On December 30, 2022, Enlivex Therapeutics Ltd., a company organized under the laws of the State of Israel (the "Company"), entered into an Agreement (the "ATM Agreement") with Cantor Fitzgerald & Co. and JMP Securities LLC, as agents (the "Agents"), pursuant to which the Company may elect to sell, from time to time through the Agents, ordinary shares, par value NIS 0.40 per share of the Company, having an aggregate offering price of up to $100.0 million (collectively, the "Offered Shares") (Filing, 6-K, Enlivex Therapeutics, DEC 30, 2022, View Source [SID1234625685]).

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Any potential sale of the Offered Shares will be made pursuant to the Company’s effective shelf registration statement on Form F-3, including the prospectus contained therein (File No. 333-264561) filed by the Company with the Securities and Exchange Commission (the "SEC") on April 29, 2022 and declared effective on May 5, 2022, as supplemented by a prospectus supplement (the "Prospectus Supplement") dated December 30, 2022 and filed with the SEC pursuant to Rule 424(b) under the Securities Act of 1933, as amended (the "Securities Act").

If the Company elects from time to time to sell ordinary shares under the Prospectus Supplement, such sales may be made in transactions that are deemed to be "at-the-market" offerings as defined in Rule 415 under the Securities Act, including sales made directly on or through the Nasdaq Capital Market, the existing trading market for the Company’s ordinary shares, or any other existing trading market in the United States for the Company’s ordinary shares, sales made to or through a market maker other than on an exchange or otherwise, directly to an Agent as principal, in negotiated transactions, or in any other method permitted by law, which may include block trades. The Agents have agreed to use commercially reasonable efforts consistent with their normal trading and sales practices to sell the Offered Shares pursuant to the ATM Agreement from time to time, based upon instructions from the Company, including any price or size limits or other customary parameters or conditions the Company may impose.

The Company is not obligated to sell any Offered Shares under the ATM Agreement. The ATM Agreement will terminate upon the earliest of (a) the sale of all of the Offered Shares and (b) the termination of the ATM Agreement by the Agents or the Company, as permitted therein.

The Company has agreed to pay the Agents an aggregate commission of 3.0% of the gross sales price from each sale of Offered Shares by either Agent pursuant to the ATM Agreement and has agreed to customary indemnification and contribution rights in favor of the Agents.

Additionally, the Company has agreed to reimburse the Agents for certain specified expenses in connection with entering into the ATM Agreement and ongoing sales thereunder. The ATM Agreement contains customary representations and warranties and conditions to the sale of the Offered Shares thereunder.

The foregoing description of the ATM Agreement is not complete and is qualified in its entirety by reference to the full text of such agreement, a copy of which is filed herewith as Exhibit 10.1 to this Report on Form 6-K and is incorporated herein by reference.

This Report on Form 6-K shall not constitute an offer to sell or the solicitation of an offer to buy the Offered Shares or any other securities, nor shall there be any offer, solicitation, or sale of securities in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state.

On December 30, 2022 Shandong Boan Biotechnology Co., Ltd. ("Boan Biotech" or the "Company"), a subsidiary of Luye Pharma Group, reported it was officially listed on the Main Board of the Stock Exchange of Hong Kong ("SEHK") under the stock code 6955.HK at an offer price of HK$19.8 per share (Press release, Boan Biotech, DEC 30, 2022, View Source [SID1234625684]). The successful listing on SEHK marks the beginning of a new phase in the development of Boan Biotech, which will be empowered by capital to forge ahead with the goal of becoming a "leading global biopharmaceutical company".

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Founded in 2013, Boan Biotech is committed to developing, manufacturing and commercializing high-quality biologics in China and overseas. It offers innovative and accessible therapeutic solutions in the key therapeutic areas, including oncology, metabolism, autoimmunity, and ophthalmology. As a fully-integrated biopharmaceutical company, Boan Biotech has established its competitive advantages with a differentiated product portfolio, a whole industry value chain system covering "R&D-production-commercialization," and commercialization capabilities that continues to mature.

Differentiated Product Portfolio and Several Drug Candidates with First-mover Advantage

Leveraging its efficient internal innovation capabilities, Boan Biotech developed all its products in-house independently. Currently, its product pipeline includes a portfolio of innovative antibody candidate drugs and biosimilar drug candidates with international intellectual property protection. They provide a clear path for the short-term commercialization of the Company and lay a sound foundation for its long-term sustainable development.

