On October 22, 2021 Castle Biosciences, Inc. (Nasdaq: CSTL), applying innovative diagnostics to transform disease management and improve patient outcomes, reported recent poster presentations on the Company’s suite of dermatologic cancer gene expression profile (GEP) tests, as well as a poster describing the study design for its inflammatory skin disease pipeline initiative at the 2021 Fall Clinical Dermatology Conference, held Oct. 21-24 (Press release, Castle Biosciences, OCT 22, 2021, View Source [SID1234591791]).

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DecisionDx-Melanoma:

DecisionDx-Melanoma is Castle’s prognostic gene expression profile test for cutaneous melanoma. The Company utilizes two proprietary algorithms, i31-ROR and i31-SLNB, to produce an integrated test result designed to provide a precise, personalized prediction of risk of recurrence and likelihood of sentinel lymph node (SLN) positivity, respectively, by integrating DecisionDx-Melanoma with traditional assessment of the clinicopathologic features of a patient’s tumor.

The company presented new data on the capabilities of these independently validated algorithms through a poster titled, "Integrating the 31-gene expression profile and clinicopathologic data to determine the risk of sentinel lymph node positivity and recurrence-free survival in cutaneous melanoma." The poster can be found here.

"The risks associated with a melanoma diagnosis can lead to several different clinical procedures, including sentinel lymph node biopsy (SLNB), and many patients experience regional recurrence, distant metastasis or even death," said Bob Cook, Ph.D., senior vice president of research and development of Castle Biosciences. "The study results demonstrated that integrating the DecisionDx-Melanoma result with assessment of clinical and pathologic features improved individualized risk prediction for SLNB positivity, regional recurrence and distant metastasis, which could help clinicians make more informed and personalized risk-stratification decisions."

Study methods and findings:

The purpose of the study was to demonstrate the combined ability of two independently validated algorithms that incorporate the DecisionDx-Melanoma result with clinicopathologic features to predict individual SLNB positivity risk and recurrence-free survival (RFS).
Using artificial intelligence techniques, two algorithms were developed:
The i31-GEP-SLNB (i31-SLNB) algorithm, developed from 1398 cases and validated in an independent cohort of 1674 cases, was developed to determine the individual likelihood of SLN positivity.
The i31-GEP-outcomes (i31-ROR) algorithm, developed from 1581 cases and validated in an independent cohort of 523 cases, was developed to provide personalized survival predictions for recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS).
The i31-SLNB algorithm identified 31.2% (135/433) of patients with a <5% likelihood of SLN positivity who could potentially forego the SLNB surgical procedure. These patients all received a low-risk i31-ROR result and had high survival rates (>98% RFS, DMFS and MSS), reinforcing the i31-ROR algorithm’s risk prediction precision.
In the SLN negative population, 20% of patients were identified as high risk by the i31-ROR algorithm and had five-year RFS rates that were like those for patients with a positive SLNB (e.g., Stage III disease) (47.7% vs. 48.7%, respectively).
Overall, using National Comprehensive Cancer Network (NCCN) treatment guidelines, the test identified 44.8% (194/433) of patients who may have been able to avoid SLNB or were re-stratified as low or high risk compared to SLN status alone.
The i31-ROR algorithm was able to stratify patients with Stage IIB-IIC melanoma according to risk of recurrence with an absolute recurrence difference of 20% at 12 months. This is of particular interest given the recent announcement of the absolute treatment effect of Pembrolizumab in patients with Stage IIB-IIC melanoma of 5.7% at 12 months.
The study data demonstrated that DecisionDx-Melanoma’s integrated test result, using both i31-ROR and i31-SLNB algorithms, identified patients who may potentially forego SLNB and provide a more precise prediction of high and low risk of recurrence for more personalized patient care decisions.
Comprehensive Diagnostic Offering:

Castle’s Comprehensive Diagnostic Offering (CDO) leverages the strengths of both myPath Melanoma and DecisionDx DiffDx-Melanoma, two GEP tests designed to provide a highly accurate, objective result to aid dermatopathologists and dermatologists in characterizing difficult-to-diagnose melanocytic lesions.

