On November 18, 2019 AVEO Oncology (NASDAQ: AVEO) reported the presentation of updated data from the Phase 3 TIVO-3 trial (Press release, AVEO, NOV 18, 2019, View Source [SID1234551433]). The data were presented on Saturday, November 16, 2019, at the 18th International Kidney Cancer Symposium in Miami, in an oral presentation titled "TIVO-3: A Phase 3 Study to Compare Tivozanib to Sorafenib in Subjects with Refractory Advanced Renal Cell Carcinoma (RCC) Overall Survival 2-Year Update" by Sumanta (Monty) Kumar Pal, M.D., Associate Clinical Professor, Department of Medical Oncology and Therapeutics Research, and Co-director, Kidney Cancer Program, at City of Hope Comprehensive Cancer Center. TIVO-3 is the Company’s Phase 3 randomized, controlled, multi-center, open-label study to compare tivozanib (FOTIVDA), the Company’s vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), to sorafenib in 350 subjects with highly refractory metastatic RCC.

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As previously presented, results for the intent to treat (ITT) population showed that tivozanib significantly improved progression free survival (PFS), the study’s primary endpoint, and overall response rate (ORR) compared to sorafenib, with responses to tivozanib more durable than sorafenib. Newly presented data include the recently announced interim overall survival (OS) hazard ratio (HR) of 0.99 within the ITT population, as well as results from two prespecified subgroup analyses of patients previously treated with a checkpoint inhibitor and a VEGF-TKI, or two VEGFR-TKIs. Superior PFS and ORR, as well as OS HRs below 1, favoring tivozanib, were observed in the prespecified subgroups. Tivozanib was shown to have lower overall rates of adverse events and fewer dose interruptions and reductions versus sorafenib, indicating better patient tolerability. A copy of the presentation is available in the Publications & Presentations section of AVEO’s website.

"Until the TIVO-3 trial results, limited prospective data existed to inform sequencing of treatment after checkpoint inhibitor therapy, the emergent standard of care in earlier-line treatment," said Dr. Pal. "Tivozanib’s outcomes within this population, as well as in those receiving two prior VEGF-TKIs, suggest an important potential role for tivozanib in the evolving refractory advanced RCC setting. Furthermore, tivozanib’s unique tolerability profile is potentially well suited to an advanced setting, where many are reluctant to accept higher rates of adverse events following multiple courses of therapy."

"Tivozanib is the first RCC treatment to show superior outcomes over another active therapy in a Phase 3 study in the third/fourth line setting, a high unmet need population that is growing due to longer survival in earlier lines of therapy," said Michael Bailey, president and chief executive officer of AVEO. "We look forward to completing a final OS analysis of TIVO-3 in June 2020 after our planned submission of a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2020. The continued separation of the PFS curves and the positive trend in OS HR observed from the first to the second interim analyses of TIVO-3, together with tenfold more patients remaining progression free and on tivozanib vs. sorafenib therapy, make us believe that the final OS HR could continue to improve."

AVEO recently provided a regulatory update following a meeting with the FDA to discuss results from the August 2019 OS analysis of the TIVO-3 trial. The Company intends to submit an update to the TIVO-3 statistical analysis plan to the FDA allowing for the final OS analysis to be conducted, followed by an NDA submission in the first quarter of 2020, and expects to report results from a final OS analysis of the TIVO-3 trial in June 2020. The FDA and the Company agreed that if, during the review, the final analysis yields an OS HR above 1.00, the Company will withdraw its NDA application. The FDA informed the Company that an Oncologic Drugs Advisory Committee panel would likely be convened to review the final tivozanib data package.

Results in Detail

Patients enrolled in the TIVO-3 trial (n=350) were randomized and stratified for prior regimen and IMDC prognostic score. Prior treatment regimens included prior checkpoint inhibitor and VEGF TKI therapies (n=91), two prior VEGF TKI therapies (n=159) and prior VEGF TKI and other therapies (n=100). Statistically significant improvements favoring tivozanib were reported for the primary endpoint of PFS (HR=0.73; p=0.0165) and secondary endpoint of ORR (18% vs. 8%; p=0.02). Improvements were also observed in patients receiving prior checkpoint inhibitor and VEGF TKI therapies and two prior VEGF TKI therapies:

Prior Checkpoint Inhibitor + VEGFR TKI

For the secondary endpoint of OS, two prespecified analyses have been conducted, the first at a data cutoff date of October 4, 2018, and the second at August 15, 2019. The OS HR, which assesses the relative risk of death for the entirety of the data set, was 0.99 (95% CI: 0.76-1.29; p=0.95) for the ITT population at the second analysis, and improvement from an HR of 1.12 observed at the first analysis. At the second analysis, OS HR for patients receiving prior checkpoint inhibitor and VEGF TKI therapies was 0.88, and 0.98 for patients treated with two prior VEGF TKI therapies. Both hazard ratios were improved from hazard ratios of 1.14 and 1.05, respectively, observed at the first analysis.

As of the August 15, 2019 data cutoff date, median OS, a point in time value of the OS when half of the patients within each arm are still alive, was 16.4 months for tivozanib (95% CI: 13.4-22.2) and 19.7 months for sorafenib (95% CI: 15.0-24.2). As of the second data cutoff date, twenty patients remained progression free on the tivozanib arm and two on the sorafenib arm, with a median duration on study of 32.5 months.

Grade 3 or higher adverse events were consistent with those observed in previous tivozanib trials. Infrequent but severe adverse events reported in greater number in the tivozanib arm were thrombotic events similar to those observed in previous tivozanib studies. The most common adverse event in patients receiving tivozanib was hypertension, an adverse event known to reflect effective VEGF pathway inhibition.

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway, New Zealand and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib is being studied in the TIVO-3 trial, which is intended to support a regulatory submission of tivozanib in the U.S. as a treatment for relapsed/refractory RCC. Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC4. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.

On November 18, 2019, Halozyme Therapeutics, Inc. (the "Company," "we," "us" or "our") reported that completed its sale of $400.0 million in aggregate principal amount of 1.25% Convertible Senior Notes due 2024 (the " Convertible Notes") in a private placement to qualified institutional buyers pursuant to Rule 144A under the Securities Act of 1933, as amended (the "Securities Act") (Filing, 8-K, Halozyme, NOV 18, 2019, View Source [SID1234551418]). The Convertible Notes were issued under an indenture, dated as of November 18, 2019, (the "Indenture") between the Company and The Bank of New York Mellon Trust Company, N.A., as trustee (the "Trustee"). In addition, the initial purchasers of the Convertible Notes (the "Initial Purchasers") exercised their option to purchase an additional $60.0 million in aggregate principal amount of the Convertible Notes. The offer and sale of the Convertible Notes and the shares of common stock issuable upon conversion of the Convertible Notes have not been registered under the Securities Act, or the securities laws of any other jurisdiction, and the Convertible Notes and such shares may not be offered or sold absent registration or an applicable exemption from registration requirements, or in a transaction not subject to, such registration requirements.

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The Company received net proceeds from the offering of approximately $446.9 million. The Company plans to use up to $200.0 million of the net proceeds from the offering to repurchase shares of the Company’s common stock, including approximately $143.1 million to repurchase approximately 8.1 million shares of its common stock concurrently with the offering in privately negotiated transactions effected through one or more of the Initial Purchasers or an affiliate thereof and $50 million to repurchase approximately 2.1 million shares of its common stock, pursuant to and subject to adjustment as provided in the ASR Agreement as described below.

The Company used approximately $26.1 million of the net proceeds from the offering to repay all outstanding amounts under its loan agreement with Oxford Finance and Silicon Valley Bank and intends to use the remainder of the net proceeds for general corporate purposes, including additional share repurchases subsequent to the offering and working capital.

The Convertible Notes will pay interest semi-annually in arrears on June 1st and December 1st of each year, beginning on June 1, 2020, at an annual rate of 1.25% and will be convertible into cash, shares of the Company’s common stock or a combination of cash and shares of the Company’s common stock, at the Company’s election, based on the applicable conversion rate at such time. The Convertible Notes are general unsecured obligations of the Company and will rank senior in right of payment to all of the Company’s indebtedness that is expressly subordinated in right of payment to the Convertible Notes, will rank equally in right of payment with all of the Company’s existing and future liabilities that are not so subordinated, will be effectively junior to any of the Company’s secured indebtedness to the extent of the value of the assets securing such indebtedness and will be structurally subordinated to all indebtedness and other liabilities (including trade payables) of the Company’s current or future subsidiaries.

