On February 14, 2017 Amgen (NASDAQ:AMGN) reported the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for BLINCYTO (blinatumomab) to include overall survival (OS) data from the Phase 3 TOWER study, supporting the conversion of BLINCYTO’s accelerated approval to full approval (Press release, Amgen, FEB 14, 2017, View Source [SID1234517716]). The sBLA also includes new data supporting the treatment of patients with Philadelphia chromosome-positive (Ph+) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The application aims to broaden BLINCYTO’s indication for the treatment of patients with relapsed or refractory B-cell precursor ALL.

BLINCYTO was previously granted breakthrough therapy designation and accelerated approval in December 2014. It is also the first FDA-approved bispecific CD19-directed CD3 T cell engager (BiTE) antibody, and the first single-agent immunotherapy to treat patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL.

“Acute lymphoblastic leukemia is one of the most aggressive B-cell malignancies, and adult patients who relapse or are refractory to treatment often go through multiple lines of therapy,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “We are excited to potentially receive full approval for BLINCYTO, the first immunotherapy to demonstrate an overall survival benefit versus standard of care chemotherapy in patients with relapsed or refractory Ph- B-cell precursor ALL, and bring a much needed new treatment option to those who are Ph+.”

Results from the TOWER study, investigating the efficacy of BLINCYTO versus standard of care (SOC) chemotherapy in adult patients with Ph- relapsed or refractory B-cell precursor ALL, were presented during the Presidential Symposium at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper). BLINCYTO has a BOXED WARNING in its product label regarding Cytokine Release Syndrome (CRS) and Neurological Toxicities.

ALL is a rare and rapidly progressing cancer of the blood and bone marrow.1,2 In adult patients with relapsed or refractory ALL, median OS is just three to five months.3 Currently, there is no broadly accepted standard treatment regimen for adult patients with relapsed or refractory ALL beyond chemotherapy.4 In adult ALL, approximately 75 percent is B-cell precursor ALL, of which 75-80 percent is Ph- and roughly half will be refractory to treatment or experience relapse.5

About the TOWER Study
The TOWER study was a Phase 3, randomized, active-controlled, open-label study investigating the efficacy of BLINCYTO versus SOC chemotherapy in 405 adult patients with Ph- relapsed or refractory B-cell precursor ALL. The study enrolled a difficult-to-treat patient population which included patients from several stages of relapse, 17 percent of whom had relapsed post-allogenic stem cell transplant (alloSCT), and excluded those with late first relapse (≥ 12 months after initial remission). Patients were randomized in a 2:1 ratio to receive BLINCYTO (n=271) or treatment with investigator choice of one of four protocol-defined SOC chemotherapy regimens (n=134). The primary endpoint was OS. Key secondary endpoints included complete remission within 12 weeks, the combined endpoint of complete remission plus complete remission with partial or incomplete hematologic recovery and event-free survival. Other secondary endpoints included remission duration, minimal residual disease (MRD) remission (<10–4), alloSCT rate and adverse event rates. The TOWER study is the confirmatory trial for BLINCYTO. Click here to read about the trial on ClinicalTrials.gov. About the ALCANTARA Study The ALCANTARA study was a Phase 2, single-arm, multicenter, open-label study investigating the efficacy and tolerability of BLINCYTO in 45 adult patients with Ph+ B-cell precursor ALL who had relapsed after or were refractory to at least one second or later (2+)-generation tyrosine kinase inhibitor (TKI), or were intolerant to 2+-generation TKI and intolerant or refractory to imatinib. BLINCYTO was administered in 28-day cycles by continuous intravenous infusion. The primary endpoint was complete remission or complete remission with partial hematologic recovery during the first two cycles. Key secondary endpoints included MRD response, rate of allogeneic hematopoietic stem cell transplantation (alloHSCT), relapse-free survival, OS and adverse events. About BLINCYTO (blinatumomab) BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the FDA, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. In November 2015, BLINCYTO was granted conditional marketing authorization in the EU for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL. About BiTE Technology Bispecific T cell engager (BiTE) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body's immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com. BLINCYTO U.S. Product Safety Information Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. Contraindications BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation. Warnings and Precautions Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI). Neurological Toxicities: Approximately 64% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to onset of any neurological toxicity was 4 days. The most common (≥ 10%) manifestations of neurological toxicity were headache, tremor, dizziness, and altered state of consciousness. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 17% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The neurological toxicity profile varied by age group. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI. Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed. Tumor Lysis Syndrome (TLS): TLS, which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events. Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs. Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Adverse Reactions

