On March 16, 2020 Can-Fite BioPharma Ltd. (NYSE MKT: CANF) (TASE:CFBI), a biotechnology company with a pipeline of proprietary small molecule drugs that address inflammatory, cancer and liver diseases, reported it has already enrolled seven patients for the compassionate use program for Namodenoson in the treatment of hepatocellular cancer (HCC), the most common form of liver cancer (Press release, Can-Fite BioPharma, MAR 16, 2020, View Source [SID1234555573]). Results of treatment in this patient group indicate that Namodenoson was found to have a good safety profile and was well tolerated, with no severe adverse events reported. Can-Fite’s compassionate use program is managed by Dr. Salomon Stemmer, a key opinion leader in the field of liver cancer, and Professor at the Institute of Oncology, Rabin Medical Center, Israel.

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The Company also reports that an additional two patients from the former Phase II study are still undergoing Namodenoson treatment, each with an overall survival of more than 2.5 years.

Recently, the Company successfully concluded an End-of-Phase II meeting with the FDA which agreed with Can-Fite’s proposed pivotal Phase III trial design of Namodenoson for the treatment of patients with advanced HCC, with underlying Child Pugh B7 (CPB7) cirrhosis to support a New Drug Application (NDA) submission and approval. In addition, the Company also submitted a Phase III protocol and Registration Plan to the European Medicines Agency (EMA) for Namodenoson and expects to receive a response from the EMA in the next few weeks. Can-Fite plans to work concurrently with the two agencies, the FDA and EMA, with the expectation to register the drug in parallel upon successful conclusion of the Phase III study.

"We are grateful to Dr. Stemmer for leading this compassionate use program, making Namodenoson available to patients who have exhausted all other treatment options. Based on the encouraging results of our recent Phase II trial, in which Namodenoson demonstrated clinical benefits in patients with underlying CPB7 cirrhosis, Can-Fite is committed to providing Namodenoson to fulfill the unmet medical need in this population," stated Can-Fite CEO Dr. Pnina Fishman.

About Namodenoson

Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). Namodenoson is being evaluated as a second line treatment for hepatocellular carcinoma, with a recently completed Phase II trial and planned Phase III trial in this indication. The drug is currently in an ongoing Phase II trial as a treatment for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug.

On March 16, 2020 Boehringer Ingelheim reported the launch of a patient outcomes database which will provide clinicians with important information when considering optimal treatment for non-small cell lung cancer (NSCLC) patients harboring specific uncommon epidermal growth factor receptor (EGFR) mutations (Press release, Boehringer Ingelheim, MAR 16, 2020, View Source [SID1234555568]). The real-world database includes all available data from such patients treated with afatinib.

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The data from 693 NSCLC patients published in the Journal of Thoracic Oncology (JTO) support the use of afatinib against the most prevalent uncommon EGFR mutations. In patients who had not previously received any form of EGFR tyrosine kinase inhibitor (TKI), treatment with afatinib demonstrated activity against major uncommon mutations (median time-to-treatment-failure (TTF): 10.8 months; 95% CI: 8.1–16.6; overall response rate (ORR): 60.0%), compound mutations (14.7 months; 95% CI: 6.8–18.5; 77.1%), other uncommon mutations (4.5 months; 95% CI: 2.9–9.7; 65.2%). Median duration of response (DoR) was 17.1, 16.6, and 9.0 months, respectively. Outcome in patients with exon 20 insertions was heterogeneous with a TTF of 4.2 months (95% CI: 2.8 – 5.3) with 3% having complete remissions and 5% being on treatment for more than 3 years.i

The pooled analysis was based on global clinical outcome data from 693 patients with NSCLC driven by uncommon EGFR mutations, who received afatinib as part of clinical trials, compassionate use or expanded access programs, phase IIIb trials, non-interventional trials and case series/studies in more than 40 countries. The mutations included: (29% major uncommon EGFR mutations [G719X, L861Q and S768I], 25% T790M, 21% exon 20 insertion, 13% other uncommon EGFR mutation, 12% compound mutation) which had been available via the new searchable database www.uncommonEGFRmutations.com.

