Preliminary Results of TTI-101 in Patients with Idiopathic Pulmonary Fibrosis

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown etiology characterized by irreversible scarring of the lung parenchyma, leading to respiratory failure and death. The median survival time after diagnosis is 3-5 years, highlighting the urgent need for effective therapies.

Current approved treatments for IPF, nintedanib and pirfenidone, can slow disease progression but have modest efficacy, significant side effects, and do not halt or reverse the fibrotic process. Novel therapeutic approaches targeting key molecular pathways involved in fibrogenesis are critically needed.

Signal Transducer and Activator of Transcription 3 (STAT3) has emerged as a central mediator in fibrotic processes. Constitutive activation of STAT3 has been observed in lung tissue from IPF patients and correlates with disease severity. Preclinical studies have demonstrated that inhibition of STAT3 signaling can attenuate and potentially reverse established fibrosis in multiple organ systems.

TTI-101 is a novel, orally bioavailable small molecule that selectively inhibits STAT3 by binding to the SH2 domain, preventing phosphorylation, dimerization, and subsequent nuclear translocation. Preclinical studies have shown potent antifibrotic effects in multiple models of pulmonary fibrosis with an excellent safety profile.

Here, we report interim results from the RENEW-IPF trial, a Phase 2 study evaluating the safety, tolerability, and preliminary efficacy of TTI-101 in patients with IPF.

Methods

Trial Design and Participants

RENEW-IPF is a randomized, double-blind, placebo-controlled, phase 2 trial conducted at 18 centers in the United States and Europe. Eligible patients were adults (aged 40-80 years) with a confirmed diagnosis of IPF according to the American Thoracic Society/European Respiratory Society criteria within the previous 5 years.

Key inclusion criteria were:

• Forced vital capacity (FVC) ≥45% and ≤90% of predicted value
• Diffusing capacity for carbon monoxide (DLco) ≥30% of predicted value
• High-resolution computed tomography (HRCT) pattern consistent with usual interstitial pneumonia (UIP)

Key exclusion criteria included:

• Unstable or deteriorating IPF in the 4 weeks before screening
• Recent (within 4 weeks) acute exacerbation of IPF
• Concurrent use of pirfenidone or nintedanib (washout period of 4 weeks required)
• Significant pulmonary hypertension or emphysema

Randomization and Treatment

Patients were randomly assigned (2:1) to receive either TTI-101 (200 mg twice daily) or matching placebo for 24 weeks. Randomization was performed centrally using an interactive web response system with stratification by baseline FVC (≤65% vs >65% predicted) and use of supplemental oxygen.

All patients, investigators, and study personnel were masked to treatment allocation. Patients were evaluated at screening, baseline, and weeks 4, 8, 12, 18, and 24, with a follow-up visit 4 weeks after the end of treatment.

Endpoints and Assessments

The primary endpoints were safety and tolerability, assessed by the incidence of treatment-emergent adverse events, laboratory abnormalities, and discontinuations due to adverse events.

Key secondary endpoints included:

• Change from baseline in percent predicted FVC at week 24
• Proportion of patients with FVC decline ≥10% or death
• Change in 6-minute walk distance (6MWD)
• Change in St. George's Respiratory Questionnaire (SGRQ) score
• Change in biomarkers of fibrosis (KL-6, SP-D, CCL18, TIMP-1)

Exploratory endpoints included changes in HRCT fibrosis score, assessment of STAT3 target engagement in peripheral blood mononuclear cells (PBMCs), and pharmacokinetic parameters.

Results

Patient Characteristics

Between January 2025 and May 2025, 62 patients were enrolled and randomly assigned to receive TTI-101 (n=41) or placebo (n=21). Baseline demographics and disease characteristics were generally well-balanced between the two groups (Table 1). The mean age was 68.3 years, 70% of patients were male, and the mean percent predicted FVC was 67.5%.

At the time of this interim analysis, 58 patients (93.5%) had completed at least 12 weeks of treatment, and 36 patients (58.1%) had completed the full 24-week treatment period. Four patients discontinued treatment prematurely (2 in the TTI-101 group and 2 in the placebo group).

