On April 1, 2019 Columbia University reported that global team of researchers led by theoretical physicist Raul Rabadan, PhD, professor of systems biology at Columbia’s Vagelos School of Physicians and Surgeons, and Núria Malats, MD, PhD, head of the Genetic and Molecular Epidemiology Group of the Spanish National Cancer Research Centre (CNIO), are working to develop a comprehensive computational framework that will identify high-risk factors for pancreatic cancer (Press release, Columbia University, APR 1, 2019, View Source [SID1234554036]).

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Armed with a new two-year, $1 million grant from the Pancreatic Cancer Collective, the team intends to attack pancreatic cancer research from multiple disciplines—genomics, mathematics and medicine—to provide an integrated, computational approach to studying genomic, environmental and immune factors that could identify populations at high risk of pancreatic cancer. The need for deeper understanding of the contributing factors to this lethal disease is pressing, as pancreatic cancer is projected to become the second leading cause of cancer-related mortality within the next decade.

Rabadan-led Team for Pancreatic Cancer Collective
Drs. Raul Rabadan and Nuria Malats
Pancreatic cancer currently has the lowest overall survival rate across all major cancers. The majority of pancreatic cancer patients overall live 8 to 12 months after diagnosis, and the instances of the disease are on the rise. While some key risk factors have been identified—age, non-genetic factors such as obesity, type-2 diabetes mellitus, and smoking, among others, and a handful of genetic mutations—currently known factors only explain a small fraction of the attributable risk of pancreatic cancer. Early detection remains a major challenge. By the time most patients are diagnosed, their prognosis is bleak.

Drs. Rabadan and Malats will co-lead the project with Ken Olive , PhD, assistant professor and core director at the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian / Columbia University Irving Medical Center ; Tal Korem , PhD, assistant professor of systems biology and core member of Columbia’s Program for Mathematical Genomics (PMG) ; Gulam Manji , MD, assistant professor of medicine and faculty member of the HICCC; Ioan Filip , postdoctoral fellow of systems biology; and Esther Molina, Miguel Servet staff scientist in Dr. Malats’ Group.

"Our interdisciplinary team of researchers—from molecular epidemiologists and clinicians to experts in tumor genomics and the microbiome—will work together to tackle this problem," says Dr. Rabadan. "We will explore large-scale datasets from the U.S. and Europe to build this new computational framework, and also study preliminary epidemiological and genetic observations that link pancreatic cancer risk to the immune system. Our goal is to create a reliable, integrated framework for identifying populations high-risk for this detrimental disease."

The researchers will focus on rare gene variants, specific DNA regions and modifications, within large clinical and molecular datasets from multiple published databanks. The datasets include the UK Biobank, European Study on Digestive Illnesses and Genetics (PanGenEU), The Cancer Genome Atlas and the International Cancer Genome Consortium. The team also plans to characterize the tumor microenvironment, specifically the microbiome and expression of proteins important for immune system regulation.

Attempting to understand the cancer biology of pancreatic tumors is arguably a far more difficult undertaking than most cancer tumors, notes Dr. Olive, an expert in pancreatic cancer research and director of the Oncology Precision Therapeutics Imaging Core at the Cancer Center, and this is in large part due to the tumor’s unique structure.

"In pancreatic cancer, some cells within the mass of a tumor that are not mutated—the stroma cells—which are part of your normal body, have been recruited to help drive tumor growth," says Dr. Olive, and this makes studying tissue samples challenging.

"These stroma cells far outnumber mutant tumor cells, and they make it very difficult to study the tumor biology," he adds "We’ve been focusing on how to tease out the biology."

As part of this new project, researchers will also use a unique dataset from the Olive lab derived from manually carving out non-malignant cells from tumor cells in tissue samples, separating the different cell types and analyzing each component. This, and other complex data sets—clinical outcomes data and microbiome data—will help in expanding the team’s integrated computational platform to identify high-risk factors for the disease.

The American Cancer Society estimates for 2019 that about 56,770 people will be diagnosed with pancreatic cancer, and about 45,750 people will die from the disease. Pancreatic cancer is slightly more common in men than in women, and to date, the most common forms of treatment are surgery, chemotherapy and radiation.

