On July 3, 2014 The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL) (External Source US FDA , Spectrum Pharmaceuticals, JUL 3, 2014, View Source [SID:1234500610]). The action was taken under the agency’s accelerated approval program.

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PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. In 2014, the National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die. PTCL represents about 10 to 15 percent of NHLs in North America.

Beleodaq works by stopping enzymes that contribute to T-cells, a type of immune cell, becoming cancerous. It is intended for patients whose disease returned after treatment (relapsed) or did not respond to previous treatment (refractory).

"This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. "Today’s approval expands the number of treatment options available to patients with serious and life-threatening diseases."

The FDA granted accelerated approval to Folotyn (pralatrexate) in 2009 for use in patients with relapsed or refractory PTCL and Istodax (romidepsin) in 2011 for the treatment of PTCL in patients who received at least one prior therapy.

The safety and effectiveness of Beleodaq was evaluated in a clinical study involving 129 participants with relapsed or refractory PTCL. All participants were treated with Beleodaq until their disease progressed or side effects became unacceptable. Results showed 25.8 percent of participants had their cancer disappear (complete response) or shrink (partial response) after treatment.

The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever (pyrexia), low red blood cells (anemia), and vomiting.

The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs. Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit. Beleodaq also received orphan product designation by the FDA because it is intended to treat a rare disease or condition.

Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.

On July 14, 2014 Jazz Pharmaceuticals reported that the company has signed a definitive agreement with Sigma-Tau Pharmaceuticals under which a subsidiary of Jazz Pharmaceuticals plc (Jazz) will acquire from Sigma-Tau rights to defibrotide in the United States (U.S.) and all other countries in the Americas (Press release, Jazz Pharmaceuticals, JUL 2, 2014, View Source [SID1234537662]). Sigma-Tau holds rights to market defibrotide in the Americas under an agreement with Gentium S.p.A., which was acquired by Jazz earlier this year. Defibrotide is a novel product that is marketed by Jazz in the European Union (EU) under the name Defitelio for the treatment of severe hepatic veno-occlusive disease (VOD) in patients over one month of age undergoing hematopoietic stem cell transplantation (HSCT) therapy. In the U.S., Jazz is working with the Food and Drug Administration (FDA) on the regulatory pathway for submission of a New Drug Application (NDA) for the potential approval of defibrotide to treat patients with severe VOD.

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As part of the agreement, Sigma-Tau would receive an upfront payment of $75 million upon closing of the transaction. Sigma-Tau would be eligible to receive milestone payments of $25 million upon the acceptance for filing by the FDA of the first NDA for defibrotide for VOD and up to an additional $150 million based on the timing of potential FDA approval of defibrotide for VOD. Jazz expects to fund the transaction with cash on hand and that the transaction will close during the third quarter of 2014, subject to customary closing conditions, including expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976.

"The acquisition of the remaining worldwide rights to defibrotide is a strong strategic fit with our specialty focus and would continue the momentum of our recent launch of Defitelio in the EU, further leveraging our global clinical and commercial expertise in hematology/oncology," said Bruce Cozadd, chairman and chief executive officer of Jazz Pharmaceuticals plc. "This transaction supports our mission to improve care for patients with serious medical conditions, and we remain committed to making targeted investments to develop and bring to market differentiated treatments for patients."

"This transaction would not only strengthen our global presence, but also demonstrate our commitment to diversify and expand our U.S. commercial portfolio with meaningful new therapies," said Russell Cox, executive vice president and chief operating officer of Jazz Pharmaceuticals plc. "We look forward to ongoing discussions with the FDA as we continue our efforts toward submission of an NDA for defibrotide in the U.S. Patients in the U.S. with severe VOD have a critical unmet medical need, and we believe that defibrotide has the potential to become an important treatment option for these patients."

About Defitelio▼ (defibrotide)
In October 2013, the European Commission granted marketing authorization under exceptional circumstances for Defitelio▼ (defibrotide) for the treatment of severe VOD in HSCT therapy. It is indicated in patients over one month of age. Defitelio is not indicated in patients with hypersensitivity to defibrotide or any of its excipients or with concomitant use of thrombolytic therapy.

In addition to its existing approved indication in the EU, defibrotide has the potential to be developed for approval in countries outside the EU and in other indications. Defibrotide has been granted orphan drug designation to treat and prevent VOD by the FDA, by the European Medicines Agency (EMA) and by the Korean Ministry of Food and Drug Safety (MFDS), orphan drug designation for the treatment of VOD by the Commonwealth of Australia-Department of Health, and Fast Track designation to treat severe VOD by the FDA.

In the EU, please consult the Defitelio summary of product characteristics before prescribing, particularly in relation to use of medicinal products that increase the risk of hemorrhage, concomitant systemic anticoagulant therapy, medicinal products that affect platelet aggregation, use in patients who have or develop clinically significant acute bleeding requiring blood transfusion, and patients who have hemodynamic instability.

▼ This medicinal product is subject to additional monitoring.

