and Ulcerative colitis Product Development Two open INDs for BT-11 Phase 1 First-in-Human testing complete Q Phase 2 studies start in Q Validation Strong animal pharmacology in 5 mouse models and a pig model of IBD, benign toxicology and proven human translation IP & Patents Comp of Matter and Method of Use, Long patent life 2035 Possible Exit Strategy IPO, M&A or Strategic Alliance at the end of Ph. 2

3 Expansible Therapeutic Pipeline 3 Product Indication Preclinical POC Preclinical INDenabling Phase I Phase II BT-11 CD BT-11 UC NX-13 UC NX-13 CD BT-63 Lupus NX-43 Onc BT-63 T1D BT-84 RA New Assets to IND by Oct 2019 Autoimmune and Immuno-oncology platform

4 Crohn s Disease and Ulcerative Colitis 4 IBD afflicts 3 million in the U.S. and 5 million people worldwide 5M afflicted $10 billion market 25% growth 70-90% will require surgery 100,000 hospitalizations Source:

5 The IBD Market: $10 billion 25% Growth 5 Autoimmune disease therapeutics market in U.S. is $100 billion Others (5%) Immunomodulators (19%) Biologics (68%) 5 ASA (8%) Biological treatment dominates most of the market share. However, it is expected to drop 11 points, down to 57%, by 2026 due to safety concerns and emerging novel technologies with significant competitive advantages

6 Unique MOA: Lanthionine Synthetase C-Like 2 6 BT-11 LANCL2 HOW LANCL2 WORKS LANCL2 activation by BT-11 intercepts IBD at two levels: by decreasing the production of inflammatory mediators (TNF, IFNγ, MCP1) and increasing anti- inflammatory molecules (IL-10, FOXP3) in the GI tract. AC CREB PKA camp 5 AMP ATP Activates IL-10 & FOXP3 Inhibits TNF- & IFN-γ First in class compounds with oral route of administration and gut restricted action IP includes: BT-11, 48 privileged scaffolds, and 3 billion new chemical entities Patent status: composition of matter claims allowed; protected in 15 countries under patents 10,028,950, 9,556,146, & 9,839,635 IP includes both method of use and composition of matter claims for IBD, Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), lupus, & Type 1 Diabetes (T1D)

7 BT-11 Target Product Profile For CD & UC 7 Product Name BT-11 Lead Competitor (TNF- blockers) First: Treatment for alleviation of signs and symptoms and induction and maintenance of clinical remission in male and female adult patients with moderate to severe CD. Prime Therapeutic Indications ROA/Dosage Second: Treatment for alleviation of signs and symptoms and induction and maintenance of clinical remission in male and female adult patients with mild to moderate UC. Oral once-a-day dosing through a tablet until symptoms alleviate (8 mg/kg in mouse and pig models) Treatment to reduce signs and symptoms and induce and maintain remission in adult patients with moderate to severe CD or UC who have not responded to other therapies. I.V. infusion Formulation Tablets (Phase 1 & 2) Sterile powder for I.V. infusion Mechanism of Action Efficacy Safety/ Tolerability Activation of the LANCL2 pathway Up-regulation = IL-10, FOXP3 Down-regulation = TNF-, IFNγ, MCP-1, IL-6 Oral efficacy confirmed in 5 mouse models (8 mg/kg p.o.) and a pig model of IBD. Benign safety profile up to 1,000 mg/kg p.o. in dogs and rats, and 100 mg/kg in humans without dose-limiting toxicities and a wide safety margin. Neutralization of TNF- Variable degrees of efficacy in 3 mouse models Increased risk for cancer (T cell lymphoma), infection and death

8 Efficacy Of BT-11 in 5 Validated Mouse Models of IBD 8 Untreated : Inflamed BT-11 Treated : Not Inflamed Oral BT-11 decreases gut inflammation by 90%, triggers 4x lesion reduction, and modulates inflammatory responses by up-regulating IL-10 and down-regulating TNF-α Source: Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability through Immunometabolic Mechanisms: Inflammatory Bowel Diseases, Volume 24, Issue 9, 16 August 2018, Pages ,

