TVRD 8-K
Tvardi Therapeutics, Inc. (TVRD)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
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| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
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| Item 7.01 | Regulation FD Disclosure. |
As previously disclosed, on December 17, 2024, Cara Therapeutics, Inc., a Delaware corporation (the “Company”), entered into an Agreement and Plan of Merger and Reorganization with Tvardi Therapeutics, Inc., a Delaware corporation (“Tvardi”), a clinical-stage biopharmaceutical company focused on the development of novel, oral, small molecule therapies targeting STAT3 to treat fibrosis-driven diseases with significant unmet need, and CT Convergence Merger Sub Inc., a Delaware corporation and wholly-owned subsidiary of the Company (“Merger Sub”), pursuant to which Merger Sub will be merged with and into Tvardi, with Tvardi surviving as a wholly-owned subsidiary of the Company (the “Merger”).
Attached hereto as Exhibit 99.1 and incorporated by reference into this Item 7.01 is an investor presentation that will be shared with potential investors into Tvardi and the post-combination company with respect to the Merger.
The information disclosed under this Item 7.01, including Exhibit 99.1 hereto, is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, nor shall they be incorporated by reference into any registration statement or other document pursuant to the Securities Act of 1933, as amended, except as expressly set forth in such filing.
Cautionary Statement Regarding Forward-Looking Statements
Certain statements contained in this Current Report on Form 8-K regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Examples of these forward-looking statements include statements regarding the Company’s plans, assumptions, expectations, beliefs and objectives with respect the Company’s intent or ability to regain compliance with the Stockholders’ Equity Requirement, the Company’s ability to successfully appeal a delisting determination if issued, the ability of the Company to comply with the listing requirements of Nasdaq and the ability of the parties to consummate the Merger on the expected timeline or at all.
Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are subject to a number of risks, including those factors discussed in the Company’s filings with the Securities and Exchange Commission, including the “Risk Factors” section of the Company’s Annual Report on Form 10-K for the year ending December 31, 2023, and its other documents subsequently filed with or furnished to the Securities and Exchange Commission, including its Form 10-Q for the quarter ended September 30, 2024. All forward-looking statements contained in this Current Report on Form 8-K speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.
Additional Information and Where to Find It
This Current Report on Form 8-K relates to a proposed acquisition transaction between the Company and Tvardi. In connection with the proposed transaction, the Company has filed with the Securities and Exchange Commission (the “SEC”) a registration statement on Form S-4 that contains a preliminary proxy statement and preliminary prospectus. The Company may also file other documents with the SEC regarding the proposed transaction. THE COMPANY URGES INVESTORS AND STOCKHOLDERS TO READ THESE MATERIALS CAREFULLY AND IN THEIR ENTIRETY WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT THE COMPANY, TVARDI, THE PROPOSED TRANSACTION AND RELATED MATTERS. Stockholders are and will be able to obtain free copies of the preliminary proxy statement, preliminary prospectus and other documents filed by the Company with the SEC (when they become available) through the website maintained by the SEC at www.sec.gov. In addition, stockholders are or will be able to obtain free copies of the preliminary proxy statement, preliminary prospectus and other documents filed by the Company with the SEC by contacting Investor Relations by email at [email protected]. Stockholders are urged to read the preliminary proxy statement, preliminary prospectus and the other relevant materials when they become available before making any voting or investment decision with respect to the proposed transaction.
Participants in the Solicitation
The Company and Tvardi, and each of their respective directors and executive officers and certain of their other members of management and employees, may be deemed to be participants in the solicitation of proxies in connection with the proposed transaction. Information about the Company’s directors and executive officers, consisting of Helen M. Boudreau, Jeffrey L. Ives, Ph.D., Christopher Posner, Susan Shiff, Ph.D., Martin Vogelbaum, Lisa von Moltke, M.D., Ryan Maynard and Scott Terrillion, including a description of their interests in the Company, by security holdings or otherwise, can be found under the captions, “Security Ownership of Certain Beneficial Owners and Management,” “Executive Compensation” and “Director Compensation” contained in the definitive proxy statement on Schedule 14A for the Company’s 2024 annual meeting of stockholders, filed with the SEC on April 22, 2024 (the “2024 Cara Proxy Statement”). To the extent that the Company’s directors and executive officers and their respective affiliates have acquired or disposed of security holdings since the applicable “as of” date disclosed in the 2024 Cara Proxy Statement, such transactions have been or will be reflected on Statements of Change in Beneficial Ownership on Form 4 filed with the SEC. Additional information regarding the persons who may be deemed participants in the proxy solicitation, including the information about the directors and executive officers of Tvardi, and a description of their direct and indirect interests, by security holdings or otherwise, are also included in a registration statement filed on Form S-4 that contains a preliminary proxy statement (and preliminary prospectus and other relevant materials) filed with the SEC. Investors should read the registration statement, preliminary proxy statement/prospectus and the other relevant materials when they become available before making any voting or investment decision with respect to the proposed transaction. These documents can be obtained free of charge from the sources indicated above.
