Developing Novel Treatments for Autoimmune Diseases

Transcription

1 A C C E L E R AT E D PAT H T O C U R E S Developing Novel Treatments for Autoimmune Diseases W W W. L A N D O S B I O P H A R M A. C O M

2 LANDOS STRENGTHS 2 Scientific, Clinical and Business Leadership Expandable Oral Therapeutic Pipeline Financially Stable Raised $10M Series A to advance Lead to Phase 1 TECHNOLOGY First-in-class oral therapeutics with a unique MoA targeting LANCL2 Advancing Lead Candidate in Crohn s and Ulcerative colitis Product Development Successful PreIND for BT-11 Into the clinic in 2018 Validation Strong animal pharmacology in 5 IBD models, toxicology and human translation Strong IP 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 AGENDA 3 Unmet Clinical Needs in IBD Targeting LANCL2 Landos Pipeline BT-11 Clinical Plan and Data Leadership Team Financials Investment Catalysts

4 CROHN S DISEASE AND ULCERATIVE COLITIS 4 IBD afflicts 2 million in the U.S. and 5 million people worldwide 5M afflicted $10B market 25% growth 70-90% will require surgery 100,000 hospitalizations

5 THE IBD MARKET: $10B 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 CREB AC PKA BT-11 LANCL2 camp 5 AMP ATP Activates IL-10 & FOXP3 Inhibits TNF- & IFN-g HOW LANCL2 WORKS LANCL2 activation by BT-11 intercepts IBD at two levels: by decreasing the production of inflammatory mediators (TNF, IFNg, MCP1) and increasing antiinflammatory molecules (IL-10, FOXP3) in the GI tract. First in class compounds with oral ROA and local GI action BT-11, 48 scaffolds, and 3 billion NCEs composition of matter claims allowed in USPT 9,556,146; 2017 & 9,839,635 in 2018; 15 countries Both method of use and composition of matter claims for IBD, RA, T1D, T2D, and influenza

7 EXPANSIBLE THERAPEUTIC PIPELINE 7 Product Indication Preclinical POC Preclinical INDenabling Phase I Phase II BT-11 CD * BT-11 UC BT-15 T2D BT-ABA-5a T2D ABA T2D BT- 12/INT10 T1D BT-110 Flu BT-13 RA BT-11 will complete CMC and GLP Tox by Q1 2018, file 2 INDs in 2018, and complete Phase I by early 2019.

8 BT-11 TARGET PRODUCT PROFILE FOR CD & UC 8 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 moderate to severe UC. Oral once-a-day dosing through a tablet until symptoms alleviate (8 mg/kg in mouse 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-, IFNg, MCP-1, IL-6 Neutralization of TNF- Efficacy in 5 validated mouse models (8 mg/kg) Variable degrees of efficacy in 3 mouse models Benign safety profile up to 1,000 mg/kg p.o. in dogs and rats without dose-limiting safety issues. Increased risk for cancer (T cell lymphoma), infection and death

9 EFFICACY OF BT-11 IN 5 VALIDATED MOUSE MODELS OF IBD 9 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-a

10 BT-11 TARGETS LANCL2 IN THE GI TRACT 10 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

11 ORAL ROUTE OF ADMINISTRATION 11 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.

12 HUMAN TRANSLATIONAL DATA 12 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 IFNg

13 BT-11 HAS DEMONSTRATED BENIGN SAFETY PROFILE 13 BT-11 is negative in genotoxicity studies such as the Ames test up to 5,000 µg/plate; herg screening Single medium/high dose in rats (0 or 500 mg/kg) 7-day assessment & recovery. Multiple Moderate dose in rats (0 or 80 mg/kg) 14-day assessment & recovery DRF Studies in rats and dogs (0, 250, 500, and 1,000 mg/kg) 7-day assessment & recovery and safety pharmacology 28-day tox assessment & recovery in male and female rats (1,000 mg/kg) GLP 12-week assessment & 2 week recovery in rats (complete) and dogs (ongoing); 9 and 6 month dosing to support continuous dosing of BT-11 (post-ind). No dose-limiting safety issues.

