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Subgroup Analyses of a Phase 3 Study in Patients with Myelodysplastic Syndromes Failing HMA Treatment: Identification of a Homogeneous Population Who Benefit from Rigosertib Therapy

In-depth analysis of ONTIME, and found that patients with the worst prognosis at entry, and thus with the greatest unmet medical need, appeared to benefit most from rigosertib treatment; namely, those with Primary AZA Failure, Very High Risk (VHR)-Revised International Prognostic Scoring System (IPSS-R), and monosomy 7 (Poster, Onconova, JUN 15, 2015, View Source;fileid=835336&filekey=758FA9A5-D91E-46AA-BC88-6A3B6C7CC728&filename=Gaidano_EHA_2015_ONTIME_subgroups.pdf [SID:1234507264]). The analyzed duration of prior hypomethylating agent (HMA) treatment inversely correlated with survival benefit.
Based on these results, a new randomized prospective controlled study in this high-risk MDS patient population comparing rigosertib to physician’s choice will be conducted to confirm these important observations.

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Actavis plc is now Allergan plc

On June 15, 2015 Actavis reported that the company has adopted Allergan plc (NYSE: AGN) as its new global name and will begin trading today under a new symbol — AGN — after ringing The Opening Bell at the New York Stock Exchange (Press release, Actavis, JUN 15, 2015, View Source;p=RssLanding&cat=news&id=2059261 [SID:1234505439]). The company name change follows the acquisition of Allergan in March 2015 and the approval of the name change by Actavis shareholders on June 5. The combination of Allergan and Actavis created one of the world’s top 10 pharmaceutical companies by revenue and a leader in a new industry model – Growth Pharma.

"Today is an exciting day for Allergan and our 30,000 employees around the world who have helped us reach this special moment," said Brent Saunders, CEO and President of Allergan. "By adopting the Allergan name, we are ensuring that our corporate identity reflects the transformation of our company within the pharmaceutical industry and our position as a dynamic new breed of company – a leader in Growth Pharma. Today, under one company name and identity, we set out on a new path forward, encouraging our employees across the globe to be bold in how we think and act, to engage and to move quickly to meet the needs of physicians, patients and customers.

"Allergan is home to world-renowned brands, the best-in-class global generics business, a premier pharmaceutical pipeline of medicines including brands, generics, biosimilars, OTC products and devices, as well as the fourth largest distributor in the U.S., which will retain the name Anda. Allergan’s fully integrated business provides unique opportunities to respond quickly to customer and patient needs, and change the lives of those who depend on us."

Allergan has initiated a rebranding campaign that will guide the transition of its facilities, operations and commercial presence around the world to the new company name. The company has launched a new global web site at www.Allergan.com. Based on feedback received from customers, the company’s U.S. and Canadian generics business will continue to operate under the Actavis name, capitalizing on its exceptional brand equity among customers.

Allergan has also today adopted a distinctive redesign of the company identity and logo. The new icon in the logo speaks to the strength of the Company’s unique capabilities, the energy and passion of its people and its forward momentum. The circular shapes personify movement; purposeful paths of change and growth; growing spheres of influence and ideas; and achievement across brands and generics.

The result is a new, momentum-building and accessible visualization that celebrates Allergan’s emergence as a Growth Pharma leader. Together, all united, all moving, resulting in an evolving, growing Company focused on a singular purpose – to power bold ideas in healthcare for people around the world.

8-K – Current report

On June 15, 2015 Karyopharm Therapeutics reported the presentation of positive clinical data for its lead product candidate, selinexor (KPT-330), a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound, at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) 2015 Annual Meeting held June 11-14, 2015 in Vienna, Austria (Filing, 8-K, Karyopharm, JUN 15, 2015, View Source [SID:1234505437]).

In an ongoing Phase 1b company-sponsored clinical trial evaluating the activity of single-agent selinexor (doses of 3-80mg/m2) in heavily pre-treated patients with diffuse large B-cell lymphoma (DLBCL), selinexor demonstrated a 43% overall response rate (partial response or better) in patients on study greater than one month, and a 31% overall response rate across all doses in the intention to treat population, with a median duration of response (DOR) of greater than nine months. Similar responses were observed in both GCB and non-GCB subtypes. The median overall survival (OS) and progression free survival (PFS) were 4.6 months and 1.7 months, respectively, for the entire study. In patients with a response to selinexor (N=12), the median OS was greater than 10 months (median not reached) and PFS was 24 months, significantly longer than those without a response (N=27; OS 3.5 months, PFS 1.2 months). Adverse events were manageable with standard supportive care and clinically significant cumulative toxicities were not observed, with several patients remaining on selinexor for more than one year.

Additional clinical data on selinexor’s activity in DLBCL, including in patients with double-hit DLBCL, will be provided in an oral presentation on Saturday June 20, 2015, at 10:50 CEST by Dr. Ramiro Garzon from the Ohio State University at the 13th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland.

