Breakthrough Clinical Results
Tectonic Therapeutic announced positive complete results from Part A of its Phase 1b clinical trial of TX45 in patients with Group 2 Pulmonary Hypertension in Heart Failure with preserved Ejection Fraction (PH-HFpEF). The trial, presented at ESC Heart Failure 2025, showed TX45 to be well-tolerated with significant improvements in left ventricular function and pulmonary hemodynamics. A single intravenous dose resulted in a 19% reduction in pulmonary capillary wedge pressure (PCWP) and a 32% reduction in pulmonary vascular resistance (PVR) in patients with combined pre- and post-capillary pulmonary hypertension. Sustained hemodynamic improvements were observed for 29 days post-dose. These results support the ongoing Phase 2 APEX trial (NCT06616974), with topline results expected in 2026. Part B of the Phase 1b trial, focusing on PH-HFrEF, is ongoing.
Key Highlights
- TX45 demonstrated a 19% reduction in PCWP and a 32% reduction in PVR.
- Sustained hemodynamic improvements were observed for 29 days post a single dose.
- TX45 was well-tolerated with no serious adverse events.
- Positive results support the ongoing Phase 2 APEX clinical trial.
Incidence and Prevalence
Pulmonary Arterial Hypertension (PAH), a specific type of pulmonary hypertension (PH), has varying global incidence and prevalence estimates depending on the study and data source. Several studies using the Global Burden of Disease (GBD) data provide the most recent and comprehensive estimates:
- A 2024 study estimated 192,000 prevalent cases globally in 2021, with an age-standardized prevalence of 2.28 cases per 100,000 population. This study also estimated 22,000 deaths attributed to PAH in 2021, with an age-standardized mortality rate of 0.27 deaths per 100,000 population. The study noted a higher prevalence in females (62% of cases) and older adults.
- Another 2024 study reported similar figures, with a global age-standardized prevalence rate of PAH in 2021 at 2.28 per 100,000, and an age-standardized mortality rate of 0.27 per 100,000. This study also highlighted regional variations, with Western Europe having the highest age-standardized prevalence rate (3.56 per 100,000) and North Africa and the Middle East having the highest age-standardized mortality rate (0.44 per 100,000).
- A 2023 study focusing on PAH specifically found a prevalence range of 0.4 to 1.4 per 100,000 persons. This study also reported a wide range for incidence (0.008 to 1.4 cases per 100,000 person-years) and 1-year survival (67% to 99%).
- A 2020 study, focusing on both PAH and Chronic Thromboembolic Pulmonary Hypertension (CTEPH), found a much wider range for PAH incidence (1.5-32 per million) and prevalence (12.4-268 per million) in adults. However, this study highlighted that recent national systematic registry data from centralized healthcare systems provided more reliable estimates, with PAH incidence around 5.8 per million and prevalence between 47.6 and 54.7 per million.
Pulmonary Hypertension (PH) overall, encompassing all five groups, has also been studied:
- A 2018 Canadian study reported that PH affects about 1% of the global population, increasing to 10% in individuals over 65 years old. Left-sided heart and lung diseases were identified as the most frequent causes of PH.
- A 2018 Canadian study focusing on PH groups 1-4 found an increasing incidence and prevalence of adult PH from 2003 to 2012 (from 24.1 to 28.7 cases/100,000 population for incidence and from 99.8 to 127.3 cases/100,000 population for prevalence). Group 2 PH (related to left heart disease) was the most common form.
It's important to note that these estimates can vary due to differences in study methodologies, diagnostic criteria, and data sources. PAH and PH remain significant global health concerns, with ongoing research efforts aiming to refine epidemiological understanding and improve patient outcomes.