Up to now, Boan Biotech has successfully commercialized two products: the first product, Boyounuo (BA1101), is the third bevacizumab biosimilar approved in China for the treatment of various cancers. The second product, Boyoubei (BA6101), is the world’s first approved denosumab biosimilar for the treatment of osteoporosis.

The Company also has 12 drug candidates, several of which are close to the commercialization stage: BA1102 (denosumab injection, Xgeva biosimilar) for tumors, BA9101 (aflibercept intraocular injection, Eylea biosimilar) for ophthalmology, and BA5101 (dulaglutide injection, Trulicity biosimilar) for metabolism are currently in Phase 3 clinical trials in China, and their progresses of development are at the forefront. In addition, BA6101 and BA1102 are also in Phase 1 clinical trials in the EU. The Company expects to submit biologics license applications ("BLA") for multiple drug candidates successively in the next two years.
In developing innovative antibodies, Boan Biotech pays attention to both "innovation value" and "commercial visibility" to build a product portfolio with differentiated features while accelerating R&D to gain more first-mover advantages. For example, BA1105, an ADCC-enhanced, fully human monoclonal antibody targeting Claudin 18.2 independently developed by the Company, has the potential to become the best targeted drug for the similar treatment of metastatic pancreatic cancer, advanced gastric cancer and adenocarcinoma of the esophagogastric junction. BA1106, a CD25 fully human monoclonal antibody, is the first anti-CD25 innovative antibody to enter the clinical stage in China for the treatment of solid tumors. BA2101, the anti-IL-4Rα fully human monoclonal antibody for autoimmune therapy, is the first new long-acting anti-IL-4Rα drug that has entered the clinical trial stage in China.

Key Strength Covering the Whole Industry Chain Underpinned by a Complete Biological Drug Operation System

Through years of accumulation, Boan Biotech has constructed a complete biological drug operation system starting from scratch. The Company has established three proprietary technology platforms, an integrated ecosystem from R&D to production and commercial operation, as well as an international professional team based in Yantai, Nanjing, Singapore and Boston, thereby laying a solid foundation for efficient development and excellent marketing of the product pipeline.

Through the three technology platforms, Boan Biotech has established a strong technological advantage. Utilizing BA-huMab (a technology platform on which Boan Biotech has developed fully human antibody transgenic mice) and the Phage Display Technology Platform helps increase the efficiency of developing fully human monoclonal antibody products. Boan Biotech is also one of the few companies in China that own proprietary transgenic mice platform. Based on its monoclonal antibody products, the Company has progressively developed specialized drugs such as bispecific antibody and ADC through Bispecific T-cell Engager Technology Platform and ADC Technology Platform, forming a differentiated product portfolio.

On December 30, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company reported that the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted a supplemental biologics license application (sBLA) for tislelizumab in patients with first-line unresectable or metastatic hepatocellular carcinoma (HCC) (Press release, BeiGene, DEC 30, 2022, View Source [SID1234625683]).

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Hepatocellular carcinoma is the most common type of primary liver cancer worldwide and is associated with a very poor prognosis.1 New cases and deaths due to HCC in China account for half of the global numbers and the 5-year survival rate for patients with HCC in China is only 14%.2

"While the incidence of HCC is increasing in China, the treatment landscape has not advanced accordingly; survival benefits with newer treatments are modest and multi-kinase inhibitors have sub-optimal tolerability," said Lai Wang, Ph.D., Global Head of R&D at BeiGene. "We believe the evidence from our rigorously conducted global clinical development program for tislelizumab in HCC support the efficacy and favorable tolerability profile and look forward to working with NMPA on this submission and bringing a new treatment option to patients with HCC in China."

The sBLA is supported by data from the RATIONALE 301 clinical trial (NCT03412773) that enrolled 674 patients from research centers across Asia, Europe, and the United States. RATIONALE 301 results were presented as a late-breaking oral presentation at the 2022 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Paris.

Tislelizumab was approved by the China NMPA as a treatment for nine indications, including conditional approval ‘for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with at least one systemic therapy’. Additional tislelizumab’s sBLAs under review at CDE include: combination with chemotherapy as a first-line treatment for patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1; combination with chemotherapy as first-line treatment in patients with unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma. Tislelizumab is not approved for use outside of China.

About Tislelizumab

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

Tislelizumab is the first investigational medicine from BeiGene’s immuno-oncology biologics program and is being evaluated in solid tumor and hematologic malignancies, as monotherapy and in combination.

