All the subjects participating in this Phase I clinical trial of chlorogenic acid for injection were patients with high-grade malignant brain glioma refractory to international standard of care including surgeries and chemoradiotherapy.
The results of the phase I clinical trial showed that chlorogenic acid for injection was safe and had very low toxicity with clear pharmacokinetic pathways, little accumulative toxicity and efficacy beyond the investigator’s estimation.
The median overall survival of patients refractory to classical treatments after administration of chlorogenic acid for injection was extended by 2 to 5 times compared with the internationally recognized survival.
Changsha, China – On the 2nd China Brain Glioma Conference held in Changsha on March 17, 2018, Prof. Li, Wenbin, the Director of Brain Glioma Department, Beijing Shijitan Hospital Affiliated to Capital Medical University, disclosed in his report that the Chlorogenic Acid for Injection developed by Sichuan Jiuzhang Biotech Co., Ltd. has completed the Phase I clinical trial for treating brain malignant glioma and obtained favorable results from the clinical trial.
Malignant brain glioma is the most common intracranial neoplasms, among which, the high-grade (grade IV) glioblastoma is the most malignant brain glioma with an incidence of 3.2/100,000 and the median survival of 14.6 months from initial diagnosis to death. This data has remained unchanged for nearly 20 years. Nearly all the patients with high-grade (grade IV) glioblastoma would relapse later inevitably even when treated with the most active treatment (including surgery, radiotherapy, and chemotherapy). The median overall survival in patients with relapsed grade IV glioblastoma was about 7.2 to 9.6 months; while the overall survival of relapsed patients refractory to the classical treatments such as temozolomide, bevacizumab, or salvage chemotherapy was only 3 to 5 months (data source: February 28, 2018, Science Translational Medicine(Pellegatta S, et al. Sci Transl Med), Huge Therapeutic Advantages of CAR T-cell Therapy Targeted at Fatal Brain Tumor).
Prof. Li Wenbin and his clinical team specifically investigated the efficacy of chlorogenic acid for injection in treating high-grade glioblastoma, based on the safety, tolerability and pharmacokinetics studies. All the subjects participating in this Phase I clinical trial of chlorogenic acid for injection were patients with high-grade malignant brain gliomas refractory to international standard of care including surgery and chemoradiotherapy (progressed disease). The results of the phase I clinical trial showed that chlorogenic acid for injection was safe and had very low toxicity (its adverse reaction should only be muscular scleroma associated with long-term injection) with clear pharmacokinetic pathways, little accumulative toxicity and efficacy beyond the investigator’s estimation.
In the effective dose group, as of March 2, 2018, the median overall survival of subjects was 10.3 months (calculated from the randomization, i.e. the first day of subjects starting study medication after enrollment) and 14.2 months (calculated from the relapse). Since the median overall survival has not reached the 50% case deaths at present, the surviving patients still continue with the follow-up. The median overall survival of patients refractory to classical treatments after administration of chlorogenic acid for injection was extended by 2 to 5 times compared with the internationally recognized survival.
During the latest follow-up (February 26, 2018), it was found that subjects who received continuous administration had a complete response (CR, disappearance of all lesions) or a partial response (PR, lesion shrinkage by more than 50%) upon treatment evaluation, which was exciting. Currently, patients with recurrent high-grade gliomas who had failed in standard treatment were in an irreversible state of “SD-PD-death”(that is, patients would progress from stable disease (SD) to disease progression (PD) to death, which currently is irreversible with any drug) with almost no CR or PR worldwide; in clinical practice, it was also found that the combination therapy regimen of chemotherapy agents such as procarbazine, lomustine and vincristine (PCV regimen) could cause tumor shrinkage in a small number of patients even in the early stage, but didn’t prolong the overall survival. In this trial, the subjects had a complete response or partial response, were in good living condition, and had significantly prolonged survival. This efficacy response was far beyond the investigator's expectation, and was a significant breakthrough!
Chlorogenic acid is a natural small molecule active substance with a molecular weight of 354.31, which is widely present in various plants. First discovered in 1897 by British scientists in sunflower plants; named chlorogenic acid in 1909; It was confirmed that the structure of chlorogenic acid was polyphenols formed by condensation of caffeic acid and quinic acid in 1947.
