About BeyondSpring

BeyondSpring Inc., a clinical stage global biopharmaceutical company, focuses on using its novel technology platform for drug discovery and development of innovative therapies to improve clinical outcomes for patients with high unmet medical needs. The company's first-in-class lead asset, Plinabulin, is being developed as a potential 'pipeline in a drug' in various cancer indications as a direct anti-cancer agent and to prevent chemotherapy-induced neutropenia (CIN). The company is also developing three small molecule immune agents, in preclinical stages. In addition, the company's subsidiary SEED is utilizing a unique Targeted Protein Degradation (TPD) platform, or 'molecular glue' technology, to develop innovative therapeutic agents from internal research and development efforts and from collaboration. SEED Therapeutics Inc. (SEED) is collaborating with Eli Lilly and Company (Eli Lilly) to discover and develop new chemical entities through this unique Targeted Protein Degradation (TPD) platform that could produce therapeutic benefits. First, the company is studying Plinabulin alone or in combination with granulocyte colony-stimulating factor (G-CSF), including pegfilgrastim, for its potential benefit in the prevention of CIN. In September 2020, the combination received Breakthrough Therapy Designation from both the Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA). Based on the PROTECTIVE-2 Phase 3 registration study results, the company filed a New Drug Application (NDA) with the FDA and the NMPA for the use of Plinabulin in combination with G-CSF for the prevention of CIN in March 2021. In November 2021, the FDA issued a Complete Response Letter for Plinabulin in combination with G-CSF for the prevention of CIN. In March 2023, the company withdrew the NDA submission for the indication of Plinabulin in combination of pegfilgrastim agents to treat CIN in adult non-myeloid cancer from the NMPA. The company will continue to communicate with the NMPA regarding the re-filing of the NDA for the CIN indication and plan to re-file the NDA by mid-2023. In addition, Plinabulin in combination with pegfilgrastim is being studied in a Phase 1 investigator-initiated trial for the reduction of neutropenia burden in multiple myeloma patients who have undergone autologous hematopoietic cell transplantation (AHCT) at Memorial Sloan Kettering Cancer Center. Second, Plinabulin is being studied as an anti-cancer agent in a randomized study of combination with docetaxel vs. docetaxel alone for second- and third- line treatment of non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) wild type (DUBLIN-3 Phase 3 registration study). The DUBLIN-3 study has completed global enrollment of 559 patients and final positive topline results from the study with significant overall survival benefit were reported in August 2021 and at the European Society for Medical Oncology (ESMO) in September 2021, with a potential NDA filing by mid-2023 in China. Finally, Plinabulin, with the potent effect of maturing immune dendritic cells, is being studied in investigator-initiated trials for its therapeutic potential in combination with various immuno-oncology agents, mainly in patients who progressed on PD-1/PD-L1 antibodies, which represent severe unmet medical needs. These studies include 1) in combination with nivolumab, a PD-1 antibody, for the treatment of NSCLC at the University of California San Diego (UCSD) and the University of Washington (Phase 1 completed); 2) in combination with nivolumab, a PD-1 antibody, and ipilimumab, a CTLA-4 antibody, for the treatment of ES-SCLC at the Rutgers University and other U.S. clinical centers (Phase 1 completed, Phase 2 ongoing for patients who progressed on PD-1/PD-L1 antibodies); 3) in combination with PD-1 or PD-L1 antibodies and radiation for the treatment of patients with various cancers who progressed from PD-1/PD-L1 antibodies at MD Anderson Cancer Center; and 4) in combination with Keytruda (pembrolizumab), a PD-1 antibody, and docetaxel for the treatment of NSCLC patients who progressed from PD-1/PD-L1 antibodies at Peking Union Medical College Hospital. Plinabulin, Lead Drug Candidate Plinabulin is a first-in-class, novel small molecule derived from a natural compound found in marine microorganisms. It is a Selective Immunomodulating Microtubule-Binding Agent, which may provide multiple therapeutic opportunities. As a low molecular weight small molecule, Plinabulin is relatively simple to manufacture. Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: a durable anti-cancer benefit due to the maturation of dendritic cells resulting in activation of tumor antigen-specific T-cells to target cancer cells; and early-onset action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells, or HSPCs. As a potential 'pipeline in a drug', Plinabulin is being broadly studied in combination with various immuno-oncology agents that could boost the effects of the PD-1 / PD-L1 antibodies and potentially allow patients who progressed on PD-1/PD-L1 antibodies to respond to PD-1/PD-L1 combination with Plinabulin. The elucidation of this mechanism was a multi-year collaborative effort among the company, University of Basel, Massachusetts General Hospital, and the University of Texas MD Anderson Cancer Center (MD Anderson). PROTECTIVE-2 Phase 3 study is the registration study to support the NDA submission for the use of Plinabulin in combination with G-CSF for the prevention of CIN. Plinabulin's effect in preventing CIN has been demonstrated in six clinical trials so far, namely Study 101, DUBLIN-3, PROTECTIVE-1 (Phase 2 and Phase 3), and PROTECTIVE-2 (Phase 2 and Phase 3), with consistent data for CIN prevention early onset benefit in week 1 after chemotherapy. In the company's registration program for CIN, Plinabulin has been studied in two Phase 2/3 clinical trials, the first in Plinabulin monotherapy compared to pegfilgrastim for the prevention of CIN caused by intermediate-risk chemotherapy with high risk factors, composed solely of Taxotere (docetaxel), in various cancer, including NSCLC, breast cancer and prostate cancer patients (PROTECTIVE-1), and the second in the Plinabulin and pegfilgrastim combination compared to pegfilgrastim alone for the prevention of CIN caused by high-risk chemotherapy, a myelosuppressive chemotherapeutic regimen composed of three agents, Taxotere (docetaxel), Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide), in breast cancer patients (PROTECTIVE-2). TAC is an example of high febrile neutropenia risk chemotherapy and is the regimen used in all G-CSF biosimilar registration studies. Based on the clinical profile observed in Study 101 and the results of the discussions between the company and the FDA, it refined its design of its two Phase 2/3 trials in CIN. The first trial, PROTECTIVE-1, is a Phase 2/3 trial of Plinabulin monotherapy compared to pegfilgrastim monotherapy in 160 patients in both Phase 2 and Phase 3 studies in various cancers, including advanced breast cancer, hormone refractory prostate cancer and advanced NSCLC patients, treated with docetaxel (intermediate febrile neutropenia risk chemotherapy with high risk factors) in the U.S., China, Russia and the Ukraine. The second trial, PROTECTIVE-2, is a Phase 2/3 trial of Plinabulin in combination with a myelosuppressive chemotherapeutic regimen composed of three agents, Taxotere (docetaxel), Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide) in 336 patients with solid tumors (breast cancer) in China and the Ukraine. This trial compares Plinabulin in combination with Neulasta (6 mg) (the Plinabulin/Neulasta Combo) to measure superiority in efficacy as compared to Neulasta monotherapy, with rate of prevention of grade 4 neutropenia as the primary endpoint per protocol. The NDA submission based on positive results in the company's PROTECTIVE-2 study, and supported by five additional clinical studies, for the use of Plinabulin in combination with G-CSF for the prevention of CIN was accepted by both the FDA and the NMPA. The indication the company is seeking is a broad label in 'concurrent administration with myelosuppressive chemotherapeutic regimens in patients with non-myeloid malignancies for the prevention of CIN', which is the indication for which the company received Breakthrough Therapy Designation from both the FDA and the NMPA. In November 2021, the FDA issued a Complete Response Letter for Plinabulin in combination with G-CSF for the prevention of CIN. In March 2023, the company withdrew the NDA submission for the indication of Plinabulin in combination of pegfilgrastim agents to treat CIN in adult non-myeloid cancer from the NMPA. Plinabulin is a Selective Immunomodulating Microtubule-Binding Agent, which activates immune defense protein GEF-H1, and leads to dendritic cell maturation and T-cell activation (La Sala 2019; Kashyap 2019) for anti-cancer benefit. High GEF-H1 immune signature patients in anti-cancer studies live much longer than the ones who have lower GEF-H1 immune signature (Kashyap 2019). The primary purpose of the Phase 2 portion of the Phase 1/2 trial was to evaluate the potential anti-cancer effect of Plinabulin in combination with docetaxel compared to docetaxel monotherapy in advanced second- and third-line NSCLC patients. Preclinical studies have identified some novel and intriguing activities of Plinabulin associated with stimulation of the immune system, consistent with Plinabulin's ability to enhance the activity of other immuno-oncology agents. The company has