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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]).

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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.

Onconova Presents Patient Selection Criteria and Intermediate Clinical Endpoints for Rigosertib in Higher-Risk Myelodysplastic Syndromes (HR-MDS) at EHA Annual Meeting

On June 15, 2015 Onconova reported the presentation of clinical data on rigosertib in HR-MDS at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna, Austria, June 11 – 14, 2015 (Press release, Onconova, JUN 15, 2015, View Source [SID:1234505432]).

Onconova collaborators from the United States and Europe presented multiple posters analyzing subgroup data, key clinical endpoints and eligibility criteria from the completed Phase 3 ONTIME trial of IV rigosertib in patients with HR-MDS previously treated with hypomethylating agents (HMAs). These data are being utilized in the design of a new global Phase 3 trial for IV rigosertib in HR-MDS, which Onconova expects to initiate in 2015, pending receipt of appropriate financing.

Electronic versions of the posters can be accessed by visiting "Posters" under the Investors and Media section of the Onconova website at www.onconova.com.

Abstract number: P616
Title: Overall Survival (OS) and Baseline Disease Characteristics in MDS Patients with Primary HMA Failure in a Randomized, Controlled, Phase III Study of Rigosertib
Primary Author: Guillermo Garcia-Manero, MD, MD Anderson Cancer Center, Houston, TX

Abstract number: P625
Title: Correlation of Overall Survival (OS) with Bone Marrow Blast (BMBL) Response in Patients (Pts) with Myelodysplastic Syndromes (MDS)
Primary Author : Lewis R. Silverman, MD, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY

Abstract Number: E1227
Title: Prognostic and Predictive Value of IPSS-R in Assessing Overall Survival (OS) in a Phase III Study of Rigosertib in Second-line Higher-risk (HR) MDS Patients
Primary Author: Lewis R. Silverman, MD; Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY

Abstract Number: E1226
Title: 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
Primary Author: Gianluca Gaidano, MD; Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

BioLineRx Presents Positive Safety and Efficacy Results for Novel Stem-Cell Mobilization Treatment at European Hematology Association Conference

On Jun 15, 2015 BioLineRx reported the presentation of positive safety and efficacy results for its lead oncology candidate, BL-8040, as a novel approach for the collection of stem cells from the peripheral blood circulation (Press release, BioLineRx, JUN 15, 2015, View Source;p=RssLanding&cat=news&id=2059112 [SID:1234505431]). Treatment with BL-8040 as a single agent was found safe and well tolerated at all doses, and resulted in efficient stem-cell mobilization and collection in all study participants. Furthermore, the results support BL-8040 as a one-day, single-dose collection regimen, which is a significant improvement compared to the current standard of care. The full Phase 1 data set was presented yesterday in an oral presentation at the 20th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Vienna, Austria.

Robust stem-cell mobilization was evident in all treated participants across the different doses tested, leading to a median 9.5-fold increase of stem cells in the peripheral blood following a single BL-8040 treatment. Two to four hours after a single administration, BL-8040 enabled collection of a stem-cell yield exceeding the number of cells required to support a transplant in all treated participants, following only one collection procedure. These results support a novel approach to stem-cell collection for transplantation purposes in patients with hematological malignancies or other indications. Importantly, the collection of CD34+ cells was accompanied by mobilization and collection of colony-forming cells, as well as T, B and NK cells.

The collected human graft was further assessed for its viability and quality in vitro and in vivo. The cells collected from the subjects treated with BL-8040 showed excellent engraftment in irradiated mice, followed by a rapid reconstitution of normal hematopoiesis.

The Phase 1 clinical trial was performed on healthy volunteers and consisted of two parts. The first part of the study was a randomized, double-blind, placebo-controlled, dose-escalation study in three cohorts of eight participants each, with each participant receiving two consecutive injections of BL-8040. Results show that BL-8040 is safe and well tolerated up to a dose of 1 mg/kg, and that dramatic mobilization of hematopoietic stem and progenitor cells (HSPCs) was observed across all doses tested. The robust mobilization supports the further use of a single injection of BL-8040 for HSPC collection.

