Comprehensive Report on LTI-03: A Novel Peptide Therapeutic for Idiopathic Pulmonary Fibrosis

I. Introduction to LTI-03

A. Overview and Chemical Identity of LTI-03

LTI-03 is an investigational biotech product identified as a caveolin-1 Scaffolding Domain 7-Mer peptide.[1] This nomenclature reflects its origin and chemical nature. The compound is also known by several synonyms, including CSP-7 (Caveolin Scaffolding Domain Peptide 7-mer) and its specific amino acid sequence, PHE-THR-THR-PHE-THR-VAL-THR.[2] These alternative names are frequently used in scientific literature and company communications.

Key chemical and regulatory identifiers for LTI-03 are crucial for its precise identification and for tracking its development. These include:

• DrugBank ID: DB18491.[5] This accession number allows for standardized cross-referencing in the DrugBank database, a comprehensive resource for drug information.
• CAS Number: 1504575-10-3.[2] The Chemical Abstracts Service (CAS) registry number is a unique numerical identifier assigned to every chemical substance, ensuring unambiguous identification.
• FDA UNII (Unique Ingredient Identifier): JE7G34JYW4.[1] This identifier is utilized by the U.S. Food and Drug Administration (FDA) for substance registration and tracking.

The specific 7-amino acid sequence of LTI-03 is Phenylalanine-Threonine-Threonine-Phenylalanine-Threonine-Valine-Threonine, commonly represented by the single-letter code FTTFTVT.[2] The consistent reporting of this FTTFTVT sequence across various stages of development and by different entities involved in its progression (including Lung Therapeutics, Aileron Therapeutics, and Rein Therapeutics) highlights the well-defined and stable nature of this peptide therapeutic. This specific sequence constitutes the active pharmaceutical ingredient. The derivation of a 7-mer from a larger protein domain (Caveolin-1 Scaffolding Domain) suggests a targeted therapeutic strategy aimed at harnessing specific biological activities inherent to that domain.

The estimated molecular formula for LTI-03 is C39​H55​N7​O11​.[4] Based on this sequence, its estimated average molecular weight is approximately 816 Daltons.[4] This relatively small molecular weight for a peptide is an important characteristic. It can be advantageous for pharmaceutical formulation, particularly for developing inhaled therapies, and may also facilitate better tissue penetration within the lung. Smaller peptides are generally more amenable to formulation into stable dry powders for inhalation, which is the intended delivery route for LTI-03, and may exhibit improved diffusion characteristics in lung tissue compared to larger protein-based therapeutics. This is a critical consideration for a drug designed to act locally within the lungs. Online peptide molecular weight calculators can be used to verify this based on the FTTFTVT sequence.[8]

Table 1: LTI-03 Key Identifiers and Properties

Property	Details	Source(s)
Name	LTI-03	User Query
English Name	LTI-03	User Query
DrugBank ID	DB18491	User Query, 5
Type	Biotech	User Query
Background	Caveolin-1 Scaffolding Domain 7-Mer	User Query, 1
CAS Number	1504575-10-3	User Query, 1
FDA UNII	JE7G34JYW4	1
Peptide Sequence	PHE-THR-THR-PHE-THR-VAL-THR (FTTFTVT)	2
Molecular Formula	Estimated C39​H55​N7​O11​	4
Molecular Weight	Estimated 816 Da (average)	4
Synonyms	CSP-7, CSP7, L-THREONINE, L-PHENYLALANYL-L-THREONYL-L-THREONYL-L-PHENYLALANYL-L-THREONYL-L-VALYL-	2

This table consolidates the primary identifiers and basic chemical properties of LTI-03, ensuring clarity and facilitating further research or cross-referencing.

B. Background: Caveolin-1 Scaffolding Domain and Rationale for Idiopathic Pulmonary Fibrosis (IPF)

LTI-03 is a synthetic peptide derived from the Caveolin-1 (Cav1) scaffolding domain (CSD).[3] Cav1 is a critical protein involved in the formation of caveolae, which are small invaginations of the plasma membrane. This protein, and particularly its CSD (amino acid residues 82-101 in the full protein), is essential for maintaining lung homeostasis. It plays a crucial role in regulating various cellular processes, including lung repair mechanisms and cellular movement, by interacting with a multitude of signaling molecules.[11]

A key pathological feature in Idiopathic Pulmonary Fibrosis (IPF) is the reduced expression of Cav1 in lung tissues.[7] This deficiency has also been observed in animal models of lung fibrosis, such as those induced by bleomycin. The decrease in Cav1 levels is thought to contribute to the dysregulation of cellular signaling pathways that promote fibrosis.

The therapeutic rationale for developing LTI-03 for IPF stems directly from this understanding of Cav1's role and its depletion in the disease state. LTI-03, as a 7-mer fragment of the CSD, is designed to mimic or restore some of the crucial functions of Cav1. The aim is to replenish the modulating and homeostatic effects of the CSD within the lung, thereby restoring the balance of important biological signals. This, in turn, is hypothesized to not only slow the progressive decline in lung function characteristic of IPF but also potentially to promote the restoration of healthy lung tissue and function.[3]

IPF is a devastating chronic lung disease characterized by progressive and irreversible scarring (fibrosis) of the lung tissue, leading to a relentless decline in respiratory function and, ultimately, death.[6] Current approved treatments, such as nintedanib and pirfenidone, offer limited efficacy, primarily slowing the rate of lung function decline, and are often associated with significant side effects that can impact patient quality of life and treatment adherence.[11] There is a substantial unmet medical need for novel therapies that are more effective and better tolerated.

