On March 24, 2023 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported that it has completed its rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) for lifileucel (Press release, Iovance Biotherapeutics, MAR 24, 2023, View Source [SID1234629381]). Lifileucel is a tumor infiltrating lymphocyte (TIL) therapy intended as a treatment for patients with advanced (unresectable or metastatic) melanoma who progressed on or after prior anti-PD-1/L1 therapy and targeted therapy, where applicable. There are no FDA approved therapies in this treatment setting.

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Frederick Vogt, Ph.D., J.D., Interim President and Chief Executive Officer of Iovance, stated, "Completing our BLA submission for lifileucel is a critical step forward in our journey to deliver the first individualized, one-time cell therapy for a solid tumor. I would like to acknowledge the patients and physicians who participated in the C-144-01 clinical trial and the FDA review team for their commitment and support, as well as our internal team for their tremendous effort in completing the first BLA submission for Iovance. Our preparations for commercialization remain on track to support a launch later this year. We look forward to continued collaboration with the FDA as they review this new class of treatment for advanced melanoma patients with limited options."

The BLA submission for lifileucel is supported by positive clinical data from the C-144-01 clinical trial in patients with advanced post-anti-PD1 melanoma. Following a successful pre-BLA meeting with the FDA, Iovance is pursuing accelerated approval in this indication. Iovance also reached agreement with the FDA regarding the registrational trial design for the Phase 3 TILVANCE-301 trial of lifileucel in combination with pembrolizumab in frontline advanced melanoma. TILVANCE-301 is intended to support full approval of lifileucel in post-anti-PD-1 advanced melanoma and is also designed to support registration for lifileucel in combination with pembrolizumab as therapy for advanced melanoma in the frontline setting. Startup activities for TILVANCE-301 are ongoing and the trial is expected to be well underway at the time of potential accelerated approval for lifileucel in advanced post-anti-PD-1 melanoma.

Marc Hurlbert, Ph.D., CEO of the Melanoma Research Alliance (MRA), said, "MRA congratulates Iovance for completing the BLA submission and moving closer toward making TIL therapy an option for people with advanced melanoma who have progressed following prior treatments. We hope for an FDA approval as quickly as possible for patients with significant unmet need who have no approved treatment options."

Following receipt of the complete rolling BLA submission for lifileucel, the FDA has 60 days to determine the acceptability of the BLA for review. The rolling BLA allowed Iovance to submit portions of the BLA to the FDA on an ongoing basis, enabling the FDA to begin review as early as possible as documents were received. The rolling BLA submission and eligibility for priority review are benefits available under the FDA’s guidance on expedited programs for serious conditions, which allow for an expedited six-month review from the time of BLA acceptance. In addition, the FDA previously granted a regenerative medicine advanced therapy (RMAT) designation for lifileucel in advanced melanoma.

On March 24, 2023 NuCana plc (NASDAQ: NCNA) reported that, following a hearing on March 24, 2023, the Technical Board of Appeal (the "TBA") of the European Patent Office (the "EPO") issued an oral judgement that NuCana’s European Patent 2955190 (the "’190 patent") is not valid (Press release, Nucana BioPharmaceuticals, MAR 24, 2023, View Source [SID1234629346]).

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The TBA reversed the previous decisions of the EPO’s Examination Division which issued NuCana’s ‘190 patent and of the EPO’s Opposition Division which upheld this patent in 2021. In July 2022, the Regional Court of Dusseldorf issued a judgement that fully endorsed the decision of the EPO’s Opposition Division.

The TBA considered a part of Claim 1 of the ‘190 patent to lack an inventive step and did not allow NuCana to overcome this finding by an appropriate amendment of the claims in line with established case law of the EPO. "This aspect of the decision is particularly disappointing," said Dr. Thorsten Bausch, Senior Partner at Hoffmann Eitle, who represented NuCana at the hearing.

This follows on from the judgement of the Patents Court of England and Wales handed down on March 21, 2023 which held that the ‘190 patent was invalid in the UK.

Neither of these decisions affect the patent protection on any of NuCana’s anti-cancer ProTides, which are covered by separate patents that were not involved in this litigation.

Hugh S. Griffith, NuCana’s Founder and CEO, said: "While we are disappointed by these decisions, they do not impact our core business of developing innovative new medicines for the treatment of patients with cancer. NuCana is well-capitalized, all of our clinical programs remain on track and we expect multiple data announcements in 2023."