Initial data from the ongoing Selinexor AraC Idarubicin Leukemia, or "SAIL," study, an investigator-sponsored Phase 2 clinical trial of selinexor with intensive chemotherapy (idarubicin and cytosine arabinoside [Ara-C]) in patients with acute myeloid leukemia (AML) that relapsed after standard intensive induction chemotherapy, were also reported. In 18 evaluable patients, the combination of selinexor (40 mg/m2) with idarubicin/Ara-C demonstrated a 56% overall response rate, including nine patients with complete remission (CR/CRi) and one patient with a partial remission. Adverse events were manageable with standard supportive care and dose adjustments.

"We are excited by these promising data presented at EHA (Free EHA Whitepaper), which continue to demonstrate the vast potential of selinexor across hematologic malignancies and provide further evidence of selinexor’s broad and durable activity, both as a single agent and in combination therapy," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "The correlation between response and prolonged survival demonstrated in heavily pretreated DLBCL patients suggests that responses to selinexor may confer a clinical benefit in this very difficult to treat population and support the ongoing

SADAL study in this group of patients. Moreover, the preliminary clinical data in patients with relapsed/refractory AML suggest that selinexor can be combined effectively with manageable side effects. These findings represent the reported clinical data of selinexor in combination with intensive chemotherapy and suggest that selinexor can enhance the activity of these agents with manageable side effects."

Selinexor data in DLBCL were described during an oral presentation by Dr. Ramiro Garzon of the Ohio State University on Saturday, June 13, entitled "Patients with Heavily Pretreated Diffuse Large B-Cell Lymphoma (DLBCL) who Respond to Oral Selinexor Therapy Show Prolonged Survival: Updated Phase 1 Results." These data from an ongoing Phase 1b clinical study of single-agent selinexor (3-80 mg/m2 oral doses) in patients with DLBCL were as of June 1, 2015 and included the following highlights:

• Among 28 response evaluable patients (per protocol defined as those patients on study for at least one month), the ORR was 43% and the disease control rate (stable disease or better) was 71%. Responses included four patients (14%) who achieved a complete response as confirmed by PET scan, eight patients (29%) who achieved a partial response and 8 patients (29%) with stable disease.

• Among 39 patients treated across all doses, the ORR was 31% and the disease control rate (stable disease or better) was 51%.

• Duration of response was greater than nine months.

• Patients with a response to selinexor (N=12), achieved OS of greater than ten months (median not reached) and PFS of 24 months which were significantly longer than those without a response (N=27; OS 3.5 months, PFS 1.2 months).

• The median overall survival (OS) and progression free survival (PFS) were 4.6 months and 1.7 months, respectively, for the entire study.

• Selinexor showed similar activity in both GCB and non-GCB subtypes of DLBCL.
In a late-breaking poster presented on Saturday, June 13, entitled "Preliminary Phase II Results of Ara-C And Idarubicin in Combination with Selective Inhibitor of Nuclear Export (SINE) Compound Selinexor (KPT-330) in Patients with Relapsed or Refractory AML," Dr. Walter Fiedler of the University Medical Center Hamburg and colleagues described preliminary data from the ongoing Phase 2 SAIL clinical trial demonstrating that selinexor in combination with standard doses of Ara-C and idarubicin is a potentially effective strategy for treating patients with AML that was relapsed or refractory after at least one line of chemotherapy. All data are as of April 27, 2015 and highlights include:

• An overall response rate of 56% was achieved based on 18 evaluable patients with three patients (17%) achieving complete remission (CR), six patients (33%) achieving complete remission with incomplete blood count recovery (CRi) and one patient (6%) achieving partial remission (PR).

• Ten patients (56%) received or were expected to receive either stem cell transplant or donor lymphocyte infusion.

• Adverse events were manageable with standard supportive care and dose adjustments.
An additional poster was presented on Saturday, June 13, entitled "XPO1 Inhibition Using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia (AML) by Targeting DNA Repair Genes" by Dr. Romero Garzon of the Ohio State University. In that preclinical study, Dr. Garzon and colleagues showed that selinexor synergizes with anthracyclines and other topoisomerase 2 inhibitors by preventing AML cells from repairing their DNA after damage by the chemotherapy. This study provides the scientific rationale for the ongoing SAIL study described above and additional studies with topoisomerase 2 inhibitors, as well as mechanistic insights into the use of selinexor with other chemotherapeutic agents.

About Selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 900 patients have been treated with selinexor in company- and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four registration-directed clinical trials of selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter’s transformation (SIRRT) and one in patients with diffuse large B-cell lymphoma (SADAL). A single-arm trial of selinexor in patients with multiple myeloma (STORM) that is also intended to be registration-directed was initiated in May 2015. In solid tumors, Karyopharm plans to initiate a registration-directed trial of selinexor to treat liposarcoma during the second half of 2015. Additional Phase 1 and Phase 2 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the company’s clinical development priorities for selinexor. The latest clinical trial information for selinexor is available at www.clinicaltrials.gov.

