On October 1, 2019 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that new data on IPH5401 and monalizumab were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain (Press release, Innate Pharma, OCT 1, 2019, View Source [SID1234539965]).

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Poster presentations highlighted:

Preliminary results of STELLAR-001, a Phase I dose-escalation study of IPH5401, an anti-C5aR antibody, in combination with durvalumab in advanced solid tumors;
One-year survival data of the first expansion cohort of the Phase II trial evaluating monalizumab in combination with cetuximab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)

"We are pleased with the continued progress of monalizumab and IPH5401. We believe that by targeting C5a receptors, IPH5401 is a potentially first-in-class therapeutic antibody for cancer treatment. The preliminary clinical data set from the STELLAR-001 dose-escalation trial prompted us to start and broaden the expansion cohorts in three different settings where anti-PD-(L)1 have shown no or limited activity," said Pierre Dodion, Chief Medical Officer of Innate Pharma. "In addition, the survival data set for the combination of monalizumab and cetuximab in head and neck cancer support further development in IO-pretreated and IO-naïve patients, populations with high unmet medical need."

Key Highlights from IPH5401’s STELLAR-001 Study
In the STELLAR-001 dose-escalation study, 14 patients were included across four doses. Six patients had NSCLC, five had HCC, two had urothelial carcinoma (UCC), and one had renal cell carcinoma (RCC).

The combination of IPH5401 and durvalumab was reported to be well tolerated. No dose limiting toxicity was reported and no dose relationship was observed regarding safety. Pharmacodynamic analyses confirmed full receptor saturation at all dose levels and provided the basis for dose selection for the expansion cohorts.

Twelve patients were evaluated for efficacy. Early activity signals were observed in HCC and NSCLC patients, which included:

One confirmed partial response was reported in a HCC patient with prior progression after nivolumab
One prolonged stable disease (40 weeks) was reported in a NSCLC patient with prior progression after nivolumab

The Company will initiate the planned expansion cohorts in NSCLC patients with secondary resistance to prior IO treatment and in IO-naïve HCC patients to generate additional safety and efficacy data as well as additional translational analyses on tumor biopsies. In addition, based on the data generated in the dose escalation, the Company plans to add an additional cohort testing IPH5401 in combination with durvalumab in IO-pretreated HCC patients, subject to regulatory approval.

Key highlights from the Phase II study of monalizumab in combination with cetuximab in patients with R/M SCCHN, one-year survival data
In a cohort of 40 SCCHN patients previously treated with chemotherapy alone or chemotherapy followed by PD-1/L1 checkpoint inhibitors, the combination of monalizumab and cetuximab demonstrated a manageable safety profile and a response rate of 27.5% (36% and 17% in IO-naïve and IO-pretreated patients, respectively). Responses were observed in platinum-resistant patients and human papillomavirus (HPV) positive and negative patients.

Additional efficacy highlights included:

Median overall survival of 8.5 months with median follow-up time of 17 months;
Trend for improved survival in IO-pretreated patients (14.1 months in IO-pretreated patients and 7.8 months in IO naïve patients); and
12-month overall survival rate of 44% (60% in IO-pretreated and 32% in IO naïve patients)
These data suggest that the combination of monalizumab and cetuximab may provide promising response rates and favorable trends in overall survival. The Company is moving forward with the planned expansion cohorts in IO-pretreated and IO-naïve R/M SCCHN patients.

About IPH5401:
IPH5401 is a potentially first-in-class therapeutic antibody that specifically binds and blocks C5a receptors (C5aR) expressed on subsets of myeloid-derived suppressor cells (MDSC) and neutrophils. Part of the innate immune system, these types of cells promote tumor growth by secreting inflammatory and angiogenic factors, potently suppress anti-tumor T and NK cells and hamper the activities of PD-1 checkpoint inhibitors.

C5a, a factor in the complement cascade, is often overexpressed in tumors, where it attracts and activates MDSCs and neutrophils in the tumor microenvironment. Preliminary evidence suggests high expression of the C5a receptor in both NSCLC and HCC.

About Monalizumab:
Monalizumab is a potentially first-in-class dual checkpoint inhibitor targeting NKG2A receptors expressed on tumor infiltrating cytotoxic CD8+ T cells and NK cells.

