On April 3, 2019 IMV Inc. (Nasdaq: IMV; TSX: IMV), a clinical stage immuno-oncology corporation, reported that preclinical research presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 demonstrated how the mechanism of action (MOA) of IMV’s proprietary DPX technology can enhance a broad spectrum of immune cell infiltration into tumors, which included T cells, Natural Killer (NK) cells, and macrophages (Press release, IMV, APR 3, 2019, View Source [SID1234534955]). Analyses also revealed the differentiated characteristics of the immune cell responses and the potential implications for enhanced anti-tumor efficacy.

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"The new preclinical data shared at this year’s AACR (Free AACR Whitepaper) Annual Meeting provides greater insight into the unique mechanism of our immunotherapy programs," said Marianne Stanford, Vice President, Research at IMV. "These data demonstrate our commitment to fully understanding how our platform impacts our product candidates, which in turn informs our clinical program designs and ability to identify patient needs that are more likely to benefit from our approach."

In the poster titled, T-distributed stochastic neighbor embedding (t-SNE) analysis of tumor infiltrating lymphocytes after treatment with a T cell activating therapy identifies a unique population of recruited CD8+ T cells and novel options for combination immunotherapy, IMV researchers used specialized data analytics to examine how DPX-based agents, when combined with cyclophosphamide (CPA), induced T cells to infiltrate tumors and attack cancerous cells. The study closely examined the types of immune cell responses and how and why they were able to affect disease.

The data indicated that this approach stimulated the infiltration of a broad base of immune cells into tumors, including T cells, NK cells, and macrophages. The specific T cell population that moved into tumors could be grouped based on the co-expression of different checkpoint molecules such as PD-1 and Tim-3. However, those stimulated to infiltrate tumors generally did not express CTLA-4 (a protein found on T cells that inhibits the immune response).

Researchers also found that combining DPX/CPA treatments with a CTLA-4-blocking antibody increased efficacy in controlling tumor growth in the animal models. The data suggested that this result was due to the antibodies acting on T cells present in the tumors, rather than those induced by treatment. This finding contrasts previously published studies with anti-PD-1 combinations in which treatment directly enhanced DPX-induced T cell responses.

"We believe there is a need for more targeted immunotherapy approaches and this work is another important step for us toward achieving this goal," said Frederic Ors, Chief Executive Officer, at IMV. "This is a new frontier in immuno-oncology drug development, and I’m proud of the work our team has done and the potential it represents to, ultimately, improve treatments for patients."

IMV’s current clinical program includes multiple phase 2 studies assessing the safety and efficacy of its lead candidate, DPX-Survivac, in combination with mCPA and Merck’s checkpoint inhibitor, Keytruda.

On April 3, 2019 Moderna, Inc., (Nasdaq: MRNA) a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, reported that Tal Zaks, M.D., Ph.D., Moderna’s Chief Medical Officer, will participate in a fireside chat at the 18th Annual Needham Healthcare Conference on Wednesday, April 10, 2019 at 11:20 a.m. ET (Press release, Moderna Therapeutics, APR 3, 2019, View Source [SID1234534973]).

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A live webcast of the presentation will be available under "Events and Presentations" in the Investors section of the Moderna website at View Source A replay of the webcast will be archived on Moderna’s website for 30 days following the presentation.

On April 3, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the European Medicines Agency (EMA) validated the Marketing Authorization Application (MAA) for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery (Press release, Daiichi Sankyo, APR 3, 2019, View Source [SID1234535008]). TGCT is also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS).

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Validation confirms that the application is complete and commences the scientific review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The EU MAA is based on results of the pivotal phase 3 ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT, which met its primary endpoint of overall response rate. Results of the phase 3 ENLIVEN study were presented during an oral presentation at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

"We are pleased that review of our submission for pexidartinib in Europe is now underway, and we look forward to working with the EMA to potentially offer the first approved systemic therapy to carefully-selected patients with TGCT," said Dale Shuster, Ph.D., Executive Director, Global Oncology R&D, Daiichi Sankyo.

"We are excited about the first-in-class potential of pexidartinib, another targeted therapy discovered by Plexxikon," said Gideon Bollag, Ph.D., Chief Executive Officer of Plexxikon Inc., Daiichi Sankyo’s small molecule structure-guided R&D center in Berkeley, CA and a member of the Daiichi Sankyo Group. "Our drug discovery process uses structural data and a specialized scaffold-like screening library to identify and optimize novel drug candidates."

