The Genome

FDA Approves New Breakthrough Medication for Cystic Fibrosis

SUMMARY:

The FDA has approved a new triple therapy medication (elexacaftor/ ivacaftor/ tezacaftor) for patients with the most common cystic fibrosis (CF) mutation (approximately 90% of the CF population). The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Due to potential benefit to the CF community, the application was reviewed and approved approximately three months prior to the planned review date.

The medication is approved for the following individuals with CF
- ≥12 years
- At least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene

Drug Mechanism of Action

With significant mutations such as F508del mutation, the CFTR protein undergoes two ‘hits’
- Improper folding leading to entrapment in endoplasmic reticulum
- Protein that does reach cell membrane does not become activated (i.e. fails to function correctly)
The drugs developed to treat CF are protein modulators
- Correctors (elexacaftor and tezacaftor): Drugs that correct CFTR protein folding
- Potentiator (ivacaftor): Activate function of the abnormal protein channel at the cell surface

KEY POINTS:

Literature Review (see ‘Learn More – Primary Sources’ below)

Heijerman et al., Lancet 2019 (n=107)

Methods: Double-blind RCT (4 weeks) | homozygous for F508del
- Elexacaftor plus tezacaftor plus ivacaftor or
- Tezacaftor plus ivacaftor for 4 weeks
Primary outcome: Absolute change from baseline in percent predicted forced expiratory volume in one second (ppFEV 1)
Results
- Primary outcome: Triple drug group had improved ppFEV 1 | Treatment difference 10.0% (95% CI, 7.4 to 12.6, p<0.0001)
- Secondary outcomes: Triple drug group also demonstrated improvement related to the following
  - Quality of life (Cystic Fibrosis Questionnaire)
  - Decreased sweat chloride concentration

Middleton et al., NEJM 2019 (n=403)

Methods: Double-blind RCT (24 weeks) | F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacaftor alone
Primary outcome: Absolute change from baseline in ppFEV 1
Results
- Primary outcome: Triple drug group had improved ppFEV 1 | Treatment difference 13.8% (95% CI, 12.1, 15.4; P<0.0001)
- Other outcome improvements
  - Reduction in rate of pulmonary exacerbations
  - Decreased sweat chloride concentration
  - Increase in BMI
Safety profile
- Similar between the groups
- Many adverse events related to CF rather than medication effects
- Rash and flu were more frequent in patients on triple therapy
- Most common adverse drug reactions included
  - Headaches | upper respiratory tract infections | Abdominal pains | Diarrhea, rashes, increased liver enzymes (ALT and AST)
- The prescribing information for triple medication includes warnings related to
  - Elevated LFTs (transaminases and bilirubin) | Use at the same time with other products that are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A) | Risk of cataracts