Non-Solicitation
This Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. No public offer of securities shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit No. |
Description | |
| 99.1 | Investor Presentation | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| CARA THERAPEUTICS, INC. | ||
| By: | /s/ Ryan Maynard | |
| Ryan Maynard | ||
| Chief Financial Officer | ||
Dated: January 21, 2025
Exhibit 99.1
1 Overview January 2025
2 Disclaimer and Forward Looking Statements This presentation and any accompanying oral commentary have been prepared by Tvardi Therapeutics, Inc. (“ Tvardi ”) for informational purposes only and not for any other purpose. All statements contained in this presentation and the accompanying oral commentary, other than statements of historical facts , a re forward - looking statements, including: statements about our expectations regarding the potential benefits, activity, effectiveness, and safety of our product candidates; our e xpe ctations with regard to the design and results of our research and development programs, preclinical studies, and clinical trials, including the timing and availability of data fr om such studies and trials; our preclinical, clinical, and regulatory development plans for our product candidates, including the timing or likelihood of regulatory filings and approvals for our product candidates; our expectations with regard to our ability to license, acquire, discover, and develop additional products candidates and advance such product candidates int o, and successfully complete, preclinical studies and clinical trials; the potential market size and size of the potential patient populations for our product candidates and any f utu re product candidates; ability to maintain existing, and establish new, strategic collaborations, licensing, or other arrangements; the scope of protection we are able to establish a nd maintain for intellectual property rights covering our initial product candidate and any future product candidates; our business strategy; and our future results of operations and fin ancial position. These statements involve substantial known and unknown risks, uncertainties and other factors that may cause our actual results, timing of results, levels of acti vit y, performance, or achievements to be materially different from the information expressed or implied by these forward - looking statements. New risks emerge from time to time. It is not pos sible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause a ctu al results to differ materially and adversely from those anticipated or implied in the forward looking statements. We may not actually achieve the plans, intentions, or expectations disclosed in our forward - looking statements, and you should n ot place undue reliance on our forward - looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the for war d - looking statements we make. The forward - looking statements in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events an d developments will cause our views to change. However, while we may elect to update these forward - looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. Except as required by law, neither we nor any other person assumes responsibility for the accuracy and comple ten ess of the forward - looking statements in this presentation and the accompanying oral commentary. You should, therefore, not rely on these forward - looking statements as repres enting our views as of any date subsequent to the date of this presentation. This presentation also contains estimates and other statistical data made by independent parties and by us relating to market si ze 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 a ddi tion, 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 unc ertainty and risk. This presentation contains trademarks, service marks, trade names and copyrights of Tvardi and other companies which are the property of their respective owners. This presentation shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall th ere be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.
3 Merger of Tvardi and Cara Therapeutics • Tvardi, a clinical - stage biopharmaceutical company focused on the development of novel, oral, small molecule therapies targeting STAT3 to treat fibrosis - driven diseases with significant unmet need, intends to merge with Cara Therapeutics, Inc. (Nasdaq: CARA) • Cara exploration of strategic alternatives initiated in July 2024 evaluating several potential merger candidates • Supported by the Board of Directors of both companies and is subject to stockholder approval and other customary closing conditions • Combined company will focus on advancing the development of Tvardi programs • Upon close, combined company is expected to be renamed "Tvardi Therapeutics, Inc." trading as Nasdaq: TVRD Overview • Merger expected to close in 1H:2025 • Pro forma company ownership: 83.0% Tvardi and 17.0% Cara (assuming Cara has net cash at closing of $22.875 million – $23.125 million), before giving effect to Tvardi financing • Pro forma company will be well capitalized including $28.3 million from recent Tvardi financing, combined with Cara’s anticipated cash at the closing of the merger • Merger and combined financings would fund the company into the 2H:2026, well past multiple Phase 2 readouts in IPF and HCC (expected 2H:2025) and prepare programs for Phase 3 development Transaction Summary • Tvardi management will operate pro forma company • Combined Board of Directors to contain six representatives from Tvardi and one from Cara Management & Board SEC S4 Filing 18 December 2024
4 Targeting STAT3: Central Mediator of Fibrosis - Driven Diseases Deep expertise in STAT3 biology Potential to serve as a disease - modifying therapy in IPF 1 Well - positioned to differentiate therapeutic impact in HCC 2 Multiple near - term data catalysts expected • Unlocking highly - validated, yet historically "undruggable" target within fibrosis - driven diseases • IPF models demonstrated reversal of fibrosis and restoration of lung function • Phase 2 blinded data suggests encouraging trends in lung function • Early signs of response in both mono - and combination therapy from completed and ongoing clinical trials • IPF Phase 2 unblinded data in 2H:2025 • HCC Phase 1b/2 topline data in 2H:2025 • TTI - 109 IND 3 submission planned for 1H:2025 1. Idiopathic pulmonary fibrosis. 2 . Hepatocellular carcinoma. 3. Investigational new drug.