The New Drug Application (NDA) for pexidartinib is currently under Priority Review in the U.S., and the FDA is expected to make a decision on approval by August 3, 2019.

ENLIVEN is a pivotal, double-blind, randomized, global multi-center phase 3 study that evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/day for 2 weeks followed by 800 mg/day for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

The ENLIVEN study met its primary endpoint of overall response rate. In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

About TGCT (PVNS/GCT-TS)

Tenosynovial giant cell tumor (TGCT), also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a rare, non-malignant tumor that can be locally aggressive. TGCT affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.[1], [2], [3]

While the exact incidence of TGCT is not known, it is estimated that the incidence of TGCT is 11 to 50 cases per million person-years, based on studies from three countries.[4],[5],[6] TGCT is subcategorized into two types: localized, which is more common and accounts for 90 percent of cases, and diffuse, which accounts for 10 percent of cases.5,6 Primary treatment of TGCT includes surgery to remove the tumor. However, in patients with a recurrent, difficult to treat, or diffuse form where the tumor can wrap around bone, tendons, ligaments and other parts of the joint, it is more difficult to remove or might not be amenable to improvement with surgery. Additional surgeries for more severe cases can lead to significant joint damage, debilitating functional impairments, and reduced quality of life and amputation may be considered.[7],[8],[9]

Recurrence rates for localized TGCT are estimated to be up to 15 percent following complete resection.2,[10],[11],[12] Diffuse TGCT recurrence rates are estimated to be about 20 percent to 50 percent following complete resection.3,10,[13] TGCT affects all age groups; the diffuse type on average occurs most often in people below the age of 40 and the localized type typically occurs in people between 30 and 50 years old.1,4,5,6

About Pexidartinib

Pexidartinib is an investigational, novel, oral small molecule that potently inhibits CSF1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT. Pexidartinib also inhibits c-kit and FLT3-ITD. Pexidartinib was discovered by Plexxikon Inc., the small molecule structure-guided R&D center of Daiichi Sankyo.

Pexidartinib has been granted Priority Review for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery, Breakthrough Therapy designation for the treatment of patients with pigmented villonodular synovitis (PVNS) or giant cell tumor of tendon sheath (GCT-TS), where surgical resection may result in potentially worsening functional limitation or severe morbidity, and Orphan Drug designation for the treatment of PVNS/GCT-TS by the U.S. Food and Drug Administration (FDA). Pexidartinib also has received Orphan Drug designation from the European Commission for the treatment of TGCT.

On January 31, 2019, the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) recognized "Progress in Treating Rare Cancers" as the "Advance of the Year," and selected pexidartinib as one of five significant advancements in rare disease treatment, calling it the first promising investigational therapy for TGCT.

Pexidartinib is an investigational compound that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: [fam-] trastuzumab deruxtecan, an antibody drug conjugate (ADC) for HER2 expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory FLT3-ITD acute myeloid leukemia (AML); and pexidartinib, an oral CSF1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

On April 2, 2019 Molecular Templates, Inc., (Nasdaq: MTEM) a clinical stage biopharmaceutical company focused on the discovery and development of Engineered Toxin Bodies (ETBs), a new class of targeted biologic therapies that possess unique mechanisms of action in oncology, reported highlights from the four poster presentations on its pipeline programs that were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019, taking place March 29 – Apr 3, 2019 at the Georgia World Congress Center in Atlanta, Georgia (Press release, Molecular Templates, APR 2, 2019, View Source [SID1234534887]). Copies of the posters presented at AACR (Free AACR Whitepaper) can be found in the Presentations section of Molecular Templates’ website at View Source

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"We believe that ETBs represent an important advance in immunotoxins as a therapeutic class of drugs. MT-3724 has demonstrated forced internalization of CD20 and has driven responses in heavily pretreated DLBCL patients. While MT-3724 development continues in Phase II, our presentations at AACR (Free AACR Whitepaper) highlight next generation pipeline programs that show key improvements in the ETB platform," said Eric Poma, Ph.D., CEO and CSO of Molecular Templates. "These advances include enhanced potency, improved tolerability, potential to dose weekly or bi-weekly, and the ability to alter the immunophenotype of tumors through antigen seeding to redirect a T-cell response to the tumor."

