Robert Frantz, MD - phaware® interview 475

Dr. Robert Frantz, a cardiologist at the Mayo Clinic, discusses current and upcoming clinical research in pulmonary arterial hypertension (PAH). He emphasizes the low participation rate of PAH patients in clinical trials and encourages patients to consider participating, as it not only benefits themselves but also helps advance medical knowledge. @MayoClinic @MayoMedEd

I am Dr. Robert Frantz. I'm a cardiologist at the Mayo Clinic in Rochester, Minnesota and Director of the Pulmonary Hypertension Clinic there. Today, I'd like to talk a little bit about what's in the pipeline in clinical research in pulmonary arterial hypertension.

The concepts include inhaled therapies that aren't really acting as vasodilators, but maybe anti-proliferatives with maybe some anti-inflammatory effect. This includes inhaled imatinib. Imatinib is a tyrosine kinase inhibitor that is known as GLEEVEC in the cancer world, but which had been shown to drop pulmonary vascular resistance in patients with pulmonary arterial hypertension years ago, but never came to market for that indication, because there were too many side effects with the oral administration, and there were rare cases of cerebral bleeding in patients that were on anticoagulation. However, the concept of inhaling the imatinib, where then you're delivering the drug right to where it needs to be, will hopefully lead to fewer off-target effects, because the blood levels are quite low. So, the IMPAHCT study is looking at this inhaled imatinib and just finished the Phase 2 study and has sort of a seamless integration of the Phase 3 that launched immediately after the Phase 2 completed. That's very interesting and it will be exciting to see where that goes.

Continuing on the theme of inhaled therapies to try to avoid systemic side effects, there's inhaled seralutinib like que sera sera. What will be will be, but we want to change PAH. This is a compound that was designed to have some of the effects of a drug like imatinib, but even more powerful at some of the receptors that imatinib hits, and also to hit a pathway on activated macrophages, which are around the blood vessels and can cause inflammation. So, that's the colony stimulating factor 1R inhibition aspect of seralutinib. Seralutinib was shown in Phase 2 studies to reduce pulmonary vascular resistance. So, if that could occur in patients with PAH in the Phase 3, then it should be associated with improvement in six-minute walk. So, the Phase 3 study, PROSERA, is randomizing patients with PAH to either inhale seralutinib or a placebo. The end-point is six-minute walk. See if we can make people function better that way. So that's also a really exciting thing that's going on.

Now, to change tack a little bit, some patients have what we call combined pre and post-capillary pulmonary hypertension, where the pulmonary artery pressures are high, but maybe the left side of the heart is stiff in how it fills, what we call heart failure with preserved ejection fraction. That then backs blood up into the lungs and back into the pulmonary arteries. Some people, they have more severe pulmonary hypertension that's causing the right ventricle to fail, as well. So, the left side of the heart is stiff, the pressure's high in the pulmonary arteries, and the right heart's also impaired. Very hard to treat with pulmonary vasodilators, because it's sort of like opening up the faucet if the sink is plugged up. You can increase flow into the lungs with a pulmonary vasodilator, but it has trouble getting out and you just cause pulmonary congestion.

The CADENCE study is taking sotatercept, which is at the FDA now for consideration for approval for pre-capillary pulmonary arterial hypertension, and the date for that review is March. The concept with using sotatercept in patients with combined pre and post-capillary PAH and a stiff left heart would be if they're suffering with right heart failure and backup of fluid on the right side, as well, that you may be able to drop that pulmonary resistance without necessarily forcing a lot more blood through the lungs, but making it easier for the right heart to pump.

So, in those patients, they'll be treated with optimal therapy to make the left side of the heart fill as well as possible, which are currently therapies like SGLT2 inhibitors, which are sodium glucose transporter type 2 inhibitors that make people dump fluid and salt and glucose in the urine and have been shown to be helpful for a stiff left heart syndrome. So, you might optimize a patient on that to try to get the left heart filling pressures down as much as possible, and then maybe put them into a study of sotatercept to try to lower pulmonary resistance to make it even easier for the right side of the heart to pump. So, unmet needs in the PAH world that are going to be met in the years to come. I think it's really exciting that this is happening.

The percentage of patients with pulmonary arterial hypertension that actually participate in clinical trials is remarkably low. Partly there may be exclusion criteria for which they're not allowed into the study. Partly it's a lot of back and forth to the center in order to have follow-up testing. So, things of that type can sort of reduce the number of patients coming in, but it's also an opportunity to get a therapy that's not yet available. If it turns out to be a therapy that's effective, you might be a couple years ahead of the game by going in a clinical trial. So, I encourage patients to consider it carefully, talk to their physicians and providers about it, and think about getting involved, because being in a clinical trial, you're not only doing something maybe good for yourself, but you may be helping another person, as well, which is a pretty cool thing.

Whenever we're seeing a patient with medical issues that aren't adequately controlled, we're thinking about the whole range of options. What do we know could be effective that's not being optimized right now, and what can we do about that? That's the low-hanging fruit. Sometimes, in pulmonary hypertension, it's recognizing that oxygen levels are low at night and detecting that and then giving people oxygen at night or treating sleep apnea. The prevalence of sleep disordered breathing resulting in low oxygen levels at night and pulmonary hypertension is remarkably high. There's no salesperson knocking on our door saying, "Hey, look for this because then we can sell you this drug for it." It's like, "Oh, you have to think of it." Maybe a problem is that the oxygen levels are low at night and that's contributing to the pulmonary hypertension and right-sided heart failure. I'm struck at how often we just do overnight oximetry and pick that up. Little things like that that are clearly within the mainstream of currently proven medicine are sometimes overlooked.

Then, if there are clinical trials, then we have to talk to our patients about what about their situation makes us think this might be or not be a good fit for them. Fortunately, most of the drugs in pulmonary hypertension that have been developed work in the majority of patients to some extent, so it's not necessarily that we know how to look at a patient say that probably won't work for you. But on the other hand, there are very specific subgroups of patients that some clinical trials are trying to find, and if the patient doesn't fit that criteria, then it doesn't make sense to go there.

So, a careful discussion and looking at the options. A neat thing people can do to take a little empowerment themselves is to look at www.clinicaltrials.gov. It's a website where you just type in pulmonary arterial hypertension or if you heard about a drug, put in the name of that drug and boom, you'll see what clinical trials are going on, often with some inclusion/exclusion criteria for you to look at and centers that might be doing the study. So, I think it behooves patients who have any kind of disease that's not adequately managed to be thinking about what's out there. Sometimes you have to be proactive to make it happen, if that study's not being done in your local area.

My name is Dr. Robert Frantz, and I'm aware that my patients are rare.

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