On July 2, 2019 Monopar Therapeutics Inc., an oncology-focused biopharmaceutical company, and the Spanish Sarcoma Group (Grupo Español de Investigación en Sarcomas, or GEIS) reported that they have entered into a clinical collaboration agreement to conduct a Phase 2 clinical trial to evaluate Monopar’s investigational drug Camsirubicin in patients with advanced soft tissue sarcoma (ASTS) (Press release, Monopar Therapeutics, JUL 2, 2019, View Source [SID1234537364]).

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Soft tissue sarcomas are a diverse and aggressive class of cancers with generally poor survival outcomes. They usually develop in the connective tissue of the body, which include cartilage, muscles, nerves, bones, deep skin tissues, fat and blood vessels. Currently, there are limited therapeutic options for advanced sarcoma patients, with median overall survival of 12-16 months. The most effective first-line drug for ASTS is doxorubicin, a drug which, while effective, has to be stopped after six to eight cycles of treatment due to the heart damage it causes at higher cumulative doses.

Camsirubicin is being developed to replace doxorubicin as first-line therapy for ASTS. "The cumulative dose limitation of doxorubicin often results in advanced sarcoma patients receiving suboptimal dosing for the treatment of their cancer. Even if they are responding, they have to stop doxorubicin treatment permanently," said Andrew Mazar, Ph.D., Monopar’s chief scientific officer. "Camsirubicin has been specifically designed to avoid the irreversible heart toxicity while retaining the anticancer activity of doxorubicin, thus removing the limitations on cumulative dose."

Under the collaboration with Monopar, GEIS will lead a multi-country, randomized, open-label Phase 2 clinical trial to evaluate Camsirubicin head to head against doxorubicin in patients with ASTS. "The favorable safety profile and efficacy observed in previous clinical studies of Camsirubicin suggest that it could be dosed higher and longer than doxorubicin, which may improve the outcomes for ASTS patients," said Dr. Claudia Valverde, president of GEIS. "Patients with ASTS have few treatments available that improve overall survival, and our network of sarcoma referral centers in Spain and across Europe are eager to evaluate Camsirubicin’s ability to improve patient outcomes."

Enrollment of the trial is expected to begin in early 2020 and will include approximately 170 ASTS patients. The primary endpoint of the trial will be progression-free survival, with secondary endpoints including overall survival and incidence of treatment-emergent adverse events. GEIS will be the study sponsor with support from Monopar.

"We are very excited to be entering into this clinical collaboration with GEIS. They have an impressive track record of working on sarcoma studies with many of the leading biotech and global pharma companies, and with working on many of the drugs that have been tested for the treatment of ASTS," said Chandler Robinson, MD, chief executive officer of Monopar.

ON July 2, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported several strategic updates to its relapse/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) program, including its lead autologous NKG2D-based CAR-T therapy, CYAD-01, as well as the next-generation NKG2D-based CAR-T candidate, CYAD-02 (Press release, Celyad, JUL 2, 2019, View Source [SID1234537363]). The Company’s management team will host a conference call tomorrow, July 2nd, at 2 p.m. CEDT / 8 a.m. EDT, to discuss each of the updates and future milestones for the program.

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Filippo Petti, CEO of Celyad noted "Over the past few years Celyad has made great strides in evaluating our NKG2D-based CAR-T therapy for the treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. We have observed that targeting NKG2D ligands with our lead CAR-T candidate CYAD-01 drives anti-leukemic activity and is well tolerated. Today marks a milestone event as we announce that the FDA has accepted our Investigational New Drug application to commence clinical trials for our next-generation, CAR-T candidate, CYAD-02, and that the FDA and FAMHP have accepted our proposal to utilize our new, proprietary ‘OptimAb’ manufacturing process for both CYAD-01 and CYAD-02. Given the recent updates to our relapsed/refractory AML program, we believe we are well-positioned to improve upon the initial signals we’ve observed to date for CYAD-01 in this difficult to treat and rapidly progressing patient population."

