On November 18, 2014 Agios Pharmaceuticals reported the first reported safety and clinical activity for AG-120 from the ongoing Phase 1 dose escalation study in patients with IDH1-mutant positive advanced hematologic malignancies, including acute myeloid leukemia (AML) (Press release Agios Pharmaceuticals, NOV 18, 2014, View Source;p=RssLanding&cat=news&id=1990940 [SID:1234500982]). Agios has exclusive U.S. development and commercial rights to AG-120, a first-in-class, oral, selective, potent inhibitor of the mutant IDH1 enzyme. Daniel Pollyea, M.D., clinical investigator at the University of Colorado School of Medicine, will present the data in a late-breaking oral presentation today at the 26th Annual EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics being held in Barcelona, Spain. The company will webcast an investor conference call from the symposium at 10:00 a.m. EST (4:00 p.m. CET) on Wednesday, November 19, 2014.

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As of October 17, 2014, the ongoing Phase 1 trial for AG-120 had enrolled 17 patients with a documented IDH1 mutation whose cancer relapsed or failed to respond (refractory) to at least one prior treatment regimen. At the time of the data cut, 14 patients with relapsed and/or refractory AML were evaluable; three patients recently initiated therapy and were not evaluable.

The initial data showed investigator assessed objective responses in seven out of 14 evaluable patients, including four complete remissions, with responses observed across the four dose levels tested, and early evidence of durability. One additional patient remains stable on study. AG-120 was well tolerated, with the majority of adverse events reported as mild to moderate. The maximum tolerated dose has not yet been reached. One patient had a dose limiting toxicity of asymptomatic grade 3 QT prolongation at the highest dose tested to date, which improved to grade 1 after AG-120 dose reduction according to treatment protocol. This patient is in complete remission and remains on AG-120. AG-120 showed favorable drug exposure and pharmacokinetics at all doses tested and also substantially reduced plasma levels of the oncometabolite 2-hydroxyglutarate (2HG), which is produced by the mutant IDH1 protein, to the level observed in healthy volunteers. The mechanism of response is consistent with differentiation, as evidenced by the maturation of the leukemic cells into infection fighting white blood cells, or neutrophils. Based on these findings, the company plans to initiate multiple expansion cohorts in the first half of 2015.

"These data show very promising evidence of clinical activity for AG-120 in AML patients with an IDH1 mutation," said Chris Bowden, M.D., chief medical officer of Agios Pharmaceuticals. "Together with the data we reported from our ongoing Phase 1 study of AG-221 in advanced hematologic cancers, our lead investigational medicine and an IDH2-mutant inhibitor, we believe IDH inhibitors could potentially change the treatment paradigm for AML patients with these mutations. We look forward to moving rapidly into multiple expansion cohorts in the first half of 2015 to further characterize the potential of AG-120."

"We are highly encouraged to see the early favorable safety profile and clinical activity of AG-120, which includes four patients who achieved complete remission," said Dr. Pollyea. "For the first time in decades, we have the potential to offer certain AML patients an improved targeted treatment for this fatal disease that has historically had limited treatment options. I am hopeful that in the future we clinicians will be able to offer well tolerated and highly effective targeted therapies for our patients who have AML harboring an IDH mutation."

Patients in the ongoing Phase 1 trial have advanced AML whose cancer was refractory to available medical treatments or relapsed after treatment. The primary objectives of the Phase 1 trial are to determine the maximum tolerated dose (MTD) and the recommended dose for further study of AG-120. Secondary objectives include characterization of the safety profile, pharmacokinetics, pharmacodynamics and early anti-tumor activity. The trial uses an open-label, dose escalating design. Patients have been enrolled to date in four cohorts of AG-120 administered at 100 mg twice a day, 300 mg once a day, 500 mg once a day and 800 mg once a day. The median age of these patients is 73 (range 42-87).

On November 18, 2014 Teva Pharmaceutical Industries reported the commercial availability of a liquid formulation of TREANDA (bendamustine HCI) Injection (Press release Teva, NOV 18, 2014, View Source;p=RssLanding&cat=news&id=1990616 [SID:1234500981]). This new liquid formulation removes the step of reconstituting lyophilized powder with sterile water prior to adding the required dose of medicine to the infusion bag and administering to a patient. By eliminating the need for reconstitution, preparation time for healthcare professionals is reduced.

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"TREANDA continues to play a valuable role in the treatment of patients with CLL or indolent B-cell NHL that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen," said Paul Rittman, Vice President and General Manager, Teva Oncology. "With the new liquid formulation of TREANDA, we are not only building on the legacy of this important product, but also furthering Teva’s commitment to continuously improving our medicines."

