Full Press Release Details
2023 2023 PLIANT THERAPEUTICS
Disclaimers This presentation has been prepared by Pliant Therapeutics,
Inc. ( we, us, our, Pliant or the "Company"). The information set forth herein does not purport to be complete or to contain all of the information you may desire. Statements contained herein are made as of the date of this presentation
unless stated otherwise, and this presentation shall not under any circumstances create an implication that the information contained herein is correct as of any time after such date or that information will be updated or revised to reflect
information that subsequently becomes available or changes occurring after the date hereof. This presentation includes forward-looking statements regarding Pliant's proprietary drug candidates, the timing of the start and conclusion of ongoing
or planned clinical trials, including the timing of, and our ability to achieve, anticipated milestones, the sufficiency of our cash, cash equivalents and short-term investments, the timing and outcome of regulatory decisions, future availability of
clinical trial data, our collaborations for our product candidates and the maintenance of those collaborations; business and results from operations; and other matters. Actual results could differ materially from those contained in any
forward-looking statements as a result of various factors, including without limitation: that Pliant's drug candidates do not advance in development or result in approved products on a timely or cost effective basis or at all; the cost, timing
and results of clinical trials; our ability to manage and mitigate the impact of the ongoing COVID-19 pandemic; that many drug candidates that have completed early-stage trials do not become approved drugs on a timely or cost effective basis or at
all; the ability to enroll patients in clinical trials; possible safety and efficacy concerns; regulatory developments; the ability of Pliant to protect its intellectual property rights, and unexpected costs, charges or expenses that reduce cash
runway. Pliant's pipeline programs are in various stages of pre-clinical and clinical development, and the process by which such pre-clinical or clinical therapeutic candidates could potentially lead to an approved therapeutic is long and
subject to significant risks and uncertainties. Pliant undertakes no obligation to update forward-looking statements as a result of new information or otherwise. For a discussion of these and other risks and uncertainties, and other important
factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" and elsewhere in the Company's most recent Annual Report on Form 10-K and
Quarterly Report on Form 10-Q on file with the Securities and Exchange Commission (the SEC ) and our other filings with the SEC. This presentation also contains estimates and other statistical data made by independent parties and by us relating to
market size and growth and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions, and estimates of our
future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk. This presentation concerns drugs that are under clinical investigation and which have not yet been
approved for marketing by the U.S. Food and Drug Administration (the "FDA"). They are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which
they are being investigated. 2023 PLIANT THERAPEUTICS 2 2
Pliant - Company Highlights Industry-Leading Fibrosis Platform
Programs Targeting High Unmet Medical Need with High-Impact, Near-Term Catalysts Built on integrin-mediated inhibition of TGF- pathway resulting in antifibrotic effect and shown to be safe Bexotegrast in Phase 2a development in
IPF and PSC Phase 2a data in IPF showed bexotegrast was well tolerated with Proprietary drug discovery platform based on novel in-house strong treatment effect on FVC and QLF compound library of integrin binders 320 mg:
positive DSMB review (IPF/ PSC); interim Lead molecule bexotegrast (PLN-74809) is highly antifibrotic in lung 12-week IPF data early 1Q 2023 and liver while well tolerated at highest doses tested IND submitted for PLN-101095: a
potential first in class small molecule dual / inhibitor addressing ICI resistance V 8 V 1 Strategic Partnership with Novartis Validates Platform Strong Financial Position Largest ($80M) upfront for a preclinical