observed in these studies that Plinabulin works at multiple early steps in the process of immune activation against cancer, in particular, to activate and mobilize tumor antigen-specific T-cells to the tumor. The potential role of Plinabulin in stimulating the activity of other immuno-oncology agents has been explored in several investigator-initiated Phase 1/2 trials. The company has explored and plans to continue to explore the role of Plinabulin in stimulating the activity of other immuno-oncology agents in clinical programs: Plinabulin + PD-1 antibody in NSCLC In September 2016, UCSD enrolled the first patient in an investigator-initiated Phase 1/2 trial of Plinabulin in combination with nivolumab in patients with metastatic NSCLC. UCSD has completed the enrollment of 18 patients. The study had achieved its Phase 1 endpoint of safety evaluation and dose selection. In addition, the Fred Hutch, together with the University of Washington, launched an investigator-initiated Phase 1/2 trial of Plinabulin in combination with nivolumab in patients with advanced NSCLC who have failed up to two previous therapies. The University of Washington study achieved the dose regimen endpoint and therefore the study site has been closed. Preliminary safety data from these two trials were presented at the American Society of Clinical Oncology-Society for Immunotherapy of Cancer (ASCO-SITC) meeting in January 2018. In the 10 patients evaluated, the combination therapy was well-tolerated, with no immune related serious adverse events. Only two patients presented with immune related adverse events, one with a grade 1 event and the other with a grade 2 event. Plinabulin + PD-1 + CTLA-4 antibodies in ES-SCLC In October 2018, the company announced the opening of an investigator-initiated Phase 1 clinical trial with a triple combination therapy, consisting of Plinabulin, nivolumab (one type of PD-1 antibody), and ipilimumab (one type of CTLA-4 antibody), for the treatment of second- and third-line SCLC. The trial, conducted through the Big Ten Cancer Research Consortium, enrolled 16 patients at Rutgers Cancer Institute of New Jersey and other clinical centers in the U.S. in the Phase 1 portion of this Phase 1/2 combined study. This study investigates whether the addition of Plinabulin results in a reduction of immune-related side effects of PD-1 and CTLA-4 antibodies and if it provides efficacy synergy. In ASCO meeting in June 2021, the company presented positive Phase 1 data from this study on 13 evaluable patients with PD-1/PD-L1 naïve or resistant tumors in second-line and beyond in SCLC, Plinabulin in combination with nivolumab and ipilimumab showed a 46% ORR. Additionally, the data demonstrated the Plinabulin combination was able to re-sensitize tumors to immune-oncology therapy, that had previously progressed on prior immunotherapies, with a 43% ORR. In October 2021, the first patient was enrolled in the Phase 2 portion of this investigator-initiated study. Up to 26 patients with histological or cytological confirmed ES-SCLC who progressed after at least one platinum-based chemotherapy regimen and checkpoint inhibitors will receive the triple combination of Plinabulin + nivolumab + ipilimumab. Patients in the Phase 2 study will continue treatment until disease progression, development of unacceptable toxicity, or one of the protocol-defined reasons for treatment discontinuation occurs. Enrollment of the Phase 2 study has been completed in February 2023. Plinabulin + PD-1/PD-L1 Antibody + Radiation in Seven Different Cancers in PD-1/PD-L1 Failed Patients In July 2018, the company entered into a sponsored research agreement with MD Anderson to evaluate the benefits of adding Plinabulin to radiation therapy plus immune checkpoint antibodies. The pre-clinical study has demonstrated that the triple combination approach (Plinabulin+radiation+PD-1 antibody) has dramatic benefits in tumor reduction (100% tumor shrinkage), increasing tumor dendritic cell maturation and increasing tumor T-cell infiltration in animal models. In June 2021, the first patient was dosed in this Phase 1/2 study at MD Anderson, for the treatment of patients after progression on PD-1 or PD-L1 antibody therapies in seven different cancer types with Plinabulin+PD-1/PD-L1 antibodies and radiation. The cancer types include bladder cancer, melanoma, Merkle cell cancer, microsatellite instability-high cancers (of any histology), NSCLC, renal cell cancer, and extensive-stage small cell lung cancer (ES-SCLC). The protocol was updated in 2022 to include patients that have any tumor type with checkpoint inhibitor approval that may or may not have progressed on previous anti-PD-1/PD-L1 mAb treatment +/- chemotherapy or anti-CTLA4 requiring further treatment in Phase 1. Enrollment