On August 23, 2024 GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, reported China’s National Medical Products Administration has approved Dupert（fulzerasib, GFH925/IBI351）for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation who have received at least one systemic therapy (Press release, GenFleet Therapeutics, AUG 23, 2024, View Source [SID1234646076]). Fulzerasib was the first China-developed KRAS G12C inhibitor that had its NDA submission accepted with Priority Review Designation in 2023, and the monotherapy was also granted two Breakthrough Therapy Designations (BTD) for treating advanced KRAS G12C-mutant NSCLC and colorectal cancer (CRC) patients.

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The NDA approval is based on the results from a single-arm registrational study (NCT05005234) intended to evaluate the efficacy and safety of fulzerasib monotherapy in advanced NSCLC patients with KRAS G12C mutation who failed or were intolerant to the standard treatment in China. The updated data from this registration study has been published in full manuscript in the Journal of Thoracic Oncology (JTO) and selected for oral presentation at the 2024 World Conference on Lung Cancer (WCLC) .

As of the data cutoff date (Dec 13, 2023), a total of 116 NSCLC subjects were enrolled and evaluable. Fulzerasib was generally well-tolerated and demonstrated encouraging antitumor activity. The confirmed objective response rate (ORR) assessed by the Independent Radiology Review Committee (IRRC) was 49.1% (95% CI: 39.7-58.6). Disease control rate (DCR) was 90.5% (95%CI: 83.7, 95.2). The median duration of response (DoR) was not reached. Median progression-free survival (PFS) was 9.7 months (95%CI: 5.6-11.0), and median overall survival (OS) was not yet reached.

NSCLC comprises approximately 85% of all lung cancer diagnoses, with KRAS being the most frequently mutated driver gene in NSCLC. The rarity of co-mutations with EGFR or ALK in KRAS-mutated scenario, substantially reduces the clinical benefits of approved EGFR or ALK-targeting therapies for KRAS-mutant or driver-gene-negative NSCLC patients. They are confronted with limited later-line therapeutic options upon disease progressing through the current first-line standard of care (SOC).

"KRAS has long been considered an ‘undruggable’ target despite being a common oncogenic driver mutation. The advent of KRAS G12C inhibitors has opened new avenues for precision medicine in cancers harboring this mutation. We are proud to be part of the clinical research and development of Dupert, the first KRAS G12C inhibitor approved in China. We hope that Dupert will soon benefit more patients with advanced lung cancer harboring KRAS G12C mutations, driving the progress of precision treatment for lung cancer." Stated Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital.

Beyond monotherapy, the combination of KRAS and EGFR inhibitors exhibits a synergistic biological mechanism and thus enables the potential of fulzerasib to serve as a first-line treatment option. In 2023, GenFleet initiated a first-line NSCLC combination study (KROCUS) of fulzerasib and cetuximab in Europe, led by world-renowned Professor Rafael Rosell. The analysis of preliminary phase II data was selected for late-breaking abstract and oral presentation at the ASCO (Free ASCO Whitepaper) conference in June 2024: as of Apr. 19 2024, a total of 33 subjects had at least one post-treatment tumor assessment. The ORR was 81.8% (95% CI: 64.5, 93) and the DCR was 100% (95% CI: 89.4, 100). The ORR was 70% among those with brain metastases (32.5% of enrolled patients).

"Initiated in 2018, the fulzerasib’s development has been moving forward rapidly and yielded positive results. We are delighted at the approval of fulzerasib in China and thankful for the collaborative efforts of Innovent Biologics and the investigators. Given the high G12C prevalence among advanced NSCLC patients in western countries, GenFleet has embarked on the KROCUS study in Europe, a pioneering trial of first-line therapy integrating KRAS and EGFR inhibitors. In specific patient populations, the KROCUS study has demonstrated efficacy and safety potentially comparable or even superior to immunotherapy combined with chemotherapy, positioning the fulzerasib/cetuximab combination as a potentially novel first-line SOC for G12C-mutated NSCLC patients." stated Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.

Alongside with NSCLC treatment, the efficacy of fulzerasib monotherapy for CRC also outperformed other single-agent KRAS G12C inhibitors in terms of ORR and mPFS; the efficacy was also comparable to combinations of other G12C inhibitors with anti-EGFR antibodies. Notably, the FDA has granted approval in April this year for GenFleet’s phase III study investigating fulzerasib in G12C-mutated refractory, metastatic CRC patients. Furthermore, fulzerasib holds the distinction of being the first G12C inhibitor that received a BTD for CRC treatment in China.

About Dupert (fulzerasib, KRAS G12C Inhibitor)

RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutations are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and NTRK 1/2/3 mutations combined.

Discovered by GenFleet Therapeutics, fulzerasib (GFH925/IBI351) is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of GFH925 towards G12C. Subsequently, GFH925 effectively inhibits the downstream signal pathway to induce tumor cells’ apoptosis and cell cycle arrest.

In September 2021, Innovent and GenFleet Therapeutics entered into an exclusive license agreement for the development and commercialization of GFH925 in China (including the Chinese mainland, Hong Kong, Macau and Taiwan) with additional option-in rights for global development and commercialization.

