Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Vertex Pharmaceuticals (Ireland) Limited, Unit 49, Block F2, Northwood Court, Santry, Dublin 9, D09 T665, Ireland
Pharmacotherapeutic group: Other respiratory system products
ATC code: R07AX32
ELX and TEZ are CFTR correctors that bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. IVA potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.
The combined effect of ELX, TEZ and IVA is increased quantity and function of F508del-CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport. With regard to non-F508del CFTR variants on the second allele, it is not clear whether and to what extent the combination of ELX, TEZ and IVA also increases the amount of these mutated CFTR variants on the cell surface and potentiates its channel open probability (or gating).
In study 445-102 (patients with an F508del mutation on one allele and a mutation on the second allele that predicts either no production of a CFTR protein or a CFTR protein that does not transport chloride and is not responsive to other CFTR modulators [IVA and TEZ/IVA] in vitro), a reduction in sweat chloride was observed from baseline at week 4 and sustained through the 24-week treatment period. The treatment difference of IVA/TEZ/ELX in combination with IVA compared to placebo for mean absolute change in sweat chloride from baseline through week 24 was -41.8 mmol/L (95% CI: -44.4, -39.3; P<0.0001).
In study 445-103 (patients homozygous for the F508del mutation), the treatment difference of IVA/TEZ/ELX in combination with IVA compared to TEZ/IVA in combination with IVA for mean absolute change in sweat chloride from baseline at week 4 was -45.1 mmol/L (95% CI: -50.1, -40.1; P<0.0001).
In study 445-104 (patients heterozygous for the F508del mutation and a mutation on the second allele with a gating defect or residual CFTR activity), the mean absolute change in sweat chloride from baseline through week 8 for the IVA/TEZ/ELX in combination with IVA group was -22.3 mmol/L (95% CI: -24.5, -20.2; P<0.0001). The treatment difference of IVA/TEZ/ELX in combination with IVA compared to the control group (IVA group or TEZ/IVA in combination with IVA group) was -23.1 mmol/L (95% CI: -26.1, -20.1; P<0.0001).
In study 445-106 (patients aged 6 to less than 12 years who are homozygous for the F508del mutation or heterozygous for the F508del mutation and a minimal function mutation), the mean absolute change in sweat chloride from baseline (n=62) through week 24 (n=60) was -60.9 mmol/L (95% CI: -63.7, -58.2)*. The mean absolute change in sweat chloride from baseline through week 12 (n=59) was -58.6 mmol/L (95% CI: -61.1, -56.1).
* Not all participants included in the analyses had data available for all follow-up visits, especially from week 16 onwards. The ability to collect data at week 24 was hampered by the COVID-19 pandemic. Week 12 data were less impacted by the pandemic.
In study 445-116 (patients aged 6 to less than 12 years who are heterozygous for the F508del mutation and a minimal function mutation), treatment with IVA/TEZ/ELX in combination with IVA resulted in reduction in sweat chloride through week 24, as compared to placebo. The LS mean treatment difference for the IVA/TEZ/ELX in combination with IVA group versus placebo for absolute change in sweat chloride from baseline through week 24 was -51.2 mmol/L (95% CI: -55.3, -47.1; nominal P<0.0001).
At doses up to 2 times the maximum recommended dose of ELX and 3 times the maximum recommended dose of TEZ and IVA, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent.
In study 445-102, mean decreases in heart rate of 3.7 to 5.8 beats per minute (bpm) from baseline (76 bpm) were observed in IVA/TEZ/ELX-treated patients.
The efficacy of IVA/TEZ/ELX in combination with IVA in patients with CF was demonstrated in six Phase 3 studies. Patients enrolled in these studies were homozygous for the F508del mutation or heterozygous for the F508del mutation and a mutation with minimal function (MF), a gating defect, or residual CFTR activity on the second allele. Not all F508del heterozygotes have been clinically evaluated with IVA/TEZ/ELX in combination with IVA.
Study 445-102 was a 24-week, randomised, double-blind, placebo-controlled study in patients who had an F508del mutation on one allele and an MF mutation on the second allele. CF patients eligible for this study were required to either have Class I mutations that predicted no CFTR protein being produced (including nonsense mutations, canonical splice mutations and insertion/deletion frameshift mutations both small (≤3 nucleotide) and non-small (>3 nucleotide)), or missense mutations which results in CFTR protein that does not transport chloride and is not responsive to IVA and TEZ/IVA in vitro. The most frequent alleles with minimal function assessed in the study were G542X, W1282X, R553X, and R1162X; 621+1G→T, 1717-1G→A, and 1898+1G→A; 3659delC, and 394delTT; CFTRdele2,3; and N1303K, I507del, G85E, R347P, and R560T. A total of 403 patients aged 12 years and older (mean age 26.2 years) were randomised and dosed to receive placebo or IVA/TEZ/ELX in combination with IVA. Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline was 61.4% (range: 32.3%, 97.1%).
