Overland Pharmaceuticals Files IPO Prospectus Highlighting Differentiated Innovation Amid Industry Winter
Recently, China’s pharmaceutical sector appears to have entered an unprecedented winter. With valuation inversions between primary and secondary markets, financing difficulties, pipeline homogenization, and challenges in pricing and hospital access, the industry is undoubtedly undergoing painful transitional growing pains.
In fact, winter is precisely the right time to identify high-quality enterprises; during more challenging periods, truly outstanding companies are better able to emerge rapidly. When evaluating leading innovative pharmaceutical companies, key primary criteria include innovative business models, innovative pipelines, and advanced clinical progress, with clinical progress being particularly critical.
Overland Pharmaceuticals is a biotechnology company founded on the philosophy of “focusing on cutting-edge innovation,” targeting two frontier niche sectors: antibody-drug conjugate (ADC) therapeutics and universal CAR-T therapies.
It is reported that Loncastuximab Tesirine (Lonca), a key ADC drug candidate in Overland Pharmaceuticals’ pipeline, received accelerated approval from the U.S. FDA in April 2021 as a monotherapy for third-line or later relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The bridging study for market approval in China is expected to submit a New Drug Application next year.
The global (including China) multicenter, randomized, controlled Phase III trial of loncastuximab tesirine in combination with rituximab (Lonca+R) for second-line and later treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), known as LOTIS-5, is ongoing. Clinical data from the 20-patient safety lead-in phase demonstrate that Lonca+R is safe and highly effective, holding promise as a new therapeutic option for second-line treatment of R/R DLBCL. In addition, Allogene Therapeutics, the technology partner of Overland Pharmaceuticals for universal CAR-T therapy, recently announced the initiation of the world’s first pivotal Phase II study of universal CAR-T cells, a development with promising prospects.
Amid the current landscape of Chinese biopharmaceutical companies, characterized by target overcrowding, high pipeline redundancy, and intense involution, high barriers to entry and innovation in R&D directions serve as the exit from this “involution trap.” Overland Pharmaceuticals is committed to maintaining a sharp focus.“Wide moat, high walls”'s cutting-edge technology platform.
Currently, Overland Pharmaceuticals is strategically positioned in two major areas: antibody-drug conjugate (ADC) therapeutics and universal CAR-T therapies. The company has established a joint venture with ADC Therapeutics, a global leader in ADC drug development.Overland Edith, Overland Pharmaceuticals is one of the few Chinese companies focused on developing CD19-targeted antibody-drug conjugate (ADC) therapeutics. In addition, Overland Pharmaceuticals has partnered with Allogene, a pioneer in universal CAR-T therapy, to establish a joint venture dedicated to the development of universal CAR-T drugs.AnnoLingLu, accelerating the development and commercialization of AlloCAR T™ cell therapy.
The barriers to ADC drugs are mainly reflected in three aspects.First, the requirements for antibodies, not all targets are suitable for antibody development, and higher antibody affinity is not always better;Next are the connexons, linking the payload and antibody; if the linkage is too tight, the payload cannot be released, whereas if it is too loose, it fails to reach the target, necessitating a careful balance.Additionally, there is "warhead", i.e., the payload.
In other words, a successful ADC drug requires the organic integration of the antibody, linker, and payload, and is by no means a simple analogy to an antibody-conjugated chemotherapy agent.
In 2000, Pfizer’s Mylotarg was approved for market launch but was later withdrawn due to excessive toxicity, epitomizing the high technical barriers associated with antibody-drug conjugate (ADC) drugs. Constrained by these formidable technical hurdles, few ADC drugs have been successfully developed, with their numbers far trailing those of monoclonal antibodies, small-molecule drugs, and chemotherapeutic agents.
CAR-T therapy has emerged as a standout in the innovative drug market in recent years. However, all CAR-T therapies approved for marketing worldwide to date are autologous products, not “off-the-shelf” drugs in the traditional sense, and are subject to numerous limitations. Autologous CAR-T therapy requires harvesting the patient’s own immune cells, processing them ex vivo, and then reinfusing them into the patient. This approach entails prolonged manufacturing lead times, challenges in standardizing production processes, and an inability to achieve large-scale manufacturing, resulting in prohibitively high costs. These factors significantly restrict the accessibility of CAR-T therapies.
