1stOncology™: Cancer Intelligence Service – Page 10594 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

PureTech Advances Wholly Owned Candidate LYT-200 into Phase 1 Trial for Potential Treatment of Metastatic Solid Tumors

On December 11, 2020 PureTech Health plc (LSE: PRTC, Nasdaq: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company dedicated to discovering, developing and commercializing highly differentiated medicines for devastating diseases, reported the initiation of its Phase 1 clinical trial of LYT-200 for the potential treatment of metastatic solid tumors that are difficult to treat and have poor survival rates (Press release, PureTech Health, DEC 11, 2020, View Source [SID1234572693]). LYT-200 is one of several novel therapeutic opportunities within PureTech’s Wholly Owned Pipeline that will be discussed today at its virtual R&D Day.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

"Each year, hundreds of thousands of people are diagnosed with solid tumors, and many will present with metastatic disease that do not respond to existing immunotherapy agents," said Zev Wainberg, M.D., co-director of the UCLA GI Oncology Program, associate professor of medicine at UCLA and the principal investigator on PureTech’s LYT-200 trial. "By targeting galectin-9, LYT-200 is designed to block foundational immunosuppressive mechanisms that shut down the body’s natural ability to fight a number of cancers. The unique mechanism of LYT-200 holds potential across a number of solid tumor types and may enable LYT-200 to be used as a single agent, as well as in combination with checkpoint inhibitors and other anti-cancer treatments."

LYT-200 is a clinical stage, fully human, monoclonal antibody (mAb), that is designed to target galectin-9, an immunosuppressive protein that simultaneously activates multiple immunosuppressive pathways in the tumor microenvironment and is prominently expressed in multiple difficult-to-treat cancers, including breast cancer, pancreatic and cholangiocarcinoma. It is currently being evaluated in the first stage of an adaptive Phase 1/2 trial. The primary objective of the Phase 1 portion of the trial is to assess the safety and tolerability of escalating doses of LYT-200 in order to identify a dose to carry forward into a subsequent Phase 2 trial. The Phase 1 will also assess LYT-200’s pharmacokinetic and pharmacodynamic profiles. Following the topline results, which are expected in the fourth quarter of 2021, PureTech intends to initiate the Phase 2 expansion cohort portion of the trial, which will further assess the recommended Phase 2 dose as a single agent or in combination with chemotherapy and anti-PD-1 therapy in multiple solid tumor types, including pancreatic cancer and cholangiocarcinoma.

"We are pleased to have initiated the Phase 1 part of our LYT-200 clinical trial, which is a dose-finding portion designed to assess safety and tolerability and explore preliminary signals of efficacy for LYT-200," said Aleksandra Filipovic, M.D. PhD, head of oncology at PureTech. "We have generated compelling preclinical data to date, which we believe support the potential of LYT-200 as a new anti-cancer therapy targeting galectin-9, both as a single agent and in combination with other anti-cancer therapies."

Dr. Zev Wainberg and Dr. Siddhartha Mukherjee, clinician and researcher at Columbia University and Pulitzer Prize-winning author of The Emperor of All Maladies and The Gene, will discuss their perspectives on the field of immuno-oncology during today’s virtual R&D Day, which will be available on the Investors section of the corporate website under Events & Presentations. To register, please sign up here.

About LYT-200

LYT-200 is a monoclonal antibody targeting a foundational immunosuppressive protein, galectin-9, for the potential treatment of solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer and cholangiocarcinoma, that are difficult to treat and have poor survival rates. PureTech has presented preclinical data demonstrating high expression of galectin-9 across breast cancer, pancreatic and cholangiocarcinoma samples and found that the highest levels of galectin-9 correlated with shorter time to disease relapse and poor survival. These data suggest that galectin-9 could be significant both as a therapeutic target for a range of cancers and as a cancer biomarker. Preclinical animal and patient-derived organoid tumor models also showed the potential efficacy of LYT-200 and the importance of galectin-9 as a target. LYT-200 is currently being evaluated in a Phase 1/2 adaptive design trial, and results from the Phase 1 portion are expected in the fourth quarter of 2021.