Study 445-103 was a 4-week, randomised, double-blind, active-controlled study in patients who were homozygous for the F508del mutation. A total of 107 patients aged 12 years and older (mean age 28.4 years) received TEZ/IVA in combination with IVA during a 4-week open-label run-in period and were then randomised and dosed to receive either IVA/TEZ/ELX in combination with IVA or TEZ/IVA in combination with IVA during a 4-week double-blind treatment period. Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline, following the run-in period was 60.9% (range: 35.0%, 89.0%).
Study 445-104 was an 8-week, randomised, double-blind, active-controlled study in patients who were heterozygous for the F508del mutation and a mutation on the second allele with a gating defect (Gating) or residual CFTR activity (RF). A total of 258 patients aged 12 years and older (mean age 37.7 years) received either IVA (F/Gating) or TEZ/IVA in combination with IVA (F/RF) during a 4-week open-label run-in period and were dosed during the treatment period and patients with the F/R117H genotype received IVA during the run-in period. Patients were then randomised and dosed to receive either IVA/TEZ/ELX in combination with IVA or remained on the CFTR modulator therapy received during the run-in period. Patients had a ppFEV1 at screening between 40-90%. The mean ppFEV1 at baseline, following the run-in period, was 67.6% (range: 29.7%, 113.5%).
Study 445-106 was a 24-week open-label study in patients who were homozygous for the F508del mutation or heterozygous for the F508del mutation and a minimal function mutation. A total of 66 patients aged 6 to less than 12 years (mean age at baseline 9.3 years) were dosed according to weight. Patients weighing <30 kg at baseline were administered two IVA 37.5 mg/TEZ 25 mg/ELX 50 mg tablets in the morning and one IVA 75 mg tablet in the evening. Patients weighing ≥30 kg at baseline were administered two IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA 150 mg tablet in the evening. Patients had a ppFEV1 ≥40% and weighed ≥15 kg at screening. The mean ppFEV1 at baseline was 88.8% (range: 39.0%, 127.1%).
Study 445-116 was a 24-week, randomised, double-blind, placebo-controlled study in patients aged 6 to less than 12 years (mean age at baseline 9.2 years) who were heterozygous for the F508del mutation and a minimal function mutation. A total of 121 patients were randomised to receive either placebo or IVA/TEZ/ELX in combination with IVA. Patients who received IVA/TEZ/ELX in combination with IVA weighing <30 kg at baseline were administered two IVA 37.5 mg/TEZ 25 mg/ELX 50 mg tablets in the morning and one IVA 75 mg tablet in the evening. Patients weighing ≥30 kg at baseline were administered two IVA 75 mg/TEZ 50 mg/ELX 100 mg tablets in the morning and one IVA 150 mg tablet in the evening. At screening, patients had a ppFEV1 ≥70% [mean ppFEV1 at baseline of 89.3% (range: 44.6%, 121.8%)], LCI2.5 result ≥7.5 [mean LCI2.5 at baseline of 10.01 (range: 6.91, 18.36)], and weighed ≥15 kg.
Patients in these studies continued on their CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa and hypertonic saline), but discontinued any previous CFTR modulator therapies, except for study medicinal products. Patients had a confirmed diagnosis of CF.
In studies 445-102, 445-103, 445-104, and 445-106, patients who had lung infection with organisms associated with a more rapid decline in pulmonary status, including but not limited to Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had an abnormal liver function test at screening (ALT, AST, ALP, or GGT ≥3 x ULN, or total bilirubin ≥2 x ULN), were excluded. Patients in studies 445-102 and 445-103 were eligible to roll over into a 192-week open-label extension study (study 445-105).
Patients in studies 445-104, 445-106, and 445-116 were eligible to roll over into separate open-label extension studies.
In study 445-102 the primary endpoint was mean absolute change in ppFEV1 from baseline through week 24. Treatment with IVA/TEZ/ELX in combination with IVA compared to placebo resulted in statistically significant improvement in ppFEV1 of 14.3 percentage points (95% CI: 12.7, 15.8; P<0.0001) (see Table 5). Mean improvement in ppFEV1 was observed at the first assessment on day 15 and sustained through the 24-week treatment period. Improvements in ppFEV1 were observed regardless of age, baseline ppFEV1, sex, and geographic region.
A total of 18 patients receiving IVA/TEZ/ELX in combination with IVA had ppFEV1 <40 percentage points at baseline. The safety and efficacy in this subgroup were consistent to those observed in the overall population. The mean treatment difference of IVA/TEZ/ELX in combination with IVA- compared to placebo-treated patients for absolute change in ppFEV1 through week 24 in this subgroup was 18.4 percentage points (95% CI: 11.5, 25.3).
See Table 5 for a summary of primary and key secondary outcomes.
