ArQule to Present Clinical Data for its Reversible BTK Inhibitor, ARQ 531, at the American Society of Hematology 2019 Annual Meeting

On November 25, 2019 ArQule, Inc. (Nasdaq: ARQL) reported that final clinical data from the company-sponsored phase 1 study of ARQ 531 will be presented on December 9, 2019 at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Orlando, Florida (Press release, Arqule, NOV 25, 2019, View Source [SID1234551637]). The poster presentation will highlight the final data set with respect to ARQ 531’s safety profile, clinical activity and durability across multiple refractory B-cell malignancies, including C481-mutant chronic lymphocytic leukemia (CLL).

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Presentation Details
Title: Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-cell Lymphoid Malignancies
Abstract #: 4298
Session Name: CLL: Therapy, excluding Transplantation: Poster III
Date: Monday, December 9, 2019
Presentation Time: 6:00- 8:00 p.m. EST
Location: Orange County Convention Center, Hall B

ArQule will host a conference call and webcast for investors on Monday, December 9, 2019 at 8:15 a.m. EST to discuss the ARQ 531 clinical data. The live webcast can be accessed in the "Investors and Media" section of our website, www.arqule.com, under "Events & Presentations" or by visiting link here. You may also listen to the call by dialing (877) 868-1831 within the U.S. or (914) 495-8595 outside the U.S. and providing conference ID 4573858. A replay will be available two hours after the completion of the call and can be accessed in the "Investors & Media" section of our website, www.arqule.com, under "Events and Presentations."

ArQule management will also be hosting an Investor Event to answer questions and discuss these data in Orlando on Monday, December 9, 2019 from 8:00–10:00 p.m. EST. Investors, sell side analysts, and industry representatives are welcome to attend. For event details and to RSVP, please email [email protected].

About BTK and ARQ 531

Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible dual inhibitor of both wild type and C481S-mutant BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. ARQ 531 has demonstrated a manageable safety profile, predictable PK, profound pharmacodynamic effects and signs of clinical activity.

Entry into a Material Definitive Agreement.

On November 25, 2019 (i) Teva Pharmaceutical Finance Netherlands II B.V. ("Teva Finance II"), a wholly owned subsidiary of Teva Pharmaceutical Industries Limited (the "Company"), issued €1,000,000,000 aggregate principal amount of 6.000% Senior Notes due 2025 (the "Euro Notes"); and (ii) Teva Pharmaceutical Finance Netherlands III B.V. ("Teva Finance III" and, together with Teva Finance II, the "Issuers"), a wholly owned subsidiary of the Company, issued $1,000,000,000 aggregate principal amount of 7.125% Senior Notes due 2025 (the "USD Notes" and, together with the Euro Notes, the "Notes") (Filing, 8-K, Teva, NOV 25, 2019, View Source [SID1234551653]).

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Teva intends to use the net proceeds from the Notes, together with cash on hand, to (i) fund the announced tender offer for a maximum combined aggregate purchase price (exclusive of accrued and unpaid interest but inclusive of tender premium) of up to $1,500,000,000 (ii) partially redeem €650,000,000 of the currently outstanding €1,660,154,000 aggregate principal amount of Teva Finance II’s 0.375% Senior Notes due 2020, (iii) pay fees and expenses in connection therewith and (iv) the extent of any remaining proceeds, for general corporate purposes, which may include the repayment of outstanding debt.

The Euro Notes were issued pursuant to a Senior Indenture, dated as of March 14, 2018 (the "Euro Notes Base Indenture"), by and among Teva Finance II, the Company, as guarantor, and The Bank of New York Mellon, as trustee, as supplemented by the Second Supplemental Indenture, dated as of November 25, 2019 (the "Euro Notes Supplemental Indenture" and, together with the Euro Notes Base Indenture, the "Euro Notes Indenture"), by and among Teva Finance II, the Company, as guarantor, The Bank of New York Mellon, as trustee, and The Bank of New York Mellon, London Branch, as paying agent. The USD Notes were issued pursuant to a Senior Indenture, dated as of March 14, 2018 (the "USD Notes Base Indenture"), as supplemented by the Second Supplemental Indenture, dated as of November 25, 2019 (the "USD Notes Supplemental Indenture" and, together with the USD Notes Base Indenture, the "USD Notes Indenture" and, together with the Euro Notes Indenture, the "Indentures"), in each case, by and among Teva Finance III, the Company, as guarantor, and The Bank of New York Mellon, as trustee.

Interest will be payable on the Notes semi-annually in arrears on January 31 and July 31 of each year, beginning on July 31, 2020, until their maturity date of January 31, 2025. The Euro Notes and the USD Notes are senior unsecured obligations of Teva Finance II and Teva Finance III, respectively, and the Notes are guaranteed on a senior unsecured basis by the Company.