Mechanism of Action
Several research articles discuss potential therapeutic targets and new agents for pulmonary arterial hypertension (PAH) that are currently under investigation. While they don't explicitly rank the top three mechanisms of action in clinical trials for unapproved PAH drugs, they highlight several promising areas:
1. Altered Glucose Metabolism: PAH is associated with metabolic reprogramming in pulmonary vascular cells, including increased glucose uptake and glycolysis. Targeting these metabolic alterations could offer new therapeutic avenues. Drugs like metformin, traditionally used for diabetes, are being explored for their potential to modulate glucose metabolism and impact vascular remodeling in PAH.
2. Tyrosine Kinase Inhibition: Tyrosine kinases play a role in cell growth and proliferation, and their dysregulation contributes to PAH pathogenesis. Imatinib, a tyrosine kinase inhibitor, has shown some promise in improving exercise capacity and pulmonary hemodynamics in PAH trials, but its use is limited by adverse effects. Inhaled formulations of tyrosine kinase inhibitors are being developed to potentially reduce systemic side effects.
3. Bone Morphogenetic Protein (BMP) / Activin Signaling: Dysfunctional BMP pathway signaling is implicated in PAH. Sotatercept, a fusion protein that traps activins and growth differentiation factors, aims to restore balance in growth signaling pathways. It has shown substantial efficacy in reducing pulmonary vascular resistance and improving exercise capacity in clinical trials and has been approved for use in the USA in 2024. Other drugs targeting this pathway are also under investigation.
4. Inflammation and Immunomodulation: Inflammation plays a crucial role in PAH development and progression. Several anti-inflammatory agents and immunotherapies are being explored, including mesenchymal stem cells and the extracellular vesicles they secrete. Targeting inflammatory mediators and immune cell responses could offer new ways to prevent or reverse PAH progression.
5. Epigenetic Modifications: Epigenetic changes, such as microRNA dysregulation and DNA methylation, contribute to pulmonary vascular remodeling in PAH. Targeting these epigenetic modifications could offer novel therapeutic strategies. Drugs like HDAC inhibitors, used in cancer treatment, are being investigated for their potential to modulate epigenetic mechanisms and impact PAH.
It's important to note that the relative importance and clinical success of these mechanisms are still under investigation. Further research and clinical trials are needed to determine their efficacy and safety in PAH treatment and to establish a definitive ranking of the most promising approaches.
Pulmonary Hypertension (PH) encompasses a group of disorders characterized by elevated blood pressure in the pulmonary arteries. Research in the past three years reveals several key unmet needs and target populations:
1. PH in Interstitial Lung Disease (PH-ILD):
- PH-ILD represents a significant unmet need due to its association with increased morbidity and mortality. The INCREASE trial demonstrated the efficacy of inhaled treprostinil, leading to its approval as the first therapy for PH-ILD. This has highlighted the need for PH screening in ILD patients and further research into PH-ILD management. A systematic review revealed a pooled prevalence of 36% for PH in ILD populations using right heart catheterization and 34% using echocardiography. Lower diffusion capacity, worse oxygenation, reduced exercise capacity, and elevated serum brain natriuretic peptide were associated with PH-ILD. Patients and carers expressed unmet needs related to symptom burden, physical limitations, and difficulties navigating the healthcare system. There is a need for standardized definitions and risk-stratified assessments for PH-ILD, as well as improved patient and clinician education and support.
2. Pulmonary Arterial Hypertension (PAH):
- Despite therapeutic advances, PAH remains a progressive disease with high morbidity and mortality, particularly in intermediate- and high-risk patients. A study using the Pulmonary Hypertension Association Registry (PHAR) found 1-, 2-, and 3-year mortality rates of 8%, 16%, and 21%, respectively. Mortality was stratified by risk scores, with higher mortality in higher-risk groups. Initial combination therapy was associated with better 1-year survival in treatment-naïve patients. There is a need for early diagnosis, aggressive treatment, and development of new therapies that target the underlying pathogenesis of PAH, such as activin signaling inhibition. A review of real-world outcomes found global adult 1-, 3-, and 5-year survival ranged from 85-99%, 65-95%, and 50-86%, respectively. This highlights the need for improved long-term prognosis in PAH.