Castle presented data validating the company’s implementation of its CDO via a poster presentation entitled "A comprehensive diagnostic offering workflow increases the rate of actionable results of the 23- and 35-gene expression profile tests for use as ancillary diagnostic tools for difficult-to-diagnose melanocytic lesions." The poster can be viewed here.

"Since Castle’s acquisition of the myPath laboratory earlier this year, we have looked forward to demonstrating the value that these two diagnostic GEP tests can offer together," said Matthew S. Goldberg, M.D., first study author and medical director at Castle Biosciences. "We are pleased to have evidence that demonstrated the complementary power of these tests, which could enable physicians to make more confident diagnoses for patients with difficult-to-diagnose melanocytic lesions and to create individualized care plans by interpreting the patient’s gene expression profile in the context of the clinical, laboratory and histopathologic information."

Study methods and findings:

This study highlighted the results of all CDO clinical cases submitted to Castle Biosciences between June 30-Aug. 31, 2021. Using the Company’s CDO workflow, all adult cases not receiving an actionable result of benign or malignant from myPath Melanoma had the opportunity to be run using DecisionDx DiffDx-Melanoma.
myPath Melanoma returned nonactionable classifications 22.3% of the time (nonactionable classifications are comprised of the combined total of intermediate risk results [12.9%] and technical failures [9.4%]).
The nonactionable cases underwent additional testing using DecisionDx DiffDx-Melanoma, at which point an additional 20.9% of originally submitted cases received an actionable result. Only 1.1% of cases received an intermediate result from both tests; the technical failure rate of both tests combined was 0.2%.
Leveraging both tests as a comprehensive diagnostic workflow substantially improved the reporting of clinically actionable results from a historic rate of 77.8% for myPath Melanoma alone to 98.7% when used in conjunction with DecisionDx DiffDx-Melanoma.
Psoriasis, Atopic Dermatitis and Related Conditions:

Inflammatory skin diseases, like psoriasis and atopic dermatitis, severely impact a patient’s quality of life. While there are many effective treatment options available for those with moderate-to-severe disease, current clinical practice relies on a costly and time-consuming trial-and-error approach to determine an individual patient’s response to systemic therapies. To answer this unmet clinical need, Castle Biosciences is developing a GEP test designed to predict response to systemic therapies for patients with moderate to severe psoriasis, atopic dermatitis and other related diseases. Personalized guidance for therapy selection and anticipated efficacy has the potential to improve patient health outcomes by enabling clinicians to select the best medication for their patients’ specific skin disease.

Castle initiated an IRB-approved clinical study to develop and validate one or more gene expression signatures to guide treatment selection in patients with psoriasis, atopic dermatitis and related conditions. The study’s design was presented via a poster titled "A study to help guide management decisions in patients with psoriasis and atopic dermatitis." The poster can be viewed here.

"Patients with psoriasis and atopic dermatitis could benefit immensely from a more straightforward path to finding an effective therapeutic treatment option for their inflammatory skin disease," said Aaron S. Farberg, M.D., the study’s first author and dermatologist at Baylor University Medical Center in Dallas. "Based on a history of success, Castle Biosciences is well positioned to potentially identify a molecular signature that could aid in finding the appropriate drug selection for a patient, based on their unique disease biology, saving patient time, money and contributing to a more effective use of healthcare resources."

Study design:

Up to 4,850 patients between two and 85 years of age diagnosed with psoriasis, atopic dermatitis or a related disorder will be prospectively enrolled in the study.
At enrollment, disease severity will be documented. Superficial layers of diseased and healthy skin will be collected from participants. Clinical data including systemic treatment type, dose, response and side effects will be logged at subsequent visits.
RNA from samples will be isolated, and an unbiased assessment of RNA expression levels using microarray will be performed.
Through this study protocol, Castle is aiming to develop a GEP test that may help guide therapeutic choice for patients with moderate-to-severe psoriasis and atopic dermatitis for whom clinical diagnosis or drug selection may be challenging, thereby potentially decreasing the amount of time and money spent on finding a successful treatment option for each patient.