Table 5. Primary and key secondary efficacy analyses, full analysis set (study 445-102):
| Analysis | Statistic | Placebo N=203 | IVA/TEZ/ELX in combination with IVA N=200 |
|---|---|---|---|
| Primary | |||
| Baseline ppFEV1 | Mean (SD) | 61.3 (15.5) | 61.6 (15.0) |
| Absolute change in ppFEV1 from baseline through week 24 (percentage points) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA -0.4 (0.5) | 14.3 (12.7, 15.8) P<0.0001 13.9 (0.6) |
| Key secondary | |||
| Absolute change in ppFEV1 from baseline at week 4 (percentage points) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA -0.2 (0.6) | 13.7 (12.0, 15.3) P<0.0001 13.5 (0.6) |
| Number of pulmonary exacerbations from baseline through week 24* | Number of events (event rate per year†) Rate ratio (95% CI) P value | 113 (0.98) NA NA | 41 (0.37) 0.37 (0.25, 0.55) P<0.0001 |
| Baseline sweat chloride (mmol/L) | Mean (SD) | 102.9 (9.8) | 102.3 (11.9) |
| Absolute change in sweat chloride from baseline through week 24 (mmol/L) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA -0.4 (0.9) | -41.8 (-44.4, -39.3) P<0.0001 -42.2 (0.9) |
| Absolute change in sweat chloride from baseline at week 4 (mmol/L) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA 0.1 (1.0) | -41.2 (-44.0, -38.5) P<0.0001 -41.2 (1.0) |
| Baseline CFQ-R respiratory domain score (points) | Mean (SD) | 70.0 (17.8) | 68.3 (16.9) |
| Absolute change in CFQ-R respiratory domain score from baseline through week 24 (points) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA -2.7 (1.0) | 20.2 (17.5, 23.0) P<0.0001 17.5 (1.0) |
| Absolute change in CFQ-R respiratory domain score from baseline at week 4 (points) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA -1.9 (1.1) | 20.1 (16.9, 23.2) P<0.0001 18.1 (1.1) |
| Baseline BMI (kg/m²) | Mean (SD) | 21.31 (3.14) | 21.49 (3.07) |
| Absolute change in BMI from baseline at week 24 (kg/m²) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA 0.09 (0.07) | 1.04 (0.85, 1.23) P<0.0001 1.13 (0.07) |
ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SD: Standard Deviation; SE: Standard Error; NA: Not Applicable; CFQ-R: Cystic Fibrosis Questionnaire-Revised; BMI: Body Mass Index.
* A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.
† Estimated event rate per year was calculated based on 48 weeks per year.
In study 445-103 the primary endpoint was mean absolute change in ppFEV1 from baseline at week 4 of the double-blind treatment period. Treatment with IVA/TEZ/ELX in combination with IVA compared to TEZ/IVA in combination with IVA resulted in a statistically significant improvement in ppFEV1 of 10.0 percentage points (95% CI: 7.4, 12.6; P<0.0001) (see Table 6). Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 geographic region.
See Table 6 for a summary of primary and key secondary outcomes in the overall trial population.
In a post hoc analysis of patients with (N=66) and without (N=41) recent CFTR modulator use, an improvement in ppFEV1 of 7.8 percentage points (95% CI: 4.8, 10.8) and 13.2 percentage points (95% CI: 8.5, 17.9), respectively was observed.
Table 6. Primary and key secondary efficacy analyses, full analysis set (study 445-103):
| Analysis* | Statistic | TEZ/IVA in combination with IVA N=52 | IVA/TEZ/ELX in combination with IVA N=55 |
|---|---|---|---|
| Primary | |||
| Baseline ppFEV1 | Mean (SD) | 60.2 (14.4) | 61.6 (15.4) |
| Absolute change in ppFEV1 from baseline at week 4 (percentage points) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA 0.4 (0.9) | 10.0 (7.4, 12.6) P<0.0001 10.4 (0.9) |
| Key secondary | |||
| Baseline sweat chloride (mmol/L) | Mean (SD) | 90.0 (12.3) | 91.4 (11.0) |
| Absolute change in sweat chloride from baseline at week 4 (mmol/L) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA 1.7 (1.8) | -45.1 (-50.1, -40.1) P<0.0001 -43.4 (1.7) |
| Baseline CFQ-R respiratory domain score (points) | Mean (SD) | 72.6 (17.9) | 70.6 (16.2) |
| Absolute change in CFQ-R respiratory domain score from baseline at week 4 (points) | Treatment difference (95% CI) P value Within-group change (SE) | NA NA -1.4 (2.0) | 17.4 (11.8, 23.0) P<0.0001 16.0 (2.0) |
ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SD: Standard Deviation; SE: Standard Error; NA: Not Applicable; CFQ-R: Cystic Fibrosis Questionnaire-Revised.
* Baseline for primary and key secondary endpoints is defined as the end of the 4-week run-in period of TEZ/IVA in combination with IVA.
