On April 3, 2017 Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK) reported that it has commenced operating as a new, refocused research and clinical development company in connection with the completion today of its previously announced transaction with Ipsen S.A. valued at up to $1.025 billion (Press release, Merrimack, APR 3, 2017, View Source [SID1234518442]). Under the terms of the agreement, Merrimack sold to Ipsen its first commercial product, ONIVYDE, including U.S. commercialization rights and its licensing agreement with Shire plc, and its development, license and supply agreement with Actavis for a generic version of doxorubicin hydrochloride (HCI) liposome injection that is marketed in the United States as DOXIL.

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Merrimack received $575 million in cash upon closing and is eligible to receive up to $450 million in additional regulatory approval-based milestone payments. Merrimack will also retain the rights to receive net milestone payments pursuant to its exclusive licensing agreement with Shire plc for the ex-U.S. development and commercialization of ONIVYDE for up to $33 million.

"The completion of this sale marks our first day as a new Merrimack: a refocused research and clinical development company, with a promising pipeline that is poised for continued long-term success and stockholder value creation," said Richard Peters, M.D., Ph.D., President and Chief Executive Officer. "Today, we have a more sustainable financial structure than at any point in Merrimack’s history, which will allow us to deliver significant cash returns to our stockholders while also funding our long-term corporate objectives and strategies into the second half of 2019. We are also moving forward focused on MM-121, MM-141 and MM-310, our three clinical programs that we believe have the highest probability of success and the highest expected return on investment. The Board of Directors and the management team are confident in the tremendous opportunities for success in our focused pipeline on behalf of cancer patients around the world and as a means to deliver additional value to our stockholders."

With the completion of the Ipsen transaction, Merrimack is now prioritizing three clinical programs:

MM-121 (seribantumab) is a first-in-class fully human monoclonal antibody that binds to the HER3 receptor and targets heregulin positive cancers. Merrimack is currently conducting the Phase 2 randomized SHERLOC study evaluating MM-121 in HRG+ non-small cell lung cancer patients in combination with docetaxel or pemetrexed and plans to initiate another Phase 2 randomized study this year in Her2 negative, hormone receptor, and heregulin positive breast cancer patients.
MM-141 (istiratumab) is a bispecific tetravalent antibody and a potent inhibitor of the PI3K/AKT/mTOR pathway by targeting IGF1-R and HER3. Currently, Merrimack is conducting the CARRIE study, a Phase 2 randomized trial evaluating MM-141 in previously untreated metastatic pancreatic cancer patients with high levels of free IGF1 in combination with nab-paclitaxel and gemcitabine.
MM-310 is an antibody-directed nanotherapeutic (ADN) that contains a novel prodrug of docetaxel and targets the EphA2 receptor, which is highly expressed in most solid tumor types. MM-310 was designed to improve the therapeutic window of docetaxel in major oncology indications, such as prostate, ovarian, bladder, gastric, pancreatic and lung cancers. A first-in-human Phase 1 study to evaluate safety and preliminary activity of MM-310 was initiated in the first quarter of 2017.
As previously announced, Merrimack intends to use the $575 million upfront payment, net of tax reserves and transaction-related and other costs, to:

Invest $125 million to develop Merrimack’s streamlined oncology pipeline such that Merrimack will be able to fund itself into the second half of 2019;
Extinguish the $175 million in outstanding Senior Secured Notes due in 2022, plus approximately $20 million of costs associated with the redemption; and
Return $140 million to Merrimack’s stockholders through a special cash dividend. The Board of Directors plans to approve the special cash dividend and announce a record date and ex-dividend date in due course.
Advisers

BofA Merrill Lynch and Credit Suisse Securities (USA) LLC are serving as financial advisers to Merrimack and Skadden, Arps, Slate, Meagher & Flom LLP is serving as legal adviser.

On April 3, 2017 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported the completion on March 31, 2017 of a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the approval of Vyxeos (cytarabine and daunorubicin) liposome for injection, an investigational treatment for acute myeloid leukemia (AML), a rapidly progressing and life-threatening blood cancer (Press release, Jazz Pharmaceuticals, APR 3, 2017, View Source [SID1234518440]). 1 The company has requested a priority review for the Vyxeos NDA, which, if granted, would accelerate the expected timing of the FDA’s review.

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Vyxeos utilizes CombiPlex technology, which encapsulates a fixed ratio of drugs in a nano-scale delivery complex. Vyxeos received Breakthrough Therapy Designation from the FDA in May 2016 for the treatment of adults with therapy-related AML or AML with myelodysplasia-related changes. Vyxeos was also granted Fast Track Designation for the treatment of elderly patients with secondary AML by the FDA, and Orphan Drug Designation by the FDA and the European Commission for the treatment of AML. The FDA grants Breakthrough Therapy Designation to expedite the development and review of new medicines that are intended to treat serious or life-threatening diseases when the clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on at least one clinically significant endpoint.