14 BT-11 OUTPERFORMS CURRENT DRUGS AND INDs 14

15 BT-11 CAN DISRUPT THE IBD Rx PARADIGM 15 Our data indicate that BT-11 could be steroid-, biologicsand even surgery-sparing 5 ASA 6 MP Immunosuppresant TNFα blockers BT-11 / LANDOS technology Corticosteroids α4b7 blockers Surgery Current therapies are modestly successful with undesired side effects

16 GO-TO-MARKET TIMELINE IND Enabling File INDs Phase 1 Phase 2a Phase 2b NDA Series A $10M Series B $30M IPO Phase 3

17 LEADERSHIP TEAM 17 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.

18 CLINICAL ADVISORY BOARD - IBD 18 FABIO COMINELLI, MD, PHD Crohn s Disease Human Clinical Trials Director of the UH Case Medical Center. 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. 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 Caphel 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). DR. 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 precrlinical models and clinical studies.

19 FINANCING 19 IND-Enabling Studies: $2.5M GLP Toxicology Studies, Safety Pharmacology, Drug ProductFormulation and CMC, IND Filing Series A (IND Enabling & Ph. I): $10M Series B Fall 2018 (Ph. 2a, 2b): $30M Estimated time to file IND: 6 months Oral Continuous Dosing: $3M Human Clinical Studies: $30M Phase 1, 2a, 2b CMC GLP Tox IND filing Phase 1 Phase 2a Phase 2b Estimated time to complete Phase 1: 1 year The FDA has responded positively to the IND-enabling plan and future clinical trials. Pre-IND meeting minutes available.

20 PHASE 2 EXIT COMPARABLES 20 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)

21 SUMMARY AND CONCLUSIONS 21 File 2 INDs by Q Complete Phase 2a studies by 2021 Start Ph. 1 human clinical testing by Q IPO by 2021 Landos is uniquely positioned to develop oral, first-in-class IBD therapeutics, a $10 billion market. Innovative MoA (LANCL2) with strong IP protection (NCEs & target). Strong animal pharmacology, MoA, toxicology, and translational data. Committed leadership with autoimmune disease and biopharma industry experience ready to execute therapeutic development plans. Partnering with Xontogeny for incremental operational expertise and access to talent. Raised $10M Series A from Perceptive Advisors and seeking $30M for Series B financing.

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

23 APPENDIX 23

24 LANDOS ACCELERATED PATH TO CURES 24

25 CURRENT IBD TREATMENT PARADIGM 25 5 ASA 6 MP Immunosuppresant TNFα blockers Severity of disease Corticosteroids α4b7 blockers Surgery Biologics for IBD cost $40,000 to $50,000/patient/year Side effects include cancer, infection and death

26 CMC STUDIES IN THE NEXT 6 MONTHS 26 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

27 Phase 1/1 SAD Study 27 Phase/Study Population Design Outcomes Comments/Purpose 1/1 Up to 40 normal healthy volunteers Study Type Study Title Objective Clinical Endpoints Subjects Single Ascending Dose Phase 1 SAD Clinical Pharmacology Study Safety, tolerability, PK Single escalating dose study of tolerability and PK of BT-11 oral administration. The goal will be to establish the human single dose MTD. Primary: To monitor safety and tolerability Secondary: PK profile and local bioavailability in humans Normal healthy volunteers (NHV) aged 18-60, male or female Study Drugs Single doses of BT-11 with control tablets administered in 4-5 cohorts of 8 Study Design Number of subjects Dosing Period IE Criteria Establish maximum tolerated dose (MTD) Subjects will be randomized to BT-11 (n=6) or placebo (n=2) in 4-5 cohorts of escalating doses. 1/100 th of NOAEL; 10 mg/kg and increasing twofold until maximum feasible dose (anticipated to be 8 g as a single dose). 8 NHV in 5 cohorts sequestered for 48 h Single dose. NHV aged 18-60, male or (functionally sterile) female.