In study 445-104 the primary endpoint was within-group mean absolute change in ppFEV1 from baseline through week 8 for the IVA/TEZ/ELX in combination with IVA group. Treatment with IVA/TEZ/ELX in combination with IVA resulted in statistically significant improvement in ppFEV1 from baseline of 3.7 percentage points (95% CI: 2.8, 4.6; P<0.0001) (see Table 7). Overall improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 geographic region, and genotype groups (F/Gating or F/RF).
See Table 7 for a summary of primary and secondary outcomes in the overall trial population.
In a subgroup analysis of patients with an F/Gating genotype, the treatment difference of IVA/TEZ/ELX in combination with IVA (N=50) compared with IVA (N=45) for mean absolute change in ppFEV1 was 5.8 percentage points (95% CI: 3.5, 8.0). In a subgroup analysis of patients with an F/RF genotype, the treatment difference of IVA/TEZ/ELX in combination with IVA (N=82) compared with TEZ/IVA in combination with IVA (N=81) for mean absolute change in ppFEV1 was 2.0 percentage points (95% CI: 0.5, 3.4). The results of the F/Gating and the F/RF genotype subgroups for improvement in sweat chloride and CFQ-R respiratory domain score were consistent with the overall results.
Table 7. Primary and secondary efficacy analyses, full analysis set (study 445-104):
| Analysis* | Statistic | Control group† N=126 | IVA/TEZ/ELX in combination with IVA N=132 |
|---|---|---|---|
| Primary | |||
| Baseline ppFEV1 | Mean (SD) | 68.1 (16.4) | 67.1 (15.7) |
| Absolute change in ppFEV1 from baseline through week 8 (percentage points) | Within-group change (95% CI) P value | 0.2 (-0.7, 1.1) NA | 3.7 (2.8, 4.6) P<0.0001 |
| Key and other secondary | |||
| Absolute change in ppFEV1 from baseline through week 8 compared to the control group (percentage points) | Treatment difference (95% CI) P value | NA NA | 3.5 (2.2, 4.7) P<0.0001 |
| Baseline sweat chloride (mmol/L) | Mean (SD) | 56.4 (25.5) | 59.5 (27.0) |
| Absolute change in sweat chloride from baseline through week 8 (mmol/L) | Within-group change (95% CI) P value | 0.7 (-1.4, 2.8) NA | -22.3 (-24.5, -20.2) P<0.0001 |
| Absolute change in sweat chloride from baseline through week 8 compared to the control group (mmol/L) | Treatment difference (95% CI) P value | NA NA | -23.1 (-26.1, -20.1) P<0.0001 |
| Baseline CFQ-R respiratory domain score (points) | Mean (SD) | 77.3 (15.8) | 76.5 (16.6) |
| Absolute change in CFQ-R respiratory domain score from baseline through week 8 (points) | Within-group change (95% CI) | 1.6 (-0.8, 4.1) | 10.3 (8.0, 12.7) |
| Absolute change in CFQ-R respiratory domain score from baseline through week 8 (points) compared to the control group | Treatment difference (95% CI) | NA | 8.7 (5.3, 12.1) |
ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SD: Standard Deviation; NA: Not Applicable; CFQ-R: Cystic Fibrosis Questionnaire-Revised.
* Baseline for primary and secondary endpoints is defined as the end of the 4-week run-in period of IVA or TEZ/IVA in combination with IVA.
† IVA group or TEZ/IVA in combination with IVA group.
An ongoing, 192-week open-label extension study to evaluate the safety and efficacy of long-term treatment with IVA/TEZ/ELX in combination with IVA is being conducted in patients who rolled over from studies 445-102 and 445-103. In this open-label extension study all patients received IVA/TEZ/ELX in combination with IVA. For patients who rolled over from studies 445-102 (N=399) and 445-103 (N=107), an interim efficacy analysis was conducted after they completed 96 weeks in study 445-105.
In study 445-105, patients from the control arms in the parent studies showed improvements in efficacy endpoints consistent with those observed in subjects who received IVA/TEZ/ELX in combination with IVA in the parent studies. Patients from the control arms as well as patients who received IVA/TEZ/ELX in combination with IVA in the parent studies, showed sustained improvements. Secondary efficacy endpoints are summarized in Table 8.
