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FDA Approves Macitentan, Tadalafil Combination Tablet For Pulmonary Arterial Hypertension

The approval, which marks the first for a once-daily, single-tablet combination therapy for pulmonary arterial hypertension, is based on findings from the phase 3 A DUE study.

The FDA has approved a single-tablet combination of macitentan and tadalafil (Opsynvi; Johnson & Johnson) for the chronic treatment of pulmonary arterial hypertension (PAH) in adults who are treatment-naïve or are already on an endothelin receptor antagonist, phosphodiesterase 5 inhibitor, or both, according to a press release from Johnson & Johnson.1

The combination is indicated for patients with PAH categorized as WHO Group I and WHO functional class II-III, and the tablet can be used in those being treated with stable doses of macitentan 10 mg and tadalafil 40 mg (taken as two 20 mg tablets), as separate tablets.

FDA approvedImage credit: wladimir1804 - stock.Adobe.Com

The approval was based on data from the phase 3, double-blind, randomized A DUE study (NCT03904693), in which the single-pill macitentan and tadalafil combination outperformed either drug as a monotherapy.2 From baseline to 16 weeks, patients with PAH treated with the single-pill combination showed greater reductions in pulmonary vascular resistance (PVR) vs those treated with macitentan or tadalafil monotherapy.

"Clinical guidelines recommend treating patients with initial and sequential dual-combination therapy, regardless of risk at initial diagnosis and follow-up. Historically, this required patients to take multiple pills because no single-tablet combination therapy targeting two or more pathways was available," Kelly Chin, MD, A DUE investigator and professor of Internal Medicine and director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, said in a statement.1 "As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients."

In the A DUE study, a total of 187 patients were randomized to receive either single-tablet macitentan and tadalafil (n = 108), mecitentan monotherapy (n = 35), or tadalafil monotherapy (n = 44). While the monotherapy groups saw similar reductions in PVR, those in the single-tablet macitentan and tadalafil group saw significantly greater reductions.2 Compared with the macitentan and tadalafil groups, the combination group experienced a 29% greater reduction (geometric mean ratio, 0.71; 95% confidence level [CL], 0.61-0.82; P < .0001) and 28% greater reduction (geometric mean ratio, 0.72; 95% CL, 0.64-0.80; P < .0001) in PVR, respectively. At randomization, 53% of patients were treatment-naïve.

There were more frequent adverse events leading to discontinuation in the combination therapy group, and the single-tablet macitentan and tadalafil formulation has a Boxed Warning due to the risk of embryo-fetal toxicity.1,2 Female patients are required to enroll in the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy program.

"People with PAH often live with the burden of taking many pills each day, which can pose challenges," James F. List, MD, PhD, Global Therapeutic Area Head, Johnson & Johnson, said.2 "We're thrilled to bring this single tablet combination therapy to patients, as it has the potential to optimize disease management and fulfill a significant unmet need in supporting recently updated treatment guidelines that call for initial or early combination treatment."

References

1. US FDA approves Opsynvi (macitentan and tadalafil) as the first and only once-daily single-tablet combination therapy for patients with Pulmonary arterial hypertension (PAH). News release. Johnson & Johnson. March 22, 2024. Accessed March 25, 2024. Https://www.Jnj.Com/media-center/press-releases/u-s-fda-approves-opsynvi-macitentan-and-tadalafil-as-the-first-and-only-once-daily-single-tablet-combination-therapy-for-patients-with-pulmonary-arterial-hypertension-pah

2. Grünig E, Jansa P, Fan F, et al. Randomized trial of macitentan/tadalafil single-tablet combination therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2024;83(4):473-484. Doi:10.1016/j.Jacc.2023.10.045


Johnson & Johnson Announces Approval Of OPSYNVI For Pulmonary Arterial Hypertension Patients

It is the first and only once-daily single-tablet combination therapy by the US Food and Drug Administration (FDA). OPSYNVI combines macitentan, an endothelin receptor antagonist (ERA), with tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, offering a streamlined treatment option for adults with PAH.

PAH, characterized by the narrowing of small pulmonary arteries and elevated blood pressure in the pulmonary circulation, poses a severe threat to patients, often leading to right heart failure. With an estimated 500 to 1,000 new cases diagnosed annually in the U.S., PAH is considered a rare and life-threatening condition.

The approval of the tablet marks a significant advancement in PAH treatment, offering a comprehensive approach to managing the disease. The medication is indicated for adults with PAH classified as World Health Organization (WHO) Group 1 and categorized as WHO functional class (FC) 2-3. It may be used as initial therapy for treatment-naïve patients or those already receiving an ERA, PDE5 inhibitor, or both.

Dr Kelly Chin, professor of internal medicine and director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, is optimistic about the treatment's potential impact on patient care.

She said: "The introduction of OPSYNVI as a single-tablet combination therapy is promising for clinicians treating PAH patients. It bridges the gap between clinical guidelines and everyday clinical practice, offering a patient-friendly approach to support initial combination therapy and rapid escalation for appropriate patients."

The FDA's approval of the tablet was based on findings from the pivotal phase 3 A DUE study, which demonstrated a superior reduction in PVR after 16 weeks compared to tadalafil or macitentan monotherapy. However, the tablet carries a Boxed Warning due to the risk of embryo-fetal toxicity, requiring female patients to enroll in the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) program.

