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The first step in treating any disease is to clarify how the disease is caused. Many questions must be answered to arrive at an understanding of what is needed to pursue new types of treatments.
In modern labs, sophisticated tools are used for shedding light on these questions. The tools are designed to uncover the molecular roots of disease and pinpoint critical differences between healthy cells and diseased cells. Researchers often use multiple approaches to create a detailed picture of the disease process. Once the picture starts to emerge, it can still take years to learn which of the changes linked to a disease are most important. Is the change the result of the disease, or is the disease the result of the change? By determining which molecular defects are really behind a disease, scientists can identify the best targets for new medicines. In some cases, the best target for the disease may already be addressed by an existing medicine, and the aim would be to develop a new drug that offers other advantages. Often, though, drug discovery aims to provide an entirely new type of therapy by pursuing a novel target.
The following tools help researchers gain insights into how disease develops:
By growing both diseased and healthy cells in cell cultures, researchers can study differences in cellular processes and protein expression.
Genes and proteins found in humans may also be found in other species. The functions of many human genes have been revealed by studying parallel genes in other organisms.
The scientific community generates huge volumes of biological data daily. Bioinformatics helps organize that data to form a clearer picture of the activity of normal and diseased cells.
These are substances, often proteins, that can be used for measuring a biological function, identifying a disease process, or determining responses to a therapy. They also can be used for diagnosis, for prognosis, and for guiding treatment.
Proteomics is the study of protein activity within a given cell, tissue or organism. Changes in protein activity can shed light on the disease process and the impact of medicines under study.
The term target refers to the specific molecule in the body that a medicine is designed to affect. For example, antibiotics target specific proteins that are not found in humans but are critical to the survival of bacteria. Many cholesterol drugs target enzymes that the body uses to make cholesterol.
Scientists estimate there are about 8,000 therapeutic targets that might provide a basis for new medicines. Most are proteins of various types, including enzymes, growth factors, cell receptors, and cell-signaling molecules. Some targets are present in excess during disease, so the goal is to block their activity. This can be done by a medicine that binds to the target to prevent it from interacting with other molecules in the body. In other cases, the target protein is deficient or missing, and the goal is to enhance or replace it in order to restore healthy function. Biotechnology has made it possible to create therapies that are similar or identical to the complex molecules the body relies on to remain healthy.
The amazing complexity of human biology makes it a challenge to choose good targets. It can take many years of research and clinical trials to learn that a new target won’t provide the desired results. To reduce that risk, scientists try to prove the value of targets through research experiments that show the target’s role in the disease process. The goal is to show that the activity of the target is driving the course of the disease.
Once the target has been set, the next step is to identify a drug that impacts the target in the desired way. If researchers decide to use a chemical compound, a technology called drug screening is typically used. With automated systems, scientists can rapidly test thousands of compounds to see which ones interfere with the target’s activity. Potent compounds can be put through added tests to find a lead compound with the best potential to become a drug.
In contrast, biologics are designed using genetic engineering. If the goal is to provide a missing or deficient protein, the gene for that protein is used for making a recombinant version of the protein to give to patients. If the goal is to block the target protein with an antibody, one common approach is to expose transgenic mice to the target so as to induce their immune systems to make antibodies to that protein. The cells that produce these specific antibodies are then extracted and manipulated to create a new cell line. The mice used in this process are genetically modified to make human antibodies, which reduces the risk of immune responses in patients.
Once a promising test drug has been identified, it must go through extensive testing before it can be studied in humans. Many drug safety studies are performed using cell lines engineered to express the genes that are often responsible for side effects. Cell line models have decreased the number of animals needed for testing and have helped accelerate the drug development process. Some animal tests are still required to ensure that the drug doesn’t interfere with the complex biological functions that are found only in higher life-forms.
If a test drug has no serious safety issues in preclinical studies, researchers can ask for regulatory permission to do clinical trials in humans. There are three phases of clinical research, and a drug must meet success criteria at each phase before moving on to the next one.
Tests in 20 to 80 healthy volunteers and, sometimes, patients. The main goals are to assess safety and tolerability and explore how the drug behaves in the body (how long it stays in the body, how much of the drug reaches its target, etc.).
Studies in about 100 to 300 patients. The goals are to evaluate whether the drug appears effective, to further explore its safety, and to determine the best dose.
Large studies involving 500 to 5,000 or more patients, depending on the disease and the study design. Very large trials are often needed to determine whether a drug can prevent bad health outcomes. The goal is to compare the effectiveness, safety, and tolerability of the test drug with another drug or a placebo.
If the test drug shows clear benefits and acceptable risks in phase 3, the company can file an application requesting regulatory approval to market the drug. In the United States, the Food and Drug Administration evaluates new medicines. In the European Union, the European Medicines Agency manages that responsibility. Regulators review data from all studies and decide whether the medicine’s benefits outweigh any risks it may have. If the medicine is approved, regulators may still require a plan to reduce any risk to patients. A plan to monitor side effects in patients is also required.
A company can continue doing clinical trials on an approved medicine to see if it works under other specific conditions or in other groups of patients, and additional trials may also be required by regulatory agencies. These are known as phase 4 studies.
The whole drug development process takes 10 to 15 years to complete on average. Very few test drugs are able to clear all the hurdles along the way.
A key early decision in drug discovery is whether to pursue a target by using a small-molecule chemical compound or a large-molecule biologic. Each has its advantages and disadvantages.
Small molecules can be designed to cross cell membranes and enter cells, so they can be used for targets inside cells. Some may also cross the blood-brain barrier to treat psychiatric illness and other brain diseases. Biologics usually cannot cross cell membranes or enter the brain. Their use is largely restricted to targets that sit on the cell surface or circulate outside the cell.
Small molecules often have good specificity for their targets, but therapeutic antibodies tend to have extremely high specificity. Most large molecules stay in the body longer, resulting in the need for less frequent dosing.