About PureTech’s Virtual R&D Day

The virtual R&D Day will showcase PureTech’s scientific leadership in lymphatics and related immune pathways and detail PureTech’s Wholly Owned Pipeline. Product candidates within this pipeline include LYT-100, a clinical-stage, anti-fibrotic and anti-inflammatory small molecule being advanced for the potential treatment of interstitial lung diseases and lymphedema, LYT-200, a clinical-stage monoclonal antibody targeting foundational immunosuppressive mechanisms for the potential treatment of solid tumors, and LYT-300, an oral form of allopregnanolone that is being advanced into IND-enabling studies for a range of neurological conditions. Additionally, the R&D Day will detail PureTech’s discovery platforms, including the Glyph technology platform, which is designed to target therapeutics to the lymphatic system and potentially enabling oral administration of natural bioactive molecules such as neurosteroids and cannabinoids, and the Orasome technology platform, which is designed to enable the oral administration of biotherapeutics, such as antisense oligonucleotides, short interfering RNA, mRNA, modular expression systems for therapeutic proteins, peptides and nanoparticles.

Bristol Myers Squibb Announces Settlement of U.S. Patent Litigation for REVLIMID® (lenalidomide) with Cipla

On December 11, 2020 Bristol Myers Squibb (NYSE: BMY) reported that its wholly owned subsidiary, Celgene, and Cipla Limited (Cipla) have settled their litigation related to patents for REVLIMID (lenalidomide) (Press release, Bristol-Myers Squibb, DEC 11, 2020, View Source [SID1234572692]).

As part of the settlement, the parties will file Consent Judgments with the United States District Court for the District of New Jersey that enjoin Cipla from marketing generic lenalidomide before the expiration of the patents-in-suit, except as provided for in the settlement, as described below.

In settlement of all outstanding claims in the litigation, Celgene has agreed to provide Cipla with a license to Celgene’s patents required to manufacture and sell certain volume-limited amounts of generic lenalidomide in the United States beginning on a confidential date that is some time after March 2022. For each consecutive twelve-month period (or part thereof), following the volume-limited entry date until January 31, 2026, the volume of generic lenalidomide sold by Cipla cannot exceed certain agreed-upon percentages. The specific volume-limited license date and percentages are confidential. In addition, Celgene has agreed to provide Cipla with a license to Celgene’s patents required to manufacture and sell an unlimited quantity of generic lenalidomide in the United States beginning no earlier than January 31, 2026.

Cipla’s ability to market lenalidomide in the U.S. will be contingent on its obtaining approval of an Abbreviated New Drug Application.

NANOBIOTIX Announces Pricing of Global Offering and Approval to List on NASDAQ Global Select Market

On December 11, 2020 NANOBIOTIX (Paris:NANO) (Euronext: NANO – ISIN : FR0011341205 – the ‘‘Company’’), a clinical-stage nanomedicine company pioneering new approaches to the treatment of cancer, reported the pricing of its initial public offering on the Nasdaq Global Select Market by way of a capital increase of 7,300,000 new ordinary shares (the "New Shares"), consisting of a public offering of 5,445,000 ordinary shares in the form of American Depositary Shares ("ADSs"), each representing the right to receive one ordinary share, in the United States (the "U.S. Offering") and a concurrent offering of 1,855,000 ordinary shares in certain jurisdictions outside of the United States to certain investors (the "European Offering" and together with the U.S. Offering, the "Global Offering") (Press release, Nanobiotix, DEC 11, 2020, View Source [SID1234572690]). The offering price was set at $13.50 per ADS in the U.S. Offering and a corresponding offering price of €11.14 per New Share based on an exchange rate of €1.00 = $1.2115 as published by the European Central Bank on December 10, 2020. The aggregate gross proceeds are expected to be approximately $98.6 million, equivalent to approximately €81.3 million, before deduction of underwriting commissions and estimated expenses payable by the Company. The Global Offering is expected to close on December 15, 2020, subject to the satisfaction of customary closing conditions.

All the securities sold in the Global Offering will be issued by the Company. The ADSs have been approved for listing on the Nasdaq Global Select Market and are expected to begin trading on December 11, 2020 under the ticker symbol "NBTX." The Company’s ordinary shares are listed on the regulated market of Euronext Paris under the ticker symbol "NANO."

The New Shares (some of which are represented by ADSs) sold in the Global Offering will be subject to an application for admission to trading on the regulated market of Euronext in Paris (Compartment B) on the same trading line as the existing shares under the same ISIN code FR0011341205 and are expected to be admitted to trading on December 15, 2020.

Jefferies LLC is acting as global coordinator and joint book-running manager for the Global Offering, and Evercore Group, L.L.C. and UBS Securities LLC are acting as joint book-running managers for the U.S. Offering. Gilbert Dupont is acting as manager for the European Offering (together, the "Underwriters").

