17 December 2021

This week in PVD

Red blood cells with lower hemoglobin may help predict PAH outcomes

A new study highlights the predictive utility of hypochromic erythrocytes — red blood cells that have decreased levels of hemoglobin (the oxygen carrier) — in patients with pulmonary arterial hypertension (PAH).

The increased presence of these erythrocytes was shown to be an independent predictor of both mortality and shorter time to clinical worsening (TTCW) in PAH, serving as a potential indicator of disease prognosis, as well as iron homeostasis — the regulation of the import and export of iron from the body’s tissues and organs (iron is an important component of hemoglobin).

The study, titled “Prognostic impact of hypochromic erythrocytes in patients with pulmonary arterial hypertension,” was published in the journal Respiratory Research.

Studies within the last decade have shown that iron deficiency in PAH patients is indicative of more severe disease and worse outcomes. However, iron supplementation has not been decisively shown to change such poor outcomes.

Iron deficiency was determined in these previous studies through blood tests for: serum ferritin (a blood protein that contains iron), iron or hemoglobin concentration, and transferrin saturation (TSAT; the value of blood iron divided by the total iron-binding capacity of the available transferrin, the protein that binds iron in the blood). These tests can however be affected by inflammation and infection, thus they may not always accurately define a person’s iron status. New tests to assess iron deficiency are therefore needed.

In the new study, a team led by researchers in Germany looked at 150 patients who had a confirmed PAH diagnosis and a concomitant iron metabolism assessment from between April 2013 and August 2017. All participants were treated at the Center for Pulmonary Hypertension, Thoraxklinik Heidelberg, in Germany.

“The aim of this study was to identify a new marker for iron deficiency and clinical outcome in PAH patients,” the team wrote.

Alembic pharma gets USFDA nod for pulmonary arterial hypertension drug selexipag

Mumbai: Drugmaker, Alembic Pharmaceuticals Limited, today announced that the company has received tentative approval from the US Food & Drug Administration (USFDA) for its Abbreviated New Drug Application (ANDA) for Selexipag Tablets, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,400 mcg, and 1,600 mcg.

The tentatively approved ANDA is therapeutically equivalent to the reference listed drug product (RLD) Uptravi Tablets, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,400 mcg, and 1,600 mcg, of Actelion Pharmaceuticals, Ltd. (Actelion).

Selexipag Tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce the risk of hospitalization for PAH.

Selexipag Tablets, 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1,400 mcg, and 1,600 mcg have an estimated market size of US$ 461 million for twelve months ending September 2021 according to IQVIA.

Alembic has received year to date (YTD) 15 approvals (11 final approvals and 4 tentative approvals) and a cumulative total of 154 ANDA approvals (134 final approvals and 20 tentative approvals) from USFDA.

To improve outcomes, identify predictive factors of PAH earlier in patients with SLE, study says

Although pulmonary arterial hypertension (PAH) is a rare occurrence in systemic lupus erythematosus (SLE), a recent report details efforts by researchers to find an easy way to identify predictive factors, since having both diseases together reduces overall survival.

A recent study described how investigators determined predictive factors for development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE).

Although previous work has shown that the 5-year survival rate in patients with SLE in China is 92.6% in females and 81.6% in males, that percentage drops to 68% when PAH is added to the mix. However, PAH diagnosis is typically delayed by about 5 years after the initial SLE diagnosis. That delay gives more time for organ damage and worse outcomes.

Writing in the International Journal of Rheumatic Diseases, authors explained the need to recognize patients with SLE at high risk of PAH for early treatment and monitoring of their pulmonary arterial systolic pressure (PASP).

PASP is typically conducted by echocardiography. In the study, the authors conducted a chart review study in an effort to identify predictive factors in patients with a first diagnosis of SLE who were admitted to a hospital in China between January 1, 2013, and December 31, 2019.

The records of 408 patients who were first diagnosed with SLE were examined. In addition, the investigators examined demographic characteristics, clinical symptoms, autoantibodies, and laboratory tests.

Aerami therapeutics goes public through SPAC merger

Aerami Therapeutics, a biopharmaceutical company focused on developing inhaled therapies for severe respiratory diseases — including pulmonary arterial hypertension (PAH) — has entered into a merger agreement with FoxWayne Enterprises Acquisition, a special purpose acquisition company (SPAC).

