On October 20, 2016 Amgen (NASDAQ:AMGN) reported that a Phase 3 study evaluating XGEVA (denosumab) versus zoledronic acid met the primary endpoint of non-inferiority (hazard ratio = 0.98, 95 percent CI, 0.85 – 1.14) in delaying the time to first on-study skeletal-related event (SRE) in patients with multiple myeloma (Press release, Amgen, OCT 20, 2016, View Source [SID1234515927]). The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met. The hazard ratio of XGEVA versus zoledronic acid for overall survival was 0.90 (95 percent CI, 0.70 – 1.16).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Adverse events observed in patients treated with XGEVA were generally consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) in the XGEVA arm of the study were diarrhea and nausea.

"Bone complications like fracture, spinal cord compression and radiation or surgery to bone are devastating for multiple myeloma patients. Many of these patients suffer from renal impairment, which has limited their treatment options," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "XGEVA’s unique mechanism of action has the potential to prevent bone complications in multiple myeloma patients regardless of their renal status, fulfilling an important unmet medical need."

Detailed results will be submitted to a future medical conference and for publication. The Company plans to submit these data to regulatory authorities.

About ‘482 Study (NCT01345019)
The ‘482 study was an international, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of bone complications in patients with newly diagnosed multiple myeloma. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE (fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE and first-and-subsequent on-study SRE and overall survival.The safety and tolerability of XGEVA were also compared with zoledronic acid.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow.1,2 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.2

Bone lesions frequently accompany multiple myeloma and can increase the risk of bone complications.3,4 Approximately 75 percent of multiple myeloma patients are treated for the prevention of bone complications.5 Preventing bone complications is an important aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.6

About XGEVA (denosumab)
XGEVA targets the RANK ligand pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has occurred in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroid, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least five months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

On October 20, 2016 TG Therapeutics, Inc. (NASDAQ:TGTX) reported the launch of a Phase 1/2 study to evaluate the safety and efficacy of TGR-1202, the Company’s oral PI3K delta inhibitor in combination with carfilzomib, the FDA-approved proteasome inhibitor, in patients with relapsed or refractory lymphoma (Press release, TG Therapeutics, OCT 20, 2016, View Source [SID1234515923]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The rationale for combining these two agents is based on extensive preclinical work conducted as part of a research collaboration supported by TG Therapeutics at the Center for Lymphoid Malignancies, Columbia University Medical Center. Portions of this work were presented in an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting in December 2015, by Dr. Changchun Deng of the Center for Lymphoid Malignancies. The presentation contained data demonstrating that the combination of TGR-1202 and carfilzomib was uniquely synergistic as compared to any other combination of a PI3K-delta inhibitor and proteasome inhibitor, including the combination of idelalisib and carfilzomib and idelalisib and bortezomib. Of particular interest, the combination of TGR-1202 and carfilzomib was found to potently inhibit cap dependent translation of c-Myc in all cell lines tested, including diffuse large B-Cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma, T-cell lymphoma, and chronic lymphocytic leukemia (CLL) cells. A more in depth presentation of the preclinical work has been submitted to a leading medical journal and is awaiting publication.

In the Phase 1 portion, the study will evaluate the safety, tolerability, and appropriate dose of carfilzomib when combined with 800mg of TGR-1202. Once a recommended Phase 2 dose is identified, the Phase 2 portion will further evaluate the safety and effectiveness of the combination at the chosen dose. TG Therapeutics will supply the TGR-1202 and assume up to 50% for the cost for the trial.

"We are very excited about the launch of this combination study, building on the extensive preclinical work completed by Dr. Deng, Dr. Owen A. O’Connor and the team from Columbia Presbyterian Medical Center, allowing us to move the science from bench to bedside and into patients in need of combination therapies. TGR-1202 continues to exhibit best-in-class safety and efficacy results and has demonstrated itself as a uniquely combinable PI3k-delta inhibitor. Our hope is that combination therapies with TGR-1202 could significantly improve the outcomes for patients with lymphoma," stated Michael S. Weiss, the Company’s Executive Chairman and Interim Chief Executive Officer."

"C-myc continues to be one of the most challenging tumor mutations to target. C-myc tumors include some of the most difficult to treat, including double hit lymphoma and triple negative breast cancer, which are generally resistant to currently available therapies leading to very poor outcomes for patients. The work we completed at Columbia appears to identify a novel mechanism for targeting c-myc by combining these two agents and we are eager to see if the work in the lab translates into helping these patients. We look forward to working with TGR-1202 and carfilzomib in this important clinical research project," stated Dr. Owen O’Connor, Director Lymphoid Malignancies at Columbia Presbyterian Medical Center.