Holders may convert their Convertible Notes at their option only in the following circumstances: (1) during any calendar quarter commencing after the calendar quarter ending on March 31, 2020, if the last reported sale price per share of the Company’s common stock exceeds 130% of the conversion price for each of at least 20 trading days during the 30 consecutive trading days ending on, and including, the last trading day of the immediately preceding calendar quarter; (2) during the five consecutive business days immediately after any five consecutive trading day period (such five consecutive trading day period, the "measurement period") in which the trading price per $1,000 principal amount of notes for each trading day of the measurement period was less than 98% of the product of the last reported sale price per share of Company’s common stock on such trading day and the conversion rate on such trading day; (3) upon the occurrence of certain corporate events or distributions on Company’s common stock, as described in the offering memorandum; (4) if we call such notes for redemption; and (5) at any time from, and including, June 1, 2024 until the close of business on the scheduled trading day immediately before the maturity date. The Convertible Notes will be convertible, regardless of the foregoing circumstances, at any time from, and including, June 1, 2024 until the close of business on the scheduled trading day immediately preceding the maturity date.

Upon conversion, the Company will pay or deliver, as applicable, cash, shares of the Company’s common stock or a combination of cash and shares of the Company’s common stock, at the Company’s election. The initial conversion rate for the Convertible Notes will be 41.9208 shares of common stock per $1,000 in principal amount of Convertible Notes, equivalent to a conversion price of approximately $23.85 per share of our common stock. The conversion rate is subject to adjustment as described in the Indenture.

Subject to certain exceptions, holders may require the Company to repurchase, for cash, all or any portion thereof in an authorized denomination of their Convertible Notes upon a "Fundamental Change" (as defined in the Indenture) at a price equal to 100% of the principal amount of the Convertible Notes being repurchased plus any accrued and unpaid interest, if any, up to, but excluding, the "Fundamental Change Repurchase Date" (as

defined in the Indenture). In addition, upon a "Make-Whole Fundamental Change" (as defined in the Indenture) prior to the maturity date of the Convertible Notes, the Company will, in certain circumstances, increase the conversion rate for a specified period of time. The Company may not redeem the Convertible Notes prior to December 1, 2022 and on or before the 40th scheduled trading day immediately before the maturity date.

The Indenture includes customary covenants, and sets forth certain events of default after which the Convertible Notes may be declared immediately due and payable and sets forth certain types of bankruptcy or insolvency events of default involving the Company or certain of its subsidiaries after which the Convertible Notes become automatically due and payable.

The foregoing description of the Indenture and Convertible Notes is qualified in its entirety by reference to the text of the Indenture and the Form of Convertible Note, copies of which are attached as Exhibits 4.1 and 4.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.

On November 18, 2019 KIYATEC, Inc. and CarThera reported that they have entered into a clinical collaboration for the purpose of advancing innovation and improving treatments for patients diagnosed with glioblastoma, a highly aggressive form of brain cancer that afflicts more than 130,000 patients worldwide per year and is characterized by historically poor clinical outcomes (Press release, KIYATEC, NOV 18, 2019, View Source [SID1234551434]). The collaboration will focus on accelerating the development and validation of their emerging technologies to improve both the selection and effectiveness of drugs commonly recommended and used to treat the disease.

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"Relevant clinical advances that improve outcomes for patients with glioblastoma have been few and far between over the last two decades," said Frederic Sottilini, CEO of CarThera. "Despite multimodal therapy, median survival remains around 15 months for these patients, virtually all of whom recur. Our goal is to optimize the selection and delivery of drug therapies to extend the lives of patients with glioblastoma."

The two companies were brought together by one of the world’s leading neuro-oncology and glioblastoma experts, John de Groot, M.D., professor and chairman ad interim, The University of Texas MD Anderson Cancer Center, who recognized the synergistic nature of their respective clinical initiatives. CarThera is currently conducting a multi-center clinical study of its novel ultrasound technology, SonoCloud-9, designed to increase the permeability of the blood brain barrier to improve the delivery of chemotherapeutic agents to the brains of patients with recurrent glioblastoma. KIYATEC is conducting a multi-center clinical study of its ex vivo 3D cell culture technology to accurately predict pre-treatment, patient-specific response to recommended standard of care cancer drugs for newly diagnosed and recurrent glioblastoma.