Overview of CYAD-01 r/r AML and MDS Clinical Program

To date, results from the Phase 1 THINK trial evaluating CYAD-01 without prior preconditioning chemotherapy for the treatment of r/r AML and MDS have shown the NKG2D-based CAR-T to be well tolerated with encouraging preliminary anti-leukemic activity in six of thirteen patients (46%) evaluable per protocol.

The company is currently evaluating the potential for CYAD-01 in the treatment of r/r AML and MDS in multiple clinical trials including the Schedule Optimization cohorts of the THINK trial, which is assessing a more frequent dosing schedule of CYAD-01, and in the Phase 1, dose-escalation DEPLETHINK trial, which is assessing CYAD-01 following the preconditioning chemotherapy cyclophosphamide and fludarabine, or CyFlu. CyFlu is the preconditioning therapy typically used with other hematological malignancies evaluating CAR-T cell therapies.

In June 2019, preliminary data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) meeting demonstrated that a denser schedule of infusions of CYAD-01 without preconditioning in Cohort 10 (Schedule Optimization) of the THINK trial and a single infusion of low dose (1×108 cells) CYAD-01 following preconditioning chemotherapy in the DEPLETHINK trial was well tolerated and led to better time-averaged engraftment of the CAR-T cells.

Strategic Drivers Aimed to Enhance NKG2D-based CAR-T for r/r AML and MDS

Based on the initial clinical data and tolerability profile for CYAD-01 from the r/r AML and MDS clinical program, Celyad aims to increase the potency of the NKG2D-based CAR-T therapy to potentially deepen the breadth, frequency and duration of clinical responses in this patient population. In particular, Celyad is focused on: 1) the optimization of treatment conditions, including denser dosing schedule or exploiting preconditioning chemotherapy; 2) optimization of the manufacturing process, including enrichment of T cells with memory-like phenotype; and 3) improving the persistence of CAR-T cell therapies through RNA interference using short hairpin RNA (shRNA) technology.

Recent Developments for r/r AML and MDS Program

CYAD-01 – Enriching Early Memory T cells in our First-in-Class, NKG2D-based CAR-T Candidate by Leveraging the OptimAb Manufacturing Process

Celyad recently submitted Chemistry, Manufacturing, and Control ("CMC") amendments to the U.S. Food and Drug Administration (FDA) and Belgium’s Federal Agency for Medicines and Health Products (FAMHP) related to "OptimAb", a modified manufacturing process for CYAD-01.

OptimAb, is designed as an iterative improvement of Celyad’s first two manufacturing processes for CYAD-01 (the LY and mAb processes) and builds upon key characteristics of both. OptimAb utilizes a shortened eight-day cell culture and incorporates a selective PI3K inhibitor. Combined with the manufacturing optimizations previously developed by the company, the OptimAb process results in a product that is enriched for T cells with a memory-like phenotype while maintaining the high level of manufacturing reliability required to support clinical development. The amendment filed with the regulatory agencies is based upon our in-house research focused on the development of a manufacturing process to enrich for T cells with memory-like phenotype.

Preclinical data based on conditions where the dose of CYAD-01 produced with the mAb manufacturing process is reduced to have minimal activity indicate that cells produced using the OptimAb manufacturing process drive improved anti-tumor activity in an aggressive AML model.

Following feedback from the FDA and FAMHP, the CMC amendments were accepted and now in effect with regulators under the current Investigational New Drug (IND) application for CYAD-01. Celyad expects to treat the first patient using the recently accepted OptimAb manufacturing process for CYAD-01 in cohort 4 (1×109 cells) of the Phase 1 DEPLETHINK trial in August 2019. Based on regulatory feedback, Celyad expects to stagger treatment of the first three subjects treated with CYAD-01 cells manufactured by OptimAb.

