On November 19, 2019 Oncoceutics, Inc. reported a publication in the journal Nature Communications demonstrating selective antagonism of the G-protein coupled receptor (GPCR) dopamine receptor D2 (DRD2) by Oncoceutics’ lead candidate imipridone, ONC201 (Press release, Oncoceutics, NOV 19, 2019, View Source [SID1234558321]).

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ONC201 was found to specifically bind and antagonize DRD2, and its functionally redundant family member DRD3, without affecting other dopamine receptors, other GPCRs, nuclear hormone receptors, kinases, or other drug targets of FDA-approved cancer therapies. Additionally, a biologically inactive isomer of ONC201 did not antagonize DRD2, indicating that antagonism of this receptor may be linked to anti-cancer efficacy as shown in other publications (Clinical Cancer Research and Neoplasia).

The publication also describes the novel approach taken by Oncoceutics collaborators in the laboratory of Olivier Elemento, PhD, Director of the Englander Institute for Precision Medicine at Weill Cornell Medicine. The researchers used a novel machine-learning platform, called BANDIT, created in the Elemento Lab that suggested DRD2 as a target of ONC201. This method used the molecular structure of ONC201, its in vitro efficacy profile, and its publicly available bioactivity assay results as inputs to compare ONC201 against all small molecules with known targets.

"This publication represents years of collaborative work that uncovered DRD2 as the first known binding target of ONC201," said Joshua Allen, PhD and Senior Vice President of R&D of Oncoceutics. "Along with downstream biomarkers, the dopamine pathway has guided tumor type selection and interpretation of activity of ONC201 in clinical trials. So far, we have observed the most robust single agent efficacy in malignancies that exhibit dysregulation of the dopamine pathway and grow in a dopamine-rich microenvironment, such as midline gliomas."

"Our findings have helped uncover imipridone small molecules as a unique chemical scaffold for targeting GPCRs," said Dr. Elemento. "We are pleased to see the clinical translation of our precision medicine efforts in ONC201 clinical trials and hope this information can be used to identify additional indications for this new therapy."

"The unique mechanism of action of ONC201 is now well defined," said Martin Stogniew, PhD and Chief Development Officer of Oncoceutics. "The most conserved downstream effect of ONC201 in tumor cells is activation of the integrated stress response. Several additional downstream effects, such as dual inactivation of Akt/ERK, induction of TRAIL and DR5, and degradation of Myc also occur in many tumor models, along with immunostimulatory effects involving NK cells and cancer stem cell depletion. These effects aggregately explain the broad antitumor activity observed in multiple models and are likely trigged by the interaction ONC201 with DRD2 and/or ClpP, a recently uncovered additional binding target of the molecule."

For further reference, please refer to additional publications on ONC201 and imipridone small molecules.

On November 19, 2019 LabCorp (NYSE: LH) reported that it has provided notice of its intention to redeem all of its outstanding Zero Coupon Convertible Subordinated Notes due 2021 (Zero Coupon Notes) for cash on Dec. 19, 2019, (Redemption Date) in accordance with the terms of the Indenture, dated as of Oct. 23, 2006, (Indenture), between LabCorp and The Bank of New York Mellon, as trustee (Trustee) and the conversion agent (Press release, LabCorp, NOV 19, 2019, View Source [SID1234552831]). The redemption price will be equal to $966.20 per $1,000 principal amount of Zero Coupon Notes at maturity, plus accrued and unpaid contingent cash interest to the Redemption Date (Redemption Price). The current outstanding aggregate principal amount at maturity of the Zero Coupon Notes is approximately $935,000.

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As a result of the issuance of the notice of redemption, the Zero Coupon Notes are convertible into cash and Common Stock of LabCorp, if any, subject to the terms of the Zero Coupon Notes and the Indenture. Zero Coupon Notes may be converted at any time before the close of business on Dec. 17, 2019, at the current conversion rate of 13.4108 shares of Common Stock per $1,000 principal amount of Zero Coupon Notes at maturity.

In order to exercise the option to convert all or a portion of the Zero Coupon Notes, holders must validly surrender their Zero Coupon Notes at any time through the close of business at 5:00 p.m., New York City time, on Dec. 17, 2019. The Trustee has informed LabCorp that, as of this date, all custodians and beneficial holders of the Zero Coupon Notes hold the Zero Coupon Notes through Depository Trust Company (DTC) accounts and that there are no certificated Zero Coupon Notes in non-global form. Accordingly, all Zero Coupon Notes surrendered for conversion must be delivered through the transmittal procedures of DTC.

