- The Janssen Pharmaceutical Company of Johnson & Johnson announced today that Health Canada approved OPSYNVI.
- OPSYNVI should be used in patients who have currently been treated concomitantly with stable doses of Macitentan 10mg and Tadalafil 40mg (20mg x 2) as separate tablets.
- PAH is a specific, rare form of pulmonary hypertension (PH) that affects the right side of the heart and causes the walls of the pulmonary arteries (blood vessels leading from the right side of the heart to the lungs).
The Janssen Pharmaceutical Companies of Johnson & Johnson announced that Health Canada approved Opsynvi (Macitentan 10mg and Tadalafil 40mg) for the long-term treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to reduce morbidity in patients of WHO functional class (FC) II or III whose PAH is idiopathic, heritable, or associated with connective tissue disease or congenital heart disease.
Opsynvi should be used in patients who have currently been treated concomitantly with stable doses of Macitentan 10mg and Tadalafil 40mg (20mg x 2) as separate tablets.
PAH is a specific, rare form of pulmonary hypertension (PH) that affects the right side of the heart and causes the walls of the pulmonary arteries (blood vessels leading from the right side of the heart to the lungs) to become thick and stiff, narrowing the space for blood to flow, and causing increased blood pressure to develop within the lungs. If left untreated, PH can lead to right ventricle failure, a serious type of heart failure.
“PAH is a progressive disease that can affect people of any age or ethnic background. While there is no cure, there have been considerable advancements in care and we now have a gold standard option to improve pulmonary vascular resistance, lessen disease morbidity and reduce right heart impact,” said Dr. Lisa Mielniczuk, director of the pulmonary hypertension programme at the Ottawa Heart Institute and Co-Vice Chair of the Pulmonary Hypertension Association of Canada’s Board of Directors. “Canadians living with PAH often have co-morbidities and are taking multiple treatments which can understandably lead to a high pill burden and reduced medication adherence. As a combination therapy, Opsynvi conveniently offers two therapies in one daily pill simplifying treatment for patients.”
Health Canada’s approval is based on three comparative bioavailability studies, which demonstrated the bioequivalence of a single dose of Macitentan 10 mg and Tadalafil 40 mg as the Opsynvi fixed dose combination tablet to opsonist (Macitentan 10 mg) and Ad circa (Tadalafil 40 mg) co-administered as individual tablets in healthy patients.
“As part of our commitment to investing in research and understanding the science to advance innovative treatment options, today marks an important day for Canadians living with Pulmonary Arterial Hypertension,” said Neil Davie, Ph.D., global therapeutic area head and research & development external innovation leader, Pulmonary Hypertension, Janssen-Cilag Ltd. “This new once daily treatment helps simplify patient care for the long-term treatment of PAH.”
Macitentan (opsonist) is indicated for the long-term treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce morbidity in patients of WHO Functional Class II or III whose PAH is either idiopathic or heritable, or associated with connective tissue disease or congenital heart disease. OPSUMIT® is effective when used as monotherapy or in combination with phosphodiesterase-5 inhibitors.
The recommended dose of opsonist is 10 mg once daily.
Tadalafil (Ad circa) is indicated for the treatment of idiopathic (“primary”) pulmonary arterial hypertension (PAH), or PAH associated with connective tissue disease, congenital heart disease or anorexigen use in patients with WHO functional class II or III who have not responded to conventional therapy.
The recommended dose of Ad circa is taken as two 20 mg tablets, once daily.
About Pulmonary Arterial Hypertension PAH:
Pulmonary hypertension is a type of high blood pressure that affects the arteries in the lungs and the right side of the heart.
In one form of pulmonary hypertension, called pulmonary arterial hypertension (PAH), blood vessels in the lungs are narrowed, blocked or destroyed. The damage slows blood flow through the lungs, and blood pressure in the lung arteries rises. The heart must work harder to pump blood through the lungs. The extra effort eventually causes the heart muscle to become weak and fail.
In some people, pulmonary hypertension slowly gets worse and can be life-threatening. Although there’s no cure for some types of pulmonary hypertension, treatment can help reduce symptoms and improve quality of life
What is Opsynvi?
Opsynvi is a fixed combination drug of Macitentan and Tadalafil.
Macitentan, sold under the brand name Opsonist, is an endothelin receptor antagonist (ERA) developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH). The other two ERAs marketed as of 2014 are baseman and ambrisentan. Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. However, Macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype. The drug received approval from the U.S. Food and Drug Administration (FDA) on October 13, 2013.