of the Phase 1 study has been completed in March 2023. Radiation with Plinabulin could help reverse immune checkpoint inhibitor resistance in immune checkpoint inhibitor-refractory tumors and generate responses that are greater than radiation with immune checkpoint inhibitor alone. Plinabulin + PD-1 + Docetaxel in NSCLC in PD-1/PD-L1 Antibody Failed Patients In March 2023, the company announced the enrollment of the first patient in an investigator-initiated Phase 2 trial of Plinabulin in combination with Merck & Co., Inc.'s anti-PD-1 therapy Keytruda (pembrolizumab) and docetaxel for previously treated patients with metastatic NSCLC and progressive disease after immunotherapy (anti-PD-1 / PD-L1 inhibitor) alone or in combination with platinum-doublet chemotherapy. This trial is conducted at Peking Union Medical College Hospital in Beijing, China. This triple-combination therapy has the potential to improve immune checkpoint inhibitors resistance and provide a new treatment option for metastatic NSCLC patients previously treated with an immunotherapy. Other Programs In addition to exploring Plinabulin's therapeutic potential in combination with immuno-oncology agents, the company has a pipeline of preclinical immuno-oncology product candidates and has utilized its research collaborators to advance these programs. BPI-002 program The company's BPI-002 program is based on an oral small molecule agent that increases T-cell co-stimulation. Due to its short pharmacokinetics half-life, it has the potential of managing immune-related adverse events better than biological long half-life agents like CTLA-4 inhibitors in combination with PD-1/PD-L1 inhibitors. In preclinical cancer models, BPI-002 has significant anti-cancer effects as a monotherapy and in combination with checkpoint inhibitors. Investigational New Drug, or IND, enabling studies and efforts related to manufacturing and safety testing have been initiated. BPI-003 program The company's IKK program, BPI-003, is based on a novel small molecule inhibitor of IKK, a protein kinase. IKK is involved in survival of some tumor cells, as well as in the production of a number of cytokines and growth factors that serve as survival factors for various tumors. The company's IKK inhibitor has shown promising activity in multiple animal models of pancreatic cancer. BPI-004 program The company's BPI-004 program is focused on a small molecule that induces the production of neo-antigens by tumor cells, allowing tumors containing no immune cells to be infiltrated by the immune system. A large proportion of human cancers do not produce antigens that are recognized by the immune system. As a result, these tumors do not respond to treatments that work through interaction with the patient's immune response. For example, these tumors will not respond to treatment with PD-1 inhibitors. A treatment that induces the tumor cells to produce antigens has the potential to make these cancers responsive to PD-1 inhibitors. SEED's Targeted Protein Degradation (TPD) platform and Pipeline The company is also investigating an alternative approach to disease treatment in which disease-causing proteins are marked for early degradation. This approach uses a protein called a ubiquitin E3 ligase to target and promote the destruction of disease-causing proteins. To trigger degradation, the target protein is labeled with poly-ubiquitin by a specific ubiquitin ligase enzyme. Poly-ubiquitin acts as an indicating tag to cellular proteasome machinery that the target protein should be destroyed. One approach to tagging the target protein is using the company's unique 'molecular glue' technology to bind the ubiquitin ligase to the target protein. The company has formed a subsidiary, SEED, to explore this unique TPD technology platform on harnessing and engineering 'molecular glue' to attack previously believed undruggable targets. Backed by a comprehensive intellectual property portfolio, SEED's mission is to positively impact human health by creating novel protein degradation therapeutics to treat various severe diseases that have limited options for patients and their families. Through ongoing collaborations with world-leading academic experts in the field, including Nobel Prize winner in TPD field, Dr. Avram Hershko, SEED is establishing a growing pipeline of novel drug candidates on a path to potential clinical and commercial success. SEED is an established leader in overcoming the significant scientific challenges to discovering 'molecular glue', which enables the development of a new class of drugs with the potential to treat many previously untreatable medical conditions through the targeting of disease-causing proteins that are resistant to inhibition with traditional drug discovery methods. SEED