Actelion Receives FDA Approval Of TRACLEER® (bosentan) For Use In Pediatric Patients With Pulmonary Arterial Hypertension

SOUTH SAN FRANCISCO, Calif., Sept. 6, 2017 /PRNewswire/ -- Actelion Pharmaceuticals US, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, announced today that the U.S. Food and Drug Administration (FDA) has approved a new 32 mg tablet for oral suspension for TRACLEER^® (bosentan) for use in pediatric patients aged three years and older with idiopathic or congenital pulmonary arterial hypertension (PAH), to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. With this approval, TRACLEER becomes the first FDA-approved medicine for pediatric PAH patients in the United States. PAH is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected person.

TRACLEER is an orally active endothelin receptor antagonist (ERA) for the treatment of patients with PAH (WHO Group 1). This approval covers a new 32 mg dosage of TRACLEER, which features a scored tablet. The tablet can be dispersed in a teaspoon of water before oral administration. The lower dosage and score lines on the tablets are designed to allow physicians to vary the prescribed dose by the weight of the patient.

"Actelion has focused on the needs of the PAH community since TRACLEER, our first treatment for PAH, was approved in 2001," said Gary Palmer, M.D., MBA, senior vice president, Medical, Actelion Pharmaceuticals US, Inc. "We're pleased our portfolio of treatments continues to grow and pediatric PAH patients will now have an FDA-approved treatment option available."

Actelion expects to make the 32 mg dosage option of TRACLEER available by the fourth quarter of 2017. The existing 62.5 and 125 mg dosages for adult use will remain available.

About Endothelin Receptor Antagonists (ERAs)
TRACLEER is an oral ERA, which is a medication that helps PAH patients by blocking the effects of the extra endothelin their bodies produce. Endothelin is a naturally occurring chemical in the body and is involved in blood flow.¹

However, patients with PAH have levels of endothelin that are higher than normal. Researchers have found that too much endothelin can cause blood vessels to tighten. It is more difficult for blood to flow through tightened blood vessels, and this can affect how well the heart works. ^1,2,3

Pulmonary Arterial Hypertension (PAH)
PAH is high blood pressure in the arteries of the lungs. It's a serious condition that can make it difficult for blood to flow through the lungs, which can force an affected individual's heart to work harder.⁴

PAH is a chronic and progressive disease. This means that over time, PAH will get worse.⁴ PAH is a rare disease and not all causes are known.⁴ While PAH can affect people at any age, the average patient is diagnosed in their late 40s. And although anyone can develop PAH, it affects almost four times as many women as men.⁵

PAH involves a change in the levels of several natural chemicals in the blood. Over time, this can cause the arteries in the lungs to become thick and stiff,⁶ which can make it difficult for blood to flow. As a result, the heart must work harder to pump blood from the right side of the heart through the arteries of the lungs.⁴

About Actelion Ltd
In June 2017, Actelion became part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Actelion's medicines have helped to expand and strengthen Janssen's portfolio with leading, differentiated in-market medicines and promising late-stage compounds. Janssen has added Pulmonary Hypertension as a therapeutic area of focus to maintain the leadership position Actelion has built in the PAH disease area.

About the Janssen Pharmaceutical Companies of Johnson & Johnson
At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenUS and www.twitter.com/JanssenGlobal.

About TRACLEER® (bosentan)
TRACLEER® (bosentan), an orally available endothelin receptor antagonist, was the first oral treatment approved for PAH. TRACLEER is commercially available in over 60 markets, including the US (since November 2001), the EU (since May 2002) and Japan (since April 2005).

TRACLEER is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adults to improve exercise ability and to decrease clinical worsening.  Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%). TRACLEER is also indicated in pediatric patients aged three years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.

IMPORTANT SAFETY INFORMATION

BOXED WARNING
Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through a restricted program called the TRACLEER REMS Program, which is a component of the TRACLEER Risk Evaluation and Mitigation Strategy (REMS). Under the TRACLEER REMS, prescribers, patients, and pharmacies must enroll in the program.

Hepatotoxicity
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER. In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were observed after prolonged (>12 months) treatment. In general, avoid using TRACLEER in patients with elevated aminotransferases (>3 x ULN) at baseline. Measure liver aminotransferases prior to initiation of treatment and then monthly. Discontinue TRACLEER if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 x ULN.

Embryo-fetal Toxicity
Based on animal data, TRACLEER is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. To prevent pregnancy, females of reproductive potential must use 2 reliable forms of contraception during treatment and for 1 month after stopping TRACLEER unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Obtain monthly pregnancy tests.

CONTRAINDICATIONS
TRACLEER is contraindicated:

• In females who are or may become pregnant
• With cyclosporine A
• With glyburide
• In patients who are hypersensitive to bosentan or any component of TRACLEER. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema.

