High Blood Pressure & Kidney Disease - NIDDK
FDA Approves Merck's New Drug For A Rare Lung Disease
Pulmonary arterial hyptertension disproportionately impacts women of color, though its ultimate cause is still a mystery.
gettyNearly 40,000 Americans are known to suffer from pulmonary arterial hypertension (PAH), a disease that causes the blood vessels in their lungs to progressively shrink, increasing both blood pressure and the risk of heart failure. Around 500 to 1,000 new cases are diagnosed every year, with the average patient only surviving about five to seven years after being diagnosed. The vast majority of people with this disease are women, and they are disproportionately Black or Hispanic.
On Tuesday, the Food and Drug Administration approved a new drug to treat this disease called sotatercept which was developed and being marketed by pharmaceutical giant Merck under the name Winrevair. This is the first new type of treatment for the disease approved in nearly a decade, and is considered by the FDA to be "first in class," meaning it's the first medicine of its kind to treat this disease. In a clinical trial, the drug reduced the risk of death or increased severity of the disease by 83%.
According to Eliav Barr, Merck's head of global clinical development and chief medical officer, patients with this disease are highly engaged with managing it, and that there's been "enormous enthusiasm and anticipation for the drug to come out," he told Forbes. "We anticipate there's going to be very vigorous uptake."
What exactly causes PAH isn't precisely understood, Dr. Panagis Galiatsatos, a research pulmonologist at Johns Hopkins School of Medicine who was not involved in developing the drug, explained to Forbes. For some patients there appears to be a genetic component, but in others it's unknown. This variety of causes and the rarity of the disease make it a "double-edged sword" for researchers trying to develop treatments, he said. "That's tough, because you struggle to know if one treatment will help out."
In patients with PAH, the blood vessels begin to grow inwardly, leaving less and less room for blood to flow freely. This increases blood pressure in the lungs, forcing the right side of the heart to pump harder. As the disease progresses, it becomes more difficult for patients to get a lot of exercise or even perform daily tasks as it becomes harder for them to breathe. Heart failure is common.
Unlike previous drugs for this disease, which either treat symptoms or alleviate blood pressure by dilating the blood vessels, sotatercept actually attacks the signaling mechanisms in the body that have gone wrong and tell the blood vessels to keep growing, explained Barr. The drug works by blocking those signals, which causes the blood vessels to return to a normal thickness, which in turn lowers blood pressure.
In a clinical trial for the drug that was published in the New England Journal of Medicine, researchers found that sotatercept, when injected at 3-week intervals, enabled patients to extend the distance they could walk in 6 minutes by over 40 meters compared to those who received a placebo. The trial also found that the risk of death or a significant worsening of the disease progression was reduced by 84% compared to placebo. "It was just a dramatic reduction in the rate of progression and worsening of clinical symptoms," said Barr.
With the drug now approved by the FDA, it will just be a "matter of weeks" before it hits the market, Barr said. And Galiatsatos said that because of the relative dearth of treatment options for patients with PAH, he expects that sotatercept will become one of the first drugs prescribed to PAH patients "sooner rather than later."
That's a sentiment shared by analysts at investment banking firm Jefferies, which in a report published earlier this year estimated $7.5 billion in peak 2024 sales for the drug based on FDA approval and its expected European approval in the second half of the year. The firm added a possible upside of over $9 billion in sotatercept sales.
Merck's scientists also think that the drug can be useful for other types of pulmonary hypertension. The company is currently conducting a phase 2 clinical trial in a group of patients who have pulmonary hypertension as a result of a certain type of heart failure. If it's successful with that group, the company could rapidly expand the number of people who can benefit from the medication.
"It's a pretty big breakthrough," Barr said, adding that he expects the drug to help patients live longer lives. "They'll see their kids growing up and they'll be able to live better lives."
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Spirometry is a standard test that doctors use to determine how well your lungs are functioning. The test works by measuring airflow into and out of your lungs.
To take a spirometry test, you sit and breathe into a small machine called a spirometer. This medical device records the amount of air you breathe in and out as well as the speed of your breath.
Doctors use spirometry tests to diagnose these conditions:
Results from spirometry tests can also suggest the presence of other conditions, such as restrictive lung disease.
But spirometry is a simple test. Alone, it is not enough to diagnose many underlying conditions. In these instances, doctors may order broader pulmonary function tests to definitely assess any underlying conditions affecting lung output.