In January 2023, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation (BTD) for fulzerasib for the treatment of patients with advanced NSCLC harboring KRAS G12C mutation who have received at least one systemic therapy. In May 2023, the CDE of China’s NMPA granted another BTD for fulzerasib for the treatment of advanced CRC patients with KRAS G12C mutation who have received at least two systemic therapies.

In August 2024, the CDE of NMPA has approved fulzerasib for the treatment of advanced NSCLC patients harboring KRAS G12C mutation who have received at least one systemic therapy.

On August 23, 2024 CanariaBio Inc, a leading late-stage biotechnology company, reported the successful completion of enrollment of 88 patients in a randomized Phase 2 study of oregovomab in combination with chemotherapy (paclitaxel and carboplatin) as neo-adjuvant treatment of patients with newly diagnosed advanced epithelial ovarian cancer (Press release, CanariaBio, AUG 23, 2024, https://www.prnewswire.com/news-releases/canariabio-inc-announces-enrollment-completion-of-randomized-phase-2-study-of-oregovomab-in-combination-with-chemotherapy-as-neo-adjuvant-treatment-of-patients-with-advanced-ovarian-cancer-302228497.html [SID1234646075]).

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This trial, known as FLORA-6 (NCT05605535) is a Phase 2, double-blinded, placebo-controlled, multi centered clinical trial in neo-adjuvant setting in patients with newly diagnosed advanced epithelial ovarian cancer. The study will assess 12 months progression free survival (PFS) rate, PFS, overall survival (OS), disease control rate, the immunological and early humoral response of concomitant oregovomab and chemotherapy.

Ovarian cancer is known for its high recurrence rate. Despite numerous clinical trials conducted, the development of an effective and specific treatment has proven challenging due to treatment resistance, toxicity, and limited efficacy. In this difficult landscape, oregovomab has the potential of emerging as a promising immunotherapeutic agent.

About Oregovomab

Oregovomab is a murine monoclonal antibody against CA 125, a biomarker commonly found in ovarian cancer. Indirect immunization with oregovomab interacts with immune modulating properties of infused paclitaxel and carboplatin resulting in synergistic clinical benefits as observed in a Phase II trial (Gynecology Oncology (2020) 156:523-529). Oregovomab is currently undergoing multiple clinical trials for the treatment of ovarian cancer in various setting including a Phase 3 study (NCT04498117, NCT05605535, NCT05335993, NCT05407584, NCT04938583)

On August 23, 2024 Abogen Biosciences ("Abogen" or the "Company") reported a publication titled "Efficient circularization of protein-encoding RNAs via a novel cis-splicing system " in Nucleic Acids Research (Press release, Abogen Biosciences, AUG 23, 2024, View Source [SID1234646074]). In the article, Abogen has revealed a highly efficient RNA circularization cis-splicing system (referred to as the "Cis-System") which enables the production of circular RNA ("circRNA") with significantly extended protein expression, reduced innate immune activation, and flexible splice site design that offers substantial market potential.

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In recent years, circular RNA technology has gained significant attention from the biopharmaceutical industry, several circular RNA start-up companies raised a total of over 1 billion dollars in financing. Among the most notable are Flagship-incubated Sail Biomedicines (formed through the merger of Laronde and Senda Biosciences), which has raised nearly $800 million, and Orna Therapeutics, founded by MIT Professor Daniel Anderson, secured over $300 million in funding and recently acquired ReNAgade Therapeutics to accelerate its clinical development.

Abogen’s Cis-System-based circRNA not only has global IP, but also improves over PIE System

The conventional technology for circRNA synthesis is the PIE method (Permuted Introns and Exons), patented by Orna and other companies. However, the Cis-System not only circumvents the patent restrictions by the PIE system, but also simplifies the circularization process and makes it more suitable for industrial production. As described in the publication, the Cis-System embeds a ribozyme core structure at one end of the precursor RNA, rendering the need for additional spacer elements between the ribozyme and the target gene. This invention significantly enhances the circularization efficiency thus offers a "scarless" and highly efficient translation process with less process-related impurities.

The Cis-System-based circRNA shows promising prospects for the future

The Cis-System reported in this study can achieve high circularization efficiency with essentially unrestricted base and sequence composition at the ends of RNA molecules, enabling truly efficient and scarless circularization. Furthermore, the Cis-System is designed to be more flexible, allowing customization based on specific therapeutic needs and compatibility with RNA molecule of different lengths. All these technological advances will lead to more sustained protein expression, reduced innate immune stimulation, and potential tissue-specific expression, which potentially bring more hopes in chronic disease treatment and immunotherapies where repeated dosing may be required.

Dr. Shaojun Qi, Senior Scientist in mRNA Innovation department at Abogen commented:

"I deeply appreciated the innovative culture at Abogen which is crucial for our success in overcoming the key bottlenecks in circular RNA technology. "

Dr. Peng Gao, Vice President of Abogen (corresponding author of the publication), commented:

"After over two years of commitment and continuous efforts, our team has finally overcome the critical technical hurdle presented in circRNA technology. Preliminary results from further studies have reinforced the great value and application potential of this technology. We hope to rapidly translate this achievement into clinical solutions to address the unmet medical needs."

