Gendicine® (recombinant human p53 adenovirus injection) is an innovative gene therapy drug developed by SiBiono GeneTech Co., Ltd (SiBiono). SiBiono owns its full intellectual property. In October 2004, SiBiono successfully obtained the New Drug License, Manufacturing Approval and GMP Certificate from the State Food & Drug Administration of China, becoming the world’s first authority approved gene therapy drug producer. Gendicine provides a novel, safe and effective therapy to fight against tumors. The launch of Gendicine has attracted worldwide attention; several media remark its success as “a milestone in the gene therapy and biotechnology field, and expected to make important contribution to the endeavor to improve the health of the mankind”.
Gendicine is genetically engineered adenovirus, comprising of two functional components: human wild-type p53 tumor suppressor gene and recombinant serotype 5 adenoviral vector. The adenoviral vector acts as the delivery vehicle to carry p53 gene into tumor cells to initiate their apoptosis.
Drug Names:
Generic Name: Recombinant Human Ad-p53 Injection
Trade Name: Gendicine
Mechanism of Action:
Gendicine is a gene therapy drug used to treat a wide variety of cancers. It is mainly composed of replication-incompetent recombinant Ad-p53 virus particles, which based on adenovirus serotype 5 and human wild-type p53 tumor suppressor gene, a key housekeeping gene, coding human wild-type P53 protein. In normal cells the expression level of P53 protein is very low, but it will be activated upon DNA damage. The up-regulation of p53 gene expression occurs at the post-translational level, and is achieved through stabilization of the protein. Upon induction, the main outcome of P53 protein activation is either cell cycle arrest or apoptotic cell death. While some tumors do not express p53, others express a mutant form of the P53 protein. p53 gene mutation rate in human tumors is up to 50~70%. Mutant forms of the P53 are not necessarily inactive, and can carry out several characteristic functions that contribute to tumorigenicity.
Post-injection intratumorally Gendicine enters tumor cells through adenovirus infection-mediated endocytosis and its carried exogenous p53 gene begins to express. Over-expressed P53 protein exerts its role of induction of tumor cell cycle arrest or apoptosis depending on the ability of P53 protein to act as sequence specific transcriptional regulator to up-regulate the expression of numerous anti-cancer genes and down-regulate the expression of numerous oncogenes. It can also directly induce the apoptosis of tumor cells without acting as transcriptional regulator to regulate any gene expression. Moreover over-expressed P53 protein acts effectively as a tumor antigen in stimulating human immune cells to assemble in tumor tissues and to selectively kill cancer cells over-expressing the p53 gene (by CTL cells) or to kill those uninfected cancer cells (by NK cells) via bystander effects. Addition to the above, it can down-regulate the expression of vascular endothelial growth factor (VEGF) gene and MDR gene, which involve respectively in the progress and metastasis of tumors or in the multi-drug resistance of tumors. By virtue of lack of DNA damage, exogenous p53 gene will not express in a normal cell, and therefore Gendicine does no harm to it.
Pharmacokinetics:
The results of in vivo animal experiments showed that these recombinant adenoviral DNA particles administrated locally or systemically have entered tumor cells within 1 hour post-injection. At 3rd hour post-injection p53 gene began to express and P53 protein was detectable. The expression rate of p53 gene increased to 47% at 12th hour, and reached the highest level at 72nd hour, then descended to 30% at 120th hour. But its expression was still detectable at 14th day. At 3 weeks post-injection the recombinant adenoviral DNA began to be digested and disintegrated. While been injected locally Gendicine distributed mainly in local tissue, and can be hardly detected in other organs and tissues. No recombinant adenoviral DNA was detected in excrements of urine, stool, or bile.
Clinical Studies:
Phase I clinical trial of intratumoral administration of Gendicine in patients with laryngeal squamous cell carcinoma was completed in Beijing Tongren Hospital to identify its safety. The results indicated that the main side effect was fever at the dose of 1ⅹ1012VP (virus particles). So the recommended dosage which should be adopted in phase II clinical trial was 1x1012vp/injection/week.
By November 2005, 4-6 years follow-up result of the 12 patients participated in the phase I clinical trial showed that 11/12 patients were alive with median survival time of 5.9 years. Follow-up time ranged from 4.0 to 6.4 years and 5-year survival rate of 91.7%. One patient aged 79 when enrolled into the clinical trial (the oldest one in the clinical trial) with poor-moderate differentiation squamous cell carcinoma died of the metastasis to liver at the age of 83 (4 years survived). It was reported by Am. Joint Committee on Cancer (AJCC) on 2002 that 5-year survival rate of laryngeal squamous cell carcinoma was 68.6-71.1% in stage I, 55.5-59.9% in stage II, and 46.4-50.1% in stage III, it was reported by Ji WenYue that it was generally 69.96% in different stages of laryngeal squamous cell carcinoma domestically.
