On September 30, 2019, Thermo Fisher Scientific Inc. (the "Company") reported that issued €800,000,000 aggregate principal amount of 0.125% Senior Notes due 2025 (the "2025 Notes"), €800,000,000 aggregate principal amount of 0.500% Senior Notes due 2028 (the "2028 Notes"), €900,000,000 aggregate principal amount of 0.875% Senior Notes due 2031 (the "2031 Notes"), €900,000,000 aggregate principal amount of 1.500% Senior Notes due 2039 (the "2039 Notes") and €1,000,000,000 aggregate principal amount of 1.875% Senior Notes due 2049 (the "2049 Notes", and, together with the 2025 Notes, 2028 Notes, 2031 Notes and 2039 Notes, the "Notes"), in a public offering (the "Euro Offering") pursuant to a registration statement on Form S-3 (File No. 333-229951), and a preliminary prospectus supplement and prospectus supplement related to the offering of the Notes, each as previously filed with the Securities and Exchange Commission (the "SEC") (Filing, 8-K, Thermo Fisher Scientific, SEP 30, 2019, View Source [SID1234551118]).

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!

On October 8, 2019, the Company plans to issue $900,000,000 aggregate principal amount of 2.600% Senior Notes due 2029 (the "USD Offering").

The Notes are subject to a Paying Agency Agreement (the "Paying Agency Agreement"), dated as of September 30, 2019, between the Company and The Bank of New York Mellon, London Branch, as paying agent. The Notes were issued under an indenture, dated as of November 20, 2009 (the "Base Indenture"), and the Eighteenth Supplemental Indenture, dated as of September 30, 2019 (the "Supplemental Indenture" and, together with the Base Indenture, the "Indenture"), between the Company, as issuer, and The Bank of New York Mellon Trust Company, N.A., as trustee. The sale of the Notes was made pursuant to the terms of an Underwriting Agreement, dated September 24, 2019 (the "Underwriting Agreement"), among the Company, as issuer, and Merrill Lynch International, Goldman Sachs & Co. LLC, Citigroup Global Markets Limited and J.P. Morgan Securities plc as lead managers of the several underwriters named in Schedule A to the Underwriting Agreement. The Underwriting Agreement was separately filed with the SEC on September 25, 2019 as Exhibit 1.1 to the Company’s Current Report on Form 8-K.

The 2025 Notes will mature on March 1, 2025, the 2028 Notes will mature on March 1, 2028, the 2031 Notes will mature on October 1, 2031, the 2039 Notes will mature on October 1, 2039 and the 2049 Notes will mature on October 1, 2049. Interest on the 2025 Notes and the 2028 Notes will be paid annually in arrears on March 1 of each year, beginning on March 1, 2020, and interest on the 2031 Notes, the 2039 Notes and the 2049 Notes will be paid annually in arrears on October 1 of each year, beginning on October 1, 2020.

Prior to February 1, 2025, in the case of the 2025 Notes (one month prior to their maturity), December 1, 2027, in the case of the 2028 Notes (three months prior to their maturity), July 1, 2031, in the case of the 2031 Notes (three months prior to their maturity), April 1, 2039, in the case of the 2039 Notes (six months prior to their maturity), and April 1, 2049, in the case of the 2049 Notes (six months prior to their maturity) (each such date, a "Par Call Date"), the Company may redeem the Notes of any series, in whole at any time or in part from time to time, at a redemption price equal to the greater of (1) 100% of the principal amount of the notes to be redeemed and (2) the sum of the present values of the remaining scheduled payments of principal and interest in respect of the notes being redeemed (not including any portion of the payments of interest accrued but unpaid as of the date of redemption and assuming that such notes to be redeemed matured on their applicable Par Call Date), discounted to the date of redemption on an annual basis (ACTUAL/ACTUAL (ICMA)), using a discount rate equal to the Comparable Bond Rate (as defined in the Indenture) plus 20 basis points, in the case of the 2025 Notes, 20 basis points, in the case of the 2028 Notes, 25 basis points, in the case of the 2031 Notes, 30 basis points, in the case of the 2039 Notes, and 35 basis points, in the case of the 2049 Notes, plus, in each case, accrued and unpaid interest on the Notes being redeemed, if any, to, but excluding, the date of redemption.