DecisionDx-SCC:

DecisionDx-SCC is Castle’s prognostic 40-GEP test designed to use a patient’s tumor biology to predict individual risk of metastasis for patients diagnosed with high-risk cutaneous squamous cell carcinoma (SCC) having one or more risk factors.

Castle presented data on DecisionDx-SCC through a poster entitled "Real-world clinical usage data demonstrates appropriate utilization of the prognostic 40-gene expression profile test for cutaneous squamous cell carcinoma with one or more risk factors."

Study methods and findings:

The objective of the study was to demonstrate independent prognostic value of DecisionDx-SCC via analyses with existing risk assessment methods and report on the early clinical usage of DecisionDx-SCC.
Summary metrics were generated on the first 1000 samples received for DecisionDx-SCC testing that met clinical testing criteria. Metrics on early clinical usage include:
Technical reliability of DecisionDx-SCC was 96.3%.
69.0% of samples received DecisionDx-SCC Class 1 results, 26.0% received DecisionDx-SCC Class 2A results and 1.3% received DecisionDx-SCC Class 2B results.
52% of tested patients had three or more risk factors.
This study demonstrated that the intended use population (high-risk SCC patients with one or more risk factors) aligned with the cases that were submitted for clinical testing.
The study also found that DecisionDx-SCC results can be applied as an adjunct to enhance SCC risk stratification and contribute to risk-appropriate surveillance and treatment decisions.
About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous melanoma metastasis or recurrence, as well as sentinel lymph node positivity, independent of traditional staging factors, and has been studied in more than 5,700 patient samples. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in four archival risk of recurrence studies of 901 patients and six prospective risk of recurrence studies including more than 1,600 patients. Impact on patient management plans for one of every two patients tested has been demonstrated in four multicenter and single-center studies including more than 560 patients. The consistent performance and accuracy demonstrated in these studies provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results.

In addition to reporting Class results, the Company also reports results that predict risk of recurrence and likelihood of sentinel lymph node positivity. Castle utilizes its proprietary algorithms, i31-ROR and i31-SLNB, to produce an integrated DecisionDx-Melanoma test result.

Through June 30, 2021, DecisionDx-Melanoma has been ordered 78,277 times for use in patients with cutaneous melanoma. More information about the test and disease can be found at www.CastleTestInfo.com.

About Castle Biosciences’ Comprehensive Diagnostic Offering for Difficult-to-Diagnose Melanocytic Lesions

Castle Biosciences’ comprehensive diagnostic offering leverages the strengths of myPath Melanoma and DecisionDx DiffDx-Melanoma. These gene expression profile tests are designed to provide a highly accurate, objective result to aid dermatopathologists and dermatologists in characterizing difficult-to-diagnose melanocytic lesions. Of the approximately 2 million suspicious pigmented lesions biopsied annually in the U.S., Castle estimates that approximately 300,000 of those cannot be confidently classified as either benign or malignant through traditional histopathology methods. For these cases, the treatment plan can also be uncertain. Obtaining highly accurate, objective ancillary testing can mean the difference between a path of overtreatment or the risk of undertreatment. Interpreted in the context of other clinical, laboratory and histopathologic information, myPath Melanoma and DecisionDx DiffDx-Melanoma are designed to reduce uncertainty and provide confidence for dermatopathologists and help dermatologists deliver more informed patient management plans.

More information about the test and disease can be found at www.CastleTestInfo.com.

About Psoriasis, Atopic Dermatitis and Related Conditions

Inflammatory skin disease accounts for a significant number of patient visits to both primary care and dermatology clinics across the U.S. every year. Psoriasis and atopic dermatitis are among the most common inflammatory skin conditions, and patient quality of life is severely impacted by these chronic diseases. Fortunately, systemic medications developed over the past 15 years have demonstrated a significant improvement in patients’ lives. In the U.S. alone, there are about 18 million patients diagnosed with psoriasis and atopic dermatitis, and approximately 450,000 patients annually are eligible for these systemic therapies. While there are now many effective treatments options available for those with moderate to severe disease, current clinical practice relies on a trial-and-error approach for therapy selection. To answer this unmet clinical need, Castle Biosciences is developing a gene expression profile test designed to predict response to systemic therapies for patients with moderate to severe psoriasis, atopic dermatitis and other related diseases. Personalized guidance for therapy selection and anticipated efficacy has the potential to improve patient health outcomes by enabling clinicians to select the best medication for their patients’ specific skin disease.