Macitentan (OPSUMIT®) is indicated for the long-term treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce morbidity in patients of WHO Functional Class II or III whose PAH is either idiopathic or heritable, or associated with connective tissue disease or congenital heart disease. OPSUMIT® is effective when used as monotherapy or in combination with phosphodiesterase-5 inhibitors.
The recommended dose of OPSUMIT® is 10 mg once daily.
Mechanism of action (MOA)
Endothelin and endothelin receptors
Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells. In the lungs, the most common ET form released is ET-1. ET-1 release can occur through both constitutive and non-constitutive pathways. Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs. ET receptors are G protein-coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway. The rise in intracellular calcium leads to contraction of the arterial smooth muscle, as well as vascular remodelling due to cell proliferation. Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.
Role of Macitentan
Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. Blocking of the ETA receptor subtype seems to be of more importance in the treatment of PAH than blocking of ETB, likely because there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells.
Tadalafil is a medication used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension. It is a tablet taken by mouth. Onset is typically within half an hour and the duration is up to 36 hours.
Tadalafil (ADCIRCA®)* is indicated for the treatment of idiopathic (“primary”) pulmonary arterial hypertension (PAH), or PAH associated with connective tissue disease, congenital heart disease or anorexigen use in patients with WHO functional class II or III who have not responded to conventional therapy.
The recommended dose of ADCIRCA® is taken as two 20 mg tablets, once daily.
Tadalafil was approved for medical use in the United States in 2003. It is available as a generic medication in the United States and United Kingdom. In 2017, it was the 282nd most commonly prescribed medication in the United States, with more than one million prescriptions
Mechanism of action (MOA):
The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. However, because sexual stimulation is required to initiate the local penile release of nitric oxide, tadalafil’s inhibition of PDE5 will have no effect without sexual stimulation.
Tadalafil is used to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension.
Tadalafil once-daily is FDA-approved for ED, for sale in 2.5, 5, 10, and 20 mg strengths. The price of the 5 mg and 2.5 mg are often similar, so some people score and split the pill.
Benign prostatic hypertrophy
A meta‐analysis found that Tadalafil 5 mg once‐daily is an effective treatment for lower urinary tract symptoms due to prostatic hyperplasia and that such treatment had a low rate of adverse effects. Tadalafil 10 mg is FDA-approved for men as a once-daily therapy to treat and prevent symptoms of benign prostatic hypertrophy (BPH), such as urinary urgency, hesitancy, weak stream, dribbling, and incontinence.
Pulmonary arterial hypertension
Tadalafil 40 mg is approved in the United States, Canada, and Japan as a once-daily therapy to improve exercise ability in patients with pulmonary arterial hypertension (PAH).
The pulmonary vascular lumen is decreased in PAH as a result of vasoconstriction and vascular remodelling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil causes pulmonary artery vasodilation, and inhibits vascular remodelling, thus lowering pulmonary arterial pressure and resistance. Right heart failure is the principal consequence of severe pulmonary arterial hypertension.
Efficacy, Safety & Tolerability of OPSYNVI:
“OPSUMIT, in combination with tadalafil, showed a 47% reduction of the primary endpoint of mean pulmonary vascular resistance (PVR) at week 16 compared with baseline in patients with PAH,” said Olivier Sitbon, M.D., Ph.D., principal investigator and professor of respiratory medicine at Université Paris-Sud. “These data are meaningful because improvement of PVR, an important indicator of right ventricular function, is a key treatment goal. Current clinical guidelines for PAH recommend upfront double oral combination therapy and this study confirms that initial oral dual combination with macitentan and tadalafil is beneficial in those patients.”
Safety and tolerability findings were consistent with previous clinical trials that supported the approval and use of OPSUMIT 10mg once-daily. The most common adverse events (AEs) in the OPTIMA study were peripheral edema (28.3%), headache (23.9%), diarrhea (19.6%), dyspnea (15.2%), anemia (13.0%) and asthenia (13.0%). Four patients had a decrease in hemoglobin below 10 g/dL and one patient had aminotransferases ≥3 times the upper limit of normal. Three patients discontinued treatment due to AEs and three patients died during the study. Causes of death were cardiac arrest, heart failure, and multiorgan failure with sepsis.1
About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology and Pulmonary Hypertension.
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