Developing Novel Treatments for Autoimmune Diseases - January 2020
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Developing Novel Treatments for
Autoimmune Diseases
January 2020
11
New Immunometabolic Targets Addressing Unmet Needs in Autoimmunity
Pioneering Research Platform
• Advanced computational platform applied to the discovery of new therapeutic targets
• Top targets identified and validated experimentally (LANCL2 and NLRX1)
Clinical Stage Asset
• Lead asset, BT-11 is an orally active, gut-restricted, first-in-class therapeutic with limited systemic exposure and a benign safety profile
• BT-11 entered Phase 2 clinical trials in UC and planning CD studies
Pipeline
• Assets in several autoimmune indications (Lupus, Irritable Bowel Syndrome, Rheumatoid Arthritis, Multiple Sclerosis, Type 1 Diabetes)
• First-in-class compounds with oral route of administration
Strong IP and Financial Position
• Composition of matter and method of use IP with long patent life
• $10M Series A with Perceptive Advisors in 2017 & $60M Series B co-led by Perceptive Advisors and RTW Investments in 2019
2
Landos Accomplishments
2017 2018 2019
• Company founded • IND filed for BT-11 in UC • Initiated patient enrollment for Phase 2 UC
• Medicinal Chemistry and preclinical • IND filed for BT-11 in CD • Publishing of Phase 1 data BT-11 in
testing on oral, gut-restricted LANCL2 Inflammatory Bowel Diseases
agonists in 5 mouse models • BT-11 tablet formulation completed
• NX-13 composition of matter patent issued
• BT-11 composition of matter patent • Completed pig studies
issued • Initiated Phase 2 study set for CD
• BT-11 clinical development initiated
• BT-11 publication in J. Med Chem. • NX-13 publications in J. Immunology and
• BT-11 translational publication in Drug and Chemical Toxicology
• $10M Series A Inflammatory Bowel Diseases
• Initiated NX-13 Preclinical studies
• Scaled up manufacturing of BT-11 • NLRX1 publication in Frontiers of
Immunology • Initiated Phase 2 UC study
• Initiated IND-enabling studies for BT-11
• Completed BT-11 Phase 1 trial • $60M Series B round
3
Landos Leadership Team
Dr. Josep Bassaganya-Riera Dr. Andrew Leber
Chairman, President, and CEO Scientific Director
Biotech entrepreneur and innovator with 20 His expertise spans immunology and
years of scientific innovation in drug development for autoimmune disease with
development, business development and specific focus on immunometabolism and
fundraising experience. development of therapeutics for CD & UC.
Dr. Raquel Hontecillas Jennifer Collette, MSA, CPA
Chief Scientific Officer Finance Director
20 years of translational experience in 15 years of experience in accounting and
immunology, drug development, and the financial systems. Her expertise is in
biotech industry focusing on infectious, technical & project accounting, budgets,
autoimmune, and metabolic diseases. controls, and financial reporting.
Jyoti Chauhan, MS, RAC Dr. Simon Lichtiger
Executive Director, Global Clinical Ops & Medical Director
Regulatory Compliance Clinical gastroenterologist and internal
Expertise encompassing strategic medicine expert with over 40 years of
regulatory liaising with focus on policy experience in CD and UC Phase 2 & 3
analysis and filings, product development clinical trials.
lifecycle & clinical trials management.
4
Landos Board of Directors
Dr. Josep Bassaganya-Riera
Chairman, President and CEO
Chris Garabedian
Xontogeny Perceptive Advisors
Board Member
Konstantin Poukalov
Perceptive Advisors
Board Member
Rod Wong
Managing Partner, RTW Investments
Board Member
5
Landos Clinical Advisory Board for CD & UC
Fabio Cominelli, MD Jean-Frederic Colombel, MD
Director of the UH Case Medical Center, Director of the Helmsley IBD Center at Mount
Cleveland, OH. Sinai, NYC, NY.
Maria T. Abreu, MD
William Sandborn, MD
Faculty of University of Miami Health System,
Chief, Division of Gastroenterology
Miami, FL.
and Professor of Medicine at UC San
Diego Health, CA.
Francisco A. Sylvester, MD Asher Kornbluth, MD
Division Chief for Pediatric Gastroenterology Clinical Professor, Mount Sinai School of
at UNC Chapel Hill, NC. Medicine, NYC, NY.