5 Mitochondria STAT3 exists as a monomer in the electron transport chain IL6 Growth Factor Receptors Cytokine Receptors Non - TRKs Extracellular Idiopathic pulmonary fibrosis, Hepatocellular carcinoma, Systemic sclerosis Cytosol Nucleus STAT3’s Canonical Function Plays a Central Role in Fibrosis - Driven Diseases G Protein Tvardi’s small m olecules inhibit STAT3 nuclear f unction… …With no impact on STAT3 mitochondrial function 1 Canonical STAT3 Nuclear Function Non - Canonical Function Intrinsic: Proliferation & Survival Extrinsic: Immune Suppression 1. Kasembeli et al. Biochem Pharmacol. 2021
6 The Dual Mechanism of Action of STAT3’s Function in the Canonical Pathway EXTRINSICALLY Up - regulates T - cell Activation Immune Activation Degradation Tvardi’s Approach Tvardi’s Impact INTRINSICALLY D own - regulates Proliferation INTRINSIC (Cellular) EXTRINSIC ( Immune) Immune Suppression Pro - proliferative cells Activation of STAT3 Deposition and Proliferation Mechanism of the Canonical Pathway Apoptotic Cell CD8+ STAT3P+ MDSC STAT3P - MDSC STAT3P+ STAT3P -
7 Sujal Shah Chairman Michael Wyzga Director Shaheen Wirk , MD Director Wallace Hall Director Cara Representative Director Seasoned Leadership: Deep R&D and Operational Expertise Dan Conn, JD, MBA CFO John Kauh , MD CMO Imran Alibhai, PhD CEO & Director David Tweardy, MD Founder & Advisor Ron DePinho, MD Founder & Advisor Keith Flaherty, MD Advisor (Oncology) Lisa Lancaster, MD Advisor (IPF) Jeff Swigris , DO Advisor (IPF) Management Team Scientific Advisory Board Board of Directors BioMatrix Partners
8 Our Pipeline Anticipated Milestone Phase 3 Phase 2 Phase 1 Discovery & Preclinical Indication Program 2H:2025 Phase 2 data Idiopathic Pulmonary Fibrosis TTI - 101 2H:2025 Phase 1b/2 topline data Hepatocellular Carcinoma TTI - 101 1H:2025 IND submission Fibrosis - driven Disease 1 TTI - 109 Phase 2 Phase 1b/2 1. We plan to commence clinical trials in fibrosis and/or oncology pending IND submission and FDA feedback.
9 CONFIDENTIAL TTI - 101 in IPF
10 IPF Unmet Need Represents a Large Commercial Opportunity • IPF is a rare, chronic, interstitial lung disease characterized by inflammation, progressive fibrosis, and lung damage • Patients with IPF have a poor prognosis, poor quality of life, and are at a higher risk of early mortality We believe there is a significant commercial opportunity for a differentiated IPF treatment Prevalence ~150K in US 1 Incidence ~50K in US 1 Survival Median <5 years 2 from time of diagnosis High unmet need remains, even with two FDA approved drugs, Ofev ® ( nintedanib ) and Esbriet® (pirfenidone) • Neither reverse / halt clinical decline: both only slow the progression of disease • Only ~25% 4 of US IPF patients initiate standard of care • E stimated >40% of patients discontinue therapy 4 Peak Sales 3 $3.8B in 2023 $1.1B in 2020 1. Raghu, et al. Am J Respir Crit Care Med. 2006 . 2. Du, et al. Respir Res . 2022 . 3. Based on $3.8B in sales of Ofev and $ 1.1B in sales of Esbriet from Boehringer Ingelheim and Genentech (Roche) filings. 4. Dempsey, et al. Ann Am Thorac Soc. 2021
11 STAT3 Activation is a Central Catalyst in the Fibrotic Cascade IL6 - / - STAT3 +/ - WT % △ Lung Collagen Denton et al. Ann Rheum Dis. 2018 ; O’Donoghue et al. EMBO Mol Med. 2012 Notch IL6 TGF β NF - KB MAPK Hedgehog PI3K/AKT Wnt Injury Triggers Fibrotic Signaling Pathways Haploinsufficiency of STAT3 (STAT3 +/ - ) protects mice from development of lung fibrosis vs. knockout of IL6 or TGF β R which still results in fibrosis Clotting & Coagulation Fibroblast Proliferation ECM Deposition Macrophage Neutrophil T - cell Platelet Activation ECM Fibrosis Myofibroblast Fibroblast Inflammatory Cell Migration P Major Drivers Feedback Loops Feedback Loops * p < 0.05
