Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06176118 |
| Other study ID # |
230458 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2024 |
| Est. completion date |
July 2026 |
Study information
| Verified date |
June 2024 |
| Source |
Vanderbilt University Medical Center |
| Contact |
Thomas Strayer, PhD |
| Phone |
615-936-0156 |
| Email |
thomas.e.strayer[@]vumc.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Based on existing literature and clinical trials, 2- hydroxbenzylamine (2-HOBA) has clear
impact on mechanisms that much of the international field of pulmonary hypertension (PH)
research agrees are central to disease progression. The investigator's preliminary data and
Phase I studies demonstrate not only a clear positive impact on reducing pulmonary vascular
resistances in Group I and II PH, and both cytokine and molecular biomarkers of disease, but
also indicated the potential for a substantial positive effect on heart function under load
stress. In this Phase II project, investigators will test the safety and efficacy of 2-HOBA
in PH patients, improving the function of the right ventricle under stress in a large animal
model, and effectiveness in the context of standard-of-care in mouse models and large
animals, to establish the remaining data needed to proceed to commercialization.
Description:
Pulmonary Hypertension (PH) is a disease in which gradual cellular occlusion of the blood
vessels in the lungs increases pulmonary vascular resistance, eventually leading to right
heart failure and death. Approved therapies in common use are all different classes of
vasodilator, which can extend life in some patients, but are not disease modifying and do not
prevent decline and death. There is thus need for new therapies for PH.
Although originating causes are different across patients, a common molecular factor across
most etiologies is an increase in reactive oxygen species leading to a set of specific
metabolic problems. These include increased insulin resistance, increased reliance on
glutamine uptake in the lungs, a shift away from normal TCA-glucose metabolism, and
suppressed fatty acid oxidation in the heart leading to increased intracellular fat. An
important part of the mechanism is a feedback loop in which ROS causes reactive lipids
particularly within the mitochondria, which then adduct to proteins causing loss of function
and further metabolic defects. One such target in PH is the mitochondrial lysine deacetylase,
Sirt3. In a recent clinical trial attempting an intervention on this metabolic axis, the only
patients in whom it succeeded were those with an unusual activating set of SNPs in Sirt3,
indicating that rescue of Sirt3 is a prerequisite for resolving disease.
This presents the possibility of rescuing the defects in metabolic function that are required
for disease progression by alleviating the upstream problem with reactive lipid species.
2-Hydroxybenzylamine (2-HOBA) is a potent scavenger of reactive lipid dicarbonyls. It blocks
the effects of reactive lipids by selectively trapping them - giving an alternate target to
bind to with a binding affinity two to three orders of magnitude stronger. We have published
that 2-HOBA treatment rescued Sirt3 activity in vivo in BMPR2 mutant mice, resulting in
normalization of metabolic markers and near normalization of pulmonary vascular resistance2,
resulting in reduced acetylation of key targets. In Phase I of this project, we found that
2-HOBA also reduced pulmonary pressures in the AKR-high fat diet model of Group II PH, the
most common form of disease, associated with metabolic syndrome. The investigators also
identified cytokines and metabolites known to be changed in PH that were corrected in our
models, which could be used as biomarkers. Metabolic changes in the hearts in response to
2-HOBA in both mouse models which the investigators believe are extremely positive -
increased ability to metabolize fatty acids, which is a key need in the right ventricle under
stress.
The investigator's preliminary studies show that 2-HOBA is a safe compound which shows great
promise in treating the core molecular defect in PH, in both the closest genetic mouse model
to human disease available (BMPR2 mutants), in a mouse model of the most common type of PH
(AKR-high fat diet) and in existing and animal toxicity and human safety trials.
Based on existing literature and clinical trials, 2- hydroxbenzylamine (2-HOBA) has clear
impact on mechanisms that much of the international field of pulmonary hypertension (PH)
research agrees are central to disease progression. Our preliminary data and Phase I studies
demonstrate not only clear positive impact on reducing pulmonary vascular resistances in
Group I and II PH, and both cytokine and molecular biomarkers of disease, but also indicated
the potential for a substantial positive effect on heart function under load stress. In this
Phase II project, investigators will test the safety and efficacy of 2-HOBA in PH patients,
improving function of the right ventricle under stress in a large animal model, and
effectiveness in the context of standard-of-care in mouse models and large animals, to
establish the remaining data needed to proceed to commercialization.