9 BT-11 Targets LANCL2 In The GI Tract 9 Cmax = 28ng/mL t 1/2 = 3.1hr K el = L/hr V d = 3.38 L/kg BT-11 systemic absorption is extremely low No dose proportionality (80 to 500 mg/kg) Limited systemic exposure No accumulation in plasma Volume of distribution is high BT-11 in the colon and colonic contents is high 90% reduction of inflammation BT-11 is stable to stomach and intestinal fluids Source: Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability through Immunometabolic Mechanisms: Inflammatory Bowel Diseases, Volume 24, Issue 9, 16 August 2018, Pages ,

10 Pharmacokinetic Summary 10 Oral Dosage > 99 % Intestinal contents Feces 8-12% % Intestinal tissue Blood Metabolized Urine Data is representative of preclinical PK from experiments conducted in mice, rats, dogs and pigs. The model further supports that BT-11 is gut-restricted.

11 Human Translational Data 11 Treating human PBMCs from Crohn s disease patients with increasing concentrations of BT-11 ex vivo induced IL-10 production and expression of FOXP3 while suppressing production of TNF and IFNγ Source: Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability through Immunometabolic Mechanisms: Inflammatory Bowel Diseases, Volume 24, Issue 9, 16 August 2018, Pages ,

12 BT-11 Outperforms Current Drugs and INDs 12 Source: Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability through Immunometabolic Mechanisms: Inflammatory Bowel Diseases, Volume 24, Issue 9, 16 August 2018, Pages ,

13 BT-11 Presents Benign Safety Profile 13 Metabolically stable in liver microsomes and hepatocytes with nonsignificant inhibition of CYP enzymes and ADRs at relevant concentrations No genetic toxicity with no induction of revertant colonies, chromosomal aberrations, or micronucleated reticulocytes up to non-precipitating doses in vitro and 2,000 mg/kg in vivo Clean safety pharmacology profile with no differences in cardiovascular, respiratory, or central nervous system function up to 1,000 mg/kg Well tolerated in pivotal 90-day GLP toxicity studies in rats and dogs with no test article-related clinical signs, body weight changes, clinical pathology changes, or gross or microscopic tissue changes with oral dosing NOAEL > 1,000 mg/kg/d. No dose limiting safety issues.

14 BT-11 Versus Standard-of-Care 14 LANCL2-targeting BT-11 BT-11 has an oral ROA BT-11 has lower COG BT-11 has a better safety profile Gut-restricted VS Biologics TNF- blockers Limited Efficacy Negative safety profile Expensive and IV ROA Systemic distribution Infliximab (IBD) BT-11 Low COG? NO YES Oral route of administration? NO YES Safety Profile? NO YES Clinic visit for treatment? Suitable for all stages of disease? YES NO NO YES

15 Landos Has Two Open INDs for BT Ulcerative Colitis IND Crohn s Disease IND Landos received Study May Proceed Notification for Phase 1 from the FDA in June and August First-in-Humans (FIH) Phase 1 Study Initiated in July 2018 and completed in October Topline FIH safety, PK and PD data from Phase 1 study completed in Q

16 Phase 1: Safety and Tolerability 16 Single Ascending Dose Cohort 1 BT-11 : mg/kg 6 active, 2 placebo Multiple Ascending Dose 7 day, once daily Cohort 2 BT-11 : mg/kg 6 active, 2 placebo Cohort 1 BT-11 : mg/kg 8 active, 2 placebo Cohort 3 Cohort 4 Cohort 5 BT-11 : mg/kg 6 active, 2 placebo BT-11 : mg/kg 6 active, 2 placebo BT-11 : mg/kg 6 active, 2 placebo Cohort 2 Cohort 3 BT-11 : mg/kg 8 active, 2 placebo BT-11 : mg/kg 8 active, 2 placebo Double-blind, placebo-controlled study in male and female normal healthy volunteers under U.S. IND

17 Lower Calprotectin Levels in BT-11 vs Placebo 17 SAD MAD All individual BT-11 cohorts and the pooled BT-11 rates are below the adverse event/patient rate in placebo. BT-11 dosed participants have lower mean day 2 (SAD) and day 7 (MAD) fecal calprotectin levels compared to placebo. Daily oral BT-11 over 7 days does not induce decrease of WBC counts or systemic immunosuppression relative to placebo.

