On June 10, 2016 Syros Pharmaceuticals reported that SY-1425, its potent and selective retinoic acid receptor alpha (RARα) agonist, was observed to inhibit the growth of cancer cells and prolong survival in an in vivo model of acute myeloid leukemia (AML) with a novel RARA biomarker discovered by the Company (Press release, Syros Pharmaceuticals, JUN 10, 2016, View Source [SID:1234513202]). Syros also announced that SY-1365, its first-in-class potent and selective cyclin-dependent kinase 7 (CDK7) inhibitor, was observed to selectively kill acute leukemia cells over non-cancerous cells and induce complete tumor regression and a significant survival benefit in in vivo models of AML. These data are being presented this week at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

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"The presentations at EHA (Free EHA Whitepaper) highlight the potential of our gene control platform to systematically analyze the non-coding, regulatory region of the genome to advance a new wave of medicines designed to control the expression of disease-causing genes"
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"The presentations at EHA (Free EHA Whitepaper) highlight the potential of our gene control platform to systematically analyze the non-coding, regulatory region of the genome to advance a new wave of medicines designed to control the expression of disease-causing genes," said Nancy Simonian, MD, Chief Executive Officer of Syros. "By pioneering the understanding of this previously unexploited region of the genome, we believe we can identify novel disease drivers in specific patient populations and develop drugs that influence multiple disease-driving genes to provide patients with a more profound and durable benefit than many of today’s targeted therapies. Based on these strong preclinical data, we are currently advancing SY-1425 into a Phase 2 trial in genomically defined subsets of relapsed or refractory AML and relapsed high-risk MDS patients and plan to advance SY-1365 into a clinical trial for acute leukemia in the first half of 2017."

SY-1425 for Novel Genomically Defined Subsets of AML and MDS Patients
The data on SY-1425, which will be detailed in an oral presentation Sunday at EHA (Free EHA Whitepaper), shows that a biomarker for a highly specialized regulatory region of non-coding DNA, known as a super-enhancer, that is associated with the RARA gene is predictive of response to treatment with SY-1425 in AML cell lines and a patient-derived xenograft (PDX) model of AML. Treatment with SY-1425 was observed to inhibit cancer growth and prolong survival in a PDX model of AML with the RARA biomarker but not in a model of AML without the biomarker. Syros found the biomarker in approximately 25 percent of AML and myelodysplastic syndrome (MDS) patient tissue samples analyzed. Highlights of the data include:

Greatly reduced tumor burden in the blood, bone marrow and spleen in a PDX mouse model with the RARA biomarker treated with SY-1425 compared to untreated mice; by contrast, no effect was seen in a PDX model of AML without the biomarker.
Prolonged survival with 100 percent of mice with the RARA biomarker treated with SY-1425 alive at the end of the 35-day study; by contrast, none of the untreated mice survived beyond 25 days; notably, no survival benefit was seen in a PDX model of AML without the biomarker.
No anti-tumor or survival benefit seen with ATRA, a less potent and non-selective retinoid, in a PDX model with the RARA biomarker.
Differentiation of AML cells with the RARA biomarker treated with SY-1425.
Using its gene control platform, Syros identified subsets of AML and MDS patients whose tumors have the RARA super-enhancer. The super-enhancer is believed to lead to over-production of the RARα transcription factor, locking cells in an immature, undifferentiated and proliferative state. Treatment with SY-1425 inhibits cancer growth by promoting differentiation of AML cells with the RARA super-enhancer. Syros is on track to initiate a Phase 2 clinical trial of SY-1425 in mid-2016 in subsets of relapsed or refractory AML and relapsed high-risk MDS patients with the RARA biomarker.

CDK7 Inhibition as a Novel Treatment Strategy for Acute Leukemia
In the preclinical studies being presented Saturday at EHA (Free EHA Whitepaper), SY-1365 was observed to preferentially kill AML and acute lymphoblastic leukemia (ALL) cells over non-cancerous cells and induce tumor regression and significantly prolong survival in models of AML. Highlights of the in vitro and in vivo data include:

Complete tumor regression, which was maintained through the end of the 38-day study, in 100 percent of treated mice in a cell-line derived xenograft model of AML.
Strong survival benefit, with treated mice surviving up to 7-1/2 weeks beyond untreated mice in a PDX model of treatment-resistant AML.
Robust, sustained and dose-dependent apoptosis in AML and ALL cells treated with SY-1365 while not inducing apoptosis in non-cancerous cells.
Potent and selective inhibition of CDK7, with only six other kinases exhibiting greater than 90 percent binding when profiled across a panel of 468 kinases at a concentration of 1μM; notably, SY-1365 was not observed to significantly bind to members of the CDK family involved in cell cycle.
Minimal effect on blood cell counts, including white blood cells, lymphocytes, neutrophils and reticulocytes, in an in vivo model, demonstrating a more favorable profile than a non-selective CDK inhibitor.
Reduced expression of cancer-contributing genes associated with super-enhancers, including oncogenic transcription factors MYB and MYC, in an AML cell line.
Synergistic activity when combined with other targeted agents in AML, including Flt3, Bcl-2 and pan-Brd inhibitors.
Certain cancers, including AML and ALL, are dependent on high and constant expression of transcription factors for their growth and survival and have been shown to be particularly responsive to selective inhibition of CDK7. Syros has generated several selective CDK7 inhibitors, which have been observed to delay tumor progression in in vivo models of additional transcriptionally addicted cancers, including MYCN-amplified neuroblastoma, small cell lung cancer and triple negative breast cancer. Syros selected SY-1365 as its development candidate based on its strong preclinical efficacy and safety and plans to begin a Phase 1/2 clinical trial of SY-1365 in acute leukemia in the first half of 2017.

On June 10, 2016 Janssen-Cilag International NV reported data from the Phase 3 MMY3003 (POLLUX) trial, which show the immunotherapy daratumumab in combination with a standard of care treatment regimen, lenalidomide (an immunomodulatory agent) and dexamethasone (a corticosteroid), achieved a significant 63 percent reduction in the risk of disease progression or death (progression-free survival, or PFS) compared to lenalidomide and dexamethasone alone in patients with multiple myeloma who had received at least one prior line of therapy (Hazard Ratio [HR]=0.37; 95 percent CI (0.27-0.52), p<0.0001) (Press release, Janssen-Cilag International, JUN 10, 2016, View Source [SID:1234513203]).1 The median PFS in the daratumumab arm has not been reached, compared with a median PFS of 18.4 months for patients who received lenalidomide and dexamethasone alone.1 Additionally, daratumumab significantly increased the overall response rate (ORR) [93 percent vs. 76 percent, p<0.0001]. 1

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"Daratumumab induced deep and durable responses when combined with standard of care, more than doubling the rates of complete response or better in these previously treated patients"
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These data will be highlighted during the Press Briefing at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) at 8:30 a.m. CEST and have been selected for inclusion in the Presidential Symposium from 4:47 – 5:00 p.m. CEST on Friday, June 10th (Abstract LB2238).

"Daratumumab induced deep and durable responses when combined with standard of care, more than doubling the rates of complete response or better in these previously treated patients," said Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece and lead author of the abstract. "These striking results underscore the clinical benefit of a treatment plan built on daratumumab for patients with one or more prior lines of therapy."

In addition to meeting the primary endpoint of significantly improved PFS at a median follow-up of 13.5 months and significantly increasing ORR compared to lenalidomide and dexamethasone alone, daratumumab doubled rates of complete response (CR) or better [43 percent vs. 19 percent, p<0.0001], including rates of very good partial response (VGPR) or better [76 percent vs. 44 percent, p<0.0001].1 The treatment effect for daratumumab was consistent across all pre-specified subgroups.

"We’re so pleased to see daratumumab delivering consistent results across the treatment continuum in multiple myeloma. MMY3003 is the second Phase 3 study with daratumumab in combination to standard therapy, to meet its primary endpoint before the final analysis," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. "These data will be discussed in more detail at EHA (Free EHA Whitepaper) today, and we look forward to what will be an extremely exciting medical meeting for Janssen Oncology."

Overall, the safety of the daratumumab combination therapy was consistent with the known safety profile of daratumumab monotherapy (D) and lenalidomide plus dexamethasone (Rd), respectively. Similar rates of treatment discontinuation due to TEAEs were observed (7 percent/8 percent) in both the experimental arm and the control arm.1 The most common (<25 percent) treatment-emergent adverse events (TEAEs) [DRd/Rd] were neutropenia (59 percent/43 percent), diarrhoea (43 percent/25 percent), fatigue (35 percent/28 percent), upper respiratory tract infection (32 percent/21 percent), anaemia (31 percent/35 percent), constipation (29 percent/25 percent), cough (29 percent/13 percent), thrombocytopenia (27 percent/27 percent) and muscle spasms (26 percent/19 percent).1 Most common grade 3/4 TEAEs (>10 percent) were neutropenia (52 percent/37 percent), thrombocytopenia (13 percent/14 percent) and anaemia (12 percent/20 percent).1 The rate of Grade 3/4 infections was 28 percent versus 23 percent, and the most common Grade 3/4 infections (≥5 percent) was pneumonia (8 percent/8 percent).1 Daratumumab-associated infusion-related reactions (48 percent of patients) were mostly grade 1/2 (grade 3/4: 5 percent/0 percent), and most (92 percent) occurred during the first infusion.1

