On April 16, 2018 Synlogic, Inc. (Nasdaq: SYBX), a clinical-stage drug discovery and development company applying synthetic biology to probiotics to develop novel living medicines, reported that preclinical data from its immuno-oncology (IO) program were featured in two presentations at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Synlogic, APR 16, 2018, View Source [SID1234525360]). The data demonstrate that, in mouse models, Synlogic’s Synthetic Biotic medicines were shown to stimulate an antitumor response and robustly reprogram the tumor microenvironment potentially enabling the treatment of a variety of cancers.

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"Our IO program highlights the potential of our Synthetic Biotic platform for the design and engineering of novel living medicines with multiple mechanisms of action to treat a broad range of diseases, including cancer," said J.C. Gutiérrez-Ramos, Ph.D., Synlogic’s president and chief executive officer. "Our approach enables us, in a single treatment, to locally deliver multiple, regulatable activities that stimulate an immune response and modulate the tumor environment in order to mobilize the immune system against the tumor and its metastases. We intend to advance our first IO program into IND enabling studies this year."

Synlogic is focused initially on developing Synthetic Biotic medicines to treat so-called "cold tumors," which lack infiltrating anti-tumor T-cells by first stimulating an innate anti-tumor response to make the tumor "hot" and then modifying the tumor microenvironment (TME) to enable T cell expansion and the development of memory, using a single agent to both prime T-cells to mount an immune response and sustain the response. Recent studies have demonstrated that activation of the stimulator of interferon genes (STING) pathway can play a critical role in the initiation of an anti-tumor immune response via activation of antigen presenting cells (APCs) and presentation of tumor antigens. The TME has long been understood to have a role in preventing or interrupting this process. Certain metabolites produced within the tumor such as kynurenine or adenosine can lead to T cell dysfunction and exhaustion, significantly blunting anti-tumor immune responses. Data presented at AACR (Free AACR Whitepaper) demonstrate the potential of Synlogic’s Synthetic Biotic medicines to manipulate both pathways to enable efficient anti-tumor activity in mouse models.

In a presentation in the late-breaking research immunology session, Activation of Innate and Adaptive Immunity via Combinatorial Immunotherapy using Synthetic Biotic Medicines,Synlogic described two new genetic circuits engineered into E. coli Nissle, an immune "initiator" STING activating circuit (SYN-STING) and an immune "sustainer" kynurenine consuming circuit (SYN-Kyn). SYN-STING can be delivered directly into the tumor enabling its localized site of action. The approach of using intra-tumoral injection elicits innate responses in the tumor but not in the circulation, potentially decreasing the risk of adverse events that may arise from the production of systemic type I interferon. In contrast to other therapeutic approaches in development, SYN-Kyn lowers levels of the kynurenine metabolite by degrading it, a mechanism that is independent of the enzyme(s) used by both immune and tumor cells to produce kynurenine (IDO1/2 and/or TDO).

In preclinical studies, Synlogic has demonstrated that:
In vitro, SYN-STING produces biologically-relevant levels of ci-di-AMP, activating APCs, while SYN-Kyn consumes kynurenine at concentrations comparable to those found in patients’ tumors;
SYN-STING treatment of either B16.F10 or A20 tumors results in robust tumor rejection or control, which correlates with an early rise in innate-immune cytokines and later results in T cell activation in tumors and tumor-draining lymph nodes;
Combining SYN-Kyn with a checkpoint inhibitor led to profound anti-tumor activity in the CT26 immunocompetent tumor model; and
A strain engineered to combine both genetic circuits (SYN-STING:Kyn) demonstrates equivalent production of ci-di-AMP and consumption of kynurenine in vitro compared to the individual strains SYN-STING and SYN-Kyn, respectively.
A second presentation entitled Metabolic Modulation of the Tumor Microenvironment using Synthetic Biotic Medicines demonstrated that engineered bacterial strains designed to consume either kynurenine (SYN-Kyn) or adenosine (SYN-Ade) effectively relieved TME immunosuppression and promoted anti-tumor activity.
In summary:
Invitro SYN-Kyn and SYN-Ade can deplete kynurenine and adenosine, respectively, at concentrations that are clinically relevant;
SYN-Kyn demonstrated rapid and near-complete reductions in tumor kynurenine levels in vivo;
A combination of either SYN-Kyn or SYN-Ade with checkpoint inhibition led to superior anti-tumor activity in the MC38 immunocompetent tumor model compared with checkpoint inhibitors alone.
About Synthetic Biotic Medicines
Synlogic’s innovative new class of Synthetic Biotic medicines leverages the tools and principles of synthetic biology to genetically engineer probiotic microbes to perform or deliver critical functions missing or damaged due to disease. The company’s two lead programs, SYNB1020 and SYNB1618, target hyperammonemia as a result of liver damage or genetic disease, and phenylketonuria, respectively. Patients with these diseases are unable to break down commonly occurring by-products of digestion that then accumulate to toxic levels and cause serious health consequences. When delivered orally, these medicines can act from the gut to compensate for the dysfunctional metabolic pathway and have a systemic effect, with the potential to significantly improve symptoms of disease for affected patient. Synlogic has earlier-stage programs that apply the broad potential of its Synthetic Biotic platform in other disease areas, from inflammatory and immune disorders to cancer.