The most common adverse reactions (≥ 20%) in the safety population studied in clinical trials were pyrexia (66%), headache (34%), nausea (27%), edema (26%), hypokalemia (26%), anemia (25%), febrile neutropenia (24%), neutropenia (22%), thrombocytopenia (20%), and abdominal pain (20%). The safety population included 225 patients weighing 45 kg or more and 57 patients weighing less than 45 kg. For some adverse reactions, there were differences in the incidence rates by age subgroup.
In patients weighing greater than or equal to 45 kg, serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia (9%), pyrexia (6%), sepsis (5%), pneumonia (5%), device-related infection (4%), neutropenia (3%), tremor (3%), overdose (3%), encephalopathy (3%), infection (2%), confusion (3%) and headache (2%).
In patients weighing less than 45 kg, serious adverse reactions were reported in 51% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia (12%), febrile neutropenia (9%), cytokine release syndrome (4%), convulsion (4%), device-related infection (4%), hypoxia (4%), sepsis (4%), and overdose (4%).
U.S. Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO at www.BLINCYTO.com.a

On February 14, 2017 Actelion Ltd (SIX: ATLN) reported its results for the full year 2016 (Press release, Actelion, FEB 13, 2017, View Source [SID1234517712]).

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FINANCIAL HIGHLIGHTS

Sales growing to CHF 2,412 million (+15% at CER)
Opsumit sales continue strong trajectory and grow to CHF 831 million (+57% at CER)
Uptravi sales reach CHF 245 million in first year of launch – driven by the US
US GAAP operating income grows to CHF 789 million (+14% at CER)
Core operating income grows to CHF 992 million (+17% at CER)
USD 30 billion proposal by Johnson & Johnson to acquire Actelion

PROPOSED TRANSACTION HIGHLIGHTS

Actelion to be acquired by Johnson & Johnson for $ 30 billion with spin-out of new R&D company, listed on Swiss stock exchange
Actelion shareholders to receive 280 US dollars per Actelion share in all-cash tender offer and one share of new R&D company for each Actelion share as stock dividend
Johnson & Johnson to acquire Actelion’s marketed products in particular its leading PAH franchise
Johnson & Johnson to also acquire global rights to Actelion’s promising advanced late-stage therapies, ponesimod and cadazolid
New R&D company launching with cash of CHF 1 billion to continue the culture of innovation with early stage R&D pipeline
Johnson & Johnson will also receive an option on an endothelin receptor antagonist (ACT-132577) currently being developed for resistant hypertension

FINANCIAL OVERVIEW

% variance
in CHF million
(except for per share data) FY 2016 FY 2015 in CHF at CER(1)
US GAAP results
Net revenue 2,418 2,045 18 15
Operating income 789 656 20 14
Net income 696 552 26 19
Diluted EPS 6.46 4.91 32 25
Core performance(2)
Product sales 2,412 2,042 18 15
Core operating income 992 814 22 17
Core net income 881 693 27 22
Core diluted EPS 8.18 6.16 33 27
Cash flow FY 2016 FY 2015
Operating cash flow 920 658
Capital expenditure (57) (44)
Free cash flow 90 (800)
Net cash position as of 31 December 495 405
CER percentage changes are calculated by reconsolidating both the 2015 and 2016 results at constant currencies (the average monthly exchange rates for 2015).
Actelion continues to measure and report core operating performance, which management believes more accurately reflects the underlying business performance. The Group believes that these non-GAAP financial measurements provide useful supplementary information to investors. These non-GAAP measures are reported in addition to, not as a substitute for, US GAAP financial performance.