Cancer, head and neck; Cancer, melanoma; Cancer, skin
It is in a multi-centre, single-agent, open-label, Phase I dose-escalation extension study to evaluate the safety and tolerability of repeated administrations of EBC-46 in patients who have successfully completed the main protocol (QB46C-H01, ANZCTR Trial ID: ACTRN12614000685617) (Clinical trial, Trial ID:ACTRN12614001207606, ANZCTR, NOV 17, 2014, View Source [SID1234517424]).
Patients will undergo a screening visit up to 3 months after completing the QB46C-H01 study. Treatment will be a single dose administered via intratumoural injection with safety monitoring for 21 days. Patients will be required to return for follow up assessments on Day 2, Day 8 (plus or minus 1 day), Day 15 (plus or minus 1 day) and Day 22 (plus or minus 1 day). Treatments will continue no sooner than 1 week since the last injection and will conclude when disease progression or intolerance presents.
Patients will initially receive the same dose level as they received in QB46C-H01 (if tolerated) or lower (if not tolerated or there is less tumour mass requiring dosing). Lower doses will be considered for patients who experienced a dose limiting toxicity (DLT) or Grade > 3 adverse event (AE) in the QB46C-H01 study or if the tumour burden requires less EBC-46.
The dose may be escalated to a higher level if that higher dose level has been demonstrated to be well-tolerated in the QB46C-H01 study (based on the incidence and severity of AEs and DLTs in the QB46C-H01 study) as determined by the Safety Review Committee.

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On November 17, 2014 Actavis plc (NYSE: ACT) and Allergan, Inc. (NYSE: AGN) reported that they have entered into a definitive agreement under which Actavis will acquire Allergan for a combination of $129.22 in cash and 0.3683 Actavis shares for each share of Allergan common stock (Press release, Allergan, NOV 17, 2014, View Source [SID:1234513407]). Based on the closing price of Actavis shares on November 14, 2014, the transaction is valued at approximately $66 billion, or $219 per Allergan share. The combination will create one of the top 10 global pharmaceutical companies by sales revenue, with combined annual pro forma revenues of more than $23 billion anticipated in 2015. The transaction has been unanimously approved by the Boards of Directors of Actavis and Allergan, and is supported by the management teams of both companies. Actavis anticipates that the expected permanent financing structure, consisting of a combination of new equity and debt, will support an investment grade rating and provide long-term financing flexibility.

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"This acquisition creates the fastest growing and most dynamic growth pharmaceutical company in global healthcare, making us one of the world’s top 10 pharmaceutical companies," said Brent Saunders, CEO and President of Actavis. "We will establish an unrivaled foundation for long-term growth, anchored by leading, world-class blockbuster franchises and a premier late-stage pipeline that will accelerate our commitment to build an exceptional, sustainable portfolio. The combined company will have a strong balance sheet, growing product portfolios and broad commercial reach extending across 100 international markets. Our combined experienced management team is dedicated to driving strong organic growth while capturing synergies and maintaining a robust investment in strategically focused R&D.

"This is a financially compelling transaction. With pro forma revenues in excess of $23 billion anticipated in 2015, this combination doubles the revenue generated by our brands business and doubles the international revenue of the combined company. Management is committed to maximizing the potential for the combined company to drive industry-leading top and bottom line growth. With this combination, we plan to transform the growth profile of our pharmaceutical business and have the ability to generate organic revenue growth at a compound annual growth rate of at least 10 percent for the foreseeable future," added Saunders. "The combination is expected to generate strong free cash flow of more than $8 billion in 2016 and substantial growth thereafter, which will enable the rapid repayment of debt. We expect that the combination will result in double-digit accretion to non-GAAP earnings within the first 12 months."

"Today’s transaction provides Allergan stockholders with substantial and immediate value, as well as the opportunity to participate in the significant upside potential of the combined company," said David E. I. Pyott, Chairman and CEO of Allergan. "We are combining with a partner that is ideally suited to realize the full potential inherent in our franchise. Together with Actavis, we are poised to extend the Allergan growth story as part of a larger organization with a broad and balanced portfolio, a meaningful commitment to research and development, a strong pipeline and an unwavering focus on exceeding the expectations of patients and the medical specialists who treat them. I am thankful for the hard work and dedication of our employees, and I’m confident they will make many valuable contributions to the combined company. Looking to the immediate future, all of us at Allergan are excited to roll up our sleeves and work closely with the Actavis team to ensure a smooth transition."