In addition, on and after the applicable Par Call Date, the Company may redeem some or all of the Notes at a redemption price equal to 100% of the principal amount of the notes to be redeemed, plus accrued and unpaid interest, if any, to, but excluding the date of redemption.

Upon the occurrence of a change of control (as defined in the Indenture) of the Company and a contemporaneous downgrade of the Notes below an investment grade rating by at least two of Moody’s Investors Service, Inc., S&P Global Ratings, a division of S&P Global, Inc., and Fitch Ratings Limited, the Company will, in certain circumstances, be required to make an offer to purchase the Notes at a price equal to 101% of the principal amount of the Notes, plus any accrued and unpaid interest, if any, to, but excluding, the date of repurchase.

The Notes are general unsecured obligations of the Company. The Notes rank equally in right of payment with existing and any future unsecured and unsubordinated indebtedness of the Company, including any debt securities issued in the USD Offering, and will rank senior in right of payment to

any existing and future indebtedness of the Company that is subordinated to the Notes. The Notes are also effectively subordinated to any existing and future secured indebtedness of the Company to the extent of the assets securing such indebtedness, and are structurally subordinated to all existing and any future indebtedness and any other liabilities of its subsidiaries.

The Indenture contains limited affirmative and negative covenants of the Company. The negative covenants restrict the ability of the Company and its subsidiaries to incur debt secured by liens on Principal Properties (as defined in the Indenture) or on shares of stock of the Company’s Principal Subsidiaries (as defined in the Indenture) and engage in sale and lease-back transactions with respect to any Principal Property. The Indenture also limits the ability of the Company to merge or consolidate or sell all or substantially all of its assets.

Upon the occurrence of an event of default under the Indenture, which includes payment defaults, defaults in the performance of affirmative and negative covenants, bankruptcy and insolvency related defaults and failure to pay certain indebtedness, the obligations of the Company under the Notes may be accelerated, in which case the entire principal amount of the Notes would be immediately due and payable.

The Company expects that the net proceeds will be approximately €4.33 billion from the Euro Offering and $890.68 million from the USD Offering, each after deducting underwriting discounts and estimated offering expenses. The Company intends to use the net proceeds of the offerings (together with cash on hand) to repay commercial paper issued to fund the redemption on September 27, 2019 of $300 million aggregate principal amount of 4.70% Senior Notes due 2020 and $800 million aggregate principal amount of 3.15% Senior Notes due 2023, and to fund the redemption of approximately $4.5 billion aggregate principal amount of outstanding senior notes issued by the Company or its subsidiaries, including all of the outstanding 6.00% Senior Notes due 2020 and 5.00% Senior Notes due 2021 issued by its subsidiary Life Technologies Corporation, of which notice was provided to holders on September 25, 2019, and all of the October 15 Redeemed Notes (as defined below).

Wilmer Cutler Pickering Hale and Dorr LLP, U.S. counsel to the Company, has issued an opinion to the Company, dated September 30, 2019, regarding the Notes. A copy of this opinion is filed as Exhibit 5.1 hereto.

The foregoing description of certain of the terms of the Indenture does not purport to be complete and is qualified in its entirety by reference to the full text of each of the Base Indenture and the Supplemental Indenture, which are filed with this report as Exhibits 4.1 and 4.2 hereto, respectively. Each of the foregoing documents is incorporated herein by reference.

On September 30, 2019 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology (I-O) company with a pipeline of immune checkpoint antibodies, adoptive cell therapies1 and cancer vaccines, reported that Jennifer Buell, PhD, Chief Operating Officer of Agenus, present an update on Agenus’ progress and host one-on-one meetings with investors at the 2019 Cantor Global Healthcare Conference on October 4th, 2019 at the InterContinental New York Barclay Hotel (Press release, Agenus, SEP 30, 2019, View Source [SID1234539919]).

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!

The presentation will be webcast live and may be accessed by visiting the "Events & Presentations" page within the Investors section of the Agenus website www.agenusbio.com or by using the link below. A replay of the webcast will be available on the Agenus website following the conference.