CYAD-02 – Next-Generation, NKG2D-based CAR-T Candidate

At the company’s R&D Day held in March 2019, management unveiled its novel shRNA platform to develop next-generation autologous and allogeneic CAR-T cell therapies, including CYAD-02, a next-generation, autologous NKG2D-based CAR-T candidate that incorporates shRNA technology to target the NKG2D ligands MICA and MICB. The single shRNA modulates the expression of both ligands which translates to encouraging increases in in vitro proliferation, in vivo engraftment and anti-tumor activity. CYAD-02 also incorporates the OptimAb manufacturing process thereby enriching for T cells with memory-like phenotype.

In late June 2019, the FDA accepted the IND application for CYAD-02 and permitted it to go into effect. The company plans to begin enrollment of a Phase 1 dose-escalation trial evaluating the safety and clinical activity of CYAD-02 with the preconditioning chemotherapy CyFlu for the treatment of r/r AML and MDS in early 2020.

The CYAD-02 Phase 1 trial will be the first CAR-T cell therapy clinical trial employing the optimized shRNA SMARTvector technology licensed from Horizon Discovery and represents the output of a strong collaboration with the company’s partner.

Upcoming Milestones for r/r AML and MDS Program based on OptimAb Manufacturing Process

Initial clinical data from cohort 4 of the Phase 1 DEPLETHINK trial for CYAD-01 using the OptimAb manufacturing process are expected by year-end 2019. Full results from cohort 4 of the DEPLETHINK trial are anticipated in first quarter 2020.
Initiate the Phase 1 dose-escalation trial evaluating CYAD-02, following preconditioning chemotherapy for the treatment of r/r AML and MDS in early 2020. Preliminary data from the Phase 1 trial are expected by mid-2020.

Conference Call and Webcast Details

Celyad will host a conference call to discuss the update to the r/r AML and MDS program on Tuesday, July 2nd, 2019 at 2 p.m. CEDT / 8 a.m. EDT. The conference call can be accessed through the following numbers:

United States: +1 877 407 9208

International: +1 201 493 6784

Conference ID: 13692100

The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events & Webcasts" section of the Company’s website. Please visit the website several minutes prior to the start of the broadcast to ensure adequate time for registration to the webcast.

Background on Acute myeloid leukemia (AML) and Myelodysplastic syndromes (MDS)

Acute myeloid leukemia (AML) is an aggressive (fast-growing) form of leukemia characterized by the abnormal growth of myeloid cells, that spread in the bone marrow, blood stream and occasionally to other organs. AML is most commonly diagnosed in males aged 65-74 years old.

With about 40,000 new cases diagnosed each year in aggregate in the United States and Europe, AML is the most common type of aggressive leukemia in adults. The five-year survival rate for people 20 and older with AML is approximately 24%. For people younger than 20 diagnosed with AML, the survival rate is 67%. It has one of the lowest survival rates of all types of leukemia.

AML can develop either de novo in a healthy individual or in patients with a predisposing disease called myelodysplastic syndrome (MDS). Myelodysplastic syndrome (MDS) can be considered a premalignant disease that affects myeloid cells. Approximately 1,400 individuals in the United States are diagnosed each year with MDS.

Standard therapies for AML include chemotherapy (cytarabine) or hypomethylating agents (azacytidine or decitabine). If these therapies fail patients will receive a blood stem cell transplant. In addition, some patients are not eligible for transplant due to a poor general health condition. Despite these treatments, most patients relapse. As such, new or improved therapies for the treatment of AML are urgently needed.

On July 2, 2019 Unum Therapeutics Inc. (NASDAQ: UMRX), a clinical-stage biopharmaceutical company focused on the development of cellular immunotherapies to treat cancer based on its novel T cell technology platforms, reported that the U.S. Food and Drug Administration (FDA) has placed a clinical hold on the Phase 1 trial (ATTCK-20-2) evaluating Unum’s ACTR087 in combination with rituximab following lymphodepleting chemotherapy with fludarabine and cyclophosphamide in patients with relapsed/refractory CD20+ B cell non-Hodgkin lymphoma (r/r NHL) (Press release, Unum Therapeutics, JUL 2, 2019, View Source [SID1234537362]). The clinical hold was initiated following the submission of a safety report by Unum to the FDA regarding one patient in the safety expansion cohort of the trial (Cohort 3) who recently experienced serious adverse events that included Grade 3 neurotoxicity and cytomegalovirus (CMV) infection, and Grade 4 respiratory distress.

