Information for patients

Introducing Tetrodotoxin

Tetrodotoxin (TTX) is a natural substance extracted and purified from the puffer fish by means of a proprietary process developed by WEX. This produces a pharmaceutical product suitable for use in medicine. The name of this product, containing tetrodotoxin as the active ingredient, is Tectin^TM.

The Puffer Fish:    A Very Intriguing Creature

There are about 120 species of puffer fish worldwide; most live in tropical or sub-tropical waters.

The puffer fish or blowfish, as it is sometimes called, has a slow and clumsy swimming style and is therefore vulnerable to predators. Its name refers to the fact that instead of escaping its enemies, it uses its elastic stomach to ingest a large quantity of water, which transforms it into a ball several times normal size. Some species have spines on their skin, making it even more difficult for predators to swallow this fish.

Tetrodotoxin:   An Effective Defense System

In addition to this capacity to grow in size, the puffer fish’s ability to produce tetrodotoxin provides it with another powerful natural defense system. Tetrodotoxin is a foul-tasting and poisonous substance to any predator who tries to prey on the puffer fish.

The tetrodotoxin of the puffer fish is mostly concentrated in specific organs such as the liver, sex organs and the skin. The meat of the puffer fish does not normally contain tetrodotoxin. Indeed, in Japan (where it is called fugu), the puffer fish is considered to be a great delicacy which can only be prepared by specially trained and licensed chefs, due to the high risk of serious or fatal poisoning if the fish is contaminated or badly prepared.

The Use of Natural Substances in Medicine

The principle of using a natural substance which is toxic at high doses but which exerts a beneficial effect at very low doses has been well known in medicine for hundreds of years. Modern examples of such useful pharmaceutical products include digitalis (digoxin), a toxic substance obtained from the foxglove plant (digitalis purpurea) which is commonly used in the treatment of serious cardiac disease. Likewise, botulinus toxin (Botox®), obtained from a deadly type of bacteria (Clostridium botulinum), is now used safely in the treatment of painful muscle spasms and in cosmetic procedures.

Similarly, tetrodotoxin accidentally ingested while eating badly prepared puffer fish is dangerous or even fatal due to the relatively large but variable quantity of toxin that may be consumed. However, under the carefully controlled extraction and purification process that is practiced in modern laboratories such as WEX, tetrodotoxin can now be converted into a useful therapeutic product which can be more safely administered in tiny and precisely measured doses.

Tetrodotoxin:   Mode of Action

Tiny doses of tetrodotoxin have been shown to block or prevent the initiation and conduction of the tiny electrical currents (called nerve impulses) that run along the nerves of the body. These nerve impulses are responsible for our sensations and also for the control of our movements and the various body functions. Tests conducted in animals have shown that tetrodotoxin has a potent pain relieving (or analgesic) effect. This is thought to be due to the product’s blocking action on nerve conduction.

Tectin^TM:   Its Characteristics and Possible Uses

The product developed by WEX Pharmaceuticals and having these properties is called Tectin^TM. It has the potential to provide a new solution to the problem of pain.

The active ingredient in Tectin^TM, tetrodotoxin, is extracted from puffer fish using advanced purification methods. It is then refined into a pharmaceutical product suitable for human use. Tectin^TM is manufactured in Canada according to Good Manufacturing Practice regulations. Each 2 milliliter glass ampoule, corresponding to one dose, contains 15 micrograms / milliliter (one microgram corresponds to 1 millionth of one gram). The product is intended for subcutaneous (under the skin) or intramuscular (into a muscle) injection.

Tectin^TM is a very powerful pain relieving agent, much more potent than morphine in animal studies. Its painkilling action starts quickly after the first dose and has a long lasting effect. Its side effects (unwanted effects) are mild to moderate and are reversible.

Because of these useful properties, Tectin^TM is under development for the treatment of moderate to severe cancer pain that is not relieved by current pain medications.

Status of Tectin^TM in Canada

Tectin^TM is currently an investigational drug in Canada. An investigational drug is a compound which has not yet been approved for marketing by Health Canada. The product is being tested in the treatment of moderate to severe cancer pain in patients who did not respond to standard treatment with other painkillers.

Possible Side Effects Associated With Tectin^TM Treatment

Until now, the side effects (unwanted effects) observed with Tectin^TM have been mild to moderate in nature. The most common side effects reported were numbness or tingling of the lips, tongue and, less often, fingers and toes. These effects usually disappeared without intervention within two hours. Nausea and vomiting have also been reported.

 

The Unmet Medical Needs Addressed By Tectin^TM

At present the management of severe cancer pain generally includes morphine and other opiate therapy (meperidine for example). Treatment with this type of medication can often cause important side effects, and is not always effective. It is estimated that in hospitalized patients with advanced cancer, nearly 80% experience pain, with 46% having severe pain in spite of their pain-relieving treatment. Moreover, the actual treatment of cancer can itself cause difficult-to-treat pain. This condition, called chemotherapy-induced peripheral neuropathy, is frequently disabling and occurs in about half of patients receiving such treatment.