Jean-Paul Clozel, MD, Chief Executive Officer, commented: "With Johnson & Johnson’s proposed acquisition of Actelion and the spin-out of a new R&D company, we have created unprecedented value for all of our stakeholders. Our current PAH portfolio and our late-stage pipeline will have expanded potential as part of Johnson & Johnson. With the creation of a new R&D company we also have the opportunity to realize the value potential we have created with our discovery engine and early-stage pipeline. I am very proud of what we’ve achieved, and I am very excited about the challenges and opportunities ahead."

Otto Schwarz, Chief Operating Officer, commented: "The significant clinical utility of Opsumit resulted in continued strong patient uptake with more than 21,000 patients currently receiving therapy. Moreover, after just one year on the US market, we can say that the Uptravi launch has been very successful by any standards, proving the high unmet medical need for oral prostacyclin therapy and validating our commercial strategy. I strongly believe that, as a part of the Johnson & Johnson family of companies, we will be able to serve even more patients by opening new markets and creating additional opportunities for our products."

André C. Muller, Chief Financial Officer, commented: "Actelion’s 2016 performance has been impressive with the company delivering record sales and earnings. The proposed transaction with Johnson & Johnson announced on 26 January will enable Actelion shareholders to not only monetize their holdings at 280 US dollars per share but also retain future upside potential with the distribution of 1 share in the newly created R&D company for every Actelion share. Both companies are now working to finalize the operational and financial details of the split and prepare the listing of the new company."

SALES UPDATE
Actelion’s excellent commercial performance during 2016 was driven by the outstanding Uptravi launch in the US and Opsumit’s sustained strong growth trajectory. During the fourth quarter of 2016, combined sales of the company’s outcome-based PAH portfolio – Opsumit, Uptravi and Veletri – reached 55% of total sales, demonstrating the significant progress made in the fundamental transformation of the PAH business.

In the US, sales increased by 25% at CER, driven by the strong Uptravi launch, the continued Opsumit momentum due to share gains in an expanding ERA market. European sales were 1% higher compared to 2015. A strong Opsumit performance and solid Tracleer use in the digital ulcer indication were impacted by continued pricing pressure and market erosion from bosentan generics, particularly in Spain. Sales in Japan increased by 19% at CER, driven by very strong sales of Opsumit (launched in June 2015), Tracleer momentum in the digital ulcer indication and Zavesca (Japanese trade name Brazaves).

Comparing average exchange rates for 2016 to 2015, the Swiss franc weakened, mostly against the US dollar, euro and Japanese yen, resulting in a positive currency variance of 63 million Swiss francs.

Sales by product – FY2016

% variance
in CHF millions FY 2016 FY 2015 in CHF at CER
Opsumit 831 516 61 57
Tracleer 1,020 1,212 -16 -18
Uptravi 245 - nm nm
Veletri 97 83 17 12
Ventavis 73 105 -30 -32
Valchlor 35 27 30 27
Zavesca 104 92 13 12
Others 8 7 7 8
Total product sales 2,412 2,042 18 15
*nm = not meaningful

Sales by product – Q4 2016

% variance
in CHF millions Q4 2016 Q4 2015 in CHF at CER
Opsumit 235 162 45 43
Tracleer 229 278 -17 -19
Uptravi 85 - nm nm
Veletri 26 23 12 9
Ventavis 15 24 -37 -38
Valchlor 10 8 20 19
Zavesca 26 24 10 10
Others 2 2 -6 -7
Total product sales 627 519 21 19
Sales by region – FY 2016

% variance
in CHF millions FY 2016 FY 2015 in CHF at CER
United States 1,306 1,026 27 25
Europe* 646 634 2 1
Japan 258 190 36 19
Rest of the world 201 192 5 6
Total product sales 2,412 2,042 18 15
*Europe = EU28 and Switzerland