Table 8. Study 445-105 Secondary efficacy analysis at extended week 96 (F/MF and F/F subjects):
| Analysis | Statistic | Study 445-105 extended* week 96 | |||
|---|---|---|---|---|---|
| Placebo in 445-102 N=203 | IVA/TEZ/ELX in 445-102 N=196 | TEZ/IVA in 445-103 N=52 | IVA/TEZ/ELX in 445-103 N=55 | ||
| Absolute change from baseline† in ppFEV1 (percentage points) | n | 161 | 169 | 45 | 45 |
| LS mean | 15.2 | 14.3 | 12.4 | 11.5 | |
| 95% CI | (13.6, 16.7) | (12.7, 15.8) | (9.6, 15.1) | (8.8, 14.2) | |
| Absolute change from baseline† in SwCl (mmol/L) | n | 157 | 166 | 42 | 45 |
| LS mean | -48.6 | -45.8 | -48.3 | -49.7 | |
| 95% CI | (-51.3, -45.8) | (-48.5, -43.0) | (-53.7, -42.8) | (-55.0, -44.4) | |
| Number of PEx during the Cumulative Triple Combination (TC) Efficacy Period‡ | Number of events | 253 | 53 | ||
| Estimated event rate per year (95% CI) | 0.21 (0.17, 0.26) | 0.21 (0.14, 0.30) | |||
| Absolute change from baseline† in BMI (kg/m²) | n | 177 | 176 | 46 | 49 |
| LS mean | 1.87 | 1.58 | 1.28 | 1.50 | |
| 95% CI | (1.61, 2.13) | (1.32, 1.84) | (0.80, 1.76) | (1.03, 1.96) | |
| Absolute change from baseline† in body weight (kg) | n | 177 | 176 | 46 | 49 |
| LS mean | 6.3 | 5.3 | 4.4 | 5.2 | |
| 95% CI | (5.5, 7.1) | (4.5, 6.2) | (3.4, 5.4) | (4.3, 6.2) | |
| Absolute change from baseline† in CFQ-R RD score (points) | n | 187 | 180 | 49 | 50 |
| LS mean | 20.1 | 21.7 | 15.6 | 18.0 | |
| 95% CI | (17.5, 22.6) | (19.1, 24.2) | (11.0, 20.1) | (13.6, 22.5) | |
ppFEV1 = percent predicted Forced Expiratory Volume in 1 second; SwCl = Sweat Chloride; PEx = Pulmonary Exacerbation; BMI = Body Mass Index; CFQ-R RD = Cystic Fibrosis Questionnaire – Revised Respiratory Domain; LS = Least Squares; CI = Confidence Interval
* Extended week 96 window included data from the week 96 visit, plus data from scheduled or unscheduled visits that occurred after week 96 for subjects with missing data at week 96.
† Baseline = parent study baseline
‡ For subjects who were randomized to the IVA/TEZ/ELX group, the Cumulative TC Efficacy Period includes data from the parent studies through 96 weeks of treatments in study 445-105. For subject who were randomized to the Placebo or TEZ/IVA g
In study 445-106 the primary endpoint of safety and tolerability was evaluated through 24 weeks in patients aged 6 to less than 12 years. Secondary endpoints were evaluation of pharmacokinetics and efficacy.
See Table 9 for a summary of secondary efficacy outcomes.
Table 9. Secondary efficacy analyses, full analysis set (N=66) (study 445-106):
| Analysis | Baseline Mean (SD) | Absolute change through week 12 Within-group change (95% CI) | Absolute change through week 24 Within-group change (95% CI)* |
|---|---|---|---|
| ppFEV1 (percentage points) | n=62 88.8 (17.7) | n=59 9.6 (7.3, 11.9) | n=59 10.2 (7.9, 12.6) |
| CFQ-R respiratory domain score (points) | n=65 80.3 (15.2) | n=65 5.6 (2.9, 8.2) | n=65 7.0 (4.7, 9.2) |
| BMI-for-age z-score | n=66 -0.16 (0.74) | n=58 0.22 (0.13, 0.30)† | n=33 0.37 (0.26, 0.48)‡ |
| Weight-for-age z-score | n=66 -0.22 (0.76) | n=58 0.13 (0.07, 0.18)† | n=33 0.25 (0.16, 0.33)‡ |
| Height-for-age z-score | n=66 -0.11 (0.98) | n=58 -0.03 (-0.06, 0.00)† | n=33 -0.05 (-0.12, 0.01)‡ |
| Number of pulmonary exacerbations†† | N/A | N/A | n=66 4 (0.12)§ |
| LCI2.5 | n=53 9.77 (2.68) | n=48 -1.83 (-2.18, -1.49) | n=50 -1.71 (-2.11, -1.30) |
SD: Standard Deviation; CI: Confidence Interval; ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CFQ-R: Cystic Fibrosis Questionnaire-Revised; BMI: Body Mass Index; N/A: Not Applicable; LCI: Lung Clearance Index.
* Not all participants included in the analyses had data available for all follow-up visits, especially from week 16 onwards. The ability to collect data at week 24 was hampered by the COVID-19 pandemic.
Week 12 data were less impacted by the pandemic.
† At week 12 assessment.
‡ At week 24 assessment.
†† A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms.
§ Number of events and estimated event rate per year based on 48 weeks per year.
Study 445-107 is a 192-week, two-part (part A and part B), open-label extension study to evaluate the safety and efficacy of long-term treatment with IVA/TEZ/ELX in patients who completed study 445-106. Efficacy endpoints were included as secondary endpoints. The analysis of Part A was conducted at 96 weeks in 64 paediatric patients aged 6 years and older. With 96 additional weeks of treatment, sustained improvements in ppFEV1, SwCl, CFQ-R RD score, and LCI2.5 were shown, consistent with the results observed in the study 445-106.
