On March 27, 2019 Eureka Therapeutics, Inc., a clinical stage biotechnology company developing novel T-cell therapies that harness the evolutionary power of the immune system, reported the publication of a proof-of-concept study in Science Translational Medicine entitled "GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR-T cells (Press release, Eureka Therapeutics, MAR 27, 2019, View Source [SID1234534677])." The study was led by researchers from Eureka, Memorial Sloan Kettering Cancer Center (MSK) and Juno Therapeutics (Juno).

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Antibody-based therapies, including bi-specific antibodies and chimeric antigen receptor (CAR) T-cell therapies targeting B cell maturation antigen (BCMA) for multiple myeloma, have shown promising clinical results, but relapses associated with low-to-negative expression of BCMA have been reported, necessitating additional targets for multiple myeloma.

The orphan G protein-coupled receptor GPRC5D has been previously identified in bone marrow cells in patients with multiple myeloma. However, the protein expression profile of GPRC5D remained elusive. Through immunohistochemical analyses, the study demonstrated that GPRC5D is expressed on malignant bone marrow plasma cells, while normal tissue expression is limited to the hair follicle, an immune-privileged site.

In 83 evaluated primary myeloma marrow samples, 65% of samples have GPRC5D expression above a 50% antigen expression cutoff on CD138+ cells. More importantly, GPRC5D expression on CD138 multiple myeloma cells was independent of BCMA expression, suggesting GPRC5D as an ideal clinical target.

In collaboration with MSK, Eureka developed antibodies targeting GPRC5D using Eureka’s proprietary E-ALPHA discovery platform. These antibodies, together with antibodies targeting BCMA and another undisclosed multiple myeloma target, were licensed by Eureka and MSK to Juno (now Celgene) in 2016 for use in CARs.

In a head-to-head comparison with BCMA-targeted CARs with an identical backbone, GPRC5-targeted CAR-T cells demonstrated efficient antigen-specific cytotoxicity in vitro, as well as comparable effect in inducing tumor regression and extending survival at different dose levels in vivo. The study further showed that tumor escape can be rescued by GPRC5D-targeted CAR T-cells in a model of BCMA-antigen loss mediated relapse.

"The study confirms GPRC5D as a viable target in multiple myeloma," said Eric Smith, M.D., Ph.D., a medical oncologist and the Director of Clinical Translation within the Cellular Therapeutics Center at MSK. "We look forward to moving this study into the clinic, including in relapsed patients after BCMA-targeted therapy."

"Targeting GPRC5D has the potential to improve the durability of response from current bi-specific and T-cell therapies that target only BCMA," said Dr. Cheng Liu, President and Chief Executive Officer at Eureka Therapeutics. "This study reflects our commitment to increasing the long-term clinical benefit for patients with multiple myeloma and other cancers, and we look forward to leveraging our E-ALPHA and ARTEMIS platforms to develop transformational new T-cell therapies that are potentially safer and more effective."

On March 27, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a Type II variation application to the European Medicines Agency (EMA) for DARZALEX▼ (daratumumab) in combination with bortezomib, thalidomide and dexamethasone (VTd) for newly diagnosed patients with multiple myeloma who are eligible for autologous stem cell transplant (ASCT) (Press release, Johnson & Johnson, MAR 27, 2019, View Source [SID1234534676]).

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The submission is supported by data from the Phase 3 CASSIOPEIA (MMY3006) study. Additional information about this study can be found at www.ClinicalTrials.gov (NCT02541383).

"With this regulatory submission, Janssen could help redefine treatment for transplant eligible patients by providing the opportunity to be treated with a daratumumab regimen for the very first time," said José Antonio Burón Vidal, Vice President, Medical Affairs, Europe, Middle East and Africa (EMEA), Janssen-Cilag, S.A. "We continue to deliver advances in multiple myeloma, and if approved, this could offer a broader range of frontline patients a new treatment option and improved outcomes."

Janssen has also submitted an application to the U.S. Food and Drug Administration (FDA) seeking approval of daratumumab-VTd for newly diagnosed patients with multiple myeloma who are eligible for autologous stem cell transplant (ASCT).