WARNINGS AND PRECAUTIONS
In clinical trials, ALT/AST elevations (>3 x ULN) were observed in 11% of patients treated with TRACLEER, accompanied by elevated bilirubin in a few cases. In a pooled analysis of pediatric studies conducted in PAH, elevations in liver aminotransferases ≥3 x ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3 x ULN) and increases in total bilirubin (≥2 x ULN) is a marker for potential serious hepatotoxicity. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid using TRACLEER in patients with moderate or severe liver impairment or elevated ALT/AST >3 x ULN prior to drug initiation.

If clinically significant fluid retention develops, with or without associated weight gain, the cause, such as TRACLEER or underlying heart failure, must be determined. Patients may require treatment or TRACLEER therapy may need to be discontinued.

Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER should be discontinued.

Decreased sperm counts have been observed in patients receiving TRACLEER. Preclinical data also suggest that TRACLEER, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.

Treatment with TRACLEER can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and need for specific treatment.

ADVERSE EVENTS
In TRACLEER pivotal trials, the most common adverse events occurring more often in TRACLEER-treated patients than in patients taking placebo were respiratory tract infection (22% vs 17%), headache (15% vs 14%), edema (11% vs 9%), chest pain (5% vs 5%), syncope (5% vs 4%), flushing (4% vs 3%), hypotension (4% vs 2%), sinusitis (4% vs 2%), arthralgia (4% vs 2%), serum aminotransferases abnormal (4% vs 2%), palpitations (4% vs 2%), and anemia (3% vs 0%).

DRUG INTERACTIONS
TRACLEER is contraindicated for use with cyclosporine A and with glyburide.

TRACLEER is metabolized by CYP2C9 and CYP3A. Co-administration with agents that are metabolized by these pathways may affect plasma concentrations of one or both agents.
When initiating lopinavir/ritonavir and other ritonavir-containing HIV regimens, dosage adjustment of TRACLEER is necessary. When co-administered with simvastatin, or other statins that are CYP3A substrates, dosage adjustment of such statins may need to be considered. When co-administered with rifampicin, a CYP3A inducer, liver function should be monitored weekly for the first 4 weeks before reverting to normal monitoring. Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals; caution should be exercised if they are used together. When co-administered with ketoconazole, a potent CYP3A inhibitor, no dose adjustment of TRACLEER is necessary, but increased effects of TRACLEER may need to be considered.

There are no clinically relevant interactions between TRACLEER and warfarin, digoxin, nimodipine, losartan, or sildenafil. Dose adjustments are not necessary when TRACLEER and sildenafil are co-administered.

TRACLEER has no significant interaction with iloprost.

LIVER ENZYME ELEVATIONS
Measure liver aminotransferases prior to initiation of treatment and then monthly.

Use of TRACLEER should generally be avoided in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult.

It is important to adhere strictly to the monthly monitoring schedule for the duration of treatment. Changes in aminotransferases may occur early or late in treatment. There have been rare postmarketing reports of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring; the contribution of TRACLEER could not be excluded.

For patients whose monthly LFTs are ≤3 x ULN, no change in monitoring schedule or dosage is required.

For patients whose monthly LFTs are >3 x ULN, close monitoring and either dose reduction or treatment cessation are necessary.

MONITORING
It is important to adhere strictly to the monthly monitoring schedule for LFTs and, if applicable, pregnancy for the duration of treatment.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and availability of TRACLEER^® (bosentan). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Actelion Ltd, Actelion Pharmaceuticals US, Inc. and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2017, including under "Item 1A. Risk Factors," its most recently filed Quarterly Report on Form 10-Q, including under the caption "Cautionary Note Regarding Forward-Looking Statements," and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

¹ TRACLEER^® (bosentan) full Prescribing Information. Actelion Pharmaceuticals US, Inc.
² McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009;53:1573-1619.
³ Goraca A. New views on the role of endothelin. Endocr Regul.2002;36:161-167.
⁴ Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818. doi:10.1056/NEJMoa1213917.
⁵ Hayes GB. How do I really know I've got PH? In: Hayes GB. Pulmonary Hypertension: A Patient's Survival Guide. 5th ed. Silver Spring, MD: Pulmonary Hypertension Association; 2012:chap 1.
⁶ Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US Contemporary Registries. Chest. 2011;139(1):128-137. doi:10.1378/chest.10-0075.

Media Inquiries:
Colleen Wilson
Actelion US
Office: 650-808-6615

Investor Contacts:
Joseph J. Wolk
Johnson & Johnson
Office: 732-524-1142

Lesley Fishman
Johnson & Johnson
Office: 732-524-3922

SOURCE Actelion Ltd