Inhaled Treatment MK-5475 Shows Promise in Phase 1 Trial for PAH

Global Phase 2/3 study to test Merck therapy now enrolling patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Merck’s investigational inhaled treatment MK-5475 was well-tolerated and showed promise among adults with pulmonary arterial hypertension (PAH) in a Phase 1 clinical trial.

Results showed that the therapy improved blood flow in patients’ lungs, but did not affect blood pressure elsewhere in the body.

“The promising pulmonary selectivity and favorable safety/tolerability profile of MK-5475 seen in this study of adult participants with PAH lays the foundation for further clinical development,” researchers wrote.

To that end, Merck is sponsoring a Phase 2/3 clinical trial (NCT04732221) dubbed INSIGNIA-PAH that aims to test the treatment against a placebo in approximately 450 adults with this rare type of pulmonary hypertension. The study is enrolling participants, ages 18–75, at dozens of sites around the world.

The findings of the Phase 1 study were detailed in “Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH),” published in the journal Respiratory Medicine. The work was funded by Merck, known as MSD outside the U.S. and Canada, and led by scientists at the company.

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Improved circulation with PAH treatment

Most approved therapies for PAH are given by injection or taken orally, which means that the active ingredients in the medicine get distributed throughout all the body’s tissues. Because PAH affects the lungs, but not other parts of the body, this can results in unwanted side effects and toxicities.

Therapies that are inhaled offer potential advantages over systemic treatments, given that they could theoretically deliver a medicine right where it’s needed in the lungs, without affecting other parts of the body.

MK-5475 is a dry-powder therapy that is administered via an inhaler. It is designed to reduce blood pressure by activating a protein called soluble guanosine cyclase. Adempas (riociguat), an oral therapy sold by Bayer that’s approved to treat PAH, works through this same biological mechanism.

“Inhaled PAH therapies like MK-5475 may provide selectivity of hemodynamic [blood flow] effects to the lung vasculature [blood vessels] thus offering significant advantages over current systemic therapies, including optimized drug delivery to the lungs at a lower overall dose with a more favorable tolerability profile,” the researchers wrote.

This two-part Phase 1 clinical trial (NCT03744637) was conducted at a single center in Moldova. In the first part, eight patients were given a single dose of MK-5475 or a placebo. Three treatments were administered at least a week apart, and the dose of MK-5475 was increased from 120 micrograms (mcg) in the first treatment to 240 mcg at the third.

In the second part of the trial, participants received various doses of MK-5475 for up to three treatments in an open-label fashion, meaning that both patients and clinicians were aware of what therapy the patients were taking and there was no placebo. During this part of the trial, participants also underwent monitoring of blood pressure in the lungs.

A total of 25 patients were included in this study. They ranged in age from 28 to 69, about three-quarters were female, and all were Caucasian.

Among them, six (24%) reported side effects related to MK-5475 treatment during the trial. All of these were mild-to-moderate in intensity, and had either resolved completely or were resolving by the end of the study. The most common adverse events reported included back pain and elevated levels of bilirubin, a waste product made when hemoglobin in red blood cells is broken down.

“In this study, single inhaled doses of MK-5475 ranging from 120 to 480 [mcg] were generally well tolerated in both male and female participants,” the researchers wrote.

Notably, no clinically relevant changes in body-wide blood pressure or heart rate were noted at any tested dose of MK-5475. Side effects related to blood vessel widening like swelling and headache, which are commonly caused by PAH therapies, were not frequently reported.

These results support the idea that “inhaled single doses of MK-5475 do not elicit unintended vasodilatory side effects commonly seen with systemic PAH therapies,” the scientists wrote.

Blood flow assessments showed that pulmonary vascular resistance (PVR), a measure of the resistance against blood flow, decreased by at least 20% in the hours after treatment with all tested doses of MK-5475.

The treatment also increased pulmonary blood volume (PBV), referring to the total amount of blood that’s in the lung’s blood vessels, the results showed.

According to the team, these findings suggest that PBV may be a useful measurement of pulmonary arterial perfusion.

“Treatment with MK-5475 showed significant improvements in pulmonary circulation as assessed by both PVR and PBV outcomes,” the scientists concluded.

The team stressed that this was a small study with a short duration, so further work is needed to definitively determine the safety and efficacy of treatment with MK-5475 in PAH.

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