Sales by region – Q4 2016

% variance
in CHF millions Q4 2016 Q4 2015 in CHF at CER
United States 342 259 32 30
Europe* 162 159 2 4
Japan 77 58 31 17
Rest of the world 47 42 10 9
Total product sales 627 519 21 19
*Europe = EU28 and Switzerland

PAH FRANCHISE
Opsumit
Sales of Opsumit (macitentan) amounted to 831 million Swiss francs for 2016, an increase of 57% at CER compared to 2015. The strong growth across all regions and all relevant markets (Opsumit is now available in almost 40 markets) was driven by solid quarterly increases in the number of patients treated in an expanding ERA market due to increased use in combination with PDE-5 inhibitors, and some upgrades from Tracleer, notably in Japan.

Uptravi
Sales of Uptravi (selexipag) amounted to 245 million Swiss francs for 2016. Since the US launch at the beginning of January 2016, patient demand has continued to increase with sales of 232 million Swiss francs (which includes 30 million Swiss francs for the build-up of inventory in the US). For the fourth quarter, US sales amounted to 77 million Swiss francs, compared to 66 million Swiss francs in the third quarter, 45 million Swiss francs in the second quarter and 15 million Swiss francs in the first quarter of 2016. In other geographies, Uptravi sales were driven by the particularly successful launch in Germany. Uptravi is also available in several other markets; it was most recently launched with full reimbursement in the Netherlands and Switzerland.

At the end of 2016, just over 2,400 patients were being treated with Uptravi globally, with more than 1,900 patients coming from the US.

Tracleer
Sales of Tracleer (bosentan) amounted to 1,020 million Swiss francs for 2016, a decrease of 18% at CER compared to 2015. This was driven to a large extent by volume erosion resulting from the significant impact of Opsumit uptake on the Tracleer patient base and by increased generic competition, notably in Spain, where generic bosentan entered the market in January 2016. Tracleer sales were supported by the digital ulcer indication in Europe and Japan.

Following the Pediatric Investigation Plan (PIP) compliance statement from the European Committee for Medicinal Products for Human Use (CHMP), applications for extension of the Supplementary Protection Certificate (SPC) were granted in all possible 19 EU countries until the end of August 2017.

Veletri
Sales of Veletri (epoprostenol for injection) amounted to 97 million Swiss francs for 2016, an increase of 12% at CER compared to 2015. This increase was mostly driven by France, Italy, Spain and the UK. Demand in Japan, where it is marketed as Epoprostenol ACT, remained strong, however sales growth was mitigated by a 12% price cut effective March 1, 2016. In February 2017, Actelion Pharmaceuticals Japan proudly announced that Epoprostenol ACT received a label extension for dosage and administration in pediatric patients with PAH.

Ventavis
Sales of Ventavis (iloprost) amounted to 73 million Swiss francs for 2016, a decrease of 32% at CER compared to 2015 due to competitive pressures, including the availability of Uptravi. Underlying units decreased by 37%.

SPECIALTY PRODUCTS
Valchlor
Sales of Valchlor (mechlorethamine) amounted to 35 million Swiss francs for 2016, an increase of 27% at CER compared to 2015. In the US, the company has made good progress in establishing Valchlor as a valuable option in the treatment algorithm for early-stage mycosis fungoides, a type of Cutaneous T-Cell Lymphoma (MF-CTCL).

In December 2016, the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), issued a positive opinion for the use of chlormethine gel 160 micrograms/g (Ledaga) for the treatment of mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) in adult patients and recommended that the European Commission approves the product. The European Commission is expected to issue a final decision by the end of February 2017.

Zavesca
Sales of Zavesca (miglustat) amounted to 104 million Swiss francs for 2016, an increase of 12% at CER compared to 2015.