About DecisionDx-SCC

DecisionDx-SCC is a 40-gene expression profile test that uses an individual patient’s tumor biology to predict individual risk of cutaneous squamous cell carcinoma metastasis for patients with one or more risk factors. The test result, in which patients are stratified into a Class 1 (low), 2A (moderate) or 2B (high) risk category, predicts individual metastatic risk to inform risk-appropriate management.

Peer-reviewed publications have demonstrated that DecisionDx-SCC is an independent predictor of metastatic risk and that integrating DecisionDx-SCC with current prognostic methods can add positive predictive value to clinician decisions regarding staging and management.

More information about the test and disease can be found at www.CastleTestInfo.com.

On October 22, 2021 Humanigen, Inc. (Nasdaq: HGEN), a clinical-stage biopharmaceutical company, reported its research partners will present Phase 1 results from a study of ifabotuzumab in glioblastoma multiforme (GBM) at the Annual Congress of the European Association of Nuclear Medicine (EANM’21) and plan to initiate a follow-on Phase 1b study in non-CNS solid tumors in early 2022 (Press release, Humanigen, OCT 22, 2021, View Source [SID1234591790]). EANM is the largest organization dedicated to nuclear medicine in Europe and represents more than 9,000 specialists from 41 different countries.

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The abstract will be presented virtually by Principal Investigator Prof. Andrew Scott, Head, Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute; Director of the Department of Molecular Imaging and Therapy, Austin Health; and Professor, School of Cancer Medicine, La Trobe University. The abstract (OP-0854) entitled: "Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma" has been published in the EANM‘21 abstract book and was chosen to be included in a TOP 3 trials session at EANM’21 that will take place from 3:05-4:35pm Central European Standard Time on October 22, 2021.1

"The biodistribution characteristics demonstrated in the Phase 1 GBM study indicate ifabotuzumab has ideal characteristics for a range of therapeutic options including the creation of an antibody-drug conjugate," said Prof. Scott. "Our preclinical studies with antibody-drug conjugate forms of ifabotuzumab have shown promising results. We hope to take this payload delivery approach into the clinic in the next 1-2 years."

The Olivia Newton-John Cancer Research Institute plans to conduct a Phase 1b dose-escalation and imaging study in non-CNS solid tumors that is scheduled to begin in early 2022. This will be led by Prof. Andrew Scott and Prof. Hui Gan, Clinical Research Lead, Olivia Newton-John Cancer Research Institute and Director, Cancer Clinical Trials Center, Austin Health.

"We are excited by the potential ifabotuzumab holds to create a novel cancer therapeutic that delivers cytotoxic agents to tumor cells while minimizing toxicity to normal tissue," said Cameron Durrant, Chairman and CEO of Humanigen. "We look forward to supporting our valued partners in Australia as they advance research of ifabotuzumab into solid tumors."

About Ifabotuzumab
Ifabotuzumab is a proprietary Humaneered monoclonal antibody that binds the EphA3 receptor, which plays an important role during fetal development but is not thought to be expressed nor play a significant role in healthy adults. EphA3 is a tyrosine kinase receptor, aberrantly expressed on the tumor vasculature and tumor stroma in many solid tumors including melanoma, breast cancer, lung cancer, colorectal cancer, GBM and prostate cancer, making it an attractive target for a range of cancers.

Humanigen has completed a Phase 1 study in multiple hematologic malignancies that suggest it is well tolerated with mild-to-moderate infusion reactions that can be managed by stopping infusion, or using medications to treat reactions (chills, fever, nausea, hypertension, and rapid heart rate).