In the first, Alexander M.M. Eggermont, Director General of the Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, and investigators from 23 countries across the world, found that giving a one-year course of 18 doses of the immunotherapy drug pembrolizumab (Keytruda) significantly reduced the risk of the cancer returning for patients with stage III melanoma who were at high risk of recurrence after surgery (Press release, EORTC, APR 16, 2018, View Source [SID1234525394]). Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes. Giving a dose of 200 milligrams of pembrolizumab every three weeks after surgery for up to a year significantly reduced the risk of recurrence for these patients the investigators found.

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Pembrolizumab works by blocking a protective mechanism of cancer cells, thus allowing the immune system to destroy them. Of the 1,019 patients recruited to the double-blind trial, 514 were randomised to pembrolizumab, and the others to placebo. For all those randomised to pembrolizumab, the 12-month recurrence-free survival rate was 75.4 percent, compared with 61.0 percent for all those randomised to placebo. The estimated hazard ratio was 0.57, indicating that risk of recurrence or death was reduced by 43 percent in patients randomised to pembrolizumab as compared to those randomised to placebo.

After a median follow-up of 1.25 years, 135 of the 514 patients randomised to pembrolizumab and 216 of the 505 patients randomised to placebo had been diagnosed with recurrent disease or had died. Patients randomised to placebo who had recurrence were offered access to pembrolizumab. "This cross-over design is unique in the world of adjuvant trials in melanoma and will permit us to analyse if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse," says Eggermont. "We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients."
The trial results are published in the New England Journal of Medicine.
Abstract no CT001 : Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial

In the second trial, investigators from eight European countries, headed by Patrick Schöffski from KU Leuven, Belgium, found that treatment with a targeted cancer drug achieved complete or partial tumour shrinkage in 50% of patients with inflammatory myofibrobastic tumour (IMFT), a very rare type of soft tissue sarcoma. Soft tissue sarcomas in themselves are very rare, accounting for just 1% of all solid tumour diagnoses, and IMFT so uncommon that there are no reliable statistics for its incidence or for mortality rates.
Many IFMTs have rearrangements of the ALK gene. Recently discovered as a target for cancer therapies, the ALK gene can be oncogenic in three ways – by forming a fusion gene with any of several other genes, by gaining additional copies or through mutations of the actual DNA code for the gene itself.
Schöffski and colleagues therefore set out to see whether the ALK inhibitor crizotinib might be a potential treatment for patients with IMFT. "Inflammatory myofibroblastic tumours are usually resistant to conventional chemotherapy and radiotherapy, so patients with unresectable or locally recurring disease have few treatment options," he says.
Because IMFT is so rare, only 35 patients with a local diagnosis of inflammatory myofibroblastic tumour could be recruited to the trial. Twenty of these patients were confirmed centrally to have the disease and received crizotinib.
Nineteen patients were evaluable for response. The objective response rate among the 12 evaluable patients with ALK-positive IFMTs who received crizotinib was 50 percent (95% confidence interval : 21.1-78.9%); two had a confirmed complete response and four had a confirmed partial response. Among the seven evaluable patients with ALK-negative IFMTs, the rate was 14.3 percent (95% confidence interval: 0.0-57.9%). In the group of patients with ALK-positive IFMT, crizotinib activity met the pre-specified response rate criteria set by the protocol.
« Limitations of the trial include that it is a noncomparative, single-arm study with a relatively small number of patients. Given the disease prevalence, a more definitive, randomised, comparative trial would not be possible, » says Schöffski.
« However, our study highlights how identifying the genetic drivers of a rare type of cancer can be used to find a new precision medicine for patients who otherwise have few treatment options," he adds. "The inclusion in our trial of a group of patients with ALK-negative inflammatory myofibroblastic tumors provides valuable insight into the selectivity of crizotinib and our understanding of this rare disease, even if we cannot formally compare the outcomes for the ALK-positive and -negative groups."
The trial results are published in The Lancet Respiratory Medicine.
Abstract no CT045 :Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE"

On April 16, 2018 Biological Dynamics, a molecular diagnostics company dedicated to improving global health outcomes by empowering global communities with low-cost, accessible cancer diagnostics, reported that new data on the company’s novel technology (ACE) will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting, at McCormick Place Convention Center on April 13 – 18 in Chicago (Press release, Biological Dynamics, APR 16, 2018, View Source [SID1234525413]).