NASH program Over $625 million raised to date including June 2020 IPO (Nasdaq: PLRX) and $230 million follow on July 2022 Significant expense offset to pipeline programs $360.2M cash balance as of September 30, 2022
Broad multi-target research collaboration $100 million loan facility ($10 million drawn) Next generation anti-fibrotic molecules targeting novel integrins Operations funded to mid-2025 2023 PLIANT THERAPEUTICS 3
The Pliant Team Experienced in Fibrosis and Drug Development Core Team
Founders Bernard Coulie, M.D., Ph.D., M.B.A. Dean Sheppard, M.D. President, CEO, and Director Professor of Medicine, Chief of the Division of Pulmonary, Critical Care, Allergy and Sleep, and Director of the Lung Biology Center. Hans Hull, J.D. Chief
Business Officer William DeGrado, Ph.D. Professor of Pharmaceutical Chemistry ric Lefebvre, M.D. Chief Medical Officer Rik Derynck, Ph.D. Keith Cummings, M.D., M.B.A. Professor, Cell and Tissue Biology, Co-Director of Chief Financial Officer
the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research Scott Turner, Ph.D. Senior Vice President, Head of Research Harold Chapman, M.D. Professor of Medicine, Division of Pulmonary, Greg Cosgrove, M.D., FCCP Critical Care,
Allergy and Sleep Vice President, Clinical Development (IPF) 2023 PLIANT THERAPEUTICS 4
Pliant's Integrin Focused Library Core Platform for Novel Pipeline
and Partner Programs Integrins Cell surface receptors that facilitate cell-cell and cell-extracellular matrix adhesion and interaction A major path of communication between the extracellular matrix, inflammatory cells, fibroblasts
Closely involved in signaling processes governing tissue fibrosis Pliant's Proprietary Library of 10,000+ Integrin Binding Compounds Emphasis on optimal pharmacokinetic and selectivity profile Broad spectrum of receptor
subfamilies including integrins, V collagen and laminin binders 2023 PLIANT THERAPEUTICS 5
Pliant Development Pipeline Clinical Anticipated Global Program Indication
Preclinical Milestone Rights Phase I Phase II Phase III Phase 2a Idiopathic 320 mg 12-Week Pulmonary Data Expected Bexotegrast Fibrosis Early 1Q 2023 (PLN-74809) Primary Phase 2a Dual selective inhibitor Sclerosing Data Expected of
/ v 6 v 1 3Q 2023 Cholangitis IND Filed; PLN-101095 Solid Tumors Phase 1 Initiation 2Q 2023 Inhibitor of / v 8 v 1 PLN-101325 DMD IND Filing Other Muscular Anti-integrin mAb of Expected 2023 Dystrophies
7 1 PLN-1474 NASH-Associated Phase 2 Initiation Liver Fibrosis Selective inhibitor of v 1 2023 PLIANT THERAPEUTICS 6 PARTNERED WHOLLY OWNED
Fibrosis - A Silent Killer Idiopathic Pulmonary Fibrosis (IPF) is a
lethal Primary Sclerosing Cholangitis (PSC) is a pathological process with limited therapeutic options progressive inflammatory liver disease resulting in scarring of bile ducts, and cirrhosis 140k patients in the U.S.; 30k-40k new
cases/year; 40k deaths/year 30k-45k patients in the U.S. Median survival: 3-5 years - Worse than some Median survival: 10-12 years without intervention common cancers Currently no FDA approved therapeutics
https://www.lungsandyou.com/ipf www.jhmicall.org 2023 PLIANT THERAPEUTICS 7 7
Bexotegrast Understanding the IPF Commercial Opportunity Current
Commercial Landscape in IPF Significant Need for New Therapeutic Options Two marketed agents - Esbriet and Ofev Esbriet and Ofev display modest slowing of IPF progression >$3 billion total global
revenues in 2021 Inconclusive evidence of survival benefit No improvement on patient quality of life Growing market with positive tailwinds Significant tolerability issues Increasing incidence of IPF with
aging population New therapies expanding treatable population Changing Treatment Landscape Bexotegrast: A Potential Preferred Treatment Option Near-term patent expiry of current treatments Targeted inhibition of fibrotic
process- tissue specific inhibition of TGF- Esbriet: First generic sold May 2022 Once daily oral administration Ofev: Loss of US market exclusivity 2025 (2026 for sscILD) Well tolerated with anti-fibrotic
effect Dose-dependent FVC benefit across all doses, as monotherapy and in combination with current treatments No discontinuations due to adverse events Bexotegrast will be evaluated as backbone therapy to be used as