"The completion of our NDA submission for Vyxeos marks a significant milestone for the company as we continue to advance our pipeline of products for hematology and oncology diseases with high unmet medical needs," said Karen Smith, M.D., Ph.D., global head of research and development and chief medical officer at Jazz Pharmaceuticals. "We look forward to working closely with the FDA toward the goal of obtaining approval of Vyxeos for patients with AML as little has changed in the pharmacologic treatment of AML in more than 40 years."

The NDA submission includes clinical data from five studies, including the pivotal Phase 3 study. Data from the Phase 3 study, which met its primary endpoint, were previously presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2016.

About Vyxeos (CPX-351)

Vyxeos (cytarabine and daunorubicin) liposome for injection, or CPX-351, is an investigational product being evaluated for the treatment of AML, and is a combination of cytarabine and daunorubicin encapsulated within a nano-scale liposome at a 5:1 molar ratio. The proposed trade name, Vyxeos, is conditionally approved by the FDA and is subject to confirmation upon approval of the NDA.

About Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a rapidly progressing and life-threatening blood cancer that rises in frequency with age.1 The American Cancer Society estimates that there will be approximately 21,380 new cases of AML and 10,590 deaths from AML in the United States in 2017.1 The median age at diagnosis is 67 and with rising age there is progressive worsening of prognosis.1,2 Advancing age is associated with increasing risk of specific chromosomal/mutational changes and risk of pre-malignant marrow disorders, which give rise to more aggressive and less responsive forms of AML.3,4 As patients age there is also reduced tolerance for intensive chemotherapy.5 As a consequence, advances in supportive care, intensive chemotherapy and bone marrow transplantation have primarily benefitted younger patients.3,5 The five-year survival rate has not improved in older patients despite of 40 years of research.5,6

On April 3, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported the first overall survival (OS) data from the Phase 3 CheckMate -067 clinical trial (Press release, Bristol-Myers Squibb, APR 3, 2017, View Source [SID1234518438]). With a minimum follow-up of 28 months, the median OS had not yet been reached in either of the two Opdivo treatment groups and was 20 months for the Yervoy monotherapy group (95% CI: 17.1-24.6). Opdivo in combination with Yervoy and as a monotherapy reduced the risk of death 45% [hazard ratio (HR) 0.55; 95% CI: 0.42-0.72; P<0.0001] and 37% (HR 0.63; 95% CI: 0.48-0.81; P<0.0001), respectively, compared with Yervoy alone. The two-year OS rates were 64% for the Opdivo plus Yervoy combination, 59% for Opdivo alone and 45% for Yervoy alone. Results will be presented today in the press program and an oral presentation during the Update, Novel Indication, and New Immuno-oncology Clinical Trials session from 3:35 to 3:50 p.m. ET (Late-Breaking Abstract CT075) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Meeting 2017 in Washington, D.C.

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The updated safety data reported in this new analysis were consistent with previously reported experience, with no cumulative toxicity noted or new safety signals identified. Grade 3/4 treatment-related adverse events occurred in 58%, 21%, and 28% of the combination, Opdivo alone and Yervoy alone groups, respectively.

"It is encouraging to see such positive data from this trial, which further supports the scientific rationale to combine Immuno-Oncology agents as a potential treatment option for this aggressive form of melanoma. These CheckMate -067 survival data bolster our understanding of potential ways to combat untreated advanced melanoma and ultimately advance cancer care for patients," said James Larkin, Ph.D., FRCP, Consultant Medical Oncologist, Department of Medical Oncology, The Royal Marsden.

The proportion of patients experiencing complete responses (CR) compared to a previous 18 month follow-up analysis increased in the combination group to 17.2% from 12.1%, in the Opdivo alone group to 14.9% from 9.8%, and in the Yervoy alone group to 4.4% from 2.2%. Progression-free survival (PFS) and objective response rates (ORR) from updated analyses were both consistent with previous reports. The risk of disease progression was significantly reduced for both the combination and Opdivo monotherapy groups, 58% (HR 0.42; 95% CI: 0.34-0.51) and 46% (HR 0.54; 95% CI: 0.45-0.66), respectively, compared to Yervoy alone. The ORR for the two Opdivo groups, in combination and alone, and the Yervoy alone group was, respectively, 58.9% (95% CI: 53.3-64.4), 44.65% (95% CI: 39.1-50.3) and 19.0% (95% CI: 14.9-23.8).

"This first disclosure of overall survival data from CheckMate -067 helps to advance our understanding of the potential longer term benefits of Opdivo in combination with Yervoy in advanced melanoma, a cancer that historically has been difficult-to-treat," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb.

