Clinical Trial for Age 2 to <6 Years
Safety Evaluated in Patients Age 2 Through 5 Years Who Are Homozygous for the F508del-CFTR Mutation
STUDY DESIGN
Trial 6 | Open-Label Safety Study1-3
Trial 6 was a 24-week, open-label study assessing the safety, tolerability, and pharmacokinetics of ORKAMBI in 60 patients age 2 through 5 years with CF who were homozygous for the F508del-CFTR mutation. Patients received ORKAMBI granules (if <14 kg: lumacaftor 100 mg/ivacaftor 125 mg, or if ≥14 kg: lumacaftor 150 mg/ivacaftor 188 mg) mixed with 1 teaspoon (5 mL) of soft food or liquid and administered orally every 12 hours with fat-containing food. All patients continued to take their prescribed CF therapies (including during the 2-week washout period). The primary endpoint was safety and tolerability up to Week 24.1,2
Trial 6 | Limitations2
- The study was open-label and not placebo controlled; therefore, causality cannot be attributed
- All patients in the study knew they were on active drug, which may have introduced bias related to awareness of treatment
Download the Clinical Brochure, including information from Trial 6 and the Extension Study in patients age 2 through 5 years.
Safety Profile in Trial 6 Was Similar to That in Patients Age 6 Years and Older1
Liver-Related AEs1
| Elevated ALT or AST | ORKAMBI Total, N=60 n(%) |
|---|---|
| >3 x ULN | 9 (15.0) |
| >5 x ULN | 7 (11.7) |
| >8 x ULN | 5 (8.3) |
- No patients had total bilirubin levels >2 x ULN1
Discontinuation and Serious AEs1,2
- Three patients (5%) discontinued ORKAMBI treatment due to ALT/AST elevation
- Four patients (7%) experienced serious AEs (one with viral gastroenteritis, one with constipation, and two with infective pulmonary exacerbations of CF)
Respiratory-Related AEs2,3
| Adverse Event (Preferred Term) | ORKAMBI Total, N=60 n(%) |
|---|---|
| Dyspnea | 3 (5.0) |
| Wheezing | 3 (5.0) |
| Chest Discomfort | 0 |
| Respiration abnormal | 1 (2.0) |
- No respiratory events led to treatment interruption or discontinuation2
Mean Absolute Within-Group Change in Sweat Chloride Concentration1,2
- From baseline at Week 24 (n=49): -31.7 mmol/L (95% CI -35.7, -27.6) reduction
- After washout, from Week 24 to Week 26 (n=47), increased to +33.0 mmol/L (95% CI: 28.9, 37.1)
There was no direct correlation between decrease in sweat chloride level and improvement in lung function (ppFEV1)1
Trial 6: Results for BMI-for-age z-Score and BMI
Mean Absolute Within-Group Change in BMI-for-age z-Score and BMI2
- BMI-for-age z-Score from baseline at Week 24 (n=57): increased to +0.29 (95% CI: 0.14, 0.45)
ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; BMI, body mass index; CI, confidence interval; ppFEV1, percent predicted forced expiratory volume in 1 second; ULN, upper limit of normal.
Important Safety Information
Use in Patients With Advanced Liver Disease
- Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced
Indications and Usage
ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.
Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
Indications and Usage
ORKAMBI® (lumacaftor/ivacaftor) is a combination of lumacaftor and ivacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.
Limitations of Use
The efficacy and safety of ORKAMBI have not been established in patients with CF other than those homozygous for the F508del mutation.
Important Safety Information
Use in Patients With Advanced Liver Disease
- Worsening of liver function, including hepatic encephalopathy, in patients with advanced liver disease has been reported. Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension while receiving ORKAMBI. Use ORKAMBI with caution in patients with advanced liver disease and only if the benefits are expected to outweigh the risks. If ORKAMBI is used in these patients, they should be closely monitored after the initiation of treatment and the dose should be reduced
Liver-related Events
- Serious adverse reactions related to elevated transaminases have been reported in patients with CF receiving ORKAMBI. In some instances, these elevations have been associated with concomitant elevations in total serum bilirubin
- It is recommended that ALT, AST, and bilirubin be assessed prior to initiating ORKAMBI, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of ALT, AST, or bilirubin elevations, more frequent monitoring should be considered. Patients who develop increased ALT, AST, or bilirubin should be closely monitored until the abnormalities resolve
- Dosing should be interrupted in patients with ALT or AST >5 x upper limit of normal (ULN) when not associated with elevated bilirubin. Dosing should also be interrupted in patients with ALT or AST elevations >3 x ULN when associated with bilirubin elevations >2 x ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming dosing
Respiratory Events
- Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of ORKAMBI compared to those who received placebo. These events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 (ppFEV1) <40). Clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended during initiation of therapy
Effect on Blood Pressure
- Increased blood pressure has been observed in some patients treated with ORKAMBI. Blood pressure should be monitored periodically in all patients being treated with ORKAMBI
Drug interactions
Substrates of CYP3A
- Lumacaftor is a strong inducer of CYP3A. Administration of ORKAMBI may decrease systemic exposure of medicinal products that are substrates of CYP3A, which may decrease therapeutic effect. Co-administration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not recommended
- ORKAMBI may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions, e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with ORKAMBI
Strong CYP3A Inducers
- Ivacaftor is a substrate of CYP3A4 and CYP3A5 isoenzymes. Use of ORKAMBI with strong CYP3A inducers, such as rifampin, significantly reduces ivacaftor exposure, which may reduce the therapeutic effectiveness of ORKAMBI. Therefore, co‑administration with strong CYP3A inducers is not recommended
Cataracts
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with ORKAMBI and ivacaftor, a component of ORKAMBI. Although other risk factors were present in some cases (such as corticosteroid use and exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with ORKAMBI
Pediatric Use
- The safety and effectiveness of ORKAMBI in patients with CF younger than 1 year of age have not been established
Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with ORKAMBI included pneumonia, hemoptysis, cough, increased blood creatine phosphokinase, and transaminase elevations. These occurred in 1% or less of patients
- The most common adverse reactions in patients age 12 years and older in Phase 3 trials (Trials 1 and 2) occurring in ≥5% of patients treated with ORKAMBI (N=369) vs placebo (N=370) and at a rate higher than placebo were dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatine phosphokinase increased, rash, flatulence, rhinorrhea, and influenza
- The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=58) and a placebo-controlled trial (Trial 4; patients treated with ORKAMBI, N=103 vs placebo, N=101) was similar to that observed in Trials 1 and 2. Additional common adverse reactions were reported in Trial 4, but were not reported in Trials 1 and 2. The adverse reactions in Trial 4 that occurred in ≥5% of patients treated with ORKAMBI with an incidence of ≥3% higher than placebo included: productive cough, nasal congestion, headache, abdominal pain upper, and sputum increased. The safety profile in patients age 2 through 5 years from an open-label trial (Trial 6; N=60) was similar to that in patients aged 6 years and older. The safety profile in patients age 1 through 2 years from an open-label trial (Trial 7; N=46) was similar to that in patients aged 2 years and older
Click here to access full Prescribing Information.
References:
1. ORKAMBI [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; September 2022. 2. McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2–5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4):325-335. doi:10.1016/S2213-2600(18)30460-0 3. McNamara JJ, McColley SA, Marigowda G, et al. Safety, pharmacokinetics, and pharmacodynamics of lumacaftor and ivacaftor combination therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR: an open-label phase 3 study. Lancet Respir Med. 2019;7(4)(suppl):1-13. doi:10.1016/S2213-2600(18)30460-0 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. VXR-HQ-88-00179(1); 2019.