This new data supports previous findings from a post-hoc analysis of the LUX-Lung trials, which demonstrated significant clinical activity of afatinib against the most prevalent uncommon mutations.ii Of the EGFR TKI prospective randomized trials to date, only IPASS (gefitinib),iii NEJ002 (gefitinib),iv and LUX-Lung 2, 3 and 6 (afatinib),v, vi included patients with uncommon EGFR mutations, meaning clinical data for other EGFR TKIs against uncommon mutations is lacking. While other TKIs have shown efficacy in a first-line setting in patients with NSCLC and common mutations (Del19, L858R), their clinical activity against uncommon mutations remains largely unknown.

Lead author Dr James Chih-Hsin Yang from the Department of Oncology at the National Taiwan University Hospital said, "The relative scarcity of prospective clinical data concerning the up to 23% of NSCLC EGFR M+ cases that fall into the ‘uncommon mutation’ category can compromise effective treatment decisions. The results from this pooled analysis, alongside the post-hoc LUX-Lung results, should support afatinib as the first-choice treatment for NSCLC patients with uncommon EGFR mutations. Additionally, the uncommon mutation database, which is going to be continuously updated as new data becomes available, will be an invaluable clinical decision-making tool for the treatment of this patient sub-population moving forward."

"The value and the richness of these new combined data establishes afatinib as the meaningful treatment option for patients with uncommon EGFR mutation in addition to its recognized role as first-line therapy for common EGFR mutations," said Dr Victoria Zazulina, Global Head of Oncology, Medicine, at Boehringer Ingelheim. "We hope that this new searchable database will inform clinical decisions and therapeutic choices for patients with various types of uncommon EGFR mutations."

The uncommon mutation data summarized within the paper are available in a searchable online database at www.uncommonEGFRmutations.com. The database can be accessed globally by clinicians and non-clinicians alike and will be regularly updated as new data becomes available.

Boehringer Ingelheim in Oncology
Cancer takes away loved ones, time and untapped potential. At Boehringer Ingelheim we are providing new hope for patients by taking cancer on. We are collaborating with the oncology community to deliver scientific breakthroughs to transform the lives of patients. Our primary focus is in lung and gastrointestinal cancers, with the goal of delivering breakthrough, first-in-class treatments that can help win the fight against cancer. Our commitment to innovation has resulted in pioneering treatments for lung cancer and we are advancing a unique pipeline of cancer cell directed agents, immune oncology therapies and intelligent combination approaches to help combat many cancers.

Boehringer Ingelheim
Improving the health of humans and animals is the goal of the research-driven pharmaceutical company Boehringer Ingelheim. The focus in doing so is on diseases for which no satisfactory treatment option exists to date. The company therefore concentrates on developing innovative therapies that can extend patients’ lives. In animal health, Boehringer Ingelheim stands for advanced prevention.

Family-owned since it was established in 1885, Boehringer Ingelheim is one of the pharmaceutical industry’s top 20 companies. Some 50,000 employees create value through innovation daily for the three business areas human pharmaceuticals, animal health and biopharmaceuticals. In 2018, Boehringer Ingelheim achieved net sales of around 17.5 billion euros. R&D expenditure of almost 3.2 billion euros, corresponded to 18.1 per cent of net sales.

As a family-owned company, Boehringer Ingelheim plans in generations and focuses on long-term success. The company therefore aims at organic growth from its own resources with simultaneous openness to partnerships and strategic alliances in research. In everything it does, Boehringer Ingelheim naturally adopts responsibility towards mankind and the environment.

