FDA Approvals: Breakthrough Drug for a Rare Form of Cystic Fibrosis

Clinical Context

The US Food and Drug Administration (FDA) has approved ivacaftor, the first available treatment targeting the defective cystic fibrosis transmembrane regulator (CFTR) protein implicated in the pathophysiology of CF. Specifically, ivacaftor targets the G551D mutation, in which the amino acid aspartic acid substitutes for glycine in position 551.

Ivacaftor was designated as an orphan drug because of the rarity of the G551D mutation. CF is the most common fatal genetic disease in white persons, with US prevalence of approximately 30,000. Of these, approximately 4%, or 1200 patients, have the G551D mutation.

Study Synopsis and Perspective

On January 31, the US FDA approved ivacaftor (Kalydeco, Vertex Pharmaceuticals, Inc) for patients 6 years and older who have a rare form of CF and carry the G551D mutation in the CFTR gene.
Defects in the CFTR gene are the basis of CF. In the G551D mutation, the amino acid glycine in position 551 is substituted with aspartic acid.
"Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis," said Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, in an FDA release. "This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease."
Ivacaftor was designated as an orphan drug, meaning it affects fewer than 200,000 people in the United States. The FDA's approval was granted ahead of the company's April 18, 2012, planned approval date.
CF is the most common fatal genetic disease in white persons and affects approximately 30,000 people in the United States. Approximately 4%, or 1200 people, carry the G551D mutation.
Approval was based on two 48-month placebo-controlled trials involving 213 patients with CF. One trial included patients 12 years and older; the other, patients 6 to 11 years old.
Ivacaftor is taken twice a day with fat-containing food. It is effective only in patients with CF who have the G551D mutation. The most common adverse effects are upper respiratory tract infection, headache, stomachache, rash, diarrhea, and dizziness.
"The FDA reviewed and approved Kalydeco in approximately three months under the agency's priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy," the agency said in a release announcing the drug's approval.
"Today marks an important milestone in our journey to find a cure for cystic fibrosis," said Robert J. Beall, PhD, president and CEO of the Cystic Fibrosis Foundation, in a statement. "Kalydeco addresses the underlying cause of CF, and the science behind the drug has opened exciting new doors to research and development that may eventually lead to additional therapies that will benefit more people living with CF."
"I think it is crucial that we now have a specific disease-focused rather than symptom-focused therapy for a challenging disease," Andrew F. Shorr, MD, MPH, FCCP, associate chief of the Department of Pulmonary & Critical Care Medicine at the Washington Hospital Center, and associate professor of medicine in the Department of Pulmonary & Critical Care Medicine at Georgetown University in Washington, DC, told Medscape Medical News.
"The basic science that went into the development of the [ivacaftor] molecule is fascinating; it really reflects the first fruits of tailored genetic therapy to arise since the discovery of the various mutations causing CF. Unfortunately, the molecule will only be useful in a small segment of the population. The follow-up data are limited and the initial trial small," he cautioned. "In addition, broad genotyping of the CF population to find those who might benefit from the drug will prove costly."

Dr. Shorr has spoken previously to Medscape Medical News about one of the trials that led to ivacaftor's approval ( N Engl J Med. 2011;365:1663-1672).

Warnings and Precautions
Because use of ivacaftor may be associated with elevated transaminase levels (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]), these levels should be tested before ivacaftor is started, every 3 months during the first year of treatment, and every year thereafter. Patients in whom increased transaminase levels develop should be closely monitored until the abnormalities resolve, and dosing should be interrupted in patients with ALT or AST exceeding 5 times the upper limit of normal. Once transaminase elevations resolve, clinicians should weigh the benefits and risks of restarting ivacaftor.
Coadministration of ivacaftor with strong cytochrome P450 3A4 (CYP3A) regulator potentiator inducers, such as rifampin and St. John's Wort, is not recommended, because these substances markedly reduce exposure of ivacaftor and may therefore decrease efficacy.
Overdosage
The highest single dose of ivacaftor used in a clinical study was 800 mg, administered in a solution formulation. No treatment-related adverse events were reported, nor have there been any reports of overdose with ivacaftor.
In a study of the effect of ivacaftor on electrocardiograms in healthy volunteers, the highest repeated dose was 450 mg, in a tablet formulation, every 12 hours for 4.5 days (9 doses). Adverse events seen more often with ivacaftor vs placebo included dizziness and diarrhea.
Although there is currently no specific antidote for overdose with ivacaftor, the patient should be treated with general supportive measures, including monitoring of vital signs and observation of clinical status.
Use in Special Populations
Ivacaftor is pregnancy category B, and it should be used during pregnancy only if clearly needed. There have been no adequate and well-controlled studies of ivacaftor in pregnant women.
Caution is recommended when ivacaftor is given to a breast-feeding mother, because the drug is excreted into the milk of lactating female rats, and excretion of ivacaftor into human milk is probable. To date, no human studies have assessed the effects of ivacaftor on breast-fed infants.
Two placebo-controlled clinical trials have shown the safety and efficacy of ivacaftor in patients 6 to 17 years old with CF who have a G551D mutation in the CFTR gene. The safety and efficacy of ivacaftor have not been established in patients with CF younger than 6 years.
Patients with mild hepatic impairment (Child-Pugh class A) need no dose adjustment of ivacaftor. For patients with moderate hepatic impairment (Child-Pugh class B), a reduced dose of 150 mg once daily is recommended. Although patients with severe hepatic impairment (Child-Pugh class C) have not been studied, exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, after the risks and benefit of treatment are considered, a dose of 150 mg once daily or less frequently should be used with caution in patients with severe hepatic impairment.
Ivacaftor has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. Although no dose adjustment is required for patients with mild to moderate renal impairment, caution is recommended when ivacaftor is used in patients with severe renal impairment, defined as creatinine clearance of 30 mL/minute or less or end-stage renal disease.
A double-blind, placebo-controlled trial suggests that ivacaftor is ineffective in patients with CF who are homozygous for the F508del mutation in the CFTR gene, and it therefore should not be used in these patients.

More information on ivacaftor is available on the FDA Web site.

Dr. Shorr has disclosed no relevant financial relationships.
Laurie Barclay, MD, contributed to this synopsis.

Clinical Implications

• The FDA has approved ivacaftor for patients at least 6 years old who have a rare form of CF associated with the G551D mutation in the CFTR gene. It is administered twice daily with fat-containing food.
• The most common adverse effects of ivacaftor are upper respiratory tract infection, headache, stomachache, rash, diarrhea, and dizziness. Elevated transaminase levels may occur. Coadministration of ivacaftor with strong CYP3A regulator potentiator inducers, such as rifampin and St. John's Wort, is not recommended.
• Ivacaftor is pregnancy category B, and caution is recommended when ivacaftor is given to a breast-feeding mother. Patients with moderate or severe hepatic impairment should have a reduced dose administered less frequently. Caution is recommended when ivacaftor is used in patients with severe renal impairment. Ivacaftor should not be used in patients younger than 6 years or in those who are homozygous for the F508del mutation in the CFTR gene.