Xinch Biopharma Files Prospectus: Pioneering Dual EP2/EP4 Antagonist and USP1 Inhibitor Programs Led by Rofecoxib Designer and Ceritinib Discoverer

Vioxx (generic name: rofecoxib; alias: rofecoxib, Vioxx) belongs to the class of cyclooxygenase-2 (COX-2) inhibitors.

Drugs that inhibit cyclooxygenase-2 (COX-2) primarily exert anti-inflammatory and analgesic effects. Therefore, Vioxx is indicated for the treatment of osteoarthritis and rheumatoid arthritis, as well as for pain relief and the management of primary dysmenorrhea, including various postoperative pains following dental and orthopedic surgeries. Furthermore, the analgesic efficacy of Vioxx is comparable to that of ibuprofen, without the associated risk of gastrointestinal bleeding.

On May 21, 1999, the FDA approved Merck’s Vioxx for market launch, and Vioxx entered the Chinese market in 2001. Statistics indicate that approximately 20 million patients worldwide have taken this medication, with Vioxx’s sales reaching as high as $2.5 billion in 2003. On September 30, 2004, Merck voluntarily announced a global recall of Vioxx, citing evidence from relevant studies that the drug could increase the risk of cardiovascular diseases.

A Legendary Drug: Briefly Brilliant, Then Suddenly Extinguished.

Dr. Wang Zhaoyin recalled that on the day Vioxx was launched, banners celebrating its approval were also displayed in Times Square, USA,“Vioxx was the first milestone in my career, the first drug molecule I designed myself.”

In just four years, a once-revered "wonder drug" has witnessed a dramatic turn of events.

The incident originated from Merck & Co.’s observation of Vioxx’s favorable activity in tumor models, which led to the decision to design clinical trials to expand its indications. In a trial named APPROVe (Adenomatous Polyp Prevention on Vioxx), patients taking Vioxx for up to 18 months had twice the risk of experiencing confirmed cardiovascular events (such as heart attacks and strokes) compared to those in the placebo group.

Based on data from the APPROVe clinical trial, Merck announced the voluntary withdrawal of Vioxx.

“I still remember that the news was announced before the New York Stock Exchange opened, and I was completely overwhelmed by it at the time.” Amid disappointment and confusion, Wang Zhaoyin chose to persevere, channeling those feelings into the driving force behind his continued research on the cyclooxygenase pathway.

Following Vioxx, Wang Zhaoyin led and participated in the research and development of multiple successful blockbuster small-molecule drugs at Merck & Co., such as Arcoxia and Tredaptive.Among them, Arcoxia is currently marketed in 84 countries and regions worldwide, including China.

His dramatic experience has driven Wang Zhaoyin to persist in researching the cyclooxygenase pathway for many years. “I aim to leverage my years of understanding of this pathway, building upon new discoveries and accumulated R&D insights, to identify drugs that are safer and more effective than Vioxx, thereby addressing unmet medical needs.”

It is well known that the prostaglandin E2 (PGE2)–PGE2 receptor (EPs) signaling pathway is central to the cyclooxygenase-mediated inflammatory pathway. The anti-inflammatory and analgesic effects of cyclooxygenase inhibitors are achieved by suppressing PGE2 synthesis, thereby blocking the PGE2–EPs receptor signaling pathway. Following the market withdrawal of Vioxx, multiple academic institutions conducted in-depth mechanistic studies on the cardiovascular effects of cyclooxygenase-2 (COX-2) inhibitors. These studies revealed that, in addition to inhibiting PGE2 synthesis, COX-2 inhibitors also restrict the synthesis of prostacyclin (PGI2) in the cardiovascular system, impairing its vasodilatory function and consequently leading to an increased incidence of cardiovascular diseases.

Further studies have demonstrated that among the four PGE2 receptors, EP1 and EP3 are not associated with inflammation, EP4 is closely correlated with inflammatory processes, while the function of EP2 remains unclear. All evidence indicates that inhibiting downstream PGE2 receptors, such as EP4, does not affect the synthesis or levels of various prostaglandins, thereby avoiding cardiovascular risks.