On March 15, 2020, Progenics Pharmaceuticals, Inc. (the "Company"), as borrower, and Lantheus Medical Imaging, Inc. ("Lantheus Medical Imaging"), a subsidiary of Lantheus Holdings, Inc., as lender, reported that it has entered into a bridge loan agreement, pursuant to which Lantheus Medical Imaging agreed to provide for a secured short-term loan to the Company on or after May 1, 2020 in an aggregate principal amount of up to $10 million (the "Bridge Loan Agreement") (Filing, 8-K, Progenics Pharmaceuticals, MAR 15, 2020, View Source [SID1234555579]). The bridge loan matures on the earlier to occur of (a) September 30, 2020 and (b) the date on which the Company enters into a debt financing or similar arrangements or any amendment to, or replacement of, its existing debt, provided by one or more third parties following the termination date of the Amended and Restated Agreement and Plan of Merger, dated as of February 20, 2020 (the "Merger Agreement"), as filed by the Company with the Securities and Exchange Commission on a Current Report on Form 8-K on February 20, 2020, in either case, having aggregate net cash proceeds that exceed the amount then required to repay all obligations under the Bridge Loan Agreement in full in cash.

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The Company will use the proceeds of the bridge loan for working capital and other general corporate purposes. The proceeds will not be used in connection with any related party transaction, the purchase or repurchase of any capital stock of the Company, acquisition of assets or other merger activity unrelated to the Merger Agreement, or in any manner that would reasonably be expected to prevent the merger from constituting a tax-free reorganization described in Section 368(a) and related provisions of the Internal Revenue Code of 1986.

The bridge loan bears interest at rate per annum of 9.5%. No amortization, interest or other payments are required to be paid under the Bridge Loan Agreement until the maturity date, provided that if the Company or any of its subsidiaries receives net cash proceeds from any debt financing or other similar arrangement entered into outside the ordinary course of business, the Company is required to prepay the bridge loan in an amount equal to such net cash proceeds within two business days thereof. The Company may make voluntary prepayments at any time and from time to time (provided that any partial voluntary prepayment will not be in an amount less than $500,000) together with accrued interest thereon, without premium or penalty.

The bridge loan is secured through the pledge to Lantheus Medical Imaging of all of the issued and outstanding shares of capital stock of Molecular Insight Pharmaceuticals, Inc., a subsidiary of the Company ("MIPI"), and any debt of MIPI owed to the Company.

The obligation of Lantheus Medical Imaging to fund the bridge loan on or after May 1, 2020 is subject to customary conditions, including, among other things, the following:

the execution and delivery of the Bridge Loan Agreement, stock pledge agreement to be entered into by and between the Company and Lantheus Medical Imaging and other specified documents and certificates delivered in connection therewith;

no change in recommendation (as defined in the Merger Agreement) of the Company’s Board of Directors; and

no material adverse effect (as defined in the Merger Agreement) or material breach by the Company under the Merger Agreement, in respect of which Lantheus Holdings, Inc. has terminated the Merger Agreement.

Without the prior consent of Lantheus Medical Imaging, the Company will not permit MIPI to (i) declare, set aside, make or pay any dividend or other distribution (whether in cash, stock or property) in respect of any of its securities, other than dividends or distributions by wholly-owned subsidiaries of MIPI to MIPI or a wholly-owned subsidiary of MIPI, (ii) split, subdivide, consolidate, combine or reclassify any of its securities or issue or allot, or propose or authorize the issuance or allotment of, any other securities or equity rights in respect of, in lieu of, or in substitution for, any of its securities, (iii) repurchase, redeem or otherwise acquire any securities or equity rights of MIPI or any subsidiary of MIPI, (iv) issue, allot, sell, grant, pledge or otherwise encumber any securities or equity rights, (v) merge or consolidate with any person, or acquire the securities in, or any material amount of assets of, any other person or (vi) incur or suffer to exist (or permit any subsidiary of MIPI to incur or suffer to exist) any Indebtedness (as defined in the Bridge Loan Agreement) owing to any affiliate of the Company (other than to the Company, MIPI or any of MIPI’s other subsidiaries). Additionally, the Company is required to cause MIPI to comply with the interim period operating covenants and the covenant to provide notice of certain material events, in each case, set forth in the Merger Agreement, with the same effect as if such covenants were fully incorporated therein, mutatis mutandis.

The Company is required to use commercially reasonable efforts to enter into a debt financing with net cash proceeds in excess of the amount then required to repay all obligations in full in cash promptly following the termination of the Merger Agreement.