"As someone who cares for patients with glioblastoma, I applaud the efforts of CarThera and KIYATEC to bring evidence-based advances to the clinic for the purpose of improving outcomes for patients with glioblastoma," said Dr. de Groot. "I envision these two technologies as being complementary with the potential to transform the way in which neuro-oncologists manage glioblastoma patients."

Under the terms of the clinical collaboration, KIYATEC will conduct ex vivo drug response profiling on glioblastoma tissue samples from patients enrolled in CarThera’s clinical study. CarThera will benefit from having ex vivo drug response profiling for patients enrolled in its study, while KIYATEC will correlate its patient-specific, pre-treatment drug response predictions with actual clinical outcomes of patients in CarThera’s study. For both companies, this collaboration represents an opportunity to enrich their portfolios of clinical evidence with the goal of helping clinicians improve outcomes for their patients with glioblastoma.

"Both of our companies are dedicated to ensuring that glioblastoma patients receive the most appropriate drug therapy at the right time, and that the efficacy of that therapy is maximized to its fullest therapeutic potential," said Matthew Gevaert, CEO and co-founder of KIYATEC. "We believe that this clinical collaboration has the potential to help us accelerate and deliver on the long-awaited promise of personalized medicine for these deserving patients."

Both companies will be sending delegates to the 24th Annual Meeting of the Society for Neuro-Oncology, November 20-24 in Phoenix, Arizona.

On November 18, 2019 AgilVax Inc., a biopharmaceutical company that discovers and develops targeted antibody-based therapeutics, reported that preclinical data describing M5, the Company’s monoclonal antibody targeting xCT, will be presented by Dr. Salameh at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s Tumor Immunology and Immunotherapy Conference being held at the Boston Marriott Copley Place in Boston, MA (Press release, Agilvax, NOV 18, 2019, View Source [SID1234551435]).

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Title:

Development of a monoclonal antibody targeting xCT/SLC7A11 expressed in metastatic cancer cells

Poster Session:

Poster Session B

Session Date:

Tuesday, November 19

Board Number (poster number):

B37

Time:

4:30 p.m. to 7:00 p.m.

Session Location:

Back Bay

"We are pleased with our continued progress on developing multiple solutions to target cancer cells overexpressing xCT and thrilled to have the opportunity to showcase our advancements in a poster presentation at such a prestigious meeting," said Dr. Joseph Patti, President and CEO of AgilVax. Dr. Patti further stated, "xCT overexpression occurs in several cancers leading to metabolic changes that reprograms cells for growth and progression. AgilVax’s antibody-based therapeutics have shown reduction of primary tumor formation and lung metastases illustrating the potential to create durable responses in patients suffering from colorectal and other metastatic cancers.

On November 18, 2019 Ascendis Pharma A/S (Nasdaq: ASND), a biopharmaceutical company that utilizes its innovative TransCon technologies to address unmet medical needs, reported financial results for the quarter ended September 30, 2019 (Press release, Ascendis Pharma, NOV 18, 2019, View Source [SID1234551454]).

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"Our achievements this year reflect our ability to bring a product from idea stage all the way through clinic, as we near the finish line for TransCon hGH and approach our planned regulatory filings in the United States (U.S.) and Europe," said Jan Mikkelsen, Ascendis Pharma’s President and Chief Executive Officer. "Our recent progress in the TransCon hGH program, including both in Europe and China, also support our strategy to establish global reach. The power of the TransCon technology is enabling us to build a leading fully integrated patient-focused biopharma company, and advance towards our ‘Vision 3×3’ goals."

He continued, "One of our driving values at Ascendis is patient focus. In response to the recent recall of NATPARA in the U.S., we recently expanded our TransCon PTH Phase 2 PaTH Forward Trial with a protocol addendum to help expedite participation of some of those patients affected by the recall. We believe the expanded trial will provide meaningful clinical data to help patients, both naïve to PTH and previously treated with PTH, and further demonstrate the value of our unique approach to product development."