monotherapy, and with current treatments Esbriet is a trademark of Genentech / Roche Ofev is a trademark of Boehringer Ingelheim International 2023 PLIANT THERAPEUTICS 8
/ Integrins Drive Cell-Matrix Interactions in
Fibrosis v 6 v 1 a b a b b / Integrins promote fibrosis by TGF- activation V 6 V 1 b TGF- is central mediator of fibrosis a b /a b Integrins activate latent TGF-b only in fibrotic tissue V 6 V 1 Systemic TGF-b blockade
carries toxicity risks Selectively blocking TGF-b in fibrotic tissues may provide a low risk, effective antifibrotic approach FIBROSIS Col1a1 Col3a1 Timp1 CTGF ATX 2023 PLIANT THERAPEUTICS 9 9
Bexotegrast Provides Profound Antifibrotic Activity Through Upstream
Inhibition of TGF- Activation bexotegrast FIBROSIS Col1a1 Col3a1 Timp1 CTGF ATX Pamrevlumab b Upstream inhibition of TGF- leads to reduction of multiple profibrotic genes Competitor programs only block one of multiple
profibrotic gene products 2023 PLIANT THERAPEUTICS 10
Pliant Compounds Have Not Shown Adverse Effects Typical of 1 Systemic
Inhibition of TGF- Pathways By targeting integrins that are upregulated specifically in fibrotic tissues, Pliant's small molecule 1 compounds may avoid toxicities associated with systemic TGF- blockade 1 Affected organ system
Systemic TGF- blockade Observed with Pliant compounds? Cardiovascular System Cardiotoxicity NO Immune System Autoimmunity/Inflammation NO GI System Autoimmunity/Inflammation NO Skin Keratoacanthomas/SCC NO Hematology Thrombocytopenia/Anemia NO
1 - Based on preclinical GLP tox studies as well as clinical trials to date. 2023 PLIANT THERAPEUTICS 11 11
Bexotegrast Nonclinical Toxicology Studies No effects of concern for
clinical advancement GLP Study category Studies completed Findings with Bexotegrast (PLN-74809) 1-Month IND-enabling NHP and mouse No findings limiting clinical advancement including 3-Month Sub-chronic NHP and mouse No
pulmonary infiltrates Repeat Dose Toxicology 1 9-Month Chronic NHP NOAEL in sub-chronic and chronic GLP tox studies at the highest dose 6-Month Chronic Mouse tested in NHPs Standard cardiac ion channel panel No findings:
Safety Pharmacology Cardiovascular/respiratory in telemetered NHP No effect on respiratory or cardiovascular parameters Ames No genotoxic findings: Genetic Toxicology In vitro micronucleus Ames negative
In vivo micronucleus Micronucleus negative Mouse Embryofetal Development No findings: Reproductive Toxicology Rabbit Embryofetal Development No embryofetal effects Mouse Fertility No effects on
fertility 600+ human subjects dosed to date with no safety concerns identified at doses up to 640 mg 1 - No observed adverse effect level. 2023 PLIANT THERAPEUTICS 12 12
Fold-change (log2) Dual / Inhibition Blocks
COL1A1 Gene Expression More v 6 v 1 than Single Inhibition in Human IPF Tissue Ex-planted lungs from 5 IPF patients Profibrotic Gene Expression Panel Sliced and cultured for 7 days Selective Dual COL1A1 COL1A1 2 SERPINE1 # MMP7
COL3A1 1 ITGB6 SNAI1 COL1A2 TIMP1 0 MMP2 ACTA2 CTGF -1 MMP1 GUSB HPRT1 -2 RPLP0 # n = 4, all others n = 5 One-way ANOVA Dunnett's mult comp to DMSO *p<0.05, **p<0.01, ***p<0.001,****p<0.0001 Decaris et al. Respir Res (2021) 22:265
2023 PLIANT THERAPEUTICS 13 DMSO SMI v 1 mAb v 6 mAb SMI + v 6 v 1 Bexotegrast (PLN- 74809) Alk5 Inh DMSO av 1 SMI av 6 mAb av 1 SMI + av 6 mAb PLN-74809 Alk5
Bexotegrast Phase 1a Data Summary Pharmacokinetics Pharmacokinetics 10000
C max Well absorbed, orally bio-available 8000 Long T : ~50 hrs - QD dosing 1/2 6000 4000 Summary PK Curves by Cohort at Steady State 2000 Day 7 0 10000 40 80 160 320 Dose (mg) 150000 320 mg AUC 0_24 160 mg 1000 80 mg 100000 40
mg 50000 100 0 0 10 20 30 40 80 160 320 Time (hr) Dose (mg) PK sampling up to 144h; only 0-24hr plotted. Doses 10mg to 40mg from Study Bexotegrast (PLN-74809)-P1-01, Day 14. Data presented as box plots (max to min) with line at median and + at mean.
Doses 80mg, 160mg and 320mg from Study Bexotegrast (PLN-74809)-104, Day 7. 2023 PLIANT THERAPEUTICS 14 14 Concentration (ng/mL) AUC (ng*hr/mL) C (ng/mL) 0_24 max
Bexotegrast Phase 1a Data Summary Safety - Well tolerated in healthy
participants Drug-Related Treatment-Emergent Adverse Events Reported in 2 Bexotegrast -Treated Healthy Participants from Seven Phase 1 Studies with Available Safety Data Participants, n (%) Bexotegrast, TEAE Preferred Term Placebo (n=52) All