Oncolytics Biotech® Inc. Collaborators Present REOLYSIN® Preclinical Data at the 9th International Conference on Oncolytic Virus Therapeutics

On June 15, 2015 Oncolytics Biotech reported that a series of oral and poster presentations are being made by the Company’s research collaborators at the 9th International Conference on Oncolytic Virus Therapeutics being held from June 13th to 16th, 2015 in Boston MA (Press release, Oncolytics Biotech, JUN 15, 2015, View Source [SID:1234505435]).

"Our preclinical program continues to identify new potential therapeutic combinations as well as advance our understanding of how REOLYSIN works," said Dr. Brad Thompson, President and CEO of Oncolytics. "This work is an important part of the ongoing development of our proprietary formulation of the human reovirus."

Dr. Richard Vile is making an oral presentation regarding previously disclosed findings around augmenting tumor-specific natural killer (NK) responses and specifically attenuating tumor-specific immunosuppression. These data also suggest that the combination of PD-1 inhibition therapy with reovirus oncolytic/immunotherapy represents a readily translatable method to enhance the therapeutic efficacy.

The first abstract/poster titled "Targeting peripheral and lymph node resistant CLL with combination reovirus therapy," was authored by Melcher, et al. The authors studied chronic lymphocytic leukemia ("CLL") and the problems associated with eradicating minimal residual disease and drug resistance. They concluded that the combination of reovirus and ABT-263 could increase direct and immune-mediated killing of peripheral disease and that reovirus in combination with Fludarabine may be useful in targeting drug-resistant lymph node disease.

The second abstract/poster titled "Oncolysis by reovirus as an immune priming mechanism with VSV-cDNA immunological boosting treats large established tumors," was authored by Melcher, et al. The authors looked at the treatment of established B16 melanoma tumors in a mouse model. They concluded that the local killing of cancer cells by one virus primed the immune system and, by using tumor antigens expressed from a second virus, it was possible to generate potent immunological responses that led to the rejection of well established tumors.

The third abstract/poster titled "Monocyte carriage and delivery of reovirus-antibody complexes for melanoma oncolysis," was authored by Melcher, et al. The authors studied preexisting antiviral immunity and found evidence that there is an alternative mechanism by which systemically administered reovirus may gain access to tumors, even in the presence of neutralizing antibodies.

Acceleron Announces Publication in Cancer Research Demonstrating Dalantercept Prevents Metastases in Preclinical Studies of Breast Cancer

On June 15, 2015 Acceleron Pharma reported that new study findings involving the use of dalantercept to block the activin receptor-like kinase 1 (ALK1) pathway for the treatment of metastatic breast cancer were published in the June 15th issue (volume 75, #12) of Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Acceleron Pharma, JUN 15, 2015, View Source [SID:1234505434]). These pre-clinical findings suggest that dalantercept, in addition to treating the primary tumor, may also have an effect on metastasis, the principal clinical issue in advanced disease.

Breast cancer patients with high levels of the ALK1 in the blood vessels of their tumor are more likely to develop metastatic disease according to the research led by Kristian Pietras, Ph.D., the Goran and Birgitta Grosskopf Professor of Molecular Medicine at Lund University in Sweden.

"Although prognosis for breast cancer is relatively good when detected in its early stages, metastatic disease is the cause of 90% of all cancer-related deaths. Therefore, learning more about the metastatic process and finding new cures to inhibit the advancement of metastatic disease is a clinical priority," said Dr. Pietras. "The role of ALK1 expression by endothelial cells in primary breast tumor vasculature is a prognostic biomarker for metastatic dissemination. We used dalantercept to inhibit ALK1 in multiple mouse models of breast cancer, and in doing so, we were able to prevent metastatic dissemination and specifically the spread of the primary breast tumor to the lungs."

The study publication is available on Acceleron’s website (www.acceleronpharma.com) in the Publications section.

About Dalantercept

Dalantercept (ACE-041) is an investigational protein therapeutic that inhibits angiogenesis by preventing BMP9, a protein in the Transforming Growth Factor-Beta (TGF-Beta) superfamily, from interacting with activin receptor-like kinase 1 (ALK1), a cell-surface receptor found on proliferating vascular endothelial cells. Dalantercept inhibits ALK1 signaling, which is required for the development of mature, functional vasculature. Dalantercept is being investigated in a randomized placebo-controlled Phase 2 study in combination with axitinib in patients with advanced renal cell carcinoma and in a Phase 1b open-label study in combination with sorafenib in patients with advanced hepatocellular carcinoma.