Biochemistry pharm – Cystic fibrosis drugs

Note to students: this CF pharm module is no longer required for the pass/fail Step 1. I originally created it during the numerical Step 1 era. So my options are: take down the module, or just keep it up (as I’ve clearly done) for those of you who like the extra pharm, but I’m letting you know this specific module isn’t mandatory anymore.

A 6-year-old Caucasian boy with a history of recurrent respiratory infections, failure to thrive, and failure to pass meconium for 72 hours after birth has genotyping performed in order to be considered for a novel treatment for his condition. Gene sequencing shows a G551D mutation in the CFTR gene, in which glycine (G) in position 551 is replaced with aspartic acid (D). He does not carry a Phe508del (ΔF508; deletion of phenylalanine at position 508) mutation. Which of the following agent(s) may be used in this patient as a result of these findings?

Dornase-alfa

Guaifenesin

Ivacaftor

Lumacaftor + Ivacaftor

Elexacaftor + Ivacaftor + Tezacaftor

—

This patient has cystic fibrosis (CF), an autosomal recessive disorder on chromosome 7 caused by a defective chloride channel.¹

CF is characterized by chronic bacterial respiratory infections, fat malabsorption secondary to exocrine pancrease insufficiency, infertility in males due to congenital bilateral absence of the vas deferens (CBAVD), and elevated concentrations of chloride in sweat.^{2, 3}

Ivacaftor^4,^{5, 6, 7}

One type of mutation responsible for CF, the G551D missense mutation, leads to a glycine that is replaced by an aspartic acid at position 551.
This enables the cystic fibrosis transmembrane regulator (CFTR) channel to make it to the cell surface, in contrast to sequestration in the RER/cytosol. The CFTR channel is still defective; it’s just merely at the correct location on the cell surface.
Ivacaftor is a CFTR modulator/potentiator that binds to this misfolded channel and increases the probability it will open.
Ivacaftor is approved for use in patients >6 yrs of age with at least one copy of the G551D-CFTR mutation.

Lumacaftor/ivacaftor^{8, 9}

Approved for the treatment of CF in patients who are homozygous for the Phe508del (ΔF508) mutation.
Lumacaftor works by increasing the trafficking of CFTR proteins to the cell surface. Ivacaftor works by enabling the opening of what would otherwise be a dysfunctional chloride channel.⁸

Elexacaftor/ivacaftor/tezacaftor^{10, 11, 12, 13, 14}

Approved by the US FDA for the treatment of cystic fibrosis in patients age ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene.^{10, 12}
Tezacaftor and elexacaftor are similar to lumacaftor. They are known as “correctors” and help traffic the defective CFTR channel to the cell surface.^{11, 13, 14}

Dornase-alfa is a recombinant deoxyribonuclease used in the treatment of CF. It functions as a mucolytic.^{15, 16}

Guaifenesin is an over-the-counter mucous expectorant that may be used in CF, although there is no evidence that it is effective for any form of lung disease.¹⁷

Bottom line: Ivacaftor is approved as a monotherapy CFTR potentiator in patients with at least one G551D mutation. This mutation leads to the misfolded CFTR channel making it to the cell surface instead of sequestration in the RER. Lumacaftor/ivacaftor and elexacaftor/ivacaftor/tezacaftor are combination therapies used in patients with the ΔF508 mutation. Elexacaftor is a potentiator similar to ivacaftor. Lumacaftor and tezacaftor are CFTR correctors that facilitate the trafficking of the channel to the cell surface.

1) https://ghr.nlm.nih.gov/gene/CFTR

2) https://www.ncbi.nlm.nih.gov/books/NBK546620/

3) https://www.nejm.org/doi/10.1056/NEJMe020070

4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626070/

5) https://err.ersjournals.com/content/22/127/66

6) https://www.ncbi.nlm.nih.gov/pubmed/24656117

7) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272825/

8) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650604/

9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495103/

10) https://www.ncbi.nlm.nih.gov/m/pubmed/31784874/

11) https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32597-8

12) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768901/