Corporate Highlights & Progress

Completed the last subject visit for the long-term clinical database for TransCon hGH, paving the way for the company’s planned Biologics License Application to the U.S. Food and Drug Administration in the first half of 2020 and the Marketing Authorisation Application to the European Medicines Agency in the second half of 2020. TransCon hGH is a long-acting prodrug of human growth hormone (hGH) in phase 3 development as a once-weekly therapy for pediatric growth hormone deficiency (GHD).
Completed the manufacturing of drug product Process Performance Qualification (PPQ) batches required to support the planned regulatory filings in 2020 for TransCon hGH. The company is now finalizing the associated analytics and preparing qualification reports.
Advanced the TransCon hGH program in Greater China with VISEN Pharmaceuticals, who initiated a phase 3 trial for TransCon hGH in pediatric GHD.
Received Orphan Designation from the European Commission for TransCon hGH, which is provided to therapies aimed at treating, preventing or diagnosing a disease that is life-threatening or chronically debilitating, affects no more than five in 10,000 persons in the European Union and which may provide significant additional benefit over existing therapies.
Announced a protocol addendum in the U.S. designed to expedite enrollment of subjects previously treated with NATPARA in the TransCon PTH PaTH Forward Trial, a global phase 2 trial evaluating the safety, tolerability and efficacy of TransCon PTH in adult subjects with hypoparathyroidism (HP). TransCon PTH is an investigational long-acting prodrug of PTH in development as a potential once-daily replacement therapy for HP, designed to provide physiologic levels of PTH for 24 hours a day, seven days a week. Under the addendum, patients previously treated with NATPARA in the U.S. will now have an expedited pathway to enroll in PaTH Forward. As a result, the company expects to exceed targeted enrollment of 40 subjects, and plans to report top-line data from the expanded trial in first quarter of 2020. The goal of PaTH Forward is to evaluate TransCon PTH control of serum and urinary calcium, and identify a titration regimen for complete withdrawal of standard of care (i.e., active vitamin D and calcium supplements).
Initiated the ACcomplisH Trial, a global, phase 2, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of TransCon CNP, a long-acting prodrug of C-type natriuretic peptide (CNP), at escalating doses in children with achondroplasia (ACH). TransCon CNP is designed to provide continuous exposure to CNP at therapeutic levels with once-weekly dosing.
Presented preclinical data for TransCon TLR7/8 Agonist, a product candidate in development for oncology, at the Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting. TransCon TLR7/8 Agonist is prodrug of resiquimod, a small molecule with immune-activating and anti-tumor properties that is transiently conjugated to a hydrogel carrier via a TransCon linker. Administered as an intratumoral injection, TransCon TLR7/8 Agonist delivered sustained local release of resiquimod over weeks directly to the tumor site and demonstrated potent anti-tumor activity as a monotherapy, as well as in combination with interleukin-2 (IL-2).
Ended the third quarter of 2019 with cash and cash equivalents of €658.7 million.
Third Quarter 2019 Financial Results

For the third quarter, Ascendis Pharma reported a net loss of €25.1 million, or €0.53 per share (basic and diluted) compared to a net loss of €34.0 million, or €0.81 per share (basic and diluted) for the same period in 2018.

Revenue for the third quarter was €2.2 million compared to €20 thousand in the same quarter of 2018. The increase relates to our November 2018 strategic investment in VISEN Pharmaceuticals.

Research and development (R&D) costs for the third quarter were €46.3 million compared to €31.5 million during the same period in 2018. Higher R&D costs in 2019 reflect an increase in personnel-related costs to support development and manufacturing of TransCon hGH, TransCon PTH and TransCon CNP, increasing clinical trial costs for the PaTH Forward Trial and the ACcomplish Trial, as well as increased costs for other research programs, including oncology.

General and administrative expenses for the third quarter were €10.0 million compared to €6.8 million during the same period in 2018. The increase is primarily due to higher personnel-related costs and other increasing costs of expanding the company and preparing to become a commercial organization.

As of September 30, 2019, Ascendis Pharma had cash and cash equivalents of €658.7 million compared to €690.4 million as of June 30, 2019. As of September 30, 2019, Ascendis Pharma had 47,739,647 ordinary shares outstanding.

Conference Call and Webcast information

Ascendis Pharma will host a conference call and webcast today at 4:30 p.m. ET to discuss its third quarter 2019 financial results. Details include:

Date Monday, November 18, 2019
Time 4:30 p.m. ET
Dial In (U.S.) 844-290-3904
Dial In (International) 574-990-1036
Access Code 5897398
A live webcast of the conference call will be available on the Investors and News section of the Ascendis Pharma website at www.ascendispharma.com. A webcast replay will also be available on this website shortly after conclusion of the event for 30 days.