6
Broad Pipeline of Candidates with Novel Mechanisms
Upcoming Milestones
Q3 2020: Phase 2 UC BT-11 Data Readout
Q3 2020: Clinical testing of NX-13
7
Projected Milestones
2020 2021
• Begin dosing BT-11 Phase 2 in CD • Begin dosing for BT-11 Phase 3 study in CD
• Scale up manufacturing of NX-13 • Begin NX-13 Phase 2 study in UC
• Begin NX-13 Phase 1 human trial • Begin BT-104 Phase 1 human trial
• Double the number of employees • Begin BT-111 Phase 1 human trial
• Data readout for BT-11 Phase 2 study in UC • Data readout for BT-11 Phase 2 CD study
• Initiate BT-11 Phase 3 study in UC
8
Advanced Computational Target Discovery Engine
Applying AI to New Therapeutic Target Identification
• Machine learning/AI-based analysis of gene
expression and proteomic data from multiple sources
• Identifies blindspots, or missing linkages, in
regulatory and immunometabolic pathways at
critical nodes for control
• AI-based filter for prognostic druggability for targets
(i.e., localization, binding domains, interactions)
• Modeling at multiple scales using ordinary
differential equation/agent-based modeling
• Accelerate development of new targets based on
predictive potency
• Platform has led to identification of five new targets
9
BT-11 Selectively Activates Novel Target LANCL2 in the Gut
10BT-11 Acts to Reduce Inflammation Through Multiple Mechanisms
• BT-11 Multimodal MoA: BT-11
– Decreases the production of inflammatory mediators tied to
IBD (TNF⍺, IFNγ, MCP1, IL-6, and IL-8)
– Increases anti-inflammatory molecules in Tregs that protect LANCL2
from autoimmunity (IL-10, FOXP3)
• BT-11 generates suppressive regulatory CD4+ T cells AC
5’AMP
cAMP
(Tregs) that restore and maintain immune tolerance in
the GI tract
– Decrease proliferation and differentiation of effector CD4+ T PKA ATP
cells (Th1 and Th17)
– Aid in epithelial cell and support the reduction of IL-8 and
chemokine-dependent neutrophil influx Activates IL-10 & FOXP3
CREB
Inhibits TNF-⍺ & IFN-γ
Leber, A., et al. J Immunol, 2019.
11Oral, gut-restricted small molecule BT-11 activates novel target LANCL2
Lanthionine Synthetase C-Like 2
• Multipronged mechanism of action targeting downstream
known immunological targets tied to autoimmune diseases,
including IBD.
• BT-11 enhances CD25/STAT5 signaling to support the stable
differentiation of regulatory CD4+ T cells with greater anti-
inflammatory functionality.
• BT-11 increases PDH activity, resulting in increased oxidative
metabolism supporting FOXP3 stability.
• BT-11 downregulates glycolytic pathways associated with
TNF-a production and effector CD4+ T cells, including
production of lactate and over-expression of ENO1.
• BT-11 increases suppressive effects of Tregs due to enhanced
immune checkpoint surface markers (LAG3 and PD-1).
Leber, A., et al. Inflammatory Bowel Diseases. 2018 24:1978-1991.
Carbo, A., et al. J Med Chem. 2016 Nov 23;59(22):10113-10126.
Leber, A., et al. J Immunol, 2019.
12BT-11 Acts Locally in the GI Tract Without Systemic Distribution
Oral > 99 % Intestinal
dosage contents
8 – 12 %
0.01 – 0.1 %
Intestinal
tissue
Blood Urine
Metabolized
13BT-11 Rebalances the Human Immune Response
Treating human PBMCs from Crohn’s disease
patients with increasing concentrations of BT-11
induced IL-10 production and expression of FOXP3
while suppressing production of TNF⍺ and IFNγ
14Better Preclinical Efficacy vs. Aminosalicylates, JAK inhibitors, anti-TNFα
Disease Activity Index 105 % Weight Loss
5
* *
* *
4 *
% weight loss
100 Vehicle
* *
Score DAI
3 BT-11
*
Anti-TNF alpha
2
95
5’ASA
***
1 *** ***
***
*** ***
0 0
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7
Days Post-DSS Days Post-DSS
Leukocytic Infiltration wild-type Leukocytic Infiltration LANCL2 -/-
4 4
* *
3 * 3
** Vehicle
Score
Score
BT-11
2 2
Anti-TNF alpha
5’ASA
1 1
**
0 0
1 2 3 4 1 2 3 4
15Highly Favorable Effects on Biomarkers Compared to Existing Treatments
Th1
Oral BT-11 treatment when compared 80 Calprotectin 2.5 CD45+ CD4+ CD8- Tbet+ IFNg+