18 Local BT-11 Concentrations in the GI Tract BT-11 is observed in high concentrations in feces after both single- and seven-day dosing. BT-11 GI concentrations are 6,000 higher than levels found in plasma. Concentrations scale with regards to oral dose level. Results confirm that BT-11 is stable with the gut and reaches the terminal colon in high concentration at proposed low dose level (500 mg, total dose) for the Phase II study.

19 Phase 2 POC UC Study Design 19 Multi-site (45 sites) in the US and Europe starting in dose levels of BT-11 vs placebo to be tested Duration is 12-wk induction and 40-wk maintenance

20 Development Timeline IND Enabling File INDs Ph 1 Phase 2 Phase 3 UC NDA SeriesA $10M Series B $60M Phase 3 CD

21 Leadership Team 21 Josep Bassaganya-Riera Chairman and CEO 20 years of business development and fundraising experience in leading biotech companies with innovative, large-scale translational programs. Preclinical and clinical expertise in Crohn s disease and ulcerative colitis. Has led large preclinical and clinical programs in IBD (>$78M). Raquel Hontecillas Chief Scientific Officer 20 years of translational experience in the biotech industry focusing on infectious, immune-mediated, and metabolic diseases. Managed an NIH-funded mucosal immunology program totaling $57M. Chris Garabedian Corporate Advisor Currently Chairman and CEO of Xontogeny, a company focused on the management of early stage life sciences companies from preclinical to clinical proof-of-concept. Helped advance a new drug to market when he was the CEO of Sarepta a $9B publicly traded company. Simon J. Tulloch, MD Clinical Advisor 25 years of pharmaceutical and biotech experience in strategic business development, clinical development and R&D management, both in Europe and the USA. Secured a $200 million R&D budget and grew the core businessfrom $700 million to $1 billion at Shire Pharmaceuticals; served as CMO of InfaCare, with successful Series A, B, and C fund raising. He played a crucial role in NDA and taking Adderall to market. He has been involved in filing over 17 INDs and several NDAs.

22 Clinical Advisory Board - IBD 22 FABIO COMINELLI, MD Crohn s Disease Human Clinical Trials Director of the UH Case Medical Center, Cleveland. 20 years of experience with human clinical trials for new therapeutics in Inflammatory Bowel Disease. WILLIAM SANDBORN, MD Crohn s Disease Human Clinical Trials Chief, Division of Gastroenterology and Professor of Medicine at UC San Diego Health. He has over 20 years of experience with human clinical trials for new Inflammatory Bowel Disease (IBD) therapeutics. FRANCISCO A. SYLVESTER, MD Pediatric IBD Division Chief for Pediatric Gastroenterology at UNC Chapel Hill and member of the CCFA Board of Trustees. Over 25 years of experience in chronic inflammatory diseases. JEAN-FREDERIC COLOMBEL, MD Preclinical and Clinical Gastroenterology Director of the Helmsley IBD Center at Mount Sinai, NYC. 20 years of experience in Crohn s disease. Chair of the International Organization of Inflammatory Bowel Disease (IOIBD). MARIA T. ABREU, MD Preclinical and Clinical Gastroenterology Faculty of University of Miami Health System. Over 15 years of experience in IBD, specializing in mucosa and associated intestinal microbiota and expertise in preclinical models and clinical studies.

23 Use of Proceeds: $60M Series B 23 DUAL UC & CD PHASE 2 2 NEW ASSETS TO IND 10% 9% 10% 5% 4% 13% Phase 2 Clinical Trials Employees & Consultants IND-Enabling Studies Discovery Studies 49% Legal and Operating Costs CMC Mfg Chronic Studies Manufacturing of cgmp tablets for Phase 2 studies. Phase 2 clinical study with UC patients (~45 sites). 12-wk induction and 40 wk maintenance Phase 2 clinical study with CD patients (~70 sites). 12-wk induction and 40 wk maintenance Scale up manufacturing of BT-63 IND-enabling studies BT-63. Scale up manufacturing of NX-13. IND-enabling studies NX-13. Filing two new INDs. Initiating Phase 1 studies. Continuing platform discovery efforts in autoimmune and immuno-oncology.