This study is currently open to enrollment at the Center for Lymphoid Malignancies, Columbia Presbyterian Medical Center, New York, NY. More information on this clinical study can be found at www.clinicaltrials.gov.

On October 20, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported the commencement of Part B of the KEYNOTE-046 clinical trial evaluating Advaxis’ Lm immunotherapy candidate, ADXS-PSA, in combination with KEYTRUDA (pembrolizumab) in patients with previously treated, metastatic castration-resistant prostate cancer (mCRPC) (Press release, Advaxis, OCT 20, 2016, View Source [SID1234515920]). In Part A of the Phase 1/2 study, 14 patients were treated with ADXS-PSA monotherapy across three dose levels, with no dose limiting toxicities, paving the way for initiating Part B of the study.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

KEYNOTE-046 is a multicenter, open-label, nonrandomized, dose determining, Phase 1/2 trial evaluating the safety of ADXS-PSA. Part B of the study is evaluating the tolerability of ADXS-PSA in combination with KEYTRUDA in 30 patients with mCRPC. Secondary objectives for this study are to evaluate antitumor activity and progression-free survival of ADXS-PSA. KEYNOTE-046 is the first-in-human study of Advaxis’ Lm immunotherapy candidate for prostate cancer. It is the second study initiated to evaluate the use of KEYTRUDA in the treatment of advanced prostate cancer.

Advaxis also announced initiation of its Phase 3 AIM2CERV study, a multicenter, placebo-controlled, randomized study of axalimogene filolisbac, or AXAL, administered in the adjuvant setting following chemotherapy and radiation in women with high-risk, locally advanced cervical cancer (HRLACC). The primary objective of the trial is disease-free survival, with secondary objectives including examining overall survival and safety. In July 2016, Advaxis received a Special Protocol Assessment for the AIM2CERV trial, as well as Fast Track designation for AXAL as an adjuvant therapy for HRLACC patients.

Several trial sites have been opened for both studies and locations are currently screening patients for enrollment. For more information on Advaxis clinical trials, visit clinicaltrials.gov.

On October 20, 2016 – Actelion Ltd (SIX: ATLN) reported its results for the first nine months of 2016 (Press release, Actelion, OCT 20, 2016, View Source [SID1234515938]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

OPERATING HIGHLIGHTS

Strong Opsumit (macitentan) trajectory and quarterly net new patient gains sustained

Excellent US launch momentum for Uptravi (selexipag) – enhanced by launches in Germany and the Netherlands

Uptravi (selexipag) approvals in Switzerland and Japan (by Nippon Shinyaku) in Q3

First all-oral combination therapy with ponesimod and dimethyl fumarate (Tecfidera) to be evaluated for patients with relapsing multiple sclerosis

FINANCIAL HIGHLIGHTS

Sales growing to CHF 1,785 million (+14% at CER) – New PAH products surpass Tracleer for the first time

Opsumit sales grow to CHF 596 million (+63% at CER)

Uptravi sales reach CHF 160 million after just 9 months on the market

US GAAP operating income grows to CHF 660 million (+17% at CER)

Core operating income grows to CHF 781 million (+14% at CER)

2016 financial guidance upgraded: core operating income growth in the mid-teen percentage range, at constant exchange rates and barring unforeseen events

% variance
in CHF million
(except for per share data) 9M 2016 9M 2015 in CHF at CER(1)
US GAAP results
Net revenue 1,791 1,525 17% 14%
Operating income 660 533 24% 17%
Net income 581 452 29% 21%
Diluted EPS 5.37 3.99 35% 27%
Core performance(2)
Product sales 1,785 1,522 17% 14%
Core operating income 781 651 20% 14%
Core net income 691 560 23% 17%
Core diluted EPS 6.38 4.94 29% 23%
Cash flow 9M 2016 9M 2015
Operating cash flow 695 533
Capital expenditure (45) (17)
Free cash flow 6 (506)
Net cash position as of 30 September 411 698

CER percentage changes are calculated by reconsolidating both the 9M 2015 and 9M 2016 results at constant currencies (the average monthly exchange rates for 9M 2015).

Actelion continues to measure, report and issue guidance on its 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: "Once again, we have delivered a very strong performance across all areas of our business. I am particularly happy with the very positive feedback we receive from physicians prescribing Uptravi. We have also made considerable progress advancing our innovative pipeline, highlighted by the recent initiation of the combination study with ponesimod in relapsing multiple sclerosis. In summary, the transformation of the company is well under way."

Otto Schwarz, Chief Operating Officer, commented: "We continue to be extremely pleased with the transformation of our PAH portfolio. For the first time, in the third quarter, more than 50% of our sales came from our new outcome-based PAH portfolio. The strong uptake of Uptravi in the US continued during the third quarter, enhanced by a strong early trajectory in Germany, resulting in a total of over 1,800 patients benefiting from this novel oral therapy at the end of September 2016."