A multicenter, randomized, open-label, parallel design phase II/III clinical trial was conducted in which patients with head and neck squamous cell carcinoma (HNSCC), the majority (85%) of them had nasopharyngeal cancer, were divided randomly into two groups: one group received gene therapy in combination with radiotherapy (GTRT) and the other group received radiotherapy alone (RT). There were no significant differences (p>0.05) in age, sex, or clinical stage, or in size of tumor lesion between the two groups of patients. Conventional or three-dimensional conformal radiotherapy was used at doses of 70 Gy administered in 35 fractions over 7–8 weeks for the RT group. For the GTRT group, Gendicine was given each week at a dose of 1×1012 VP 3 days before radiotherapy, for a total of 8 weeks. Radiotherapy in the GTRT group was the same as that used in the RT group. Objective tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) according to tumor response criteria World Health Organization (WHO) . The data showed that the response rate in the GTRT group was 93%, with 64% showing complete regression (CR) and 29% partial regression (PR). The response rate in the RT group was 79% with 19% of the patients showing CR and 60% PR. There is a significant difference (p<0.01) between the two groups in terms of both the CR rate and the PR rate. The CR rate in the GTRT group was 3-fold higher than that in the RT group. We concluded that Gendicine in combination with radiotherapy showed obviously synergistic effects.
By September 2005, the follow-up was carried out for 78 patients participated in the phase II/III clinical trial including 40 cases in the GTRT group and 38 cases in the RT Group. The mean follow-up time was 39.4 months. The results showed that the median disease-free survival time, 3-year disease-free survival rate and 3-year overall survival rate are 38 months, 74.3% and 78.8% respectively in the GTRT group and 32 months, 61.7% and 69.4% in the RT group.
In the phase I and II/III clinical trials, the main side effect noted was only grade I/II self-limited fever, beginning within 2-4 hours post-injection and lasting about 2-6 hours, in near 80% cases or in 32% person-times. The 3 to 6 years follow-up results showed no other side effects and special symptoms or syndromes for survival patients.
Indications:
Gendicine is approved by SFDA for the treatment of nasopharyngeal carcinoma in combination with radiotherapy.
Based on the clinical trial results in more than 20 varieties of malignant tumors worldwide, recombinant human adenovirus p53 product has been used to treat solid tumors alone or in combination with radiotherapy, chemotherapy or other therapies.
Dosage and Administration:
The routes of Gendicine administration include direct intratumor injection and others (intravenous infusion, arterial infusion, intrathoracic/intraperitoneal infusion, etc.) with 1ⅹ1012VP/injection/week, 6 weeks/course of treatment. More courses of treatment can be adopted according to patient's disease status.
When combined with other therapies like radiotherapy, hyperthermia, radiofrequency ablation therapy, and so on, Gendicine should be administrated 48-72hrs prior to other therapies. Gendicine can be applied simultaneously with chemotherapy.
Gendicine should be taken out before injection and allowed to thaw completely at room temperature. Mix with iodinated oil injection for Transcatheter Arterial Chemoembolization (TACE). Dilute with 0.9% Sodium Chloride Injection before use. Dilute to 2-10 ml for intratumoral injection, 20-50 ml for arterial infusion, 100 ml for intravenous infusion, and 100-1000ml for intrathoracic/intraperitoneal infusion.
Adverse Reactions:
The mainly observed side effect is self-limited fever ranging from 37.5℃ to 39.5℃ occurring usually 2 to 4 hrs after administration and lasting for approximately 2 to 6 hrs. The fever tends to relieve spontaneously without intervention.
Generally, fever occurs in the beginning of the treatment, and then decreases gradually in severity and incidence. Other rare side effects include chills, pain at the injection site, uncomfortable, fatigue, nausea, and diarrhea. Usually, no special management is needed as the symptom relieves automatically, however symptomatic treatment may be employed according to circumstances. No increase in the side effects that are commonly caused by radiotherapy or chemotherapy, such as bone marrow inhibition effect, injury in liver, kidney and heart, were observed when used in combination with Gendicine. No allergic reaction has been observed.
Contraindications:
1. Contraindicated for pregnant woman or during breastfeeding.
2. Contraindicated in patients with infection all over and infection-induced fever.
Drug Interactions:
As being living recombinant viruses reformed with genetic technology, Gendicine must not be administrated simultaneously combined with effective anti-virus drugs.
Overdosage:
Maximum tolerated dose has not been determined according to available clinical trial data both at home and abroad. Overdose may cause relatively intense fever or allergic reaction.
Specification: 1ⅹ1012VP/vial.
Storage: Stored at -20℃ during storage and transportation. Guard against freezing and thawing repeatedly.
Package: Packed in 2ml serum bottle, 1vial/case.
Expiry: 36 months.
Approved Words and No.: National Medicine Approval license S20040004
Manufacturer:
Enterprise Name: Shenzhen SiBiono GeneTech Co., Ltd.
Address: 19 Langshan Rd. Shenzhen Hi-Tech Industrial Park (North), Shenzhen, P.R. China
Zip code: 518057
Tel: 86-755-33065255 86-755-86026259
Fax: 86-755-33065222
Web site: www.sibiono.com