Type of Offering

The New Shares will be issued through a capital increase without shareholders’ preferential subscription rights by way of a public offering and under the provisions of Article L.225-136 of the French Commercial Code (Code de commerce) and pursuant to the 2nd and 7th resolutions of the Company’s extraordinary general shareholders’ meeting held on November 30, 2020.

The offering price per New Share in euros is equal to the volume weighted average price of the Company’s ordinary shares on the regulated market of Euronext in Paris over the last three trading days preceding the start of the offering (i.e., December 7, 8 and 9, 2020), minus a discount of 9.80%, and has been determined by the Company pursuant to the 2nd resolution of the Company’s extraordinary general shareholders’ meeting held on November 30, 2020.

Option to Purchase Additional Shares

The Company has granted the Underwriters an option to purchase (the "Underwriters’ Option"), for a 30-day period (until January 9, 2021), up to 1,095,000 additional ADSs, which represents 15% of the aggregate amount of the New Shares to be issued in the Global Offering, at the same offering price.

Stabilization

In connection with the Global Offering, Jefferies LLC, acting as stabilization agent, may over-allot the securities or effect transactions with a view to supporting, stabilizing, or maintaining the market price of the securities at a level higher than which might otherwise prevail in the open market. However, there is no assurance that the stabilization agent will take any stabilization action and, if begun, may be ended at any time without prior notice. Any stabilization action or over-allotment shall be carried out in accordance with all applicable rules and regulations and may be undertaken on the regulated market of Euronext in Paris and on the Nasdaq Global Select Market.

Dilution

The 7,300,000 New Shares to be issued in the Global Offering (5,445,000 of which are ordinary shares represented by ADSs) will result in a dilution of approximately 28% of the Company’s outstanding share capital on a non-diluted basis excluding the exercise of the Underwriters’ Option, and approximately 32% of the Company’s outstanding share capital on a non-diluted basis, in the case of a full exercise of the Underwriters’ Option.

Estimated Proceeds from the Global Offering

The gross proceeds of the issuance of the New Shares are expected to be approximately $98.6 million (€81.3 million), assuming no exercise of the Underwriters’ Option.

The Company estimates that the net proceeds of the Global Offering will be approximately $86.7 million (€71.5 million), after deducting approximately $6.9 million (€5.7 million) in underwriting commissions and approximately $5.0 million (€4.1 million) in estimated offering expenses.

The Company expects to use the net proceeds from the Global Offering to advance the overall development of NBTXR3, prioritizing the treatment of locally advanced head and neck cancers, as follows (assuming an exchange rate of €1.00 = $1.2115, the exchange rate on December 10, 2020):

approximately $48.5 million (€40 million) to advance its clinical trial of NBTXR3 in the United States and Europe for the treatment of locally advanced head and neck cancers through an interim analysis of efficacy data,
approximately $18.2 million (€15 million) to advance the development of its other clinical and pre-clinical programs, and
the remainder for working capital funding and other general corporate purposes.
As of September 30, 2020, the Company had cash and cash equivalents of €42.4 million (non audited). The Company believes that the net proceeds from the Global Offering, together with its cash and cash equivalents, will be sufficient to fund its operations through the first quarter of 2023.

Underwriting

The Global Offering is subject to an underwriting agreement entered into on December 10, 2020. The underwriting agreement does not constitute a "garantie de bonne fin" within the meaning of Article L. 225-145 of the French Commercial Code (Code de commerce).

Documentation

The Company has filed a registration statement, including a prospectus, relating to these securities with the U.S. Securities and Exchange Commission ("SEC"), which was declared effective by the SEC on December 10, 2020. The securities referred to in this press release will be offered only by means of a prospectus in the United States. Copies of the final prospectus relating to and describing the terms of the Global Offering can be obtained, when available, from Jefferies LLC, 520 Madison Avenue New York, NY 10022, or by telephone at 877-547-6340 or 877-821-7388, or by email at [email protected]; or from Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, New York 10055, or by telephone at 888-474-0200, or by email at [email protected]; or from UBS Securities LLC, Attention: Prospectus Department, 1285 Avenue of the Americas, New York, New York 10019, or by telephone at 888-827-7275, or by email at [email protected].