André C. Muller, Chief Financial Officer, commented: "The excellent commercial performance has enabled us to increase our R&D effort to advance both the late and earlier stage pipeline, whilst continuing to deliver strong earnings growth. Our focus on the bottom line, coupled with strong sales enables us to increase guidance. Barring unforeseen events, we now expect 2016 core operating income growth in the mid-teen percentage range at constant exchange rates."

SALES UPDATE
Actelion’s strong performance continued during the third quarter of 2016 driven by the outstanding Uptravi launch in the US and Opsumit’s ongoing growth dynamics. For the first time, during the third quarter of 2016, sales of the company’s outcome-based PAH portfolio, Opsumit, Uptravi and Veletri, exceeded 50% of total sales, demonstrating the extent of the transformation of the PAH franchise.

In the US, sales increased by 23% at CER, driven by the strong Uptravi launch, continued Opsumit momentum and ERA market share gains. European sales were at the same level as 2015, despite increased Opsumit uptake and Tracleer use in the digital ulcer indication, but mitigated by continued pricing pressure and market erosion from generics, particularly in Spain. Sales in Japan increased by 20% at CER, mostly driven by very strong sales of Opsumit (launched in June 2015), Tracleer in digital ulcer indication, Veletri and Zavesca (Japanese trade name Brazaves).

Comparing average exchange rates for the first nine months of 2016 to the first nine months of 2015, the Swiss franc weakened, mostly against the US dollar, euro and Japanese yen, resulting in a positive currency variance of 54 million Swiss francs.
Sales by product – 9M 2016
% variance
in CHF millions 9M 2016 9M 2015 in CHF at CER
Opsumit 596 354 68 63
Tracleer 790 934 -15 -18
Uptravi 160 - nm* nm
Veletri 71 60 18 13
Ventavis 58 81 -28 -31
Valchlor 26 19 34 30
Zavesca 78 68 15 13
Others 6 5 12 14
Total product sales 1,785 1,522 17 14
*nm = not meaningful

Sales by product – Q3 2016
% variance
in CHF millions Q3 2016 Q3 2015 in CHF at CER
Opsumit 218 147 49 45
Tracleer 244 289 -16 -18
Uptravi 70 - nm nm
Veletri 23 22 7 2
Ventavis 15 24 -39 -40
Valchlor 8 7 10 8
Zavesca 26 24 11 9
Others 2 2 1 -1
Total product sales 606 514 18 15

Sales by region – 9M 2016
% variance
in CHF millions 9M 2016 9M 2015 in CHF at CER
United States 964 766 26 23
Europe* 485 475 2 0
Japan 182 132 38 20
Rest of the world 155 149 4 6
Total product sales 1,785 1,522 17 14
*Europe = EU28 and Switzerland

Sales by region – Q3 2016
% variance
in CHF millions Q3 2016 Q3 2015 in CHF at CER
United States 325 271 20 18
Europe* 163 157 3 3
Japan 66 45 45 20
Rest of the world 52 40 30 29
Total product sales 606 514 18 15
*Europe = EU28 and Switzerland

PAH FRANCHISE
Opsumit
Sales of Opsumit (macitentan) amounted to 596 million Swiss francs for the first nine months of 2016, an increase of 63% at CER compared to the first nine months of 2015. This increase continues to be driven by new patient starts with commercial availability in over 30 countries. The continued increase in patients benefitting from Opsumit is driven by referral of treatment-naïve patients together with increased use in combination with PDE-5 inhibitors, and some upgrades from Tracleer, notably in Japan.

Uptravi
Sales of Uptravi (selexipag) amounted to 160 million Swiss francs for the first nine months of 2016. Since the US launch at the beginning of January 2016, patient demand has continued to increase with sales of 126 million Swiss francs (excluding initial inventory build of 30 million Swiss francs). For the third quarter, revenues from patient demand in the US amounted to 66 million Swiss francs compared to 45 million Swiss francs in the second quarter and 15 million Swiss francs in the first quarter of 2016. Uptravi was successfully launched in Germany in mid-June 2016 with sales reaching 3 million Swiss francs in an underdeveloped market in terms of prostacyclin usage. At the end of September, about 1,800 patients were using Uptravi globally.
During the third quarter 2016, Uptravi was approved in Switzerland and Japan (where it will be co-promoted by Nippon Shinyaku, who will record the sales) pending pricing and reimbursement approval.