On March 13, 2020 Major venture capitalist firm Flagship Pioneering has brought together two of its sister biotech companies to create a new, singly focused effort (Press release, Torque Therapeutics, MAR 13, 2020, View Source,autoimmune%20disorders%20and%20infectious%20diseases [SID1234573748]).

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Torque Therapeutics and Cogen Immune Medicine now become Repertoire Immune Medicines, a combined biotech looking to tap into the curative powers of our immune system to prevent, treat and cure cancer, autoimmune disorders and infectious diseases.

Torque CEO John Cox, an ex-Biogen exec who also shepherded its spinoff Bioverativ through its $11.6 billion acquisition by Sanofi, becomes the new company’s chief.

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Torque has been working on what it calls "deep-primed adoptive cell transfer" treatments it believes can surmount the hurdles that limit the use of cell therapy in cancer. These include getting past the microenvironment around a tumor that quashes the immune system and shuts down T-cell function.

The company "deep-primes" T cells to target multiple tumor antigens and puts cytokine and immunomodulators on their surfaces to call forth an immune response in the tumor microenvironment, the company says. Its first program, TRQ-1501, primes T cells to carry IL-15, a cytokine that promotes the proliferation of natural killer cells.

This will continue under the new biotech but will combine the work of Cogen, which also tapped the power of a patient’s immune system to fight disease. Now, it’s working on technologies for its so-called DECODE discovery and DEPLOY product platforms that "allow in-depth characterization of the immune synapse and the ability to rationally design, and clinically develop, multi-clonal immune medicines."

Repertoire has three discovery technologies that are at the heart of its immune synapse deciphering platform:

MCR, cell-based reporter assays to experimentally quantify MHC-specific peptide display and de-orphan TCR clonotypes across virtually unlimited peptide-MHC libraries;
‍CIPHER, MHC multimer-based assays to detect and measure TCR clonotypes, peptide-MHC reactivity and phenotypes on a single-cell level;
CAPTAN, internally developed deep-learning computational tools to classify platform hits and leverage large data sets to predict TCR reactivity beyond what is currently possible.
It said in a statement it is currently working on clinical trials "using autologous T cells primed against cancer antigens and tethered to IL-15." Specifically, Repertoire is testing its first dose escalation safety trial with TRQ15-01, using its PRIME platform to prepare the patient’s T cells and its TETHER platform to link an IL-15 nanogel immune modulator to the T cells.

"Repertoire is pioneering a new class of therapies based on high throughput, high content interrogation of the intrinsic ability of T cells to prevent, or cure diseases," said Noubar Afeyan, Ph.D., CEO of Flagship Pioneering and co-founder and chairman of Repertoire Immune Medicines.

He added: "Our products will be designed to leverage the highly evolved, potent and clinically-validated mechanism of the natural immune synapse to provide immune security to patients. With these ambitious goals in mind, we are pleased to have a proven leader, John Cox, as CEO to realize our shared vision to dramatically improve outcomes for those in need or at risk."

On March 13, 2020 X4 Pharmaceuticals, Inc., a Delaware corporation ("X4") and its qualified subsidiaries, including without limitation X4 Therapeutics, Inc. (together with X4, the "Borrower") entered into a First Amendment to the Amended and Restated Loan and Security Agreement dated June 27, 2019 (collectively the "Amended Loan Agreement") with Hercules Capital, Inc., and Hercules Capital Funding Trust 2019-1 (collectively the "Lender" or "Hercules"), which provides for aggregate maximum borrowings of up to $50.0 million (Filing, 8-K, X4 Pharmaceuticals, MAR 13, 2020, View Source [SID1234555647]).