In study 445-116, treatment with IVA/TEZ/ELX in combination with IVA in patients aged 6 to less than 12 years resulted in statistically significant improvement through 24 weeks in the primary endpoint (LCI2.5). The LS mean treatment difference for the IVA/TEZ/ELX in combination with IVA group versus placebo for the absolute change in LCI2.5 from baseline through week 24 was -2.26 (95% CI: -2.71, -1.81; P<0.0001).
The European Medicines Agency has deferred the obligation to submit the results of studies with IVA/TEZ/ELX in combination with IVA in one or more subset of the paediatric population in cystic fibrosis (see section 4.2 for information on paediatric use).
The pharmacokinetics of ELX, TEZ and IVA are similar between healthy adult subjects and patients with CF. Following initiation of once-daily dosing of ELX and TEZ and twice-daily dosing of IVA, plasma concentrations of ELX, TEZ and IVA reach steady state within approximately 7 days for ELX, within 8 days for TEZ, and within 3-5 days for IVA. Upon dosing IVA/TEZ/ELX to steady state, the accumulation ratio is approximately 3.6 for ELX, 2.8 for TEZ and 4.7 for IVA. Key pharmacokinetic parameters for ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older are shown in Table 10.
Table 10. Mean (SD) pharmacokinetic parameters of ELX, TEZ and IVA at steady state in patients with CF aged 12 years and older:
| Dose | Active Substance | Cmax (μg/mL) | AUC0-24h,ss or AUC0-12h,ss (μg∙h/mL)* |
|---|---|---|---|
| IVA 150 mg every 12 hours/TEZ 100 mg and ELX 200 mg once daily | ELX | 9.15 (2.09) | 162 (47.5) |
| TEZ | 7.67 (1.68) | 89.3 (23.2) | |
| IVA | 1.24 (0.34) | 11.7 (4.01) |
SD: Standard Deviation; Cmax: maximum observed concentration; AUCss: Area Under the Concentration versus time curve at steady state.
* AUC0-24h for ELX and TEZ and AUC0-12h for IVA
The absolute bioavailability of ELX when administered orally in the fed state is approximately 80%. ELX is absorbed with a median (range) time to maximum concentration (tmax) of approximately 6 hours (4 to 12 hours) while the median (range) tmax of TEZ and IVA is approximately 3 hours (2 to 4 hours) and 4 hours (3 to 6 hours), respectively. ELX exposure (AUC) increases approximately 1.9- to 2.5-fold when administered with a moderate-fat meal relative to fasted conditions. IVA exposure increases approximately 2.5- to 4-fold when administered with fat-containing meals relative to fasted conditions, while food has no effect on the exposure of TEZ (see section 4.2).
As exposures of ELX were approximately 20% lower after administration of the IVA/TEZ/ELX granules relative to the reference IVA/TEZ/ELX tablet, the formulations are not considered interchangeable.
ELX is >99% bound to plasma proteins and TEZ is approximately 99% bound to plasma proteins, in both cases primarily to albumin. IVA is approximately 99% bound to plasma proteins, primarily to albumin, and also to alpha 1-acid glycoprotein and human gamma-globulin. After oral administration of IVA/TEZ/ELX in combination with IVA, the mean (±SD) apparent volume of distribution of ELX, TEZ and IVA was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively. ELX, TEZ and IVA do not partition preferentially into human red blood cells.
ELX is metabolized extensively in humans, mainly by CYP3A4/5. Following oral administration of a single dose of 200 mg 14C-ELX to healthy male subjects, M23-ELX was the only major circulating metabolite. M23-ELX has similar potency to ELX and is considered pharmacologically active.
TEZ is metabolized extensively in humans, mainly by CYP3A4/5. Following oral administration of a single dose of 100 mg 14C-TEZ to healthy male subjects, M1-TEZ, M2-TEZ and M5-TEZ were the three major circulating metabolites of TEZ in humans. M1-TEZ has similar potency to that of TEZ and is considered pharmacologically active. M2-TEZ is much less pharmacologically active than TEZ or M1-TEZ and M5-TEZ is not considered pharmacologically active. Another minor circulating metabolite, M3-TEZ, is formed by direct glucuronidation of TEZ.
IVA is also metabolized extensively in humans. In vitro and in vivo data indicate that IVA is metabolized primarily by CYP3A4/5. M1-IVA and M6-IVA are the two major metabolites of IVA in humans. M1-IVA has approximately one-sixth the potency of IVA and is considered pharmacologically active. M6-IVA is not considered pharmacologically active.
The effect of the CYP3A4*22 heterozygous genotype on TEZ, IVA and ELX exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of TEZ, IVA or ELX is considered necessary. The effect in CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data are available for such patients.
