Active metabolite in Uptravi, MRE-269, shows benefit in CTEPH
MRE-269 found to stop growth of CTEPH lung cells in study
MRE-269, an active metabolite of Uptravi (selexipag), is more effective at stopping the growth of lung cells from people with chronic thromboembolic pulmonary hypertension (CTEPH) than it is in healthy lung cells, a study found.
Researchers also discovered that MRE-269 may do this by increasing the activity of ID1 and ID3, two genes that are involved in controlling how cells proliferate, or grow.
“The anti-proliferative effect of MRE-269 may contribute to its therapeutic benefit in the treatment of CTEPH,” the researchers wrote.
Uptravi is approved for the oral treatment of adults with pulmonary arterial hypertension, known as PAH, a rare type of pulmonary hypertension (PH). It works to delay disease progression among patients and reduce the risk of hospitalization.
The study, “Anti-proliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension,” was published in the journal Pulmonary Circulation.
Testing MRE-269 in cells from CTEPH patients vs healthy people
CTEPH is a type of pulmonary hypertension that occurs when blood clots block blood flow and raise pressure in the blood vessels — called the pulmonary arteries — that supply the lungs.
For some people with CTEPH, surgery may not be an option, and doctors might prescribe medication to make it easier for blood to flow. One such medication is Uptravi, which was approved for the treatment of CTEPH in Japan in 2021.
In people with PAH, for which Uptravi has been approved since 2015 in the U.S., the medication works in a way similar to prostacyclin, a substance in the body that causes the blood vessels to relax and widen.
It is less clear how Uptravi might work in people with CTEPH. To learn more, a team of researchers in Japan isolated PASMCs, or smooth muscle cells from the pulmonary arteries, from three CTEPH patients who had never taken medication for their disease.
These PASMCs were of various shapes. This was in contrast with control PASMCs from sex-matched healthy individuals, all of which were elongated and small in size.
The researchers focused on the action of MRE-269, the active metabolite of Uptravi. First, they grew the PASMCs in the lab together with a growth factor known as PDGF. Then they added MRE-269 at various concentrations.
In the presence of of 3 micromoles per liter (3 mcmol/L) of MRE-269, PDGF-induced growth was reduced to 49.9% in normal PASMC-3 cells, whereas a much lower MRE-269 concentration of 0.01 mcmol/L reduced growth to 64.2% in PASMCs from CTEPH patients.
“These results suggest that MRE-269 has a more potent antiproliferative effect on PASMCs from CTEPH patients,” the researchers wrote.
To understand how MRE-269 might stop PASMCs from growing, the researchers looked at which genes were turned on or turned off in the participants’ cells. They compared healthy PASMCs with PASMCs from CTEPH patients in those treated with MRE-269 versus those given a placebo.
The results showed that ID1 and ID3 were not as active in PASMCs from CTEPH patients as they were in healthy PASMCs. The team also found that treatment with MRE-269 increased their activity versus the placebo.
When the researchers used RO1138452, an inhibitor of the protein receptor to prostacyclin, they were able to dampen the effect of MRE-269 in the activity of ID1 and ID3.
These findings suggest that MRE-269 might work by both relaxing and widening the blood vessels and stopping the growth of PASMCs in CTEPH patients.
Both the vasodilatory and the anti-proliferative effect of MRE-269 may contribute to the efficacy of [Uptravi] in CTEPH.
“This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH,” the researchers wrote.
“Both the vasodilatory and the anti-proliferative effect of MRE-269 may contribute to the efficacy of selexipag [Uptravi] in CTEPH,” they concluded.