12 Pedroza et al. Rheum. 2017 ; Tight skin (Tsk - 1) mice spontaneously develop fibrosis as a result of a duplication in the fibrillin - 1 gene TTI - 101 Inhibited Activation of STAT3 and Key Pro - fibrotic Mediators in Sclerosis TTI - 101 Decreased Hypodermal Fibrosis in Tsk - 1 Mice Control mice + DMSO Tsk - 1 mice + DMSO Tsk - 1 mice + TTI - 101 These mechanisms are individually targeted in clinical trials; TTI - 101 observed to down - regulate all factors simultaneously via STAT3 inhibition Results from this GEM model with TTI - 101 also replicated in a chemically induced skin fibrosis model TTI-101 Inhibits STAT3 Activation A c t i v a t e d S T A T 3 ( p Y - S T A T 3 ) TTI - 101 Inhibited STAT3 Activation TTI - 101 Inhibited Profibrotic Mediators
13 STAT3 is Activated in Major Compartments of IPF - Affected Mouse and Human Lung Tissue Pedroza et al. FASEB J. 2016 Activated STAT3 is overexpressed in IPF h uman lung tissue Activated STAT3 is similarly overexpressed in lung tissue of murine IPF pY - STAT3 / GAPDH Fold Induction pY - STAT3 / Actin Fold Induction Alveolar Epithelial Cells Alveolar Fibroblasts Alveolar Macrophages Normal pY - STAT3 pY - STAT3 pY - STAT3 pY - STAT3
14 Reduction of Lung Fibrosis and Statistically Significant Improvement of Oxygen Saturation Observed with TTI - 101 * TTI - 101 dosed therapeutically 14 days after bleomycin ( Bleo ) induction of fibrosis, whereas most experimental therapeutics are dosed prophylactically to demonstrate an effect of fibrosis Pedroza et al. FASEB J. 2016 Untreated Bleo + Control TTI - 101 + 14 days after Bleo IPF pathogenesis IPF induced by bleomycin reversed with TTI - 101 Fibrosis Diminished Lung Function Masson’s Trichrome Mouse Lung Tissue
15 Injury Triggers Fibrotic Signaling Pathways Inflammatory Mediators ECM Fibrosis Excess ECM Deposition Macrophage Neutrophil T - cell Platelet Activation Myofibroblast Triggers formation of myofibroblasts Approved and Discontinued Therapies Target Single Mechanisms of IPF Clotting & Coagulation Inflammatory Cell Migration Fibroblast Proliferation ECM Deposition Company Trial Status Drug(s) FDA approved Pirfenidone Discontinued GB0139 Discontinued Simtuzumab Discontinued GLPG - 1690 Company Trial Status Drug(s) FDA approved Nintedanib Discontinued Pamrevlumab Discontinued BMS - 986020 Company Trial Status Drug(s) Discontinued PRM - 151 Discontinued Tralokinumab Discontinued Carlumab Adapted from Wynn. Exp Med. 2011
16 Injury Triggers Fibrotic Signaling Pathways Inflammatory Mediators ECM Fibrosis Excess ECM Deposition Macrophage Neutrophil T - cell Platelet Activation Myofibroblast Triggers formation of myofibroblasts TTI - 101’s Impact on Both Intrinsic (Deposition) and Extrinsic STAT3 Canonical Functions Associated with IPF Clotting & Coagulation Inflammatory Cell Migration Fibroblast Proliferation ECM Deposition ↓ ECM deposition ↓ Fibroblast Activation and Proliferation TTI - 101 CTGF TTI - 101 Ki67 Col3a1 Mmp2 TTI - 101 TTI - 101 TTI - 101 Demonstrated a Dose - Dependent Decrease in Validated Targets Associated with Proliferation (Deposition) No Bleomycin Bleomycin + Placebo Bleomycin + 12.5 mg/kg TTI - 101 Bleomycin + 25 mg/kg TTI - 101 Bleomycin + 50 mg/kg TTI - 101 ↓ Myeloid Infiltration and Macrophage Activation TTI - 101 Ccl2 TTI - 101 IL - 6 TTI - 101 ↓ Clotting and Coagulation PAI - 1 (Serpine1) Ptafr TTI - 101 Kauh et al. CHEST . 2024 - Bleomycin - induced IPF mouse model: therapeutically treated with TTI - 101 9 days after induction of fibrosis using bleomycin.
17 TTI - 101’s Impact on Both Intrinsic and Extrinsic (Degradation) STAT3 Canonical Functions Associated with IPF TTI - 101 Demonstrated a Dose - Dependent Increase in the Modulation and Activity of T - cells (Degradation): No Bleomycin Bleomycin + Placebo Bleomycin + 12.5 mg/kg TTI - 101 Bleomycin + 25 mg/kg TTI - 101 Bleomycin + 50 mg/kg TTI - 101 ↑ Induction of T - cell Maturation / Activation TTI - 101 TTI - 101 STAT1 IFN γ TTI - 101 Perforin NK granule protein 7 TTI - 101 ↑ Cytotoxic Effect of T and NK Cells ↑ Extrinsic Apoptotic Pathway Granzyme A Granzyme B TTI - 101 TTI - 101 Guanylate Binding Protein 3 XAF1 TTI - 101 TTI - 101 ↑ Inflammasome / Interferon Response Kauh et al. CHEST . 2024 - Bleomycin - induced IPF mouse model: therapeutically treated with TTI - 101 9 days after induction of fibrosis using bleomycin.
