Orkambi for Cystic Fibrosis

Last updated Sept 26, 2022, by Lindsey Shapiro, PhD

Fact-checked by José Lopes, PhD


What is Orkambi for CF?

Orkambi (ivacaftor/lumacaftor) is an approved oral treatment for people with cystic fibrosis (CF) caused by the F508del mutation in the CFTR gene.

It was developed by Vertex Pharmaceuticals.

How does Orkambi work?

CF is caused by mutations in the CFTR gene, disrupting the function of CFTR channels involved in moving ions, like chloride and sodium, across cell membranes. The F508del mutation is the most common CF-causing mutation, and leads to the production of a misfolded CFTR protein that’s degraded before it reaches the cell surface.

Orkambi is a combination of two compounds — lumacaftor and ivacaftor — that target the defective CFTR channels in people with two copies of the F508del mutation, one inherited from each parent.

Lumacaftor is a CFTR corrector that works to help the CFTR protein form in the right shape and reach the cell’s surface. Ivacaftor is a CFTR potentiator that hold channels open, allowing the flow of ions to be restored. Together, the compounds help maintain a proper water-to-salt ratio in the cell, preventing the buildup of the thick and sticky mucus characteristic of CF.

Of note, ivacaftor, marketed by Vertex as Kalydeco, is approved in the U.S., Canada, and Europe for patients 4 months and older with a range of CF-causing mutations.

Who can take Orkambi?

The U.S. Food and Drug Administration (FDA) first approved Orkambi in 2015 for CF patients age 12 and older with two copies of the F508del mutation. This U.S. approval was expanded to include patients ages 6 to 11 in 2016, and again to include children starting at age 2 in 2018.

In September 2022, the FDA cleared the use of Orkambi to treat children starting at 12 months of age.

Orkambi is also approved to treat children and adults with two F508del mutations in Europe, Australia, and Canada, among other countries.

Who should not take Orkambi?

Orkambi is currently only approved for patients with F508del mutations in both CFTR gene copies (homozygous mutations). Its efficacy and safety has not been established in people with one F508del gene mutation or other CF-causing mutations.

How is Orkambi administered?

Orkambi is available as oral tablets or granules. Doses differ based on age and weight as follows:

  • Children ages 1–2
    • Weighing 15 up to 20 pounds (7–9 kg): one packet of granules (75 mg lumacaftor/94 mg ivacaftor) every 12 hours, mixed with one teaspoon of a fat-containing soft food or liquid
    • Weighing 20 up to 31 pounds (9–14 kg): one packet of granules (100 mg lumacaftor/125 mg ivacaftor) every 12 hours, mixed with one teaspoon of a fat-containing soft food or liquid.
    • Weighing 31 or more pounds (14 or more kg): one packet of granules (150 mg lumacaftor/188 mg ivacaftor) every 12 hours, mixed with one teaspoon of a fat-containing soft food or liquid.
  • Children ages 2-5
    • Weighing less than 31 pounds (up to 14 kg): one packet of granules (100 mg lumacaftor/125 mg ivacaftor) every 12 hours, mixed with one teaspoon of a fat-containing soft food or liquid.
    • Weighing 31 or more pounds (14 or more kg): one packet of granules (150 mg lumacaftor/188 mg ivacaftor) every 12 hours, mixed with one teaspoon of a fat-containing soft food or liquid.

Granules are small and white to off-white in color and provided in unit-dose packets. Examples of soft foods or liquids include pureed fruits, yogurt or pudding, milk or juice. All foods should be at or below room temperature. Once the granules are mixed into the food, they should be ingested within one hour.

  • Children ages 6–11: two tablets (100 mg lumacaftor/125 mg ivacaftor) every 12 hours. Tablets are pink, oval-shaped, film-coated, and labeled in black ink with “1V125” on one side.
  • Patients 12 and older: two tablets (200 mg lumacaftor/125 mg ivacaftor) every 12 hours. Tablets are pink, oval-shaped, film-coated, and labeled with “2V125” in black ink on one side.

For all patients, a fat-containing meal or snack, with foods such as eggs, avocados, nuts or dairy, should be eaten just before or after the appropriate dose to help the body better absorb the medication.

Missed doses should be taken with a fat-containing food if within six hours of the time the medication is usually taken. If more than six hours have elapsed, the dose should be skipped. Patients should not take a double dose of Orkambi.

Doses may need to be adjusted for some patients with liver impairments or those using certain medications that could interact with Orkambi. Patients should speak with their healthcare providers about the appropriate dose for their particular case.

Orkambi in clinical trials

TRAFFIC, TRANSPORT, and PROGRESS trials

Orkambi was approved for patients ages 12 and older based on the results of three Phase 3, Vertex-funded trials: TRAFFIC (NCT01807923), TRANSPORT (NCT01807949), and PROGRESS (NCT01931839).