Following multiple dosing in the fed state, the mean (±SD) apparent clearance values of ELX, TEZ and IVA at steady state were 1.18 (0.29) L/h, 0.79 (0.10) L/h and 10.2 (3.13) L/h, respectively. The mean (SD) terminal half-lives of ELX, TEZ and IVA following administration of the IVA/TEZ/ELX fixed-dose combination tablets are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively. The mean (SD) effective half-life of TEZ following administration of the IVA/TEZ/ELX fixed-dose combination tablets is 11.9 (3.79) hours.
Following oral administration of 14C-ELX alone, the majority of ELX (87.3%) was eliminated in the faeces, primarily as metabolites.
Following oral administration of 14C-TEZ alone, the majority of the dose (72%) was excreted in the faeces (unchanged or as the M2-TEZ) and about 14% was recovered in urine (mostly as M2-TEZ), resulting in a mean overall recovery of 86% up to 26 days after the dose.
Following oral administration of 14C-IVA alone, the majority of IVA (87.8%) was eliminated in the faeces after metabolic conversion.
For ELX, TEZ and IVA there was negligible urinary excretion of unchanged medicine.
ELX alone or in combination with TEZ and IVA has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15). Following multiple doses of ELX, TEZ and IVA for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had an approximately 25% higher AUC and a 12% higher Cmax for ELX, 73% higher AUC and a 70% higher Cmax for M23-ELX, 20% higher AUC but similar Cmax for TEZ, 22% lower AUC and a 20% lower Cmax for M1-TEZ, and a 1.5-fold higher AUC and a 10% higher Cmax for IVA compared with healthy subjects matched for demographics. The effect of moderately impaired hepatic function on total exposure (based on summed values of ELX and its M23-ELX metabolite) was 36% higher AUC and a 24% higher Cmax compared with healthy subjects matched for demographics (see sections 4.2, 4.4, and 4.8).
Following multiple doses of TEZ and IVA for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher Cmax for TEZ, and a 1.5-fold higher AUC but similar Cmax for IVA compared with healthy subjects matched for demographics.
In a study with IVA alone, subjects with moderately impaired hepatic function had similar IVA Cmax, but an approximately 2.0-fold higher IVA AUC0-∞ compared with healthy subjects matched for demographics.
ELX alone or in combination with TEZ and IVA has not been studied in patients with severe renal impairment [estimated glomerular filtration rate (eGFR) less than 30 mL/min] or in patients with endstage renal disease.
In human pharmacokinetic studies of ELX, TEZ and IVA, there was minimal elimination of ELX, TEZ and IVA in urine (only 0.23%, 13.7% [0.79% as unchanged medicine] and 6.6% of total radioactivity, respectively).
Based on population pharmacokinetic (PK) analysis, exposure of ELX was similar in patients with mild renal impairment (N=75; eGFR 60 to less than 90 mL/min) relative to those with normal renal function (N=341; eGFR 90 mL/min or greater).
In population PK analysis conducted in 817 patients administered TEZ alone or in combination with IVA in phase 2 or phase 3 studies indicated that mild renal impairment (N=172; eGFR 60 to less than 90 mL/min) and moderate renal impairment (N=8; eGFR 30 to less than 60 mL/min) did not affect the clearance of TEZ significantly (see sections 4.2 and 4.4).
The pharmacokinetic parameters of ELX (244 males compared to 174 females), TEZ and IVA are similar in males and females.
Race had no clinically meaningful effect on ELX exposure based on population PK analysis in whites (N=373) and non-whites (N=45). The non-white races consisted of 30 Blacks or African Americans, 1 with multiple racial background and 14 with other ethnic background (no Asians).
Very limited PK data indicate comparable exposure of TEZ in whites (N=652) and non-whites (N=8). The non-white races consisted of 5 Blacks or African Americans and 3 Native Hawaiians or other Pacific Islanders.
Race had no clinically meaningful effect on the PK of IVA in whites (N=379) and non-whites (N=29) based on a population PK analysis. The non-white races consisted of 27 African Americans and 2 Asians.
Clinical trials of IVA/TEZ/ELX in combination with IVA did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults (see sections 4.2 and 4.4).
ELX, TEZ and IVA exposures observed in phase 3 studies as determined using population PK analysis are presented by age group in Table 11. Exposures of ELX, TEZ and IVA in patients aged 2 to less than 18 years are within the range observed in patients aged 18 years and older.