The A DUE study was a phase 3, multicenter trial comparing the efficacy and safety of OPSYNVI to macitentan and tadalafil monotherapies in adult patients with PAH. The study demonstrated the tablet's superiority in reducing Pulmonary Vascular Resistance (PVR) after 16 weeks compared to monotherapy options.

James List, global therapeutic area head at Johnson & Johnson, highlighted the significance of the treatment in streamlining PAH management.

He said: "People with PAH often face the challenge of taking multiple pills daily, impacting their quality of life. OPSYNVI offers a promising solution to optimize disease management, aligning with updated treatment guidelines that advocate for initial or early combination treatment."

The tablet represents a pivotal addition to Johnson & Johnson's PAH portfolio, addressing all three foundational pathways recommended by guidelines – nitric oxide, endothelin, and prostacyclin. The medication's approval underscores the company's commitment to advancing treatment options and improving outcomes for PAH patients.


FDA Approves Winrevair, Merck's Novel Treatment For Pulmonary Arterial Hypertension

Winrevair is the first FDA-approved activin signaling inhibitor therapy for pulmonary arterial hypertension.

Image Credit: Adobe Stock Images/Dr_Microbe

Merck announced that the FDA has approved Winrevair (sotatercept-csrk) to treat adults with pulmonary arterial hypertension (PAH). According to the company, this marks the first time an activin signaling inhibitor therapy, which aims to improve vascular cell proliferation balance, has been cleared for the treatment of PAH. The approval was based on promising results stemming from the Phase III STELLAR trial, showing that Winrevair increased six-minute walk distance from baseline by 41 meters at week 24, also reducing the potential for death by 84% and potential worsening of the condition.1

"Pulmonary arterial hypertension is a rare, progressive and ultimately life-threatening disease in which blood vessels in the lungs thicken and narrow, causing significant strain on the heart," said STELLAR trial investigator Marc Humbert, MD, PhD, professor of medicine, director, Pulmonary Hypertension Reference Center, Université Paris-Saclay, in a press release. "Based on the Phase III STELLAR trial, adding Winrevair to background PAH therapy demonstrated significant clinical benefits compared to background PAH therapy alone. This approval is an important milestone, as it offers healthcare providers a novel therapeutic option that targets a new PAH treatment pathway."

Last week, the FDA also approved Johnson & Johnson's Opsynvi, a combination of macitentan and tadalafil, for the treatment of PAH. This medication focuses on patients who are treatment-naïve, already on an inhibitor, or currently treated concomitantly with stable doses of macitentan 10 mg and tadalafil 40 mg as separate tablets. For this treatment, the FDA based its approval on data from the Phase III A DUE study, which found that it showed greater reduction in Pulmonary Vascular Resistance after 16 weeks versus tadalafil or macitentan monotherapy.2,3

"Clinical guidelines recommend treating patients with initial and sequential dual-combination therapy, regardless of risk at initial diagnosis and follow-up. Historically, this required patients to take multiple pills because no single-tablet combination therapy targeting two or more pathways was available," said Kelly Chin, MD, professor of internal medicine, director, pulmonary hypertension program, UT Southwestern Medical Center, investigator in the A DUE study, in a press release. "As administration of macitentan and tadalafil together are commonly prescribed for initial therapy for PAH, the introduction of a single tablet combining both is promising for clinicians treating patients as it may help bridge the gap between clinical guidelines and everyday clinical practice, while offering a patient-friendly approach to support initial combination therapy and rapid escalation for the appropriate patients."

Other results from the STELLAR trial include:

  • Improvements in FC baseline at week 24 in 29% of patients.
  • An overall improvement in pulmonary vascular resistance.
  • Improvement in baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels.1
  • "PAH remains a debilitating disease with high morbidity and mortality," said Eliav Barr, MD, SVP, head, global clinical development, chief medical officer, Merck Research Laboratories, in a press release. "This approval of Winrevair is an important milestone and a testament to our science-led strategy and focus on the development of innovations that can help people affected by rare diseases like PAH. We are proud to bring this novel medicine to patients."

    Merck expects that Winrevair should be available in select specialty pharmacies by the end of next month.1

    References

    1. FDA Approves Merck's WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1). Merck. March 26, 2024. Accessed March 27, 2024. Https://www.Merck.Com/news/fda-approves-mercks-winrevair-sotatercept-csrk-a-first-in-class-treatment-for-adults-with-pulmonary-arterial-hypertension-pah-who-group-1/

    2. U.S. FDA Approves OPSYNVI® (macitentan and tadalafil) as the First and Only Once-Daily Single-Tablet Combination Therapy for Patients with Pulmonary Arterial Hypertension (PAH). PR Newswire. March 22, 2024. Accessed March 27, 2024. Https://www.Prnewswire.Com/news-releases/us-fda-approves-opsynvi-macitentan-and-tadalafil-as-the-first-and-only-once-daily-single-tablet-combination-therapy-for-patients-with-pulmonary-arterial-hypertension-pah-302097530.Html

    3. FDA Approves Single-Tablet Combination of Macitentan and Tadalafil for Pulmonary Arterial Hypertension. Pharmaceutical Executive. March 25, 2024. Accessed March 27, 2024. Https://www.Pharmexec.Com/view/fda-approves-single-tablet-combination-of-macitentan-and-tadalafil-for-pulmonary-arterial-hypertension






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