In 2021, a Phase 1 safety and bioimaging study of ifabotuzumab, supported by Cure Brain Cancer Foundation, and Humanigen, showed specific and reproducible targeting of the tumor and its microenvironment, with no normal tissue uptake, in all patients. Future development plans, in conjunction with our research partners in Australia, are intended to confirm highly specific tumor uptake in non-CNS solid tumors with the intention of creating an antibody-drug conjugate by linking ifabotuzumab to a cytotoxic (cell-killing) agent.

On October 22, 2021 Servier, a global independent pharmaceutical group, reported that the primary objective (progression free survival) of the Phase III SOLSTICE trial has not been met (Press release, Servier, OCT 22, 2021, View Source [SID1234591789]). SOLSTICE was designed to evaluate the superiority of LONSURF (trifluridine/tipiracil) + bevacizumab over capecitabine + bevacizumab in 1st line unresectable metastatic colorectal cancer (mCRC) in patients non-eligible for intensive therapy. The trial will continue as planned given that no deleterious effects and no new safety issues have been raised in either study arm.

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Data from the primary analysis will be presented at an upcoming medical congress.

"We remain committed to improving outcomes in mCRC and we will continue to follow patients as planned in order to perform the main secondary endpoint analysis on overall survival in 2023," said Patrick Therasse, M.D., Ph. D., Head of Late Stage and Life Cycle Management, and Deputy Head Oncology and Immuno-Oncology Therapeutic Area, Servier. "The clinical value of LONSURF in its current indications remains unchanged, and the ongoing Phase III SUNLIGHT trial (LONSURF + bevacizumab versus LONSURF in 3rd line mCRC) is proceeding as planned."

Nearly 1.4 million people are diagnosed with colorectal cancer (CRC) each year worldwide,1 equating to 10% of the global cancer cases.1 In Europe, CRC is the second most common cause of cancer death,2 and metastatic (when the cancer has spread from the primary site to other parts of the body) patients have a 5-year survival rate of just 11%.2 Standard chemotherapy regimens for mCRC include fluoropyrimidines, oxaliplatin, irinotecan or targeted treatments, such as those that target vascular endothelial growth factors (VEGF) or endothelial growth factor receptors (EGFR).

"Metastatic colorectal cancer patients who are not well enough to undergo intensive chemotherapy have limited options, and quality of life is a priority," said Professor Thierry André, MD, Saint Antoine Hospital, Paris, France, and Lead Investigator for the SOLSTICE study. "We are continuously searching for new ways to give these patients efficient treatment with low toxicities."

Servier is committed to developing new treatments to support patients in their fight against gastrointestinal cancer.

About SOLSTICE
SOLSTICE is an open-label, randomized, multicentre Phase III trial in 856 unresectable metastatic colorectal cancer patients who are not candidates for, or do not require, intensive therapy. Patients were randomized 1:1 to receive 1st line LONSURF + bevacizumab versus capecitabine + bevacizumab. The primary objective is to demonstrate superior progression free survival with LONSURF + bevacizumab over capecitabine + bevacizumab. The first patient was enrolled in March 2019.

For more information on SOLSTICE, please visit www.ClinicalTrials.gov (View Source). The ClinicalTrials.gov Identifier is NCT03869892.

About LONSURF
LONSURF consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase (TP) inhibitor, tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.

In the EU, LONSURF is indicated as monotherapy for the treatment of adult patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti- VEGF agents, and anti-EGFR agents. LONSURF is also indicated as monotherapy for the treatment of adult patients with metastatic gastric cancer (mGC), including adenocarcinoma of the gastroesophageal junction (mGEJC), who have been previously treated with at least two prior systemic treatment regimens for advanced disease.

As of October 2021, LONSURF has been approved in 96 countries for the treatment of advanced mCRC and in 80 countries for the treatment of advanced mGC/mGEJC.

LONSURF was discovered and developed by Taiho Pharmaceutical Co., Ltd. In June 2015, Taiho Pharmaceutical and Servier entered into an exclusive license agreement for the co-development and commercialization of LONSURF in Europe and other countries outside of the United States, Canada, Mexico, and Asia.