Application will be made to list the New Shares on the regulated market of Euronext in Paris pursuant to a listing prospectus subject to an approval from the French Autorité des Marchés Financiers ("AMF") and comprising the 2019 Universal Registration Document (Document d’Enregistrement Universel) of the Company filed with the AMF on May 12, 2020 under number R.20-010, as completed by a first amendment to such Universal Registration Document filed with the AMF on November 20, 2020 under number D.20-0339-A01 and a second amendment to such Registration Document, which will be filed on December 11, 2020 as well as a Securities Note (Note d’opération), including a summary of the prospectus. Following the filing of the second amendment to the 2019 Universal Registration Document, copies of the 2019 Universal Registration Document, as amended, will be available free of charge at the Company’s head office located at 60 rue de Wattignies, 75012 Paris, France, on the Company’s website (www.nanobiotix.com) and on the AMF’s website (www.amf-france.org).

The final prospectus will also be available at www.sec.gov. This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, 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.

Risk Factors

Investors should carefully consider the risk factors likely to affect the Company’s business as described in Section 1.5 "Risk Factors" in the 2019 Universal Registration Document, in Section 3 "Risk Factors" of the first amendment to the 2019 universal registration document and in Section 4 "Risk Factors" of the second amendment to the 2019 universal registration document expected to be filed with the AMF on December 11, 2020 before making an investment decision. If any of these risks are realized, the Company’s business, financial condition, operating results and prospects could be materially and adversely affected. In addition, other risks, not identified or considered significant by the Company, could have the same adverse effect and investors could lose all or part of their investment.

Allocation of the Share Capital

The following table presents the expected allocation of the Company’s share capital following the settlement and delivery of the New Shares (5,445,000 of which are ordinary shares represented by ADSs):

Positive Results of CONTESSA, a Phase 3 Study of Tesetaxel in Patients with Metastatic Breast Cancer, Presented at the 2020 San Antonio Breast Cancer Symposium (SABCS)

On December 11, 2020 Odonate Therapeutics, Inc. (NASDAQ: ODT), a pharmaceutical company dedicated to the development of best‑in‑class therapeutics that improve and extend the lives of patients with cancer, reported that positive results from CONTESSA, a Phase 3 study of tesetaxel in patients with metastatic breast cancer (MBC), were presented in an oral presentation at the 2020 San Antonio Breast Cancer Symposium (SABCS) (Press release, Odonate Therapeutics, DEC 11, 2020, View Source [SID1234572689]). The results were presented by Joyce O’Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Texas Oncology and Chair, Breast Cancer Research, US Oncology, and Co‑Principal Investigator of CONTESSA (please click here for slides).

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with MBC. CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21‑day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21‑day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21‑day cycle) in 685 patients randomized 1:1 with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard‑of‑care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin‑dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression‑free survival (PFS) as assessed by the Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC. CONTESSA is being conducted at 180 investigational sites in 18 countries in North America, Europe and Asia.

CONTESSA met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for the approved dose of capecitabine alone, an improvement of 2.9 months. The risk of disease progression or death was reduced by 28.4% [hazard ratio=0.716 (95% confidence interval: 0.573-0.895); p=0.003] for tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone.

The ORR as assessed by the IRC was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for the approved dose of capecitabine alone (p=0.0002). The DCR as assessed by the IRC was 67% for tesetaxel plus a reduced dose of capecitabine versus 50% for the approved dose of capecitabine alone (p<0.0001). While OS data are immature, a recent interim analysis indicated the absence of an adverse effect on OS with tesetaxel plus a reduced dose of capecitabine. A protocol‑specified final analysis of OS is expected to occur in 2022.

Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with findings from previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients were: neutropenia (70.9% for tesetaxel plus capecitabine vs. 8.3% for capecitabine alone); diarrhea (13.1% for tesetaxel plus capecitabine vs. 8.9% for capecitabine alone); hand‑foot syndrome (6.8% for tesetaxel plus capecitabine vs. 12.2% for capecitabine alone); febrile neutropenia (13.1% for tesetaxel plus capecitabine vs. 1.2% for capecitabine alone); fatigue (8.6% for tesetaxel plus capecitabine vs. 4.5% for capecitabine alone); hypokalemia (8.6% for tesetaxel plus capecitabine vs. 2.7% for capecitabine alone); leukopenia (9.8% for tesetaxel plus capecitabine vs. 0.9% for capecitabine alone); and anemia (8.0% for tesetaxel plus capecitabine vs. 2.4% for capecitabine alone).