NKG2A is an inhibitory checkpoint receptor for HLA-E. By expressing HLA-E, cancer cells can protect themselves from killing by NKG2A+ immune cells. HLA-E is frequently overexpressed in the cancer cells of many solid tumors and hematological malignancies. Hence, monalizumab may re-establish a broad anti-tumor response mediated by NK and T cells. Monalizumab may also enhance the cytotoxic potential of other therapeutic antibodies.

AstraZeneca (LSE/STO/NYSE: AZN) obtained full oncology rights to monalizumab in October 2018 through a co-development and commercialization agreement initiated in 2015. The ongoing clinical development for monalizumab is focused on investigating monalizumab in combination strategies.

About Durvalumab:
Durvalumab, a human monoclonal antibody directed against PD-L1, blocks PD-L1 interaction with PD-1 and CD80 on T cells, countering the tumor’s immune-evading tactics and inducing an immune response.

As part of a broad development program, durvalumab is being investigated as monotherapy and in combination with IO, small molecules, and chemotherapies across a range of tumors and stages of disease.

About Cetuximab:
Cetuximab is an anti-EGFR monoclonal antibody blocking oncogenic signaling and inducing Fcγ receptor-mediated antibody dependent cellular cytotoxicity (ADCC). NK cells mediate cetuximab-induced ADCC against SCCHN. Genetic and preclinical experiments suggest that ADCC can be enhanced by NK-stimulators.

The activity of cetuximab single agent in R/M SCCHN is limited with a 12.6% ORR, a median PFS of 2.3 months and a median OS of 5.8 months (Vermorken et al, JCO 2007).

On October 1, 2019 ORPHELIA Pharma, a French biopharmaceutical company dedicated to the development and marketing of paediatric drugs in the fields of oncology and neurology, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending the issuance of a marketing authorization for Ivozall (Press release, ORPHELIA Pharma, OCT 1, 2019, View Source [SID1234539964]).

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Ivozall is a solution for infusion containing 1 mg/ml clofarabine and supplied in 20 ml-vials. Clofarabine is an essential medicine for the treatment of relapsed or refractory Acute Lymphoblastic Leukaemia (ALL) in children. Ivozall will be the first generic form of clofarabine to be authorised under the European centralized procedure.

« We are particularly pleased with this decision which comes after continuous efforts of our company together with our partners », comments Jeremy Bastid, Chief Development Officer of ORPHELIA Pharma. « This positive opinion is a key milestone in the process of making Ivozall, our first medicinal product in oncology, available to the paediatric community ».

« The CHMP has acknowledged the interest of Ivozall in improving health of children with ALL. We are eagerly awaiting the marketing authorisation expected for November 2019 », highlights Hugues Bienaymé, General Manager of ORPHELIA Pharma. « We anticipate to make Ivozall available to the hospital centres treating ALL patients in some countries from February 2020 », added Gilles Alberici, Chairman of ORPHELIA Pharma. « Other countries will be handled by ORPHELIA distributors, to be selected in the course of 2020 ».

About Acute Lymphoblastic Leukaemia

Acute Lymphoblastic Leukaemia is a cancer associated with the uncontrolled proliferation of lymphoblasts that invade the bone marrow. The disease progresses rapidly and aggressively and requires immediate treatment. ALL is a rare disease, with around 7,000 people diagnosed each year in Europe. The majority of ALL cases occurs in children. Although rare, ALL is the most common type of childhood cancer. Clofarabine is indicated for the treatment of ALL in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response.

On September 30, 2019 Shanghai Henlius Biotech and PT Kalbe Genexine Biologics (hereinafter referred to "KG Bio"), a holding subsidiary to PT Kalbe Farma, an Indonesian pharmaceutical company, today entered into an Exclusive License Agreement for HLX10 – a recombinant humanized anti-programmed cell death (PD-1) monoclonal antibody (mAb) injection independently developed by Henlius (Press release, Shanghai Henlius Biotech, SEP 30, 2019, View Source [SID1234635133]). With the collaboration, KG Bio will be granted exclusive rights to develop and commercialize HLX10 in relation to (i) the first monotherapy for the treatment of solid tumour (MSI-high) (ii) the two combination therapies and (iii) two new indications KG Bio may in license in accordance with the Agreement in the Asia Pacific territory including the Philippines, Indonesia, Malaysia, Singapore, Thailand, Laos, Myanmar, Cambodia, Brunei and Vietnam. The estimated maximum payment may reach the total value of US$ 692 million including 1) non-creditable payment of US$10 million; 2) commercial sales milestone payments not exceeding US$650 million depending on the level of accumulative net sales of relevant products; 3) regulatory milestone payments not exceeding US$22 million; 4) US$10 million to fund the trials of two combination therapies to be initiated and performed by Henlius.