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In November 2018, Unum announced it was deprioritizing ACTR087 as its lead product candidate in combination with rituximab to treat patients with r/r NHL in order to advance its new ACTR construct, ACTR707, in this setting. As a result of this decision, in May 2019, Unum announced its completion of enrollment in the Phase 1 ATTCK-20-2 trial with ACTR087. FDA has agreed that patients who previously received ACTR087 and have ongoing clinical responses may continue to receive rituximab infusions, with continued monitoring for adverse events. Unum will continue to work closely with the FDA to further review these events and continues to plan to report data from the ATTCK-20-2 trial at the end of 2019.

On July 2, 2019 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento"), a clinical stage, antibody-centric biopharmaceutical company developing new therapies to turn malignant cancers into manageable and possibly curable diseases, reported the closing of its previously announced underwritten public offering of 8,333,334 shares of its common stock, Series A warrants to purchase up to an aggregate of 8,333,334 shares of its common stock, Series B warrants to purchase up to an aggregate of 8,333,334 shares of its common stock and Series C warrants to purchase up to an aggregate of 8,333,334 shares of its common stock at a public offering price of $3.00 per share and accompanying warrant combination, before deducting underwriting discounts and commissions and estimated offering expenses payable by Sorrento (Press release, Sorrento Therapeutics, JUL 2, 2019, View Source [SID1234537361]). The net proceeds to Sorrento from this offering are expected to be approximately $23.1 million, after deducting underwriting discounts and commissions and other estimated offering expenses. Sorrento currently intends to use the net proceeds from the offering for the continued clinical development of its RTX, CEA CAR-T and CD38 CAR-T programs and general research and development, working capital and general corporate purposes.

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JMP Securities and H.C. Wainwright & Co. acted as joint book-running managers for the offering.

The securities described above were offered by Sorrento pursuant to a shelf registration statement on Form S-3 (File No. 333-221443) previously filed with the Securities and Exchange Commission (the "SEC") on November 9, 2017, amended on December 1, 2017 and declared effective by the SEC on December 6, 2017. A final prospectus supplement and accompanying prospectus related to the offering was filed with the SEC on June 28, 2019 and is available on the SEC’s website at View Source Copies of the final prospectus supplement and the accompanying prospectus relating to the offering may also be obtained from JMP Securities LLC, 600 Montgomery Street, Suite 1100, San Francisco, California 94111, Attention: Prospectus Department, by calling (415) 835-8985 or by e-mail at [email protected] or H.C. Wainwright & Co., LLC, 430 Park Avenue, 3rd Floor, New York, NY 10022, by calling (646) 975-6996 or by e-mail at [email protected].

This press release does not constitute an offer to sell or the solicitation of an offer to buy, 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 the registration or qualification under the securities laws of any such state or jurisdiction.

On July 2, 2019 Medtronic plc (the "Company") (NYSE:MDT) reported that its wholly-owned subsidiary Medtronic Global Holdings S.C.A. ("Medtronic Luxco") has closed a registered public offering (the "Offering")of €250,000,000 principal amount of Floating Rate Senior Notes due 2021, €750,000,000 principal amount of 0.00% Senior Notes due 2022, €1,000,000,000 principal amount of 0.25% Senior Notes due 2025, €1,000,000,000 principal amount of 1.00% Senior Notes due 2031, €1,000,000,000 principal amount of 1.50% Senior Notes due 2039 and €1,000,000,000 principal amount of 1.75% Senior Notes due 2049 (collectively, the "Notes") (Press release, Medtronic, JUL 2, 2019, View Source;p=RssLanding&cat=news&id=2402852 [SID1234537360]). The Floating Rate Senior Notes due 2021 are further issuances of, fully fungible with, rank equally in right of payment with and form a single series with the €500,000,000 principal amount of Floating Rate Senior Notes due 2021 initially issued by Medtronic Luxco on March 7, 2019. All of Medtronic Luxco’s obligations under the Notes are fully and unconditionally guaranteed by the Company and Medtronic, Inc. ("Medtronic, Inc."), a wholly-owned indirect subsidiary of Medtronic Luxco, on a senior unsecured basis.

