A Single-Tablet Combination Is Helping to Bridge the Gap Between Clinical Guidelines and Everyday Clinical Practice in PAH

Sean Studer is Vice President of Medical Affairs at Johnson & Johnson Pulmonary Hypertension

Sponsored by Johnson & Johnson

Pulmonary arterial hypertension (PAH) is a rare, insidious condition that can have a significant impact on patients’ physical, psychological, and social well-being.^1-3 PAH is a form of pulmonary hypertension (PH), and is a progressive and debilitating condition that, if left untreated, can lead to right ventricle heart failure, and early death.⁴

Early diagnosis, close monitoring of a patient’s disease progression (also known as risk assessment), and treatment are critical to helping improve outcomes.^1,5

To learn more about the current state of PAH care, HCPLive sat down with Sean Studer, Vice President, Medical Affairs at Johnson & Johnson Innovative Medicine, to discuss the rapidly evolving treatment landscape and what recent updates mean for those connected to this disease.

Can you give us a bit more background on PAH, including prevalence in the U.S. and current challenges in the space?

An estimated 500-1000 new cases of PAH are diagnosed each year in the U.S., classifying PAH as a rare condition.⁶ This can present challenges because, due to its rare nature, PAH is diagnosed, on average, over two years from symptom onset, delaying appropriate treatment.^1,2 The European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines for the diagnosis and treatment of PH recommend physicians conduct regular risk assessments in PAH patients at diagnosis, as well as at follow-up visits, to make informed decisions regarding their patients’ treatment plans.¹

Although uninterrupted treatment is critical in supporting optimal clinical outcomes, treatment regimens can be cumbersome due to high pill burden and complex insurance processes; treatment discontinuation rates remain high.^1,7 In March 2024, the U.S. Food and Drug Administration (FDA) approved a single-tablet combination therapy that can help physicians manage the disease in line with clinical guidelines.^8,9 This therapy has the potential to simplify the dosing regimen by reducing the number of pills PAH patients take.⁹

In clinical practice, the ESC/ERS Guidelines can be referred to as a “roadmap” to guide care teams in their management of patients with PAH.¹ What can a healthcare professional (HCP) learn from these clinical guidelines?

The ESC/ERS Guidelines summarize evidence to support care teams in considering management strategies for patients with PAH. They are developed by international experts after careful consideration of the scientific and medical evidence available at the time of drafting. The ultimate goal is facilitating decision-making for healthcare professionals in their daily practice to encourage optimal patient outcomes.¹

In the latest ESC/ERS Guidelines update from 2022, the main treatment goal for patients with PAH is to achieve and/or maintain a low-risk status. Risk status is measured by exercise capacity, worsening of symptoms or signs of right heart failure, and right ventricular function.¹

The Guidelines also recommend targeting one or more of three pathways that mediate PAH – the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway.¹

In your opinion, what are some of the most common challenges healthcare providers and patients face in managing PAH? How is Johnson & Johnson helping to address these challenges?

Targeting different PAH-specific pathways has shown clear clinical benefits; however, the current treatment regimens can be burdensome.⁷ In fact, patients with PAH and various comorbidities often take a large number of pills each day.^11,12

The 2022 ESC/ERS Guidelines recommend initial dual-combination therapy with an endothelin receptor antagonist (ERA), and a phosphodiesterase type 5 inhibitor (PDE5i), for patients with PAH who don’t have cardiopulmonary comorbidities. For those with cardiopulmonary comorbidities, HCPs should consider starting monotherapy with either a PDE5i or an ERA and then individualizing treatment.¹ Until recently, this meant patients on combination therapy had to take multiple pills, as there wasn’t a single tablet available that combined multiple pathways.

In March 2024, we received approval by the U.S. Food and Drug Administration for OPSYNVI® (macitentan/tadalafil). This is a single-tablet combination that includes macitentan, an ERA, and tadalafil, a PDE5i, indicated for the chronic treatment of adults with PAH (World Health Organization [WHO] Group I) and WHO Functional Class II-III.⁸ Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability.⁸

Select Important Safety Information

Please scroll down to continue reading Important Safety Information and please read full Prescribing Information, including BOXED WARNING, for OPSYNVI®.

Could you tell us more about the clinical efficacy and safety data that contributed to the approval of OPSYNVI®?