Adverse events resulting in treatment discontinuation in ≥1% of patients were: neutropenia or febrile neutropenia (4.2% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); neuropathy (3.6% for tesetaxel plus capecitabine vs. 0.3% for capecitabine alone); sepsis or septic shock (1.8% for tesetaxel plus capecitabine vs. 0.6% for capecitabine alone); diarrhea (0.9% for tesetaxel plus capecitabine vs. 1.5% for capecitabine alone); and hand-foot syndrome (0.6% for tesetaxel plus capecitabine vs. 2.1% for capecitabine alone). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone.

Tesetaxel dose reductions occurred in 76% of patients treated with tesetaxel plus capecitabine, primarily due to neutropenia. Dose reductions occurred in 61% of patients treated with capecitabine alone, primarily due to hand-foot syndrome. The relative delivered dose intensity, which accounts for not only the frequency, but also the magnitude of reductions and treatment adherence, was higher in patients treated with tesetaxel plus capecitabine. Specifically, 81% of the intended dose of tesetaxel through cycle 12 was delivered in patients treated with tesetaxel plus capecitabine versus 76% of the intended dose of capecitabine through cycle 12 in patients treated with capecitabine alone.

Grade 2 alopecia (hair loss) occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. There were no treatment-related hypersensitivity reactions.

"Tesetaxel represents a potential important clinical advance for patients with metastatic breast cancer," said Joyce O’Shaughnessy, M.D. "There remains a significant unmet medical need for novel therapies that offer quality‑of‑life advantages for patients with metastatic breast cancer."

"The PFS improvement observed in CONTESSA, along with once‑every‑three‑weeks oral dosing and low rates of clinically significant hair loss and neuropathy, could make tesetaxel an important new treatment option for patients with metastatic breast cancer," said Andrew Seidman, M.D., Medical Director, Bobst International Center, Memorial Sloan Kettering Cancer Center and Professor of Medicine, Weill Cornell Medical College, and Co‑Principal Investigator of CONTESSA.

"We would like to thank all of the investigators, study team personnel, and especially the patients and their caregivers who made CONTESSA possible," said Kevin Tang, Chief Executive Officer of Odonate. "We look forward to working closely with global regulatory authorities to make tesetaxel available to patients with metastatic breast cancer. We plan to submit a New Drug Application for tesetaxel to the FDA in mid‑2021."

The Company will host a Virtual Investor and Analyst Event today at 1:00 p.m. CT / 2:00 p.m. ET.

Virtual Investor and Analyst Event Information

Date: December 11, 2020
Time: 1:00 p.m. CT / 2:00 p.m. ET
Webcast Link: Please click here
Dial-in (domestic): (866) 300-4090
Dial-in (international): (636) 812‑6660
Conference ID: 8698553

About Tesetaxel

Tesetaxel is an investigational, orally administered chemotherapy agent that belongs to a class of drugs known as taxanes, which are widely used in the treatment of cancer. Tesetaxel has several pharmacologic properties that make it unique among taxanes, including: oral administration with a low pill burden; a long (~8-day) terminal plasma half-life in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing; no history of hypersensitivity (allergic) reactions; and significant activity against chemotherapy-resistant tumors. In patients with metastatic breast cancer, tesetaxel was shown to have significant, single-agent antitumor activity in two multicenter, Phase 2 studies. Tesetaxel currently is the subject of three studies in breast cancer, including a multinational, multicenter, randomized, Phase 3 study in patients with metastatic breast cancer, known as CONTESSA. Positive results of CONTESSA were recently presented at the 2020 San Antonio Breast Cancer Symposium.

About CONTESSA

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel, an investigational, orally administered taxane, in patients with metastatic breast cancer (MBC). CONTESSA is comparing tesetaxel dosed orally at 27 mg/m2 on the first day of each 21-day cycle plus a reduced dose of capecitabine (1,650 mg/m2/day dosed orally for 14 days of each 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day dosed orally for 14 days of each 21-day cycle) in 685 patients randomized 1:1 with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)‑negative MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in MBC. Where indicated, patients must have received endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. The primary endpoint is progression-free survival (PFS) as assessed by an Independent Radiologic Review Committee (IRC). The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC.

BAVENCIO® (AVELUMAB) RECEIVES POSITIVE CHMP OPINION FOR FIRST-LINE MAINTENANCE TREATMENT OF LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA

On December 11, 2020 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of BAVENCIO (avelumab) as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who are progression-free following platinum-based chemotherapy (Press release, EMD Serono, DEC 11, 2020, View Source [SID1234572687]). The CHMP positive opinion will now be reviewed by the European Commission (EC), with a decision expected in early 2021.