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Through the collaboration with KG Bio and Kalbe Farma, Henlius will strengthen its market access to Southeast Asia for HLX10 as a part of its international strategy through Kalbe Farma’s extensive sales networking in the market with the aim of sharpening its global competitiveness and brand awareness in the field of immuno-oncology. Moreover, the overall population of Southeast Asia hits 650 million, which translates into significant unmet needs. With the long-term commitment to "affordable innovation", through the collaboration, Henlius will also provide patients in Southeast Asia access to high-quality, affordable and novel biological therapies.

The collaboration also further strengthens the globalization of its immuno-oncology combination therapy in Southeast Asia. Although Anti-PD-1 mAb, as a broad-spectrum immunosuppressant, can be widely applied in the immunotherapy of cancer, it shows low efficacy as mono-therapy. Henlius thus adopts "Combo plus Global" strategy to differentiate its immuno-oncology combination therapy strategy with proprietary mAbs including HLX10 and HLX20 (anti-PD-L1 mAb) as backbones in combination with other therapies and with global multi-center clinical trials ongoing in various countries and regions worldwide.

Looking into the future, Henlius will proactively expand its global presence through continued strategic collaboration with international leading pharmaceutical companies, underscoring its mission to deliver quality products and effective treatment to patients worldwide.

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]).

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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, Cardinal Health Funding, LLC ("CHFunding"), an indirectly owned receivables financing subsidiary of Cardinal Health, Inc. (the "Company"), Griffin Capital, LLC, an indirectly owned receivables financing subsidiary of the Company, Wells Fargo Bank, N.A., Liberty Street Funding LLC, The Bank of Nova Scotia, Atlantic Asset Securitization LLC, Credit Agricole Corporate and Investment Bank New York Branch, U.S. Bank National Association, PNC Bank, National Association, Victory Receivables Corporation and MUFG Bank, Ltd. ("MUFG Bank"), entered into a Fourth Amendment and Joinder (the "RPA Amendment") to the Fourth Amended and Restated Receivables Purchase Agreement (as amended, the "Receivables Purchase Agreement") (Filing, 8-K, Cardinal Health, SEP 30, 2019, View Source [SID1234540011]). The RPA Amendment extends the term of the Company’s $1.0 billion committed receivables sales facility program until September 30, 2022. The RPA Amendment is filed as Exhibit 10.1 to this Current Report on Form 8-K and the foregoing description is qualified by reference to the full text of the RPA Amendment set forth in Exhibit 10.1.

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In connection with the RPA Amendment, the Company, CHFunding and MUFG Bank entered into Amendment No. 3 to Seventh Amended and Restated Performance Guaranty (the "Guaranty Amendment"), which requires the Company to maintain a maximum Consolidated Net Leverage Ratio at the end of every fiscal quarter from September 2019 through December 2020 of no greater than 4.00-to-1.00. The maximum ratio permitted at the end of any fiscal quarter will reduce to 3.75-to-1.00 in March 2021. The Guaranty Amendment is filed as Exhibit 10.2 to this Current Report on Form 8-K and the foregoing description is qualified by reference to the full text to the Guaranty Amendment set forth in Exhibit 10.2.

From time to time, the financial institutions party to the Receivables Purchase Agreement or their affiliates have performed, and may in the future perform, various commercial banking, investment banking and other financial advisory services for the Company, for which they receive customary fees and expenses. Wells Fargo Bank, N.A. serves as a dealer under the Company’s commercial paper program. In addition, MUFG Bank, Wells Fargo Bank, N.A., The Bank of Nova Scotia, PNC Bank, National Association, Credit Agricole Corporate and Investment Bank and U.S. Bank National Association or their affiliates currently act as members of the lending syndicate under the Company’s revolving credit facility.