"Pancreatic cancer has become one of the most deadly cancers," notes Dr. Rabadan. "Identifying genetic and epidemiological markers can elucidate risk factors that could lead to early detection. Our aim is that this project can greatly improve our ability to screen and identify highly susceptible individuals of this lethal disease."

Drs. Rabadan and Malats’ co-led project was announced March 30 by the Pancreatic Cancer Collective, a partnership of Lustgarten Foundation and Stand Up To Cancer (SU2C) , at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) . Dr. Rabadan’s expertise lies in the cross section of mathematical genomics, tumor evolution and cancer research. In the spring of 2018, SU2C awarded him the Philip A. Sharp Innovation in Collaboration award. At Columbia, Dr. Rabadan also is a professor of biomedical informatics, a faculty member of the HICCC and the founding director of the Program for Mathematical Genomics.

On April 1, 2019 LabCorp (NYSE: LH) reported that it will release its first quarter of 2019 financial results before the market opens on Tuesday, April 30, 2019, followed by a conference call and webcast beginning at 9:00 a.m. EDT to discuss the results (Press release, LabCorp, APR 1, 2019, View Source;p=RssLanding&cat=news&id=2392950 [SID1234534812]). Interested parties can access the conference call by dialing 844-634-1444 within the U.S. and Canada, or 1-615-247-0253 internationally, using the passcode 7459328.

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An audio replay of the conference call will be available from 1:00 p.m. EDT on April 30, 2019, until 11:30 a.m. EDT on May 14, 2019, by dialing 855-859-2056 within the U.S. and Canada, or 1-404-537-3406 internationally, using the passcode 7459328.

The earnings release, accompanying financial information, and a real-time webcast of the conference call will be available on the LabCorp Investor Relations website. The webcast will be archived and accessible through April 24, 2020.

On April 1, 2019 AC Immune SA (NASDAQ: ACIU), a Swiss-based, clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, reported that it will present at the H.C. Wainwright Global Life Sciences Conference in London, UK, taking place April 7 – 9, 2019 (Press release, AC Immune, APR 1, 2019, View Source [SID1234534830]).

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Prof. Andrea Pfeifer, Ph.D., CEO of AC Immune SA will present an update on AC Immune’s broad clinical and preclinical pipeline of therapeutic and diagnostic candidates to treat neurodegenerative diseases associated with misfolded proteins. The Company’s pipeline features nine therapeutic and three diagnostic product candidates, with five currently in clinical trials and has collaborations with major pharmaceutical companies including Roche/Genentech, Eli Lilly and Janssen.

AC Immune utilizes two proprietary discovery platforms, SupraAntigen and Morphomer, to design, discover and develop small molecule and biological therapeutics as well as diagnostic products intended to diagnose, prevent and modify neurodegenerative diseases. These platforms have been validated through collaborations with major pharmaceutical companies, most recently a transformative agreement with Lilly for Tau Morphomer small molecules in Alzheimer’s disease and other Tau-related neurodegenerative diseases, with a total deal value of approx. CHF 1.8 billion.

H.C. Wainwright Global Life Sciences Conference
Date: April 9, 2019 | 1:30 – 1:50pm BST
Presenter: Prof. Andrea Pfeifer, CEO, AC Immune

On April 1, 2019 Turning Point Therapeutics, Inc., a clinical-stage precision oncology company designing and developing novel drugs to address treatment resistance, reported its data from four studies at AACR (Free AACR Whitepaper) 2019, highlighting potent activity of its kinase inhibitors, including repotrectinib against targeted oncogene drivers and many of their resistance mutations, and TPX-0022, a novel MET/CSF1R/SRC inhibitor (Press release, Turning Point Therapeutics, APR 1, 2019, View Source [SID1234534846]).

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Two studies highlighted the higher potency of repotrectinib as compared to other proxy investigational and the currently approved ROS1 and TRK tyrosine kinase inhibitors (TKIs), Xalkori and Vitrakvi, against fusion ROS1s, wildtype TRK, and many resistance mutations, including solvent front, gatekeeper, and compound mutations.