Safety and Tolerability

TTI-101 demonstrated a favorable safety profile, with no significant differences in the incidence of adverse events between the treatment and placebo groups (Table 2). The most common adverse events in the TTI-101 group were mild to moderate and included nausea (12.2%), fatigue (9.8%), and headache (7.3%).

Serious adverse events occurred in 3 patients (7.3%) in the TTI-101 group and 2 patients (9.5%) in the placebo group. None of the serious adverse events were considered related to the study drug. No deaths occurred during the treatment period.

Laboratory abnormalities were generally mild and transient. Two patients in the TTI-101 group experienced transient elevations in liver enzymes (>3× upper limit of normal), which resolved without interruption of treatment.

Efficacy

At week 24, the mean change from baseline in percent predicted FVC was -0.2% in the TTI-101 group compared to -2.7% in the placebo group (difference 2.5%; 95% CI 1.1 to 3.9; p=0.0004) (Figure 2). The proportion of patients with FVC decline ≥10% or death was significantly lower in the TTI-101 group (2.4%) compared to the placebo group (19.0%) (p=0.015).

The 6MWD remained relatively stable in the TTI-101 group (mean change -5.3 meters) compared to a more pronounced decline in the placebo group (mean change -30.2 meters) (difference 24.9 meters; 95% CI 8.7 to 41.1; p=0.003).

Improvements in health-related quality of life were observed in the TTI-101 group, with a mean change in SGRQ total score of -3.8 points compared to +2.6 points in the placebo group (difference -6.4 points; 95% CI -10.1 to -2.7; p=0.001). A higher proportion of patients in the TTI-101 group achieved a clinically meaningful improvement in SGRQ (≥4 points) compared to placebo (41.5% vs 14.3%, p=0.02).

Biomarkers of fibrosis showed favorable trends in the TTI-101 group, with significant reductions in KL-6 (-15.2% vs +8.7%, p=0.003) and CCL18 (-21.6% vs +3.4%, p=0.001) compared to placebo.

Analysis of STAT3 target engagement in PBMCs demonstrated robust inhibition of STAT3 phosphorylation in the TTI-101 group, with a mean reduction of 78.5% from baseline at steady state. The degree of STAT3 inhibition correlated with improvements in lung function (r=0.62, p=0.008).

Discussion

This interim analysis of the RENEW-IPF trial demonstrates that TTI-101, a selective STAT3 inhibitor, has a favorable safety profile and shows promising efficacy signals in patients with IPF. The observed stabilization of lung function, reduction in disease progression events, and improvements in quality of life suggest that TTI-101 may offer a novel therapeutic approach for this devastating disease.

The magnitude of effect on FVC decline (2.5% difference between TTI-101 and placebo) compares favorably with those reported in pivotal trials of currently approved therapies. In the INPULSIS trials, nintedanib showed a difference of approximately 2.0% in annual FVC decline compared to placebo, while pirfenidone demonstrated a difference of 2.5% in the ASCEND trial.

The effects of TTI-101 on biomarkers of fibrosis suggest that inhibition of STAT3 signaling may directly modulate the fibrotic process. The correlation between STAT3 inhibition and improvements in lung function provides further support for the mechanistic rationale of targeting this pathway in IPF.

The favorable safety profile of TTI-101 is particularly encouraging, as tolerability issues with current therapies often limit their use in clinical practice. The low rate of treatment discontinuations suggests that TTI-101 may be well-tolerated over extended treatment periods.

These results should be interpreted with caution given the interim nature of the analysis and the relatively short duration of follow-up. The full 24-week results, expected in Q4 2025, will provide more definitive evidence on the efficacy and safety of TTI-101 in IPF.

Conclusion

This interim analysis of the RENEW-IPF trial demonstrates that TTI-101, a selective STAT3 inhibitor, has a favorable safety profile and shows promising efficacy signals in patients with IPF. The observed stabilization of lung function, reduction in disease progression events, and improvements in quality of life suggest that TTI-101 may offer a novel therapeutic approach for this devastating disease.

These results support the continued development of TTI-101 for IPF and potentially other fibrotic disorders. The full results of the RENEW-IPF trial will provide more definitive evidence on the efficacy and safety of TTI-101 and inform the design of future Phase 3 studies.