Implementation

Reducing cancer recurrence after surgery and adjuvant therapy drugs.

There are two common types of bladder cancer, treatment of non-muscle-invasive bladder cancer and surgical treatment of muscle-invasive bladder cancer, of which non-muscle-invasive bladder cancer (non muscle-invasive bladder cancer) or superficial bladder cancer (superficial bladder cancer) accounts for 75% to 85% of all bladder tumors. Certain factors are closely associated with the prognosis of non-muscle-invasive bladder cancer. Among these factors, the number of tumors, frequency of tumor recurrence, especially at 3 months postoperatively, tumor size, and tumor grade are strongly associated with recurrence. The factors most associated with tumor progression include pathologic grading of the tumor and tumor stage. The prognosis for tumors at the bladder neck is poor.

The main treatment options are surgical resection and postoperative adjuvant therapy. The surgical resection treatment is based on an assessment of the nature of the tumor, the depth of infiltration, and the choice of conservative transurethral resection of bladder tumor (TUR-BT) with postoperative radiation and chemotherapy, and close postoperative follow-up is required. An alternative, more radical surgical treatment is radical cystectomy, in which the patient's entire bladder is directly removed.

Recurrence occurs in 10% to 67% of patients within 12 months after TUR-BT and 24% to 84% of patients within 5 years after surgery. There are two peak periods of recurrence after TUR-BT for non-muscle invasive bladder cancer, 100 to 200 days after surgery and 600 days after surgery.

Because of the concern of recurrence, more and more patients are opting for the radical treatment, i.e. radical cystectomy. Although the recurrence of this resection will be lower, the quality of patient's survival is namely lower, such as the need for abdominal wall stoma, lifelong wearing of urinary collection bags, urinary incontinence and other inconvenient situations.

Clinically speaking, in order to reduce the problem of high recurrence and progression after surgery, adjuvant bladder perfusion therapy is generally used for bladder cancer patients after surgery. The perfusion drugs include chemotherapeutic drugs such as epirubicin or mitomycin, etc. It has been clinically proven that bladder perfusion chemotherapy can reduce the tumor recurrence rate by 40%. Another is postoperative bladder perfusion immunotherapy with BCG, for example, for intermediate-risk non-muscle-infiltrating bladder uroepithelial carcinoma, the probability of tumor recurrence after surgery is 45% and the probability of progression is 1.8% with BCG perfusion. However, BCG perfusion has more side effects and needs to be used with caution.

Our design this year is to make rLon protein into a biologic enzyme preparation that can be used to achieve perfusion therapy after bladder cancer surgery.

The advantage of this is that the literature validates that rLon protein can effectively prolong the survival cycle of bladder and rectal cancer in mice by perfusion, while avoiding more side effect problems such as immune reactions of enzyme protein preparations entering the human body directly.

Drug development: preclinical studies

At present, we have completed the purification of Lon protein, and the next step is to verify its effectiveness at the cellular level as well as in animal experiments.
In addition to confirming the effectiveness, safety is another important factor in moving from cellular to animal studies.

A variety of possible side effects, including immune factors, need to be considered, and we need to continuously optimize our therapies to obtain safe and useful data for IND (Investigational New Drug) applications to the CFDA/FDA.

Drug Development: Clinical Trials

Assuming we can obtain the expected data prior to clinical trials, we will prioritize the initiation of unregistered clinical trials (Non-IND) prior to enrolling in formal clinical trials to reduce development costs. During the Non-IND phase, we will focus more on the efficacy and safety aspects of the treatment itself. The subsequent phases of clinical registration will be similar to other drugs: Phase I - pharmacological and human safety evaluation trials, human tolerance observations of the drug and pharmacokinetics, and dosing regimen development; Phase II - drug efficacy evaluation and drug-to-patient preliminary assessment of efficacy and safety; Phase III - investigation of a larger group with longer follow-up to assess the relationship between efficacy and risk.

Because our treatment is a form of targeted gene therapy, we need to consider the target population and the unknown risks that gene therapy may pose.
During the course of the clinical trial, we can assess the efficacy of the treatment through pharmacodynamic, genomic and proteomic studies to better select patients who could benefit from the treatment.
Finally, if all criteria are met, we will commercialize our product.

Safety factors

The drug will be evaluated in a minimum of two animal species (e.g. rat and dog) for acute toxicity, subacute toxicity, long-term toxicity, safety pharmacology, genotoxicity, reproductive toxicity, carcinogenicity, sensitization, dependence, etc. Thus, key results such as toxic target organs, maximum tolerated dose, and dose without significant toxic reactions were obtained. The results of these toxicity evaluations can provide a basis for determining the starting dose for the first human trials of new drugs and for developing risk prevention and control measures for human clinical trials. For some new drugs that need to be taken for long-term treatment of chronic diseases, longer-term toxicological experimental studies are required.

The most important elements

We understand that the life cycle of a drug is extremely long and tedious: it must go through many regulated stages to ensure its safety, efficacy and quality for patients. lon protein drugs may still have very many unknowns as to whether they will make it to the clinic and to the market, but we are willing to work for it.