Alexander Drilon, M.D., Clinical Director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and an investigator in the Phase 1 portion of the ongoing TRIDENT-1 study of repotrectinib, said, "As physicians adopt next-generation sequencing to identify genomic alterations in different cancers, there is an increased need for precision therapies that target specific oncogenes, such as TRK and ROS1. Repotrectinib was found to have 10-fold or higher increased potency when compared to proxy investigational and the currently approved TRK inhibitors against wildtype (WT) TRK fusions and solvent-front mutations. The findings — while early — are significant and warrant continued clinical study."

Data for TPX-0022, a novel, internally developed MET/CSF1R/SRC inhibitor approaching IND submission in 1H 2019, were presented for the first time at the conference. TPX-0022 was designed to target MET-driven tumor cells, but also modulate the tumor microenvironment by inhibition of CSF1R. This dual modulation has demonstrated significant tumor growth inhibition in preclinical models.

The data shown in two posters highlighted the ability of TPX-0022 to potently inhibit MET-driven cancer cells and the associated signaling of known cancer pathways, inhibiting tumor growth and reducing tumor associated macrophages. This dual mechanism of action showed tumor regression and growth inhibition in multiple xenograft tumor models harboring MET amplification or MET exon 14 skipping mutations.

"We are excited to share why we believe our lead asset, repotrectinib, is a potential best-in-class ROS1 and TRK targeted TKI," said Athena Countouriotis, M.D., chief executive officer. "This is based on multiple factors, including our ongoing Phase 1 TRIDENT-1 data and what we have shown at AACR (Free AACR Whitepaper) in terms of preclinical potency against fusion ROS1s and resistance mutations, as well as WT and resistance mutations within TRKA-C. We remain encouraged by the potential for repotrectinib to make a difference in the lives of patients with a range of oncogene drivers, both patients who have yet to be treated with a kinase inhibitor, as well as those who have been treated with a prior kinase inhibitor and developed treatment resistance through a specific mutation."

Turning Point Therapeutics plans to initiate a registrational Phase 2 portion of the TRIDENT-1 Study in the second half of 2019.

Dr. Countouriotis added: "While in late stage preclinical development, our MET/CSF1R/SRC kinase inhibitor, TPX-0022, has demonstrated promising preclinical activity in an important pathway for the regulation of tumor growth. We look forward to submitting our IND in the first half of 2019 and beginning our Phase 1 study in the second half of 2019."

Additional highlights from the four studies include:

Title: Repotrectinib, a next generation TRK inhibitor, overcomes TRK resistance mutations including solvent front, gatekeeper and compound mutations
Session: Sunday Mar 31, 2019, 1:00 PM – 5:00 PM
Abstract Number: 4000

Repotrectinib was shown to be more than 10-fold as potent as a LOXO-195 proxy against wildtype TRK fusions and solvent-front mutations, and more than 100-fold more potent against certain gatekeeper mutations. Repotrectinib was the only TRK inhibitor active against the compound mutation TRKA G595R/F589L (double mutation of solvent front and gatekeeper) in preclinical Ba/F3 cells. In xenograft tumor models, repotrectinib demonstrated significant tumor regression against wildtype or mutated TRK fusions. In the ongoing TRIDENT-1 clinical trial repotrectinib was active against the solvent front mutation ETV6-TRKC G623E in an entrectinib-resistant patient with a salivary gland tumor (-82%, confirmed partial response, RECIST v1.1). Tumor regression (-33%) was achieved in a larotrectinib-resistant cholangiocarcinoma patient with LMNA-TRKA G595R and F589L mutations.

Title: Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations
Session: Monday April 1, 2019, 8:00 AM – 12:00 PM
Abstract Number: 4832

Repotrectinib demonstrated higher potency as compared to other ROS1 inhibitors against multiple ROS1 fusions and mutations, especially the solvent front and gatekeeper mutations. In xenograft tumor models, repotrectinib treatment resulted in tumor regression against wildtype or solvent-front ROS1 fusion genes. Repotrectinib demonstrated a strong inhibition profile against wildtype and various mutated ROS1s across different fusion partners when compared to many other ROS1 TKIs.