About the MMY3003 (POLLUX) Trial1

The MMY3003 (POLLUX) trial is a Phase 3, multinational, open-label, randomised, multicentre, active-controlled study in 569 patients with multiple myeloma who received a median of one prior line of therapy. Patients were randomised to receive either daratumumab combined with lenalidomide and dexamethasone, or lenalidomide and dexamethasone alone. Participants were treated until disease progression, unacceptable toxicity or if they had other reasons to discontinue the study. Nineteen percent of patients received three or more prior lines of therapy. Eighty-six percent of patients received prior treatment with proteasome inhibitor (PI); 55 percent received prior treatment with an immunomodulatory agent (including 18 percent with lenalidomide); and 44 percent received prior treatment with a PI and immunomodulatory agent. Twenty-seven percent of patients were refractory to their last line of prior therapy; 18 percent were refractory to a PI; and none were refractory to lenalidomide.

On May 20, 2016, the MMY3003 trial was stopped early after meeting its primary endpoint of significantly improved PFS in a pre-planned interim analysis. Based on the recommendation of an Independent Data Monitoring Committee (IDMC), patients in the control treatment arm were offered the option to receive daratumumab following confirmed disease progression.

About Daratumumab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.2-4Daratumumab induces rapid tumour cell death through apoptosis (programmed cell death)5,6 and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).5,7,8 Daratumumab has also demonstrated immunomodulatory effects that contribute to tumour cell death via a decrease in immune suppressive cells including T-regs and myeloid-derived suppressor cells.5,9 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed. For more information, please see www.clinicaltrials.gov.

In May 2016, daratumumab was conditionally approved by the European Commission for monotherapy of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.5 Daratumumab was approved under an accelerated assessment, a process reserved for medicinal products expected to be of major public health interest, particularly from the point of view of therapeutic innovation.10

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.11,12 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, patients progress within 60 days of their last therapy.13,14 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.15 Accounting for approximately one percent of all cancers and 15 percent to 20 percent of haematologic malignancies worldwide,16 multiple myeloma is designated as an orphan disease in both Europe and the US. Globally, it is estimated that 124,225 people were diagnosed, and 87,084 died from the disease in 2015.17,18 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone fracture or pain, low red blood counts, fatigue, calcium elevation, kidney problems or infections.12 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.19

On June 10, 2016 Cantargia AB reported that the patent application, with application number 13/979,475 that has now received a Notice of Allowance from the USPTO refers to a method for using IL1RAP as target molecule for treatment of solid tumours (Press release, Cantargia, JUN 10, 2016, View Source [SID:1234513204]). The patent covers treatment of several different forms of solid tumours, including breast cancer, colorectal cancer, lung cancer and malignant melanoma. The issuance of a Notice of Allowance indicates that the USPTO intends to approve the company’s patent application. Certain administrative steps remain before the patent is formally granted.

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"Cantargia has passed yet another very important milestone in the development of our CAN04 product candidate", Göran Forsberg, CEO of Cantargia AB, says. "Once the patent has been formally approved in the US we will have protection in the area of solid tumours in the three largest markets, USA, Europe and Japan."

On June 10, 2016 Nordic Nanovector ASA (OSE: NANO) reported that pharmacokinetic analyses of a clinical study in patients with non-Hodgkin lymphoma (NHL) demonstrate that pre-dosing with the anti-CD37 antibody HH1, prior to injection with Betalutin (177Lu-HH1) significantly increases the pharmacokinetic exposure of NHL tumour cells to Betalutin (p < 0.001) while protecting against haematological side effects (Press release, Nordic Nanovector, JUN 10, 2016, View Source [SID:1234513205]).

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The study, part of the ongoing Lymrit 37-01 Phase 1/2 trial of Betalutin in NHL, evaluated 13 NHL patients who received different doses of Betalutin either with or without HH1 pre-dosing. The analysis will be presented in an ePoster at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Copenhagen, Denmark, 9-12 June) by Dr Arne Kolstad, a senior consultant in medical oncology and radiotherapy at Oslo University Hospital, Radiumhospitalet and a member of Nordic Nanovector’s Scientific Advisory Board. The poster is available here EHA (Free EHA Whitepaper) 2016 and at www.nordicnanovector.com in the section: Product Info/Scientific Posters.