The global tislelizumab clinical development program includes more than 11,500 subjects enrolled to-date in 21 registration-enabling trials, from more than 30 countries and regions.

About RATIONALE 301

RATIONALE 301 (NCT03412773) is a global, Phase 3, randomized, open-label study of tislelizumab compared with sorafenib as a first-line treatment in adult patients with unresectable HCC. The primary endpoint of the study is non-inferiority of Overall Survival between the two treatment groups. The key secondary endpoint is Overall Response Rate, as assessed by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Other secondary endpoints include other efficacy assessments such as Progression Free Survival, Duration of Response, and Time to Progression per BIRC, as well as measures of health-related quality of life, and safety and tolerability.

On December 30, 2022 AskGene Pharma Inc. reported that the first patient completed their first dose (Cycle 1, Day 1) in the phase I clinical trial of ASKG315 in Shanghai, China (Press release, AskGene Pharmaceuticals, DEC 30, 2022, View Source [SID1234625682]). The study is an open label, multicenter phase I clinical trial evaluating the safety, tolerability, and pharmacokinetics of ASKG315 for injection in patients with locally advanced or metastatic solid tumors. ASKG315 is the first IL-15 prodrug in clinical development in the world.

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Jian-Feng (Jeff) Lu, Ph.D., CEO of AskGene commented: "ASKG315 is the second cytokine prodrug incubated from our propriety SmartKine cytokine prodrug platform technology. Preclinical data showed that ASKG315 selectively stimulated NK cells and CD8+ T cells. We are looking forward to achieving initial clinical proof of concept of the molecule as well as the platform. With multiple clinical programs, AskGene is establishing its global leading position in the field of cytokine prodrug."

Barbara Hickingbottom, J.D., M.D., Chief Medical Officer of AskGene commented: "Cytokines are natural immune stimulants, which cannot be used widely due to their short half-lives and narrow therapeutic windows. AskGene expects to use its proprietary technology to overcome these challenges. With the recent clearance of the ASKG915 IND by FDA, and an IL-2 prodrug in clinical development through a partnership, AskGene now has three cytokine prodrug programs in clinical development. We are very excited about the progress made in 2022 and look forward to the upcoming POC data from our clinical studies in 2023".

About ASKG315

ASKG315 is a novel and proprietary IL-15 prodrug discovered and developed by AskGene. It is the world’s first IL-15 prodrug moved into clinical development. Preclinical data of ASKG315 showed that this molecule selectively stimulated NK cells and CD8+ T cells in cynomolgus monkeys. Compared to previous generations of cytokine drugs, the prodrug design significantly extended the half-life, effectively improved the safety window, and reduced toxicity. ASKG315 has the longest half-life in cynomolgus monkeys among similar cytokine drugs in development.

On December 30th, 2022 AskGene Pharma Inc. reported that the United States Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for the clinical development of ASKG915, a novel and proprietary anti-PD-1-IL-15 prodrug fusion molecule for the treatment of cancer (Press release, AskGene Pharmaceuticals, DEC 30, 2022, View Source [SID1234625681]). Under this IND, AskGene will soon initiate a phase 1 study in the United States to investigate the safety, tolerability, pharmacokinetics, and efficacy of ASKG915 in patients with advanced solid tumors. ASKG915 will be the first anti-PD-1-IL-15 prodrug fusion molecule moving into clinical development in the world.

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Jian-Feng (Jeff) Lu, Ph.D., CEO of AskGene commented: "We are pleased that we received IND clearance for ASKG915, which is our third cytokine prodrug program entering clinical development. This important milestone brings us closer to delivering a truly bifunctional molecule with synergistic effect of an IL-15 agonist and PD-1 blockage to treat oncology patients. ASKG915 is expected to benefit patients who do not respond to current immunotherapies."

About ASKG915

ASKG915 is the world’s first PD-1 antibody-IL-15 prodrug fusion molecule to enter clinical development. The molecule can achieve tumor targeting through the anti-PD-1 antibody and be locally activated at the tumor site. It is also designed to allow high enough of a dosage so that the anti-PD-1 antibody has full PD-1 blockage functionality. Preclinical data showed that ASKG915 has extended PK, significantly better efficacy than an anti-PD-1 antibody monotherapy, and an expanded therapeutic window. ASKG915 is expected to benefit patients who are not responding to existing anti-PD-1 antibody therapies. A Phase I clinical trial is expected to start in the first half of 2023.