The opinion was based on positive findings from the Phase III JAVELIN Bladder 100 trial, results of which were published in The New England Journal of Medicine in September.1 BAVENCIO is the only immunotherapy to significantly prolong overal survival (OS) in locally advanced or metastatic UC in the first-line setting in a Phase III trial.

"Patients living with locally advanced or metastatic urothelial carcinoma in Europe are in urgent need of more treatment options that have the potential to extend their lives," said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "The overall survival results from JAVELIN Bladder100 show the potential benefits of a first-line maintenance approach with BAVENCIO as a significant advancement for patients with locally advanced or metastatic urothelial carcinoma."

Bladder cancer is the tenth most common cancer worldwide.2 In Europe alone, nearly 200,000 people are diagnosed with bladder cancer each year and more than 60,000 patients die from the disease, despite available treatments.3 UC, which accounts for about 90% of all bladder cancers, becomes harder to treat as it advances, spreading through the layers of the bladder wall.4,5 For patients with advanced UC, the five-year survival rate is 5%.6 About 4% of bladder cancers are diagnosed at an advanced stage.7

"BAVENCIO is the only immunotherapy treatment to demonstrate in the first-line setting the ability to help patients with locally advanced or metastatic urothelial carcinoma live longer," said Danny Bar-Zohar, M.D., Global Head of Development for the Biopharma business of Merck KGaA, Darmstadt, Germany. "Now with this positive opinion, we have come a big step closer to being able to offer a new option that may shift the treatment paradigm for patients in Europe."

In June 2020, the US Food and Drug Administration (FDA) approved BAVENCIO for the maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy. Additional regulatory applications have been submitted in Japan and other countries.

About JAVELIN Bladder 100

JAVELIN Bladder 100 (NCT02603432) is a Phase III, multicenter, multinational, randomized, open-label, parallel-arm study investigating first-line maintenance treatment with BAVENCIO plus best supportive care (BSC) versus BSC alone in patients with locally advanced or metastatic UC. A total of 700 patients whose disease had not progressed after platinum-based induction chemotherapy as per RECIST v1.1 were randomly assigned to receive either BAVENCIO plus BSC or BSC alone. The primary endpoint was OS in the two primary populations of all patients and patients with PD-L1+ tumors.

About BAVENCIO (avelumab)

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.8-10 In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications

BAVENCIO (avelumab) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

BAVENCIO in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

BAVENCIO is currently approved for patients in 50 countries for at least one use.

BAVENCIO Important Safety Information from the US FDA-Approved Label BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), lif e-threatening (Grade 4), or recurrent moderate

(Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with fatal, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or lif e-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with fatal, and 11 (0.6%) with Grade 3.

BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and axitinib for moderate (Grade

2) hepatotoxicity and permanently discontinue the combination for severe or lif e-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with axitinib, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinued for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or lif e-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and control hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or lif e-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or lif e-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for lif e-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or af ter treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently

discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune- mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune- mediated adverse reaction that recurs and for any lif e-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune- mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe or lif e-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade

1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or lif e-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO in combination withaxitinib can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3- 4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise

females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient with locally advanced or metastatic urothelial carcinoma (UC) receiving BAVENCIO plus best supportive care (BSC) as first-line maintenance treatment. In patients with previously treated locally advanced or metastatic UC, fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

The most common adverse reactions (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO plus BSC (vs BSC alone) as f irst- line maintenance treatment were fatigue (35% vs 13%), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2.3%). In patients with previously treated locally advanced or metastatic UC receiving BAVENCIO, the most common adverse reactions (all grades, ≥20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Selected laboratory abnormalities (all grades, ≥20%) in patients with locally advanced or metastatic UC receiving BAVENCIO plus BSC (vs BSC alone) as f irst- line maintenance treatment were blood triglycerides increased (34% vs 28%), alkaline phosphatase increased (30% vs 20%), blood sodium decreased (28% vs 20%), lipase increased (25% vs 16%), aspartate aminotransferase (AST) increased (24% vs 12%), blood potassium increased (24% vs 16%), alanine aminotransferase(ALT) increased (24% vs 12%), blood cholesterol increased (22% vs 16%), seruma mylase increased (21% vs 12%), hemoglobin decreased (28% vs 18%), and white blood cell decreased (20% vs 10%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

The most common adverse reactions (all grades, ≥20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).