The development of LTI-03 as a CSD-derived peptide represents a targeted therapeutic strategy. By directly addressing a known molecular deficiency (reduced Cav1) and aiming to restore homeostatic signaling pathways within the lung, LTI-03's mechanism is distinct from broader anti-inflammatory or anti-fibrotic agents. The selection of a 7-mer peptide suggests a focused effort to isolate the most pharmacologically active and pharmaceutically deliverable portion of the CSD. This approach of restoring Cav1-mediated homeostasis via a peptide fragment, particularly when delivered locally via inhalation, holds the promise of a potentially improved side effect profile compared to existing systemic IPF therapies. This is a critical consideration, as the adverse effects of current treatments often limit their use or lead to dose reductions or discontinuation.

II. Developer and Formulation

A. Corporate History (Lung Therapeutics, Aileron Therapeutics, Rein Therapeutics)

The development of LTI-03 has traversed several corporate entities, reflecting the dynamic nature of biopharmaceutical research and development.

Initially, LTI-03 was developed by Lung Therapeutics, Inc..11 This company was responsible for the early-stage development, including the sponsorship of the Phase 1a clinical trial (NCT04233814) designed to assess the safety and pharmacokinetics of LTI-03 in healthy volunteers.11

On October 31, 2023, Aileron Therapeutics, Inc. acquired Lung Therapeutics, Inc..[35] Following this acquisition, Aileron Therapeutics shifted its strategic focus towards orphan pulmonary and fibrotic diseases, with LTI-03 becoming a lead asset in its pipeline.[7]

Subsequently, in January 2025, Aileron Therapeutics underwent a rebranding and emerged as Rein Therapeutics, Inc., trading under the NASDAQ ticker symbol "RNTX".[3] Rein Therapeutics has continued the clinical advancement of LTI-03, notably initiating Phase 2 trials for IPF.[3]

The persistence of LTI-03's development program through these corporate transitions—from Lung Therapeutics to Aileron and subsequently to Rein Therapeutics—suggests a sustained confidence in its therapeutic potential and value as a clinical asset. Such continuity, despite the inherent risks and costs of drug development and corporate restructuring, is a positive indicator for the program's viability.

B. Formulation for Inhalation

LTI-03 is specifically formulated as an excipient-free dry powder intended for direct administration to the lungs via a dry powder inhaler (DPI).[6] This delivery method is crucial for targeting the diseased lung tissue directly in IPF.

Significant research has gone into optimizing this formulation. Air-jet milling technology has been employed to micronize the neat peptide powder.[7] This process achieved a mass median aerodynamic diameter (MMAD) of 1.58±0.1μm with a fine particle fraction (FPF) of 93.3±3.3%.[7] These particle size characteristics are considered optimal for achieving deep lung deposition, which is essential for the drug to reach the affected alveolar regions in IPF.

The resulting dry powder formulation of LTI-03 has been reported to be chemically and physically stable, both after the micronization process and during storage.[7] Stability is a critical attribute for any pharmaceutical product, particularly for inhaled peptides which can be prone to degradation.

In addition to the excipient-free formulation, lyophilized formulations of CSP7 trifluoroacetate (an LTI-03 salt form) with excipients such as mannitol and lactose were also investigated. These studies demonstrated good stability of the peptide in solution and as lyophilized cakes. Notably, lactose was found to significantly decrease the formation of peptide aggregates, a common challenge in peptide formulation.[7]

The intellectual property surrounding these formulation advancements is protected. Rein Therapeutics was granted two U.S. Patents (No. 12,280,088 and No. 12,280,089) in April 2025. These patents cover novel formulation strategies and administration methods for the dry powder form of LTI-03 for the treatment of respiratory diseases, including IPF.[27]

The development of a stable, excipient-free DPI formulation with particle characteristics optimized for deep lung delivery represents a significant technical achievement for a peptide-based therapeutic. This targeted delivery approach is designed to maximize local drug concentrations in the lung, the site of IPF pathology, while minimizing systemic exposure. This, in turn, could lead to enhanced efficacy at potentially lower overall doses and a more favorable safety profile compared to systemically administered drugs, a particularly important consideration given the side effect burden of current systemic IPF treatments.

III. Mechanism of Action

LTI-03, a 7-mer peptide derived from the Caveolin-1 Scaffolding Domain (CSD), exerts its therapeutic effects in Idiopathic Pulmonary Fibrosis (IPF) through a novel dual mechanism. This mechanism involves both the inhibition of profibrotic signaling pathways and the promotion of alveolar epithelial cell (AEC) survival and regeneration.[3] This multifaceted approach distinguishes LTI-03 from current IPF therapies, which primarily focus on slowing fibrotic progression without significant regenerative capacity.

