CZ48: Extraordinary Potential

CHRISTUS Stehlin Foundation is conducting human clinical trials for CZ48, a promising anticancer drug  developed in the Foundation’s labs. CZ48 has shown remarkable activity against a variety of human tumors in preclinical testing.

In 2008, the Foundation’s 2,800-page application to conduct clinical human trials with CZ48 was approved by the FDA. Phase I clinical testing began at the University of New Mexico Cancer Center, and were expanded to The University of Texas Health Science Center at San Antonio.

The purpose of Phase I trials is to determine the drug’s safety (toxicity) and safe dosage range and to identify side effects. To date, clinical results  have confirmed those demonstrated in the lab: most patients have experienced manageable and mild side effects, which holds great promise for this exciting new drug.

Background

CZ48 is a compound synthesized by Stehlin scientists from camptothecin, a natural product isolated from a Chinese tree, Camptotheca acuminata. Camptothecin and many of its derivatives completely eliminate cancer tumors in laboratory animals. But when the drugs are used in humans, enzymes often convert the drug molecules from an active form (lactone) into an inactive form (carboxylate), eliminating their anticancer effect.

Because camptothecin is so effective in its active state, Stehlin researchers sought to stabilize it. In 1995, Foundation scientists synthesized CZ48, a stable “prodrug” derivative of camptothecin. The structure of the CZ48 molecule prevents it from being converted to its inactive form while it circulates in the human bloodstream.

How It Works

At the tumor site, esterase (an enzyme) converts CZ48 back into the active drug camptothecin, killing the cancer cells. The effectiveness of camptothecin in human cancer chemotherapy is reduced by the fact that it’s often inactivated in the human bloodstream. The inactivation results when a structural feature of the drug molecule (a lactone ring) is altered (opened); while the ring remains closed, the drug retains its anticancer activity. A major drawback of camptothecin as an antitumor agent is that, once injected, often less than 5 percent of the drug stays in active form, the rest being converted to the open ring (carboxylate) form.

CZ48 is the 20(S)-propionate ester of camptothecin synthesized in Stehlin Foundation labs. Due to a structural change in the camptothecin molecule (adding a propionate side chain at position C-20), the lactone ring in CZ48 is less susceptible to opening. Once CZ48 is transported into the tumor cells, esterase cleaves the propionate side chain and the drug becomes active, killing the cancer cells. The advantage of CZ48 versus camptothecin and other non-ester camptothecin derivatives is that a larger percentage of drug reaches the tumor in active form.

Low Toxicity

In pre-clinical studies, CZ48 killed cells of in 22 different human cancers transplanted into the Foundation’s athymic “nude” mice. Perhaps more impressive, toxic reactions were insignificant at the dosages necessary to produce the anticancer effects. In fact, test animals have been treated with up to 100 times the effective dose without significant signs of toxicity.

Most antitumor medications have a ‘therapeutic index’ between 1:1 and 1:4. Therapeutic index is the ratio of the therapeutic dose to the dose shown to be toxic.  With low toxic dose values (< 4), physicians have very little room to increase a patient’s drug dosage to obtain desired results. In CZ48, Stehlin has observed very little toxicity even at more than 20 times the therapeutic dose. At least initially, this indicates an extremely low toxicity for a cancer medication.

Preclinical Results Published

The results of the preclinical experimentation on CZ48 were published in the prestigious scientific journal Cancer Research in June 2009. The article, “Crystalline Camptothecin-20(S)-O-Propionate Hydrate: A Novel Anticancer Agent with Strong Activity Against 19 Human Tumor Xenografts,” detailed both the striking results and the lack of toxicity of the compound. Cancer Research is the official publication of the American Association of Cancer Research.

Comparison to Existing Drugs

Both camptothecin derivatives on the market today Camptosar® (irinotecan, Pharmacia/Pfizer) and Hycamtin® (topotecan, GlaxoSmithKline) are engineered to be soluble. Solubility is helpful because the drugs can be administered intravenously, allowing their doses to be titrated much more closely (important for drugs with low therapeutic indexes). CZ48 is designed to be delivered orally, in capsule form. While this is a distinct departure from other cancer chemotherapeutic agents, it is one of the drug’s greatest strengths. An oral formulation can be administered by the patient without a physician or hospital visit, reducing both time and cost. It is also expected to improve patient compliance, a major issue in cancer medications.

Human Clinical Trials Begin

FDA approval of an investigational drug application is itself a remarkable accomplishment, since less than one-tenth of one percent of all newly-derived chemical compounds developed for cancer treatment are allowed to be tested on humans.

Clinical trials follow a highly regulated and structured protocol (see Cancer Research Q&A) and take years to complete. They also are enormously expensive, and the cost is borne by the drug developer (CHRISTUS Stehlin Foundation), not by the patient or their hospital. Recent studies estimate the average cost of getting a drug through clinical trials at from $55 to $100 million.

Phase I

The goal of the first stage of drug testing in human subjects is to assess its safety, tolerability, pharmacodynamics (what the drug does in the body), and pharmacokinetics (what the body does to the drug). In anticancer drugs, testing usually includes a small number of patients (20-100) in the final stages of metastatic (incurable) disease. Participation in the study is voluntary, and patients are fully informed of the study’s purpose, duration, procedures, risks, and potential benefits. The trials also include “dose ranging,” in which the drug is administered in escalating quantities to determine the optimal amount for therapeutic effect.

CZ48 clinical trials are underway at the University of New Mexico Cancer Center in Albuquerque and The University of Texas Health Science Center at San Antonio. The 30-patient study is expected to conclude in 2012 with a projected cost of $1.5 million. If Phase I results are as expected, the study will expand (more study participants) into Phase II, designed primarily to assess how well the drug works.

Research Continues

Though the development of CZ48 has progressed into human trials, research designed to improve the compound continues. A subject of extensive research is CZ48’s bioavailability – the amount of the drug delivered to the cancer site. Data from the Phase I clinical trials indicate that the level of CZ48 in the blood of test subjects is lower than expected. Tests reveal that the biotransformation of the drug in the human liver is markedly greater in humans than in the Foundation’s mouse experiments involving human tumors. To improve bioavailability, emerging drug technologies such as micronization and hot melt extrusion are being tested.

One way to elevate drug absorption is to decrease the size of the particle. Stehlin has partnered with Nanomaterials Technology (NT) in Singapore to micronize CZ48. Preliminary results on nanoparticle material delivered from NT indicate the micronized CZ48 is significantly more effective at lower dosages than the original CZ48 molecule.  Specifically, only about 25 percent of the quantity of the original CZ48 molecule is required of the micronized form to achieve complete tumor inhibition.

The Foundation also is testing CZ48 compounds altered by PharmaForm in Austin through hot melt extrusion and spray drying. Initial findings from testing of this form of CZ48 are equally encouraging.

Extraordinary Potential

Given its activity both in vivo and in vitro, the Foundation believes CZ48 is the most promising compound of its type. If proven in human testing, CZ48 will be a significant improvement over many of the drugs used today against a variety of metastatic cancers.