The validation of the PGE2-EP4 inflammatory signaling pathway has provided the pharmaceutical industry with a new direction for the safe and effective treatment of inflammatory pain. In 2007, the Merck & Co. research team led by Wang Zhaoyin rapidly designed and synthesized MF-766, a selective EP4 antagonist clinical candidate. However, due to strategic adjustments in Merck’s pipeline, this compound never advanced into clinical trials. Meanwhile, multiple research groups have elucidated the role of the PGE2-EP4 signaling pathway in tumor cell proliferation, migration, and the suppression of immune cell function, thereby establishing selective EP4 antagonists as a prominent new target in cancer immunotherapy.

After returning to China in 2012 to start a business, Wang Zhaoyin quickly and successfully developed a highly active EP4-selective antagonist, leveraging his years of accumulated experience and knowledge in the cyclooxygenase pathway. Due to early-stage funding constraints, he transferred the rights to the compound, which is currently in Phase 1b clinical trials.

In 2017, introduced by a friend, Wang Zhaoyin, a chemist, met Li Nanxin, a biologist.

Li Nanxin previously had 15 years of experience in new drug research and development at Novartis. He served as Technical Director and Deputy Director of the Oncology Center at the Novartis Institutes for BioMedical Research Genomics Institute (GNF). He was awarded the highest honor at Novartis, the President's Award. He was internationally recognized for being the first to discover the EGFR-Ras signaling pathway, which has been included as a fundamental biological theory in classic biology textbooks such as Gene and The Biology of Cancer.

During his tenure at Novartis, Li Nanxin led the research and development of two newly launched drugs: ceritinib and encorafenib.Unlike most professionals working at large pharmaceutical companies, Li Nanxin’s role is not confined to a single segment of the workflow.Li Nanxin is the discoverer of ceritinib and led its preclinical development. He was involved in every stage, from early target validation and compound screening to translational medicine research, and also participated throughout in decision-making and management during the clinical trial phases of ceritinib.

During Li Nanxin’s development of ceritinib, the project encountered a particularly challenging phase. At that time, the drug had already entered the IND-enabling stage, but Pfizer concurrently disclosed preliminary clinical efficacy data for its compound (crizotinib). The published data indicated that crizotinib’s mechanism of action was virtually identical to that of ceritinib.

“What should be done with the ceritinib molecule?” This question weighed heavily on Li Nanxin’s mind during that period. Fortunately, leveraging his knowledge of translational medicine, Li rapidly innovated and established a crizotinib-resistance model from scratch. Centering on these models, he led and validated the efficacy of ceritinib, successfully advancing it to clinical approval and market launch within just two and a half years.

In 2018, NewQi Pharma was co-founded by two scientists with complementary expertise who had successfully led the R&D and commercialization of multiple novel small-molecule drugs. Li Nanxin serves as Founder, Chairman, and CEO, while Wang Zhaoyin serves as Co-Founder and Chief Chemist. The company is dedicated to the development of targeted anti-tumor and immunotherapeutic agents.。

Currently, Xinqi Bio is headquartered in Guangzhou, with R&D centers and laboratories established in Shanghai and San Diego, USA. Its core team possesses profound theoretical knowledge of new drug development and extensive practical experience in pharmaceutical R&D, with members offering complementary expertise and having collaborated for many years.

Currently, over 15% of malignant tumors worldwide are caused by chronic inflammation, with the COX-PGE2-EPs signal transduction pathway being a core inflammatory pathway. Common drugs targeting this pathway include non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors, both of which work by inhibiting cyclooxygenase to block the COX-PGE2-EPs receptor signaling pathway. In terms of safety, inhibition of cyclooxygenase leads to an imbalance in various prostaglandin levels in the body, particularly by suppressing the synthesis of thromboxane A2 and PGI2, thereby increasing the risk of gastrointestinal bleeding and cardiovascular events. In contrast, inhibition of downstream EP receptors does not cause such imbalances in prostaglandin levels, resulting in a safety profile distinct from that of NSAIDs and selective COX-2 inhibitors.