28 Phase 1/2 MAD Study 28 Phase/Study Population Design Outcomes Comments/Purpose 1/2 Up to 40 normal healthy volunteers Multiple Ascending Dose Safety, tolerability, PK Establish maximum tolerated dose (MTD) Study Type Study Title Objective Clinical Endpoints Subjects Study Drugs Study Design Number of subjects Dosing Period IE Criteria Phase 1 MAD Cinical Pharmacology Study 7-d repeat escalating dose study of tolerability and PK of BT-11 oral administration. The goal will be to establish the human repeat dose MTD. Primary: To monitor safety and tolerability Secondary: PK profile and local bioavailability in humans 40 normal healthy volunteers (NHV) aged 18-60, male or female 7-d dosing of BT-11 or placebo control tablets Subjects will be randomized to BT-11 (n=8) or placebo (n=2) in 4 cohorts of escalating doses. 1/100 th of NOAEL; 10 mg/kg and increasing twofold until maximum feasible dose (anticipated to be 8 g as a single dose). 40 NHV (10 NHV in 4 cohorts) 7-d daily dosing NHV aged 18-60, male or (functionally sterile) female.

29 Power Calculations for BT-11 Clinical Trials 29 Based on preliminary results from human peripheral blood mononuclear cells, we estimate a minimum mean difference between vehicle and BT-11 to be 1.7 with a SD 1.8 for the main endpoint measures. For an alpha = 0.05 and a projected 40% increase in variance, a sample size 18 will achieve 81% statistical power in a two-tailed test. Most studies using CDAI use 50 patients per group. SES-CD has added statistical efficiency to patients per group.

30 Phase 1b UC PK/Biomarker Study 30 Phase/Study Population Design Outcomes Comments/Purpose 1b Up to 72 UC patients DB, RCT, placebocontrolled 12-wk Safety, tolerability, PK Establish PK and biomarkers in UC Study Type Study Title Objective Clinical Endpoints Subjects Study Drugs Study Design Number of subjects Dosing Period IE Criteria Phase 1b UC Study 12-wk study of tolerability and PK of BT-11 oral administration. The goal will be to establish the PK profile and biomarkers in UC Primary: To monitor safety and tolerability Secondary: PK profile, biomarkers, and local bioavailability in humans 72 UC patients aged 18-60, male or female 12-wk dosing of BT-11 low dose (n=18), BT-11 medium dose (n=18), BT-11 high dose (n=18) or placebo tablets (n=18) Subjects will be randomized to BT-11 at 8 mg/kg (n=10) or placebo (n=10), PK at d 1, d7; cytokines (IFN-g, TNF-a, IL-6, IL-10) in PBMC and LPMC, CRP, and fecal calprotectin. 72 mild to moderate UC patients 12-wk daily dosing Mild to moderate UC patients aged 18-60, male or (functionally sterile) female.

31 Phase 2 CD Proof-of-Concept (POC) Study 31 Phase/Study Population Design Outcomes Comments/Purpose moderate to severe CD patients Study Type Study Title Objective Clinical Endpoints Subjects Study Drugs Dose Range Finding Study DB, RCT placebocontrolled 12-wk 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. 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. Secondary Endpoints are safety, PK modeling, and biomarkers. 130 CD patients with moderate to severe disease aged 18-60, 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 to 48 wk of responders. Number of subjects Dosing Period 130 patients with moderate to severe CD for 90 days. 90-day daily dosing. IE Criteria CD patients with moderate to severe diseases aged 18-60, male or female. SES-CD > 6

32 Phase 2 UC Proof-of-Concept (POC) Study 32 Phase/Study Population Design Outcomes Comments/Purpose moderate to severe UC patients Study Type Study Title Objective Clinical Endpoints Subjects Study Drugs Dose Range Finding Study DB, RCT placebocontrolled 12-wk 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 UC patients with moderate to severe 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. Secondary Endpoints are safety, PK modeling, and biomarkers. 130 CD patients with moderate to severe disease aged 18-60, male or female Oral once-a-day tablet dosing for 12 wk (proposed extension to 49 wk). Study Design UC 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 to 48 wk of responders. Number of subjects Dosing Period IE Criteria 130 patients with moderate to severe UC for 90 days. 90-day daily dosing. UC patients with moderate to severe disease (Mayo Score 6-12) at baseline with endoscopy score >2, disease progression on ASA (Mesalamine failures) aged 18-60, male or female.

33 BT-11 VERSUS STANDARD-OF-CARE 33 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

34 BT-11 & LANCL2 PUBLICATIONS 34 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 In press

35 BT-11/LANCL2 PUBLICATIONS 35 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: Lu P, Hontecillas R, Horne WT, Carbo A, Viladomiu M, Pedragosa M, Bevan DR, Lewis SN, Bassaganya-Riera J. Computational modelingbased 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:

36 PATENT LIST 36