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The net proceeds from the Offering will be approximately €4.9 billion, after deducting estimated underwriting discounts and commissions and expenses related to the Offering payable by Medtronic Luxco. The net proceeds of the Offering will be used to fund the previously announced cash tender offers (the "Tender Offers") for several series of outstanding notes (the "Tender Offer Notes") issued by Medtronic, Inc., Medtronic Luxco and Covidien International Finance S.A. ("CIFSA"), a wholly-owned indirect subsidiary of Medtronic plc (collectively with Medtronic, Inc. and Medtronic Luxco, the "Offerors"), and to pay accrued and unpaid interest, premiums, fees and expenses in connection with the Tender Offers. The Tenders Offers were subject to a financing condition, which condition was satisfied by the closing of the Offering. Any remaining net proceeds of the Offering will be used for repayment of other indebtedness and general corporate purposes.

Information Relating to the Offering

Barclays Bank PLC, Goldman Sachs & Co. LLC and Merrill Lynch International were the joint book-running managers for the Offering. The Offering was made by means of a prospectus and prospectus supplement, copies of which may be obtained for free by visiting EDGAR on the U.S. Securities and Exchange Commission website at www.sec.gov. Alternatively, copies of the prospectus and prospectus supplement for the Offering may be obtained by contacting Barclays Bank PLC, toll-free at +1-888-603-5847, Goldman Sachs & Co. LLC, toll-free at +1-866-471-2526 or Merrill Lynch International, toll-free at +1-800-294-1322.

Information Relating to the Tender Offers

Barclays Capital Inc., BofA Merrill Lynch and Goldman Sachs & Co. LLC are acting as the dealer managers (the "Dealer Managers") for the Tender Offers. The information agent and tender agent is Global Bondholder Services Corporation ("Global Bondholder"). Copies of the Offer to Purchase and related offering materials are available by contacting Global Bondholder at +1-866-470-4200 (U.S. toll-free) or +1-212-430-3774 (banks and brokers). Questions regarding the Tender Offers should be directed to Barclays Capital Inc., Liability Management Group at +1-212-528-7581 (collect) or +1-800-438-3242 (toll-free), BofA Merrill Lynch, Liability Management Group, at +1-980-387-3907 (collect) or +1-888-292-0070 (toll-free) or Goldman Sachs & Co. LLC, Liability Management Group, at +1-212-357-0215 (collect) or +1-800-828-3182 (toll-free).

None of the Offerors, the Company or their affiliates, their respective boards of directors or managing members, the Dealer Managers, Global Bondholder or the trustee with respect to any series of Tender Offer Notes is making any recommendation as to whether holders of Tender Offer Notes ("Holders") should tender any Tender Offer Notes in response to any of the Tender Offers, and neither the Offerors nor any such other person has authorized any person to make any such recommendation. Holders must make their own decision as to whether to tender any of their Tender Offer Notes, and, if so, the principal amount of Tender Offer Notes to tender.

This press release shall not constitute an offer to sell, a solicitation to buy or an offer to purchase or sell any securities. The Tender Offers are being made only pursuant to the Offer to Purchase and only in such jurisdictions as is permitted under applicable law.

The full details of the Tender Offers, including complete instructions on how to tender Tender Offer Notes, are included in the Offer to Purchase. The Offer to Purchase contains important information that should be read by Holders of Tender Offer Notes before making a decision to tender any Tender Offer Notes. The Offer to Purchase may be downloaded from Global Bondholder’s website at View Source or obtained from Global Bondholder, free of charge, by calling toll-free at +1-866-470-4200 (bankers and brokers can call collect at +1-212-430-3774).