Following the successful development of selective EP4 antagonists, a persistent question in this field has been the role of another PGE2 receptor, EP2, in inflammatory pathways and tumor immunity. Both EP2 and EP4 are Gαs-coupled receptors that activate adenylate cyclase to increase cAMP levels, and they exhibit similar expression and distribution patterns in tumor tissues and immune cells. Only in the past two years have data from gene knockout studies and small-molecule antagonist trials demonstrated that simultaneous inhibition of both EP2 and EP4 is required to effectively suppress tumor growth and immune evasion.

Therefore, compared with EP4 or EP2 selective antagonists, dual inhibition of EP2 and EP4 is more effective in suppressing tumor growth and immune evasion. In terms of safety, unlike cyclooxygenase inhibitors, downstream dual inhibition of the EP2/EP4 pathway does not affect the synthesis and levels of various prostaglandins in vivo, thereby posing no gastrointestinal or cardiovascular safety risks.

Leveraging new experimental data and Wang Zhaoyin’s decades of expertise in the cyclooxygenase pathway, NewQi Bio has strategically positioned its EP2/EP4 dual antagonist pipeline to address the two major disease areas of cancer and inflammatory pain., which is significantly different from other cyclooxygenase pathway inhibitors, such as industry-available EP4-selective antagonists.

In terms of indicationsEP2/EP4 are highly expressed in tissues of gastric cancer, esophageal cancer, pancreatic cancer, colorectal cancer, and lung cancer. EP2/EP4 dual antagonists as monotherapy demonstrate potential therapeutic efficacy across multiple cancer types.

In addition to monotherapy,, EP2/EP4 dual antagonists can also enhance the response rate to immune checkpoint inhibitor antibody therapy, indicating broad prospects for combination therapy. Furthermore, recent literature reports have found that a significant number of patients who are non-responsive to immune checkpoint inhibitor antibody therapy and have a poor prognosis exhibit elevated COX-IS scores (Cyclooxygenase-PGE2-EPs inflammatory pathway signaling). EP2/EP4 dual antagonists hold promise for improving the immunotherapy response rates in this patient population. The COX-IS scoring tool has the potential to serve as a biomarker for identifying suitable candidates for EP2/EP4 dual antagonist therapy, with higher COX-IS scores predicting better therapeutic efficacy.

It is evident that XinQi Bio’s EP2/EP4 dual antagonist holds promise as a potential first-in-class, dual-target molecule. Currently, XinQi’s compound is in the IND-enabling stage, with simultaneous Investigational New Drug (IND) applications in China and the United States expected in the first half of next year.

In addition to the dual EP2/EP4 targets, New Qi Biologics has also laid out synthetic lethality targets such as USP1 (Ubiquitin-Specific Peptidase 1), comprehensively and systematically targeting the tumor microenvironment to develop novel small-molecule oncology therapeutics.

By leveraging the synthetic lethality mechanism, inhibition of USP1 in tumor cells with BRCA mutations or homologous recombination deficiency (HRD) can induce cell death due to severe DNA damage. Therefore, USP1 inhibitors are applicable for indications such as ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer characterized by BRCA mutations or HRD. USP1 inhibitors may also demonstrate efficacy in patients who are non-responsive or resistant to PARP inhibitors. In addition to monotherapy, USP1 inhibitors exhibit synergistic effects with PARP inhibitors; combination therapy can enhance therapeutic outcomes and prevent or delay the onset of resistance.Currently, the project is in the IND-enabling stage and is expected to enter the IND stage next year.

“Benefiting from the core team’s proven track record in leading the R&D and successful commercialization of multiple innovative small-molecule drugs, XinQi Bio’s numerous pipelines under development are progressing rapidly and systematically. ‘All our projects follow a dual-filing strategy in China and the United States, with IND applications for several pipelines expected to be submitted by the end of this year and next year.’”

As the project advances rapidly, Xinqi Bio is actively pursuing its next round of financing. Regarding future plans, Li Nanxin stated, “We hope that Xinqi Bio will leverage multiple products with differentiated advantages as entry points to continuously deliver first-in-class small-molecule drugs. Of course, we also welcome collaboration with partners across the upstream and downstream segments of the industry chain to jointly promote sector development.”