Actelion Submits Application to EMA Seeking Approval of OPSUMIT® (macitentan) for the Treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Actelion Pharmaceuticals Ltd, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, today announced the submission of a Type II Variation to the European Medicines Agency (EMA) seeking to expand the indication of OPSUMIT^® (macitentan) to include the treatment of adults with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) of WHO Functional Class (FC) II to III to improve exercise capacity.

CTEPH is a rare form of pulmonary hypertension (PH) and a life-threatening complication of pulmonary embolism in which scar-like tissue forms around unresolved blood clots in the lungs which block or narrow the arteries. Without intervention or treatment, the disease continues to progress, eventually resulting in right ventricular failure (heart failure) and subsequently death¹.

Surgery to clear the blockages in the lungs is the preferred treatment option for CTEPH and is potentially curative^2,3. However, a substantial proportion (up to 50%) of CTEPH patients are deemed inoperable⁴ and current pharmacological treatment options for these patients are limited to one licensed therapy only^5,6.

If approved, OPSUMIT would be the first therapy in its class (endothelin receptor antagonists or ERA) available in the EU for the treatment of inoperable CTEPH.

“MERIT-1 provides the first randomized controlled trial data involving patients on monotherapy and combination therapy, addressing a key unmet need in CTEPH,” said Martin Fitchet, M.D., Global Head, Actelion Research & Development, Janssen Research & Development, LLC. “If approved, OPSUMIT has the potential to become a valuable treatment option in inoperable CTEPH. Building on its 20-year heritage of unprecedented innovation in pulmonary hypertension, Actelion is committed to addressing the unmet needs that persist in this severe and life-limiting disease. Ultimately our vision is to transform pulmonary hypertension into a chronic, manageable condition.”

The filing is based on data from the randomized clinical trial, MERIT-1 which showed significant improvements in the primary and secondary endpoints of pulmonary vascular resistance (PVR) and six-minute walk distance (6MWD), respectively, for patients treated with macitentan compared with placebo⁷. The benefits of macitentan were seen irrespective of whether patients were receiving treatment with other PAH therapies at baseline (most commonly phosphodiesterase type 5 [PDE5] inhibitors)⁷. Macitentan was well tolerated in this patient population and safety was generally consistent with the known safety profile for macitentan from previous clinical studies in PAH⁷. The study results were presented at the American Thoracic Society (ATS) 2017 and European Respiratory Society (ERS) 2017 and published in The Lancet Respiratory Medicine.

OPSUMIT is an orally active ERA that is currently approved in the EU as monotherapy or in combination for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO FC II to III⁸. In July this year, the US Food and Drug Administration (FDA) accepted for review Actelion’s supplemental New Drug Application for OPSUMIT for the treatment of adults with inoperable CTEPH to improve exercise capacity and pulmonary vascular resistance (PVR).

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Notes to the Editor

ABOUT CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH)
CTEPH is a unique form of pulmonary hypertension (PH) caused by chronic obstruction of the pulmonary arteries. The obstructions can result from blood clots that become stuck to the walls of the pulmonary arteries. The lining of the pulmonary arteries then begins to form excess tissue around the clots, transforming them into fibrous scar tissue that is attached to the artery wall. This creates a blockage that restricts the blood flow and increases the blood pressure, causing pulmonary hypertension and chronic stress to the right side of the heart – with the risk of developing right-side heart failure over time¹.

In total, just over 2,600 patients are estimated to be diagnosed with CTEPH each year across France, Germany, Italy, Spain and the UK, although the actual incidence is thought to be higher⁹.

Pulmonary thromboendarterectomy (PEA) remains the preferred treatment for CTEPH. However, certain CTEPH patients are not operative candidates due to the nature of the disease, location of the thrombi or multiple co-morbid conditions⁴. New medical treatment options are therefore needed for the effective management of this patient group.

ABOUT THE MERIT-1 STUDY ⁷
MERIT-1 (Macitentan in the treatment of Inoperable chronic Thromboembolic pulmonary hypertension) was a prospective, randomized, placebo-controlled, double-blind, multicenter, parallel-group study to assess the efficacy, safety and tolerability of 10mg macitentan in patients with inoperable CTEPH.

In MERIT-1, 80 inoperable patients (WHO Functional Class [FC] II to IV) were randomized in a 1:1 ratio into two treatment groups (macitentan 10mg or placebo) over a 24-week treatment period. The study started in August 2014 and was completed in September 2016. Patients with symptomatic PH in WHO FC III or IV at baseline were allowed to receive PAH background therapy throughout the study, including phosphodiesterase type 5 (PDE5) inhibitors and/or oral/inhaled prostanoids. All patients included in the study underwent independent operability assessment based on local or central adjudication committees.

After 16 weeks of treatment, there was a significant reduction in the primary endpoint, pulmonary vascular resistance (PVR) for macitentan compared with placebo (p=0.041). The efficacy observed was consistent across all sub-groups, including patients receiving background PAH specific therapy at baseline (61% of patients), including PDE5 inhibitors (59% of patients).

The study also showed a significant positive effect of macitentan compared to placebo on exercise capacity, one of the secondary endpoints. After 24 weeks of treatment, the mean change in 6MWD from baseline was an increase of 35 meters in patients treated with macitentan and 1 meter in those receiving placebo (p=0.033).

Macitentan was well tolerated in this patient population and safety was in general consistent with the known safety profile for macitentan from previous clinical studies. The most frequently (≥10%) reported adverse events that occurred with higher frequency on macitentan vs. placebo were peripheral edema (23% vs. 10.0%) and decrease in hemoglobin (15% vs. 0%).

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 progression¹⁰.

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 PAH¹⁰.

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 III⁸.

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 disease⁸.

OPSUMIT is very likely to cause major birth defects. It is contraindicated for use in pregnancy. In the U.S., OPSUMIT is distributed under a risk evaluation and mitigation strategy (REMS)¹⁰.

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.

REFERENCES

1. Medrek S and Safdar Z. Methodist Debakey Cardiovasc J 2016; 12:195-8.
2. Galie N, et al. Eur Respir J 2015; 46:903-75.
3. Madani M, et al. Ann Am Thorac Soc 2016; 13 Suppl 3:S240-7.
4. Madani M, et al. Eur Respir Rev 2017; 26:170105.
5. Kim NH, et al. Heart 2017; 103:599-606.
6. Ghofrani HA, et al. N Engl J Med 2013; 369:319-29.
7. Ghofrani HA, et al. Lancet Respir Med 2017; 5:785-94.
8. OPSUMIT (macitentan) Summary of Product Characteristics. Actelion Pharmaceuticals Ltd.
9. Gall H, et al. Eur Respir Rev 2017; 26:160121.
10. OPSUMIT (macitentan) full Prescribing Information. Actelion Pharmaceuticals US, Inc.

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