Targaceuticals Point Way To Developing Safer Drugs

Targeceuticals, in theory, are rather simple chemically yet quite elegant molecules. Protarga creates a targaceutical by joining a known pharmaceutical agent to a fatty acid lipid vector that is taken up by the cells being targeted for treatment. The result is directed delivery of the pharmaceutical agent, which should provide greater therapeutic effectiveness and a better safety profile. The process is chemically easy, requiring only one step, and usually cost-effective with generally high yields of the targaceutical.

The company uses the fatty acid docosahexaenoic acid (DHA) as its lipid vector. DHA is a naturally occurring essential fatty acid, necessary for human tissue growth and development. Most of the DHA that human tissues need is obtained through dietary intake.

In developing anticancer agents, DHA works well because tumor cells avidly accumulate fatty acids to fuel their swift, unregulated growth. By attaching an anticancer drug to DHA, tumor cells receive large amounts of the pharmaceutical agent as they absorb the fatty acid to grow. Normal cells, which grow at a much slower rate, do not take up a significant amount of the targaceutical, reducing side effects of the chemotherapy.

DHA also works well for pharmaceutical agents intended to treat neurological disorders because it plays a significant role in neurological tissues. It is vigorously transported into the central nervous system and accounts for a high proportion of the total fatty acid content of neurons, including both nerve terminals and synapses.

DHA comprises approximately 22 percent of the total fatty acid content of the cortical gray matter, 16 percent in the hippocampus, and in lower proportions in white matter and in some subcortical regions. The brain is almost completely dependent on exogenous intake of DHA.

Bradley and his colleagues at Protarga and Harvard hypothesized that by linking the known atypical antipsychotic clozapine to DHA, they could increase the effectiveness of the clozapine by targeting its effects to the brain and at the same time reduce the peripheral activity of the drug while it is linked to DHA as it circulates through the bloodstream.

So far DHA-clozapine has been studied only in animal models. The Protarga-Harvard collaboration’s most recent results were detailed in a report in the February Neuropsychopharmacology with Ross J. Baldessarini, M.D., a professor of psychiatry at Harvard University, as the lead author.

In rats, DHA-clozapine, which Protarga has given the trade name Clozaprexin, is a long-acting central depressant that appears to have powerful and prolonged antidopaminergic activity after both oral and parenteral administration.

“Our data tend to indicate that Clozaprexin is essentially inactive until it is cleaved back into free clozapine by enzymes once it is in the brain,” Bradley told Psychiatric News. This should help to limit some of the significant peripheral side effects associated with free clozapine circulating in the bloodstream, such as low blood pressure, weight gain, new-onset insulin-resistant diabetes, and bone marrow toxicity.

Bradley explained that once the drug candidate is in the brain, there are somewhat lower levels of total free clozapine (the drug’s Cmax, which is the peak or highest concentration of the drug in the tissue following a dose) than would be expected from administering straight clozapine; however, the behavioral activity appears to be much higher, as measured in the group’s animal studies by monitoring movement and arousal, as well as response to a direct central dopamine agonist, apomorphine.

Because many of clozapine’s centrally mediated side effects, such as excessive sedation and epileptic seizures, are thought to be directly related to the drug’s Cmax rather than steady state levels, Bradley said that it is highly likely that DHA-clozapine will not only have “markedly reduced peripheral side effects, but potentially fewer central adverse effects as well.”

Bradley cautioned that the research has a long way to go, and “as for centrally mediated side effects, that’s really still up in the air—only the clinical trials will tell us that.”

In the animal studies, DHA-clozapine proved to be 10 times more potent than clozapine and much longer acting, with substantial effects still apparent at 24 hours after administration. Moreover, Bradley said, DHA-clozapine produced even weaker cataleptic effects than clozapine.

Carol Tamminga, M.D., a professor of psychiatry at the Maryland Psychiatric Research Center at the University of Maryland in Baltimore, reviewed the research for Psychiatric News. Tamminga, who is also a member of the American Journal of Psychiatry Editorial Board, thinks these admittedly preliminary results look promising.

“Anything we could do to make clozapine safer would be a very significant advance,” Tamminga said. “And although the DHA-clozapine combination is a long way from being available to prescribe to patients, the early data look good.”

Tamminga, who specializes in psychopharmacological interventions and is an expert in the field of schizophrenia, noted that clozapine is virtually unique in its superior effectiveness, including treatment for otherwise medication-refractory patients. In particular, she said, the drug is notable for its statistically significant ability to limit suicidal risk in this population. However, it is typically relegated to second-tier status because of its potentially severe adverse events.

“Clozapine can be very effective in treating the symptoms of schizophrenia,” Tamminga said, “making it an obvious target for [Protarga] to attempt to reconfigure in order to reduce the potential for serious adverse events. If they are successful at both increasing efficacy and reducing the side-effect profile, patients will gain a valid additional option for treatment.”

Protarga is now forming a clinical advisory board to support an Investigational New Drug Application with the FDA that, if approved, would allow clinical trials in humans.