Date: Friday, October 4, 2019

Time: 8:20 A.M. ET

Webcast: View Source

On September 30, 2019 Sarcoma Research Groups in Spain, France and Italy, in collaboration with PharmaMar (MSE:PHM), reported that have presented the results of the metastatic patient group cohort from the single-arm, phase II multicenter study of trabectedin in combination with low-dose radiation therapy for the treatment of Soft Tissue Sarcoma (STS) (Press release, PharmaMar, SEP 30, 2019, View Source [SID1234539935]). The results were presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, which is being held from September 27th to October 1st in Barcelona.

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!

The study, led by Dr. Martín Broto, oncologist at the Virgen del Rocío University Hospital in Seville (Spain), has reached its primary endpoint of Overall Response Rate (ORR), with 55.6% of responses to the treatment.

Trabectedin in combination with a low-dose of radiotherapy has shown relevant activity in a wide range of soft tissue sarcoma types in patients with advanced metastatic disease, giving other therapeutic options for tumor reduction beyond the first line of treatment.

In addition, this combination has shown a significant impact on Progression Free Survival (PFS) and Overall Survival (OS) in patients with advanced disease who have received a median of two previous lines of treatment. The six-month median for PFS was 75%, while the six-month median for OS was reached by 86% of patients.

Legal warning
This press release does not constitute an offer to sell or the solicitation of an offer to buy securities, and shall not constitute an offer, solicitation or sale in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of that jurisdiction.

On September 30, 2019 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported promising safety and efficacy data of TG4001 in combination with avelumab (BAVENCIO), a human anti-programmed death ligand (PD-L1) antibody, in HPV-16+ recurrent or metastatic malignancies (including oropharyngeal cancers) (Press release, Transgene, SEP 30, 2019, View Source [SID1234539954]). These Phase 1b data have been presented in a poster (#1210P) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain. TG4001 is a therapeutic vaccine based on a Vaccinia vector (MVA), which is engineered to express HPV-16 antigens (E6 & E7). It has been administered to more than 300 individuals in previous trials, demonstrating good safety, significant HPV clearance rate and promising efficacy results.

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!

In the Phase 1b part of the trial, 9 heavily pretreated patients received either one of the two tested doses of TG4001 combined with a fixed dose of avelumab. The Phase 2 part of the trial started in October 2018 and will enroll 40 patients.

Key results of the Phase 1b trial are:

3 of the 6 patients treated with the higher dose of TG4001 showed durable partial responses1.
No dose-limiting toxicity was observed, confirming a good safety profile of the combined regimen.
T cell responses against the HPV-16 E6 and E7 antigens were detected in patients’ blood at day 43.
The combination regimen was able to prime the immune system and modified positively the tumors microenvironment. Patients displayed increased immune cells infiltrates (including CD8 T cells) and an increased expression of genes associated with innate and adaptive immune response.
An increase in PD-L1 expression in the tumor cells was seen.
Dr. Maud Brandely, MD, PhD, Chief Medical Officer of Transgene, commented, "These Phase 1b results with a combination treatment regimen containing TG4001 are promising. In this heavily pretreated population, the quality of the responses, in particular the duration of the responses, and the immune changes in the tumor, give us great confidence that we will see a positive outcome from the ongoing Phase 2 part of the trial. The results also confirm our conviction that a HPV-16 targeted therapeutic vaccine would be able to stimulate the immune response, and can advantageously be combined with an immune checkpoint inhibitor. Based on these results, I believe that the combination of TG4001 and an ICI could potentially offer a much-improved treatment option than single agent immune checkpoint inhibitor for patients with HPV-16+ recurrent or metastatic malignancies. Patient accrual in the Phase 2 part of the trial is in line with our expectations and the next clinical readout is expected in 1H 2020."

