Great hopes for schizophrenics

About Prof. Avraham Nodelman's research in developing a new drug for schizophrenia

Schizophrenia (shesat in Hebrew) is a common psychiatric disease (affecting about 1% of the population), characterized by psychotic symptoms, thought disorders, hallucinations and mental breakdown. It is customary to divide the symptoms of the disease into "positive" and "negative". The "positive" symptoms (in the sense of an addition to the behavior considered normal) are auditory hallucinations, paranoid delusions and more. In contrast, symptoms such as complete indifference, lack of contact with the environment, and lack of emotional adjustment to what is happening are called "negative symptoms".

Various theories have been proposed to explain the development of the disease. Supporters of the developmental theory claim that the disease is related to some defect during pregnancy. This hypothesis is mainly based on epidemiological studies, in which a connection was discovered between problems such as viral infection or extreme stress of the mother during pregnancy and between the chances of the fetus suffering from schizophrenia in the future.
In contrast to existing drugs of the first and second generation, it was found that the drug improves the cognitive abilities of the patients and even restores abilities such as memory, organized thought and the ability to listen

A second theory, the dopaminergic theory, holds that schizophrenia is related to an excess of the neurotransmitter dopamine. This theory is supported, among other things, by studies that have shown that substances used as dopamine D2 receptor blockers are effective as antipsychotics. Thus, substances from the phenothiazine family, which initially were mainly used to treat allergies, were discovered in the sixties of the last century to have anti-schizophrenic properties.

Before these drugs were put into use, those who were defined as schizophrenic were admitted to a mental hospital and treated with electric shocks, insulin injections and other harsh methods. Drugs from the phenothiazine family, known as first-generation drugs or "typical drugs", caused a change in relation to schizophrenia patients and reduced hospitalization rates in mental hospitals. However, shortly after, the side effects began to appear: convulsions, tremors, muscle stiffness and involuntary movements similar to Parkinson's disease (characterized by a lack of dopamine).

Another theory, the serotonergic theory, holds that disturbances in the neurotransmitter serotonin (5-HT) are the cause of the disease. In the XNUMXs, new generation drugs began to appear, called "A-Typical drugs", which affect the serotonin receptor. It has been proven that even these drugs have serious side effects - weight gain, diabetes, sexual dysfunction and more.

Crossing the barrier

Another theory holds that the combination of an excess of dopamine with the deficiency of the inhibitory neurotransmitter, Gamma-Aminobutyric Acid known as GABA, is what causes the severe symptoms of schizophrenia. In the post-mortem analyzes of schizophrenics, a significant decrease of the GABA-secreting nerve cells was found. Developing a drug based on this theory encountered a barrier called the blood-brain barrier. This barrier is a membrane structure that selectively separates the blood fluid from the cerebrospinal fluid (CSF) and is important for protecting the brain from pollutants and other harmful factors. Many substances, especially hydrophilic substances (soluble in water) such as the substance GABA, cannot cross the barrier and pass from the blood to the brain, where they are supposed to act.

Prof. Avraham Nodelman, founder of the Medicinal Chemistry major at Bar-Ilan University, in collaboration with Dr. Ada Rafali, Dr. Irit Gilad and Prof. Avraham Weizman from Tel Aviv University and the Felsenstein Institute, is leading the development of a drug that aims to overcome the blood-brain barrier and is intended for treatment in schizophrenia patients.

The researchers' idea was to connect GABA to an existing drug for schizophrenia, which is known for its ability to cross the blood-brain barrier. Prof. Nodelman chose perphenazine (a first-generation drug) because connecting to it is chemically possible, with the goal that it will serve as a carrier for the GABA molecule and inject it into the brain.

"When developing a drug like this, there are many questions," explains Prof. Nodelman, "Will the drug survive and not break down in the blood? Will the connection between the two substances actually succeed in overcoming the blood-brain barrier? After that, will the two components of the drug act synergistically in the brain, and what is the activity of the molecule as a whole?"

At this point, Prof. Nodelman and his colleagues contacted the pharmaceutical company Bioline Rx in Israel, who helped finance the research. The new drug was called BL-1020 and experiments began in rats in order to test the hopes placed on the new substance.

First and foremost, it was necessary to prove that the GABA component indeed succeeds in penetrating the brain when it is connected to the tested carrier. To this end, the researchers used radioactively labeled BL-1020 and looked for the labeled substance in the rats' brains. The results showed that the BL-1020 penetrates the brain intact.

Later, the researchers were interested in testing the difference between the side effects of paraphenazine alone and the side effects of the new drug. The researchers stood the rats on their hind limbs and placed their front limbs on a flat pole raised about five cm above the surface they were standing on. This position of the rat reminds of a pianist and therefore the experiment was called the "piano experiment". When paraphenazine was given orally to rats, they could not move their forelimbs and remained in the "pianist" position. On the other hand, in the rats that received the new material there was no hindrance to the movement of the limbs and the rats returned to standing on the straight surface.

This experiment proved that the new substance does not cause the side effects typical of treatment with paraphenazine alone.

At this stage, when it has been proven that the new drug is able to reach the brain and even neutralizes the side effects of the first generation drug, the most important thing remains to be proven - that the drug is indeed effective.