Should Zero Coupon Notes be converted, LabCorp would be required to pay holders in cash for the accreted principal amount of the securities to be converted, with the remaining amount, if any, to be satisfied with shares of Common Stock. The shares required for settlement of the Zero Coupon Notes are included in LabCorp’s computation of fully diluted earnings per share.

Original issue discount and contingent cash interest on the Zero Coupon Notes will cease to accrue on and after the Redemption Date, and the only remaining right of holders of the Zero Coupon Notes will be to receive payment of the Redemption Price.

On November 19, 2019 CRISPR Therapeutics (Nasdaq:CRSP), a biopharmaceutical company focused on developing transformative gene-based medicines for serious diseases, reported that it is commencing an underwritten public offering of 4,250,000 common shares (Press release, CRISPR Therapeutics, NOV 19, 2019, View Source [SID1234551537]). In addition, the underwriters will have a 30-day option to purchase up to 637,500 additional common shares at the public offering price less the underwriting discount.

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Goldman Sachs & Co. LLC, Piper Jaffray & Co. and Jefferies LLC are acting as joint book-running managers for the offering. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed or as to the actual size or terms of the offering.

The common shares will be offered and sold pursuant to the Company’s previously filed automatically effective shelf registration statement on Form S-3 (File No. 333-227427) filed with the U.S. Securities and Exchange Commission (the "SEC") on September 19, 2018. This press release shall not constitute an offer to sell or a solicitation of an offer to buy, 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.

The offering will be made only by means of a prospectus. A copy of the prospectus supplement relating to the offering will be filed with the SEC and may be obtained, when available, from Goldman Sachs & Co. LLC by mail at 200 West Street, New York, NY 10282, Attention: Prospectus Department, by telephone at (866) 471-2526, or by email at [email protected]; from Piper Jaffray & Co., Attn: Prospectus Department, 800 Nicollet Mall, J12S03, Minneapolis, MN 55402, by telephone at (800) 747-3924, or by email at [email protected]; or from Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, by telephone at (877) 547-6340, or by email at [email protected].

On November 19, 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 it now has preliminary data from its clinical trial of WP1220 for the treatment of cutaneous T-cell lymphoma ("CTCL"), which was published in Blood in conjunction with the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition to be held December 7-10, 2019 (Press release, Moleculin, NOV 19, 2019, View Source [SID1234551470]).

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"For years, p-STAT3 (the activated form of STAT3) has been considered an ‘undruggable’ target because of the difficulty of reaching and affecting this cell-signaling protein," commented Walter Klemp, Moleculin’s Chairman and CEO. "Some consider it to be a master regulator of cancer-related gene transcription, so we believe the ability to show a therapeutic effect from a p-STAT3 inhibitor could be considered a significant breakthrough in cancer research."

Results: There were 6 patients screened, and 5 patients enrolled between March and July 2019. Three are evaluable for both safety and efficacy after completing 3 months of treatment, with 2 ongoing and evaluable for safety. The only AE reported potentially related to study drug in one of the five patients was a mild contact dermatitis not requiring treatment. CAILS scores on index lesions were significantly decreased in the first 3 patients, who were stages IA, IB, and IIB, respectively, at entry. A composite score was obtained for all treated lesions for each patient, and percent changes were calculated from baseline to Day 84. There was a median reduction of 70.8% (range 62.1%-76.2%) for the 3 patients. Improvement was noted as early as 7 days after initiation of treatment, and maintenance of improvement was also shown at follow up (1 month after discontinuation, as per protocol). The fourth patient has also shown an initial reduction in the composite CAILS score after 56 days (26.7%), and is continuing on treatment. Evaluations of the biopsy samples for histopathology and status of p-STAT3 in treated lesions are in progress.

Conclusions: WP1220, an inhibitor of p-STAT3, has shown demonstrable safety and significant efficacy after at least 3 months of topical treatment in 3 patients with progressive MF, with a continuing trend towards improvement in additional patients currently in treatment. This is the first demonstration that inhibition of the STAT3 activation pathway with topical therapy has impacted the course of this disease. The trial is continuing, and updated and more comprehensive data from this study as well as assessment of STAT3 phosphorylation in treated lesions will be reported.

