On December 6, 2018 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported an expansion of its existing cell therapy collaboration with Novartis, to include the ex vivo development of innovative cell therapies using certain ocular stem cells (Press release, Intellia Therapeutics, DEC 6, 2018, View Source [SID1234531945]). As part of the updated collaboration terms, Novartis will have the right to develop CRISPR/Cas9-based products for one or more targets using these stem cells. Intellia will receive a one-time $10 million cash payment and, consistent with the original collaboration agreement, Intellia also is eligible to receive downstream success-based milestones and royalties.

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With the collaboration expansion announced today, Intellia will gain expanded rights to Novartis’ lipid nanoparticle (LNP) technology for all genome editing applications in both in vivo and ex vivo settings. This licensed LNP technology is the foundation of Intellia’s proprietary modular delivery system of CRISPR/Cas9 for its in vivo product pipeline. Intellia retains rights to all other in vivo and ex vivo applications of CRISPR/Cas9, including for eye disorders, subject to certain in vivo target selection options by Novartis set forth in the original agreement.

"Genome editing enhancements made by CRISPR/Cas9 will enable the next generation of cell therapies. With our collaborator, Novartis, we are broadening the ex vivo application of our CRISPR/Cas9 technology from hematopoietic stem cells, or HSCs, to ocular stem cells. We are pleased to expand our relationship with Novartis, and to continue to work together to develop cell therapies," said Intellia President and Chief Executive Officer John Leonard, M.D. "Broader rights to Novartis’ LNP technology will assist our efforts to apply this technology in ex vivo settings for the development of proprietary cell therapies, just as we have done to develop our proprietary modular delivery system for in vivo products in the liver and other organs."

On December 6, 2018 GT Biopharma, Inc. (OTCQB: GTBP and Euronext Paris GTBP.PA) ("GT Biopharma" or the "Company"), an immuno-oncology biotechnology company focused on innovative treatments based on the Company’s proprietary NK-engager and Bispecific Antibody Drug Conjugate platforms, reported that it presented data demonstrating the effectiveness of the Company’s Tri-specific Killer Engagers (TriKEs) for the treatment of acute myeloid leukemia (AML) presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, GT Biopharma , DEC 6, 2018, View Source [SID1234539518]).

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Jeffrey Miller, MD, Deputy Director, Masonic Cancer Center, University of Minnesota commented, "These studies demonstrate the adaptability of the TriKE platform to optimize TriKE constructs and candidate selection in order to address unmet medical needs. We continue to work with our partners at GT Biopharma in moving the TriKE platform forward."

The Company’s TriKE product candidates are single-chain, tri-specific scFv recombinant fusion proteins composed of the variable regions of the heavy and light chains (or heavy chain only) of anti-CD16 antibodies, wild-type or a modified form of IL-15 and the variable regions of the heavy and light chains of an antibody designed to precisely target a specific tumor antigen. GT Biopharma utilizes the NK stimulating cytokine human IL-15 as a crosslinker between the two scFvs which is designed to provide a self-sustaining signal leading to the proliferation and activation of NK cells thus enhancing their ability to kill cancer cells mediated by antibody-dependent cell-mediated cytotoxicity (ADCC). GT Biopharma has an exclusive worldwide license agreement with the University of Minnesota to further develop and commercialize cancer therapies using proprietary TriKE technology developed by researchers at the university to target NK cells to cancer.

"We continue to be encouraged by the data from our Trike program being conducted by leading NK cell experts at the University of Minnesota. These findings have supported us with the confidence to proceed with our first-in-class TriKE, Phase 1 study," commented Raymond Urbanski, M.D., Ph.D., Chief Executive Officer of GT Biopharma. "We are grateful to renowned NK cell expert, Jeffrey Miller, MD, Deputy Director, Masonic Cancer Center, University of Minnesota and his team, and look forward to providing further updates as we continue to advance what we believe to be a potentially revolutionary product candidate."

Graduate student, Upasana Sunil Arvindam, MSc, BSc, working with Drs. Miller and Felices at the University of Minnesota, presented the abstract titled, "CD16-IL15-CLEC12A Tri-specific Killer Engager (TriKE) Drives NK Cell Expansion, Activation, and Antigen Specific Killing of Cancer Stem Cells in Acute Myeloid Leukemia," as part of the Acute Myeloid Leukemia: Novel Therapy, Excluding Transplantation: Poster I session at ASH (Free ASH Whitepaper). To access the presented poster, click here.

For the preclinical study, Dr. Arvindam and her team developed a 1615CLEC12A TriKE molecule to target AML cells using Natural Killer (NK) cells. This molecule contains an anti-CD16 camelid nanobody to activate NK cells, an anti-CLEC12A single chain variable fragment (scFv) to engage cancer targets, and an IL-15 molecule that drives NK cell priming, expansion and survival.

