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ITM and CNL Sign Memorandum of Understanding to Pursue Global Development and Production of Rare Medical Radioisotope, Actinium-225

On October 18, 2021 ITM Isotope Technologies Munich SE, a leading radiopharmaceutical biotech company, and Canadian Nuclear Laboratories (CNL), Canada’s premier nuclear science and technology organization, reported that the companies have signed a Memorandum of Understanding (MoU) to explore the development and industrial-scale production of Actinium-225, an extremely rare alpha-emitting radioisotope with heightened potential in precision oncology (Press release, ITM Isotopen Technologien Munchen, OCT 18, 2021, View Source [SID1234591461]). Under the terms of the agreement, the organizations will collaborate on the development, manufacturing, and distribution pathways for the medical radioisotope. Further details of the agreement have not been disclosed.

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Targeted Alpha Therapy (TAT) has been rapidly gaining growing interest from the scientific and medical community. Alpha-emitters, particularly Actinium-225, are in high demand for their ability to cause irreparable damage to cancer cells. Notably, Actinium-225 emits powerful, high-energy alpha particles with a short penetration range, which enables highly precise treatment of tumor cells, including hard-to-target micro metastases, with minimal impact to surrounding healthy tissue. In preclinical studies, TAT has shown remarkable results, destroying cancer cells by effectively breaking the bonds in their DNA. Actinium-225 can be labelled to a variety of peptide ligands or antibodies to specifically target cancer cells in a wide range of tumor indications.

As the current annual global production of Actinium-225 is miniscule, one of the biggest challenges in harnessing the full potential of the alpha-emitter is ensuring its supply. CNL and ITM have the expertise and infrastructure in place to work to sufficiently bypass the supply hurdle to develop and produce this coveted radioisotope with huge therapeutic potential.

"CNL is very excited to enter into this agreement with ITM, an industry leader that shares our ambition of bringing the next-generation of medical radioisotopes to the global market," commented Joe McBrearty, CNL’s President and CEO. "It is also an exciting evolution of CNL’s work in the field of medical radioisotopes, and makes use of our capabilities in target development, radiochemistry, radioisotope analysis and by-product management. Working with ITM, we hope to leverage these capabilities to accelerate the development of this promising new isotope, and to establish a commercial pipeline for what we believe will be a ground-breaking new cancer treatment."

"It is always a pleasure to work alongside another radiotherapeutic industry leader like CNL in the development of a radioisotope with the potential to address a high unmet need. We look forward to sharing our expertise in the global production and supply of the highest quality radioisotopes in our shared mission of exploring the otherwise untapped potential of Actinium-225, commonly referred to as the ‘rarest drug on earth’. We are eager to unveil the therapeutic value of this radioisotope which we believe has the potential to unlock revolutionary TAT treatments," said Steffen Schuster, CEO of ITM.

ITM is a world leader in the development, production and global supply of radiotherapeutics and diagnostics, and maintains an evolving precision oncology pipeline. Coupled with CNL’s extensive scientific infrastructure and vast experience in developing and distributing medical radioisotopes, the companies are very well-positioned to produce and provide this highly sought-after radioisotope to the global industry.

Under the terms of the agreement, CNL will be responsible for the research and development as well as the production of Actinium-225. The company is already developing and producing Actinium-225 in research-scale quantities using Thorium-229 generators. ITM will be responsible for further processing Actinium-225 to Good Manufacturing Practices (GMP) standard and will subsequently have the primary responsibility for associated regulatory processes, marketing and sales of the product. CNL and ITM aim to leverage their capabilities towards establishing a continuous commercial supply of GMP-grade Actinium-225 for the global market. Both parties are working towards signing a more formal agreement in the form of a Collaborative Venture.

Entry into a Material Definitive Agreement

On October 18, 2021, Thermo Fisher Scientific (Finance I) B.V. ("Thermo Fisher International"), an indirect, wholly-owned finance subsidiary of Thermo Fisher Scientific Inc. (the "Company"), reported that issued €1,750,000,000 aggregate principal amount of 0.800% Senior Notes due 2030 (the "2030 Notes"), €1,500,000,000 aggregate principal amount of 1.125% Senior Notes due 2033 (the "2033 Notes"), €1,250,000,000 aggregate principal amount of 1.625% Senior Notes due 2041 (the "2041 Notes") and €750,000,000 aggregate principal amount of 2.000% Senior Notes due 2051 (the "2051 Notes", and, together with the 2030 Notes, the 2033 Notes and the 2041 Notes, the "Notes") in a public offering (the "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, OCT 18, 2021, View Source [SID1234591460]). The Company has fully and unconditionally guaranteed the Notes on a senior unsecured basis (the "Guarantee" and, together with the Notes, the "Securities").

