Transcatheter patent ductus arteriosus closure in extremely premature infants
Seralutinib Effective In Managing Pulmonary Arterial Hypertension: Lancet
In the field of pulmonary arterial hypertension (PAH), where morbidity and mortality rates remain alarmingly high, a new inhaled drug can greatly enhance the outcomes in patients. A recent study called as the TORREY trial unveiled promising results regarding the efficacy and safety of a new inhaled drug, the Seralutinib, in managing this life-threatening condition. The findings were published in The Lancet Respiratory Medicine.
The TORREY trial revealed that Seralutinib, an inhaled kinase inhibitor, targets the crucial pathways involved in PAH progression. Seralutinib disrupts inflammatory, proliferative and fibrotic pathways driving pulmonary vascular remodeling in PAH by inhibiting platelet-derived growth factor receptor, the colony stimulating factor 1 receptor and mast or stem cell growth factor receptor kinases.
This phase 2, randomized, multicenter, double-blind, placebo-controlled study enrolled a total of 86 adult patients with PAH from various hospital and community sites. The participants were randomly assigned to receive either Seralutinib or a placebo via dry powder inhaler over a span of 24 weeks. The patients were already receiving standard background therapy for PAH. The primary endpoint of the trial was the change in pulmonary vascular resistance (PVR) from baseline to 24 weeks.
The results observed that patients treated with Seralutinib expressed a significant reduction in PVR when compared to the patients receiving the placebo. Also, the least squares mean difference in PVR change between the Seralutinib and placebo groups was clinically significant at -96.1 dyne·s/cm5 (p=0.03). While generally well-tolerated, the most common treatment-emergent adverse event in both groups was cough which was reported in 38% of the placebo group and 43% of the Seralutinib group.
These findings hold profound benefits for the management and treatment of PAH. This trial offers hope for patients with this debilitating condition by demonstrating the efficacy of inhaled Seralutinib in reducing PVR. The safety profile of the drug suggests its potential as a valuable addition to existing PAH therapies. Further investigation and development will guide forward this innovative therapy against pulmonary arterial hypertension by offering renewed prospects for patients throughout the globe.
Source:
Frantz, R. P., McLaughlin, V. V., Sahay, S., Escribano Subías, P., Zolty, R. L., Benza, R. L., Channick, R. N., Chin, K. M., Hemnes, A. R., Howard, L. S., Sitbon, O., Vachiéry, J.-L., Zamanian, R. T., Cravets, M., Roscigno, R. F., Mottola, D., Osterhout, R., Bruey, J.-M., Elman, E., … Ghofrani, H.-A. (2024). Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial. In The Lancet Respiratory Medicine. Elsevier BV. Https://doi.Org/10.1016/s2213-2600(24)00072-9
Pulmonary Arterial Hypertension: Her Symptoms Were Getting Worse. Then She Joined A Clinical Trial
Heather Kauffman, 49, says she entered a clinical trial for a new drug to treat pulmonary arterial hypertension (PAH) in 2021 with a dose of cautious optimism.
Her physician, Dr. Vallerie McLaughlin, a leading expert in pulmonary hypertension at the University of Michigan Medical School, first approached her two years earlier with the possibility of enrolling in the phase III STELLAR study for a new drug to treat PAH.
Kauffman's work schedule made it hard for her to commit to the study, but when her day-to-day health continued to worsen, she agreed to do it.
For Kauffman, PAH (a rare form of pulmonary hypertension that can be life threatening) has been a throughline stretching across her whole life. During childhood, her younger brother, BJ, passed away at just five years old from the condition.
By the time she was diagnosed at the end of 2017, it was a grim discovery to learn she and BJ shared the same disease, bringing with it personal fears over her own health.
Flash forward to 2024, and Kauffman describes her experience in the STELLAR trial to be, well, "stellar."
The drug, sotatercept, was designed to treat adults with PAH to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.
