Scientific breakthroughs in the past 20 years have advanced our understanding of genetics and its role in causing diseases. These breakthroughs also have ushered in a new era in which doctors can prescribe a particular therapy based on an individual's DNA.
More and more people with cystic fibrosis are benefitting from this type of personalized, or precision, medicine because of the advancement of drugs known as modulators. Each of the two U.S. Food and Drug Administration (FDA)-approved modulators -- ivacaftor (Kalydeco®) and lumacaftor/ivacaftor (Orkambi®) -- are prescribed for people with CF who have specific mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
Approximately 60 percent of people with cystic fibrosis could benefit from these CFTR modulators. But with more than 1,700 mutations of the CFTR gene, CF researchers are trying to increase the number of CFTR mutations that these drugs are approved to treat. To do that, they are working on a process called “theratyping.” Essentially, theratyping matches therapies, or medications, to specific types of mutations to allow even more people with CF to reap the benefits of CFTR modulators.
How Will Theratyping Play a Role in Personalized Medicine?
The primary goal of theratyping is to identify which mutations respond to certain CFTR modulators, thereby helping people with rare CFTR mutations gain access to already approved CFTR modulators quickly and safely.
The conventional process for determining whether a drug successfully targets a particular mutation has been through clinical trials in people with CF who have a specific mutation. Clinical trials are feasible when there are enough people with that mutation to test, but this process becomes problematic for individuals whose mutations are so rare that only a handful of other people have them in the world. (About 1,000 of the 1,700 CFTR mutations occur in fewer than five people.)
For this reason, researchers are testing CFTR modulators on cells affected by rare CFTR mutations to see if the proteins they produce show improved function. If the lab tests show positive results, drug companies could then submit these lab results to the FDA to show the drug is likely to be effective for people with these specific rare CFTR mutations.
The FDA already has demonstrated a willingness to use lab results as a factor in deciding whether to expand eligibility for an approved drug. The agency relied on a combination of lab results, clinical data, and and the drug's established safety record to expand the use of ivacaftor to people with CF who have at least one of 23 residual function mutations.
It can be difficult to determine which biological changes (called biomarkers) signal that a drug is working. Many clinical trials fail because promising lab results are not borne out in clinical trials. The challenge with theratyping is to link changes in cell function following exposure to modulators in a laboratory to actual symptom improvements in patients.
What Are Researchers Doing to Put Theratyping Into Practice?
To understand what needs to be done to implement theratyping, it helps to know more background about how scientists test drugs in the lab.
In preclinical testing -- work done before a drug is tested in clinical trials -- researchers create “models” of a patient's system by taking cell samples from different parts of the body or creating cells expressing mutant versions of CFTR. To conduct numerous tests, they put the cells into a medium where the cells divide into a group of identical cells. This cell line is then used for testing in place of an actual patient.
Researchers expose the cells to compounds or conduct other experiments to replicate what might happen in your body. They look for certain biomarkers that indicate whether a drug is working.
The Cystic Fibrosis Foundation Therapeutics Lab in Lexington, Mass., houses a collection of cells with different CF-causing mutations, including some nonsense mutations, which are used to test whether certain compounds are worth developing further into drugs. The lab's scientists also are spearheading a new initiative to collect and grow cells from other people with rare mutations. These cells will be critical for screening studies to identify new potential drugs and other treatment options for rare mutations, and they will be made available to other CF researchers to advance research. The Foundation will be collecting these cells at sites around the U.S. as part of an observational study called RARE.
In addition to this work, the Foundation has supported two observational studies -- GOAL and PROSPECT -- in which researchers are trying to match clinical changes in a patient's health after taking a CFTR modulator with changes that can be seen in cells in the lab.
In the PROSPECT study, for example, researchers have collected nasal cell samples from individuals with CF to see how these cells respond to lumacaftor/ivacaftor in the lab. Then they will compare the cellular response to the person's response in real life, to identify new biomarkers in the lab that signal positive or negative health effects. Likewise, in the GOAL study, researchers are looking at the effects of ivacaftor on people with CF and comparing them to changes observed in the lab.
The CF Foundation hopes that the findings from the GOAL and PROSPECT studies will eventually lead to tests that can help doctors select the medication that will have the most benefit for individuals. Researchers also believe these studies and others like it will lead to a greater understanding of what happens when individuals with CF take CFTR modulators and help provide insights that will lead to treatments for other CF mutations.
In the meantime, the Foundation is working with researchers on the next generation of drugs that will address other mutations as well as therapies that could help all individuals with CF regardless of their mutation.
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FDA-approved drug information is available at dailymed.nlm.nih.gov/dailymed.