Since 2000, under the leadership of Chairman Zhang, Jie, Jiuzhang Biotech has conducted systematic research and development on chlorogenic acid. In 2002, the Company achieved industrialized extraction, isolated allergenic vegetable protein and realized the transformation of chlorogenic acid extract to chlorogenic acid drug substance. On 30 August 2013, the Company has obtained the clinical trial approval for chlorogenic acid for injection and drug substance (2013L01855, 2013L01856) from the CFDA (CHINA FOOD AND DRUG ADMINISTRATION).
Up to now, Jiuzhang Biotech has been granted 23 invention patents, 1 utility model patent and 2 US patents associated with chlorogenic acid; in addition, it has 27 domestic patents and 26 international patents under substantive review. In December 2016, the Phase I/II Clinical Study on Innovative Class I New Drug Chlorogenic Acid for Injection was listed by the National Health and Family Planning Commission and the Ministry of Science and Technology in the national science and technology major new drug discovery projects in 13th Five-year plan, which was also a major science and technology support project in Sichuan Province.
Jiuzhang Biotech has established strategic partnership with the Institute of Materia Medica affiliated to Chinese Academy of Medical Science and further investigated the mechanism of anti-tumor action from different aspects. The results showed that chlorogenic acid for injection was a novel small molecule natural drug for anti-tumor immunity, mainly fighting against tumors by relieving immunosuppression and inducing tumor cell differentiation.
On one hand, it can modulate targeted immune checkpoints, relieve immunosuppression and promote proliferation of CD4T lymphocytes; on the other hand, it can induce the differentiation of malignant tumor cell, making it transform from poorly differentiated status with higher malignancy to well differentiated status with lower malignancy.
Especially in the nonclinical and clinical studies of malignant brain glioma, it is found that chlorogenic acid for injection can penetrate through the blood-brain barrier and adjust the proportion of immune cells at the lesion site, facilitate the aggregation of tumor-killing M1 macrophages around the lesions and inhibit the M2 type macrophages that help with the migration and proliferation of tumor cells, thus inhibiting the metastasis and proliferation of glioma. Relevant basic findings have been published in Scientific Reports (Xue N et al. 2017; 7: 39011).
Chlorogenic Acid Inhibits Glioblastoma Growth Through Transforming Macrophage from M2 to M1 type by repolarization, elaborated and demonstrated the mechanism of chlorogenic acid for injection to promote the apoptosis of malignant tumor cells and inhibit tumor growth. The results of pharmacodynamics and mechanism showed that chlorogenic acid for injection was broad-spectrum in antitumor aspects and can be used to treat a variety of tumors such as lung cancer, prostate cancer, cervical squamous cell carcinoma, lymphoma and colorectal cancer.
In view of the broad-spectrum antitumor effect of chlorogenic acid for injection, Jiuzhang Biotech initiated a phase Ib/IIa clinical trial study on patients with advanced lung carcinoma in addition to the phase II clinical study on the treatment of recurrent high-grade glioblastoma.
Drug development for brain glioma is a difficult problem in drug research worldwide. There had been no new drug discovered in the past 20 years. Academician Zhao Jizong of Beijing Tiantan Hospital affiliated to Capital Medical University said when interviewed by Chinese Medical Information that brain glioma was a very important part of neurosurgical tumors, accounting for more than half the brain tumors. Current precision research will provide new techniques for the pathogenesis, diagnosis and treatment of brain glioma, and play an important role in the treatment of brain glioma.
The results of the Phase I clinical trial of chlorogenic acid for injection not only demonstrated its safety, but also increased the survival of patients with recurrent brain glioma by 2-3 times. As supported by National Major Special Projects in New Drug Discovery, results of Phase I clinical trial was highly concerned by experts both at home and abroad upon publication.
Further clinical trial results are expected. If subsequent results further demonstrated its efficacy, this will be a great news for glioma patients all over the world. Chlorogenic acid for injection may become a blockbuster innovation drug from local China, boosting China's presence in global pharmaceutical innovation.
About Jiuzhang Biotech
Sichuan Jiuzhang Biotech Co., Ltd., founded in 1999, is committed to the screening, molecular structure modification and comprehensive application study of natural active products, as a high-tech enterprise integrating research, production and sales. After long-term, in-depth pharmacy and clinical research, the company has for the first time researched and developed the chlorogenic acid monomer as a drug in the whole world and applied it to the treatment of major diseases (cancers). In 2013, the company had obtained the clinical approval for chlorogenic acid drug substance and preparations (Approval No.: 2013L01856 and 2013L1855) issued by the CFDA (CHINA FOOD AND DRUG ADMINISTRATION), registered as Class I and II chemical drugs.