Jostein Dahle, Nordic Nanovector CSO, commented: "The results presented in this poster continue to support our hypothesis that pre-dosing provides a protective effect on healthy tissues when used prior to Betalutin treatment."

The Lymrit 37-01 study is a Phase 1/2 open label, single injection ascending dose study investigating three dose levels of Betalutin and different pre-dosing regimens in patients with relapsed NHL with the aim of identifying an optimal dose regimen to take into the Phase 2 PARADIGME study, which is expected to start in 2H 2017.

On June 10, 2016 Galena Biopharma, Inc. (NASDAQ:GALE), a biopharmaceutical company committed to the development and commercialization of targeted oncology therapeutics that address major unmet medical needs, reported that the U.S. Food and Drug Administration (FDA) has granted two orphan-drug designations for Galena’s two cancer immunotherapy peptides derived from Folate Binding Protein (FBP) for the treatment (including prevention of recurrence) of ovarian cancer: one for GALE-301 (E39), and one for GALE-301 (E39) and GALE-302 (E39’) (Press release, Galena Biopharma, JUN 10, 2016, View Source [SID:SID1234515198]). In clinical trials, GALE-301, and GALE-301/GALE-302 are combined with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF) for the treatment of ovarian cancer in the adjuvant setting.

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"Ovarian cancer is a very aggressive disease with almost fifty percent of women recurring within five years after their initial treatment1," said Mark W. Schwartz, Ph.D., President and Chief Executive Officer. "This designation supports our efforts to advance our FBP-targeted immunotherapy program consisting of GALE-301 and GALE-302 to prevent cancer recurrence in this underserved patient population."

The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S.2 Orphan designation qualifies the sponsor of the drug for various development incentives including marketing exclusivity in the U.S. for seven years after product approval3, tax credits, and exemption from the prescription drug user fee.
Sources: 1U.S. Ovarian Cancer View Source; 2FDA Website – Developing Products for Rare Diseases & Conditions; 3FDA Frequently Asked Questions on Patents and Exclusivity

About GALE-301 and GALE-302
GALE-301 and GALE-302 are cancer immunotherapies that consist of a peptide derived from Folate Binding Protein (FBP) combined with GM-CSF for the treatment (including prevention of recurrence) of ovarian cancer in the adjuvant setting. GALE-301 is the E39 peptide, while GALE-302 is an attenuated version of this peptide, known as E39’. FBP is a well-validated therapeutic target that is highly over-expressed in ovarian, endometrial and breast cancers, and is the source of immunogenic peptides that can stimulate cytotoxic T lymphocytes (CTLs) to recognize and destroy FBP-expressing cancer cells. Two trials are ongoing with FBP peptides in gynecological cancers: the GALE-301 Phase 2a portion of the Phase 1/2a clinical trial is ongoing in ovarian and endometrial adenocarcinomas (ClinicalTrials.gov Identifier: NCT01580696); the GALE-301 plus GALE-302 Phase 1b clinical trial is ongoing in breast and ovarian cancers (ClinicalTrials.gov Identifier: NCT02019524).

About Ovarian Cancer
New cases of ovarian cancer occur at an annual rate of 12.1 per 100,000 women in the U.S., with an estimated 21,290 cases for 2015. Although ovarian cancer represents about 1.3% of all cancers, it represents about 2.4% of all cancer deaths, or an estimated 14,180 deaths in 2015. Approximately 1.3% of women will be diagnosed with ovarian cancer at some point during their lifetime (2010 – 2012 data). The prevalence of ovarian cancer in the U.S. is about 192,000 women, and the five-year survivorship for women with ovarian cancer is 45.6%.

Due to the lack of specific symptoms, the majority of ovarian cancer patients are diagnosed at later stages of the disease, with an estimated 75% of women presenting with advanced-stage (III or IV) disease. These patients have their tumors routinely surgically debulked to minimal residual disease, and then are treated with platinum- and/or taxane-based chemotherapy. While many patients respond to this treatment regimen and become clinically free-of-disease, the majority of these patients will relapse. Depending upon their level of residual disease, the risk for recurrence after completion of primary therapy ranges from 60% to 85%. Unfortunately for these women, once the disease recurs, treatment options are limited and the disease remains incurable.