Teva Finance II may redeem the Euro Notes, in whole or in part, at any time or from time to time, upon at least 10 days’, but not more than 60 days’, prior notice. The Euro Notes will be redeemable at a redemption price equal to the greater of (1) 100% of the principal amount of the Euro Notes to be redeemed or (2) the sum of the present values of the Remaining Scheduled Payments (as defined in the Euro Notes Indenture) of the Euro Notes being redeemed discounted, on a semi-annual basis (assuming a 360-day year consisting of twelve 30-day months), at the applicable Reinvestment Rate (as defined in the Euro Notes Indenture), plus accrued and unpaid interest thereon, if any (including Additional Interest, if any), to, but not including, the redemption date; provided that if Teva Finance II elects to redeem the Euro Notes at any time on or after October 31, 2024 (three months prior to the maturity date of the Euro Notes), Teva Finance II may redeem the Euro Notes, in whole or in part, at a redemption price equal to 100% of the principal amount of the Euro Notes then outstanding to be redeemed, plus accrued and unpaid interest thereon, if any, to, but not including, the redemption date.

Teva Finance III may redeem the USD Notes, in whole or in part, at any time or from time to time, upon at least 10 days’, but not more than 60 days’, prior notice. The USD Notes will be redeemable at a redemption price equal to the greater of (1) 100% of the principal amount of the USD Notes to be redeemed or (2) the sum of the present values of the Remaining Scheduled Payments (as defined in the USD Notes Indenture) of the USD Notes of such series being redeemed discounted, on a semi-annual basis (assuming a 360-day year consisting of twelve 30-day months), using a discount rate equal to the sum of the Treasury Rate (as defined in the USD Notes Indenture) plus 50 basis points, plus accrued and unpaid interest thereon, if any (including Additional Interest, if any), to, but not including, the redemption date; provided that if Teva Finance III elects to redeem the USD Notes at any time on or after October 31, 2024 (three months prior to the maturity date of the USD Notes), Teva Finance III may redeem the USD Notes, in whole or in part, at a redemption price equal to 100% of the principal amount of the USD Notes then outstanding to be redeemed, plus accrued and unpaid interest thereon, if any, to, but not including, the redemption date.

The terms of the Indentures, among other things and subject to specified exceptions, limit the ability of (a) the Company and its subsidiaries to (i) create liens upon certain of their property and (ii) enter into sale-leaseback transactions; and (b) the applicable Issuer and the Company to merge, consolidate or sell, lease or convey all or substantially all of their assets. The Indentures provide for customary events of default, which include (subject in certain cases to customary grace and cure periods), among others, nonpayment of principal or interest; breach of other covenants or agreements in the Indentures; acceleration of certain other indebtedness; failure of the Company’s guarantee to be enforceable; and certain events of bankruptcy or insolvency. The Notes were issued in private offerings exempt from the registration requirements of the Securities Act of 1933, as amended (the "Securities Act"), to qualified institutional buyers in accordance with Rule 144A and to non-U.S. persons in offshore transactions in reliance on Regulation S under the Securities Act.

In connection with the sale of the Euro Notes, Teva Finance II and the Company entered into a Registration Rights Agreement, dated as of November 25, 2019, with the initial purchasers party thereto. In connection with the sale of the USD Notes, Teva Finance III and the Company entered into a Registration Rights Agreement, dated as of November 25, 2019, with the initial purchasers party thereto. Under the terms of each Registration Rights Agreements, the applicable Issuer and the Company agreed to use reasonable best efforts to file a registration statement with respect to a registered exchange offer to exchange the Notes for new notes with terms substantially identical to the Notes, to cause the exchange offer registration statement to be declared effective by the Securities and Exchange Commission and to consummate the exchange offer on or before the 365th day after November 25, 2019. The Issuers and the Company may be required to provide shelf registration statements to cover resale of any series of Notes under certain circumstances. If the Issuers and the Company fail to satisfy these and other obligations contained in the Registration Rights Agreements, additional payments of interest will accrue on the Notes.

The foregoing summary descriptions of the Euro Notes Base Indenture, Euro Notes Supplemental Indenture, USD Notes Base Indenture, USD Notes Supplemental Indenture, each series of Notes and the Registration Rights Agreements are not complete and are qualified in their entirety by reference to the Euro Notes Base Indenture, the Euro Notes Supplemental Indenture, the form of Euro Notes, the Euro Notes Registration Rights Agreement, the USD Notes Base Indenture, the USD Notes Supplemental Indenture, the form of USD Notes and the USD Notes Registration Rights Agreement, which are filed as Exhibits 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7 and 4.8, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.