OPSYNVI® combines two proven treatments with well-established efficacy and safety profiles into one pill to be taken once daily.⁸ OPSYNVI® was evaluated in the A DUE (NCT03904693) study, a multicenter, double-blind, randomized, active-controlled, Phase 3 study.⁸ This study evaluated the efficacy and safety of OPSYNVI® compared to macitentan and tadalafil monotherapies in 187 adult PAH patients in WHO FC II or III, across 76 sites in 16 countries.⁹

The A DUE study showed that OPSYNVI® led to a marked improvement in pulmonary hemodynamics. This was demonstrated by a statistically significant and clinically relevant reduction of pulmonary vascular resistance, or PVR, from the start of the study to Week 16, compared to macitentan or tadalafil monotherapy.⁸

PVR was chosen as the primary endpoint for the A DUE study because of its clinical relevance, plus it allowed for an efficacy assessment in a relatively small sample size within a short observation period.⁹

The most common (≥10%) side effects in patients receiving OPSYNVI® were edema/fluid retention (21%), anemia (19%), and headache/migraine (18%).^8,9 The results also showed that the safety profile of OPSYNVI® was consistent with the known safety profiles of macitentan and tadalafil monotherapies.

In your opinion, how might OPSYNVI® impact the conversations HCPs and patients are having in regard to treatment options?

When the A DUE data was published, we heard from physicians that macitentan/tadalafil may help the PAH treatment landscape. In my opinion, there are three key unmet needs that OPSYNVI® can help address: reducing the number of pills for patients, facilitating healthcare professionals to adopt clinical guidelines, and managing costs for patients.^9,10

This single-tablet combination therapy streamlines the treatment regimen, especially for patients who are already on an ERA, PDE5i, or both. OPSYNVI® offers two dosing options: one for patients who are new to any PAH therapy or transitioning from ERA monotherapy, and another for patients moving from a stable-dose PDE5i monotherapy or ERA plus PDE5i as separate pills.⁸

Having a single tablet that combines both macitentan and tadalafil is promising for clinicians because it could help bridge the gap between treatment guidelines for early use of combination therapy and everyday clinical practice. With its one-pill, one-fill prescription, OPSYNVI® can help reduce the complexity of two separate prescriptions and prior authorizations. Additionally, patients won’t pay more for OPSYNVI® than they would for another branded ERA. This means they won’t have out-of-pocket costs for a separate PDE5i prescription.

In my 20 years of experience as a provider, I found shared decision-making to be one of the most important factors in driving better patient outcomes. I encourage providers to have open conversations with their patients about their treatment goals, any barriers they may have, and options that fit their clinical and personal needs. We know that HCPs are excited about OPSYNVI® as an available treatment option, and patients can be equally motivated when they learn about the value of this treatment.

If you would like to learn more, you can visit OPSYNVI.com for more information.

It has been a notable year for the PAH community, in light of several recently approved therapies expanding the treatment toolbox care teams have at their disposal. Could you tell us more about how Johnson & Johnson is supporting patients and care teams in this increasingly complex landscape?

Our team at Johnson & Johnson has been committed for 20+ years to transforming PAH into a condition that can be managed long-term. Our comprehensive PAH portfolio is backed by extensive clinical research that now includes treatments that address all three foundational and guideline-recommended pathways for this disease.^1,8,13,14

Recently, we launched OnePAH.com, which offers a suite of educational and support resources. This platform helps patients with PAH feel empowered and connected through community resources such as Johnson & Johnson’s Breathe In, Speak Out. Patients who have been prescribed a PAH medicine by Johnson & Johnson can also enroll in our PAH Companion withMe programs* for additional support. For care teams, OnePAH.com also provides digital tools to educate on the diagnosis and management of this rare condition.

From my perspective, the future of PAH care involves expanding the treatment options that allow individualized care based on patient characteristics, including risk of disease progression, comorbidities, and background therapy. As the PAH landscape continues to evolve, Johnson & Johnson is proud to support the healthcare professionals who are on the front lines and making a difference in the lives of PAH patients.

*PAH Companion withMe requires a completed patient authorization form to enroll.

INDICATION AND IMPORTANT SAFETY INFORMATION

OPSYNVI® is the combination of macitentan and tadalafil indicated for the chronic treatment of adults with pulmonary arterial hypertension (PAH, WHO Group I and WHO Functional Class [FC] II-III).