doses (n=283) Drug-related Drug-related Headache 4 (1.4) 2 (3.8) Most Bexotegrast-related AEs were mild (82%) and Constipation 4 (1.4) 0 (0.0) none were severe Nausea 3 (1.1) 0 (0.0) Dizziness 2 (0.7) 0 (0.0) Abdominal pain 2 (0.7) 0 (0.0)
Palpitations 2 (0.7) 0 (0.0) Am J Respir Crit Care Med 2022;205:A2437 2023 PLIANT THERAPEUTICS 15
BAL Cell pSmad2 (% change) Bexotegrast Phase 1b Proof of Biological
Mechanism Strong PK/PD Relationship - C above IC max 50 Results in Predicted Biological Effect Phase 1b Expansion Trial Investigating Higher Data Presented June 2019 Doses Data Presented February 2022 Mean PK/PD Response in Subjects with
Alveolar pSMAD2/SMAD2 Randomized, double-blind, placebo-controlled Cmax > 700ng/mL (All Time Points) Alveolar pSMAD2/SMAD2 Treatment duration: 7 days 150 BAL samples taken at 6 hours and 24 hours after last dose on day 7
20 1000 100 0 800 50 PART 1 PART 2 -20 600 -40 0 400 -60 80 mg once-daily * 320 mg once-daily -50 200 160 mg once-daily -80 0 -100 -100 0 6 12 18 24 Day 7 (hours post dose) TGF- signaling inhibition PLN-74809 pSmad2 * = p < 0.05 vs placebo
and Cmax < 700 ng/mL group 2023 PLIANT THERAPEUTICS 16 Baseline all placebo Cmax < 700 ng/mL Cmax 700-900 ng/mL Cmax > 900 ng/mL % Change from Baseline Bexotegrast (PLN-74809) plasma concentration (ng/mL)
Concentration (ng/mL) (Dashed Lines) Bexotegrast Demonstrated Significant
pSmad2 Suppression Relative to Baseline at 24 Hours Alveolar pSmad2/Smad2 Percentage Change from Baseline at 24 Hours Mean PK/PD Response Alveolar pSmad2/Smad2 Mean PK/PD Response Alveolar pSmad2/Smad2 Mean PK/PD Response (Part 1: 80 m %g Change
from and 160 mg)Baseline at 24 hr % Change from Baseline at 24 hr 250 80 mg 160 mg 250 5000 0 200 200 150 150 -20 100 100 1000 50 50 p<0.0001 -40 p<0.0001 **** **** 0 0 p<0.0001 p<0.0001 **** -60 **** -50 -50 100 -100 -100 Baseline 0 6
12 18 24 Placebo 80mg 160mg Placebo 80mg 160mg (Day -1) Time (hr) (Day 7) Percent change pSmad2/Smad2 was statistically significant at Durable reduction in pSmad2/Smad2 for 24 hours at 80 and 160 mg both doses of Bexotegrast (PLN-74809) vs. placebo
(p<0.0001) Placebo (n=8) Bexotegrast (PLN-74809) 80 mg QD (n=7) 160 mg QD (n=8 at 6hrs and n=5 at 24hrs) BAL - bronchoalveolar lavage; pSmad2/Smad2 - ratio of phosphorylated Smad2 to total Smad2; QD - once daily
2023 PLIANT THERAPEUTICS 17 pSmad2/Smad2 (%Change) pSmad2/Smad2 (%Change) pSmad2/Smad2 (% Change) (Solid Lines)
Bexotegrast Demonstrated Durable pSmad2 Suppression Relative to Placebo
at 6 Hours and 24 Hours at All Dose Levels pSmad2/Smad2 percentage change from baseline, delta versus placebo in Part 1 and Part 2 80 mg QD 0 160 mg QD 320 mg QD -50 -100 -150 -200 6 24 6hr 24hr Time (h) (Day 7) Placebo (n=8/4) Bexotegrast
(PLN-74809) 80 mg QD (n=7) The difference in pSmad2/Smad2 % change was calculated for each treatment 160 mg QD (n=8 at 6hrs and n=5 at 24hrs) value vs. the mean placebo value at each timepoint 320 mg QD (n=4 at 6hrs and n=5
at 24hrs) pSmad2/Smad2 - ratio of phosphorylated Smad2 to total Smad2 2023 PLIANT THERAPEUTICS 18 Delta % change pSmad2/Smad2 % Delta vs. Placebo vs. Placebo
Tissue pSmad Levels are Highly Significantly Correlated with Extractable
Collagen Levels in normal and fibrotic lungs Reduction in Pulmonary pSmad Appears to Be a Marker for Reduction of Fibrosis Diagnostic open lung biopsies from 10 patients with ILD and suspected IPF 2-3 distinct lung regions sampled
from each patient 5 controls (non-transplanted lungs) Total pSmad3 had a strong correlation vs. extractable Collagen I (Western Blot) Adapted from Chapman HA et al. March 12, 2020; 382:1068-1070 2023 PLIANT THERAPEUTICS 19
Putting the Phase 1b pSmad2 Data into Perspective Durable pSmad2
suppression at all dose levels relative to placebo at 6 hours and 24 hours Dose- and plasma concentration-dependent response with up to 92% and 76% suppression of pSmad2 from baseline at 6 and 24 hours, respectively Bexotegrast well tolerated with
no serious or severe adverse events Bexotegrast inhibits activation of TGF- , a key molecular driver of fibrosis in the lung, as measured by pSmad2 Bexotegrast may disrupt the fibrosis pathway and affect disease progression in
IPF patients De-risks the ongoing Phase 2a INTEGRIS-IPF trial, and future development programs 2023 PLIANT THERAPEUTICS 20 20
Bexotegrast Phase 2a PET Trial - Receptor Occupancy v