A. Dual Role: Anti-fibrotic and Alveolar Epithelial Cell (AEC) Protection/Regeneration

The primary therapeutic strategy of LTI-03 is to concurrently address two fundamental pathological processes in IPF: the excessive fibrotic activity and the damage and loss of AECs.

1. Anti-fibrotic Effects: LTI-03 actively inhibits and attenuates fibrotic responses within the lung. This is achieved by modulating key signaling pathways that are involved in the activation of fibroblasts, the primary cell type responsible for the excessive deposition of extracellular matrix (ECM) proteins, such as collagen, which leads to the characteristic scarring and stiffening of lung tissue in IPF.[7]
2. AEC Protection and Regeneration: Beyond its anti-fibrotic actions, LTI-03 promotes the protection and enhances the viability of AECs.[3] AECs, particularly type I (AEC1) and type II (AEC2) cells, are essential for maintaining the structural integrity and gas exchange function of the alveoli. In IPF, these cells are often damaged and undergo apoptosis or senescence. LTI-03 has been shown to sustain AEC2s in IPF lung organoid models and to support the differentiation of AEC2s into AEC1s, a crucial step in alveolar repair and regeneration.[3]

This dual mechanism is particularly significant because current FDA-approved treatments for IPF, nintedanib and pirfenidone, primarily work by targeting fibrotic pathways to slow the decline in forced vital capacity (FVC). However, they do not possess significant direct regenerative effects on the damaged alveolar epithelium.[11] LTI-03's potential to both protect and regenerate AECs while simultaneously inhibiting fibrosis offers a more comprehensive therapeutic approach. If clinically validated, this could translate to not only slowing disease progression but also potentially achieving a degree of lung function stabilization or even restoration beyond the capabilities of current standard-of-care therapies.

B. Molecular Interactions: Caveolin-1, p53, mdm2, and Other Signaling Pathways

LTI-03, as a peptide fragment of the Caveolin-1 Scaffolding Domain (CSD), is believed to exert its effects by interacting with a wide array of intracellular signaling molecules. The CSD of Cav1 is known to bind to proteins that possess a complementary caveolin binding domain (CBD).[3] It is estimated that approximately 30% of endogenous proteins may contain such CBD motifs.[15] Several proteins implicated in IPF pathogenesis, including growth factor receptors like Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR), and Platelet-Derived Growth Factor Receptor (PDGFR), have been identified as containing CBDs, suggesting they are potential interaction partners for CSD-derived peptides like LTI-03.[3]

A key aspect of LTI-03's mechanism involves the modulation of the p53 tumor suppressor protein and its negative regulator, mouse double minute 2 homolog (mdm2). The effects of LTI-03 on this axis are notably cell-type specific:

• In injured AECs: These cells often exhibit increased Cav1 expression, which in turn leads to elevated levels of p53. High p53 in AECs can trigger senescence and apoptosis, contributing to lung damage. LTI-03 (CSP7) intervenes by down-regulating p53 in these injured AECs. This is thought to occur through inhibition of Cav1's interaction with protein phosphatase 2A catalytic subunit (PP2A_C) and Sirtuin 1 (Sirt1). This disruption leads to increased mdm2-mediated degradation of p53, thereby promoting AEC viability and protecting against the development of fibrosis.[11]
• In fibrotic lung fibroblasts (fLfs): In contrast to AECs, fLfs in fibrotic lungs typically show low levels of Cav1 and p53, but high levels of mdm2. This environment favors mdm2-mediated degradation of p53, contributing to fibroblast proliferation and ECM production. LTI-03 is proposed to directly bind to mdm2 in fLfs, thereby inhibiting mdm2-mediated degradation of p53. This action restores baseline p53 levels in fibroblasts, which in turn helps to restrain their excessive proliferation and ECM deposition.[6]

This cell-type specific, differential modulation of the p53/mdm2 axis by LTI-03 represents a sophisticated regulatory mechanism. Rather than simply activating or inhibiting a pathway globally, LTI-03 appears to restore a homeostatic balance by exerting opposing effects on p53 levels depending on the specific cellular context of Cav1 and mdm2 expression in AECs versus fibroblasts. Such nuanced action is a highly desirable characteristic for a therapeutic agent aiming to correct complex pathological states like IPF.

Beyond the p53/mdm2 axis, Cav1 and its CSD are known to influence other critical signaling pathways involved in fibrosis:

• TGF-β Signaling: Transforming Growth Factor-beta (TGF-β) is a potent pro-fibrotic cytokine. Cav1 is known to antagonize fibrotic processes by, in part, inhibiting TGF-β signaling. LTI-03 (CSP7) has been shown to suppress the expression of profibrotic cytokines, including TGF-β and Connective Tissue Growth Factor (CTGF).[11]
• Other Pathways: The CSD of Cav1 can interact with a broad range of signaling proteins. Cav1 itself has been shown to inhibit Wnt signaling, β-catenin-mediated transcription, and the activation of growth factor signaling components like EGFR, MEK1, and Erk2.[11] Additionally, CSD peptides have been reported to inhibit IκB degradation, which would impact the NF-κB inflammatory pathway.[59]

C. Impact on Key Cellular Players in IPF (Fibroblasts, AECs)

The dual mechanism of LTI-03 translates into distinct beneficial effects on the two primary cell types implicated in IPF pathology:

• Alveolar Epithelial Cells (AECs): LTI-03 actively promotes the survival and viability of AECs. It protects these critical cells from apoptosis and senescence, processes that are rampant in the IPF lung and contribute to the loss of functional alveolar units. Furthermore, LTI-03 has demonstrated the ability to support the differentiation of AEC2s (progenitor cells in the alveolus) into AEC1s (the primary gas-exchanging cells), which is a vital step in alveolar repair and regeneration.[3]
• Fibrotic Lung Fibroblasts (fLfs): In parallel with its protective effects on AECs, LTI-03 counteracts the detrimental activities of fLfs. It inhibits their activation, reduces their excessive proliferation, and curtails their migration and invasion into healthy lung tissue. Crucially, LTI-03 also inhibits the transition of fibroblasts into a more aggressive, pro-fibrotic mesenchymal phenotype and reduces their overproduction of ECM components, such as collagen.[7] Preclinical studies using precision cut lung slices from IPF patients have shown that LTI-03 reduces the expression of key profibrotic proteins like Collagen-1α1 (Col-1α1) and Platelet-Derived Growth Factor Receptor beta (PDGFRB).[3]

By simultaneously fostering AEC health and mitigating the pro-fibrotic behavior of fibroblasts, LTI-03 addresses both the epithelial injury and the aberrant repair/fibrotic response that drive IPF progression. This comprehensive approach contrasts with therapies that may primarily target fibroblasts, potentially leaving the underlying epithelial damage unaddressed. A therapy that only halts fibroblast activity might slow scar formation but would not inherently promote the repair of the damaged epithelium, which is essential for restoring lung function. LTI-03's strategy, therefore, offers a more holistic means of intervention.

D. Modulation of Biomarkers (e.g., solRAGE, profibrotic proteins)

The mechanistic actions of LTI-03 are reflected in its ability to modulate key biomarkers associated with IPF pathology:

• Soluble Receptor for Advanced Glycation End-products (solRAGE): LTI-03 has been shown to dose-dependently stimulate the production of solRAGE.[3] solRAGE is considered an important biomarker indicative of AEC1 health. Increased levels of solRAGE may reflect protection or regeneration of these critical gas-exchange cells. This is a particularly noteworthy finding, as improving AEC health is a largely unaddressed aspect of current IPF treatments. An increase in a marker of AEC1 health, alongside the reduction of fibrotic markers, would provide strong support for LTI-03's dual mechanism and its potential to lead to functional lung improvement.
• Profibrotic Transcripts and Proteins: Consistent with its anti-fibrotic mechanism, LTI-03 broadly attenuates the expression of various profibrotic transcripts and proteins, as well as downregulating the activity of their corresponding signaling pathways.[3] This includes markers like Col-1α1 and PDGFRB, as observed in ex vivo studies.

The ability of LTI-03 to favorably modulate these biomarkers provides early pharmacodynamic evidence of its engagement with relevant pathological pathways in IPF.

IV. Preclinical Development

The preclinical development of LTI-03 has encompassed a range of in vitro, ex vivo, and in vivo animal models to establish its efficacy and safety profile prior to human clinical trials.

A. In Vitro and Ex Vivo Efficacy Studies

To assess the direct effects of LTI-03 on human lung tissue and cells, researchers have utilized advanced ex vivo and in vitro model systems.

• Precision Cut Lung Slices (PCLS) from IPF Patients: Studies using PCLS obtained from lungs of IPF patients undergoing transplantation have provided valuable insights. In this system, LTI-03 demonstrated a broad attenuation of profibrotic transcripts and proteins, including Col-1α1 and PDGFRB, and their associated signaling pathways.[3] Furthermore, LTI-03 dose-dependently stimulated the production of solRAGE, a biomarker indicative of AEC1 health.[3] A significant observation from these PCLS studies was that, unlike the approved IPF drug nintedanib, LTI-03 did not induce cellular necrosis or apoptosis.[3]
• 3D Alveolospheres from IPF and Normal Donor Lungs: Three-dimensional (3D) alveolosphere cultures, derived from both IPF and normal donor lungs, have been used to model alveolar regeneration. In these systems, LTI-03 (and a related peptide, LTI-2355) demonstrated the ability to sustain AEC2s in IPF lung organoids/alveolospheres.[3] At a concentration of 10.0μM, LTI-03 increased the size of IPF alveolospheres compared to placebo. Importantly, LTI-03 appeared to protect normal lung alveolospheres, whereas nintedanib exhibited growth-inhibiting or toxic effects on organoids derived from normal donor lungs.[3]

The use of human IPF PCLS and 3D alveolospheres provides robust preclinical evidence with enhanced translational relevance compared to animal models alone. The observation that LTI-03, unlike an approved standard-of-care drug, did not induce necrosis or apoptosis in PCLS and demonstrated protective effects on normal lung organoids, constitutes a significant positive early safety signal. This suggests a potentially superior therapeutic window for LTI-03, which is critical for a chronic disease requiring long-term treatment.

