Aptorum Group(APM) - 2023 Q4 - Annual Report

Corporate Structure and Financials - Aptorum's authorized share capital is $100,000,000, divided into 9,999,996,000,000 Class A Ordinary Shares and 4,000,000 Class B Ordinary Shares, each with a par value of $0.00001[339]. - The company has three variable interest entities (VIEs), with Mios and Scipio being consolidated into Aptorum's financial statements[340]. - Aptorum entered into a private placement agreement in May 2021, issuing 138,793 Class A Ordinary Shares at $28.82 per share, raising approximately $4,000,000[353]. - In June 2023, Aptorum sold $3,000,000 in unsecured convertible notes, which were converted into 1,000,000 Class A Ordinary Shares[356]. - A merger agreement was approved in March 2024, where Aptorum will merge with YOOV Group, with existing YOOV shareholders owning approximately 90% of the combined company[357]. - Following the merger, Aptorum's shareholders will own approximately 10% of the outstanding shares of the combined company[357]. - The company underwent a ten-for-one share consolidation on January 23, 2023, changing the par value of Class A and Class B Ordinary Shares to $10.00[354]. - The company entered into a Split-Off Agreement on March 1, 2024, to transfer assets and liabilities of its legacy business to Aptorum Therapeutics Limited, with Jurchen Investment Corporation acquiring 100% of ATL's shares[360]. - As of April 8, 2024, CGY Investments Limited and DSF Investment Holdings Limited converted a total of 446,842 Class B Ordinary Shares into Class A Ordinary Shares on a one-for-one basis, resulting in 1,796,934 Class B Ordinary Shares outstanding[362]. Research and Development - The PathsDx Test technology, a rapid pathogen identification and detection diagnostics technology, is co-developed with A*STAR and is currently in progress[345]. - The Company completed Pre-IND discussions with the US FDA on ALS-4 in March 2023, receiving positive feedback on the overall development strategy[389]. - The Company announced the completion of the End of Phase 1 meeting for SACT-1 with the US FDA, which agreed with the proposed clinical development plan for Phase 1/2 trials[389]. - The Company is co-developing the Paths Test technology with Accelerate Technologies, aiming for rapid pathogen identification and detection[386][392]. - The Company plans to merge its subsidiary Paths Innovation Limited with Universal Sequencing Technology Corporation, subject to various conditions including due diligence and shareholder approvals[396]. - The Company intends to streamline operations by terminating clinic services and suspending non-lead R&D projects to focus on lead projects[393]. - The Company has ceased pursuing passive healthcare-related investments to focus resources on current business operations[393]. - The company is selectively expanding its portfolio with potential products that may attain orphan drug designation and satisfy unmet medical needs, focusing on innovations with superior scientific quality and significant market demand[404]. - Collaborations with leading academic institutions and CROs are being strengthened to access external innovation and expertise, which is considered a vital and cost-efficient strategy for product development[405]. - The company intends to aggressively seek government grants from the United States, the United Kingdom, Hong Kong, Singapore, and other regions to fund project development in the biotechnology sector[405]. - The drug discovery programs are primarily based on licenses from universities and conducted via sponsored research arrangements (SRAs), which provide significant value for the company's business[407]. - The company is managing the development of drug candidates through various subsidiaries, referred to as "Project Companies," focusing on market potential and scientific expertise[409]. - License agreements with universities and licensing entities include terms such as worldwide licenses, upfront payments, and royalty rates, which are crucial for the development of lead projects[410]. Clinical Trials and Drug Development - ALS-4 is a small molecule targeting bacterial infections caused by Staphylococcus aureus, including MRSA, with an estimated 33% of people carrying Staphylococcus aureus and 2% carrying MRSA[420]. - ALS-4 demonstrates potent activity against Staphylococcus aureus pigment formation in vitro, with an IC50 of 20 nM, indicating its potential effectiveness against antibiotic-resistant bacteria[426]. - ALS-4 demonstrated 63.8% wound closure in MRSA-infected mouse model, outperforming oral Linezolid (48.4%) and topical Mupirocin (43.2%) at Day 7[428]. - In a non-lethal MRSA bacteraemia mouse model, ALS-4 showed statistically significant reduction in bacterial counts in major organs compared to control and vancomycin groups[429]. - ALS-4's Phase 1 clinical trial was completed in January 2022 with 72 healthy subjects, showing no serious adverse events[431]. - The company plans to submit an IND application for ALS-4 to initiate a Phase 2 clinical study targeting Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in 2025[432]. - The exclusive license agreements for ALS-4 require the company to pay less than 10% of net sales as royalties and up to US$1 million in regulatory milestones[435]. - The cost of bringing a repurposed drug like SACT-1 is estimated at around US$300 million, significantly lower than the cost for new drug development[440]. - SACT-1 has shown effectiveness against neuroblastoma cell lines, particularly in high-risk groups, with a 5-year survival rate of 40-50%[443]. - The maximum tolerable dose of SACT-1 in rodent models was determined to be higher than 