On March 24, 2023 Mersana Therapeutics, Inc. (the "Company") reported that it has entered into a Fourth Amendment to Loan and Security Agreement (the "Fourth Amendment"), by and among the Company, Oxford Finance LLC, in its capacity as collateral agent (in such capacity, the "Agent") and a lender, Silicon Valley Bridge Bank, N.A. (as the successor in interest to Silicon Valley Bank) as a lender ("SVB"), and the other parties thereto as lenders (collectively, the "Lenders") (Filing, 8-K, Mersana Therapeutics, MAR 24, 2023, View Source [SID1234629345]). The Fourth Amendment further amended that certain Loan and Security Agreement dated as of October 29, 2021 by and among the Company, the Lenders and the Agent (as amended by the First Amendment to Loan and Security Agreement dated as of February 17, 2022, the Second Amendment to Loan and Security Agreement dated as of October 17, 2022 and the Third Amendment to Loan Agreement dated as of December 27, 2022, the "Loan Agreement").

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The Fourth Amendment modified the covenant applicable to the Company’s obligation to maintain Collateral Accounts (as defined in the Loan Agreement) at SVB, which may be a securities account invested in money market mutual funds. Pursuant to the Fourth Amendment, the Company is permitted to conduct its banking activities, including, without limitation, cash management, letters of credit and business credit cards, with financial institutions which are not SVB or SVB’s affiliates. In addition, the Fourth Amendment reduced the minimum amounts that the Company is obligated to maintain in Collateral Accounts at SVB to be the lesser of (i) one hundred five percent (105.00%) of the outstanding principal amount of the Term Loans (as defined in the Loan Agreement) advanced solely by SVB (and for purposes of clarity, no other Lender) and (ii) the dollar value of all Collateral Accounts of the Company and certain of its subsidiaries at all financial institutions.

As of the Amendment Date, this obligation requires the Company to maintain a Collateral Account at SVB with 105% of the $12.5 million borrowed from SVB under the Loan Agreement. The Company did not pay any fees to Lenders in connection with the Fourth Amendment, and the Fourth Amendment did not otherwise modify the Company’s obligations under the Loan Agreement.

The foregoing description of the Fourth Amendment does not purport to be complete and is qualified in its entirety by reference to the Fourth Amendment, which will be filed as an exhibit to the Company’s Quarterly Report on Form 10-Q for the fiscal quarter ending March 31, 2023.

On March 24, 2023 Integra LifeSciences Holdings Corporation (the "Company") reported that it has entered into an amended and restated credit agreement with a syndicate of lending banks, Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, Citibank N.A., JPMorgan Chase Bank, N.A., Morgan Stanley MUFG Loan Partners, LLC, PNC Bank, N.A., Truist Securities, Inc. and Wells Fargo Bank, N.A., as Co-Syndication Agents, and The Bank of Nova Scotia, BMO Harris Bank N.A., BNP Paribas, Capital One, National Association, Citizens Bank, N.A., DNB Bank ASA, New York Branch, Santander Bank, N.A. and TD Bank, N.A., as Co-Documentation Agents (the "Amendment and Restatement") (Filing, 8-K, Integra LifeSciences, MAR 24, 2023, View Source [SID1234629312]).

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The Amendment and Restatement makes an aggregate principal amount of up to $2.075 billion available to the Company through the following facilities: (i) a $1.3 billion revolving credit facility, and (ii) a $775 million term loan facility, which includes a $60 million sublimit for the issuance of standby letters of credit and a $60 million sublimit for swingline loans. The Amendment and Restatement extends the credit facility’s maturity date from February 3, 2025 to March 24, 2028, subject to certain springing maturity conditions.

Borrowings under the Amendment and Restatement bear interest, at the Company’s option, at a rate equal to (i) term SOFR (as defined in the amendment and restatement) in effect from time to time plus 0.10% plus the applicable rate (ranging from 1.00% to 1.75%) or (ii) the highest of (x) the weighted average overnight Federal funds rate, as published by the Federal Reserve Bank of New York, plus one half of 1.0%, (y) the prime lending rate of Bank of America, N.A. or (z) the one-month Term SOFR plus 1.0%. The applicable rates are based on the Company’s consolidated total leverage ratio (defined as the ratio of (a) consolidated funded indebtedness as of such date to (b) consolidated EBITDA for the period of four consecutive fiscal quarters ending on such date) at the time of the applicable borrowing.

The Company will also pay an annual commitment fee of 0.15% to 0.30% on the daily amount by which the commitments under the revolving credit facility exceed the outstanding loans and letters of credit under the revolving credit facility.

A copy of the Amendment and Restatement is attached as Exhibit 10.1 to this Current Report on Form 8-K and is incorporated by reference herein.