The Merck-manufactured drug – an injectable administered every three weeks that is sold under the brand name Winrevair – was just approved in March by the Food and Drug Administration (FDA), according to a release.
This first-in-class activin signaling inhibitor marks a significant milestone in tackling the condition. Along with the recent FDA approval of Opsynvi, which is a daily tablet that combines existing drugs macitentan and tadalafil, it's currently a promising period for PAH treatment.
Sotatercept marks the first time in nearly a decade that a brand-new PAH treatment has been approved.
"I had told [Dr. McLaughlin] from the very beginning, 'my brother passed away in 1982, there was nothing for him, there was nothing that they could do,'" Kauffman told Healthline. "So, I had told her that I would like to be part of research…and be part of anything that would further the research of this disease."
PAH is a condition that causes a narrowing of the blood vessels in your lungs, resulting in impaired blood flow throughout the lungs.
People living with PAH will develop high blood pressure in the pulmonary arteries that need to transport blood deficient in oxygen from the heart to the lungs, according to the National Heart, Lung, and Blood Institute.
Those with PAH will see their hearts overexert themselves as they try to work in overdrive to pump blood to the lungs. This can have a negative domino effect on your overall health. When left untreated, the condition is fatal.
The condition is very rare. Only 500 to 1,000 people are diagnosed with PAH annually in the United States.
When asked to put in context how PAH differs from other forms of pulmonary hypertension, Dr. Kristin Highland, a specialist in pulmonary medicine at Cleveland Clinic who was also part of the sotatercept clinical trial, explained that there are various features that overlap between the different groups that fall under the wider pulmonary hypertension umbrella. PAH is classified as "group 1."
Highland told Healthline that "group 2" pulmonary hypertension is the most common type, known as "post-capillary," with pressures elevated on both the right and left sides of the heart. PAH, along with groups 3 and 4, are considered pre-capillary forms of pulmonary hypertension, meaning that "left-side of the heart, and left-sided pressures, are normal."
All groups have abnormalities of lung blood vessels, and PAH "is a diagnosis of exclusion," meaning doctors will cross out associations with the other groups (like group 3 being the result of pulmonary disorders like chronic hypoxia or group 4 resulting from blood clots that break off elsewhere in the body, lodge in the lungs, and then fail to dissolve, for two examples) to derive a PAH diagnosis.
"In PAH, the lesion is confined to the pulmonary arteriole with abnormalities of all layers of the blood vessel that results in a vasculopathy, or thickening and narrowing, of the blood vessel, which then increases the resistance in the pulmonary vascular bed leading to pulmonary hypertension, or increased pressure in the lung," Highland added. "This eventually culminates in the right heart failing in its ability to pump blood through the lungs."
Highland explained that one challenge that comes from this condition is that PAH can often be misdiagnosed or underdiagnosed due to the fact that symptoms can resemble those of other conditions.
She said there is often a delay in diagnosis that stretches more than two years.
While living with PAH, Highland said patients often subconsciously "slow down" in response to their symptoms. This means the condition might be missed entirely by a doctor until someone does something out of character, like go on an arduous hike.
"When patients are breathless at rest, they have extremely advanced disease," Highland explained. "Common things being common, patients are usually diagnosed with asthma, COPD, left heart failure, being obese, and out of shape."
She said that as the disease advances, the right heart becomes further strained, and the individual might experience fatigue, chest pain, swelling of the stomach or lower extremities, dizziness, or fainting, among other symptoms. Highland noted that fainting may "indicate the right heart is really struggling."
Thinking back to the time right before her diagnosis, Kauffman said she thought her symptoms were tied to anxiety because her husband had just been deployed to the Middle East. She would experience shortness of breath, and her heart would race.
She noticed just going to work seemed to expend a lot of oxygen, and she would even have to sit in the car and take a break before heading in to the office.
She went to the urgent care and ultimately was admitted to the ER. She was diagnosed with PAH three days later.