Before a spirometry test, you can do several things to ensure you can breathe comfortably and receive an accurate result, such as:
A spirometry test typically happens in a doctor's office. In some cases, when more in-depth tests are necessary, it may take place at a respiratory laboratory.
Here's what happens during a spirometry procedure:
If you have evidence of a breathing disorder, your doctor might give you an inhaled medication called a bronchodilator to open up your lungs after the first round of tests.
They'll often ask you to wait 15 minutes before taking another set of measurements. Afterward, your doctor will compare the results of the measurements to see whether the bronchodilator helped increase your airflow.
Few complications typically occur during or after a spirometry test. Yet you may want to be aware of some possible effects.
You may feel dizzy or have some shortness of breath just after performing the test. In this case, tell your doctor immediately. In very rare cases, the test may trigger severe breathing problems.
When you do this test, it will increase the pressure in your head, chest, stomach, and eyes as you breathe out. So, it is unsafe if you have heart problems or hypertension or if you've had surgery on your chest, abdomen, head, or eyes.
A spirometry test itself has few risks, but there is a minor risk of infection. This may occur due to contamination of the spirometer tubing and mouthpieces if they are not disinfected properly.
The American Thoracic Society and the European Respiratory Society have official technical standards for conducting spirometry. These include disinfection guidelines and recommend disposable mouthpieces with filters to avoid spreading infections.
"Normal" results for a spirometry test vary from person to person. They're based on your:
Your doctor calculates your predicted "normal" value before you do the test. Once you've done the test, they look at your test score and compare it with the predicted score. It is typically reported that a score of 80% or more of this predicated value indicates typical lung function. Yet some research from 2018 claims that this figure is inaccurate.
Spirometry measures two key factors: expiratory forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). Your doctor also looks at these as a combined number known as the FEV1/FVC ratio.
If you have obstructed airways, the amount of air you can blow out of your lungs quickly will be reduced. This translates to a lower FEV1 and FEV1/FVC ratio.
FVC measurementOne of the primary spirometry measurements is FVC, the greatest total amount of air you can forcefully breathe out after breathing in as deeply as possible. If your FVC is lower than expected, something is restricting your breathing.
An "abnormal" FVC could be due to restrictive or obstructive lung disease. You could have an obstructive or restrictive lung disease by itself, but it's also possible to have a mixture of these two types at the same time.
Different spirometry measurements are required to determine which type of lung disease is present.
FEV1 measurementThe second key spirometry measurement is FEV1. This is the maximum air you can force out of your lungs in 1 second.
This measurement can help your doctor evaluate how severe your breathing issues are. An FEV1 reading that's lower than expected shows you might have a significant breathing obstruction.
Your doctor will use your FEV1 measurement to grade how severe any breathing concerns are.
FEV1/FVC ratioDoctors often analyze the FVC and FEV1 separately, then calculate your FEV1/FVC ratio. The FEV1/FVC ratio is a number that represents the percentage of your lung capacity you're able to exhale in 1 second.
In the absence of restrictive lung disease that affects FEV1/FVC ratio, the higher the percentage a doctor calculates from your FEV1/FVC ratio, the healthier your lungs are.
A low ratio suggests that something is blocking your airways
Spirometry produces a graph that shows your flow of air over time. If your lungs are healthy, your FVC and FEV1 scores are plotted on a graph that could look something like this:
If your lungs are obstructed in some way, your graph might instead look like this:
If your doctor finds that your results fall into the "abnormal" category, they'll likely perform other tests to determine whether a breathing disorder causes impaired breathing. These could include chest X-rays, sinus X-rays, and blood tests.
The primary lung conditions that will cause unexpected spirometry results include obstructive diseases, such as asthma and COPD, and restrictive diseases, such as interstitial pulmonary fibrosis.
Your doctor may also screen for commonly occurring conditions with breathing disorders that can worsen your symptoms. These include heartburn, hay fever, and sinusitis.
Spirometry tests are standard procedures doctors use to assess lung function. These tests measure how much air a person can force out of their lungs within 1 second and in total.
The results of a spirometry test can help diagnose obstructive lung disease and other respiratory conditions.
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Ongoing Breathing Problems Continue After COVID
In September 2022, I saw Joe Potter, a 40-year-old patient who flew to Philadelphia from Kansas to be treated for a rare condition.