INHIBITOR Therapeutics Submits Investigational New Drug Application for Treatment of Patients with Late-Stage Prostate Cancer

On November 25, 2019 INHIBITOR Therapeutics, Inc. (OTCQB: INTI), a biopharmaceutical company focused on the discovery, development and commercialization of innovative therapeutics to inhibit progression of cancerous and non-cancerous proliferation disorders, reported that the company has submitted an Investigational New Drug (IND) Application to the U.S. Food and Drug Administration (FDA) to seek clearance to initiate an IND-opening clinical study as a two-part, multi-center, randomized, double-blind, placebo-controlled, Phase 2b clinical trial that will evaluate the efficacy and safety of SUBA-Itraconazole capsules dosed in combination with docetaxel and prednisone in patients with metastatic castrate resistant prostate cancer (mCRPC) (Press release, Inhibitor Therapeutics, NOV 25, 2019, View Source [SID1234551673]). The proposed trial will be named PREDICT (Prostate Response Evaluating Docetaxel Itraconazole Combination Therapy).

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Nicholas Virca, INHIBITOR’s President and CEO, said: "Following a pre-IND meeting with FDA in the first half of this year, FDA granted us a face-to-face End-of-Phase-2 (EoP2) meeting, which I am pleased to announce occurred last month. During that meeting, we gained FDA guidance and agreement on our protocol and statistical analysis plan for our proposed PREDICT trial. FDA indicated that we can follow the 505(b)(2) regulatory pathway given previous FDA approval of itraconazole. Assuming positive results demonstrating an improvement in radiographic progression-free survival (rPFS) as our primary endpoint, FDA indicated that the general design and planned analysis of our study would adequately address the objectives necessary to support a New Drug Application (NDA) submission. Further, FDA indicated that the final analysis of the key secondary endpoint of overall survival (OS) can occur following submission of the NDA for approval in the United States."

Mr. Virca continued: "I would like to acknowledge the stellar efforts of our regulatory and clinical team members over the last nine months to achieve this level of progress for our SUBA-Itraconazole Prostate program. Approximately 23,000 men in the U.S. are diagnosed each year with late-stage mCRPC that no longer responds well to androgen deprivation therapy (ADT) or previous treatment with chemotherapy or newer stand-alone anti-androgen therapies such as abiraterone, enzalutamide or apalutamide. We believe that SUBA-Itraconazole Prostate has the potential to address an unmet need in these patients, who exhibit disease progression or who have discontinued the other therapies due to toxicity or other reasons."

About Itraconazole in Prostate Cancer

In late-stage prostate cancer, up-regulation of the Hedgehog pathway in cells results in oncogene expression, which can interfere with the binding of ADT drugs to the androgen receptor (AR), causing biochemical resistance leading to mCRPC. Itraconazole acts on the essential Hedgehog signaling pathway component called smoothened (SMO) in human cells in a different manner than the FDA-approved drug vismodegib by preventing the ciliary accumulation of SMO normally caused by the Hedgehog pathway. Itraconazole also has a much shorter half-life than vismodegib, which may be the reason it appears to have fewer side effects than what has been reported for vismodegib in recent publications regarding its use in treating basal cell carcinoma. Thus, itraconazole may be more suitable than vismodegib for use in combination with chemotherapy due to its lower toxicity profile. Itraconazole has been tested as a treatment for mCRPC in a multi-institutional Phase 2 trial led by a prominent U.S. university and published in 2013.This trial showed that 90% of men with prostate specific antigen (PSA)-doubling times of less than 6 months, who achieved therapeutic levels of itraconazole, showed promising PSA reductions that correlated significantly with rPFS. The improved bioavailability of SUBA-Itraconazole may provide additional benefits to prostate cancer patients in two ways: 1) by achieving higher therapeutic levels of itraconazole at lower doses than those reported in the Phase 2 study, which used the generic formulation of the drug, and 2) by reducing the dose of chemotherapy based on enhanced uptake of docetaxel in the presence of itraconazole.

Chi-Med Announces Surufatinib Granted FDA Orphan Drug Designation for Pancreatic Neuroendocrine Tumors

On November 25, 2019 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that the U.S. Food and Drug Administration ("FDA") has granted Orphan Drug designation to surufatinib for the treatment of pancreatic neuroendocrine tumors ("NET") (Press release, Hutchison China MediTech, NOV 25, 2019, View Source [SID1234551638]).

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"NET is an area of significant unmet medical need. The current treatment options are very limited," said Christian Hogg, CEO of Chi-Med. "The FDA granting Orphan designation is a positive step and continues to reinforce the importance of our research and development in bringing surufatinib to more patients in need."

If approved by the FDA as an orphan treatment, surufatinib will be entitled to seven years of market exclusivity for the approved indication. Orphan Drug designation also affords certain development cost benefits in the U.S.