Dr. Sandra Silberman, Chief Medical Officer for New Projects at Moleculin, added: "this is the first topical delivery of a p-STAT3 inhibitor that we know of for CTCL, where there is a significant unmet need for improved treatment of the lesions associated with this potentially deadly skin cancer. But, we believe the significance

of this data goes well beyond CTCL, as it speaks to the targeting of p-STAT3 as a general strategy. We are excited to share these preliminary results in association with ASH (Free ASH Whitepaper), especially because we believe showing activity here could have exciting implications for the future of STAT3 inhibitors in general. Although this is a relatively small pilot study, we believe the results justify an expansion to a larger patient population in a Phase 2 clinical trial."

On November 19, 2019 Genmab A/S (Nasdaq: GMAB) reported that the European Commission (EC) has granted marketing authorization for DARZALEX (daratumumab) in combination with lenalidomide and dexamethasone (Rd) as treatment for adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT) (Press release, Genmab, NOV 19, 2019, View Source [SID1234551468]). The EC approval follows a positive opinion issued for DARZALEX by the CHMP of the European Medicines Agency (EMA) in October 2019. In August 2012, Genmab granted Janssen Biotech, Inc. (Janssen) an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

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"We are pleased that with this approval, patients in the European Union newly diagnosed with multiple myeloma who are not candidates for transplant will now have two potential options for treatment with DARZALEX containing regimens. We look forward to seeing the combination therapy of DARZALEX with lenalidomide and dexamethasone launched in Europe," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The approval was based on data from the Phase III MAIA (MMY3008) study of daratumumab in combination with Rd as treatment for patients with newly diagnosed multiple myeloma, who are not candidates for high dose chemotherapy and ASCT. Data from this study was published in The New England Journal of Medicine and was presented as a Late-Breaking Abstract at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2018.

About the MAIA (MMY3008) study
The Phase III study (NCT02252172) is a randomized, open-label, multicenter study that includes 737 newly diagnosed patients with multiple myeloma who are not candidates for high dose chemotherapy and ASCT. Patients were randomized to receive either treatment with daratumumab in combination with lenalidomide (an immunomodulatory drug) and dexamethasone (a corticosteroid) or treatment with lenalidomide and dexamethasone alone. In the daratumumab treatment arm, patients received 16 milligrams per kilogram (mg/kg) weekly for the first 8 weeks (Cycles 1 and 2), every other week for 16 weeks (Cycles 3 to 6) and then every 4 weeks (Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide is administered at 25 mg orally on days 1 through 21 of each 28-day cycle, and dexamethasone is administered at 40 mg once a week for both treatment arms. Participants in both treatment arms will continue Rd until disease progression or unacceptable toxicity. The primary endpoint of the study is progression free survival.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Approximately 16,830 new patients were expected to be diagnosed with multiple myeloma and approximately 10,480 people were expected to die from the disease in the Western Europe in 2018.2 Globally, it was estimated that 160,000 people were diagnosed and 106,000 died from the disease in 2018.3 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.4

About DARZALEX(daratumumab)
DARZALEX (daratumumab) intravenous infusion is indicated for the treatment of adult patients in the United States: in combination with bortezomib, thalidomide and dexamethasone as treatment for patients newly diagnosed with multiple myeloma who are eligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy; in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI); and as a monotherapy for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.5 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (U.S. FDA) approval to treat multiple myeloma. DARZALEX intravenous infusion is indicated for the treatment of adult patients in Europe: in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant; 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; for use 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; and as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy6. The option to split the first infusion of DARZALEX over two consecutive days has been approved in both Europe and the U.S. In Japan, DARZALEX intravenous infusion is approved for the treatment of adult patients: in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for the treatment of relapsed or refractory multiple myeloma; in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. DARZALEX is the first human CD38 monoclonal antibody to reach the market in the United States, Europe and Japan. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. Daratumumab triggers a person’s own immune system to attack the cancer cells, resulting in rapid tumor cell death through multiple immune-mediated mechanisms of action and through immunomodulatory effects, in addition to direct tumor cell death, via apoptosis (programmed cell death).5,6,7,8,9,10

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. A comprehensive clinical development program for daratumumab is ongoing, including multiple Phase III studies in smoldering, relapsed and refractory and frontline multiple myeloma settings. Additional studies are ongoing or planned to assess the potential of daratumumab in other malignant and pre-malignant diseases in which CD38 is expressed, such as amyloidosis, NKT-cell lymphoma and B-cell and T-cell ALL. Daratumumab has received two Breakthrough Therapy Designations from the U.S. FDA for certain indications of multiple myeloma, including as a monotherapy for heavily pretreated multiple myeloma and in combination with certain other therapies for second-line treatment of multiple myeloma.