400mg/kg, indicating a favorable safety profile compared to standard chemotherapies[446]. - A pediatric formulation of SACT-1 has been developed to address the needs of neuroblastoma patients under 5 years old, showing significant tumor reduction in combination with standard chemotherapy[448]. - SACT-1 demonstrated a tumor size reduction of up to 54.2% in a xenograft mouse model of neuroblastoma over a 22-day period when administered at 60mg/kg in combination with standard of care (SOC) chemotherapy[449]. - The Phase 1 clinical trial for SACT-1 was completed with no serious adverse events reported, and the FDA granted Orphan Drug Designation for SACT-1 in January 2022[451]. - The company plans to submit an IND application to the FDA for a Phase 1b/2a trial of SACT-1 in 2025[452]. - PathsTest technology aims to identify over 1300 pathogens with 99% accuracy within 24-48 hours, significantly improving current diagnostic capabilities[457]. - PathsTest is currently undergoing clinical validation and pre-commercialization processes throughout 2023[461]. - The company has entered into an exclusive license agreement for PathsTest with Accelerate Technologies, with development milestones of up to $250,000[462]. Regulatory and Compliance - The company is a foreign private issuer, exempt from certain provisions applicable to U.S. domestic public companies, including less frequent reporting requirements[373]. - The company faces legal and operational risks associated with doing business in Hong Kong, with no current operations or VIEs in mainland China[376]. - The company’s Class A Ordinary Shares may face trading prohibitions under the Holding Foreign Companies Accountable Act if the PCAOB cannot inspect its auditors for two consecutive years[381]. - The PCAOB has secured access to inspect registered public accounting firms in mainland China and Hong Kong, but future obstruction by PRC authorities could affect this access[381]. - As of the date of the annual report, none of the subsidiaries or consolidated VIEs have made any dividends or distributions to the Company, and no cash dividends are anticipated in the foreseeable future[384]. - The company is subject to extensive regulations in the U.S. and other countries, which require significant time and financial resources for compliance[496][497]. - The regulatory approval process for new drug products is lengthy and expensive, with no guarantee of timely approval[501]. - The company intends to focus its marketing efforts primarily in the U.S., Canada, Europe, and PRC if it obtains marketing approval for its drug candidates[498]. - The FDA requires annual progress reports on clinical trials and immediate notification of serious adverse events within 15 days[508]. - The NDA submission process includes detailed information on product development and must be accepted for filing within 60 days for substantive review[510]. - The FDA may issue a complete response letter detailing deficiencies in the NDA that must be addressed before approval[511]. - The Hatch-Waxman Act allows for a patent term extension of up to five years for drugs, but cannot exceed a total of 14 years from the approval date[516]. - The Affordable Care Act increased rebate liability for branded drugs from 15.1% to 23.1% of the average manufacturer price[524]. - The company may need to conduct pharmacoeconomic studies to demonstrate the cost-effectiveness of products for third-party payor coverage[521]. - Canadian regulations require compliance with Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP) for drug approval[529]. - The drug approval process in Canada involves preclinical toxicology studies to ensure safety before human testing[531]. - A No Objection Letter (NOL) from Health Canada is required to initiate clinical trials, typically received within 30 days[532]. - Clinical trials in Canada follow a three-phase structure, with oversight by Research Ethics Boards (REBs) to ensure compliance with Good Clinical Practices (cGCP)[533]. - Investigational drugs must comply with current Good Manufacturing Practice (cGMP) regulations, and Health Canada can suspend trials if health risks are identified[534]. - After successful Phase 3 trials, a New Drug Submission (NDS) is compiled and submitted to Health Canada for market approval[535]. - A Drug Establishment License (DEL) application must be submitted 90 days prior to the NDS to ensure manufacturing compliance with GMP[537]. - The NDS approval process can take several years and is subject to user fees that increase annually due to inflation[538]. Intellectual Property - The patent portfolio for SACT-1 includes four active national phase patent applications globally, with two US patents granted in 2022 and 2023[453]. - The company has filed multiple patent applications, including two Paris Convention applications in 2022 and 2023, covering innovative methods for pathogen detection[463]. - The company holds exclusive licenses for 4 U.S. patents and 2 PRC patents related to its Lead Projects, ALS-4 and Paths Test, with expiration dates ranging from 2038 to 2041[480][482]. - The Paths Test project has an exclusive license for 4 U.S. patents and 1 European patent, with expiration dates from 2027 to 2041[485]. - The company may seek patent term extensions and marketing exclusivity periods to maintain exclusive rights to its products[485]. - The biotechnology and pharmaceutical industries are characterized by extensive litigation regarding patents, which may affect the company's ability to protect its inventions[490]. - The company relies on unpatented trade secrets and know-how, but monitoring and preventing disclosure of these secrets is challenging[491].