About VOD
Hepatic veno-occlusive disease (VOD) is an early complication in patients undergoing HSCT therapy. In its severe form, VOD can be life-threatening and is associated with multi-organ failure and is fatal in over 80% of patients.1,2 HSCTs are performed with curative intent in patients with hematological malignancies, selected solid tumors and some non-malignant disorders, such as serious hemoglobinopathies.3,4 Studies have reported a wide range of incidence rates for VOD, suggesting that 5-15% of patients undergoing HSCT develop VOD.2,5,6

Conference Call Information
Jazz Pharmaceuticals will host a conference call and live audio webcast today at 8:30 a.m. EDT/1:30 p.m. IST to discuss this transaction and related matters. Interested parties may access the live audio webcast and slide presentation via the Investors & Media section of the Jazz Pharmaceuticals website at www.jazzpharmaceuticals.com. Please connect to the website prior to the start of the conference call to ensure adequate time for any software downloads that may be necessary to listen to the webcast. A replay of the webcast will be archived on the website for one week.

Audio Webcast/Conference Call:
U.S. Dial-In Number: +1 866 543 6403
Outside the U.S. Dial-In Number: +1 617 213 8896
Passcode: 11784518

A replay of the conference call will be available through July 9, 2014 and accessible through one of the following telephone numbers and entering the passcode:

Replay U.S. Dial-In Number: +1 888 286 8010
Replay Outside the U.S. Dial-In Number: +1 617 801 6888
Passcode: 47229125

On July 2, 2014 Nicox S.A. (NYSE Euronext Paris: COX) reported it has signed an agreement to acquire all of the outstanding equity of Aciex Therapeutics, Inc., a private, US-based, ophthalmic development pharmaceutical company with a strong near-term pipeline of therapeutics addressing major segments of the ophthalmic market, including allergy and inflammation (Press release, NicOx, JUL 2, 2014, View Source [SID:1234512784]). The acquisition will significantly broaden and strengthen Nicox’s therapeutic development pipeline, which would include two phase 3 candidates (latanoprostene bunod, currently being developed by Nicox’s partner Bausch + Lomb, and Aciex’s AC-170 for allergic conjunctivitis). In addition, the proposed acquisition brings other therapeutic candidates which could enter clinical studies within 12 to 18 months and a collaborative research agreement on preclinical Syk/JAK inhibitors. The completion of the acquisition remains subject to the approval of Nicox’s shareholders and other customary conditions.

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Aciex’s therapeutic pipeline includes:

• AC-170 for allergic conjunctivitis, which has completed two phase 3 trials and for which Nicox plans to seek a pre-NDA meeting before the submission of a New Drug Application (NDA);

• AC-155, in development for post-operative inflammation and pain, which is expected to enter phase 2 studies in 2015;

• A collaborative research agreement with Portola Pharmaceuticals, Inc. for small molecule dual Syk/JAK inhibitors for potential topical ophthalmic treatments;

• A portfolio of clinical and pre-clinical product candidates targeting areas including ocular allergy, dry eye and other inflammatory eye conditions, and

• A proprietary manufacturing process that can be used to repurpose existing drugs by producing novel, patentable nanocrystalline forms.

Michele Garufi, Chairman and Chief Executive Officer of Nicox, said: "This proposed acquisition is another significant step forward in Nicox’s strategy of creating an international ophthalmic company built around therapeutics and diagnostics with its own commercial infrastructure in the United States and in the major European markets. The combination with Aciex would enable Nicox to expand its therapeutic pipeline to target major segments of the ophthalmic sector, including the $816 million US allergic conjunctivitis market1 . Together with the expansion of our diagnostics franchise, this acquisition further enhances our ability to create a unique company with a transatlantic commercial presence as well as a diversified proprietary product portfolio."

Les Kaplan, Ph.D, Executive Chairman of Aciex, and Thomas Cavanagh, President of Aciex, added: "We are excited about the opportunity to combine our robust pipeline derived from our collaboration with Ora, Inc., with the financial and commercial strengths of Nicox. With a portfolio of programs now either in or approaching the clinic, we believe that this transaction will accelerate their development and commercialization. We look forward to working with the Nicox team to ensure the success of the expanded business."

Under the proposed acquisition, Nicox will acquire all outstanding shares of Aciex on a cash-free debt-free basis through a reverse triangular merger, governed by US laws and regulations. Aciex shareholders will receive an upfront payment of $65 million entirely in the form of 20,627,024 newly issued Nicox shares, plus contingent value rights (CVRs) giving right to Nicox shares based on the potential US FDA approval(s) of AC-170 and of two additional undisclosed products within a pre-determined period. These CVRs are defined as follows: $35 million for the US approval of AC 170 on or before the earlier of 18 months after the date of filing of an NDA with the FDA or December 1, 2016; or $10 million if the approval is granted after this date, but on or before the earlier of 30 months after the date of filing of an NDA with the FDA or December 1, 2017; and $10 million each for the following two US product approvals by July 1, 2021. These could potentially bring the total consideration to a maximum of $120 million. In general, and subject to certain negotiated exceptions, the Nicox shares issued to Aciex stockholders will be subject to lock-up restrictions.2
MTS Securities, LLC, an affiliate of MTS Health Partners L.P., is serving as the exclusive financial advisor to Nicox in this transaction. Mintz Levin Cohn Ferris Glovsky and Popeo, P.C. is serving as US legal counsel to Nicox and Clifford Chance Europe LLP is serving as French legal counsel to Nicox. Aquilo Partners, L.P. acted as the exclusive financial advisor to Aciex in this transaction, and WilmerHale is serving as the legal advisor to Aciex. Nicox’s shareholders will be invited to vote on this proposed transaction at a dedicated Extraordinary General Meeting (EGM) which is expected to be held in the Fall. A report containing additional information will be made available to the shareholders prior to the EGM