to other treatment modalities:
2.0
60
% CD45
1.5
• Lower fecal calprotectin levels
μg/g
40
• Lower Th1 inflammatory cells in the 1.0
*
colon 20
* 0.5
• Lower Th17 inflammatory cells in 0
*
0.0
the colon
• Higher numbers of Treg anti- Treg Th17
0.8 CD4+ CD25+ FOXP3+ IL10+ 2.0
inflammatory cells in the colon that CD3+ CD4+ RORgt+ IL17+
express FOXP3 and IL-10 0.6 * 1.5
% CD45
% CD45
0.4 1.0
0.2 0.5 *
0.0 0.0
16BT-11 Phase 1 Dose-Finding Study in Healthy Volunteers
Completed BT-11 Phase 1 Study (SAD/MAD)
• Study Objective: To assess the safety and tolerability of BT-11 after single and multiple ascending oral dose
administration in healthy volunteers, and to characterize the PK profile of BT-11
• Study Design: This is a double-blind, placebo-controlled, ascending dose, multicohort trial. The study was
conducted with a single ascending dose (SAD) phase and a multiple ascending dose (MAD) phase
• Population: Male or female normal healthy volunteers (NHV) aged 18 and over at the time of signing the
informed consent, no prior use of any prescription medication
• Study Dosing:
– For SAD five dose target ranges of BT-11 (depending on body weight the doses in each cohort were 7.7 mg/kg;
25.0 mg/kg; 50.0 mg/kg; 75 mg/kg and 100.0 mg/kg) were evaluated
– For MAD (once daily for 7 days), three dose target ranges of BT-11 (depending on body weight the doses in
each cohort were 7.7 mg/kg; 50.0 mg/kg; and 100.0 mg/kg) were evaluated
17Phase 1 Dose-Finding Study Establishes Positive Safety Profile
Oral dosing of BT-11 does not induce systemic immunosuppression (observed with other IBD therapeutics)
Single Ascending Dose Multiple Ascending Dose
18BT-11 Reaches High Concentrations Within the Gut
• BT-11 is observed in high concentrations in feces after both single- and seven-day dosing
• GI concentrations are 6,000 times higher than Cmax levels found in plasma
• Results confirm that BT-11 is stable within the gut and reaches the rectum in high concentration at proposed low
dose level (7-14 mg/kg, total doses for the planned Phase 2 studies)
19BT-11 Reduces Calprotectin in Stool, an Indicator of Inflammation in IBD
• Fecal calprotectin is a biochemical measurement of the protein calprotectin in the stool
• Elevated fecal calprotectin indicates the migration of neutrophils to the intestinal mucosa, which occurs during
intestinal inflammation
SAD: Calprotectin (day 2) MAD: Calprotectin (day 7)
20IBD Treatment Paradigm
Mild to Moderate UC Moderate to Severe CD
IL-12/IL-23
Stelara
Immunosuppressants Oral Approaches S1P1,
Aminosalicylates (5-ASA) 6-MP, Azathioprine, TNF-alpha inhibitors JAK Pathways
Balsalazide, Mesalamine Cyclosporine, Methotrexate Humira*, Remicade, Cimzia Xeljanz, Ozanimod, Etrasimod
Corticosteroids Alpha-4-beta-7 integrin Surgery
Prednisone Entyvio Proctocolectomy,
Ileostomy
*Targeting a projected
2024 annual market of Landos Therapeutic Candidates
$4B in UC and $5B in CD BT-11 & NX-13
(GlobalData)
21UC and CD Sales – 2019 and Forecasted 2024
BT-11 & NX-13 BT-11 & NX-13
are uniquely are uniquely
positioned to positioned to
capture capture
patients prior patients prior
to biologics to biologics
targeting a targeting a
total UC total CD
market share market share
about $4B in about $5B in
2024 2024
22Phase 2 Study Design in ulcerative colitis
23Phase 2 Study Design in Crohn’s disease
24NX-13: Pipeline Asset Overview
• Indications: Ulcerative Colitis and Crohn’s Disease
• Mechanism of Action: Activation of the NLRX1 pathway to decrease cellular reactive oxygen species and NF-kB
activation and to reduce differentiation of effector CD4+ T cells.
• Therapeutic Efficacy: Oral efficacy confirmed in 3 mouse models and PBMCs from UC and CD patients
• Drug Profile: NX-13 is orally active, gut-restricted allowing target engagement within the GI tract without systemic
distribution
• Safety/Tolerability: Benign safety profile up to 1,000 mg/kg p.o. in 7-day rat studies. Full IND-enabling studies
are ongoing with projected completion by Q2 2020.