18 Mechanistic Data Revealed TTI - 101 Down - regulated Deposition (Injury) and Up - regulated Degradation (Repair) ↑ Deposition ↑ Clotting & coagulation ↑ Immunomodulation ↑ Fibroblast proliferation ↑ ECM deposition IPF ↓ Degradation ↓ T - cell responses ↓ Deposition x Attenuation of clotting & coagulation x Reverse fibroblast activation x Reverse ECM deposition IPF + ↑ Degradation x Induce T - cell maturation and activation x Induce cytotoxic effect of NK - and T - cells Repair Injury Kauh et al. CHEST . 2024
19 TTI - 101’s Demonstrated Dose - Dependent PK exposure, PD and Improved Lung Function TTI - 101 observed to preferentially accumulate 4x in lung vs plasma Pharmacokinetics TTI - 101 observed to dose dependently inhibit pY - STAT3 Pharmacodynamics TTI - 101 improved lung function (at human equivalent doses of 400 and 800 mg/day) serving as proof of concept for ongoing Phase 2 trial Lung Function TTI - 101 TTI - 101 pY - STAT3 Levels * * # 0 8 16 24 90 95 Days S O 2 % 0 8 16 24 90 95 Days S O 2 % 0 8 16 24 90 95 Days S O 2 % 0 8 16 24 90 95 Days S O 2 % * p<.05 vs. placebo # p<.05 vs. bleomycin No Bleomycin Bleomycin + Placebo Bleomycin + 12.5 mg/kg TTI - 101 Bleomycin + 25 mg/kg TTI - 101 Bleomycin + 50 mg/kg TTI - 101 N=10 per arm Days Treatment with TTI - 101 (9 days post fibrosis induction) # Kauh et al. CHEST . 2024 - Bleomycin - induced IPF mouse model: therapeutically treated with TTI - 101 9 days after induction of fibrosis using bleomycin.
20 Clinical Proof of Mechanism – Phase 1 Well - Established Target Preclinical Biological Activity Next Step: IPF Clinical POC x STAT3 is a central mediator in fibrosis x TTI - 101 designed to target the canonical pathway of STAT3 STAT3 correlates with high mortality in IPF patients 1 x Well - tolerated x High blood exposure (PK) x Hits STAT3 target (PD) Reduced pY - STAT3 in humans 3 x No Phase 1 SAD / MAD HV study needed per FDA; progressed straight to Phase 2 REVERT IPF trial Phase 2 clinical trial underway x Targets full pathogenesis of IPF x TTI - 101 in additional fibrotic mouse models demonstrated downregulation of key factors Observed to reduce fibrosis and improve lung function 2 TTI - 101 is Designed to Address the Unmet Need in IPF 1. Celada et al. Sci Transl Med. 2018 . IPF Transplant - free survival over the course of 3.5 years post - diagnosis in a cohort of patients (n=55) based on STAT3 expression. Activated STAT3 (pY - STAT3) induces the expression of STAT3 transcript. 2 . Pedroza et al. FASEB J. 2016 . 3. Tsimberidou et al. Clin Cancer Res. 2025 . 8/10 patients had elevated pY - STAT3 at baseline; elevated pY - STAT3 defined as H - score >30 on a 0 - 300 scale.
21 REVERT IPF : Double Blind Randomized Phase 2 Study of TTI - 101 • Oral dosing (BID) • 12 - week d ouble blind, randomized, placebo - controlled study • Alone or in combination with nintedanib • Enrollment of mild and moderate IPF subjects • 1º & 2º Objectives: Safety & PK • Exploratory Objectives: • Phase 3 endpoints: ᶭ FVC, △ DLCO, HRCT, 6MWT • Biomarkers TTI - 101 800 mg/day (N=25) TTI - 101 400 mg/day (N=25) Placebo (N=25) Randomization Treatment Period 12 weeks Early blinded clinical data has demonstrated encouraging trends (28 US Sites, N = 75) 1 1. NCT05671835 : On July 17, 2024, the independent Safety Monitoring Committee (SMC ) conducted a benefit - risk analysis of the preliminary unblinded data from the Phase 2 IPF clinical trial data across all doses and recommended continuation of the 400 mg/day and 800 mg/day dose and discontinuation of the 1,200 mg/day dose. On September 30, 2024, the SMC completed a follow - up unblinded benefit - risk analysis and noted that it did not see any significant safety concerns and recommended continuation of the clinical trial without modi fi cation.