Additional Therapeutic R&D Pipeline Background

The acquisition of Aciex will complement Nicox’s leading position in the therapeutic application of nitric oxide (NO)-donating compounds for ophthalmic use. Nicox’s lead asset, latanoprostene bunod, is currently in phase 3 trials for the reduction of intraocular pressure in glaucoma and ocular hypertension conducted by its licensing partner Bausch + Lomb. Nicox is also selecting the lead compounds from its internal research portfolio for the next-generation of NO-donors for the treatment of elevated intraocular pressure (IOP).

The combined therapeutic pipeline of Nicox and Aciex will include:

• AC-170 – a novel formulation of cetirizine (a leading antihistamine marketed under brand names including Zyrtec ), being developed for topical application in the eye for the first time for the treatment of allergic conjunctivitis. Two phase 3 safety and efficacy studies have demonstrated statistically significant results for AC-170 over vehicle control for the primary endpoint of ocular itching. Treatment emergent adverse events were similar in severity and frequency in the active and placebo groups. Nicox plans to seek a pre-NDA meeting by Q1 2015.

• Latanoprostene bunod – an NO-donating prostaglandin F2-alpha analog in phase 3 clinical development for the reduction of intraocular pressure in patients with glaucoma and ocular hypertension. Latanoprostene bunod is based on Nicox’s proprietary NO-donating research platform and was licensed to Bausch + Lomb in March 2010. Top-line phase 3 results are expected in Q4 2014.

• AC-155 – a novel nanocrystalline form of fluticasone (a leading corticosteroid marketed under brand names including Flonase and Flovent ), also being developed for topical application in the eye for the first time. It uses Aciex’s proprietary manufacturing process and is being developed for postoperative inflammation and pain. Fluticasone’s approximately ten-fold greater affinity than dexamethasone for the glucocorticoid receptor might allow reducing its dosing frequency. AC-155 is expected, pending FDA agreement, to move directly into a phase 2 clinical trial in 2015, following toxicity studies and IND filing.

• Aciex has a collaborative research agreement with Portola Pharmaceuticals, Inc., signed in 2013, that provides Aciex with exclusive rights to jointly develop Portola’s preclinical small molecule dual Spleen Tyrosine Kinase (Syk) and Janus Kinase (JAK) inhibitors for topical ophthalmic indications. These are targeted at ophthalmic diseases including ocular allergy, dry eye and other inflammatory eye conditions, for which there is a promising potential for Syk and JAK inhibition.

• Aciex’s extensive pipeline includes a number of additional clinical and pre-clinical programs that principally target ocular allergy, ocular inflammation and blepharitis and which offer opportunities for both in-house development and external collaborations. The pipeline has been developed through a close partnership with Ora, Inc., a leading ophthalmic Contract Research Organization (CRO) and development company. Nicox will continue to work closely with Ora following completion of the acquisition.

• Aciex has a proprietary manufacturing process, applicable to certain classes of molecules, which can be used to produce novel, patentable nanocrystalline forms of existing drugs in a number of therapeutic fields, including ophthalmology.

Nicox’s Commercial Presence

The Nicox Group is present in the US and in Europe. The acquisition of Aciex follows the recent expansion of Nicox’s commercial presence for its ophthalmic diagnostics franchise in the US to support its recently launched products, including Sjö for the early detection of Sjögren’s syndrome in patients with dry eye symptoms, and RetnaGene for comprehensive risk assessment for advanced age-related macular degeneration (AMD). The US team also promotes AdenoPlus , launched in late 2012, a point-of-care test to aid in the differential diagnosis of acute conjunctivitis. Two other diagnostic tests, one targeting both adenoviral and allergic conjunctivitis and the other targeting ocular herpes, are in development.

In Europe, Nicox markets Xailin, a proprietary brand of tear lubricants for relief of dry eye symptoms, and AdenoPlus . An additional range of products is also marketed in Italy through the Group’s subsidiary Eupharmed, acquired at the end of 2013. Nicox has established its own commercial sales forces in the US and in Europe’s five largest markets (France, Germany, Italy, Spain, and the UK). In addition, Nicox has already established partnerships with third parties for the marketing and sale of its products in several additional territories including Switzerland, Turkey, Benelux, South Africa and Poland, and Nicox is working on securing distribution agreements in other key international markets, including Japan.