First Randomized Controlled Trial in Portopulmonary Hypertension Shows OPSUMIT® (macitentan) Significantly Improved Pulmonary Vascular Resistance Compared with Placebo

Actelion Pharmaceuticals Ltd, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, has announced the results of the first randomized controlled trial in portopulmonary hypertension (PoPH), which showed OPSUMIT^® (macitentan) significantly improved pulmonary vascular resistance (PVR) compared with placebo, meeting the primary endpoint of the study. Presented as a late-breaking oral presentation at the European Respiratory Society (ERS) meeting in France, the PORtopulmonary hypertension Treatment wIth maCitentan ─ a randOmized clinical trial (PORTICO) showed the safety of macitentan in PoPH was consistent with that observed in previous clinical trials.

PoPH is a subset of pulmonary arterial hypertension (PAH), associated with portal hypertension (increased blood pressure in the portal vein)¹ often due to cirrhosis². PoPH is increasingly recognized and evidence suggests that it is the fourth most common form of PAH³. In many cases, patients with PoPH are only diagnosed as part of an assessment for liver transplantation; however, severe PAH is a contraindication for liver transplant due to poor post-operative prognosis⁴.

"The findings of PORTICO are relevant because if patients with PoPH can be treated to successfully lower pulmonary vascular pressure and resistance, more patients may be eligible for liver transplant as they will potentially have a better prognosis for this surgery,” said the lead investigator, Olivier Sitbon, MD, PhD, Professor of Respiratory Medicine at the South Paris University. “The fact that the hepatic safety profile of macitentan in patients with PoPH was consistent with that observed in previous trials is particularly reassuring, as PoPH patients are typically excluded from PAH clinical trials on safety grounds.”

Data supporting the use of PAH therapies in PoPH are extremely limited and are mostly from single-center, open-label studies^5-7. To date, none of the approved PAH treatments have been shown to improve cardiopulmonary hemodynamics in PoPH in a randomized controlled clinical trial.

In the PORTICO trial⁸, patients were randomized to receive macitentan 10mg (n=43) or placebo (n=42) once daily. After 12 weeks of treatment, macitentan significantly improved PVR (primary endpoint met, 35% reduction vs placebo, p<0.0001), mean pulmonary arterial pressure (mPAP; macitentan reduced mPAP by 5.99 mmHg vs placebo, p<0.0001) and cardiac index (macitentan increased cardiac index by 0.52 L/min/m² vs placebo, p=0.0009)⁹.

There was no significant difference between macitentan and placebo groups in six-minute walk distance (6MWD) or WHO Functional Class (FC). The most common adverse events (macitentan vs placebo) were peripheral edema (25.6 vs 11.9%) and headache (16.3 vs 16.7%)⁹.

OPSUMIT is an orally active endothelin receptor antagonist (ERA) that is currently approved in the US and Europe for the treatment of PAH^10,11.

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Notes to the Editor

ABOUT PORTOPULMONARY HYPERTENSION (PoPH)
PoPH is a form of pulmonary arterial hypertension (PAH) associated with portal hypertension with or without underlying chronic liver disease¹². However, as cirrhosis is the most common cause of portal hypertension, advanced liver disease is often encountered in patients with PoPH².

The symptoms associated with PoPH are similar, if not identical, to most other forms of PAH. They are non-specific and can range from mild breathlessness and fatigue during normal daily activity to symptoms of right heart failure and severe restrictions on exercise capacity and ultimately, reduced life expectancy⁴. The diagnosis of PoPH is often only made as part of an assessment for liver transplantation⁴, which can lead to a significant delay in diagnosis and patient care.

To date, no other approved PAH treatment besides OPSUMIT has demonstrated benefit in PoPH in a dedicated randomized controlled clinical trial.

ABOUT THE PORTICO STUDY ⁹
PORTICO (PORtopulmonary hypertension Treatment wIth maCitentan ─ a randOmized clinical trial) is a Phase IV, prospective, randomized, placebo-controlled, double-blind, multicenter, parallel-group study to assess the efficacy and safety of macitentan 10 mg in patients with PoPH.