As with all new patients, I first took his medical history, which included a yearlong quest for answers as to what caused his ongoing breathing problems.
Joe's symptoms became apparent in April 2022 after getting COVID.
Not long after recovering, he experienced ongoing shortness of breath. He ended up in the ER with double pneumonia and was prescribed standard medications.
But after completing the treatment, his breathing problems persisted. His primary care doctor referred him to a local pulmonologist.
Joe noted it became especially hard to breathe when he was lying flat. He said trying to draw in a breath felt like hitting a wall. He spent the next 6 months sleeping upright in a recliner.
His pulmonologist referred him for a sleep study, which showed his oxygen levels while sleeping dipped dangerously low. He was prescribed a bilevel positive airway pressure, also known as BiPAP. The device includes a mask that fits over the nose and/or mouth and blows air via a tube into the airways to keep them open while you sleep.
Despite better sleep with the BIPAP machine, his problems continued. He had to stop working as a welder due to job-site dust and grime that exacerbated his breathing troubles. Nor could he play in his beloved local softball league because he couldn't run to first base without losing his breath.
Joe's pulmonologist continued with more tests. After a bronchoscopy, a procedure to look in the airway and lungs using a thin flexible tube, his doctor thought a collapsed trachea might be the cause.
He was diagnosed with tracheobronchomalacia (TBM), where the walls of the airway are weak and collapse when a patient breathes or coughs. Because the condition is so rare, his pulmonologist suggested he seek surgical treatment at a specialized center and referred him to me.
When Joe arrived at Temple University Hospital, I ordered a bronchoscopy to confirm TBM and determine the best course of treatment. His results showed some airway collapse but it was not severe, nor was he coughing, which is another prominent symptom of TBM.
The problem runs deeper
A CT scan of his chest showed his diaphragm, the main muscle that facilitates breathing, was slightly elevated on both sides. I sent him to get a sniff test to confirm my hunch.
The sniff test uses x-ray video to see how your diaphragm moves when you inhale quickly. Normally when you sniff, the diaphragm moves down. If it moves upward on inhale, that signals dysfunction, which is what we saw on Joe's test.
An ultrasound ultimately revealed the true diagnosis: bilateral diaphragmatic paralysis, an uncommon condition.
The diaphragm is a thin, dome-shaped muscle that sits beneath the lungs and heart. When the diaphragm contracts, it moves downward, allowing the lungs to expand in the chest cavity and air to move into the lungs as one inhales. When it relaxes, it moves upwards, causing a decrease in lung size as one exhales.
When this muscle is weakened, it may become harder for a person to breathe. This is called diaphragm paralysis, a condition that is often misdiagnosed and undertreated.
It is caused by damage to the phrenic nerve, which runs through your spine, neck, heart, and lungs and controls the diaphragm. Phrenic nerve damage is often caused by trauma, such as spinal cord injury, or neurologic diseases such as ALS.
It can also be caused by viral infections, which I believe was the case for Joe, given his COVID history. I have seen an uptick in cases of diaphragm paralysis since the COVID pandemic and worldwide studies have shown patients who had COVID may experience long-term diaphragm weakness.
Some patients can benefit from losing weight or starting a pulmonary rehab program to reduce the burden on the diaphragm. For those with an impaired quality of life like Joe, surgery can offer a long-term solution.
If the cause is thought to be a viral infection, we recommend waiting six months to a year after infection as there are reports of the phrenic nerve recovering on its own. That did not happen for Joe, so in January 2023, he had surgery to correct the paralysis on his right diaphragm.
Plication is a minimally invasive procedure performed robotically through small incisions to reshape the diaphragm by suturing it onto itself to make it more stiff and flat, allowing the lung more room to expand and therefore helping the patient breathe better.
Following the first surgery on the right diaphragm, he could once again breathe while lying flat. He returned to some normal everyday activities with more ease.
In telemedicine follow-up appointments, he noted that he still felt some resistance when drawing in a breath so we brought him back for surgery in October to correct the paralysis on his left side.
He's now breathing completely normally with no feeling of obstruction. He returned to work in January and is even running again.
Dr. Charles Bakhos is a thoracic surgeon at Temple University Hospital and Vice Chief of the Department of Thoracic Medicine and Surgery at the Lewis Katz School of Medicine at Temple University.
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