On October 22, 2021 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported that it will report its third-quarter 2021 financial results on Tuesday, November 2, 2021 after the financial markets close (Press release, Vertex Pharmaceuticals, OCT 22, 2021, View Source [SID1234591785]). The company will host a conference call and webcast at 4:30 p.m. ET. To access the call, please dial (866) 501-1537 (U.S.) or +1 (720) 545-0001 (International).

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The conference call will be webcast live and a link to the webcast can be accessed through Vertex’s website at www.vrtx.com in the "Investors" section. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. An archived webcast will be available on the company’s website.

On October 22, 2021 Thermo Fisher Scientific Inc. (the "Company") reported that issued $1,000,000,000 aggregate principal amount of 18-Month Floating Rate Senior Notes due 2023 (the "18-Month Floating Rate Notes"), $500,000,000 aggregate principal amount of Floating Rate Senior Notes due 2023 (the "2023 Floating Rate Notes"), $500,000,000 aggregate principal amount of Floating Rate Senior Notes due 2024 (the "2024 Floating Rate Notes" and, together with the 18-Month Floating Rate Notes and the 2023 Floating Rate Notes, the "Floating Rate Notes"), $1,350,000,000 aggregate principal amount of 0.797% Senior Notes due 2023 (the "2023 Notes") and $2,500,000,000 aggregate principal amount of 1.215% Senior Notes due 2024 (the "2024 Notes" and, together with the 2023 Notes, the "Fixed Rate Notes", and together with the Floating Rate 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 22, 2021, View Source [SID1234591781]).

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The Notes were issued under an indenture, dated as of November 20, 2009 (the "Base Indenture"), and the Twenty-Third Supplemental Indenture, dated as of October 22, 2021 (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 Floating Rate Notes are subject to a Calculation Agency Agreement, dated as of October 22, 2021, between the Company and The Bank of New York Mellon Trust Company, N.A., as calculation agent.

The 18-Month Notes will mature on April 18, 2023, the 2023 Floating Rate Notes will mature on October 18, 2023, the 2024 Floating Rate Notes will mature on October 18, 2024, the 2023 Notes will mature on October 18, 2023 and the 2024 Notes will mature on October 18, 2024. Interest on the Floating Rate Notes will be paid quarterly in arrears on January 18, April 18, July 18 and October 18 of each year, commencing on January 18, 2022. Interest on the Fixed Rate Notes will be paid semi-annually in arrears on April 18 and October 18 of each year, commencing on April 18, 2022.

Prior to October 18, 2022, the Company may redeem each series of Fixed Rate Notes, 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 Fixed Rate 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 Fixed Rate 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 Fixed Rate Notes to be redeemed matured on October 18, 2022), discounted to the date of redemption on a semi-annual basis (assuming a 360-day year of twelve 30-day months), at the Treasury Rate (as defined in the Indenture) plus, in each case, 7.5 basis points and accrued and unpaid interest on the Fixed Rate Notes being redeemed, if any, to, but excluding, the date of redemption.

In addition, on and after April 18, 2022, with respect to the 18-Month Floating Rate Notes, and October 18, 2022, with respect to the 2023 Floating Rate Notes, the 2024 Floating Rate Notes and the Fixed Rate Notes, the Company may redeem some or all of each series of 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.

In the event that the Company does not consummate the previously announced acquisition of PPD, Inc. (the "PPD Acquisition") on or prior to October 15, 2022 or the merger agreement related thereto is terminated at any time prior to such date, the Company will be required to redeem all of the 2023 Floating Rate Notes, the 2024 Floating Rate Notes, the 2023 Notes and the 2024 Notes (collectively, the "SMR Notes") on a special mandatory redemption date at a redemption price equal to 101% of the aggregate principal amount of the SMR Notes, plus accrued and unpaid interest, if any, to, but excluding, the special mandatory redemption date.

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 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 and 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.

Wilmer Cutler Pickering Hale and Dorr LLP, counsel to the Company, has issued an opinion to the Company, dated October 22, 2021, regarding the Notes. A copy of this opinion is filed as Exhibit 5.1 hereto.

The foregoing description is qualified in its entirety by reference to the full text 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.