The Securities were issued under an indenture, dated as of August 9, 2016 (the "Base Indenture"), and the Third Supplemental Indenture, dated as of October 18, 2021 (the "Supplemental Indenture" and, together with the Base Indenture, the "Indenture"), among Thermo Fisher International, as issuer, the Company, as guarantor, and The Bank of New York Mellon Trust Company, N.A., as trustee.

Prior to July 18, 2030, in the case of the 2030 Notes, July 18, 2033, in the case of the 2033 Notes, April 18, 2041, in the case of the 2041 Notes and April 18, 2051, in the case of the 2051 Notes (each such date, a "Par Call Date"), Thermo Fisher International may redeem the Notes of any such 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 2030 Notes, 20 basis points, in the case of the 2033 Notes, 25 basis points, in the case of the 2041 Notes and 30 basis points, in the case of the 2051 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 the Notes of any series, in whole at any time or in part from time to time, 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, Thermo Fisher International 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 accrued and unpaid interest, if any, to, but excluding, the date of repurchase.

The Notes are general unsecured obligations of Thermo Fisher International. The Notes rank equally in right of payment with existing and any future unsecured and unsubordinated indebtedness of Thermo Fisher International and rank senior in right of payment to any existing and future indebtedness of Thermo Fisher International that is subordinated to the Notes. The Notes are also effectively subordinated to any existing and future secured indebtedness of Thermo Fisher International 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 Guarantee is a general unsecured obligation of the Company. The Guarantee ranks equally in right of payment with existing and any future unsecured and unsubordinated indebtedness of the Company and will rank senior in right of payment to any existing and future indebtedness of the Company that is subordinated to the Guarantee. The Guarantee is also effectively subordinated to any existing and future secured indebtedness of the Company to the extent of the assets securing such indebtedness, and is structurally subordinated to all existing and any future indebtedness and any other liabilities of its subsidiaries (other than, with respect to Thermo Fisher International, the Notes).

The Indenture contains limited affirmative and negative covenants of the Company and Thermo Fisher International. 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 each of the Company and Thermo Fisher International to merge or consolidate or sell all or substantially all of their respective 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 Thermo Fisher International under the Notes may be accelerated, in which case the entire principal amount of the Notes would be immediately due and payable.

Wilmer Cutler Pickering Hale and Dorr LLP, U.S. counsel to the Company and Thermo Fisher International, has issued an opinion to the Company and Thermo Fisher International, dated October 18, 2021, regarding the legality of the Securities, and Linklaters LLP, Dutch counsel to Thermo Fisher International, has issued an opinion to Thermo Fisher International, dated October 18, 2021, regarding the Notes. Copies of these opinions are filed as Exhibits 5.1 and 5.2 hereto, respectively.

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.

Sirnaomics to Present STP705, the Company’s Lead Drug Candidate, for the Treatment of Cutaneous Squamous Cell Carcinoma in situ, at the 2021 Fall Clinical Dermatology Conference

On October 18, 2021 Sirnaomics, Inc., a biopharmaceutical company engaged in the discovery and development of RNAi therapeutics against cancer and fibrotic diseases, reported that Professor Brian Berman, M.D., Ph.D., Professor Emeritus, Dermatology and Dermatologic Surgery, University of Miami will be giving a talk on the clinical study result of the Company’s lead drug candidate, STP705, at the 2021 Fall Clinical Dermatology Conference, as the principal investigator (Press release, Sirnaomics, OCT 18, 2021, View Source [SID1234591459]). The Company will also exhibit a poster at the conference highlighting results from a Phase IIa clinical trial of STP705 for the treatment of cutaneous squamous cell carcinoma in situ (nonmelanoma skin cancer). The hybrid conference is taking place in person at the Wynn Las Vegas hotel in Las Vegas, NV, USA from October 21-24, 2021.

Talk: New and Future Innovations in Dermatologic Care
Title: Advances in Therapeutic Technology: STP705 siRNA for in situ Squamous Cell Carcinoma
Presenter: Brian Berman, M.D., Ph.D., Professor Emeritus, Dermatology and Dermatologic Surgery, University of Miami; Co-Director Center for Clinical and Cosmetic Research, Aventura, FL, USA
Overview: Clinical trial results showing STP705, used to target TGF-β1 and COX-2 siRNAs for the treatment of nonmelanoma skin cancer, has demonstrated rates of histological clearance that rival surgical excision combined with improved cosmetic appearance.
Date and Time: October 21, 2021, from 10:20 AM to 10:55 AM PT
Location: Wynn Las Vegas,Cristal 2, 4, 6
Poster:

Title: Open Label, Phase I/II, Dose Escalation Study to Evaluate Safety and Efficacy of Intralesional Injection of a TGF-β1/COX-2 dual targeting small interfering (si)RNA therapeutic, in Adult Patients with Cutaneous Squamous Cell Carcinoma in situ (isSCC)
Date and Time: October 21, 2021, from 7:00 AM to 4:30 PM PT; October 22, 2021, from 7:00 AM to 12:30 PM PT
Location: Wynn Las Vegas,Cristal 1, 3, 5

