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Chugai Receives Orphan Drug Designation for Polatuzumab vedotin in Diffuse Large B-Cell Lymphoma from the MHLW

On November 20, 2019 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that polatuzumab vedotin, an anti-CD79b antibody-drug conjugate under development, received orphan drug designation by the Ministry of Health, Labour and Welfare (MHLW) for diffuse large B-cell lymphoma (DLBCL) (Press release, Chugai, NOV 20, 2019, View Source [SID1234551465]). This designation is based on the results of overseas phase Ib/II clinical studies (GO29044 study and GO29365 study) in patients with untreated DLBCL and relapsed or refractory DLBCL.

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"While the standard therapy for untreated DLBCL is a combination of Rituxan and chemotherapy, the disease recurs in about 40 percent of the patients. There are high unmet medical needs in treating such recurrent DLBCL because many of those patients inadequately respond to subsequent autologous stem cell transplantation," said Dr. Yasushi Ito, Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit. "We continue to work on preparing for the regulatory submission so that we can provide polatuzumab vedotin as one of the new treatment options to patients as soon as possible."

About polatuzumab vedotin
Polatuzumab vedotin is a first-in-class anti-CD79b antibody-drug conjugate (ADC), comprising the anti-CD79b humanized monoclonal antibody and a tubulin polymerization inhibitor attached together using a linker. The CD79b protein is expressed specifically in the majority of B-cells, making it a promising target for the development of new therapies1, 2). Polatuzumab vedotin binds to CD79b and destroys these B-cells through the delivery of an anti-cancer agent, which is thought to suppress the effects on normal cells3, 4). Polatuzumab vedotin is being developed by Roche using Seattle Genetics ADC technology and is currently being investigated for the treatment of several types of non-Hodgkin’s lymphoma.

About diffuse large B-cell lymphoma (DLBCL)
DLBCL is one of the histologic subtypes of non-Hodgkin’s lymphoma (NHL), which is categorized as aggressive disease that progresses on a monthly basis. DLBCL is the most common form of NHL, accounting for 30-40 percent of NHL5-7). DLBCL frequently occurs in middle-aged and older people, mainly in their 60’s8). The median age at diagnosis has been reported to be 649).

The combination of Rituxan and chemotherapy is the standard therapy for untreated DLBCL; however, recurrence has been observed in about 40% of the patients due to insufficient therapeutic effect10). In addition, although autologous stem cell transplantation (ASCT) is recommended in eligible patients with recurrent or refractory DLBCL, ASCT cannot be performed in about half of these patients due to failure of salvage chemotherapy prior to ASCT11). Furthermore, no standard therapy has been established for patients ineligible for ASCT due to reasons including age or complications12).

Salvage chemotherapy: A therapy mainly used in patients with hematologic malignancy who experienced no therapeutic effects (refractory), or recurrence/relapse of the disease is referred to as a salvage chemotherapy or salvage therapy. Applicable treatment may vary depending on the type of cancer, most of which will be combination therapies consisting of multiple drugs including anticancer agents13).

About orphan drugs
Based on Pharmaceuticals and Medical Devices Law, orphan drugs are designated by the Minister of Health, Labour and Welfare and granted priority review. The designation criteria are as follows: The number of patients who may use the drug is less than 50,000 in Japan; The drug is indicated for the treatment of serious diseases and there is a significant medical value such as no alternative appropriate drug or treatment, or high efficacy or safety expected compared to existing products; there is a theoretical rationale for using the product for the targeted disease and the development plan is reasonable.

Sources

Dornan D, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood 2009; 114:2721-2729
Pfeifer M, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015; 29:1578-1586
Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010; 21:5-13
ADC Review. What are antibody-drug conjugates? [Internet; cited June 2019]. Available from: View Source (accessed in November 2019)
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th Edition. Lyon, International Agency for Research on Cancer; 2017
Aoki R, Karube K, Sugita Y, Nomura Y, Shimizu K, Kimura Y, et al. Distribution of malignant lymphoma in Japan: Analysis of 2260 cases.2001-2006. Pathol Int 2008; 58(3):174-82
Chihara D, Ito H, Matsuda T, Shibata A, Katsumi A, Nakamura S, Tomotaka S, et al. Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol 2014 Feb; 164(4):536-45
Niitsu N, The Journal of the Japanese Society of Internal Medicine 97:1588-1594, 2008
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol 1998; 16:2780-95
Friedberg JW. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011:498-505
Gisselbrecht C, Glass B, Mounier N, Gill DS, Linch DC, Trneny M, et al. Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era. J Clin Oncol 2010; 28: 4184-90
Japanese Society of Hematology. Practical Guidelines for Hematological Malignancies, 2018, Kanehara & Co., Ltd. (Japanese only)
Center for Cancer Control and Information Services, National Cancer Center. Glossary "salvage therapy" View Source (accessed in November 2019)

Athenex Announces Key Company Activities at San Antonio Breast Cancer Symposium

On November 19, 2019 Athenex, Inc. (NASDAQ: ATNX), a global biopharmaceutical company dedicated to the discovery, development and commercialization of novel therapies for the treatment of cancer and related conditions, reported that its abstract for the Phase III study of oral paclitaxel and encequidar (Oral Paclitaxel) in metastatic breast cancer has been selected for the press program of the 2019 San Antonio Breast Cancer Symposium (SABCS) (Press release, Athenex, NOV 19, 2019, View Source [SID1234573892]). The Company will deliver an oral presentation at SABCS, taking place in San Antonio, Texas, on Friday, December 13, 2019. After the oral presentation, the Company plans to discuss the results in a Key Opinion Leader (KOL) webcast event for the investment community.

"We look forward to presenting additional data and analyses at SABCS from the pivotal Phase III study of Oral Paclitaxel in metastatic breast cancer," said Dr. Johnson Lau, Athenex’s Chairman and Chief Executive Officer. "We are excited by the opportunity to share these updates with oncologists, patients and researchers to highlight Oral Paclitaxel’s potential to positively impact outcomes for people living with metastatic breast cancer."

Oral Presentation Details:
Abstract Title: Oral Paclitaxel with Encequidar: The first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: a Phase III clinical study in metastatic breast cancer.
Session: General Session 6
Date and Time: Friday, December 13, 2019 at 3:15pm CT
Location: Hall 3 / Henry B. Gonzalez Convention Center, San Antonio, Texas
For more information, please visit View Source
Abstracts that have been selected for the press program will only have titles posted to the SABCS website until the embargo lifts on December 13, when the complete abstract will post online.

KOL Webcast Event

On December 13, 2019, after the oral presentation, the Company plans to review the Phase III clinical data presented at SABCS during a webcasted event for the investment community. Further details will be made available in a separate announcement.

Athenex Exhibit Booth

Attendees at SABCS are invited to visit the exhibit booth hosted by Athenex Oncology at the conference (booth #627/629), December 10 to 13, from 10:45am to 5pm CT daily.

The Orascovery platform was initially developed by Hanmi Pharmaceuticals and licensed exclusively to Athenex for all major worldwide territories except Korea, which is retained by Hanmi.

Publication in Nature Communications Confirms DRD2 as Target of ONC201

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]).

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.

Conversion Right Triggered for LabCorp’s Zero Coupon Convertible Subordinated Notes Due 2021

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.

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.

CRISPR Therapeutics Announces Proposed Public Offering of Common Shares

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.

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].