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Abstracts from two studies examining the application of the company’s technology as an isolation platform for a novel class of biomarkers, such as extracellular vesicles (EVs), and as a cell-free DNA (cfDNA)-based diagnostic assay, will be presented:

Novel AC Electrokinetic Platform for Rapid Isolation and Characterization of Extracellular Vesicles from NSCLC Patients
Presented by Raj Krishnan, Ph.D., CEO of Biological Dynamics, on April 16 at 1:00 p.m. CT in Section 44. (Late-breaking abstract # LB-174)
Diagnostic Application of Novel ACE Technology: Treatment Response Monitoring via Quantification of Cell-Free DNA (cfDNA) in Plasma from Late-Stage Cancer Patients
Presented by Robert Kovelman, Ph.D., Biological Dynamics’ Sr. Director of Assay Development and Clinical Affairs, on April 17 at 8:00 a.m. CT in Section 27. (Abstract # 3666)
Biological Dynamics announced on Friday, April 13, the addition of two new members to its Board of Directors. Irwin Jacobs, founding Chairman and CEO Emeritus of Qualcomm and Chairman Emeritus of the Salk Institute for Biological Studies, and Martin J. Wygod, founder of Medco Containment Services Inc. and former Chairman of WebMD Health Corp., have joined Biological Dynamics’ Board of Directors. (Read more here.)

On April 16, 2018 Innovation Pharmaceuticals (OTCQB:IPIX) ("the Company"), a clinical stage biopharmaceutical company, is pleased to report additional information from the Company’s successfully completed Phase 2 clinical trial of Brilacidin-OM (see NCT02324335) for the indication of decreasing the incidence of Severe Oral Mucositis (SOM) (WHO Grade ≥3) in Head and Neck Cancer (HNC) patients receiving chemoradiation (Press release, CellCeutix, APR 16, 2018, View Source [SID1234525812]).

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These additional data align with previously released Brilacidin-OM results showing a risk reduction in the incidence of SOM, including up to an 80.3% risk reduction in the incidence of SOM among patients receiving more aggressive chemotherapy. Other previously released results indicate Brilacidin-OM also delayed onset of SOM. The Company is developing Brilacidin-OM under FDA Fast Track designation as a convenient, and clearly differentiated, therapy aimed to decrease incidence of SOM.
Initial Instance Duration of SOM was defined as the number of days from initial WHO Grade ≥3 during radiation therapy to the first WHO Grade 2 or lower OM Grade. Overall Duration of SOM was defined as the number of days from initial WHO Grade ≥3 during radiation therapy to the day prior to the next OM assessment after the last WHO Grade ≥3 during/after radiation therapy. Note: 50th percentiles are from Kaplan-Meier analysis. Patients who did not experience SOM have duration set to 0.

Previously, the Company reported statistically significant results showing Brilacidin-OM reduced the incidence of SOM in HNC patients receiving cisplatin administered in a high-dose regimen (80-100 mg/m2), approximately every 21 days. For the Modified Intent-to-Treat (mITT) population, Brilacidin-OM in the high-dose chemotherapy regimen reduced the incidence of SOM by 65.0% ([incidence control- incidence active]/incidence control) as compared with placebo (Brilacidin: 25.0%; placebo: 71.4%; p=0.0480). For the Per Protocol (PP) population, Brilacidin-OM in the high-dose chemotherapy regimen similarly reduced the incidence of SOM by 80.3% as compared with placebo (Brilacidin: 14.3%; placebo: 72.7%; p=0.0249).

Exploratory Endpoint: Unplanned Office Visits, Emergency Department Visits, and/or Hospital Admissions Due to OM

Positive OM assessment endpoints are additionally supported by zero (0) of the patients in the Brilacidin-OM group having unplanned office visits, ED visits, or hospital admissions due to OM, compared to four (4) patients in the placebo group.

Other Study Observations

Regardless of the oral sites irradiated (at least two sites from: buccal mucosa, floor of mouth, ventral/lateral tongue, and soft palate), the incidence by patient of Severe OM on Brilacidin-OM relative to placebo was consistently reduced.