B. Animal Model Efficacy Data

LTI-03 (CSP7) has demonstrated anti-fibrotic efficacy in various animal models of lung fibrosis:

• Bleomycin (BLM)-induced and TGF-β-induced Pulmonary Fibrosis: In mouse models where lung fibrosis was induced by bleomycin or by adenoviral delivery of TGF-β1, LTI-03 administered intraperitoneally (at a dose of 1.5mg/kg) was shown to attenuate established pulmonary fibrosis.[6]
• Airway Delivery in Animal Models: When LTI-03 was formulated as a dry powder and delivered directly to the airways via inhalation in mouse models of fibrosis, it effectively reduced lung collagen content.[7] Notably, airway delivery was found to be as efficacious as intraperitoneal injection but at an approximately 30-fold lower dose, highlighting the efficiency of targeted lung delivery.[12]
• Cigarette Smoke (CS)-Induced Lung Injury and COPD Models: In preclinical models of CS-induced lung injury and Chronic Obstructive Pulmonary Disease (COPD), LTI-03 (CSP7) demonstrated the ability to reverse CS-induced airway mucus hypersecretion and alveolar wall damage.[7]

The consistent efficacy observed across multiple animal models, utilizing different fibrotic stimuli (BLM, TGF-β, CS) and various routes of administration (intraperitoneal, inhalation), strengthens the evidence for LTI-03's anti-fibrotic potential. The success with the inhaled formulation at lower doses further supports the rationale for this delivery route in clinical development.

C. Summary of Preclinical Safety and Toxicology

Preclinical safety and toxicology studies are paramount for any investigational drug. For LTI-03 (CSP7), the available information indicates a favorable profile:

• General Tolerability: LTI-03 is generally reported as being well-tolerated in animal models of pulmonary fibrosis.[6]
• Formal Toxicology Studies: Formal toxicology studies conducted in rats and dogs have suggested that LTI-03 is safe and well-tolerated.[6]
• Genotoxicity: CSP7 was assessed for genotoxic potential and was found to be neither mutagenic in the in vitro Ames test nor carcinogenic in the in vivo mouse micronucleus assay.[11]
• Comparative Safety in Ex Vivo Models: As mentioned previously, in ex vivo studies using human IPF PCLS and normal lung organoids, LTI-03 did not induce cellular necrosis or apoptosis, unlike nintedanib.[3]

The positive outcomes from these preclinical safety assessments, including formal toxicology evaluations and genotoxicity testing, supported the progression of LTI-03 into human clinical trials. The lack of direct cytotoxicity compared to an approved IPF drug in human-derived tissue models is a particularly noteworthy differentiating safety feature. However, it is important to note that specific No Observed Adverse Effect Levels (NOAELs) from these comprehensive toxicology studies are not detailed in the provided information.[6]

D. Preclinical Pharmacokinetics (ADME)

Detailed preclinical pharmacokinetic data, including absorption, distribution, metabolism, and excretion (ADME) parameters, are limited in the available source materials. However, the demonstrated efficacy of LTI-03 when delivered via the airway (either by nebulization or as a dry powder) in animal models implies sufficient lung deposition and retention to achieve a pharmacological effect.[6] Information from an NIH grant abstract indicates that non-GLP pharmacokinetic studies and systemic biodistribution analysis following airway delivery were planned as part of the preclinical development program (Aim II of a project).[57] While specific parameters such as Cmax, Tmax, half-life, or detailed tissue distribution ratios from these preclinical models are not provided, the successful outcomes in efficacy studies using inhalation suggest that the formulation achieves adequate drug concentrations at the target site in the lungs.

V. Clinical Development in Idiopathic Pulmonary Fibrosis (IPF)

The clinical development program for LTI-03 has progressed through early-phase studies in healthy volunteers and IPF patients, with a Phase 2 efficacy trial currently underway. The table below provides a summary of these key clinical trials.

Table 2: Summary of LTI-03 Clinical Trials in Idiopathic Pulmonary Fibrosis

Trial ID (NCT #)	Phase	Official Title / Focus	Status	Patient Population	Key Endpoints (Primary; Secondary/Exploratory)	Brief Summary of Key Results (Safety & Efficacy/Biomarkers)	Key Dates (Start; Completion)	Developer/Sponsor	Source(s)
NCT04233814	Phase 1a	Safety, Tolerability and Pharmacokinetic Study of LTI-03 in Healthy Adult Subjects	Completed	71 Healthy Volunteers (18-55 years)	Safety, Tolerability, PK	Well-tolerated, no SAEs, doses 2.5-10mg tolerated, no significant impact on respiratory function. PK assessed.	N/A; Completed	Lung Therapeutics, Inc.	3
NCT05954988	Phase 1b	A Study to Evaluate LTI-03 in Recently Diagnosed, Treatment Naïve Subjects With IPF	Completed	~24 IPF Patients (treatment-naïve or off anti-fibrotics for $\ge$2 months)	Safety, Tolerability; Biomarkers	Generally well-tolerated. Cohort 1 (2.5mg BID): Positive trend 7/8 biomarkers; significant decrease in GAL-7, TSLP, Col-1α1; increased solRAGE. Cohort 2 (5mg BID) & Combined: Positive trend 7/8 biomarkers; 4 significant (IL-11, CXCL7, TSLP, GAL-7); 5 dose-dependent (inc. COL1A1, SPD); SPD decreased 5% in Cohort 2. No SAEs (C1), no drug-related discontinuations (C2).	N/A; Cohort 2 enrollment completed mid-Sep 2024	Lung Therapeutics, Inc. / Aileron Therapeutics / Rein Therapeutics	3
NCT06968845 (RENEW Trial)	Phase 2	A Phase 2 Study of LTI-03 in Patients With Idiopathic Pulmonary Fibrosis	Recruiting / Initiated	~120 IPF Patients (diagnosed within 5 years, may be on SoC)	Incidence of TEAEs; Efficacy (FVC, ppFVC, HRCT)	N/A (Ongoing)	First patient dosed May 2025; Topline interim data expected H1 2026	Rein Therapeutics	3