She calls it "fate" and a "series of fortunate events," given the reality that most people go two or three years before a diagnosis.
According to the release, Winrevair will be available in specialty U.S. Pharmacies by the end of April.
When asked how significant it is to have this new treatment available on the market, McLaughlin, Kauffman's doctor who enrolled her in the trial, said it's exciting to have this new drug. Everything in the past 30 years targeted "the same three pathways," she explained, and "this is the first agent that really has the potential to reverse remodel the disease."
"I think this is a huge step. It's really exciting to have a drug that starts getting at the underlying molecular issues with the disease and might have some anti-proliferations and reverse modeling," McLaughlin added. "The breadth of the trial positivity was incredible…We are very excited about what it really marks, which is more advancements, right? We are learning more and more about PAH every day, and to have companies invest in our space and develop drugs with novel mechanisms of actions is really fantastic."
She said there are currently "a number of other clinical trials" taking place, and she expects more PAH medications will be available in the near future.
Highland pointed out that the first FDA-approved drug PAH, epoprostenol, wasn't available until 1996. That means there were countless other people like Kauffman's brother BJ who were living with this disease with no treatment in sight. Before that first drug's approval, Highland said the expected survival of someone with PAH was under three years.
"The available therapies for PAH since then have focused on vasodilation, although most of these drugs have pleiotropic effects. The three classes of drugs have focused on augmenting the prostacyclin pathway or the nitric oxide pathway or blocking the endothelin pathway," Highland added. "Patients usually need to be on combination therapy. Patients also often need to be on diuretics and oxygen. Pulmonary rehabilitation is also very beneficial."
Highland added that while this is an encouraging time, survival for PAH is estimated to be at just 86% at the one-year marker, 67% at the three-year marker, and only 54% at five years, according to a French registry. Highland stressed that this reality for people diagnosed with PAH means "additional and more effective therapies are needed."
Since being on the drug, Kauffman said she's noticed a "night and day" difference in managing her symptoms. She recalls going in for her first shot in August 2021, and she just knew she had received the drug and not the study's placebo.
"Immediately that night, my breathing changed. It wasn't, like, drastic, but I felt different, and then, the next day, I slept for like 22 out of the 24 hours," she recalled. "For each shot, things were getting better and better."
Once on the medication, Kauffman said she was walking farther and able to do more. Her daughter plays travel softball, and she was able to go with her on weekends and participate with the other parents and families.
However, Kauffman emphasized this is not a cure. She is also on other medications with side effects that give her extreme leg pain, which she said brings her more discomfort than PAH at the moment.
"I'm no longer thinking like I'm not going to be here. I'm looking forward to things," Kauffman said of past fears that she might not have many years left with her family. "My daughter is going to be 16, and it's just things like that. I'm just super hopeful. I just feel better."
Dietary Changes May Treat Pulmonary Hypertension
image:
"Dis-moi ce que tu manges, je te dirai qui tu es", "You are what you eat" written the famous French Gourmet Jean Anthelme Brillat-Savarin, in la Physiologie du goût, 1825. Rachedi et al., reveal the metabolic origin of pulmonary vascular stiffening. They propose a diet poor in glutamine (Gln) and serine (Ser) to improve lung vascular fitness and reduce progression of pulmonary hypertension. This sketch depicts a gardener tending to a tree (Lung). The gardener is shown filtering "Gln" and "Ser" from the tree's nutrients (diet), leading to lush and green foliage on one side (healthy lung). On the unfiltered side, the foliage is brown and dying from disease (pulmonary hypertension)."
view moreCredit: Thomas Bertero Lab
Blood vessels in the lungs aren't like the others in the body. This difference becomes clear in pulmonary hypertension, in which only the lungs' blood vessels stiffen progressively, leading to chronic lung disease, heart failure and death. The underlying reasons for this organ-specific vessel stiffening remained a mystery until University of Pittsburgh researcher Stephen Chan and colleagues made a surprising discovery about these blood vessel cells in patients with pulmonary hypertension—they're hungry.