3. Methamphetamine-Associated PAH (Meth-APAH):
- Meth-APAH is a distinct clinical phenotype of PAH, predominantly found in the western United States. Studies show that Meth-APAH patients have worse functional class, hemodynamics, quality of life, and survival compared to idiopathic PAH. They also have higher healthcare utilization and are less likely to receive triple or parenteral therapy. Further research is needed to understand the mechanisms of Meth-APAH and optimize treatment strategies.
4. Group 3 PH:
- Group 3 PH, secondary to hypoxia lung diseases, represents a high unmet clinical need. There is a need for a deeper understanding of the pathological and adaptive mechanisms, particularly the interplay of oxidative stress and inflammation, to inform the development of novel drug targets and effective treatments. Current PAH therapies have not shown benefit in controlled trials of group 3 PH.
5. PH due to Left Heart Disease (LHD):
- PH-LHD is a frequent complication with diagnostic challenges, particularly in heart failure with preserved ejection fraction. A new hemodynamic definition and a three-step diagnostic approach have been proposed. Recent trials have not shown a benefit of PAH-approved therapies in PH-LHD.
6. Caregivers of PH Patients:
- Caregivers of individuals with COPD, a common comorbidity of PH, experience significant burden. Research is needed to develop effective interventions to support caregivers and address their unmet needs, which include information, education, and access to resources.
7. General PH Research:
- There is a need for standardized nomenclature and methods to evaluate evidence-based practices and patient outcomes in PH. Further research is needed to identify rigorous measurement tools to characterize caregiver burden and develop evidence-based interventions. Bibliometric analysis shows an increasing trend in PAH research, with the United States leading in publications and international collaborations.
In summary, PH research continues to evolve, with a focus on understanding the distinct pathophysiology of different PH subtypes, developing targeted therapies, and addressing the unmet needs of patients and their caregivers. The development of novel therapeutic targets, such as activin signaling inhibition, and the use of combination therapies offer hope for improved outcomes in the future.
Drug used in other indications
Tetrathiomolybdate (TTM), also known as TX45, has been investigated in clinical trials for several indications besides pulmonary hypertension. These include:
- Wilson disease: A phase III clinical trial showed TTM stabilized neurological function, with significant recovery in 81% of patients at 3 years. A second phase III trial was ongoing.
- Idiopathic pulmonary fibrosis: A phase I/II trial demonstrated TTM's efficacy, leading to FDA Orphan Drug status.
- Cancer: Several phase II trials showed mixed efficacy.
- Age-related macular degeneration: A phase I trial reported negative results.
- Psoriasis: A phase II trial was conducted, but no data are available.
- Alzheimer's disease: A phase II trial was ongoing.
- Primary biliary cirrhosis: A phase III trial was ongoing.
The intervention models for these trials varied depending on the indication:
- Wilson disease: The phase III trial likely involved a randomized, controlled design, comparing TTM to standard of care or placebo. The ongoing phase III trial likely followed a similar design.
- Idiopathic pulmonary fibrosis: The phase I/II trial likely had a dose-escalation component (phase I) followed by a randomized, controlled component (phase II) comparing TTM to placebo or standard of care.
- Cancer: The phase II trials likely involved a single-arm design or a randomized, controlled design comparing TTM to standard chemotherapy regimens.
- Age-related macular degeneration: The phase I trial likely involved a dose-escalation design to assess safety and tolerability.
- Psoriasis and Alzheimer's disease: The phase II trials likely involved a single-arm design or a randomized, controlled design comparing TTM to placebo or standard of care.
- Primary biliary cirrhosis: The phase III trial likely involved a randomized, controlled design comparing TTM to placebo or standard of care.
The specific details of the intervention models, including randomization procedures, control groups, and outcome measures, would be available in the published trial protocols or results.