Quest Diagnostics to Introduce Ki-67 IHC MIB-1 pharmDx, the First Companion Diagnostic for Eli Lilly and Company’s Verzenio® (abemaciclib), a CDK4/6 Inhibitor for Certain People with HR+ HER2- High Risk Early Breast Cancer

On October 18, 2021 Quest Diagnostics (NYSE: DGX), the world’s leading provider of diagnostic information services, reported that it will provide clinical laboratory testing using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) immunohistochemistry companion diagnostic (Press release, Quest Diagnostics, OCT 18, 2021, View Source,-the-First-Companion-Diagnostic-for-Eli-Lilly-and-Companys-Verzenio-R-abemaciclib-,-a-CDK4-6-Inhibitor-for-Certain-People-with-HR-HER2-High-Risk-Early-Breast-Cancer [SID1234591458]).

On October 13, the U.S. Food and Drug Administration (FDA) approved Eli Lilly and Company’s Verzenio (abemaciclib), in combination with endocrine therapy (tamoxifen or an aromatase inhibitor), for the adjuvant treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test. Ki-67 is a marker of cellular proliferation. Verzenio is the first and only CDK4/6 inhibitor approved for this patient population.

In aligned actions, the FDA also granted pre-market approval to Ki-67 IHC MIB-1 pharmDx (Dako Omnis) from Agilent Technologies, Inc. as a companion diagnostic for Verzenio. Quest is the first laboratory to have validated the test in conjunction with Agilent. Since the validation of an IVD assay can take weeks, Quest is committed to providing the test as soon as possible, with plans to make it nationally available by the end of the month.

"The imminent addition of Ki-67 IHC MIB-1 pharmDx (Dako Omnis) testing to our oncology menu underscores our commitment to providing precision medicine innovations with potential to improve outcomes for patients with cancer," said Kristie Dolan, General Manager, Oncology Franchise, Quest Diagnostics. "It also reflects our ability to create value-producing relationships across healthcare, building on our long-standing precision medicine collaboration with Agilent."

Quest Diagnostics is a leading diagnostics services provider in oncology and genetics. Covering the breadth of diagnostic services, from screening and diagnosis to treatment selection, prognosis and monitoring recurrence, the company’s expertise spans nearly all cancers, including breast, thyroid, lung cancer, colorectal, prostate, cervical, multiple myeloma and leukemia/lymphoma, among others.

About Early Breast Cancer and Risk of Recurrence
It is estimated that 90 percent of all breast cancers are detected at an early stage. Although the prognosis for HR+ HER2- EBC is generally positive, 20 percent of patients will experience recurrence potentially to incurable metastatic disease.1 Risk of recurrence is greatest within the initial two to three years post-diagnosis, particularly in patients with node-positive, high risk EBC.2 Factors associated with high risk of recurrence include: positive nodal status, large tumor size (≥5 cm), high tumor grade (Grade 3), and high rate of cellular proliferation [Ki-67 score (≥20%)].3

Node-positive means that cancer cells from the tumor in the breast have been found in the lymph nodes in the armpit area. Although the breast cancer is removed through surgery, the presence of cancer cells in the lymph nodes signifies that there is a higher chance of the cancer returning and spreading.

About Breast Cancer
Breast cancer has now surpassed lung cancer as the most commonly diagnosed cancer worldwide in females, according to GLOBOCAN. With approximately 685,000 deaths in 2020, breast cancer is the fifth-leading cause of cancer death worldwide.4 In the U.S., it is estimated that there will be 281,550 new cases of breast cancer in 2021.5 Approximately 70 percent of all breast cancers are of the HR+ HER2- subtype.5

About Verzenio (abemaciclib)
Verzenio abemaciclib is a targeted treatment known as a CDK4/6 inhibitor. Verzenio is a non-chemotherapy oral tablet.

Verzenio works inside the cell to block CDK4/6 activity and help stop the growth of cancer cells, so they may eventually die (based on preclinical studies).* Cyclin-dependent kinases (CDK)4/6 are activated by binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4/6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly’s first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

INDICATIONS FOR VERZENIO
Verzenio (abemaciclib) in combination with endocrine therapy (ET) is indicated for the adjuvant treatment of adult patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score of ≥20% as determined by an FDA-approved test.

Verzenio is indicated for the treatment of HR+ HER2- advanced or metastatic breast cancer:

in combination with an aromatase inhibitor for postmenopausal women, and men, as initial endocrine-based therapy
in combination with fulvestrant for adult patients with disease progression following endocrine therapy
as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting
Please see full Prescribing Information for Verzenio.

Corporate Presentation October 2021

On October 18, 2021, PDS Biotechnology Corporation reported its corporate presentation (Presentation, PDS Biotechnology, OCT 18, 2021, View Source [SID1234591457]).