• Clinical studies: Phase I studies in normal healthy volunteers and UC patients
- Safety, Tolerability and Pharmacokinetics of Oral NX-13 in NHVs
- First Subject to be Dosed: Q2 2020
25NX-13: Potential for Complementary or Combination IBD Therapy
• NLRX1 is a mitochondria-associated receptor with the ability to modulate immune responses
• NX-13 has site-specific binding to NLRX1
• NX-13 increases oxidative phosphorylation in immune cells, resulting in decreased NF-κB activity and
lower production of inflammatory cytokines
• Potent effects in IBD models
Calprotectin in Stool
CD45RBhi adoptive transfer model DSS challenge model of colitis
Leber, A., et al. J Immunol, 2019.
26Summary and Conclusions
Two Open INDs
for UC and CD in • Landos is uniquely positioned to develop new oral, first-in-class
June and August therapeutics for autoimmune diseases
2018
• Innovative MoA based on novel targets (LANCL2, NLRX1) with strong
intellectual property protection
Completed Phase 1
human clinical • Extensive animal pharmacology, MoA, toxicology, benign safety profile
trials for BT-11 in and human translational data
2018
• Committed leadership with autoimmune disease and biopharma
industry experience in effectively executing clinical development plans
Initiated global
Phase 2 clinical • Strong financial position with backing of investors co-led by
study for BT-11 in Perceptive Advisors, RTW Investments, and a robust crossover
UC in 2019 syndicate
27Thank you
Dr. Josep Bassaganya-Riera
jbr@landosbiopharma.com
www.landosbiopharma.com
28BT-11 & LANCL2 Publications
Leber, A., Hontecillas, R., Zoccoli-Rodriguez, V., Colombel, J-F., Chauhan, J., Ehrich, M., Farinola, N., Bassaganya-Riera, J. Safety,
tolerability and PK of BT-11, an oral, gut-restricted LANCL2 agonist investigational new drug for IBD: A randomized, double-blind,
placebo-controlled Phase 1 clinical trial, Inflammatory Bowel Diseases 2019. PMID: 31077582
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, 2019. PMID: 30760618 DOI: 10.4049/jimmunol.1801446
Leber, A., Hontecillas, R., Zoccoli-Rodriguez, V., Ehrich, M., Davis, J., Chauhan, J., Bassaganya-Riera, J. Nonclinical toxicology and
toxicokinetic profile of an oral LANCL2 agonist, BT-11. Int J Tox, 2019. PMID: 30791754 DOI: 10.1177/1091581819827509
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. Inflammatory Bowel Diseases. 2018 24:1978-1991.
PMID: 29718324 PMCID: PMC6241665
Carbo A., Gandour RD, Hontecillas R, Philipson N, Uren A, Bassaganya-Riera J. An N,N Bis(benzimidazolylpicolinoyl)piperazine (BT-11):
A Novel LANCL2-Based Therapeutic for Inflammatory Bowel Disease. J Med Chem. 2016 Nov 23;59(22):10113- 10126. PubMed PMID:
27933891.
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. 2016 Sep;35(5):521-9. doi: 10.1177/1091581816646356. PubMed PMID: 27230993; PubMed Central PMCID: PMC5033715.
29NX-13 & NLRX1 Publications
Leber, A., Hontecillas, R., Zoccoli-Rodriguez, V., Bienert, C., Chauhan, J. and Bassaganya-Riera, J. Activation of NLRX1 by NX-13
ameliorates IBD through immunometabolic mechanisms in CD4+ T cells. J Immunol, PMID: 31694910
Leber, A., Hontecillas, R., Zoccoli-Rodriguez, V., Ehrich, M., Chauhan, J. and Bassaganya-Riera, J. Exploratory Studies with NX-13: Oral
toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1. Drug and
Chemical Toxicology, PMID: 31650868
Leber, A., Hontecillas, R., Tubau-Juni, N., Zoccoli-Rodriguez, V., Abedi, V., and Bassaganya-Riera, J. NLRX1 Modulates
Immunometabolic Mechanisms Controlling the Host-Gut Microbiota Interactions during Inflammatory Bowel Disease. Front Immunol,
2018. PMID: 29535731
Leber, A., Hontecillas, R., Tubau-Juni, N., Zoccoli-Rodriguez, V., Hulver, M., McMillan, R., Eden, K., Allen, IC., and Bassaganya-Riera, J.
NLRX1 regulates effector and metabolic functions of CD4+ T cells. J Immunol, 2017 PMID: 28159898
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