The CLEC12A TriKE was developed in a mammalian cell system to ensure that appropriate post-translational modifications are present. The researchers confirmed that the TriKE binds specifically to HL-60 and THP-1 target cells that express CLEC12A compared to Raji cells that do not express CLEC12A. Treatment of peripheral blood mononuclear cells (PBMCs) with the CLEC12A TriKE drives a significant increase in NK cell specific proliferation over 7 days as measured by Cell Trace dilution compared to treatment with a CLEC12A scFv or IL-15 alone (69.7 ± 6.7% vs 11.9 ± 2.5% vs 38.4 ± 7.3%). In these assays, the efficacy of the CLEC12A TriKE was comparable to the CD33 TriKE. The data demonstrates that the CLEC12A TriKE drives NK cell specific proliferation, degranulation, cytokine secretion, and killing of tumor targets in vitro. Apart from AML, CLEC12A is expressed on cancer cells and LSCs in patients with myelodysplastic syndromes (MDS).

The presented preclinical findings highlight the clinical potential of the CLEC12A TriKE individually or in combination with the CD33 TriKE for the treatment of MDS and AML and ultimately led to the establishment of a first-in-human Phase 1 study with GTB-3550 (OXS-3550), its first-in-class (TriKE), for the treatment of AML, MDS and mastocytosis, which GT Biopharma recently announced. The study will be led by Principal Investigator, Sarah A. Cooley, MD, MS, Associate Professor, Division of Hematology, Oncology and Transplantation at Masonic Cancer Center, University of Minnesota.

The abstract titled, "Induced Pluripotent Stem Cell-Derived NK Cells Genetically Modified to Express NKG2C/DAP12 Mediate Potent Function When Targeted through an NKG2C/IL-15/CD33 Tri-Specific Killer Engager (TriKE)," was presented in an oral presentation by graduate student Emily Chiu, PhD, Medical School, University of Minnesota. To access the presentation slides, click here.

Having demonstrated stable expression and intact signaling of NKG2C/DAP12 in iNK cells, Dr. Chiu and her team next created a TriKE molecule with single chain Fv fragments specific for NKG2C (on iNK cells) and CD33 (on AML cells), as well as IL15 (to support iNK cell survival and proliferation). Without the addition of NKG2C/CD33/IL15 TriKE, the frequencies of both NKG2C iNK cells and NKG2C/DAP12 iNK cells producing IFNg was relatively low (< 10%). Addition of NKG2C/IL15/CD33 TriKE in the assay markedly increased the frequency of IFNg production by both NKG2C iNK cells (19.1%) and NKG2C/DAP12 iNK cells (25.8%). Finally, the team directly tested the ability of the NKG2C/IL15/CD33 TriKE molecule to trigger target killing by engineered iNK cells monitored over a 24hour period. THP1 target cells were dye labeled and plated in wells with either NKG2C iNK cells or NKG2C/DAP12 iNK cells at a 5:1 effector-to-target ratio with or without NKG2C/CD33/IL15 TriKE. The researchers found that in the absence of TriKE, there was no killing of THP1 targets. In contrast, both NKG2C iNK cells and NKG2C/DAP12 iNK cells mediated robust THP1 killing with the addition of NKG2C/CD33/IL15 TriKE, with NKG2C/DAP12 iNK cells exhibiting the strongest response.

Results from the study provided a proof-of-concept that iNK cells engineered to express NKG2C/DAP12 can be used in combination with a novel NKG2C/IL15/CD33 TriKE molecule to effectively target cancer cells. Engaging NK cells through NKG2C, restricted to adaptive NK cells or genetically modified iPSC will be more specific than CD16, which will bind to CD16A on NK cells but also have off-target binding to CD16B on neutrophils. Because of the enormous expansion and engineering capacity of the iNK cell platform, the Company believes it is in a unique position to create an "off-the-shelf" NK cellular therapy that is targeted, specific and efficacious.

About Acute Myelogenous Leukemia (AML)

AML is the most common form of adult leukemia with 21,000 new cases expected in 2018 alone, according to the American Cancer Society. AML patients typically receive frontline therapy, most commonly chemotherapy, which includes cytarabine and an anthracycline, a therapy that has not changed in over 40 years. However, there remains a significant unmet need in these therapies with about half of AML patients experiencing relapses or requiring alternative therapies. The Company is developing GTB-3550 to serve as a relatively safe, cost-effective, and easy-to-use therapy for resistant/relapsing AML and could also be combined with chemotherapy as frontline therapy thus targeting the larger patient population

On December 6, 2018 Novartis reported additional analysis from the global Phase III SOLAR-1 trial investigating the alpha-specific PI3K inhibitor BYL719 (alpelisib) in combination with fulvestrant in men and postmenopausal women with PIK3CA mutated hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer (Press release, Novartis, DEC 6, 2018, https://www.novartis.com/news/media-releases/novartis-investigational-byl719-alpelisib-plus-fulvestrant-consistently-improved-pfs-patients-pik3ca-mutated-hrher2-advanced-breast-cancer-new-solar-1-analyses [SID1234531929]).