Poster Title: TAK-169, an Exceptionally Potent CD38 Targeted Engineered Toxin Body, as a Novel Direct Cell Kill Approach for the Treatment of Multiple Myeloma
Poster highlights:

TAK-169 is able to efficiently internalize and directly kill CD38-expressing cells with potency seen at picomolar or sub-picomolar concentrations.
Preclinical data suggest that TAK-169 may provide benefit to patients who have progressed after or are unlikely to respond to CD38-targeted antibody therapy.
TAK-169 has demonstrated potent cytotoxicity across a range of myeloma cell lines with a range of CD38 expression in vitro as well as in patient-derived samples including those with previous exposure to daratumumab.
TAK-169 retains activity in the presence of daratumumab.
In xenograft models, complete regressions were observed using both once-weekly and bi-weekly schedules of TAK-169.
TAK-169 was tolerated in cynomolgus monkeys (highest non-severely toxic dose [HNSTD] of 750 mcg/kg weekly) at doses where evidence of pharmacodynamic effect (NK cell depletion) was observed. In comparison, the HNSTD of MT-3724 was 150 mcg/kg with visible signs of capillary leak syndrome (CLS); dosing MT-3724 at 450 mcg/kg showed severe CLS in cynomolgus monkeys.
Poster Title: The Safety and efficacy Profile of a PD-L1-Directed, Engineered Toxin Body, as a Novel Targeted Direct-Cell Kill Approach for the Treatment of PD-L1-Expressing Cancers
Poster highlights:

Molecular Templates has developed PD-L1-targeting ETBs as an approach to directly target tumor cells and overcome resistance mechanisms against PD-1 and PD-L1 antibodies.
MT-6020, a human and cynomolgus cross-reactive, PD-L1-targeted, ETB binds to cell lines expressing non-human primate PD-L1 and elicits cytotoxic responses comparable to those observed on human tumor target cells.
MT-6035 is built upon the MT-6020 scaffold and can also deliver a viral peptide for cell surface presentation and targeting by a specific antiviral CTL population for a second and complementary mechanism for tumor cell destruction, referred to as antigen seeding.
MT-6020 and MT-6035 represent a novel approach to targeting and destroying tumors expressing PD-L1 that is unlikely to be inhibited by resistance mechanisms to current checkpoint inhibitors, is well tolerated in relevant toxicity models, and has the capacity for activity in indications where standard of care has failed.
Poster Title: Combination of CD20-targeted Engineered Toxin Body, MT-3724, with Chemotherapy or IMiDs for the Treatment of Non-Hodgkin’s Lymphoma
Poster highlights:

MT-3724, a CD20-targeted ETB, has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory (R/R) non-Hodgkin’s lymphoma (NHL) patients in a Phase I clinical study.
The combination of MT-3724 with chemotherapeutic agents (doxorubicin, gemcitabine, bendamustine, and vincristine) or an immunomodulatory (IMiD) agent (lenalidomide) all demonstrated additive or synergistic cytotoxicity of NHL cell lines.
Clinical studies to evaluate MT-3724 as single agent and in combination with gemcitabine and oxaliplatin (GEMOX) or lenalidomide are underway and expected to generate data in 2019.
Poster Title: Design and Characterization of Bispecific Engineered Toxin Bodies for Targeted Cancer Therapy
Poster highlights:

Bispecific ETBs that target two epitopes on the same receptor, or two distinct cell surface molecules both expressed on cancer cells, may allow for enhanced activity profiles. These possibilities include:
activity in the presence of a competitive binding protein
sustained activity when one target molecule is shed or downregulated
synergistic binding events to increase overall potency
increased specificity towards cancer over normal tissue.
Bispecific ETBs have been generated to engage a variety of target combinations, relevant to both solid and hematologic cancer treatment.
MTEM is exploring therapeutically relevant target combinations to facilitate the development of a bispecific clinical lead.

On April 2, 2019 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported that the first patient treated with FT500 successfully completed an initial safety assessment (Press release, Fate Therapeutics, APR 2, 2019, View Source [SID1234534903]). The patient received three once weekly doses of FT500, and the treatment cycle was well-tolerated with no dose-limiting toxicities or serious adverse events reported during the initial 28-day observation period. The universal, off-the-shelf natural killer (NK) cell product candidate is the first-ever cell therapy derived from an induced pluripotent stem cell (iPSC) administered to a patient in the U.S.

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"The ability to effectively and efficiently deliver multiple doses of a cellular immunotherapy ‘on demand’ brings us closer to our goal of transforming the treatment of cancer for more patients. This initial observation of tolerability from the first-ever cancer patient to receive multiple doses of a universal, off-the-shelf cell product derived from a clonal master iPSC line provides early clinical validation of our proprietary iPSC product platform for off-the-shelf cancer immunotherapy," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "In addition to our clinical progress with FT500, our engineered iPSC-derived NK cell product candidates continue to exhibit a highly-differentiated therapeutic profile in preclinical models and we look forward to generating initial clinical data with FT516 and FT596 in 2019."