Poster presentation – September 30, 2019, 12:00-13:00 – Poster Area Hall 4
Title: Phase Ib/II trial of TG4001 (Tipapkinogene sovacivec), a therapeutic HPV-vaccine, and Avelumab in patients with recurrent/metastatic HPV16 positive cancers (ID 2536)
Poster #1210P | Presenter: Christophe Le Tourneau (Institut Curie, Paris, France)

The abstract is available on the ESMO (Free ESMO Whitepaper) website.
The poster is available on Transgene’s website (Publication section) www.transgene.fr.

About the trial
This multi-center, open-label trial is assessing the safety and tolerability, as well as the anti-tumor activity of this immunotherapy combination regimen (TG4001 + avelumab) in approximately 50 patients with HPV-16 positive cancers who had failed at least one line of systemic treatment for R/M disease (NCT03260023). Prof. Christophe Le Tourneau, M.D., PhD, Head of the Department of Drug Development and Innovation (D3i) at the Curie Institute, and a world expert in head and neck cancers, is the Principal Investigator of the study. The trial is conducted in collaboration with Merck KGaA, Darmstadt, Germany, a leading science and technology company which in the US and Canada operates its biopharmaceutical business as EMD Serono, and Pfizer Inc (NYSE: PFE).
In the Phase 1 part, 9 patients were enrolled to either one of the two doses of the vaccine (5×106 and 5×107 pfu). TG4001 was administered SC weekly for 6 weeks, every 2 weeks up to M6, and every 12 weeks thereafter. Avelumab was given IV at 10 mg/kg every 2 weeks. Tumor response was assessed by RECIST 1.1. For translational and immunological assessments, PBMC samples were collected longitudinally and tissue samples were collected at baseline and D43.
The Phase 2 part of the trial started in October 2018. 40 patients will be enrolled. They will receive the highest TG4001 dose tested in the Phase 1b part of the trial (5×107 pfu), in combination with avelumab at 10 mg/kg. The primary endpoint of the Phase 2 part is overall response rate. Secondary endpoints include progression free survival, overall survival, disease control rate and other immunological parameters. The interim readout is expected in 1H 2020.

More information on the trial is available on clinicaltrials.gov.

A conference call in English is scheduled on October 3, 2019, at 2:30 p.m. CET.

Webcast link to conference call:
https://channel.royalcast.com/webcast/transgene/20191003_1/

Participant telephone numbers:

France: +33 (0) 1 7037 7166

United Kingdom: +44 (0) 20 3003 2666

United States: +1 212 999 6659

Confirmation code: Transgene

A replay of the call will be available on the Transgene website (www.transgene.fr) following the live event.

***

About HPV-Positive Cancers
HPV-positive cancers comprise a variety of malignancies, including head and neck cancers and anogenital cancers. Squamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous group of cancers that can affect the oral cavity, pharynx, and larynx. The incidence of HPV16-related SCCHN has significantly increased in recent years. HPV16 infection is associated with more than 85% of oropharynx squamous cell carcinomas (Kreimer et al., 2005), i.e. approximately 10,000 patients at metastatic stage and receiving a second line of treatment. Other HPV16-positive cancers include cervical, vaginal, vulvar and penile cancers, i.e. approximately 15,000 cancers at metastatic stage and eligible for a second line of treatment. (Source: meta-analysis, IARC, Globocan, SEER – EU28, USA, 2022).

Current treatments include surgical resection with radiotherapy, chemoradiotherapy or immune checkpoint inhibitors. However, better options are needed for advanced and metastatic HPV+ cancers. It is thought that immunotherapy combined with immune checkpoint inhibitors could provide a promising potential treatment option that would address this strong medical need. With immune checkpoint inhibitors, median overall survival remains inferior to 11 months and median progression-free survival is between 2 and 4 months. In this heterogenous group of malignancies, overall response rates are around 10-15%.

About TG4001
TG4001 is an investigational therapeutic vaccine based on a non-propagative, highly attenuated Vaccinia vector (MVA), which is engineered to express HPV-16 antigens (E6 & E7) and an adjuvant (IL-2). TG4001 is designed to have a two-pronged antiviral approach: to alert the immune system specifically to HPV-16-infected cells that have started to undergo precancerous transformation (cells presenting the HPV-16 E6 and E7 antigens) and to further stimulate the infection-clearing activity of the immune system through interleukin 2 (IL-2). TG4001 has been administered to more than 300 individuals, demonstrating good safety, significant HPV clearance rate and promising efficacy results (Harper et al., Gynecologic Oncology, 2019). Its mechanism of action and good safety profile make TG4001 an excellent candidate for combinations with other therapies in HPV-mediated solid tumors.