Sales in the US were strong, due to a relatively low prior year base as a consequence of an inventory adjustment. In Europe, sales were flat due to the launch of generic miglustat (for the type 1 Gaucher disease indication only), which mitigated the continued strong, double-digit growth in the Niemann-Pick type C (NP-C) indication. Globally, the number of patients receiving Zavesca grew by 6%, compared to 2015, which was driven by a 13% increase in the treatment of patients with NP-C.

CORE R&D EXPENDITURE
The excellent commercial performance enabled Actelion to advance both the late and earlier stage pipeline, resulting in increased R&D expenditure which translates into a ratio of R&D core operating expenses to sales of 21%, slightly higher than in 2015. Core R&D expenses amounted to 509 million Swiss francs, an increase of 25% at CER. This increase was driven by higher clinical trial expenses, mainly driven by the strong recruitment in the Phase III OPTIMUM study (ponesimod in multiple sclerosis; announced in April 2015) and the Phase III IMPACT study (Cadazolid in Clostridium difficile associated diarrhea), as well as costs related to the preparation and initiation of Phase II studies for Actelion’s new ERA in specialty cardiovascular disorders and DORA in insomnia.

CORE OPERATING INCOME
Core operating income amounted to 992 million Swiss francs, an increase of 17% at CER.

CORE EPS
Diluted core earnings per share were CHF 8.18 for the full year 2016, an increase of 27% at CER compared to the same period of 2015.

DELIVERING VALUE TO SHAREHOLDERS
In-keeping with its commitment to maximizing shareholder value, Actelion returned 428 million Swiss francs to shareholders through the second-line share buyback as well as the increased dividend of CHF 1.50 per share, paid in May 2016. Actelion’s shares performed strongly throughout 2016 regardless of the extraordinary volatility created by the strategic discussions initiated in late November. The unaffected share price performance up until the strategic discussions became public was an increase of approximately 15%. At the end of the year, Actelion’s stock traded at 220.5 Swiss francs per share, an increase of 58% for the calendar year. The resulting total shareholder return (TSR) for 2016 amounted to 59%.

On 26 January 2017, Actelion and Johnson & Johnson jointly announced that they have entered into a definitive transaction agreement under which Johnson & Johnson will launch an all-cash tender offer in Switzerland to acquire all of the outstanding shares of Actelion for 280 US dollars per share. Additionally, Actelion shareholders will receive one share of a newly created R&D company that will be spun out concurrently with the closing of the proposed transaction.

CLINICAL DEVELOPMENT PIPELINE
The pipeline continued to strengthen with substantial progress made with several compounds:

The ongoing Phase III program IMPACT investigating cadazolid treatment in patients suffering from Clostridium difficile-associated diarrhea is progressing well; results are expected in the first half of 2017.
In the third quarter of 2016, Actelion announced the initiation of the Phase III POINT study, which investigates the use of combination therapy with ponesimod, an orally active, selective sphingosine-1-phosphate receptor 1 (S1P1) immunomodulator, and dimethyl fumarate (Tecfidera) for patients with relapsing multiple sclerosis (RMS). The POINT study – which will be conducted under a Special Protocol Assessment (SPA) agreement with the FDA – is the first to assess the concurrent administration of two oral therapies in MS with the objective to improve disease control in this progressive, debilitating neurological disorder. Ponesimod is also being studied in the Phase III OPTIMUM study to compare the efficacy and safety of ponesimod with teriflunomide (Aubagio) in patients with RMS. The study is making good progress, with enrollment expected to be complete in Q1 2017.
Also in the third quarter of 2016, the company advanced its new dual orexin receptor antagonist (DORA) into Phase II development in patients with insomnia. The Phase II program consists of two studies, one in adult and one in elderly patients, and is designed to evaluate the effect of Actelion’s DORA versus placebo on sleep maintenance and sleep initiation, as well as next-day residual effect and next-day performance. The study in adults also includes a zolpidem reference arm. The decision to move into a Phase II program was based on excellent data collected from the preclinical and Phase I clinical program, as well as a thorough understanding of the potential of dual orexin receptor antagonism on sleep efficacy and architecture.
With macitentan (Opsumit), the company is conducting a pediatric study, TOMORROW, to evaluate the effect of macitentan on delaying disease progression in children with PAH using a pediatric formulation of macitentan. Recruitment is expected to start in Q1 2017.
Actelion will assess the efficacy and safety of macitentan in stable Fontan-palliated adolescents and adults in the Phase III study RUBATO. The primary objective of this study is to assess the effect of macitentan as compared to placebo on exercise capacity through cardiopulmonary exercise testing (peak VO2). The duration of the study is expected to be approximately 28 months; the start is planned for mid-2017.
A Phase II study with macitentan, MERIT, assessed the efficacy, safety and tolerability of macitentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The study was completed in September 2016 and delivered very positive results, meeting its primary endpoint of a significant reduction in pulmonary vascular resistance (PVR) with macitentan compared with placebo, and also showing a significant positive effect on exercise capacity for macitentan over placebo.
A Phase III study with macitentan, MAESTRO, assessed the effects of macitentan on exercise capacity in patients with Eisenmenger Syndrome. The study was completed in January 2017, but did not meet the primary endpoint of significantly improving exercise capacity with macitentan compared with placebo.
Lucerastat is being evaluated for the treatment of Fabry disease. In an initial Phase Ib study, patients receiving enzyme replacement therapy who were treated with lucerastat demonstrated a marked decrease in the accumulation of metabolic substrates thought to be responsible for the lesions characteristic of this disease. Actelion is currently in discussions with health authorities to move directly to Phase III.
Compound Indication Study Status
Phase III Cadazolid1 Clostridium difficile-associated diarrhea IMPACT Ongoing
Macitentan1 Pediatric PAH TOMORROW Initiating
Macitentan1 Portopulmonary hypertension (PoPH) PORTICO Ongoing
Macitentan1 Fontan-palliated patients RUBATO Initiating


Ponesimod1

Multiple sclerosis OPTIMUM Ongoing
Ponesimod1 Multiple sclerosis POINT Ongoing
Phase II Cenerimod2 Systemic lupus erythematosus - Ongoing
Clazosentan2 Reversal of vasospasm associated with aneurysmal subarachnoid hemorrhage REVERSE Ongoing
Dual Orexin Receptor Antagonist2 Insomnia - Ongoing
Endothelin Receptor Antagonist
(ACT-132577)2 Specialty cardiovascular disorders - Ongoing
Macitentan1 Chronic thromboembolic pulmonary hypertension MERIT Complete
Phase Ib Lucerastat2 Fabry disease - Complete
Phase I New Chemical Entity2 Cardiovascular disorders - Ongoing
New Chemical Entity2 Inflammatory disorders - Ongoing
Selective Orexin 1 Receptor Antagonist2 Neurological disorders - Ongoing
T-type Calcium Channel Blocker2 Neurological disorders - Ongoing
1 Upon completion of the proposed transaction these assets would be developed by Johnson & Johnson
2 Upon completion of the proposed transaction these assets would be developed by the new R&D company

HUMAN RESOURCES
At the end of 2016, Actelion employed 2,624 permanent employees worldwide, an increase of 3% (or 77 permanent positions) compared to the end of 2015.

ANNUAL REPORT
Full details on the progress made in 2016 are available in Actelion’s 2016 Annual Report, at www.actelion.com/annual-report.

NOTES TO SHAREHOLDERS:
The next General Meeting of Shareholders will take place on or around 05 April, 2017, the date will be confirmed with the publication of the offer prospectus by Johnson & Johnson on or around 16 February 2017.

In light of the expected completion of the proposed transaction with Johnson & Johnson, the Board of Directors will propose to carry forward the 2016 accumulated profit and therefore not distribute any cash dividend.

RESULTS DAY CENTER
Investor community: To make your job easier, we provide links to all relevant documentation, such as a full financial review, reconciliation US-GAAP to Core results and geographical breakdown by product, from the Results Day Center on our corporate website: www.actelion.com/results-day-center.