Across cumulative radiation dose intervals, patients in the Brilacidin-OM group consistently reported less often feeling the sensation "swollen" (approximately half of that reported for the placebo group). "Burning" sensation also was reported consistently less frequently in the Brilacidin treatment group.

Patients in the Brilacidin-OM group appeared to trend more favorably over the course of chemoradiation treatment according to Eastern Cooperative Oncology Group (ECOG) Performance Status—a common set of criteria used in oncology trials to assess debility.

Management Comments

"Drug makers, the world-over, have spent decades and enormous sums in both money and resources trying to develop an effective OM drug in a bid to address dire patient needs as well as capture a tremendous market opportunity," commented Leo Ehrlich, Chief Executive Officer at Innovation Pharmaceuticals. "Yet, there is currently no drug approved to treat, let alone prevent, severe OM in patients with Head and Neck Cancer. Most Pharmas currently conducting OM trials target shortening the duration of severe OM as their primary endpoint, not reduction of incidence, like we did. The Brilacidin-OM Phase 2 trial met its primary objective and its key secondary objectives. As we continue to analyze subset data, we are extremely enthusiastic about observed trends. Hundreds of thousands of patients would benefit from a preventative OM treatment and we’re excited that Brilacidin-OM may one day provide these patients a much-needed breakthrough treatment option."

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On April 16, 2018 Oregon Health & Science University (OHSU) Knight Cancer Institute and Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data demonstrating that CG’806, a highly potent pan-FLT3/pan-BTK inhibitor, kills malignant cells in samples from patients with various hematologic malignancies and demonstrates superiority to other kinase inhibitors (Press release, Aptose Biosciences, APR 16, 2018, View Source c=116148&p=RssLanding&cat=news&id=2342649 [SID1234525328]). The data were presented in a poster on Sunday, April 15, at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference being held April 14-18, in Chicago, IL.

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The poster, entitled CG’806, a first-in-class pan-FLT3/pan-BTK inhibitor, demonstrates superiority to other FLT3 and BTK inhibitors against primary patient samples, demonstrated the broad activity of CG’806 against primary bone marrow specimens from patients with various hematologic malignancies. CG’806 is a small molecule that potently inhibits wild type (WT) FLT3, as well as FLT3 housing the ITD mutation or with point mutations in the tyrosine kinase domain (TKD, including D835G, D835Y, D835H) or in the gatekeeper region (F691L); it also inhibits BTK WT and BTK-C481S. As part of the Beat AML Initiative, researchers at OHSU tested CG’806 against freshly isolated primary samples from patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and other hematologic malignancies to determine its potency and range of action. Against AML patient samples, CG’806 was evaluated relative to other FLT3 inhibitors. In parallel, CG’806 and ibrutinib, a covalent BTK inhibitor approved for CLL and certain other B-cell malignancies, were compared directly for sensitivities on primary CLL samples and various B-cell and other hematologic malignancies. CG’806 was shown to have greater potency against a broader subset of AML samples relative to other FLT3 inhibitors, including midostaurin, gilteritinib, quizartinib, sorafenib, crenolanib, and dovitinib. This was especially true in FLT3-ITD and FLT3-TKD positive cases, although enhanced activity was also observed in FLT3 WT samples. CG’806 was also shown to have greater potency and range of activity on primary CLL samples than ibrutinib.

"The clinical benefit of current FLT3 inhibitors in AML is transient, as resistance develops after several months of treatment," said Stephen E. Kurtz, Ph.D., lead author and Research Assistant Professor at the OHSU Knight Cancer Institute. "Similarly, ibrutinib, a covalent BTK inhibitor approved for CLL and certain other B-cell malignancies, is limited by acquired resistance, as well as refractory disease and tolerance challenges. As a pan-FLT3/pan-BTK inhibitor – especially in the absence of observed toxicity in murine AML models – CG’806 offers important potential to address these limitations."

"CG’806 appears superior to other FLT3 and BTK inhibitors, and the wealth of data supporting its development in AML and B-cell malignancies continues to grow," said William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "These studies are critical for understanding how to develop and position CG’806 as we prepare for clinical development in these challenging hematologic malignancies."
Separately, Aptose researchers also announced new data on CG’806 presented at AACR (Free AACR Whitepaper) (see press release here). Both poster presentations will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The posters can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.
For more information on Beat AML refer to View Source

About CG’806

CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK multi-kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates acute myeloid leukemia (AML) tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG’806 may be developed for various B cell malignancy patients (including CLL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. CG’806 is currently in preclinical development in partnership with CrystalGenomics