22 Change in FVC from Baseline at 12 weeks in Recent IPF Studies with Background Anti - fibrotic therapy PLN - 74809 320mg (2023) 3 BMS - 986278 (2023) 2 BI 1015550 (2022) 1 No placebo groups had mean FVC values (including standard error) near or above baseline Certain data on this slide are based on cross - study comparisons and are not based on any head - to - head clinical trials. Cross - stu dy comparisons are inherently limited and may suggest misleading similarities and differences. The values shown in the cross - study comparisons are directional and may not be directly comparable. Adapted from 1. Richeldi et al. NEJM. 2022 2. Corte et al. Am J Respir Cri Care Med . 2023 3. Pliant Corporate Presentation 2024 ↓FVC ↓FVC ↓FVC
23 REVERT IPF : Preliminary Blinded Percent Change in FVC from Baseline (N=38) Stable −1% to 1% ~ − 35 to +35ml Decrease < −1% Increase > 1% 34% Increase 26% Stable 39% Decrease ↓ in FVC from baseline ↑ in FVC from baseline Trial Design: 1:1:1 Randomization TTI - 101 800 mg/day (N=25) TTI - 101 400 mg/day (N=25) Placebo (N=25) Natural course of IPF: decline in FVC Blinded d ata suggests >50% of subjects have FVC values near or above baseline 0 Near or above baseline is clinically significant * Trial is blinded to Sponsor, investigators and patients; unknown exposure to 400mg/day of TTI - 101, 800mg/day of TTI - 101 or placebo. Data as of September 2024. Preliminary data for e fficacy - evaluable patients defined as: patients with acceptable baseline and at least one on - treatment pulmonary function test (PFT). At the time of analysis, the absolute FVCs comparing percent change from baseline to last visit on treatment were available for the following timepoints: 12 weeks (n=19); 8 weeks (n=9); 4 weeks (n=10). Increase in FVC levels from baseline defined as >1% change from baseline FVC; stable FVC levels from baseline defined as −1% to 1% change from baseline FVC; decrease in FVC levels from baseline defined as <−1% change from base lin e FVC. Due to the preliminary and blinded nature of the data, this interim data set was not subject to the standard quality control measures typically associated with final clinical trial results.
24 Cross Trial Comparison of Baseline Characteristics Sponsor REVERT IPF NCT05671835 N = 45 INTEGRIS - IPF 3 NCT04396756 N = 112 BMS 2 NCT04308681 N = 276 1305 - 0013 Trial 1 NCT04419506 N=147 Trial TTI - 101 Bexotegrast BMS986278 ( admilparant ) BI 1015550 ( nerandomilast ) Agent ≥25% ≥30% ≥25% ≥25% DLCO ≥40% ≥45% ≥40% ≥45% FVC predicted ≥0.7 ≥0.7 ≥0.7 ≥0.7 FEV1/FVC Ratio Nintedanib 53% Nintedanib 43% Pirfenidone 38% ~66% background therapy Nintedanib 29% Pirfenidone 21% Background antifibrotic therapy 73.8 78.1 76.5 77.7 Baseline ppFVC (mean) Certain data on this slide are based on cross - study comparisons and are not based on any head - to - head clinical trials. Cross - stu dy comparisons are inherently limited and may suggest misleading similarities and differences. 1. Richeldi et al. NEJM 2022 2. Corte et al. Am J Respir Cri Care Med . 2023 3. Lancaster et al. Am J Respir Crit Care Med 2024 . ppFVC : percent predicted FVC ; REVERT IPF baseline data as of S ept . 2024 REVERT IPF trial has broadest enrollment criteria REVERT IPF population has lowest baseline ppFVC
25 Driving inhibition of STAT3 activation to address both IPF disease pathologies (downregulating deposition and upregulating degradation) REVERT IPF Phase 2 trial ongoing with clinically relevant endpoints and collection of STAT3 - mediated biomarkers Results from ongoing Phase 2 REVERT IPF trial expected in 2H:2025 Compelling and validated target central mediator in fibrosis STAT3: Well - Established Biology Differentiated Approach Clinical PoC Underway Near - Term Clinical Milestones Key Takeaways: TTI - 101 in IPF
26 CONFIDENTIAL TTI - 101 in HCC
27 TTI - 101 Reversed Multiple Pathogenic Steps of Liver Cancer in a NASH - induced HCC Model Inflammation Fibrosis/Cirrhosis HCC STAT3 - mediated pathogenesis TTI - 101 STAT3 - inhibition in NASH - induced HCC TTI - 101 Tumor volume Microsteatosis Placebo TTI - 101 TTI - 101 Fibrosis Placebo TTI - 101 After formation of tumors at 11 months, we observed treatment with TTI - 101 therapeutically reduced inflammation, fibrosis, and tumor growth Jung KH et al. Clin Cancer Res. 2017 – Genetically engineered HepPTEN - murine model which replicates nonalcoholic steatohepatitis (NASH) induced hepatocellular carcinoma (HCC)