In Europe, daratumumab is indicated:1

in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant
as monotherapy for the treatment 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
in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
About the CASSIOPEIA Trial2

The randomised, open-label, two-arm, multicentre, Phase 3 study is sponsored by the French Intergroupe Francophone du Myelome (IFM) in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and Janssen R&D, LLC. The study includes participants with previously untreated multiple myeloma eligible for high dose chemotherapy and ASCT. In the first part of the study, on which the filing is based, participants were randomised to receive either induction (before transplantation) and consolidation (after transplantation) treatment with daratumumab combined with bortezomib, thalidomide and dexamethasone or bortezomib, thalidomide and dexamethasone alone. The primary endpoint is the proportion of patients that achieve a stringent Complete Response (sCR) rate after consolidation therapy. In the second part of the study, patients that achieved a response will undergo a second randomisation to either receive maintenance treatment of daratumumab or no further treatment (observation). The primary endpoint of this part of the study is progression free survival (PFS). The total duration for each participant in the study will be approximately 138 weeks. The end of the study will occur approximately five years after the last participant is randomised in the second phase of the study. Disease assessments will be performed every four weeks in the first phase of the study and then every eight weeks in the second phase of the study.

About daratumumab

Daratumumab is a first-in-class3 biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.4 Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.1 A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.1 Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.2,5,6,7,8,9,10,11 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.12,13 For more information, please see www.clinicaltrials.gov.

For further information on daratumumab, please see the Summary of Product Characteristics at View Source

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.14

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.15 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.16 Almost 40 percent of patients with MM do not reach five-year survival.17

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.18 Refractory MM is when a patient’s disease progresses within 60 days of their last therapy.19,20 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.21 While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.22 Patients who relapse after treatment with standard therapies, including proteasome inhibitors and immunomodulatory agents, have poor prognoses and few treatment options available.23

On March 27, 2019 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors, reported the pricing of an underwritten public offering of an aggregate of 5,250,000 units at a public offering price of $1.00 per unit (Press release, Moleculin, MAR 27, 2019, View Source [SID1234534675]). Each unit is comprised of one share of common stock and 0.5 of a warrant to purchase one share of common stock for a total of 5,250,000 shares of common stock and warrants to purchase 2,625,000 shares of common stock.

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Moleculin Biotech, Inc. is a clinical-stage pharmaceutical company focused on the treatment of highly resistant cancers. (PRNewsfoto/Moleculin Biotech, Inc.)

Each warrant will have an exercise price of $1.10 per share and is exercisable immediately. The warrants will expire five years from the date of issuance. The shares of common stock and the accompanying warrants included in the units can only be purchased together in this offering but will be issued separately and will be immediately separable upon issuance. The offering is expected to close on or about March 29, 2019, subject to customary closing conditions.

The gross proceeds of the offering are expected to be $5.25 million, prior to deducting the underwriting discount and other estimated offering expenses.

Oppenheimer & Co. Inc. is acting as the sole underwriter for the offering. Roth Capital Partners, LLC and Maxim Group LLC are acting as financial advisors to the Company.

The Company intends to use the net proceeds of the offering to fund its planned clinical trials, preclinical programs, for other research and development activities and for general corporate purposes.

The securities described above are being offered pursuant to a prospectus supplement and an accompanying prospectus forming part of a shelf registration statement on Form S-3 (No. 333-219434) previously filed with and declared effective by the Securities and Exchange Commission (SEC). A final prospectus supplement and the accompanying prospectus relating to and describing the terms of the offering will be filed with the SEC and will be available on the SEC’s website at View Source Copies of the final prospectus supplement and the accompanying prospectus may be obtained, when available, from Oppenheimer & Co. Inc., Attention: Syndicate Prospectus Department, 85 Broad Street, 26th Floor, New York, New York 10004, by telephone at (212) 667-8055, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On March 27, 2019 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer and, through our license to Santen Pharmaceutical Co. Ltd., wet age-related macular degeneration, reported that preclinical data from TRC105 and TRC253, as well as Phase 2 clinical data from TRC102, will be presented at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, to be held from March 29 to April 3, 2019, in Philadelphia, PA (Press release, Tracon Pharmaceuticals, MAR 27, 2019, View Source [SID1234534674]).