A. Phase 1a Study in Healthy Volunteers (NCT04233814)

The initial human clinical evaluation of LTI-03 was conducted in a Phase 1a trial (NCT04233814), officially titled "A Randomized, Double-Blind, Placebo-Controlled, Ph 1a, First-in-Man, Single Ascending Dose & Multiple Ascending Dose Safety, Tolerability and PK Study of a Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in Healthy Adult Subjects".[11] This study, sponsored by Lung Therapeutics, Inc., has been completed.[3]

The trial was designed as a randomized, double-blind, placebo-controlled study involving 71 healthy, non-smoking male and female volunteers aged between 18 and 55 years.[33] It incorporated both single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. The primary objectives were to assess the initial safety, tolerability, and pharmacokinetic (PK) properties of LTI-03 administered via inhalation.[3]

Results - Safety and Tolerability: LTI-03 demonstrated a favorable safety and tolerability profile in this healthy volunteer population. Key findings include:

• The drug was reported as safe and well-tolerated.[33]
• No serious adverse events (SAEs) were reported during the study.[33]
• There were no discontinuations due to adverse events.[33]
• Inhaled doses of LTI-03 ranging from 2.5 mg to 10 mg were well-tolerated.[33]
• Preliminary findings indicated no significant impact on respiratory function in these healthy individuals.[11]

Results - Pharmacokinetics (PK): Pharmacokinetic parameters were assessed as part of the study objectives.[3] However, specific PK parameters such as maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life are not detailed in the provided source materials.[62] Access to such data would be important for a complete understanding of the drug's disposition in humans and for informing dose selection in subsequent patient trials.

The successful completion of this Phase 1a study, demonstrating good safety and tolerability of an inhaled peptide in healthy volunteers, represented a critical early de-risking milestone for the LTI-03 development program. It established an initial safe dose range that could be explored in patients with IPF. For an inhaled therapeutic, demonstrating local lung tolerability (no significant impact on respiratory function) is as vital as confirming systemic safety.

B. Phase 1b Study in IPF Patients (NCT05954988)

Following the positive results in healthy volunteers, LTI-03 advanced to a Phase 1b clinical trial (NCT05954988) in patients with IPF. The official title of this study is "A Randomized, Double-Blind, Placebo-Controlled, Dose Escalation, Safety, Tolerability and Pharmacodynamic Biomarker Study of Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in Recently Diagnosed, Treatment Naïve Subjects with IPF".[7] This trial has been completed [43], with enrollment for its second cohort finalized in mid-September 2024.[7]

Design: This multi-center study employed a randomized, double-blind, placebo-controlled, dose-escalation design. It enrolled approximately 24 patients recently diagnosed with IPF who were either treatment-naïve or had not received anti-fibrotic agents for at least two months prior to participation. Patients were randomized in a 3:1 ratio to receive either inhaled LTI-03 or placebo. The study evaluated two dose levels of LTI-03 across two sequential cohorts:

• Cohort 1: Low-dose LTI-03 at 2.5 mg administered twice daily (BID).
• Cohort 2: High-dose LTI-03 at 5 mg BID. The treatment duration for both cohorts was 14 consecutive days.[3]

Objectives: The primary objective was to evaluate the safety and tolerability of LTI-03 in IPF patients.[3] Exploratory objectives included the measurement of multiple protein biomarkers to assess pharmacodynamic activity.[3]

Results - Safety and Tolerability (Cohorts 1 & 2):

LTI-03 was reported to be generally well-tolerated in both the low-dose (Cohort 1) and high-dose (Cohort 2) groups.17

• In Cohort 1 (2.5 mg BID), no serious adverse events (SAEs) were reported.[42]
• In Cohort 2 (5 mg BID), there were no drug-related adverse events that led to discontinuation of the trial.[17]
• A safety marker for inflammation, pAKT in peripheral blood mononuclear cells (PBMCs), indicated that LTI-03 did not induce inflammation in PBMCs in either cohort.[17] It is important to note that while general tolerability was reported, detailed listings of specific adverse events, their frequencies, or direct comparisons to placebo adverse event rates are not available in the provided source materials for either cohort.[16]

Results - Biomarkers:

The exploratory biomarker analysis yielded promising results indicative of LTI-03's biological activity in IPF patients:

• Cohort 1 (Low Dose - 2.5 mg BID):
• A positive trend was observed in seven out of eight evaluated IPF biomarkers.[7]
• Evidence showed reduced expression of multiple profibrotic proteins typically produced by pathologic basal-like cells and fibroblasts.[42]
• Statistically significant decreases were observed for the biomarkers Galectin-7 (GAL-7), Thymic Stromal Lymphopoietin (TSLP), and Collagen Type I Alpha 1 Chain (Col-1α1).[42]
• LTI-03 stimulated the production of soluble Receptor for Advanced Glycation End-products (solRAGE), a marker indicative of type I epithelial cell health.[42]
• Cohort 2 (High Dose - 5 mg BID) and Combined Cohort 1+2 Analysis:
• In Cohort 2, a positive trend was also observed in seven out of eight biomarkers.[9]
• When data from Cohort 1 and Cohort 2 were combined, four biomarkers showed statistically significant improvement: Interleukin-11 (IL-11), C-X-C Motif Chemokine Ligand 7 (CXCL7, also known as NAP-2), TSLP, and GAL-7.[11]
• Five biomarkers demonstrated dose-dependent effects when comparing the low-dose and high-dose cohorts: COL1A1, CXCL7, TSLP, GAL-7, and Surfactant Protein D (SPD).[9]
• Notably, SPD, an indicator of epithelial cell health that is linked to lung function decline in IPF, decreased by 5% in the high-dose Cohort 2 after 14 days of treatment.[17]

Table 3: Key Biomarker Changes with LTI-03 in IPF Clinical Trial NCT05954988

Biomarker	Change Observed with LTI-03	Statistical Significance	Dose Cohort(s) Showing Effect	Implied Biological Effect	Source(s)
Galectin-7 (GAL-7)	Reduced expression / Statistically significant decrease	Yes (C1; Combined C1+C2)	Low (2.5mg BID); High (5mg BID); Combined	Reduced fibrosis/inflammation	17
Thymic Stromal Lymphopoietin (TSLP)	Reduced expression / Statistically significant decrease	Yes (C1; Combined C1+C2)	Low (2.5mg BID); High (5mg BID); Combined	Reduced inflammation/fibrosis	17
Collagen Type I Alpha 1 Chain (Col-1α1)	Reduced expression / Statistically significant decrease (C1) / Dose-dependent effect	Yes (C1)	Low (2.5mg BID); High (5mg BID)	Reduced fibrosis (collagen deposition)	17
Soluble Receptor for Advanced Glycation End-products (solRAGE)	Stimulated production	N/A (Positive trend)	Low (2.5mg BID)	Improved AEC1 health/epithelial protection	42
Interleukin-11 (IL-11)	Statistically significant decrease	Yes (Combined C1+C2)	Combined	Reduced fibrosis/inflammation	11
C-X-C Motif Chemokine Ligand 7 (CXCL7 / NAP-2)	Statistically significant decrease / Dose-dependent effect	Yes (Combined C1+C2)	Low (2.5mg BID); High (5mg BID); Combined	Reduced inflammation	11
Surfactant Protein D (SPD)	Decreased by 5% (C2) / Dose-dependent effect	N/A (Positive trend, % change given)	High (5mg BID)	Improved epithelial health / Reduced lung injury	17

C1 = Cohort 1; C2 = Cohort 2; Combined C1+C2 refers to analysis of data from both cohorts together.

The positive biomarker results from the Phase 1b trial, particularly the observed dose-dependent effects and the achievement of statistical significance for several key markers after a short 14-day treatment period, provide crucial early human validation of LTI-03's proposed dual mechanism of action in patients with IPF. This evidence of target engagement and favorable biological response, coupled with a good safety profile, strongly supported the rationale for advancing LTI-03 into the larger, longer-duration Phase 2 RENEW trial to assess its clinical efficacy on lung function parameters like FVC.

C. Phase 2 RENEW Study (NCT06968845)

Building on the encouraging Phase 1b data, Rein Therapeutics initiated the RENEW Phase 2 trial (NCT06968845) for LTI-03 in IPF patients.[3] The official title is "A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability and Efficacy of Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in Patients With Idiopathic Pulmonary Fibrosis".[5]

Status and Design: The RENEW trial is currently recruiting participants, with the first patient dosed in May 2025.[3] It is a multi-center, randomized, double-blind, placebo-controlled study designed to enroll approximately 120 patients diagnosed with IPF within 5 years of screening. Patients may be receiving standard-of-care (SoC) antifibrotic therapy concurrently. The trial will be conducted across up to 50 sites globally, including locations in the United States, United Kingdom, Germany, Austria, and Poland.[11] Participants will be randomized into two dose cohorts, receiving either low-dose (2.5 mg BID) or high-dose (5 mg BID) LTI-03, or placebo, for a treatment period of 24 weeks, followed by a 4-week follow-up period.[11]

Endpoints:

• The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) from Day 1 through Week 24, assessing the safety and tolerability of LTI-03.[11]
• The key secondary endpoint focuses on the efficacy of LTI-03, measured by changes in forced vital capacity (FVC), percent predicted FVC (ppFVC), and quantitative assessment of lung fibrosis using high-resolution computed tomography (HRCT). The HRCT analysis will be conducted in collaboration with Qureight Ltd., utilizing their deep-learning AI image analysis platform for a more detailed examination of LTI-03's potential to modulate pro-fibrotic activity and protect alveolar epithelial cells.[11] The trial is also designed to assess the activity of inhaled dry powder LTI-03 across multiple biomarkers and measure the potential for healthy tissue regeneration.[11]

Topline interim data from the RENEW trial are anticipated in the first half of 2026.[3] The design of the RENEW trial, which includes patients who may be on current standard-of-care antifibrotic therapies and incorporates advanced HRCT imaging with AI-driven analysis, reflects a commitment to rigorously evaluate the efficacy and safety of LTI-03 in a clinically relevant IPF population. This trial will be pivotal in determining the future therapeutic role of LTI-03.