Title: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling
Session: Monday April 1, 2019, 8:00 AM – 12:00 PM
Abstract Number: 3719

TPX-0022 potently inhibited cell proliferation of the MET-amplified MKN-45 (IC50 < 0.2 nM) and SNU-5 (IC50 < 0.2 nM) gastric cancer cells. TPX-0022 caused suppression of MET auto-phosphorylation at an IC50 of approximately 0.3 nM in MKN-45 cell line. TPX-0022 also potently inhibited the phosphorylation of MET downstream signaling effectors, including AKT, ERK, STAT3 and PLCγ2 in a dose-dependent manner. In the cancer cell line and patient-derived xenograft tumor models from gastric, lung and liver cancers harboring MET amplification or MET exon14 skipping mutations, TPX-0022 caused dramatic tumor regression and tumor growth inhibition. The tumor inhibitory effect was associated with drastic inhibition of MET activity.

Title: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC inhibits tumor growth by promoting anti-tumor immune responses
Session: Monday April 1, 2019, 8:00 AM – 12:00 PM
Abstract Number: 3749

TPX-0022 demonstrated potent CSF1R inhibitory activity and the ability to inhibit tumor growth and promote a pro-inflammatory anti-tumor microenvironment. In contrast, the potency of a proxy compound of the type II CSF1R inhibitor PLX-3397 demonstrated a strong dependency on the concentration of mouse CSF1, as the anti-proliferation IC50 shifted from <0.1 nM to 146.4 nM when CSF1 concentration changed from baseline to 1 ng/mL. Finally, in the MC38 syngeneic mouse model, TPX-0022 effectively reduced tumor associated macrophages (TAM), altered the polarity of TAMs toward a more M1 phenotype, increased cytotoxic T cells and inhibited the growth of MC38 tumors.

About Repotrectinib

Repotrectinib (TPX-0005) is a potent and orally bioavailable investigational small molecule kinase inhibitor of ROS1, TRKs and ALK. The clinical benefits of targeting ROS1, TRK, or ALK fusion kinases have been demonstrated with multiple kinase inhibitors already approved or in clinical studies. The successes of these therapies are often overshadowed by the development of acquired resistance. The acquired solvent front mutations including ROS1 G2032R, TRKA G595R and TRKC G623R, and ALK G1202R render common clinical resistance to the current ROS1, TRK, and ALK inhibitors.

Repotrectinib has demonstrated potency against wildtype and mutated ROS1, TRK and ALK kinases, especially the clinically significant solvent front mutations, gatekeeper mutations, and emerging compound mutations after multiple lines of treatment. Repotrectinib may provide a new opportunity to inhibit the abnormal signaling of ROS1, TRK or ALK in solid malignancies, and overcome multiple resistance mechanisms seen in resistant patients. Repotrectinib is currently being evaluated in a Phase 1/2, open-label, multi-center, first-in-human study of the safety, tolerability, pharmacokinetics and anti-tumor activity in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements called TRIDENT-1 (www.clinicaltrial.gov number NCT03093116). Interested patients and physicians can also contact the TP Therapeutics Oncology Clinical Trial Hotline at 1-858-276-0005 or email [email protected].

On April 1, 2019 Cytori Therapeutics (NASDAQ: CYTX) ("Cytori" or the "Company") reported its fourth quarter and year-end 2018 financial results and provided updates on corporate activities (Press release, Cytori Therapeutics, APR 1, 2019, View Source [SID1234534864]). Also announced was a transaction to divest certain cell therapy assets to Lorem Vascular of Melbourne, Australia yielding $4MM in non-dilutive funding to the Company .

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Fourth quarter 2018 net loss was $2.2 million, or $0.16 per share. Operating cash burn for the fourth quarter of 2018 was approximately $2.5 million. Cytori ended the year with approximately $5.3 million of cash and cash equivalents.

"This transaction sale accomplishes a number of important objectives for the company," said Dr. Marc Hedrick, Cytori President & Chief Executive Officer. "Most critically it allows us to further increase the focus on our clinical stage oncology pipeline while bringing in non-dilutive capital. We also are able to maintain our most valuable cell therapy assets, including Japan that has a forthcoming trial readout in our ADRESU trial."

