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 Strengths Scientific, Clinical and Business Leadership 2 Financially Stable Expandable Oral Therapeutic Pipeline Raised $10M Series A from Perceptive Advisors, a $3.5B fund, to advance Lead to Phase 1; Landos will be raising $31-60M Series B for Phase 2 CLINICAL STAGE TECHNOLOGY First-in-class oral therapeutics with a unique mechanism of action targeting LANCL2 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 Phase 2 studies start in 2019 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 Crohn s Disease and Ulcerative Colitis 3 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:

4 The IBD Market: $10B 25% Growth 4 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

5 Unique MOA: Lanthionine Synthetase C-Like 2 5 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. CREB AC 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)

6 Expansible Therapeutic Pipeline 6 Product Indication Preclinical POC Preclinical INDenabling Phase I Phase II BT-11 CD * BT-11 UC NX-13 UC/CD BT-63 T1D BT-63 Lupus INT10 CDI BT-110 Flu BT-13 RA New Assets to IND by Oct 2019

7 BT-11 Target Product Profile For CD & UC 7 Product Name BT-11 Lead Competitor (TNF- blockers) Prime Therapeutic Indications ROA/Dosage 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. 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) and a pig model of IBD. Benign safety profile up to 1,000 mg/kg p.o. in dogs and rats without dose-limiting safety issues. 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 Oral Route Of Administration 10 In support of it local action in the GI tract, oral and rectal BT-11 administration protects from IBD, but I.V. administration of BT-11 fails to protect from IBD. 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 ,

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 sign, 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 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 anticipated in Q

15 Phase 1: Safety and Tolerability 15 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

16 Phase 2 UC: Induction phase followed by maintenance phase extension study (based on interim futility analysis at wk 12) 16 High or Low Dose Induction Phase Stage 1 - Phase 2, randomized, double-blind, placebo-controlled, parallel-group (Efficacy and Safety) INDUCTION PHASE Arm 1 BT-11 (500 mg) (n=65) Arm 2 BT-11 (1,000 mg) (n=65) Arm 3 Placebo (n=65) Interim Analysis at Week 12 to evaluate efficacy and safety UC Patients with mild to moderate disease achieving clinical remission move to maintenance study. Maintenance Phase Stage 2 Study Extension MAINTENANCE PHASE (52 weeks) Extension Arm (randomized, double-blind), placebo controlled, to evaluate long term efficacy and safety

17 Development Timeline IND Enabling File INDs Ph 1 Phase 2 Phase 3 UC NDA Series A $10M Series B $60M IPO $200M Phase 3 CD

18 Leadership Team 18 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 $4B publicly traded company. Simon J. Tulloch, MD Senior 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 business from $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.

19 Clinical Advisory Board - IBD 19 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.

20 Financing Series B Scenarios ( ) 20

21 Phase 2 Exit Comparables 21 Plexxikon: Daiichi Sankyo $835M upfront with $130M in milestones (SMALL MOLECULE) Nogra Pharma: Celgene acquired Mongersen (GED0301) for $710M upfront with $1.9B in development and sales milestones (ORALLY ACTIVE AND LOCALLY ACTING SMALL MOLECULE) Protagonist: J&J commits $990M for an oral Crohn s drug PTG-200 targets IL-23 receptor (ORAL PEPTIDE THERAPEUTIC) Theravance: J&J launched a $1B partnership on the pan-jak inhibitor (TD-1473) with $100M cash upfront in a milestone-driven deal (ORALLY ACTIVE AND LOCALLY ACTING SMALL MOLECULE)

22 Summary and Conclusions 22 Two Open INDs June and August 2018 Begin Ph 2 clinical testing by Q Completed Ph 1 human clinical testing Q IPO by Q Landos is uniquely positioned to develop oral, firstin-class IBD therapeutics, a $10 billion market. Innovative MoA (LANCL2) 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 therapeutic development plans. Financial backing of Perceptive Advisors and partnering with Xontogeny for incremental operational expertise and access to talent. Seeking $60M private placement for Series B financing round.