Tracleer
Sales of Tracleer (bosentan) amounted to 790 million Swiss francs for the first nine months of 2016, a decrease of 18% at CER compared to the first nine months of 2015, equally driven by lower underlying volume and average price. The decrease is mainly due to lower referrals of new patients as well as switches in countries where Opsumit is available, increased generic competition, notably in Spain, continued pricing pressure in Europe and lower inventories in the US.
Tracleer sales were supported by the digital ulcer indication in Europe and Japan and continued solid demand in markets where Opsumit is not yet available.

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 19 EU countries until the end of August 2017.

Veletri
Sales of Veletri (epoprostenol for injection) amounted to 71 million Swiss francs for the first nine months of 2016, an increase of 13% at CER compared to the first nine months of 2015. This increase was mostly driven by successful market penetration, notably in France, and also Italy, Spain and UK. Demand in Japan remained solid, but sales were impacted by a 12% price cut effective from 01 March 2016.

Ventavis
Sales of Ventavis (iloprost) amounted to 58 million Swiss francs for the first nine months of 2016, a decrease of 31% at CER, compared to the first nine months of 2015. This is due to the competitive environment, including the availability of Uptravi. Underlying units decreased by 18%.

SPECIALTY PRODUCTS

Valchlor
Sales of Valchlor (mechlorethamine) amounted to 26 million Swiss francs for the first nine months of 2016, an increase of 30% at CER, compared to the first nine months of 2015. In the US, the company is continuing its efforts to establish Valchlor as an option in the treatment algorithm for early-stage mycosis fungoides, a type of Cutaneous T-Cell Lymphoma (MF-CTCL). In France, patients benefited from the drug under a temporary nominative authorization for use ("ATU") program initiated during the second half of 2014.

The regulatory dossier is currently under review with the European Medicines Agency (under the trade name Ledaga).

Zavesca
Sales of Zavesca (miglustat) amounted to 78 million Swiss francs for the first nine months of 2016, an increase of 13% at CER compared to the first nine months of 2015. Sales in the US were strong due to a relatively low prior year base as a consequence of last year’s inventory adjustment. In Europe, sales decreased by 2% mainly due to the launch of generic miglustat (approved for the type 1 Gaucher disease indication only). Sales in Japan were 16% higher, driven by increased patient demand in the Niemann-Pick type C indication.

The global number of patients receiving therapy grew by 7% compared to the first nine months of 2015, driven by a 16% increase in Niemann-Pick type C demand.

CLINICAL DEVELOPMENT PIPELINE
The pipeline continued to strengthen with substantial progress made with several compounds:
In the third quarter, 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 double blind long-term extension of the Phase II study as well as in the Phase III study OPTIMUM to compare the efficacy and safety of ponesimod with teriflunomide in patients with RMS. Enrollment for the OPTIMUM study is on target to be completed around the end of 2016.

Also in the third quarter, 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), we are entering into a pediatric study, TOMORROW, to evaluate the effect of macitentan on delaying disease progression in children with PAH using a pediatric formulation of macitentan. The global trial design has received endorsement from the US FDA (through a pediatric Written Request) and in the EU (through a Paediatric Investigation Plan). Enrollment is expected to start around the end of 2016.

A Phase II study, MERIT, assesses the efficacy, safety and tolerability of macitentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The study is on schedule to deliver results by the end of the year.
Enrollment of participants in the ongoing Phase III program IMPACT investigating cadazolid treatment in patients suffering from Clostridium difficile-associated diarrhea is progressing well and is on target to be completed around the end of 2016.

Compound Indication Study Status
Phase III Cadazolid Clostridium difficile-associated diarrhea IMPACT Ongoing
Macitentan Eisenmenger syndrome MAESTRO Ongoing
Macitentan Pediatric PAH TOMORROW Initiating


Ponesimod

Multiple sclerosis OPTIMUM Ongoing
Ponesimod Multiple sclerosis POINT Initiating
Phase II Cenerimod Systemic lupus erythematosus - Ongoing
Clazosentan Reversal of vasospasm associated with aneurysmal subarachnoid hemorrhage REVERSE Ongoing
Dual Orexin Receptor Antagonist Insomnia - Ongoing
Endothelin Receptor Antagonist Specialty cardiovascular disorders - Ongoing
Macitentan Chronic thromboembolic pulmonary hypertension MERIT Ongoing
Macitentan Combined pre- and post-capillary pulmonary hypertension MELODY Complete
Ponesimod Graft-versus-host disease - Ongoing
Phase Ib Lucerastat Fabry disease - Complete
Phase I New Chemical Entity Cardiovascular disorders - Ongoing
New Chemical Entity Inflammatory disorders - Ongoing
Selective Orexin 1 Receptor Antagonist Neurological disorders - Ongoing
T-type Calcium Channel Blocker Neurological disorders - Ongoing

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.