Universal CAR-T TherapyUniversal CAR-T therapies, which can be manufactured at scale and prepared in advance for immediate patient use, possess an “off-the-shelf” characteristic that can overcome cost barriers, promote the widespread adoption of CAR-T therapy, and enable broad clinical application. Regarded as the ultimate solution for CAR-T therapy, they are highly acclaimed within the industry.
In summary,ADC drugs and universal CAR-T therapies are both high-barrier products that truly embody a high degree of innovation., which is worth significant strategic investment by enterprises.
As of now, there are more than 50 companies worldwide engaged in the research and development of antibody-drug conjugate (ADC) therapeutics. Although numerous, these enterprisesZhang Xiaolei, Co-Founder and CEO of Overland PharmaceuticalsEmphasizing the need to “look at the details,” there are in fact substantial differences among companies in their technological platforms and target portfolios.
Overland Pharmaceuticals is one of the few companies currently focused on developing CD19-targeted antibody-drug conjugate (ADC) therapies. In April 2021, the U.S. FDA granted accelerated approval to Lonca, an Overland Pharmaceuticals product, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) who have received two or more prior lines of systemic therapy, including those with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.This is currentlyThe world's first and only approved CD19-targeting ADC drug.
“It is well known that control of warhead toxicity is one of the major factors contributing to the low success rate in ADC drug development. Toxins can accumulate in the body and are not easily metabolized, requiring companies to possess strong capabilities in managing toxicity risks. Lonca employs PBD (pyrrolobenzodiazepine dimer cytotoxin), an extremely potent toxin with the highest toxicity among those used in the industry. Consequently, very few companies in the field utilize PBD for drug development.”
“We take pride in having identified the optimal balance between efficacy and safety risks for Lonca through early-phase clinical trials, establishing a precision science-based dosing regimen, and successfully developing a first-in-class ADC drug that has received high recognition from the FDA.”Overland Pharmaceuticals' Chief Development Officer, Luo Fengindicates.
Currently, there is no standard treatment regimen for patients with third-line and later-stage diffuse large B-cell lymphoma (DLBCL), leaving a significant unmet need. The launch of Lonca provides this patient population with a novel monotherapy option. According to Luo Feng, monotherapy and third-line-plus treatment represent merely the initial step for Lonca, not the endpoint; Overland Pharmaceuticals is actively working to expand its use into second-line and even first-line settings. Clinical challenges such as advanced age and poor tolerance to R-CHOP therapy in certain patient subsets will serve as effective entry points for Lonca’s adoption in first-line treatment.
“Overall, for Lonca, we aim to buildChemotherapy-Free Drug Combinations. Lonca and rituximab represent an excellent combination, with efficacy far superior to that of chemotherapy regimens. Meanwhile,Clinically Oriented Drug Development, providing patients with more mature, effective, and convenient solutions is our goal.“For example, Lonca is administered as a 30-minute intravenous infusion once every three weeks. It requires no premedication and does not necessitate close monitoring for side effects or neurotoxicity. Its lower dosing frequency reduces the treatment burden on both hospitals and patients, better addressing real-world clinical needs,” said Luo Feng.
Notably, detailed safety and efficacy results from the safety lead-in phase of LOTIS-5 were officially disclosed at the 10th Annual Meeting of the American Society of Hematologic Oncology (ASHO) in 2022. LOTIS-5 is the first global multicenter, randomized, controlled Phase III clinical trial to evaluate the Lonca+R combination regimen (simultaneously targeting CD19 and CD20) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Data from the safety lead-in phase showed that 15 out of 20 patients achieved disease response after treatment with Lonca+R (ORR: 75%), including 8 patients who achieved complete response (CRR: 40%).This suggests that the Lonca+R combination regimen holds promise as a new second-line treatment option for R/R DLBCL.
“Lonca is expected to be launched in the Chinese market in 2024.” Zhang Xiaolei expressed great anticipation for Lonca’s launch in China.
In addition to ADC drugs, Overland Pharmaceuticals has also delivered notable performance in the field of universal CAR-T therapies.
As is well known, the manufacturing process of CAR-T therapies is complex and presents high technical barriers. It is particularly challenging to isolate, culture, and produce CAR-T cells that exhibit specific and potent cytotoxic activity against tumor cells.
Furthermore, the technical threshold for universal CAR-T is higher than that for autologous CAR-T. How to break through the immune barriers between donors and recipients—thereby avoiding both graft-versus-host disease (GVHD) and host-versus-graft (HVG) reactions—while enabling universal CAR-T cells to exert their anti-tumor effects in patients, represents another challenge facing universal CAR-T therapy.
