BeyondSpring(BYSI) - 2021 Q4 - Annual Report

Financial Activities - BeyondSpring Inc. completed its initial public offering in March 2017, raising gross proceeds of $54.3 million from selling 174,286 ordinary shares[369] - In November 2020, the company raised $86.3 million from an underwritten offering, selling 8,625,000 ordinary shares[372] - Wanchunbulin received an upfront payment of RMB 200 million (approximately $31 million) from Hengrui for the exclusive commercialization of Plinabulin in Greater China[374] - The company is eligible to receive up to approximately $780 million in potential milestones from its collaboration with Lilly for the development of new chemical entities[373] - SEED received a $15 million upfront payment and could earn up to approximately $780 million in potential milestones from the collaboration with Lilly[435] - Wanchunbulin received an upfront payment of RMB 200 million (approximately $31 million) and could receive regulatory and sales milestones of up to RMB 1.1 billion (approximately $171 million) from Hengrui[442] Drug Development and Clinical Trials - Plinabulin, the lead drug candidate, has been administered to over 700 patients with advanced cancer and is generally well-tolerated[381] - The DUBLIN-3 Phase 3 study for Plinabulin in combination with docetaxel has completed global enrollment of 559 patients, with positive topline results reported in August 2021[377] - The company has completed two Phase 2/3 trials for CIN and submitted NDAs in the U.S. and China[440] - The ongoing Phase 1/2 trial of Plinabulin in combination with nivolumab has enrolled 18 patients, with preliminary safety data showing no serious immune-related adverse events[423] - The Phase 1/2 study at MD Anderson includes seven cancer types, with updates allowing for any tumor type with checkpoint inhibitor approval[427] - The company aims to develop Plinabulin as a "pipeline in a drug" across multiple cancer indications[439] - The company is conducting clinical trials under two INDs, with all trials supervised by qualified investigators in accordance with Good Clinical Practice (GCP) regulations[472] Clinical Efficacy and Market Potential - The PROTECTIVE-2 Phase 3 study demonstrated a statistically significant improvement in the prevention of grade 4 neutropenia, improving from 13.6% to 31.5% (p=0.0015) when Plinabulin was combined with pegfilgrastim[387] - The current U.S. CIN market is approximately $4 billion and is expected to grow significantly due to updated NCCN guidelines, which now qualify over 70% of chemotherapy patients for prophylaxis[384] - The addressable market for CIN prevention has increased by over 100% due to changes in treatment guidelines, targeting intermediate-risk chemotherapy patients[384] - The global NSCLC market is projected to grow at a rate of 10% per year, with estimated sales of $26.7 billion in 2021 and $44.6 billion by 2026[8] - Approximately 230,000 patients are diagnosed with lung cancer annually in the U.S., with NSCLC accounting for about 87% of cases[9] Regulatory and Compliance - The NDA submission for Plinabulin in combination with G-CSF for CIN prevention was accepted by both the FDA and NMPA, seeking a broad label for concurrent administration with myelosuppressive regimens[7] - The FDA aims to review 90% of NDA applications with "Priority" status within 6 months and 90% of "Standard" applications within 10 months[479] - The FDA may issue a complete response letter detailing deficiencies that must be addressed before approval, which can range from minor labeling changes to requiring additional clinical trials[480] - The Hatch-Waxman Act allows for a patent restoration term of up to five years, but cannot extend the total patent term beyond 14 years from the product's approval date[486] - The FDCA provides a five-year period of non-patent marketing exclusivity for the first applicant to gain approval of an NDA for a new chemical entity[488] - The NMPA in China oversees the approval and regulation of pharmaceutical products, requiring compliance with multiple laws and regulations[504] - The PRC Drug Administration Law has undergone several revisions to strengthen the supervision and administration of pharmaceutical products, with the latest revision in August 2019[506] Competitive Landscape - The competition includes large pharmaceutical companies like Bristol-Myers Squibb and Merck, which market drugs for cancer treatment that may compete with the company's product candidates[458] - The company faces competition from firms with greater resources, which could impact its commercial opportunities if they develop more effective or safer products[462] - The patent landscape is complex, with the potential for existing patents to limit the company's ability to commercialize its product candidates[455] Intellectual Property - The patent portfolio includes 122 patents in 40 jurisdictions, with 21 issued U.S. patents as of March 21, 2022[446] - The company has secured a number of issued patents for its product candidates, but the breadth of claims from pending applications remains uncertain[452] - The biotechnology and pharmaceutical industries face extensive litigation regarding patents and intellectual property rights, impacting the ability to protect inventions[453] Safety and Adverse Events - Plinabulin demonstrated a statistically significant reduction in grade 3 and 4 neutropenia adverse events from 26% in the docetaxel monotherapy arm to 7% in the Plinabulin plus docetaxel arm in Study 101 (p=0.002) [1] - In the Phase 3 DUBLIN-3 study, Plinabulin reduced docetaxel-induced grade 4 neutropenia in NSCLC patients with a p-value of less than 0.0001 [2] - The PROTECTIVE-1 trial showed that Plinabulin had a non-inferiority outcome compared to Neulasta for days with grade 4 neutropenia (DSN) in the first cycle of chemotherapy [3] - In the Phase 2 portion of PROTECTIVE-1, 14% of patients treated with either Plinabulin or Neulasta experienced grade 4 neutropenia, establishing a recommended dose of 40 mg for Phase 3 [4] - The PROTECTIVE-2 trial demonstrated a primary endpoint of 31.5% prevention of grade 4 neutropenia in the Plinabulin and pegfilgrastim combination compared to 13.6% in pegfilgrastim alone (p=0.0015) [5] - In the Phase 3 portion of PROTECTIVE-2, the incidence of profound neutropenia was 21.6% in the combination group versus 46.4% in the pegfilgrastim group (p=0.0001) [6] Future Directions and Innovations - Plinabulin has shown potential to enhance the activity of other immuno-oncology agents, with preclinical studies indicating it activates immune responses earlier in the immune activation process[414] - In a preclinical colon cancer model, the combination of Plinabulin and a PD-1 antibody resulted in tumors that were approximately 25% smaller compared to control[417] - The triple combination of Plinabulin, anti-PD-1, and radiation achieved a 100% complete response in a breast cancer model unresponsive to PD-1 antibody alone[418] - Plinabulin combined with PD-1/PD-L1 antibodies and radiation showed 100% tumor shrinkage in pre-clinical studies[426] - The combination of Plinabulin, nivolumab, and ipilimumab in SCLC showed a 46% ORR, indicating potential efficacy synergy and re-sensitization of tumors previously resistant to PD-1/PD-L1 inhibitors[424] Regulatory Changes and Impact - The NMPA's revised Provisions for Drug Registration adopted a conditional approval mechanism for vaccines urgently needed for public health emergencies[540] - The NMPA has established priority procedures for drugs with significant clinical value, including urgently needed clinical drugs and innovative vaccines[533] - The National People's Congress released the Fourteenth Five-Year Plan, aiming to improve the accelerated review and approval mechanism for innovative drugs, vaccines, and medical devices[534] - Conditional approval may be granted for drugs treating severe diseases or those urgently needed for public health, based on early clinical trial indicators showing efficacy[537]