Since as far as we know rats do not suffer from schizophrenia, the researchers had to find a condition that would simulate symptoms of the disease in the rat. It is known that people addicted to amphetamines or cocaine show behavior similar to that of those with schizophrenia because these substances cause, among other things, an increased secretion of dopamine or prevent the reabsorption of dopamine from the space between the nerve cells.

Thus, a rat injected with amphetamines begins to run, move its head and climb walls (in the literal sense of the phrase).

The researchers treated these behaviors as a model for schizophrenic symptoms and tested the effect of the new drug on the rats' behavior. When amphetamine was injected into the test rats they tried to climb the walls over 100 times over two hours and involuntary head movements appeared (over 400 head movements over two hours). When the researchers also injected GABA as expected there was no change in the rats' behavior, since the GABA encountered the blood-brain barrier. When the rats were given the drug paraphenazine alone they stopped climbing. In contrast, when the rats received BL-1020, both head movements and climbing attempts ceased.

For the help of humans

At this stage, after it was proven in rats that the drug does reach the brain, reduces the side effects and is even effective in reducing the symptoms characteristic of schizophrenia in the animal models, it was decided to submit an application for clinical research in humans. The clinical study began in June 2006 when in the first stage the effectiveness of the drug was not tested but only its safety. At this stage, 48 healthy volunteers participated, 12 of whom received a placebo, i.e. a dummy drug without an active substance. First, the participants received very low doses of the drug, and when these were proven to be non-toxic, the concentration was increased. At this stage it was proven that a relatively high dose of paraphenazine, which would have caused side effects if given alone, was tolerated when it was given with GABA in the new drug.

In other words, as expected only the BL-1020 molecule in its entirety does not cause the side effects typical of paraphenazine. Another experiment in healthy volunteers demonstrated the strong binding of maculacola to dopaminergic receptors similar to paraphenazine, but without the expected side effects of paraphenazine.

The second phase of the clinical study began in October 2007 and schizophrenic patients participated in it. Among other things, the purpose of this phase was to determine the safety and effectiveness as well as the desired dosage of the drug. First, different concentrations were tested in 36 patients (Phase IIa) and later the efficacy and safety of the drug was tested in 363 schizophrenia patients (Phase IIb) where each patient received treatment for six weeks. This phase ended in September 2009 and verified the hypotheses and hopes regarding the new substance: almost no side effects were seen, there were positive effects and a decrease in schizophrenic symptoms.

Moreover, it was found that the drug significantly improves the cognitive abilities of the patients. This finding is particularly important, because existing first and second generation drugs fail to restore the cognitive abilities of those affected by the disease. In other words, not only does the new drug not cause the side effects typical of existing drugs, but it also restores cognitive abilities such as memory, organized thought, the ability to speak and listen, and more. Moreover, due to the severe side effects of the first and second generation drugs, only about 40% of patients persist in the drug treatment and many of the patients end their lives.

Prof. Nodelman and his partners are very optimistic about the success of the drug. "The substance has many properties that characterize a good medicine", he explains. "It is a molecule that is easy to prepare and clean, the material is stable and non-toxic, the drug can be taken orally and since it is water soluble it can also be injected, and more."

Since the new drug is free, it seems, of serious side effects, it is hoped that the response to taking it will be higher than the response to the existing drugs and therefore it will be able to greatly help those suffering from the disease.

In a conversation with Prof. Nodelman, he tells more about the development of the drug.

How did the idea of ​​adding GABA to an existing drug to create the new drug come about?
"It has been published in the literature that among patients treated with drugs that act on the central nervous system, such as sedatives or antidepressants, the incidence of brain cancer is lower than in the general population. This is how the idea arose to add an anti-cancer agent, such as butyric acid, to a psychiatric drug to treat cancer patients. Although this direction was not successful, this led us to mention another substance, which, although it does not have anti-cancer properties, is similar in structure to butyric acid, and this is GABA. Since GABA is unable to cross the blood-brain barrier, the idea came up to connect it to an antipsychotic substance as a carrier and we chose paraphenazine, which chemically allows GABA to connect to it."

Did you register a patent for the development of the drug?
"Yes, absolutely. The patent belongs to Bar-Ilan University and Tel Aviv University. A license to use the patent was granted to Bioline Rx."

Are you recruiting more patients for the clinical study?
"I am constantly approached by people interested in participating in the clinical research. It is not yet known where the third phase of the study will take place. It is possible that there will be recruitments in Israel."

Assuming that the third phase of the clinical research will pass successfully, when is the drug expected to be released on the market?
"The drug is not expected to be marketed before 2014. Even if the trial itself will only last a few months, it takes a long time to collect all the reports, analyze the data and get approval from the Food and Drug Administration (FDA)."

Do you think that the drug may also be suitable for other psychiatric disorders, in addition to schizophrenia?
"BiolineRX predicts that the drug could be suitable for other cognitive diseases such as Alzheimer's."

Dina Volodarsky has a master's degree in life sciences from the Weizmann Institute and a bachelor's degree in life sciences from the Hebrew University.

The article was published in Galileo magazine, February 2010

On the same topic on the science website

• Bioline R.X has finished recruiting patients for phase 2B of the clinical trials
• A revolutionary drug for schizophrenia developed at Bar Ilan has successfully undergone clinical trials