The current pain relief treatment thus remains unsatisfactory for many patients.

Tectin^TM is therefore being developed to fill the need for an effective analgesic (painkiller) that is much better tolerated than current drugs , causes less addiction, and shows no cross tolerance (i.e. decreased effectiveness) with morphine for the relief of uncontrolled moderate or severe cancer-related pain.

Tetrodotoxin: Clinical Experience

Early tetrodotoxin clinical research was performed in China in approximately 2,000 patients. Among the many patients studied a sample of 11 patients with advanced cancer and continuing pain in spite of painkillers, received tetrodotoxin for 3 days. Patients reported pain relief within 5-30 minutes and the effect lasted 20 to 30 days.

Two Canadian safety studies (also called Phase I studies) were performed in healthy volunteers to assess the safety of Tectin^TM administered by intramuscular injection. The results showed that the product is well tolerated. The most common side effects reported by the subjects were numbness and tingling particularly in the lips and tongue, and to a lesser degree in the fingers and toes. These side effects disappeared within 2 hours. The information from a second study confirmed that administration of tetrodotoxin by subcutaneous injection (injection under the skin) has an effect similar to that achieved when it is injected into a muscle.

Two early stage studies (also called Phase II studies) were conducted in cancer patients with insufficiently controlled pain. In the first study, 24 patients received Tectin^TM. Fifty-five percent (55%) of patients experienced pain relief and 71% of patients benefited from their tetrodotoxin treatment. This study indicated that tetrodotoxin was effective and well tolerated. The product was further assessed in 73 patients with cancer pain in spite of best available treatment. The patients were assigned at random (like tossing a coin) either to tetrodotoxin or to a placebo (an inactive substance). The study showed that, although there were more pain relief responders (pain relief is also known as the “study endpoint”) in the Tectin^TM treated group, the difference between the two groups of the study was not statistically meaningful. Thus, although the information obtained suggested that tetrodotoxin was somewhat effective, the trial was stopped because results were not conclusive. This indicated the need to perform further studies.

Preliminary results from a long-term study indicate that the pain relief seen with Tetrodotoxin with repeated cycles of 4-day treatment is maintained (treatment up to 400 days) and that no tolerance (i.e. no decrease in effectiveness with time) is seen.

Ongoing Clinical Study

Further to the above results, a more definitive study (also called a Phase III study) of Tectin^TM has been started and is currently ongoing. This study (TEC-006) is entitled :

A multicentre, randomized, double-blind, placebo-controlled parallel design trial of the efficacy and safety of subcutaneous tetrodotoxin (Tectin^TM) for moderate to severe inadequately controlled cancer-related pain

The study aims to determine the safety and effectiveness of Tectin^TM in relieving pain and improving quality of life. In addition, the time to the start of the pain relief and its duration will be studied and also whether Tectin^TM helps in reducing the use of other painkiller medications. Physical and emotional functioning of patients will also be measured.

One-hundred and twenty (120) cancer patients with moderate to severe pain insufficiently relieved by their current painkiller treatment will be assigned at random (like tossing a coin) to either the Tectin^TM group or to the placebo (an inactive substance) group. Tectin^TM (or placebo) will be injected under the skin at a dose of 30 micrograms (a microgram is equal to one-millionth of a gram). This will be done twice daily for 4 days. The patients will be evaluated and followed for at least 15 days or more until pain returns.

At the end of the study, each patient will have the opportunity of receiving additional tetrodotoxin (active medication only), with the agreement of their doctor.

Other Studies

A major problem which limits the dose of chemotherapy that can be given to cancer patients is the occurrence of chemotherapy-induced peripheral neuropathy. This often causes patients to experience numbness, tingling or burning sensations beginning in the extremities. Symptoms can be extremely painful or disabling, causing significant loss of function and quality of life. There are few effective treatments for this chemotherapy-related pain.

Animal tests conducted with tetrodotoxin indicate that it may be effective medication in chemotherapy-induced pain. Due to this unmet medical need, an additional Canadian study with Tectin^TM is in the planning stages and will be initiated soon. This study (TEC-007) is entitled:

A multicentre, randomized, double-blind, placebo-controlled Phase IIa clinical study of tetrodotoxin (Tectin^TM) in the treatment of moderate to severe neuropathic pain caused by chemotherapy in patients with cancer

The study aims to determine the safety and effectiveness of Tectin^TM in patients with neuropathic pain caused by chemotherapy. In addition, the time to the start and the duration of the pain relief; whether Tectin^TM helps in reducing the use of other painkillers and whether Tectin^TM helps in reducing symptoms, other than pain, will also be studied.

Other Indications

WEX is currently focusing its efforts on the development of Tectin^TM for cancer pain. However the Company is also producing pre-clinical and clinical information on other possible clinical uses for Tectin^TM. Appropriate clinical studies for these other indications will be considered in due course.

 

Donna Shum

(604) 676-7896

donnas@wexpharma.com