Treat the Pathway, not the Gene (from Precision Medicine and the Reinvention of Human Disease)

Treat the key pathway, not the genetic mutation (from Precision Medicine and the Reinvention of Human Disease)

Some of the earliest and most successful Precision Medication drugs have targeted specific mutations occurring in specific subsets of diseases. One such example is ivacaftor, which targets the G551D mutation present in about 4% of individuals with cystic fibrosis [135]. It is seldom wise to argue with success, but it must be mentioned that the cost of developing a new drug is about $5 billion [136]. To provide some perspective, $5 billion exceeds the total gross national product of many countries, including Sierra Leone, Swaziland, Suriname, Guyana, Liberia, and the Central African Republic. Many factors contribute to the development costs, but the most significant is the incredibly high failure rate of candidate drugs. About 95% of the experimental medicines that are studied in humans fail to be both effective and safe. The costs of drug development are reflected in the rising costs of drugs.

When a new drug is marketed to a very small population of affected individuals, the cost of treating an individual may be astronomical. Americans should not pin their hopes on the belief that one day, the FDA or CMS (which administrates Medicare) will step in and put a stop to the price rises. The Food and Drug Administration can approve or reject drugs, but it does not regulate prices. Likewise, Medicare is not permitted to consider cost when it decides whether a treatment can be covered. Knowing this, some notable pharmaceutical companies have raised the prices of medications far beyond their manufacturing costs [137–139]. In effect, the cost of curing curable diseases may exceed our ability to pay for those cures [139].

It is strongly in the interests of society to develop drugs that have the widest possible user market [140]. Drugs that target a mutation that is specific for a few individuals with a rare disease, or a tiny subpopulation of individuals who have a common disease, are highly problematic.

Our experiences with disease convergence teach us that clinical phenotypes are influenced by the activities of pathways and are seldom restricted to a specific mutation in a specific gene. We know this because rare diseases that exhibit locus heterogeneity affect different genes, but often target the same pathway. Likewise, acquired phenotypes of genetic diseases often involve inhibitors of the same key pathways that drive their genetic counterparts, without involving the protein product of the genetic form of the disease. We also know that the acquired version of most genetic diseases account for the bulk of disease occurrences. Therefore, if we want to develop treatments that benefit the greatest number of individuals affected by a disease, it would be far more practical to find treatments that target the disease-driving pathways than to design drugs that target a specific gene mutation involved in a small subset of affected patients.

Before closing, here are a few points worth considering (to be discussed in later blogs):

• As a generalization, any drug that can block a pathway, without producing serious side effects, may serve as a candidate treatment for all of the diseases that are driven by the pathway.

• Individuals in the early stages of common diseases, before multiple disease pathways converge to produce an intractable clinical phenotype, may be particularly amenable to treatments that interfere with the pathways that promote the ensuing steps in pathogenesis.

The topic of clinical trials designed to test drugs targeting convergent disease pathways is discussed in Precision Medicine and the Reinvention of Human Disease, Section 9.6, “Fast, Cheap, Precise Clinical Trials.”

- Jules Berman

key words: precision medicine, precision treatment, clinical trials, cost of precision medicine, pathways, convergent pathways, jules j berman Ph.D., M.D.