Opsumit Shows Promise for Portopulmonary Hypertension in Phase 4 Trial - Pulmonary Hypertension News

Opsumit Shows Promise for Portopulmonary Hypertension in Phase 4 Trial - Pulmonary Hypertension News

Opsumit Shows Promise for Portopulmonary Hypertension in Phase 4 Trial - Pulmonary Hypertension News

Posted: 17 Jun 2019 05:00 AM PDT

Treatment for 12 weeks with Actelion Pharmaceuticals' Opsumit (macitentan) significantly improved blood vessels' resistance in patients with portopulmonary hypertension without causing further damage to the liver, data from the PORTICO Phase 4 trial show.

The study, "Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial" was published in the journal Lancet Respiratory Medicine.

Portopulmonary hypertension (POPH) is a condition characterized by pulmonary arterial hypertension (PAH) together with elevated pressure in the portal vein — the vein responsible for directing blood from parts of the gastrointestinal tract to the liver.

POPH is a common complication of advanced liver disease; while liver transplant is the most effective treatment strategy, severe PAH is a contraindication for this procedure as it reduces its chances of success and worsens the overall prognosis.

This means that it is necessary to first treat PAH in these patients so that they can undergo a liver transplant. However, few studies have explored the efficacy of anti-PAH therapies in POPH.

In the Phase 4 PORTICO (NCT02382016) study, researchers evaluated the safety and efficacy of Opsumit in POPH patients.

Opsumit is an oral therapy approved in the U.S. and Europe for treatment of PAH symptoms and to slow the progression of disease. It works by reducing the contraction and narrowing of blood vessels, which can help reduce their resistance to blood flow, and lower blood pressure in the lungs.

The PORTICO trial randomized 85 patients (older than 18) with symptomatic POPH to receive either 10 mg of Opsumit (43 patients) daily, or a placebo (42 patients) for 12 weeks. This was followed by a 12-week open-label period where all eligible patients — 91% and 98% in the Opsumit and placebo groups, respectively — were given Opsumit.

Results showed that after 12 weeks of Opsumit treatment, POPH patients had a significant reduction in pulmonary vascular resistance (by 35%), and in mean pulmonary arterial pressure (mPAP).

The treatment also increased the patients' cardiac index, compared to those treated with a placebo. The cardiac index measures the amount of blood ejected by the heart in a unit of time divided by the body surface area.

There were no changes in blood pressure of the right atrium of the heart, nor in the levels of NT-proBNP (a marker of right heart dysfunction) between the two groups. Also, no significant differences in disease severity or in the six-minute walk distance test (which assesses exercise capacity and endurance) were found between the two groups.

Of note, liver function and the pressure in the liver's main blood vessel did not worsen with Opsumit treatment.

However, the team observed some secondary effects associated with Opsumit. The most frequent adverse effect was peripheral edema (swelling in the hands and lower legs), seen in 26% of Opsumit-treated patients, compared to 12% in the placebo group. Additional side effects included headache and bronchitis.

In total, 21% of Opsumit-treated patients reported at least one serious adverse effect, compared to 14% in the placebo group. Among Opsumit-treated patients, four stopped treatment because of adverse events, namely hypersensitivity, inflammation in the lungs' tiny air sacs (alveoli), worsening of PAH, or anemia.

In the open-label phase, 30% of patients receiving Opsumit had at least one serious adverse effect, and 12% discontinued the treatment because of side effects.

Overall, the results show that "treatment with [Opsumit] in patients with portopulmonary hypertension resulted in improvement in pulmonary vascular resistance, without leading to further adverse liver conditions in patients with mildly or moderately impaired liver function," researchers stated.

"Although no functional improvements were seen over this timescale, the findings from this study indicate that macitentan might be a therapeutic option in patients with portopulmonary hypertension," the team concluded.

The Significance of Databases for PAH - MD Magazine

Posted: 30 May 2019 12:00 AM PDT

Patients who present with symptoms of pulmonary arterial hypertension could land on any spot of a spectrum which indicates minimal to significant risk of comorbidities, and even mortality. The uncommon, burdensome condition often requires that patients are receiving optimized therapy early and aggressively following diagnosis.

That puts pressure on investigators to broaden their access to clinical data. In an interview with MD Magazine®, Rich Channick, MD, director of the Acute and Thromboembolic Disease Program at the UCLA Medical Center, and Prof. Sean Gaine, director of the National Pulmonary Hypertension Unit in Ireland, explained the utility of national, international registries of PAH patients, and how it influences their ability to identify low- and high-risk patients.

MD Mag: How critical are broad database in assessing care of patients with a rare, chronic condition such as PAH?

Channick: Yeah, I mean there's a lot of creative ways to get data. A lot of people are using claims data, insurance claims, instead of getting a big data. You can find a lot of patience. And now with coding, diagnostic codes, you look at pulmonary hypertension as a code for an insurance claim.

Obviously, there's a lot of different insurance companies. It's different in other countries, but you can really then look at different testing that has been done, what drugs are getting used, and patterns of use. You often can't get very granular, as we say, a higher view. But you can look at it a lot of patients.

Gaine: Yeah, in fact, we saw it at our session today, that we were presenting the GRIPHON data from the VA (Veterans Affairs). So the VA is an enormous database, and patients who attend VA have pulmonary hypertension—some of them—and you can gather data from there. So there are those are national registries that we pour through, not just registries from drug trials and seeing how patients are using them, but the national registries. And we learn a lot from them.

We've learned in the last few years that PAH as a disease seems to be sort of shifting—or at least what we're seeing is older patients that we wouldn't have seen previously. So we have to reset where to look for the disease. We used to say, "Oh, this is a disease of idiopathaty from the arterial hypertension." Formerly, primary pulmonary hypertension was a disease in young women in their mid-30s. So you knew where to look, in the sense of when a young woman arrived in breathless. You thought, this is unusual, maybe it's primary pulmonary hypertension, maybe it's idiopathic pulmonary hypertension.

Now we've learned from these registries that it's not necessarily always the case. You may have a 55 year old person who comes in says, "I'm breathless." You're thinking, well you're not doing any exercise, that's why you're breathless. But, in fact—normal pulmonary function, normal chest, X-ray, ECG. They need to go for an echo, and the echo is the number 1 screening tool to see if a person has problems with the right ventricle. So again, in primary care, someone comes in and it just doesn't fit, think of an echo as a really valuable screening tool.

Channick: Yeah, the last thing I'd say about registries—especially all the registries in Europe and elsewhere—is they have allowed us to start to look at things like risk stratification. One of the big mantras in pulmonary hypertension is determining what risk category are patients in, based on composite parameters—coming up with scores where we can actually profile a patient.

And when you treat a patient with these therapies, they determine whether they are into what we call the low-risk category, meaning they'll have a good prognosis. We quantify that. So, these registries have really allowed us both to develop some of these scores, and then validate them to show that it actually are predictive.

And that's really how we're treating. We have the GRIPHON subgroup to really look at the ability of the agent to lower risk, to put people into a low-risk category—that's really important in our treatment.

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