Link for the Original Paper

Shaojun Qi, Huiming Wang, Guopeng Liu, Qianshan Qin, Peng Gao, Bo Ying, Efficient Circularization of Protein-Encoding RNAs via a Novel Cis-Splicing System, *Nucleic Acids Research*, 2024;, gkae711, [View Source]" target="_blank" title="View Source]" rel="nofollow">View Source(View Source)

On August 19, 2024, Veru Inc. (the "Company") delivered notice to Jefferies LLC (the "Agent") to terminate its Open Market Sales Agreement, dated May 12, 2023 (the "Sales Agreement"). Termination of the Sales Agreement is effective September 3, 2024, pursuant to Section 7(b) of the Sales Agreement (Filing, 8-K, Veru, AUG 23, 2024, View Source [SID1234646073]). The Company is not subject to any termination penalties related to the termination of the Sales Agreement.

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Pursuant to the terms of the Sales Agreement, the Company could issue and sell, from time to time through or to the Agent, shares of its common stock as set forth in the Sales Agreement with an aggregate value of up to $75 million. As a result of the termination of the Sales Agreement, the Company will not issue or sell any additional shares of common stock under the Sales Agreement. Since inception of the Sales Agreement, the Company sold 1,367,415 shares of common stock resulting in net proceeds to the Company of $1.1 million.

The foregoing description of the Sales Agreement is not complete and is qualified in its entirety by reference to the full text of the Sales Agreement, a copy of which was filed as Exhibit 1.1 to the Company’s Current Report on Form 8-K filed with the Securities and Exchange Commission on May 12, 2023, and incorporated herein by reference.

On August 23, 2024, Labcorp Holdings Inc. (the "Company") and certain of its subsidiaries, reported to have entered into a three-year $300 million accounts receivable securitization facility (the "Securitization Facility") with PNC Bank, National Association ("PNC"), as administrative agent (Filing, 8-K, LabCorp, AUG 23, 2024, View Source [SID1234646071]). The Securitization Facility permits Labcorp Receivables (as defined below) to draw up to a total of $300 million, subject to the outstanding amount of the eligible receivables pool and other factors. The Securitization Facility contains an accordion to increase the facility limit up to $700 million subject to satisfaction of certain conditions.

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In connection with the Securitization Facility, on August 23, 2024, Laboratory Corporation of America Holdings ("LCAH") and Laboratory Corporation of America (the "Originators") sold and/or contributed all of their existing, and committed to continue to sell and/or contribute their future accounts receivable and certain related assets to Labcorp Receivables LLC, a special purpose vehicle and wholly-owned subsidiary of the Company and LCAH (the "Labcorp Receivables") pursuant to the terms of the Sale and Contribution Agreement, dated as of August 23, 2024 (the "Sale Agreement"), among the Originators, any additional originators from time to time party thereto, LCAH, as servicer, and Labcorp Receivables. Pursuant to the Receivables Purchase Agreement, dated as of August 23, 2024 (the "Receivables Purchase Agreement"), among Labcorp Receivables, the purchasers from time to time party thereto (the "Purchasers") and PNC Capital Markets LLC, Labcorp Receivables may sell and/or obtain financing for the accounts receivable assets and grants a security interest in all of its assets. LCAH will service the accounts receivables on behalf of Labcorp Receivables for a fee. In addition, pursuant to a Performance Guaranty, dated August 23, 2024 by the Company in favor of PNC, the Company has agreed to guarantee the performance of the Originators and LCAH, in its capacity as servicer, of their respective obligations under the agreements governing the Securitization Facility. Neither the Company nor the Originators guarantee the collectability of the receivables under the Securitization Facility.

Labcorp Receivables is a separate legal entity with its own separate creditors who will be entitled to access Labcorp Receivables assets before the assets become available to the Company. Accordingly, Labcorp Receivables assets are not available to pay creditors of the Company or any of its subsidiaries (other than Labcorp Receivables), although collections from the receivables in excess of amounts required to repay the Purchasers and other creditors of Labcorp Receivables may be remitted to the Company.

Loans or investments under the Securitization Facility accrue interest at a rate equal to a daily SOFR rate or term SOFR rate plus 0.10% SOFR adjustment or a base rate, in each case, plus an applicable margin. Additionally, Labcorp Receivables will pay certain additional fees to the agents and the Purchasers under the Securitization Facility.

The Sale Agreement and the Receivables Purchase Agreement contain customary representations and warranties, affirmative and negative covenants, and events of default (subject to cure periods), including, among others, failure by Labcorp Receivables to pay amounts when due, certain defaults on other material indebtedness, a change of control and bankruptcy and insolvency events.

The foregoing descriptions of the Receivables Purchase Agreement, the Sale Agreement and the Performance Guaranty do not purport to be complete and are qualified in their entirety by reference to the full text of such agreements, copies of which are filed herewith as Exhibits 10.1, 10.2 and 10.3, respectively, and the terms of which are incorporated herein by reference.