28 Phase 1 Clinical Trial: TTI - 101 Monotherapy Led to Durable Partial Responses in Fibrotic Tumors Baseline Cycle 5, Day 1 Cycle 3, Day 1 Diameter Length in mm (% Change from Baseline) 41mm (0%) 14mm ( - 66%) 21mm ( - 49%) 14mm ( - 70%) 19mm ( - 59%) 46mm (0%) Target Lung Met Target Liver Met Partial Responder A: HCC • Failed sorafenib, pembro, nivo , nivo+bev • Best Response: 42% Reduction in Sum of Targets Overall • Sustained PR for 10 months Partial Responder B: HCC • Failed lenvatinib , nivo • Best Response: 66% Reduction in Sum of Targets Overall • Sustained PR for 14 months Tsimberidou et al. Clin Cancer Res. 2025
29 Tolerability PK / PD Biological Activity • Well - t olerated BID oral dosing • No DLTs *Most severe AE counted per subject by grade (G1/2=grade 1 or 2, G3=grade 3) **5 subjects started on F2 and transitioned to F3 ***Elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) is the sum of elevated ALT and AST events TRAEs Occurring in >10% of Patients • Exposure s in humans above the level required for efficacy in preclinical oncology and fibrosis models • Linear PK from DL1 - 3 • C min above the IC 90 for STAT3 induced growth • Exposure plateaued at DL3, resulting in a RP2D of 12.8mg/kg/day Median % Change from Baseline in pY - STAT3 H - Score (proportion and intensity of pY - STAT3 staining) All patients with paired biopsies n=8 All SD patients with paired biopsies n=3 -80% -60% -40% -20% 0% ↓79% Among Stable Disease 8/10 patients had elevated pY - STAT3 at baseline; elevated pY - STAT3 defined as H - score >30 on a 0 - 300 scale ↓55% Overall • 100% of patients with elevated pY - STAT3 levels at baseline demonstrated decrease within ~6 weeks of TTI - 101 therapy • 55% decrease in pY - STAT3 overall; 79% in SD • Enhanced biological activity in fibrotic cancers with ORR that exceeds current standard of care in HCC • Current expected ORR in 2L HCC is <5% 35% 47% 3, 18% Best Overall Response Among HCC Patients, N=17 Median prior therapies=2 Paired Biopsies after ~6 weeks of TTI - 101 Partial Response Stable Disease Progressive Disease Phase 1: TTI - 101 Monotherapy Clinical Trial Summary F3 N=7** F2 N=47 F1 N=15 Formulation G3 G1/2 G3 G1/2 G3 G1/2 Grade, n (%) 0 (0) 2 (29) 6 (13) 16 (34) 3 (20) 3 (20) Diarrhoea 1 (14) 0 (0) 1 (2) 6 (13) 0 (0) 4 (26) Nausea 0 (0) 0 (0) 0 (0) 4 (8) 0 (0) 6 (40) Fatigue 1 (14) 1 (14) 4 (8) 1 (2) 1 (7) 1 (7) Elevated ALT/AST*** 0 (0) 2 (4) 3 (20) Dose reduction 0 (0) 2 (4) 0 (0) Dose discont. Tsimberidou et al. Clin Cancer Res. 2025 ; SD: Stable Disease; TREAE: Treatment related adverse events; F1 - 3: Formulation 1 - 3
30 0 20 40 60 80 100 120 0 90 180 270 360 450 540 Days Sum of Targets Non-Target Lesion Preclinical Model POC Established for STAT3 Inhibition + ICI Phase 1 Trial Responder Overcame ICI Resistance After TTI - 101 Monotherapy → → Ph 2: Danvatirsen (STAT3 ASO) + Durvalumab (ICI) in 2L HNSCC 2 Danvatirsen key limitations: • Observed AEs: Thrombocytopenia and transaminitis • Onerous dosing: IV 3x week 1 then Q weekly • Poor PD: Inhibition of STAT3 not observed in tumor, only in stroma Danvatirsen development suspended by AZN/Ionis Strong Rationale for Combo Therapy with STAT3 TTI - 101 Dan+Durva 2 Durva 3 23% 9% ORR 7% 0% CR TTI - 101 additive to 1L SoC (ICI + Bev) 1 Progression due to non - target lesion New Response ICI + Bev Rechallenge Sum of Tumor Responses After ICI Failure, On TTI - 101 Therapy and After ICI+Bev Rechallenge 4 0 20 40 60 80 100 120 ICI Failure: Nivolumab 1 cycle Lesion Measurement (diameter long, mm) 1. Adapted from Zhao, Y et al. Hepatology. 2021 2. Cohen et al. Ann Oncol. 2018 3. Siu et al. JAMA Oncol. 2019 . ICI: Immune Checkpoint Inhibition; Bev: Bevacizumab. Certain data on this slide are based on cross - study comparisons and are not based on any head - to - head clinical trials. C ross - study comparisons are inherently limited and may suggest misleading similarities and differences. The values shown in the cross - study comparisons are directional and may not be directly comparable. 4. Tsimberidou et al. Clin Cancer Res. 2025 TTI - 101 Treatment: 14 cycles
31 Overview of Current Treatment Landscape + Role of TTI - 101 TTI - 101 is Designed to Provide a Distinct and Synergistic Mechanism for Unmet Need in HCC • HCC is 3 rd leading cause of cancer deaths in the world 1 • Annually in the US, >42,000 new cases of HCC and ~32,000 deaths recorded 2 • Incidence has more than tripled since 1980 3 HCC Disease Overview Triplet Anti - PD - (L)1 Combos + TTI - 101 Potential SoC with TTI - 101 Doublet Anti - PD - 1s + TTI - 101 Monotherapy TTI - 101 1. World Health Organization (WHO) 2. WHO US Statistics 3. American Cancer Society 4. Represents range of ORRs from previous studies (MORPHEUS, Tempest, IMBrave150). 5. Listed 2nd line ORR expected to be <5% as 2nd line therapies inhibit VEGF/angiogenesis as common mechanism with bevacizumab and pembrolizumab (anti - PD - 1) has common mechanism with atezolizumab (anti - PDL - 1). Anti - PD - (L)1 + Anti - VEGF 10 - 27% ORR 4 Standard of Care First Line TKIs & Anti - VEGF Therapy <5% ORR 5 Second Line No Available Therapies Third Line ~70% do not respond and eventually >95% progress >90% do not respond and progress