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In SOLAR-1, the addition of BYL719 to fulvestrant nearly doubled median progression-free survival (PFS) in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who progressed on or after an aromatase inhibitor (AI) compared to fulvestrant alone. In this analysis, BYL719 plus fulvestrant also showed consistent clinically meaningful treatment benefit after progression on an AI or after receiving up to one additional line of therapy for advanced breast cancer[1]. These data will be presented today during an oral presentation at the 2018 San Antonio Breast Cancer Symposium (SABCS) (Abstract #GS3-08).

Approximately 40% of patients living with HR+ advanced breast cancer have a PIK3CA mutation, which over activates the PI3K pathway[2]. When activated, the PI3K pathway is associated with tumor growth, resistance to endocrine treatment and a poor overall prognosis[3],[4]. Currently there are no approved treatments for breast cancer that specifically target this mutation.

"PIK3CA mutation is the most common actionable alteration in ER+ breast cancer, so it is encouraging to see a meaningfully prolonged PFS with BYL719 combination therapy in patients with PIK3CA mutated breast cancer who progressed on an aromatase inhibitor and who received up to one additional line of therapy prior to treatment with BYL719 plus fulvestrant," said Dejan Juric, MD, Director, Termeer Center for Targeted Therapies, Massachusetts General Hospital Cancer Center. "With the SOLAR-1 trial results, we can confidently say that identifying and targeting PIK3CA mutations is clinically important as we apply the precision oncology paradigm to breast cancer and continuously look for new treatment solutions to extend the lives of patients with this disease."

BYL719 in combination with fulvestrant consistently improved median PFS in patients with PIK3CA mutated HR+/HER2- advanced breast cancer who progressed within 12 months of AI treatment (mPFS: 11.0 months vs 6.8 months for fulvestrant alone) or received up to one additional line of therapy for advanced breast cancer (mPFS: 10.9 months vs 3.7 months, respectively).

Most adverse events were mild to moderate in severity and generally manageable through dose interruption, dose reductions and medical management. Treatment discontinuation rate due to adverse events in those with a PIK3CA mutation receiving BYL719 plus fulvestrant was 3% compared to 2% for fulvestrant alone. The most frequent all-grade adverse events (>=40%) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%) and rash (40% vs 6%). The most common grade 3/4 events (>=10%) were hyperglycemia (37% vs <1%) and rash (13% vs <1%)[1].

Mutation status of participants in SOLAR-1 was identified by a clinical trial assay developed by Qiagen*. A significant PFS benefit was observed for BYL719 plus fulvestrant in patients with a PIK3CA mutation regardless of whether the mutation was identified by a tumor tissue test or ctDNA test, suggesting the potential viability of using liquid biopsies to identify PIK3CA mutation status (tissue positive HR=0.65; mPFS 11.0 months; plasma positive HR=0.56; mPFS 10.9 months)[1].

Novartis has entered into agreements with both Qiagen and Foundation Medicine** to develop flexible companion diagnostic solutions for BYL719 that utilize both tumor tissue and plasma sample types.

"Our work to develop an effective PI3K inhibitor started more than two decades ago, and learning from multiple clinical trial experiences, we have been able to advance an investigational targeted therapy for patients with this specific breast cancer," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "SOLAR-1 is the first breast cancer trial to show potential utility of liquid biopsies. We are excited to collaborate with Qiagen and Foundation Medicine on tissue and plasma tests that, if approved, may help oncologists identify patients who could benefit from BYL719 plus fulvestrant."

The SOLAR-1 trial is ongoing to evaluate secondary endpoints, including overall survival and will be presented and discussed in the future. Overall survival (OS) results were immature at the time of data cut-off after 52% of events (HR=0.73; 95% CI 0.48-1.10; p=0.06; median not estimable vs 26.9 months). The prespecified O’Brien-Fleming stopping boundary was not crossed. Discussions with health authorities regarding the SOLAR-1 data have begun.

About SOLAR-1
SOLAR-1 is a global, Phase III randomized, double-blind, placebo-controlled trial studying investigational BYL719 in combination with fulvestrant for postmenopausal women with PIK3CA-mutated HR+/HER2- advanced or metastatic breast cancer that progressed on or following aromatase inhibitor treatment with or without a CDK4/6 inhibitor[1].