"This combination will greatly enhance our U.S. and international commercial opportunities," said Paul Bisaro, Executive Chairman of Actavis. "In the U.S., the combination makes us more relevant to an even broader group of physicians and customers. Overseas, it will enhance our commercial position, expand our portfolio and broaden our footprint in Canada, Europe and Southeast Asia and other high-value growth markets, including China, India, the Middle East and Latin America."

The combined company will be led by Brent Saunders, CEO and President of Actavis, and Paul Bisaro will remain Executive Chairman of the Board. The integration of the two companies will be led by the senior management teams of both companies, with integration planning to begin immediately in order to transition rapidly to a single company. Additionally, two members of the Allergan Board of Directors will be invited to join the Actavis Board of Directors following the completion of the transaction.

Financially Compelling Transaction
The growth profile of the combined pharmaceutical business will be unparalleled in the industry with the ability for double-digit revenue and earnings growth while maintaining investments to grow and develop our product portfolios and pipeline. The addition of Allergan’s portfolio, including multiple blockbuster therapeutic franchises, doubles the revenues of Actavis’ North American Specialty Brands business. On a pro forma basis for full year 2015, the combined company will have three blockbuster franchises each with annual revenues in excess of $3 billion in Ophthalmology, Neurosciences/CNS and Medical Aesthetics/Dermatology/Plastic Surgery. The specialty product franchises in Gastroenterology, Cardiovascular, Women’s Health, Urology and Infectious Disease treatments will have combined revenues of approximately $4 billion.

Actavis projects that the transaction will generate at least $1.8 billion in annual synergies commencing in 2016, in addition to the $475 million of annual savings previously announced by Allergan in connection with Project Endurance. Actavis also plans to maintain annual R&D investment of approximately $1.7 billion, ensuring the appropriate resource allocation to continue driving exceptional organic growth.

Significantly Expanded Brand Pharmaceutical Portfolio Supported by a World-Class North American Sales and Marketing Organization

Allergan’s blockbuster franchises in Ophthalmology, Neurosciences, and Medical Aesthetics/Dermatology/Plastic Surgery will complement Actavis’ existing blockbuster CNS, Gastroenterology and Women’s Health franchises to create a leading portfolio across a broad range of therapeutic areas.
The companies’ combined U.S. sales force will have extraordinary marketing reach and increased relevance with more than a dozen medical specialists, including primary care physicians, ophthalmologists, optometrists, dermatologists, aesthetic physicians, plastic surgeons, neurologists, psychiatrists, infectious disease specialists, cardiologists, pulmonologists, gastroenterologists, OB-GYNs and urologists.

Expanded Commercial Opportunities Across Global Markets

The combination of Actavis and Allergan will greatly enhance international commercial opportunities by positioning the combined company to extend its blockbuster franchise strategy on a global scale.
The company will have approximately $5 billion in pro forma 2015 international revenue.
Together Actavis and Allergan will have a commercial presence across 100 markets, including an enhanced presence across Canada, Europe, Southeast Asia and Latin America and a strong footprint in China and India.
The combined company will benefit from Allergan’s global brand equity, industry-leading consumer marketing capabilities and strong consumer awareness of key Allergan products, including BOTOX.
The combined company will have the unique opportunity to drive growth in international markets through its enhanced portfolio of brands, generics, branded-generic and over-the-counter products.

Expanded Pharmaceutical R&D Pipeline

The combined company will provide a strong commitment to R&D, with an exceptional level of annual investment of approximately $1.7 billion, focused on the strategic development of innovative and durable value-enhancing products within brands, generics, biologics and OTC portfolios.
The combination is expected to add approximately 15 projects in near- and mid-term development to Actavis’ robust development portfolio.

Additional Details
Actavis anticipates that the permanent financing structure, expected to include a combination of equity and debt, will support an investment grade rating and provide long-term financing flexibility. Actavis expects to finance the cash portion of the consideration with a combination of new senior unsecured notes, term loans and equity securities. The company has committed bridge facilities from JP Morgan Chase Bank, N.A., Mizuho Bank and Wells Fargo and commitments to replace its existing facilities to the extent they are not amended to permit the acquisition and the related financing. The transaction is not subject to a financing condition.

The transaction is subject to the approval of the shareholders of both companies, as well as customary antitrust clearance in the U.S., the EU and certain other jurisdictions, and is anticipated to close in the second quarter of 2015. J.P. Morgan is serving as exclusive financial advisor to Actavis and Cleary Gottlieb Steen & Hamilton LLP is serving as Actavis’ lead legal advisor. Goldman, Sachs & Co. and BofA Merrill Lynch are serving as financial advisors to Allergan. Latham & Watkins, Richards, Layton & Finger, P.A. and Wachtell, Lipton, Rosen & Katz are serving as legal counsel to Allergan.