In addition, on March 24, 2023, the Company and the subsidiary guarantors of the Company entered into a ratification agreement to the Amendment and Restatement with Bank of America, N.A., as Administrative Agent (the "Ratification Agreement"). A copy of the Ratification Agreement is attached as Exhibit 10.2 to this Current Report on Form 8-K and is incorporated by reference herein.

ITEM 2.03 CREATION OF A DIRECT FINANCIAL OBLIGATION OR AN OBLIGATION UNDER AN OFF-BALANCE SHEET ARRANGEMENT OF A REGISTRANT

The information set forth in Item 1.01 above is incorporated by reference into this item.

ITEM 9.01 FINANCIAL STATEMENTS AND EXHIBITS

(d) Exhibits

10.1
Seventh Amended and Restated Credit Agreement, dated as of March 24, 2023, among Integra LifeSciences Holdings Corporation, the lenders party thereto, Bank of America, N.A., as Administrative Agent, Swing Line Lender and L/C Issuer, Citibank N.A., JPMorgan Chase Bank, N.A., Morgan Stanley MUFG Loan Partners, LLC, PNC Bank, N.A., Truist Securities, Inc. and Wells Fargo Bank, N.A., as Co-Syndication Agents, and The Bank of Nova Scotia, BMO Harris Bank N.A., BNP Paribas, Capital One, National Association, Citizens Bank, N.A., DNB Bank ASA, New York Branch, Santander Bank, N.A. and TD Bank, N.A., as Co-Documentation Agents.
10.2
Ratification Agreement, dated as of March 24, 2023, between Integra LifeSciences Holdings Corporation, the Subsidiary Guarantors of Integra LifeSciences Holdings Corporation and Bank of America, N.A., as Administrative Agent.

On March 24, 2023 Biocept, Inc. (Nasdaq: BIOC), a leading provider of molecular diagnostic assays, products and services, reported enrollment of the first patient in the FORESEE clinical trial with the Company’s proprietary cerebrospinal fluid assay CNSide (NCT05414123) (Press release, Biocept, MAR 24, 2023, View Source [SID1234629311]). This first patient was seen at the UT Southwestern Medical Center, one of the largest and most respected hospitals in the nation.

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The FORESEE trial is a multicenter, prospective clinical trial expected to enroll 40 patients with breast or non-small cell lung cancer (NSCLC) who have suspicious or confirmed leptomeningeal metastases (LM). The goal of the FORESEE trial is to evaluate the performance of CNSide in monitoring the LM’s response to treatment and to assess the impact of CNSide on treatment decisions made by physicians.

Standard-of-care methods to diagnose or assess the treatment response of LM (i.e., clinical evaluation, MRI and cytology) have limited sensitivity and specificity. This creates challenges for physicians to manage LM or determine the best course of treatment. CNSide is a Laboratory Developed Test (LDT) that is used commercially at the physician’s discretion, with samples processed in Biocept’s CLIA-certified, CAP-accredited laboratory.

"The enrollment of the first patient in the FORESEE clinical study is a major milestone for the management of patients with leptomeningeal disease," said Michael Youssef, MD, Assistant Professor in the Department of Neurology and the Department of Hematology and Oncology at UT Southwestern Medical Center. "We are excited to be at the forefront of this innovation, which will greatly benefit patients."

Priya Kumthekar, MD, Associate Professor of Neurology and Medicine (hematology and oncology) at the Feinberg School of Medicine at Northwestern University and Principal Investigator of the FORESEE trial, said, "I am impressed by the ease of use and the versatility of the CNSide technology, and how it can facilitate disease diagnosis and management for our leptomeningeal patients who are truly in need of improved diagnostics and therapeutics."

"The FORESEE trial evaluates the medical and clinical utility, when compared to standard of care, of the CNSide laboratory test, a revolutionary technology designed to detect cells in the cerebral spinal fluid of central nervous system brain metastasis patients," said Sam Riccitelli, Chairman and interim President and CEO of Biocept. "The test can be used to detect the presence of tumor, as well as guide and monitor therapy, an area of critical need for these terminally ill patients."

Dr. Kumthekar is a consultant to Biocept and Dr. Youssef has no financial interest in Biocept.

About CNSide

Using our proprietary CNSide assay to analyze and interrogate CSF-TCs and cfDNA for certain biomarkers, physicians can be better informed about the actionable molecular information associated with a patient’s metastatic cancer and develop a personalized cancer treatment plan. Through CNSide, Biocept’s test menu focuses on cancer biomarkers that are clinically actionable based on clinical treatment guidelines listed by the National Comprehensive Cancer Network (NCCN). For more information, please visit https://biocept.com/technology/.