The trial randomized 572 patients. Patients were allocated based on tumor tissue assessment to either a PIK3CA-mutated cohort or a PIK3CA non-mutated cohort. Within each cohort, patients were randomized in a 1:1 ratio to receive continuous oral treatment with BYL719 (300mg once daily) plus fulvestrant (500 mg every 28 days + Cycle 1 Day 15) or placebo plus fulvestrant. Stratification was based on visceral metastases and prior CDK4/6 inhibitor treatment[1].

The primary endpoint is local investigator assessed PFS using RECIST 1.1 for patients with a PIK3CA mutation. Secondary endpoints include but are not limited to overall survival, overall response rate, clinical benefit rate, health-related quality of life, efficacy in PIK3CA non-mutated cohort, safety and tolerability[1].

For the primary SOLAR-1 analysis, mutation status was determined by tumor tissue via polymerase chain reaction (PCR) analysis. Plasma ctDNA samples were also collected at baseline as a secondary endpoint. Plasma ctDNA mutation status of participants in SOLAR-1 was identified by an assay developed by Qiagen.

About BYL719 (alpelisib)
BYL719 is an investigational, orally bioavailable, alpha-specific PI3K inhibitor. In breast cancer cell lines harboring PIK3CA mutations, BYL719 has been shown to potentially inhibit the PI3K pathway and have antiproliferative effects. In addition, cancer cell lines with PIK3CA mutations were more sensitive to BYL719 than those without the mutation across a broad range of different cancers[5].

On December 6, 2018 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company focused on the development of oncology drug candidates, all of which are based on license agreements with The University of Texas System on behalf of the M.D. Anderson Cancer Center, reported it will host a conference call to discuss the recent discovery of a use of one its molecule for cancer treatment and provide a business update (Press release, Moleculin, DEC 6, 2018, View Source [SID1234531947]). The call will be at 4:30 p.m. ET on Wednesday, December 12, 2018.

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Participants can dial (800) 860-2442 or (412) 858-4600 to access the conference call, or can listen via a live Internet web cast, which is available in the Investor Relations section of the Company’s website at www.moleculin.com. A webcast replay will be available in the Investors section of the Company’s website at www.moleculin.com for 90 days. A teleconference replay will be available at (877) 344-7529 or (412) 317-0088, confirmation code 10126965, through December 19, 2018.

On December 6, 2018 Novocure (NASDAQ:NVCR) reported that the results of a retrospective post-hoc sub-group analysis of its EF-14 phase 3 pivotal trial in newly diagnosed glioblastoma (GBM) have been published in the Journal of Neuro-Oncology (Press release, NovoCure, DEC 6, 2018, View Source [SID1234531931]). The analysis demonstrated that more time on Optune predicted increased survival in patients who received Optune plus temozolomide compared to patients who received temozolomide alone. Optune is a noninvasive, portable medical device that delivers Tumor Treating Fields to people with GBM. Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and causing certain cancer cells to die.

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"The total amount of time the device is worn, also known as monthly Optune usage – or treatment compliance – matters greatly for patients with GBM, one of the most aggressive forms of cancer," said Steven A. Toms, MD, Professor of Neurosurgery and Medicine, and Vice Chair of the Department of Neurosurgery at Lifespan Health System, and the Warren Alpert Medical School of Brown University in Providence, Rhode Island, and author of the article. "Optune plus temozolomide has proven to provide long-term quality survival to patients with newly diagnosed GBM. Therefore, the importance of monthly Optune usage should be reinforced with patients by their health care providers."

Data from this sub-group analysis demonstrated that patients using Optune 50 percent or more of the time had a survival benefit compared to those who used temozolomide alone (n=388/450, OS HR 0.67, 95% CI 0.45–0.99). Patients who used Optune more than 90 percent of the time experienced a median overall survival of 24.9 months (n=43; OS HR 0.52, 95 percent CI 0.35–0.79) and a predicted 5-year survival rate of 29.3 percent versus a median overall survival of 16.0 months and a predicted 5-year survival rate of 4.5 percent for patients who used temozolomide alone. Monthly usage was a predictor of survival, independent of other prognostic factors such as Karnofsky Performance Status, age or MGMT methylation status.

Novocure’s phase 3 pivotal EF-14 trial compared Optune in combination with temozolomide to temozolomide alone in a total of 695 patients with newly diagnosed GBM. The trial was designed to test both progression free survival and overall survival. The trial demonstrated unprecedented five-year survival results in newly diagnosed GBM for those patients treated with Optune in combination with temozolomide. Those patients experienced an extension of overall survival without added systemic toxicity compared to patients treated with temozolomide alone. The data also showed that Optune-treated patients were able to maintain their mental, emotional and physical well-being longer than those treated with temozolomide alone, as measured for up to one year.