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Dr. Mark Schoonderwoerd and colleagues from Leiden University will present a poster featuring data from preclinical studies of TRC105 and PD-1 checkpoint inhibitors. The presentation details are as follows:

Poster Title: Synergistic inhibition of cancer invasion and metastasis by combined anti-PD1-TRC105-mediated Endoglin targeting on cancer-associated fibroblasts and endothelial cells
Abstract Link: View Source!/6812/presentation/3044
Session Category: Combination Approaches to Novel Therapies
Location: Section 12, Poster Board 291/12
Date: Sunday, March 31, 2019
Time: 1:00pm – 5:00pm EDT
Dr. Tammy Bush and colleagues from Janssen Research and Development will present a poster featuring preclinical data from TRC253, a small molecule antagonist of mutant and wild-type androgen receptor. The presentation details are as follows:

Poster Title: Antitumor activity of JNJ-63576253 (TRC253), a small molecule antagonist of F877L mutant and wild-type androgen receptor
Abstract Link: View Source!/6812/presentation/6162
Session Category: Novel Therapeutics and Pathways
Location: Section 14, Poster Board 2179/1
Date: Monday, April 1, 2019
Time: 1:00pm – 5:00pm EDT
Dr. Geraldine Coyne and colleagues from the National Cancer Institute will present a poster featuring data from the Phase 2 clinical trial of TRC102 and Temodar (temozolomide) in subjects with colorectal cancer. The presentation details are as follows:

Poster Title: A Phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed metastatic colorectal carcinoma
Abstract Link: Late-Breaking Abstracts are embargoed until March 29, 2019
Session Category: Late-Breaking Research – Molecular and Cellular Biology/Genetics 2
Location: Section 41, Poster Board LB-293/10
Date: Wednesday, April 3, 2019
Time: 8:00am – 12:00pm EDT
Posters will be available on the company’s website following presentation.

About TRC105 (carotuximab)

TRC105, the oncology formulation of carotuximab, is a novel, clinical stage antibody to endoglin, a protein overexpressed on proliferating endothelial cells that is essential for angiogenesis, the process of new blood vessel formation. TRC105 is currently being studied in the pivotal Phase 3 TAPPAS trial in patients with angiosarcoma as well as multiple Phase 1 and Phase 2 clinical trials in other tumor types. TRC105 has received orphan designation for the treatment of soft tissue sarcoma in both the US and EU. The ophthalmic formulation of TRC105, DE-122, is currently being studied in the randomized Phase 2 AVANTE trial in patients with wet AMD. For more information about the clinical trials, please visit TRACON’s website at www.traconpharma.com/clinical_trials.php.

About TRC253

TRC253 is a novel, orally bioavailable small molecule that is a potent, high affinity competitive inhibitor of the androgen receptor (AR) and AR mutations, including the F877L mutation. The AR F877L mutation results in an alteration in the AR ligand binding domain that confers resistance to therapies for prostate cancer. Therapies targeting the AR have demonstrated clinical efficacy by extending time to disease progression, and in some cases, the survival of patients with metastatic castration-resistant prostate cancer. However, resistance to these agents is often observed and several molecular mechanisms of resistance have been identified, including gene amplification, overexpression, alternative splicing, and point mutation of the AR. TRC253 is currently being studied in a Phase 1/2 clinical trial in prostate cancer. For more information about the clinical trial, please visit TRACON’s website at www.traconpharma.com/clinical_trials.php

About TRC102

TRC102 (methoxyamine) is a novel, clinical-stage small molecule inhibitor of the DNA base excision repair pathway, which is a pathway that causes resistance to alkylating and antimetabolite chemotherapeutics. TRC102 is currently being studied in multiple Phase 1 and Phase 2 clinical trials sponsored by the National Cancer Institute or Case Comprehensive Cancer Center. For more information about the clinical trials, please visit TRACON’s website at www.traconpharma.com/clinical_trials.php.

On March 27, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported data highlights from six presentations showcasing technology advances in the company’s antibody-drug conjugate (ADC) platform and an immuno-oncology program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 being held March 29-April 3, 2019 in Atlanta (Press release, Seattle Genetics, MAR 27, 2019, View Source [SID1234534673]).