Two additional patients have also been treated with FT500 as a monotherapy in the first dose cohort of 1×108 cells per dose and are currently within the initial 28-day observation period. The FT500 clinical trial is a two-arm study in up to 64 patients for the treatment of advanced solid tumors. The study is designed to assess the safety and activity of three once weekly doses of FT500 as a monotherapy and in combination with one of three FDA-approved checkpoint inhibitor therapies – nivolumab, pembrolizumab or atezolizumab – in patients that have failed or have confirmed disease progression on checkpoint inhibitor therapy. Patients that are clinically stable following the initial 28-day observation period are eligible to receive a second treatment cycle.

FT516 Novel CD16 Receptor Promotes High-Affinity Engagement with Monoclonal Antibody Therapy
Today the Company presented preclinical data for FT516, its universal, off-the-shelf NK cell product candidate derived from a clonal master iPSC line engineered to express a novel CD16 Fc (hnCD16) receptor, at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Atlanta, Georgia. FT516 is the first-ever cell therapy derived from a genetically engineered pluripotent stem cell cleared for clinical testing in the world, and the Company is preparing to initiate clinical investigation of FT516 in the U.S. in patients with certain relapsed/refractory hematologic malignancies, including acute myelogenous leukemia as a monotherapy, non-Hodgkin’s lymphoma in combination with rituximab, and multiple myeloma in combination with elotuzumab.

While CD16 is naturally expressed on NK cells and mediates antibody-dependent cellular cytotoxicity, numerous clinical studies with FDA-approved tumor-targeting antibodies have demonstrated that patients with CD16 high-affinity variant 158V have improved clinical outcomes. However, only about 15% of humans are homozygous for 158V. Additionally, the expression of CD16 on NK cells in cancer patients can undergo considerable down-regulation, which significantly inhibits the cell’s anti-tumor activity. The novel CD16 Fc receptor expressed by FT516 has been designed to overcome these inherent deficiencies: it is comprised of the high-affinity 158V variant and is resistant to down-regulation.

In preclinical studies using a B-cell lymphoma line, the Company showed that approximately 70% of peripheral blood NK cells down-regulated CD16 expression upon co-culture with rituximab, while CD16 expression on FT516 remained resistant to down-regulation. These differences resulted in a significant anti-tumor benefit in vivo where, in a human lymphoma cancer model, mice treated with peripheral blood NK cells and rituximab had a median survival time of 39 days as compared to mice treated with FT516 and rituximab, where the median survival time was not yet reached at 100 days.

FT596 CAR and CD16 Modalities Exert Synergistic Anti-Tumor Activity
The Company also presented today at AACR (Free AACR Whitepaper) new preclinical data for FT596, the Company’s first iPSC-derived chimeric antigen receptor (CAR) NK cell product candidate that is designed to concurrently target multiple tumor-associated antigens. FT596 is derived from a clonal master iPSC line engineered to express a proprietary CAR targeting CD19, a hnCD16 Fc receptor, and a novel IL-15 receptor fusion.

In a mixed co-culture assay, the Company showed that the concurrent activation of the CAR and hnCD16 targeting modalities of FT596 exert synergistic anti-tumor activity. Increased degranulation (CD107a) and cytokine release (interferon-gamma and TNF-alfa) were observed upon concurrent activation of both the CAR and CD16 receptors in CD19+CD20+ Raji cancer cells with rituximab as compared to activation of each receptor alone, suggestive that dual antigen engagement may elicit a deeper and more durable response. Additionally, in a cellular cytotoxicity assay designed to model CD19 antigen escape, FT596 combined with rituximab was able to effectively eliminate leukemia and lymphoma cancer cells that were positive for CD19 antigen expression as well as those that were null for CD19 antigen expression.

About FT500
FT500 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line. FT500 is being investigated in an open-label, repeat-dose Phase 1 clinical trial for the treatment of advanced solid tumors in up to 64 patients, both as a monotherapy and in combination with FDA-approved checkpoint inhibitor therapy. Despite the favorable response rates observed with checkpoint inhibitor therapy, the majority of patients do not respond and many responders relapse. One common mechanism of resistance to checkpoint inhibitor therapy is associated with loss-of-function mutations in genes critical for antigen presentation. A potential strategy to overcome resistance is through the administration of allogeneic NK cells, which have the inherent capability to recognize and directly kill tumor cells with these mutations.