Vertex Announces FDA-Approval of New Triple Drug Compound Effective for the Most Common Mutation in Cystic Fibrosis

Vertex Announces FDA-Approval of New Triple Drug Compound Effective for the Most Common Mutation in Cystic Fibrosis

Yesterday, the CF Foundation and Vertex announced that the FDA had approved a triple-drug compound that is designed to be effective for the most common—and most severe—mutation in cystic fibrosis (CF). The new drug, Trikafta, joins the original CF modulator drug (ivacaftor, aka ‘Kalydeco’) and the double drug (ivacaftor and lumacaftor, aka ‘Orkambi’) in the arsenal of drugs designed to treat the underlying defect in CF, rather than just symptoms. With the addition of Trikafta, there are now treatment options for the majority of individuals with CF.

Collectively, these drugs are known as small molecule compounds. They act at the molecular level to alter the effects of a genetic defect. They do not edit or impact the genetic information that causes CF, but they give the cell new instructions that can help it to override the bad instructions caused by specific genetic defects.

Small molecule compounds target and attempt to correct specific genetically-based defects. For this reason, they are much more effective for the targeted genes/mutations for which it was designed. In the case of the CF small molecule drugs, the first one, ivacaftor, was specifically designed for one known type of mutation on the CF gene. It is very effective for this mutation, but the mutation only impacts 4% of the CF population. Ivacaftor was also somewhat effective for similar mutations, but it was not as effective for other types of mutation. That is why Vertex started working on combo drugs for more common mutations in CF. With the addition of Trikafta, most individuals with CF now have a small molecule treatment option.

What Does this Mean for PCD?

The genetic defects that cause PCD are not related to the genetic defects that cause CF. They are entirely genetically distinct disorders that both result in genetic defects of mucociliary clearance. The end result may be similar, but the pathway to it is distinct.

CF involves a single gene, called CFTR, with multiple types of mutations on that single gene. By carefully studying and understanding what each of these mutations do (a process that is still ongoing and has been since 1989), the CF Foundation was able to classify mutation type and then start looking for therapeutic solutions. This is why gene research is so critical in disorders like PCD and CF. It is not just useful for diagnosis. Understanding your genetics will also be important for therapeutic options in the future.

In contrast, there are more than 44 genes involved in PCD, many of them much larger than CFTR and each with multiple mutations. Like in CF, these mutations cause different defects and require different solutions. We are in the process of identifying and categorizing PCD genetic defects to help find therapeutic targets for them. This is a significantly bigger project in PCD than in CF, however, technological advances are moving this discovery phase in PCD along at a much faster pace than the early efforts in CF.

Because drugs like Trikafta are designed for specific genetic defects in CF, their effectiveness in PCD is unknown, but is believed to be limited. Only one of these agents, ivacaftor, has been studied in conjunction with another drug (the Parion CLEAN-PCD study) in PCD and it was studied in a very, very small patient group. The results of that study have not yet been published.

These drugs are also very, very expensive, ranging from $250,000 to $311,000 per person, per year. For insurance companies to justify that expense, they need to make a significant impact on health and quality of life. As these drugs are ‘designer’ drugs for specific mutations, they are much more effective for the specific application for which they were designed. This is why there are multiple drugs for CF now, not just one. Even if they have some impact in other mutations or other disorders, the cost may not be justifiable for the level of improvement seen.

It is also important to remember that every therapy carries some risk. Sometimes the risk is very small, and it is easy to do a risk/benefit analysis. Sometimes the risk/benefit analysis is less clear.

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