development of novel drugs and targeted therapies, always with the best interests of patients in mind, Sheng said. Targeted therapies focus on treating the underlying mechanism of the disease to modify the disease course. Treatment or palliation of symptoms is also important, Sheng said, but Genentech’s philosophy is to develop disease-modifying medications. Even patients with the same basic indication for treatment can have different mechanisms of disease. To define the most appropriate population for treatment, and work toward personalized health care, more diagnostic tests that differentiate these subsets are also needed.
Although some are pessimistic about the “broken business model” of the modern pharmaceutical industry, Sheng said Genentech remains optimistic about the future of the industry. Tremendous technological advances have been made in the understanding of basic biological mechanisms. Much is known about disease pathways, which are beginning to be linked into a systems biology. Sheng anticipated that in another few decades, thousands of plausible or rational disease targets would be identified for possible drug treatment. To truly personalize health care, thousands of targets and thousands of drugs are needed.
The standard flow of drug discovery starts with a basic understanding of the mechanisms of the disease. Then drug targets are identified based on rational understanding. Those targets are “druggable,” meaning they can be attacked by small molecules, proteins, antibodies, or maybe in the future, gene therapy with small interfering RNAs. Differentiated molecular medicines are then developed to attack these targets, tailored to the groups for which they are most effective.
Sex difference is one obvious way to describe subgroups of a patient population. Another is genetic groups, which are independent of sex. Race and age also have significant effects on disease. In general, Sheng said, drug development in neuroscience is at a disadvantage because the basic workings of the brain and its disease mechanisms are still poorly understood.
Sex differences can provide information about disease mechanisms and clues about why people contract a disease. Sex differences also affect the quality of animal disease models, and should guide choices of animal models. Most importantly, from a treatment point of view, sex can affect how a drug is metabolized and how well the patient responds to the drug.
How should sex differences be considered during drug development? One could analyze sex differences in a “blanket fashion.” This means covering sex differences at a purely descriptive level, with no hypothesis, regardless of the amount of labor or time expended and without thinking about the cost. This would entail including equal numbers of males and females