Individually, macitentan reduces the risk of clinical worsening events and hospitalization, and tadalafil improves exercise ability.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

• Pregnancy: OPSYNVI® may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. If OPSYNVI® is used during pregnancy, advise the patient of the potential risk to a fetus.
• Hypersensitivity: OPSYNVI® is contraindicated in patients with a history of a hypersensitivity reaction to macitentan, tadalafil, or any component of the product.
• Concomitant Organic Nitrates: OPSYNVI® is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of OPSYNVI®.
• Concomitant Guanylate Cyclase (GC) Stimulators: OPSYNVI® is contraindicated in patients using GC stimulators such as riociguat.

WARNINGS AND PRECAUTIONS

Embryo-fetal Toxicity and Macitentan-Containing Products REMS:
Due to the risk of embryo-fetal toxicity, OPSYNVI® is available for females only through a restricted program called the Macitentan-Containing Products REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.

Notable requirements of the Macitentan-Containing Products REMS Program include:

• Prescribers must be certified with the program by enrolling and completing training.
• All females, regardless of reproductive potential, must enroll in the Macitentan-Containing Products REMS Program prior to initiating OPSYNVI®. Male patients are not enrolled in the REMS.
• Females of reproductive potential must comply with the pregnancy testing and contraception requirements.
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive OPSYNVI®.

Hepatotoxicity

• ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure.
• In the double-blind arm of the A DUE study, the incidence of elevated aminotransferases >3 x ULN was 1.0%, and >8 x ULN was 1.0% for OPSYNVI®. In the combined double-blind/open-label arm, the incidence was 3.4% and 1.1%, respectively.
• Discontinuations for hepatic adverse events in the double-blind and combined double-blind/open-label arms of the study for OPSYNVI® were 0.9% and 2.2%, respectively.
• Obtain liver enzyme tests prior to initiation of OPSYNVI® and repeat during treatment as clinically indicated.
• Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSYNVI®. Consider re-initiation of OPSYNVI® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
• Do not initiate OPSYNVI® in patients with elevated aminotransferases (> 3 x ULN) at baseline. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied; therefore, avoid use of OPSYNVI®.

Hypotension

• OPSYNVI® has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing OPSYNVI®, physicians should carefully consider whether patients with underlying cardiovascular disease could be adversely affected by such vasodilatory effects. Patients with pre-existing hypotension, autonomic dysfunction, or left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators.

Hemoglobin Decrease

• Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and were observed in clinical studies with OPSYNVI® and OPSUMIT®. These decreases occurred early and stabilized thereafter.
• In the placebo-controlled study of OPSUMIT® in PAH, OPSUMIT® 10 mg caused a mean decrease in hemoglobin from baseline to up to 18 months of about 1.0 g/dL compared to no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® 10 mg group and in 3.4% of the placebo group. Similar results were observed in the trial with OPSYNVI®.
• Decreases in hemoglobin seldom require transfusion. Initiation of OPSYNVI® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.

Worsening Pulmonary Veno-Occlusive Disease (PVOD)

• Since there are no clinical data on administration of OPSYNVI® to patients with PVOD, administration of OPSYNVI® to such patients is not recommended. Should signs of pulmonary edema occur when OPSYNVI® is administered, the possibility of associated PVOD should be considered. If confirmed, discontinue OPSYNVI®.

Visual Loss and Hearing Impairment

• Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION.
• Use of OPSYNVI® in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, is not recommended.
• Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil.

Fluid Retention

• Peripheral edema and fluid retention are known clinical consequences of PAH and known effects of ERAs, and heart failure has been reported in patients taking OPSYNVI®. In the clinical study of OPSYNVI® in PAH, the incidence of peripheral edema/fluid retention was 20.6% in the active-controlled and 17.3% in the double-blind/open-label arm.
• Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment.
• Monitor for signs of fluid retention after OPSYNVI® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause, such as OPSYNVI® or underlying heart failure, and the possible need to discontinue OPSYNVI®.

Combination With Other PDE5 Inhibitors

• Tadalafil, a PDE5 inhibitor and a component of OPSYNVI®, is also indicated for erectile dysfunction. Instruct patients taking OPSYNVI® not to take other PDE5 inhibitors.

Decreased Sperm Counts and Prolonged Erection

• Macitentan may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.
• There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors like tadalafil. Patients with conditions that might predispose them to priapism, or in patients with anatomical deformation of the penis are at an increased risk. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.