Our lead clinical stage asset, Doxorubicin Hydrochloride Cytori, formerly called ATI-0918, is an important potential therapy for Breast and Ovarian Cancer, Multiple Myeloma and Kaposi’s Sarcoma. Our current development program is focused in Europe where we believe there is a potential market opportunity of $120 million annually. In Q1 2019, Cytori submitted a letter of intent to file a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Doxorubicin Hydrochloride Cytori. Doxorubicin Hydrochloride Cytori is being developed as a generic version of Janssen’s Caelyx pegylated liposomal doxorubicin. The Company continues to evaluate potential development and commercialization partnering opportunities for Doxorubicin Hydrochloride Cytori with a focus on Europe and China. European approval and launch of Doxorubicin Hydrochloride Cytori is projected to be in late 2020.

Our second clinical stage oncology focused asset is ATI-1123, a phase II ready, patented, albumin-stabilized pegylated liposomal docetaxel. In 2018, the Company received an orphan drug designation from the U.S. FDA for the indication of small cell lung cancer and is pursuing a 505(b)(2) new drug application (NDA) pathway in the U.S. which may offer an accelerated clinical timeline and lower development cost. The Company is exploring near term development strategies and intends to advance this program aggressively in 2019.

Cytori’s ADRESU pivotal urinary incontinence trial using Cytori Cell Therapy has completed enrollment and anticipates data read out in the second quarter of 2019. If the data is positive, Cytori intends to seek expedited approval and reimbursement for the Japanese market for this indication. In Q1 2019, Cytori received approval from the United States Food & Drug Administration to expand the enrollment criteria for its RELIEF clinical trial of intravenously delivered Cytori Cell Therapy for patients with severe burn injuries.

Q4 2018 and Full Year 2018 Financial Performance

Q4 2018 and full year operating cash burn was $2.5 million and $12.0 million, compared to $4.2 million and $18.1 million for the same periods in 2017, respectively.
Q4 2018 and full year product revenues were $0.4 million and $2.7 million, compared to $0.7 million and $2.7 million for the same periods in 2017, respectively.
Q4 2018 and full year contract revenues were $0.7 million and $3.0 million, compared to $0.9 million and $3.7 million for the same periods in 2017, respectively.
Cash and debt principal balances at December 31, 2018 were approximately $5.3 million and $13.0 million, respectively.
Q4 2018 adjusted net loss was $2.8 million or $0.20 per share, compared to a net loss of $4.3 million or $1.00 per share for the same period in 2017. The adjusted net loss excludes a non-cash beneficial conversion feature (a non gaap measure) related to the issuance of our Series C convertible preferred shares in the third quarter of 2018 of $2.5 million, as well as a credit of $0.6 million related to a change in fair value of warrant liability (a non gaap measure). Q4 2018 net loss allocable to common stockholders was $2.2 million, or $0.16 per share.
Full year 2018 adjusted net loss was $14.9 million or $1.71 per share, compared to $21.0 million or $6.48 per share for the same period in 2017. The adjusted net loss excludes a non-cash beneficial conversion feature (a non gaap measure) related to the issuance of our Series C convertible preferred shares in the third quarter of 2018 of $2.5 million, as well as a credit of $2.2 million related to a change in fair value of warrant liability (a non gaap measure). Full year 2018 net loss allocable to common stockholders was $15.1 million, or $1.74 per share.
Selected Key Anticipated Milestones:

Doxorubicin Hydrochloride Cytori: File Market Authorization Application to the European Medicines Agency in late 2019 or early 2020.
ATI-1123: Clarify the FDA 505(b)(2) pathway applicability and announce clinical development plan in mid 2019.
Cell Therapy Japan: Report ADRESU urinary incontinence pivotal clinical trial results in Q2 2019.
Management Conference Call Webcast

Cytori will host a management conference call at 5:30 p.m. Eastern Time today to further discuss its progress. The webcast will be available live and by replay two hours after the call and may be accessed under "Webcasts" in the Investor Relations section of Cytori’s website. If you are unable to access the webcast, you may dial in to the call at +1.877.402.3914, Conference ID: 8766078.