The goal of this merger is to accelerate the development of Aerami’s therapeutic pipeline.

SPACs, also known as “blank check companies,” are essentially shell companies with no commercial operations that are set up by investors with the purpose of raising money through an initial public offering to fund the merger or acquisition of a private company. Once merged, the private company becomes public.

The deal, which is expected to close in the first months of 2022, will see the combined company be named Aerami Therapeutics Holdings, Inc., and be led by Steve Thornton, Aerami’s CEO, along with the rest of the company’s current management. The combined company’s common stock is expected to remain listed on the Nasdaq Capital Market.

“We are deeply committed to advancing inhaled therapies that address severe respiratory and chronic diseases,” Thornton said in a press release. “This transaction is expected to provide significant capital and a platform to accelerate the development of our [treatment] candidates including taking our lead product, inhaled imatinib for the treatment of pulmonary arterial hypertension, into a planned Phase 2/3 trial in 2022.”

Robb Knie, FoxWayne’s CEO, added: “We see immense opportunities in Aerami’s approach to delivering inhaled therapies for targeted indications that present large unmet medical needs, including pulmonary arterial hypertension, a debilitating disease for which there currently are no available disease modifying therapies.”

Increased lung uric acid deteriorates pulmonary arterial hypertension

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage-driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia-induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA-induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L-norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats.

Risk factors for pulmonary hypertension combined with obstructive sleep apnea

Lower daytime arterial oxygen pressure (PaO2) is a risk factor for obstructive sleep apnea (OSA) in older male patients with pulmonary hypertension (PH), according to a single-center study published in BMC Pulmonary Medicine.

OSA is more common in patients with PH than without PH. However, the degree of correlation is generally mild and therefore OSA is often overlooked in the diagnosis, risk stratification, and treatment of PH.

To address the lack of data on the association between PH and OSA, researchers at Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science designed a study to understand the incidence and clinical characteristics of OSA in patients with PH and to explore possible predictors of PH combined with OSA. They included patients with PH diagnosed by right heart catheterization who underwent overnight cardiorespiratory monitoring from 2018 to 2020.

Out of 140 patients with PH studied, investigators found that 35 (25%) had OSA, concluding that OSA is relatively frequent in patients with PH, especially in patients with chronic thromboembolic PH and patients with lung disease- or hypoxia-associated PH. The researchers also found that patients who had OSA were mostly male and had a higher age and a lower daytime arterial oxygen pressure. Logistic regression analysis was run to determine the risk factors for OSA in PH patients and it confirmed that older age, male sex, and lower daytime arterial blood oxygen pressure correlated with OSA in PH patients.

Aerovate launches clinical trial of AV-101 in PAH

Aerovate Therapeutics is starting a Phase 2b/3 clinical trial that will test AV-101, the company’s experimental inhaled formulation of imatinib, in people with pulmonary arterial hypertension (PAH).

“We are excited and humbled to initiate this Phase 2b/Phase 3 trial of AV-101. Starting enrollment represents an important milestone for Aerovate Therapeutics and advances our goal of improving the lives of patients suffering from rare cardiovascular diseases,” Tim Noyes, Aerovate’s CEO, said in a press release.

The trial, called IMPAHCT (NCT05036135), is currently enrolling participants at the University of Kansas Medical Center in Kansas City, Kansas, with additional sites planned to open later. The study is open to adults with PAH ages 18 to 75.

In the Phase 2b portion of the trial, participants will be assigned randomly to one of three doses of AV-101, or a placebo.

The main goal of the Phase 2b portion is to determine the effect on pulmonary vascular resistance (PVR) — resistance to blood flow in the lungs’  blood vessels — after 24 weeks, or about six months. Safety, tolerability, and other clinical measures also will be assessed.

Results of the Phase 2b part of the trial are expected midway through 2023, according to Aerovate.

Based on findings from the Phase 2b portion, a single dosage of AV-101 will be selected for the Phase 3 portion, where participants will get that dose of AV-101 or a placebo for 24 weeks. The main goal of the Phase 3 part is to evaluate the effect of treatment on the 6-minute walk distance (6MWD), which measures how far a person can walk in six minutes. It is a common measure of overall physical fitness in people who are able to walk.

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