As a leading enterprise in the field of universal CAR-T cells, Allogene has cultivated deep expertise over many years, accumulating extensive experience. Its universal CAR-T technology platform, based on TALEN gene-editing technology, has been extensively validated in various hematologic malignancies, including leukemia, lymphoma, and myeloma. Overland Pharmaceuticals has licensed four universal CAR-T therapies from Allogene targeting BCMA, CD70, FLT3, and DLL3, with its primary pipeline focusing on hematologic tumors such as multiple myeloma, as well as solid tumors. These products are manufactured using peripheral blood from healthy donors through gene editing, enabling large-scale production, advance preparation, and long-term storage. The expected cost reduction to levels affordable by national medical insurance will break the deadlock of high-priced CAR-T drugs, improve accessibility, and benefit more patients.
Overland Pharmaceuticals has first addressed the manufacturing challenges of off-the-shelf CAR-T therapies.Unlike other drugs that follow the “R&D in China, manufacturing abroad” model, Overland Pharmaceuticals has decided to manufacture its CAR-T therapy domestically. To this end, the company has taken the lead in establishing a universal CAR-T drug production base in Lingang, Shanghai.
Zhang Xiaolei stated, “The hallmark of universal CAR-T cells is their suitability for industrialized manufacturing; a single production run can meet the clinical needs of a substantial number of patients. Moreover, their extended frozen shelf life enables eligible patients to receive timely treatment upon arrival at the hospital. Our ultimate goal is to leverage local industrialized production to reduce cell therapy costs to a level affordable within the national medical insurance framework. The manufacturing process for allogeneic cells is highly complex, and we are establishing our own cell production base, which may represent the forefront of allogeneic cell therapy manufacturing capabilities in China.”
“Meanwhile, Overland Pharmaceuticals is also laying out its third-generation cell therapy products, leveraging stem cell technology to prepare cell-based drugs and creating cutting-edge, fully independently developed frontier cell therapies,” introduced Luo Feng.
Zhang Xiaolei stated, “We aim to develop innovative products with high clinical value that address patients’ urgent and unmet medical needs. This requires not only differentiated technologies, novel targets, and a comprehensive R&D platform, but also the collective strength of our team.”
In terms of R&D team building, Overland Pharmaceuticals differs from most startup biotech companies.Zhang Xiaolei pointed out: “Entrepreneurship is not about capital hype; it is crucial to have a reliable team that can stay grounded and focus on the work.”
In less than two years since its establishment, Overland Pharmaceuticals has built a comprehensive R&D chain, comprising six major departments: Preclinical Translational Medicine, Clinical Operations, Clinical Medicine, Biostatistics and Data Management, Pharmacovigilance (PV), and Clinical Pharmacology. This end-to-end structure forms a fully integrated functional team, with core members being seasoned professionals who have many years of industry experience.
The rapid progress of Lonca serves as a strong testament to the professionalism and high execution capabilities of the Overland Pharmaceuticals team.According to Luo Feng, “The company introduced Lonca at the end of 2019 and submitted four Clinical Trial Applications (CTAs) within just over a year, completing the bridging registration clinical trials three months ahead of schedule.” Such a highly efficient and comprehensive team structure is remarkably scarce among biotechnology companies, providing sustained momentum for the company’s continuous exploration of new targets and the rapid development of its pipeline.
However, it must be acknowledged that against the backdrop of centralized volume-based procurement (VBP), Chinese innovative pharmaceutical companies are facing unprecedented challenges, with many such enterprises and investment institutions reaching a critical juncture.
“Chinese pharmaceutical companies must not bury their heads in the sand like ostriches; they need to accelerate their search for new opportunities."In the long term, drawing on the U.S. experience, China’s innovative drug market still has considerable room for growth. As population aging intensifies and residents’ health needs rise, the outlook for China’s innovative drug market remains promising. Successful companies will need distinct positioning, focusing on differentiated innovative products."
A review of Overland Pharmaceuticals’ pipeline layout reveals that“Innovation” and “differentiation” are precisely the distinguishing features of the company’s pipeline strategy.“In the future, in addition to ADC drugs and universal CAR-T therapies, Overland Pharmaceuticals is also focusing on bottleneck products such as small nucleic acid drugs and cancer vaccines, with the aim of addressing tangible patient needs,” summarized Zhang Xiaolei.