stands out from its competitors through the discovery and use of its unique technology platforms for 'molecular glue' discovery, focused on platforms addressing the most challenging aspect of this effort, which is to select the E3 ligase to glue to the disease-causing protein to mark it for degradation. In November 2020, SEED entered into a research collaboration and license agreement, or the Collaboration Agreement, with Eli Lilly, to discover and develop new chemical entities that could produce therapeutic benefit through targeted protein degradation (TPD). In connection with this collaboration, the company and certain of its subsidiaries transferred certain contracts and intellectual property related to certain platform technology for the Ubiquitin Platform Technology to SEED, and the company granted SEED an exclusive sublicense with respect to certain rights to intellectual property and other materials related to the Ubiquitin Platform Technology. Strategy The key elements of the company's strategy are to develop plinabulin as a 'pipeline in a drug' in multiple cancer indications; advance plinabulin through global clinical trials and obtain regulatory approvals in both the U.S. and China; maximize the value of partnering with Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Hengrui), a leading oncology R&D and commercialization company in China; partner with one or more global pharmaceutical companies to commercialize Plinabulin in the U.S. and the rest of world; and maximize the value of SEED's targeted protein degradation (TPD) technology platform. The company's strategy in developing Plinabulin as an anti-cancer agent is in its unique mechanism as a potent dendritic cell maturation agent, which leads to tumor antigen specific T-cell activation. Commercialization In August 2021, Wanchunbulin, the company's partially owned Chinese subsidiary, entered into an exclusive commercialization and co-development agreement with Hengrui to further develop and commercialize Plinabulin in Greater China. Under the terms of the agreement, Dalian Wanchunbulin Pharmaceuticals Ltd. (Wanchunbulin) granted Hengrui exclusive rights to commercialize and co-develop Plinabulin in the Greater China markets, including mainland China, Hong Kong, Macau and Taiwan. Wanchunbulin retains the manufacturing rights of Plinabulin in the Greater China markets and will receive all Plinabulin net sales proceeds in such markets. In the U.S. and for the rest of world, the company plans to seek a commercialization partner to maximize Plinabulin's potential in multiple cancer indications. Intellectual Property As of March 15, 2023, the company owned or co-owned 159 patents, in 41 jurisdictions, including 22 issued U.S. patents. The company also owned 17 pending U.S. non-provisional patent applications, as well as corresponding patent applications pending in other jurisdictions and three pending U.S. provisional patent applications. In addition, the company owned five pending international patent applications related to Plinabulin filed under the PCT, which it plans to file nationally in the U.S. and in other jurisdictions directed to use of Plinabulin in combination with an anti-CD47 agent for treating cancer, use of Plinabulin in treating immune checkpoint inhibitor-resistant patients, use of Plinabulin as a monotherapy in treating certain cancers, kits and methods for providing and administering plinabulin, and Plinabulin impurities. The company's patent portfolio as of March 15, 2023, included 20 issued U.S. patents directed to Plinabulin and Plinabulin analogs, their synthesis and their use in the treatment of various disorders. In particular, the company owned 16 issued U.S. patents directed to the Plinabulin composition of matter, methods of synthesizing Plinabulin, polymorphic forms of Plinabulin, and methods of treating various disorders with Plinabulin, including docetaxel-induced neutropenia and certain other CIN, various cancers, such as lung cancer, NSCLC, breast cancer, skin cancer, prostate cancer, myeloma, RAS mutant tumors, and brain tumors, and fungal infections, and methods of using Plinabulin for inhibiting cell proliferation, promotion of microtubule depolymerization, and inducement of vascular collapse in a tumor. These U.S. patents were scheduled to expire between 2023 and 2038, excluding any potential patent term restorations. The patent portfolio also contained counterpart patents granted in 40 foreign jurisdictions, including Japan, South Korea, China, Europe and other countries. Research and Development The company's research and development expenses were $25.6 million for the year ended December 31, 2022. History BeyondSpring Inc. was founded in 2010. The company was incorporated under the laws of the Cayman Islands in 2014.