Avelumab Approved Indications
Avelumab (BAVENCIO) in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
The US Food and Drug Administration (FDA) also granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) 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. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Avelumab is currently approved for patients with MCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

Avelumab Important Safety Information from the US FDA-Approved Label
The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis and hepatitis [including fatal cases], colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions [which can be severe and have included fatal cases]), infusion-related reactions, hepatotoxicity, major adverse cardiovascular events (MACE) [which can be severe and have included fatal cases], and embryo-fetal toxicity.
Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO monotherapy include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, peripheral edema, decreased appetite/hypophagia, urinary tract infection and rash. Common adverse reactions (reported in at least 20% of patients) in patients receiving BAVENCIO in combination with axitinib include diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain and headache. Clinical chemistry and hematology laboratory value abnormalities reported in at least 10% of patients include hyponatremia, lymphopenia, GGT increased, blood triglyceride increased and lipase increased, and grade 3-4 lymphopenia, anemia, elevated cholesterol and liver enzymes.
For full Prescribing Information and Medication Guide for BAVENCIO, please see www.BAVENCIO.com.

On September 30, 2019 Evotec SE (Frankfurt Stock Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809) and Indivumed GmbH reported that the first milestone has been successfully achieved in their joint collaboration to identify new therapeutic targets for the treatment of colorectal cancer (Press release, Evotec, SEP 30, 2019, View Source;announcements/press-releases/p/evotec-and-indivumed-achieve-milestone-in-joint-strategic-drug-discovery-collaboration-5849 [SID1234539900]).

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!

Under the terms of the collaboration agreement, Evotec received full access to the colorectal cancer ("CRC") multi-omics data of IndivuType. The milestone of selecting three novel drug targets was achieved in less than three months.

The first set of identified targets will now be progressed towards first-in-class therapeutics for the treatment of CRC using Evotec’s multimodality drug discovery and development platforms. Four additional candidate targets identified by Indivumed’s bioinformatic and analytics will also enter the joint development programme.

Indivumed’s commitment to generating high quality and extensive cancer patient information is complementary and synergistic to Evotec’s expertise in analysing highly complex multi-omics data. Evotec will be responsible for subsequent partnering of the programmes and/or the platform.

Dr Cord Dohrmann, Chief Scientific Officer of Evotec, said: "The rapid identification of truly novel drug targets reflects the power of our approach to precision medicine that we are pursuing together with Indivumed. The rigorous quality standards employed by Indivumed in the generation of the IndivuType multi-omics patient database enables novel insights into target-disease associations in colorectal cancer which are expected to deliver more effective treatment options."

Prof. Dr Hartmut Juhl, Chief Executive Officer of Indivumed, said: "We are pleased with the rapid progress being made in our collaboration with Evotec to discover novel drugs that will advance the treatment of colorectal cancer (CRC) patients and potentially other cancer entities. IndivuType has enabled CRC subpopulations to be characterised based on molecular phenotypes with greater precision than has been possible before. As a result, the targets that have been identified are expected to deliver more effective and durable drugs to transform CRC patient care."

DOWNLOADS
Press release
PDF, 253.9 KB
About Colorectal Cancer ("CRC")
Colorectal cancer, a cancer that starts in the colon or rectum is the third most common malignancy and the fourth leading cause of cancer-related deaths worldwide. Rapid increases in both CRC incidence and mortality are now observed in Eastern Europe, Asia, and South America. In contrast, CRC incidence and mortality rates have been stabilising or declining in the USA, Australia, New Zealand, and several Western European countries. The reasons for decreasing trends in CRC mortality are knowledge of risk factors, early detection and prevention, and improvements in perioperative care. Since the five-year overall survival for patients with metastatic CRC is poor (14%), there yet remains a strong need to develop new therapeutics for this disease.