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

24 APPENDIX 24

25 Phase 2 UC Proof-of-Concept (POC) Study 25 Phase/Study Population Design Outcomes Comments/Purpose mild to moderate UC patients DB, RCT PC, PG, MC 12- wk induct/52 wk maint. Clinical remission, biomarkers, PK Establish POC efficacy safety of BT-11 in CD Study Type Study Title Objective Clinical Endpoints Subjects Study Drugs Study Design Number of subjects Dosing Period IE Criteria Dose Range Finding Study Phase 2 randomized, double-blind placebo controlled, multicenter study to evaluate the efficacy/safety of oral BT-11 in UC patients with mild to moderate disease. To establish POC efficacy and safety of orally administered BT-11 in UC patients. Co-Primary Endpoints are clinical remission based on: abdominal pain, rectal bleeding, and reduction in MCS to 0-1 (endoscopic mucosal healing) at wk 12 and 52. Secondary Endpoints are safety, PK modeling, and biomarkers. 195 UC patients with mild to moderate disease aged 18-75, male or female Oral once-a-day tablet dosing for 12 wk (proposed extension arm of 52 wk). UC patients will be randomized to low (n=65) or high (n=65) dose oral BT-11, or placebo (n=65). Visits at baseline and d 45 and 90 to collect blood, feces and endoscopy. Extension to 52 wk for responders. 195 patients with moderate to severe UC. 90-day daily dosing (induction phase) with extension of 52 wks (maintenance phase). UC patients with mild to moderate disease (Mayo Score 4-10) at baseline with endoscopy score >2, disease progression on ASA (Mesalamine failures) aged 18-75, male or female.

26 Phase 2 CD: Induction phase followed by maintenance phase extension study (based on interim futility analysis at wk 12) 26 High or Low Dose Induction Phase Stage 1 - Phase 2, randomized, double-blind, placebo-controlled, parallel-group (Efficacy and Safety) INDUCTION PHASE Arm 1 BT-11 (High Dose) (n=65) Arm 2 Placebo (n=65) Interim Analysis at Week 12 to evaluate efficacy and safety CD Patients with moderate to severe disease achieving clinical remission move to maintenance study. Maintenance Phase Stage 2 Study Extension MAINTENANCE PHASE (52 weeks) Extension Arm (randomized, double-blind), placebo controlled, to evaluate long term efficacy and safety

27 Phase 2 CD Proof-of-Concept (POC) Study 27 Phase/Study Population Design Outcomes Comments/Purpose moderate to severe CD patients Study Type Study Title Objective Dose Range Finding Study DB, RCT, PC, PG, MC, 12- wk induct/52-wk maint Clinical remission, biomarkers, PK Establish POC efficacy safety of BT-11 in CD Phase 2 randomized, double-blind placebo controlled, multicenter study to evaluate the efficacy/safety of oral BT-11 in CD patients with moderate to severe disease. To establish POC efficacy and safety of orally administered BT-11 in CD patients. Clinical Endpoints Co-Primary Endpoints are clinical remission based on: abdominal pain, stool frequency (PRO2) and 50% reduction SES-CD from baseline (endoscopic mucosal healing) at wk 12 and 52. Secondary Endpoints are safety, PK modeling, and biomarkers. Subjects Study Drugs 130 CD patients with moderate to severe disease aged 18-75, male or female Oral once-a-day tablet dosing for 12 wk (proposed extension to 48 wk). Study Design CD patients will be randomized to oral BT-11 (n=65) or placebo (n=65). Visits at baseline and d 45 and 90 to collect blood, feces and endoscopy. Extension arm to 52 wk. Number of subjects Dosing Period 130 patients with moderate to severe CD for 90 days. 90-day daily dosing (induction phase) with extension into a maintenance phase up to 52 weeks. IE Criteria CD patients with moderate to severe diseases aged 18-75, male or female. SES-CD > 6.

28 CMC Studies 28 The CMC profile of BT-11 Drug Substance: Easy and inexpensive production with low COG Low solubility and low absorption Reproducible chemistry with only 4-step synthesis 99% purity even at lab scale Stable and scalable The CMC profile of BT-11 Drug Product: Current formulation is a tablet No unusual risks for tablet formulation anticipated ROA for BT-11 will be oral in humans Exploring oral modified release formulation Site-directed release to improve efficacy/dose frequency

29 BT-11 Versus Standard-of-Care 29 LANCL2-targeting BT-11 BT-11 will have an oral ROA BT-11 will have lower COG BT-11 will have a better safety profile VS Biologics TNF- blockers Limited Efficacy Negative safety profile Expensive and IV ROA

30 BT-11 & LANCL2 Publications 30 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 ,

31 BT-11/LANCL2 Publications 31 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, BassaganyaRiera 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: Lu P, Hontecillas R, Horne WT, Carbo A, Viladomiu M, Pedragosa M, Bevan DR, Lewis SN, Bassaganya-Riera J. Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like 2. PLoS One. 2012;7(4):e doi: /journal.pone PubMed PMID: ; PubMed Central PMCID: PMC 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): Lu P, Bevan DR, Lewis SN, Hontecillas R, Bassaganya-Riera J. Molecular modeling of lanthionine synthetase C-like 2: a potential target for the discovery of novel type 2 diabetes prophylactics and therapeutics. J Mol Model Mar;17(3): doi: /s y. PubMed PMID:

32 Patent List 32 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