About CheckMate -067

CheckMate -067 is a Phase 3, double-blind, randomized trial that evaluated the combination of Opdivo plus Yervoy or Opdivo monotherapy versus Yervoy monotherapy in 945 patients with previously untreated advanced melanoma. Patients in the combination group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg (Q3W) for four doses followed by Opdivo 3 mg/kg every two weeks (Q2W). Patients in the Opdivo monotherapy group (n=316) received Opdivo 3 mg/kg Q2W plus placebo. Patients in the Yervoy monotherapy group (n=315) received Yervoy 3 mg/kg every three weeks for four doses plus placebo. Patients were treated until progression or unacceptable toxic effects. OS and PFS were co-primary endpoints for the trial. Secondary endpoints included ORR, efficacy by tumor PD-L1 expression level and safety.

The Opdivo plus Yervoy combination and Opdivo monotherapy provided OS benefits across clinically relevant subgroups of patients versus Yervoy alone. Specifically, in patients with BRAF mutations, the combination reduced the risk of death 57% (HR 0.43; 95% CI: 0.28-0.66) and Opdivo monotherapy reduced the risk of death 40% (HR 0.60; 95% CI: 0.40-0.89) compared to Yervoy alone. In patients without BRAF mutations (Wild-type patients), the combination reduced the risk of death 38% (HR 0.62; 95% CI: 0.48-0.80) and Opdivo monotherapy reduced the risk of death 36% (HR 0.64; 95% CI: 0.49-0.83) compared to Yervoy alone. In patients with PD-L1 expression ≥5%, Opdivo in combination with Yervoy and Opdivo monotherapy resulted in a 40% (HR 0.60; 95% CI: 0.36-1.00) and 44% (HR 0.56; 95% CI: 0.34-0.90) reduction in risk of death, respectively, compared to Yervoy alone. In patients with PD-L1 expression <5%, the combination and Opdivo monotherapy resulted in a 45% (HR 0.55; 95% CI: 0.42-0.72) and a 35% (HR 0.65; 95% CI: 0.50-0.84) reduction in risk of death, respectively, compared to Yervoy alone.

The trial was not designed to statistically compare the two Opdivo groups. However, descriptive analyses found the combination treatment provided a relative reduction in the risk of death of 12% (HR 0.88; 95% CI: 0.69-1.12) when compared with Opdivo alone and reduced the risk of death for patients expressing PD-L1 <1% by 26% (HR 0.74; 95% CI: 0.52-1.06) and PD-L1 <5% by 16% (HR 0.84; 95% CI: 0.63-1.12) when compared to Opdivo alone. Survival between the two Opdivo containing groups was similar in patients expressing PD-L1 ≥1% (HR 1.03; 95% CI: 0.72-1.48) and PD-L1 ≥5% (HR 1.05; 95% CI: 0.61-1.83).

About Metastatic Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 87,000 new diagnoses of melanoma and more than 9,700 related deaths are estimated for 2017. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 388,262, with 98,288 related deaths. Melanoma is mostly curable when treated in its early stages. However, patients in the United States diagnosed with advanced melanoma classified as Stage IV historically have a five-year survival rate of 15% to 20% and 10-year survival of about 10% to 15%.

On April 3, 2017 Bicycle Therapeutics, a biotechnology company pioneering a new class of therapeutics based on its proprietary bicyclic peptide (Bicycle) product platform, reported that the company will present preclinical data supporting the ongoing development of its lead molecule, BT1718 (Press release, Bicycle Therapeutics, APR 3, 2017, View Source [SID1234518437]). This program is the first example of its Bicycle Drug Conjugate technology, which allows toxic payloads to be targeted to tumour types of high unmet medical need. BT1718 targets Type 1 Matrix Metalloproteinase (MT1-MTP), which is highly expressed in many solid tumours, including triple negative breast cancer and non-small cell lung cancer. The data will be presented in three poster presentations at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), being held in Washington, DC from April 1 through April 5, 2017.

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Details for the poster presentations at the 2017 AACR (Free AACR Whitepaper) Annual Meeting are as follows:
Title: Development of BT1718, a novel Bicycle Drug Conjugate for the treatment of lung cancer
Session Title: Novel Molecular Targets 1
Abstract #: 1167/12
Date & Time: April 3, 2017, 8:00 a.m. – 12:00 p.m. EST

Title: Bicyclic peptides for PET imaging of MT1-MMP expressing tumors
Session Title: Clinical Laboratory and Imagine Correlates
Abstract #: 3719/4
Date & Time: April 4, 2017, 8:00 a.m. – 12:00 p.m. EST

Title: BT1718, a novel bicyclic peptide-maytansinoid conjugate targeting MT1-MMP for the treatment of solid tumors: Design of bicyclic peptide and linker selection
Session Title: Novel Drug Delivery Technology
Abstract #: 5144 / 16
Date & Time: April 5, 2017, 8:00 a.m. – 12:00 p.m. EST