ADVERSE REACTIONS

• The most common adverse reactions (occurring in ≥ 10% of the OPSYNVI®-treated patients) from the double-blind study data were edema/fluid retention (21%), anemia (19%), and headache/migraine (18%). The incidence of treatment discontinuations due to adverse events among patients receiving OPSYNVI® in the double-blind phase of the study was 8%. The most frequent adverse reactions leading to discontinuation were anemia and hemoglobin decreased (2% grouped) and peripheral edema and peripheral swelling (2% grouped).

DRUG INTERACTIONS

• Nitrates: Administration of nitrates within 48 hours after the last dose of OPSYNVI® is contraindicated.
• Strong CYP3A4 Inducers: Strong inducers of CYP3A4, such as rifampin, significantly reduce macitentan exposure. Use of OPSYNVI® with strong CYP3A4 inducers should be avoided.
• Strong CYP3A4 Inhibitors: Concomitant use of strong CYP3A4 inhibitors like ketoconazole, increases exposure to both macitentan and tadalafil. Avoid concomitant use of OPSYNVI® with strong CYP3A4 inhibitors such as ritonavir, ketoconazole and itraconazole. Use other PAH treatment options when strong CYP3A4 inhibitors are needed.
• Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors:
  • Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole, is predicted to increase macitentan exposure approximately 4-fold. Avoid concomitant use of OPSYNVI® with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone).
  • Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSYNVI® should be avoided.
• Alpha-Blockers: PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators and the concomitant administration of these agents may lead to symptomatic hypotension in some patients. Therefore, the combination of OPSYNVI® and doxazosin is not recommended.
• Antihypertensives: PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Small reductions in blood pressure occurred following coadministration of tadalafil with selected antihypertensive medications compared with placebo.
• Alcohol: Substantial consumption of alcohol in combination with OPSYNVI® can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.

USE IN SPECIFIC POPULATIONS

Pregnancy

• OPSYNVI® is contraindicated during pregnancy. Macitentan, a component of OPSYNVI®, may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female.
• If the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus.

Lactation

• There are no data on the presence of tadalafil, macitentan, and/or their metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breastfed infants from OPSYNVI®, advise women not to breastfeed during treatment with OPSYNVI®.

Females and Males of Reproductive Potential

• Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating OPSYNVI®, monthly during treatment and one month after stopping treatment with OPSYNVI®. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus.
• Contraception: Female patients must choose one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) during treatment with OPSYNVI® and for 1 month after treatment with OPSYNVI®. If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method.
• Male Infertility: Based on findings in animals, macitentan may impair fertility in males of reproductive potential. There have been no studies evaluating the effect of tadalafil on fertility in men or women.

Pediatric Use

• The safety and efficacy of OPSYNVI® in children has not been established.

Renal Impairment

• The use of OPSYNVI® is not recommended in patients undergoing dialysis. Avoid use of OPSYNVI® in patients with severe renal impairment (creatinine clearance 15-29 mL/min).

Hepatic Impairment

• OPSYNVI® must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (> 3 × ULN).

Please read full Prescribing Information, including BOXED WARNING, for OPSYNVI®.

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References
1. Humbert M, et al. Eur Heart J. 2022;43(38):3618-3731.
2.Vachiéry JL, Gaine S. Eur Respir Rev. 2012;21(126):313-320.
3. McCollister D, et al. Respir Res. 2016 Jun 14;17(1):72.
4. Chang KY, et al. J Am Heart Assoc. 2022;11(9):e024969.
5. Lau EM, et al. Nat Rev Cardiol. 2015 Mar;12(3):143-55.
6. American Lung Association. Learn About Pulmonary Arterial Hypertension. Available at https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-arterial-hypertension/learn-about-pulmonary-arterial-hypertension. Accessed October 2020.
7. Narechania S, et al. J Cardiovasc Pharmacol Ther. 2020;25(2):131-141.
8. OPSYNVI® Prescribing Information. Titusville, NJ: Actelion Pharmaceuticals US, Inc.
9. Grünig E, et al. J Am Coll Cardiol. 2024;83(4):473-484.
10. Paoli, CJ, et al. JHEOR. 2024;11(1):8.
11. Grady D, et al. Pulm Circ. 2018;8(1):2045893217743616.
12. Lauffenburger JC, et al. J Gen Intern Med. 2017;32(6):619-625.
13. UPTRAVI® Prescribing Information. Titusville, NJ: Actelion Pharmaceuticals US, Inc.
14. OPSUMIT® Prescribing Information. Titusville, NJ: Actelion Pharmaceuticals US, Inc