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"Our expertise in empowered-antibody innovation drives a substantial, advancing pipeline of clinical and preclinical programs, including both ADCs and immuno-oncology agents," said Dennis Benjamin, Ph.D., Senior Vice President of Research at Seattle Genetics. "For example, the research presented in an oral presentation at AACR (Free AACR Whitepaper) illustrates why we believe SGN-CD228A is well positioned for IND-enabling studies and a phase 1 study is planned in multiple tumor types. The program features a novel ADC targeted to CD228, which is highly expressed in several types of cancer. The ADC employs our proprietary auristatin technology and has shown antitumor activity in vitro and in vivo."

Abstracts can be found at www.aacr.org and include the following:

SGN-CD228A: A novel humanized anti-CD228 antibody-drug conjugate for the treatment of solid tumors (Abstract #2688)
Date: Monday, April 1, 2019
Time: 3:00 p.m. – 5:00 p.m. ET, Oral Presentation at 3:20 p.m. ET, Room B401

The cell-surface protein CD228 is highly expressed in several types of cancer, including melanoma, mesothelioma, non-small cell lung (NSCLC), breast, colorectal and pancreatic cancers. SGN-CD228A is an auristatin-based ADC targeted to CD228. The preliminary data show antitumor activity in preclinical evaluations in melanoma, NSCLC and triple negative breast cancer.

Antibody-drug conjugates of NAMPT inhibitors: Discovery, optimization and preclinical characterization (Abstract #983)
Date: Monday, April 1, 2019
Time: 8:00 a.m. – 12:00 p.m. ET, Poster Session

At the AACR (Free AACR Whitepaper) Annual Meeting 2018, data were presented showing ADCs with a proprietary NAMPT inhibitor payload have a unique mechanism of action and an encouraging therapeutic window. This poster presentation will highlight preclinical results from the optimization of the novel payload and linker strategy, and application to ADCs, which data indicate drive tumor regression in models of Hodgkin lymphoma, non-Hodgkin lymphoma and acute myeloid leukemia (AML). The targeted delivery approach using ADCs demonstrates an improved safety profile relative to previously described unconjugated NAMPT inhibitors.

TIGIT directed human antibody modulates T-regulatory and effector cell function (Abstract #4986)
Date: Wednesday, April 3, 2019
Time: 8:00 a.m. – 12:00 p.m. ET, Poster Session

The immune checkpoint receptor TIGIT negatively regulates the function of adaptive (T cell) and innate (natural killer or NK) cells and blockade of TIGIT signaling may elicit an antitumor immune response. Preclinical data from an antibody program targeting TIGIT demonstrate in vitro activation of T cells and antitumor activity in several syngenic models.

Development of patient-derived acute myeloid leukemia xenograft models (Abstract #1062)
Date: Monday, April 1, 2019
Time: 8:00 a.m. – 12:00 p.m. ET, Poster Session

This poster presentation is focused on successfully establishing a collection of AML xenograft models that more accurately reflect the antigen expression and molecular genetics of AML patients. These models will enable a more precise assessment of therapeutic candidates in preclinical testing.

Functional cell surface proteomics of acute myeloid leukemia enables predictive modeling of antibody-drug conjugate cytotoxicity (Abstract #4546)
Date: Wednesday, April 3, 2019
Time: 8:00 a.m. – 12:00 p.m. ET, Poster Session

This poster profiles the cell surface landscape of more than 100 primary hematologic samples comprising leukemic blasts from patients treated in the Beat AML research consortium along with normal bone marrow cells from healthy donors. Based on cell surface proteomics, a number of highly expressed antigens were identified and targeted ADCs were evaluated on a panel of AML cell lines. CD317 was determined as a novel target for AML.

Tisotumab vedotin induces anti-tumor activity through MMAE-mediated, Fc-mediated, and Fab-mediated effector functions in vitro (Abstract #221)
Date: Sunday, March 31, 2019
Time: 1:00 p.m. – 5:00 p.m. ET, Poster Session

Tisotumab vedotin is an investigational ADC designed to target Tissue Factor (TF) antigen on TF-expressing cell surfaces and deliver the cell-killing agent monomethyl auristatin E (MMAE) directly inside TF-expressing cells. The Tissue Factor antigen target is overexpressed in the vast majority of patients with cervical cancer and in many other solid tumors, including ovarian, lung, pancreatic, colorectal and head and neck. This poster presentation evaluates tisotumab vedotin’s antitumor activity through several mechanisms, including immunogenic cell death, bystander cytotoxicity, and antibody-dependent cellular phagocytosis in vitro.