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The Amended Loan Agreement consists of (i) a term loan of $25.0 million (including the $20.0 million previously outstanding under the Amended and Restated Loan and Security Agreement dated June 27, 2019) and an additional $5.0 million drawn at the closing of the first amendment on March 13, 2020 (the "Closing Date") (the "Tranche 1 Term Loan Advance"), (ii) subject to the achievement of certain performance milestones and other conditions, a right of the Borrower to request that the Lender make additional term loan advances in an aggregate amount of up to $7.5 million through June 30, 2021 the ("Tranche 2 Term Loan Advance"), (iii) subject to the achievement of certain performance milestones and conditions, a right of the Borrower to request that the Lender make additional term loan advances in an aggregate amount of up to $7.5 million through June 30, 2022 ( "Tranche 3 Term Loan Advance") and (iv) subject to the Lender’s investment committee’s sole discretion, a right of the Borrower to request that the Lender make additional term loan advances in an aggregate amount of up to $10.0 million through December 31, 2022 ("Tranche 4 Term Loan Advance").

Borrowings under the Amended Loan Agreement bear interest at a variable rate equal to a per annum rate of interest equal to the greater of either (i) 3.75% plus the prime rate as reported in The Wall Street Journal, and (ii) 8.75%. In an event of default, as defined in the Amended Loan Agreement, and until such event is no longer continuing, the interest rate applicable to borrowings under the Amended Loan Agreement would be increased by 4.0%.

Borrowings under the Amended Loan Agreement are repayable in monthly interest-only payments through January 1, 2022, and in equal monthly payments of principal and accrued interest from February 1, 2022 until the maturity date of the loan, which is July 1, 2023. X4 may prepay all, but not less than all, of the outstanding borrowings, subject to a prepayment premium of up to 2.0%, 1.0% or 0.5% of the principal amount outstanding as of the date of repayment, in each case depending on when such repayment is made. In addition, the Amended Loan Agreement provides for payments by the Borrower to Hercules of (i) $795,000 payable upon the earlier of November 1, 2021 or the repayment in full of all obligations under the Amended Loan Agreement, and (ii) 4.0% of the aggregate principal amount of all Term Loan Advances drawn under the Amended Loan Agreement (which payment amount would be $2.0 million if X4 borrowed the aggregate maximum principal amount of $50.0 million), payable upon the earlier of the maturity of the Amended Loan Agreement or the repayment in full of all obligations under the Amended Loan Agreement.

Borrowings under the Amended Loan Agreement are collateralized by substantially all of the Borrower’s personal property and other assets except for their intellectual property (but including rights to payment and proceeds from the sale, licensing or disposition of the intellectual property). Under the Amended Loan Agreement, the Borrower has agreed to affirmative and negative covenants to which the Borrower will remain subject until maturity or repayment of the loan in full. The covenants include, without limitation:

(a) Effective immediately upon the date the outstanding principal amount of the advances under the Amended Loan Agreement exceeds $25.0 million, Borrower at all times thereafter shall maintain cash in an account or accounts of Borrower in which Hercules has a first priority security interest, in an aggregate amount greater than or equal to the greater of (i) $30.0 million or (ii) 6 multiplied by a metric based on prior months’ cash expenditures ("RML"); provided, however, that from and after Borrower’s achievement of certain performance milestones, the required level shall be reduced to the greater of (x) $20.0 million, or (y) 3 multiplied by the current RML; and provided further, that subject to the achievement of certain milestones, this covenant shall be extinguished.

(b) Restrictions on the Borrowers’ ability to incur additional indebtedness, pay dividends, encumber its intellectual property, or engage in certain fundamental business transactions, such as mergers or acquisitions of other businesses, with certain exceptions.

The Borrower’s obligations under the Amended Loan Agreement are subject to acceleration upon occurrence of specified events of default, including payment default, insolvency and a material adverse change in the Borrower’s business, operations or financial or other condition.

In addition, under the Amended Loan Agreement, Hercules has the right to participate, in a cumulative amount of up to $3.0 million in the aggregate, of which $1.0 million has already been exercised as of the Closing Date, and subject to exceptions as provided in the Amended Loan Agreement, in any future offering of X4’s equity securities for cash that is solely for financing purposes and is broadly marketed to multiple investors.

The foregoing description of the Amended Loan Agreement does not purport to be complete and is qualified in its entirety by reference to the Amended Loan Agreement, which is attached hereto as Exhibit 10.1 and is incorporated herein by reference.