24 Summary and Conclusions 24 Strong Execution and Efficient Use of Capital Two Open INDs June and August 2018 Completed Ph 1 human clinical testing Q Begin Ph 2 clinical testing by Q Landos is uniquely positioned to develop oral, gutrestricted, first-in-class IBD therapeutics, a $10 billion market. Innovative MoA (LANCL2, NLRX1) with strong IP protection (NCEs & target). Strong animal pharmacology, MoA, toxicology, and human translational data. Committed leadership with autoimmune disease and biopharma industry experience ready to execute clinical development plans. Financial backing of Blue Chip investors such as Perceptive Advisors. $60M Series B crossover round.

25 25 LANDOS BIOPHARMA 1800 Kraft Drive, Suite 216 Blacksburg, VA 24060

26 APPENDIX 26

27 BT-11 & LANCL2 Publications 27 Carbo A, Gandour RD, Hontecillas R, Philipson N, Uren A, Bassaganya- Riera J. An N,N Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C-Like 2-Based Therapeutic for Inflammatory Bowel Disease. J Med Chem Nov 23;59(22): PubMed PMID: Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability through Immunometabolic Mechanisms. Inflammatory Bowel Diseases Journal. Volume 24, Issue 9, 16 August 2018, Pages ,

28 BT-11/LANCL2 Publications 28 Leber, A., Hontecillas, R., Zoccoli-Rodriguez, V., Chauhan, J., Bassaganya-Riera, J. Oral treatment with BT-11 ameliorates IBD by enhancing Treg responses in the gut. J Immunol, In press. Leber, A., Hontecillas, R., Zoccoli-Rodriguez, V., Ehrich, M., Davis, J., Chauhan, J., Bassaganya-Riera, J. Nonclinical toxicology and toxicokinetic profile of an oral Lanthionine Synthetase C-like 2 agonist, BT-11. Int J Tox, In press. Leber A, Hontecillas R. Zoccoli-Rodriguez V, Bassaganya-Riera J. Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability through Immunometabolic Mechanisms. Imflammatory Bowel Diseases In press. Carbo A, Gandour RD, Hontecillas R, Philipson N, Uren A, Bassaganya-Riera J. An N,N Bis(benzimidazolylpicolinoyl)piperazine (BT-11): A Novel Lanthionine Synthetase C-Like 2-Based Therapeutic for Inflammatory Bowel Disease. J Med Chem Nov 23;59(22): PubMed PMID: Bissel P, Boes K, Hinckley J, Jortner BS, Magnin-Bissel G, Were SR, Ehrich M, Carbo A, Philipson C, Hontecillas R, Philipson N, Gandour RD, Bassaganya-Riera J. Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease. Int J Toxicol Sep;35(5): doi: / PubMed PMID: ; PubMed Central PMCID: PMC Lu P, Hontecillas R, Philipson CW, Bassaganya-Riera J. Lanthionine synthetase component C-like 2: a new drug target for inflammatory diseases and diabetes. Curr Drug Targets Jun;15(6): Review. PubMed PMID: Bassaganya-Riera J, Guri AJ, Lu P, Climent M, Carbo A, Sobral BW, Horne WT, Lewis SN, Bevan DR, and Hontecillas R. ABA regulated inflammation via ligand-binding domain-independent activation of PPARg. J. Biol. Chem. 286(4):

29 Patent List 29 Jurisdiction Patent/Application Number United States of America Patent No. 10,028,950 United States of America Patent No. 9,556,146 United States of America Patent No. 9,839,635 United States of America Application No. 15/ World Intellectual Property Org. Application No. PCT/US2015/ Russian Federation Application No Japan Application No Canada Application No. 2,965,472 Brazil Application No European Patent Office Application No Republic of Korea Application No India Application No New Zealand Application No Australia Application No China Application No Turkey Application No. 2017/09705 Israel Application No Hong Kong Application No