Surufatinib is under investigation in multiple solid tumors in China and the U.S., both as a monotherapy and in combination with immunotherapies.

Surufatinib is the second novel oncology drug discovered by Chi-Med to successfully complete a Phase III trial in China. A New Drug Application ("NDA") for surufatinib for the treatment of patients with advanced non-pancreatic NET was accepted for review by the China National Medical Products Administration (NMPA) on November 11, 2019.

About FDA Orphan Drug Designation

The FDA Orphan Drug Designation Program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rarer diseases/disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug.

About Surufatinib

Surufatinib (previously known as HMPL-012 or sulfatinib) is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor ("VEGFR") and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies. Surufatinib is in several late-stage and proof-of-concept clinical trials in China and proof-of-concept clinical trials in the U.S.

According to Frost & Sullivan, the market for anti-angiogenesis VEGF/VEGFR inhibitors in China has grown from US$500 million in 2015 to over US$1.5 billion in 2019 and is expected to reach US$5 billion by 2026.

Chi-Med currently retains all rights to surufatinib worldwide.

Non-Pancreatic neuroendocrine tumors in China: In 2015, we initiated the SANET-ep study, a Phase III study of surufatinib in advanced neuroendocrine tumors – extra-pancreatic patients in China for whom there is no effective therapy. In June 2019, a 198 patient interim analysis was conducted, leading the independent data monitoring committee to determine that the study met the pre-defined primary endpoint of progression-free survival ("PFS") and should be stopped early.

Pancreatic neuroendocrine tumors in China: In 2016, we initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pancreatic neuroendocrine tumors in China. The primary endpoint is PFS. We expect an interim analysis in the first half of 2020 and enrollment to complete in 2020 (clinicaltrials.gov identifier: NCT02589821).

Neuroendocrine tumors in the U.S. and Europe: We are planning a U.S. registration study in neuroendocrine tumors patients based on the encouraging data from the Phase II and Phase III studies of surufatinib in neuroendocrine tumors in China (clinicaltrials.gov identifier: NCT02267967), and the ongoing Phase Ib study in the U.S. (clinicaltrials.gov identifier: NCT02549937).

Biliary tract cancer in China: In March 2019, we initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The primary endpoint is overall survival (OS) (clinicaltrials.gov identifier NCT03873532).

Immunotherapy combinations: In November 2018 and September 2019, we entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies. This included global collaborations to evaluate the combination of surufatinib with Tuoyi, approved in China by Shanghai Junshi Biosciences Co. Ltd, and with Tyvyt, approved in China by Innovent Biologics, Inc.

About Neuroendocrine Tumors (NET)

Neuroendocrine tumors form in cells that interact with the nervous system or in glands that produce hormones. They can originate in various parts of the body, most often in the gut or the lungs and can be benign or malignant. Neuroendocrine tumors are typically classified as pancreatic neuroendocrine tumors or non-pancreatic neuroendocrine tumors. Approved targeted therapies include Sutent and Afinitor for pancreatic neuroendocrine tumors, or well-differentiated, non-functional gastrointestinal or lung neuroendocrine tumors.

According to Frost and Sullivan, there were 19,000 newly diagnosed cases of neuroendocrine tumors in the U.S. in 2018. Importantly, neuroendocrine tumors are associated with a relatively long duration of survival compared to other tumors. As a result, there were approximately 141,000 estimated patients living with neuroendocrine tumors in the U.S. in 2018 of which over 90%, or approximately 132,000, were non-pancreatic neuroendocrine tumor patients.

In China, there were approximately 67,600 newly diagnosed neuroendocrine tumor patients in 2018 and, considering the current incidence to prevalence ratio in China, potentially as many as 300,000 patients living with the disease in the country1. It is estimated that approximately 80% of the patients living with neuroendocrine tumors in China are non-pancreatic neuroendocrine tumor patients.

1 According to Frost & Sullivan, in 2018, there were 19,000 newly diagnosed cases of NETs in the U.S and an estimated 141,000 patients living with NETs. The current incidence to prevalence ratio in China is estimated at 4.4, lower than the 7.4 ratio in the U.S. due to lower access to treatment options.

Genetron Closes $71 Million D Round for Cancer Diagnostics

On November 25, 2019 Genetron, a Beijing-North Carolina genomics company, reported that closed a $71 million Series D Round to develop cancer molecular diagnostics products and services (Press release, ChinaBio, NOV 25, 2019, View Source [SID1234551655]). The company’s offerings include risk assessment, early screening, molecular pathology diagnosis, medication guidance and prognosis monitoring. Its products address the needs of cancer patients and high-risk groups as well as people who show no signs of disease. The company also works with biopharmas to discover biomarkers for precision medicine drugs. The funding was led by Vivo Capital, CICC Healthcare Investment Fund and Alexandria Venture Investments

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