32 REVERT Liver Cancer : Phase 2 Study of TTI - 101 in HCC • Overall Response Rate (ORR) • Duration of Response ( DoR ) • Progression - free survival • Overall survival • Liver stiffness (elastogram) • Biomarkers (IL - 6/AFP) • pY - STAT3 in tumor (21 US Sites) Phase 1b Dose Finding (up to N=54) Phase 2 Expansion (N=100) TTI - 101 RP2D (N=30) TTI - 101 (N=12) Last Line: no available therapies that will confer clinical benefit RP2D Last Line Rationale: Confirmation of P1 PoC TTI - 101 monotherapy A TTI - 101 RP2D + pembrolizumab (N=30) TTI - 101 + pembrolizumab (N=11) RP2D 2 nd Line Rationale: TTI - 101 overcomes anti - PD - (L)1 resistance 2 nd Line: progressed on anti - PD - (L)1 first line B TTI - 101 RP2D + atezo / bev (N=40) TTI - 101 + atezo / bev (N=up to 24) RP2D 1 st Line Rationale: TTI - 101 is synergistic with anti - PD - L1 and anti - angiogenic inhibition 1 st Line : treatment naïve C NCT05440708 ; Dayyani et al. JCO . 2024 Early clinical data suggests clinical benefit across treatment lines
33 REVERT Liver Cancer : Interim Phase 1b/2 Data 67% 33% 50% 50% 8% 33% 58% Preliminary radiographic change from baseline RECIST measurements (best response). Data as of Aug 2024. This interim data set wa s not subject to the standard quality control measures typically associated with final clinical trial results. 1. Tempest press release 23 Apr 2023 of Phase 2 Study. Tempesttx.com 2. Roche Phase 2: Finn et al. J Clin Oncol. 2023 3. Roche Phase 3: Finn et al. NEJM . 2020 . † Certain data on this slide are based on cross - study comparisons and are not based on any head - to - head clinical trials. Cross - study comparisons are inherently limited and may sugges t misleading similarities and differences. The values shown in the cross - study comparisons are directional and may not be directly comparable. Cohort A: TTI - 101 Monotherapy at RP2D Cohort B: TTI - 101 (RP2D) + Pembro Cohort C: TTI - 101 + Atezo/Bev *One patient on protocol for 6 weeks. Patient discontinued combination due to an unrelated AE. After recovery from AE, patient continued with atezo/ bev and investigator reported complete response. Patient considered non - evaluable for efficacy. As DCR (disease control rate: CR+PR+SD) and ORR (objective response rate: CR+PR) are based on intent to treat population of all patients this patient is only included in denominator. N=21 N=8 N=12* ORR DCR Publication Date Study 33% 92% Ongoing REVERT HCC Prelim 10% 63% 2023 Tempest 1 11% 56% 2023 MORPHEUS 2 27% 74% 2020 - 22 IMBrave150 3 Early results compare favorably to 3 rd party trials † : * Partial Response Stable Disease Progressive Disease *
34 Inhibition of STAT3 activation to have dual therapeutic effect on cancer cells – overcoming tumorigenesis and immune suppression REVERT HCC trial Phase 2 assessing activity in both monotherapy and combination therapy in areas of unmet need Topline results from ongoing Phase 2 REVERT HCC trial expected in 2H:2025 STAT3 long recognized as prime target in oncology; >95% of patients with HCC have activated STAT3 in their tumors STAT3: Well - Established Biology Differentiated Approach Clinical PoC Underway Near - Term Clinical Milestones Key Takeaways: TTI - 101 in HCC
35 Near - Term Anticipated Value - Creating Milestones TTI - 101 HCC P2 Topline Readout TTI - 101 IPF P2 Unblinded Readout Transaction Announced TTI - 109 IND Submission Expected Transaction Closes 2H 1H 2H 2025 2024 Pro forma company to be well - capitalized with a frequent cadence of inflection points and a runway ~1 year post P2 readouts
36 Targeting STAT3: Central Mediator of Fibrosis - Driven Diseases Deep expertise in STAT3 biology Potential to serve as a disease - modifying therapy in IPF 1 Well - positioned to differentiate therapeutic impact in HCC 2 Multiple near - term data catalysts expected • Unlocking highly - validated, yet historically "undruggable" target within fibrosis - driven diseases • IPF models demonstrated reversal of fibrosis and restoration of lung function • Phase 2 Clinical PoC ongoing • Evaluating both mono - and combination therapy from an ongoing clinical trial • IPF Phase 2 unblinded data in 2H:2025 • HCC Phase 1b/2 topline data in 2H:2025 • TTI - 109 IND 3 submission planned for 1H:2025 1. Idiopathic pulmonary fibrosis. 2 . Hepatocellular carcinoma. 3. Investigational new drug.