In the second part of the Phase 1 study, eight healthy participants received a single injection of BL-8040 at the highest dose of 1 mg/kg, and four hours later underwent a single, standard leukapheresis procedure. Robust and rapid stem-cell mobilization was evident in all treated participants, supporting a novel approach to stem-cell collection. The median level of collected stem cells was higher than 11 x 106 cells per kg, and the level of HPSCs in the peripheral blood circulation 24 hours after injection of BL-8040 enabled an additional apheresis on Day 2, if needed. These data support the use of BL-8040 as a single-agent, single-injection, one-day regimen for the collection of stem cells.

"We are very happy to report these outstanding results supporting BL-8040 as an effective one-day monotherapy for collection of sufficient stem cells for hematopoietic cell transplantation. This is a major improvement over currently available procedures, which are lengthier and sometimes require the combination of several agents and multiple time-consuming apheresis sessions. Moreover, we see an improvement in composition of the collected cells, suggesting the potential of a better quality graft that may improve stem cell transplantation outcomes," said Dr. Kinneret Savitsky, CEO of BioLineRx. "We intend to meet with the U.S. Food and Drug Administration (FDA) in order to discuss our next steps in the clinical development program for this indication, including the design of the planned follow-up Phase 2 study. In addition, we are looking forward to reporting top-line results from the on-going Phase 2 study of BL-8040 for treating relapsed and refractory acute myeloid leukemia patients, which we expect in the fourth quarter of 2015. We also look forward to initiating clinical studies for BL-8040 in three additional indications over the next few months, thus expanding and enhancing the potential of our oncology platform."

At the same conference, the Company also presented positive preclinical results for the treatment of acute myeloid leukemia (AML) at a poster session. The results show that BL-8040 rapidly and efficiently induces cell death of AML cells, and demonstrates for the first time that CXCR4 inhibition is associated with induction of terminal differentiation of AML cells.

About Stem-Cell Mobilization

High-dose chemotherapy followed by stem-cell transplantation has become an established treatment modality for a variety of hematologic malignancies, including multiple myeloma, as well as various forms of lymphoma and leukemia. Modern peripheral stem-cell harvesting often replaces the use of traditional surgical bone marrow stem-cell harvesting. In the modern method, stem cells are mobilized from the bone marrow using granulocyte colony-stimulating factor (G-CSF), often with the addition of a mobilizing agent such as Plerixafor (Mozobil), harvested from the donor’s peripheral blood by apheresis, and infused to the patient after chemotherapy ablation treatment. This treatment is highly effective, the peripheral stem cells are easier to collect, and the treatment allows for a quicker recovery time and fewer complications.

About BL-8040

BL-8040 is a clinical-stage drug candidate for the treatment of acute myeloid leukemia, as well as other hematological indications. It is a short peptide that functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis (growth of new blood vessels in the tumor), metastasis (spread of the disease to other organs or organ parts) and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a Phase 1/2, open-label, dose escalation, safety and efficacy clinical trial in 18 multiple myeloma patients, BL-8040, when combined with G-CSF, demonstrated an excellent safety profile at all doses tested and was highly effective in the mobilization of hematopoietic stem cells and white blood cells from the bone marrow to the peripheral blood. Additionally, in a Phase 1 stem-cell mobilization study in healthy volunteers, BL-8040 as a single agent was safe and well tolerated at all doses tested and resulted in efficient stem-cell mobilization and collection in all study participants. Importantly, the results of this study support the use of BL-8040 as one-day, single-dose collection regimen, which is a significant improvement upon the current standard of care.

BL-8040 also mobilizes cancer cells from the bone marrow and may therefore sensitize these cells to chemo- and bio-based anti-cancer therapy. Importantly, BL-8040 has also demonstrated a direct anti-cancer effect by inducing apoptosis. Pre-clinical studies show that BL-8040 inhibits the growth of various tumor types including multiple myeloma, non-Hodgkin’s lymphoma, leukemia, non-small cell lung carcinoma, neuroblastoma and melanoma. BL-8040 significantly and preferentially stimulated apoptotic cell death of malignant cells (multiple myeloma, non-Hodgkin’s lymphoma and leukemia). Significant synergistic and/or additive tumor cell killing activity has been observed in-vitro and in-vivo when tumor cells were treated with BL-8040 together with Rituximab, Bortezomib, Imatinib, Cytarabine and the FLT-3 inhibitor AC-220 (in NHL, MM, CML, AML, and AML-FLT3-ITD models, respectively). In addition, the current Phase 2 clinical trial in AML patients has demonstrated robust mobilization and apoptosis of cancer cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.