Table 11. Mean (SD) ELX, M23-ELX, TEZ, M1-TEZ and IVA exposures observed at steady state by age group and dose administered:
| Age/Weight group | Dose | ELX AUC0-24h,ss (μg∙h/mL) | M23-ELX AUC0-24h,ss (μg∙h/mL) | TEZ AUC0-24h,ss (μg∙h/mL) | M1-TEZ AUC0-24h,ss (μg∙h/mL) | IVA AUC0-12h,ss (μg∙h/mL) |
|---|---|---|---|---|---|---|
| Patients aged 2 to <6 years, 10 kg to <14 kg (N=16) | IVA 60 mg qAM/ TEZ 40 mg qd/ ELX 80 mg qd and IVA 59.5 mg qPM | 128 (24.8) | 56.5 (29.4) | 87.3 (17.3) | 194 (24.8) | 11.9 (3.86) |
| Patients aged 2 to <6 years, ≥14 kg (N=59) | IVA 75 mg q12h/ TEZ 50 mg qd/ ELX 100 mg qd | 138 (47.0) | 59.0 (32.7) | 90.2 (27.9) | 197 (43.2) | 13.0 (6.11) |
| Patients aged 6 to <12 years weighing <30 kg (N=36) | IVA 75 mg q12h/ TEZ 50 mg qd/ ELX 100 mg qd | 116 (39.4) | 45.4 (25.2) | 67.0 (22.3) | 153 (36.5) | 9.78 (4.50) |
| Patients aged 6 to <12 years weighing ≥30 kg (N=30) | IVA 150 mg q12h/ TEZ 100 mg qd/ ELX 200 mg qd | 195 (59.4) | 104 (52) | 103 (23.7) | 220 (37.5) | 17.5 (4.97) |
| Adolescent patients (12 to <18 years) (N=72) | IVA 150 mg q12h/ TEZ 100 mg qd/ ELX 200 mg qd | 147 (36.8) | 58.5 (25.6) | 88.8 (21.8) | 148 (33.3) | 10.6 (3.35) |
| Adult patients (≥18 years) (N=179) | IVA 150 mg q12h/ TEZ 100 mg qd/ ELX 200 mg qd | 168 (49.9) | 64.6 (28.9) | 89.5 (23.7) | 128 (33.7) | 12.1 (4.17) |
SD: Standard Deviation; AUCss: Area Under the Concentration versus time curve at steady state; qd: once daily; qAM: once each morning; qPM: once each evening; q12h: once every 12 hours.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
The No Observed Adverse Effect Level (NOAEL) for fertility findings was 55 mg/kg/day (2 times the maximum recommended human dose (MRHD) based on summed AUCs of ELX and its metabolite) in male rats and 25 mg/kg/day (4 times the MRHD based on summed AUCs of ELX and its metabolite) in female rats. In rat, at doses exceeding the maximum tolerated dose (MTD), degeneration and atrophy of seminiferous tubules are correlated to oligo-/aspermia and cellular debris in epididymides. In dog testes, minimal or mild, bilateral degeneration/atrophy of the seminiferous tubules was present in males administered 14 mg/kg/day ELX (15 times the MRHD based on summed AUCs of ELX and its metabolite) that did not resolve during the recovery period, however without further sequelae. The human relevance of these findings is unknown.
ELX was not teratogenic in rats at 40 mg/kg/day and at 125 mg/kg/day in rabbits (approximately 9 and 4 times, respectively, the MRHD based on summed AUCs of ELX and its metabolite [for rat] and AUC of ELX [for rabbit]) with developmental findings being limited to lower mean foetal body weight at ≥25 mg/kg/day.
Placental transfer of ELX was observed in pregnant rats.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Placental transfer of TEZ was observed in pregnant rats.
Juvenile toxicity studies in rats exposed during postnatal day 7 to 35 (PND 7-35) showed mortality and moribundity, even at low doses. Findings were dose related and generally more severe when dosing with tezacaftor was initiated earlier in the postnatal period. Exposure in rats from PND 21-49 did not show toxicity at the highest dose which was approximately two times the intended human exposure. Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are likely not relevant for the indicated paediatric population of 2 years of age and older, for whom P-glycoprotein expression levels are equivalent to levels observed in adults.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
The NOAEL for fertility findings was 100 mg/kg/day (5 times the MRHD based on summed AUCs of IVA and its metabolites) in male rats and 100 mg/kg/day (3 times the MRHD based on summed AUCs of IVA and its metabolites) in female rats.
In the pre- and post-natal study IVA decreased survival and lactation indices and caused a reduction in pup body weights. The NOAEL for viability and growth in the offspring provides an exposure level of approximately 3 times the systemic exposure of IVA and its metabolites in adult humans at the MRHD. Placental transfer of IVA was observed in pregnant rats and rabbits.
Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through day 35 at IVA exposure levels of 0.21 time the MRHD based on systemic exposure of IVA and its metabolites. This finding has not been observed in foetuses derived from rat dams treated with IVA on gestation days 7 to day 17, in rat pups exposed to IVA through milk ingestion up to postnatal day 20, in 7-week-old rats, nor in 3.5- to 5-month-old dogs treated with IVA. The potential relevance of these findings in humans is unknown (see section 4.4).
Combination repeat-dose toxicity studies in rats and dogs involving the co-administration of ELX, TEZ and IVA to assess the potential for additive and/or synergistic toxicity did not produce any unexpected toxicities or interactions. The potential for synergistic toxicity on male reproduction has not been assessed.
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