VI. Regulatory Status

LTI-03 has achieved certain regulatory milestones that facilitate its development for the treatment of IPF, a rare and serious lung condition.

• FDA Orphan Drug Designation: The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to LTI-03 for the treatment of Idiopathic Pulmonary Fibrosis. The FDA Orphan Drug designation number is 761920.[2] This designation is granted to drugs intended for rare diseases or conditions affecting fewer than 200,000 people in the U.S. It provides significant development incentives, including potential market exclusivity for seven years upon approval, tax credits for qualified clinical testing, and waiver of FDA application fees.
• FDA Fast Track Designation: The provided source materials do not explicitly state that LTI-03 or CSP-7 has received Fast Track Designation from the FDA for IPF.[7] It is mentioned that LTI-01, another product candidate from the same developer (Rein Therapeutics, formerly Aileron/Lung Therapeutics), received Fast Track Designation for a different indication (loculated pleural effusions).[21]
• EMA Orphan Designation: There is no explicit mention in the provided documents that LTI-03 or CSP-7 has received Orphan Medicinal Product Designation from the European Medicines Agency (EMA) for IPF under the current or previous developers (Rein Therapeutics, Aileron Therapeutics, or Lung Therapeutics).[20] The EMA orphan designation EU/3/23/2871, mentioned in one document for the treatment of IPF, is for a different active substance, bersiporocin (DWN12088), sponsored by Propharma Group The Netherlands B.V., and is not related to LTI-03.[87]

The FDA Orphan Drug Designation for LTI-03 underscores the recognition of IPF as a serious and rare condition with unmet medical needs and provides important support for the continued development of this novel peptide therapeutic.

VII. Conclusion

LTI-03 (CSP-7), a synthetic 7-mer peptide derived from the Caveolin-1 Scaffolding Domain, represents a novel investigational therapeutic for Idiopathic Pulmonary Fibrosis. Its development is based on a strong scientific rationale targeting the known deficiency of Caveolin-1 in IPF lungs. The proposed dual mechanism of action—simultaneously promoting alveolar epithelial cell survival and regeneration while inhibiting key profibrotic signaling pathways—offers a potentially more comprehensive approach to treating IPF compared to existing therapies that primarily focus on slowing fibrotic progression. The cell-type specific modulation of the p53/mdm2 axis is a particularly sophisticated aspect of its mechanism, suggesting an ability to restore cellular homeostasis in a targeted manner.

Preclinical studies, including those utilizing human IPF PCLS and 3D alveolosphere models, have provided encouraging evidence of LTI-03's anti-fibrotic and pro-epithelial health effects. Notably, these ex vivo studies also suggested a favorable safety profile for LTI-03 compared to the standard-of-care drug nintedanib, particularly regarding cellular toxicity. Efficacy in multiple animal models of lung fibrosis, coupled with successful formulation as a stable, excipient-free dry powder for inhalation optimized for deep lung delivery, further supports its therapeutic potential.

Early-phase clinical trials have been positive. The Phase 1a study in healthy volunteers (NCT04233814) established the safety and tolerability of inhaled LTI-03. The subsequent Phase 1b study in IPF patients (NCT05954988) not only confirmed its good safety profile but also demonstrated promising pharmacodynamic activity through favorable modulation of multiple IPF-related biomarkers. The observed dose-dependent effects and statistically significant changes in several key biomarkers after a short treatment duration provide early human validation of LTI-03's mechanism of action and its potential to impact the underlying pathology of IPF.

The ongoing Phase 2 RENEW trial (NCT06968845) is a critical next step. Its robust design, including the evaluation of clinical efficacy endpoints such as FVC and HRCT changes over a 24-week period in a larger IPF patient population (including those on standard-of-care), will be crucial in determining the true clinical benefit and therapeutic promise of LTI-03. The FDA Orphan Drug Designation provides significant support for its continued development.

While the journey to becoming an approved therapy is long and challenging, the data accumulated so far for LTI-03 suggest it is a promising candidate with a distinct mechanism of action and a favorable early safety profile. The results from the RENEW trial will be eagerly anticipated by the IPF research and patient communities. Key data gaps that remain to be fully elucidated include detailed human pharmacokinetic and pharmacodynamic profiles with longer-term dosing, and ultimately, robust demonstration of clinical efficacy in improving patient-centered outcomes in IPF.

Disclaimer: This report is based on the analysis of the provided research snippets and is intended for informational purposes only. It does not constitute medical advice or an endorsement of LTI-03.

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