Chan, Vitalant Chair in Vascular Medicine and Professor of Medicine in the Division of Cardiology at the University of Pittsburgh, and his team collaborated with the team of Thomas Bertero at the Université Côte d'Azur in France. They found that hypertensive pulmonary blood vessel cells have a voracious appetite for two amino acids, glutamine and serine, and—as happens with any unbalanced diet—there are consequences. This metabolism of glutamine and serine is a key driver of pulmonary hypertension disease progression.
The findings were published May 2 in the journal Cell Metabolism.
Amino acids are the building blocks of proteins, which help build cellular structures, carry out biological functions, and regulate tissue and organ function. As hypertensive pulmonary blood vessels metabolize glutamine and serine, they create two new amino acids, called proline and glycine. Proline and glycine are the primary building blocks of collagen protein, which makes up 30% of our body's total protein and provides a structural framework for our skin, muscles, bones and connective tissues. The appetite for glutamine and serine and the resulting elevated levels of proline and glycine in hypertensive pulmonary blood vessel cells drive the overproduction of collagen, which leads to vessel stiffening and impaired function—the hallmark feature of pulmonary hypertension.
Using rodent models for the disease, the researchers saw that drugs that limit cellular uptake of glutamine and serine deprived hypertensive pulmonary blood vessels of their craving. In turn, the lack of cellular glutamine and serine metabolism halted the excess production of collagen building blocks and collagen production. Knowing amino acids are most often absorbed through our diets, the team also discovered that reducing the dietary intake of glutamine- and serine-rich foods helped reduce collagen overproduction.
"For the first time, we have a dietary maneuver that may serve as an effective therapy for the disease," says Chan, who also directs the Vascular Medicine Institute and Center for Pulmonary Vascular Biology and Medicine at the University of Pittsburgh School of Medicine and UPMC.
For patients with pulmonary hypertension, avoiding foods rich in serine and glutamine, or eating foods with these amino acids depleted, might bolster the effectiveness of current medications. "It opens up a new way that we could treat this disease, because now—instead of just relying on medications and transplantation—there are possibly effective lifestyle interventions," says Chan.
Chan's team also harnessed the characteristic appetite of these cells to create a new diagnostic test for pulmonary hypertension using positron emission tomography (PET) scan technology and a glutamine imaging tracer. The imaging tracer acts like a GPS monitor to track where glutamine goes in the body. As a result, cells hungry for the amino acid light up on the PET scan, and the intensity of that light shows how ravenous cells are for glutamine and where those cells are in the body. This screening will enable earlier disease diagnosis and implementation of lifestyle and pharmacological interventions and allow doctors to check the efficacy of medications in slowing disease progression.
Method of ResearchExperimental study
Subject of ResearchAnimals
Article TitleDietary intake and glutamine-serine metabolism control pathologic vascular stiffness
Article Publication Date2-May-2024
COI StatementS.Y.C. Has served as a consultant for Merck, Janssen, and United Therapeutics. S.Y.C. Is a director, officer, and shareholder in Synhale Therapeutics. S.Y.C. Has held research grants from WoodNext, Bayer, and United Therapeutics. S.Y.C. And T.B. Have filed patent applications regarding the targeting of metabolism in pulmonary hypertension. G.Y., Z.-K.Y., and O.O. Are listed as inventors in patents not related to this work, which are filed by MSKCC. O.O. Receives royalties from MSKCC, Johnson & Johnson, Jazz, and Y-mAbs and owns shares in Angiogenex, for which he is an unpaid member of the SAB, all of which are not related to this work.
Disclaimer: AAAS and EurekAlert! Are not responsible for the accuracy of news releases posted to EurekAlert! By contributing institutions or for the use of any information through the EurekAlert system.
Comments
Post a Comment