In PORTICO, 85 patients with a confirmed diagnosis of PoPH were randomized in a 1:1 ratio into two treatment groups (macitentan 10mg or placebo) over a 12-week double-blind treatment period. The study started in June 2015 and was completed in October 2017.

The study met its primary endpoint; after 12 weeks of treatment, there was a significant reduction of 35% in pulmonary vascular resistance (PVR) for macitentan compared with placebo (geometric mean ratio [95% CI]: 0.65 [0.59, 0.72] p<0.0001).

The study also showed a significant positive effect of macitentan compared with placebo on mean pulmonary arterial pressure (mPAP) and cardiac index. After 12 weeks of treatment, macitentan significantly improved mPAP (macitentan reduced mPAP by 5.99 mmHg vs placebo, p<0.0001) and cardiac index (macitentan increased cardiac index by 0.52 L/min/m² vs placebo, p=0.0009). There was no significant difference between groups in change from baseline for six-minute walk distance (6MWD) or WHO Functional Class (FC).

Macitentan was well tolerated in this patient population and safety was in general consistent with the known safety profile for the treatment from previous clinical studies. The most frequently (≥10%) reported adverse events (macitentan vs placebo) were peripheral edema (25.6 vs 11.9%) and headache (16.3 vs 16.7%). There was a mean decrease in hemoglobin with macitentan of 1.8 g/dL. No patients discontinued the study due to liver enzyme elevations, and only one patient treated with macitentan experienced alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3x upper limit of normal.

ABOUT OPSUMIT (macitentan)
OPSUMIT, an orally available endothelin receptor antagonist, resulted from a tailored drug discovery process in Actelion's laboratories.

In the US, OPSUMIT is indicated for the treatment of PAH, WHO Group I to delay disease progression¹¹.

Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment). OPSUMIT also reduced hospitalization for PAH¹¹.

In Europe, OPSUMIT is indicated, as monotherapy or in combination, for the long-term treatment of PAH in adult patients of WHO Functional Class (FC) II to III¹⁰.

The effectiveness of OPSUMIT was established in a long-term study in PAH patients with predominantly WHO FC II-III symptoms treated for an average of two years. Patients were treated with OPSUMIT monotherapy or in combination with PDE5 inhibitors or inhaled prostanoids. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease¹⁰.

OPSUMIT is very likely to cause major birth defects. In both the US and Europe, it is contraindicated for use in pregnancy^10,11. In Europe, contraindications for OPSUMIT also include patients with severe hepatic impairment and those with elevated aminotransferase levels three times upper limit of normal; it is also not recommended in patients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of OPSUMIT¹⁰. Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended¹⁰. In the US, OPSUMIT is distributed under a risk evaluation and mitigation strategy (REMS); baseline liver enzymes should be obtained and patients treated with OPSUMIT should be monitored as clinically indicated¹¹.

ABOUT ACTELION
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 this important disease area. Learn more at www.actelion.com. Follow us at @actelion_com.

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. Actelion Pharmaceuticals Ltd is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenUS and www.twitter.com/JanssenGlobal.

Cautions Concerning Forward-Looking Statements

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding OPSUMIT^® (macitentan). 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 Pharmaceuticals Ltd, any of the other Janssen Pharmaceutical Companies 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 global 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 31 December, 2017, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in the company’s most recently filed Quarterly Report on Form 10-Q 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. Neither the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

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8. NCT02382016; PORTICO; https://www.clinicaltrials.gov.
9. Sitbon O, et al. Efficacy and safety of macitentan in portopulmonary hypertension: the PORTICO trial. European Respiratory Society International Congress 2018; OA267.
10. OPSUMIT (macitentan) Summary of Product Characteristics. Actelion Pharmaceuticals Ltd. February 2018.
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