TRAFFIC and TRANSPORT collectively enrolled 1,108 CF patients age 12 and older who had two copies of the F508del mutation. Participants were randomly assigned to receive lumacaftor (600 mg once daily or 400 mg every 12 hours) with ivacaftor (250 mg every 12 hours) or a placebo for six months. Results showed that the primary goal of these trials was met, with Orkambi-treated patients seeing significant improvements in lung function compared with the placebo group. Treated patients also experienced fewer hospital admissions and lower antibiotic usage.

Patients were then invited to participate in the PROGRESS extension trial, with participants continuing at their assigned Orkambi dose or moving to Orkambi if they had previously been in the placebo group. Results showed that participants continued to see significant improvements over a period of 96 weeks (about two years), showing a 42% slower annual rate of lung function decline compared with untreated patients in a matched registry. Orkambi treatment also led to a more healthy body-mass index or BMI, a measure of body fat based on height and weight.

Other trials

Orkambi’s expanded approval to children ages 6 to 11 was supported by two additional Phase 3 trials: one an open-label study (NCT01897233) and the other placebo controlled (NCT02514473); both evaluated the treatment’s safety and efficacy among patients in that age group.

Among 268 children across the two studies, 166 received oral Orkambi (200 mg of lumacaftor and 250 mg ivacaftor) and 102 received a placebo every 12 hours for six months. As in previous trials, Orkambi was safe, well-tolerated, and led to improved lung function. Orkambi also lowered sweat chloride levels, elevations in which are a hallmark feature of CF.

An open-label Phase 3 trial (NCT02797132) investigated the effects of lumacaftor (at 100 mg and 150 mg doses) and ivacaftor (at 125 mg and 188 mg doses) granules in children ages 2 through 5. A total of 60 children were treated every 12 hours for six months, with clinical benefits and safety responses similar to those seen in previous trials.  An open-label extension of that trial (NCT03125395) showed treatment to have been safe and effective for more than two years among these children.

The newest extension of Orkambi was supported by data from an open-label Phase 3 clinical trial (NCT03601637) that investigated the safety of Orkambi in children ages 1 up to 2 years old with two copies of the F508del mutation. Children were treated for 24 weeks with Orkambi.

Orkambi was generally well-tolerated in these young children, and had a safety and pharmacokinetic profile consistent with studies in older children. Pharmacokinetics refers to a treatment’s movement into, through and out of the body.

The treatment was also effective in reducing sweat chloride concentrations. Improving trends in pancreatic function and intestinal inflammation were observed.

A rollover Phase 3 open-label study (NCT04235140) of that trial was initiated in 2020 to evaluate the long-term safety of Orkambi in these toddlers and is estimated to finish in 2024.

Common side effects of Orkambi

The most common side effects associated with Orkambi treatment in patients 12 and older are:

  • Difficult or labored breathing (dyspnea)
  • Cold-like symptoms and nasal discharge (nasopharyngitis)
  • Gastrointestinal symptoms (nausea, diarrhea, flatulence)
  • Infections — influenza and upper respiratory
  • Fatigue
  • Elevated blood levels of the creatine phosphokinase enzyme
  • Rash

Side effects in children under 12 are similar to those in teenagers and adults, with cough, nasal congestion, headache, stomach pain and an increase in sputum also reported.

Respiratory events

Respiratory problems, including difficult or abnormal breathing and chest discomfort, are more commonly observed when starting Orkambi. Patients who experience these symptoms should report them to their healthcare provider, as additional monitoring may be necessary.

Liver abnormalities

Elevated levels of some liver enzymes have been observed in patients using Orkambi. Liver function should be monitored every three months during the first year of treatment and annually thereafter. In patients with signs of significantly disrupted liver function, treatment should be suspended until symptoms resolve and the risks and benefits of restarting discussed. Patients with advanced liver disease should be closely monitored if using Orkambi, and the dose should be reduced.

Blood pressure

Increased blood pressure has been reported in some patients. It’s recommended that blood pressure is periodically monitored in all people using Orkambi.

Cataracts

Cataracts, a clouding of the lens of the eyes, have been reported in some children using Orkambi. Eye exams are recommended in pediatric patients initiating Orkambi, with regular exams to follow.

Menstrual abnormalities

Some women treated with Orkambi in clinical trials reported menstrual abnormalities, including a lack of menstruation, menstrual cramps, and excessive or prolonged menstrual bleeding. These side effects occurred more frequently in women who were using hormonal contraceptives while taking Orkambi.

Contraception, pregnancy, and breastfeeding

Orkambi may lower the effectiveness of hormonal contraceptives. These contraceptives should not be relied upon as an effective method of birth control when using Orkambi.

Insufficient data exist regarding the effects of Orkambi on pregnancy or breastfeeding in humans. Data from animal models showed no harmful effects to a developing fetus with maternal exposure to Orkambi. Both lumacaftor and ivacaftor were secreted in the breast milk of lactating rats.

Patients who are pregnant, wish to become pregnant, or wish to breastfeed while using Orkambi should discuss the matter with their healthcare professionals.