Incremental Innovation in the Development of Biopharmaceuticals Part 2

Incremental Innovation in the Development of Biopharmaceuticals Part 2

04.04.13 | By Jennifer Wall

Eric A. Utt, Ph.D., Director, Worldwide Policy for Pfizer, wraps up the second of a two-part series on incremental innovation. During the 1940s and 1950s, tuberculosis patients were housed in sanitariums, frequently alongside patients who had been institutionalized with various mental illnesses. At this time, mental disorders such as schizophrenia and depression were not accessible to effective drug treatments. In an attempt to improve the anti-tuberculosis effects of isoniazid, Roche scientists synthesized a related compound, iproniazid. Clinicians treating tuberculosis patients in sanitariums reported unexpected side effects. In tuberculosis patients treated with iproniazid, the drug not only showed anti-tuberculosis activity, but also caused euphoria and psycho stimulation. In fact, the drug was intentionally used off label to improve the depressed mood of chronically ill patients with tuberculosis. Researchers at Northwestern University followed up on this observation, demonstrating that iproniazid is a potent inhibitor of a class of enzymes in the body called monoamine oxidases. In addition, N. S. Kline, J. C. Saunders, and M. Loomer were interested in the biochemical and pharmacological actions of iproniazid in animals and its clinical side effects in tuberculosis patients. They designed an open clinical trial with iproniazid. In the study, patients who had been institutionalized for an average of 20 years with stable depression were chosen at random, without regard for the particular underlying diagnoses. After several weeks of treatment with iproniazid, roughly 70% of the patients were reported to show significant improvement in their depression symptoms. Numerous follow up studies confirmed those findings. That is the how and the why behind iproniazid (trade name Marsilid) becoming the world's first modern antidepressant. With the discovery of monoamine oxidases (MOAs) and their inhibitors (MOAIs) altered the theory of depression as a mental illness. MOAs were shown to be involved in the metabolism of several neurotransmitters, including serotonin. That discovery gave way to the biochemical basis for depression upon which the development of modern selective serotonin reuptake inhibitors, or SSRIs, is based. While important for the many reasons cited above, MOAIs like Marsilid were associated with severe, often intolerable side effects. This resulted in the search for new compounds that were similarly efficacious, but had a better side effect profile. Today, we have a whole host of related medicines that perform outstandingly against depression with reduced side effects. This important development began with the discovery of antibiotic activity in a previously unexamined chemical compound, isoniazid, back in 1912. This is the way of science, and of scientists. One simply does not "order up" a new medicine. We build upon seemingly minor discoveries and observations until they converge to lead up to new approaches and new conclusions about disease biology and its treatment. This is why it is so vital that society supports science, including educating the next generation of scientists, funding academic research and teaching institutions, encouraging biotechnology pioneers, and developing a robust commercial enterprise to translate scientific discoveries into useful products. We don't know where the next new medicine will come from, but we do know that without the process of incremental innovation, there will be no new discoveries that lead to the next wave of life-saving and life-changing medicines.


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