Elexacaftor and tezacaftor 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. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.
The combined effect of elexacaftor, tezacaftor and ivacaftor 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 elexacaftor, tezacaftor and ivacaftor 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 [ivacaftor and tezacaftor/ivacaftor] 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared to tezacaftor/ivacaftor in combination with ivacaftor 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor group was -22.3 mmol/L (95% CI: -24.5, -20.2; P<0.0001). The treatment difference of ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor compared to the control group (ivacaftor group or tezacaftor/ivacaftor in combination with ivacaftor 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor resulted in reduction in sweat chloride through week 24, as compared to placebo. The LS mean treatment difference for the ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor 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 tezacaftor and ivacaftor, 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 ivacaftor/tezacaftor/elexacaftor-treated patients.
The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. Following initiation of once-daily dosing of elexacaftor and tezacaftor and twice-daily dosing of ivacaftor, plasma concentrations of elexacaftor, tezacaftor and ivacaftor reach steady state within approximately 7 days for elexacaftor, within 8 days for tezacaftor, and within 3-5 days for ivacaftor. Upon dosing ivacaftor/tezacaftor/elexacaftor to steady state, the accumulation ratio is approximately 3.6 for elexacaftor, 2.8 for tezacaftor and 4.7 for ivacaftor. Key pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor at steady state in patients with CF aged 12 years and older are shown in Table 1.
Table 1. Mean (SD) pharmacokinetic parameters of elexacaftor, tezacaftor and ivacaftor 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 elexacaftor and tezacaftor and AUC0-12h for ivacaftor
The absolute bioavailability of elexacaftor when administered orally in the fed state is approximately 80%. Elexacaftor 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 tezacaftor and ivacaftor is approximately 3 hours (2 to 4 hours) and 4 hours (3 to 6 hours), respectively. Elexacaftor exposure (AUC) increases approximately 1.9- to 2.5-fold when administered with a moderate-fat meal relative to fasted conditions. Ivacaftor 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 tezacaftor.
As exposures of elexacaftor were approximately 20% lower after administration of the ivacaftor/tezacaftor/elexacaftor granules relative to the reference ivacaftor/tezacaftor/elexacaftor tablet, the formulations are not considered interchangeable.
Elexacaftor is >99% bound to plasma proteins and tezacaftor is approximately 99% bound to plasma proteins, in both cases primarily to albumin. Ivacaftor 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor, the mean (±SD) apparent volume of distribution of elexacaftor, tezacaftor and ivacaftor was 53.7 L (17.7), 82.0 L (22.3) and 293 L (89.8), respectively. Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells.
Elexacaftor is metabolized extensively in humans, mainly by CYP3A4/5. Following oral administration of a single dose of 200 mg 14C-elexacaftor to healthy male subjects, M23-ELX was the only major circulating metabolite. M23-ELX has similar potency to elexacaftor and is considered pharmacologically active.
Tezacaftor 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 tezacaftor in humans. M1-TEZ has similar potency to that of TEZ and is considered pharmacologically active. M2-TEZ is much less pharmacologically active than tezacaftor or M1-TEZ and M5-TEZ is not considered pharmacologically active. Another minor circulating metabolite, M3-TEZ, is formed by direct glucuronidation of tezacaftor.
Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4/5. M1-IVA and M6-IVA are the two major metabolites of ivacaftor in humans. M1-IVA has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6-IVA is not considered pharmacologically active.
The effect of the CYP3A4*22 heterozygous genotype on TEZ, ivacaftor and elexacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of TEZ, ivacaftor or elexacaftor 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 elexacaftor, tezacaftor and ivacaftor 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 elexacaftor, tezacaftor and ivacaftor following administration of the ivacaftor/tezacaftor/elexacaftor 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 tezacaftor following administration of the ivacaftor/tezacaftor/elexacaftor fixed-dose combination tablets is 11.9 (3.79) hours.
Following oral administration of 14C-elexacaftor alone, the majority of elexacaftor (87.3%) was eliminated in the faeces, primarily as metabolites.
Following oral administration of 14C-tezacaftor 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-ivacaftor alone, the majority of ivacaftor (87.8%) was eliminated in the faeces after metabolic conversion.
For elexacaftor, tezacaftor and ivacaftor there was negligible urinary excretion of unchanged medicine.
Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15). Following multiple doses of elexacaftor, tezacaftor and ivacaftor 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 elexacaftor, 73% higher AUC and a 70% higher Cmax for M23-ELX, 20% higher AUC but similar Cmax for tezacaftor, 22% lower AUC and a 20% lower Cmax for M1-TEZ, and a 1.5-fold higher AUC and a 10% higher Cmax for ivacaftor compared with healthy subjects matched for demographics. The effect of moderately impaired hepatic function on total exposure (based on summed values of elexacaftor and its M23-ELX metabolite) was 36% higher AUC and a 24% higher Cmax compared with healthy subjects matched for demographics.
Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher Cmax for tezacaftor, and a 1.5-fold higher AUC but similar Cmax for ivacaftor compared with healthy subjects matched for demographics.
In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar ivacaftor Cmax, but an approximately 2.0-fold higher ivacaftor AUC0-∞ compared with healthy subjects matched for demographics.
Elexacaftor alone or in combination with tezacaftor and ivacaftor 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 elexacaftor, tezacaftor and ivacaftor, there was minimal elimination of elexacaftor, tezacaftor and ivacaftor 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 elexacaftor 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 tezacaftor alone or in combination with ivacaftor 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 tezacaftor significantly.
The pharmacokinetic parameters of elexacaftor (244 males compared to 174 females), tezacaftor and ivacaftor are similar in males and females.
Race had no clinically meaningful effect on elexacaftor 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 tezacaftor 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 ivacaftor 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 ivacaftor/tezacaftor/elexacaftor in combination with ivacaftor did not include sufficient number of patients aged 65 years and older to determine whether response in these patients is different from younger adults.
Elexacaftor, tezacaftor and ivacaftor exposures observed in phase 3 studies as determined using population PK analysis are presented by age group in Table 2. Exposures of elexacaftor, tezacaftor and ivacaftor in patients aged 2 to less than 18 years are within the range observed in patients aged 18 years and older.
Table 2. Mean (SD) elexacaftor, M23-ELX, TEZ, M1-TEZ and ivacaftor 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.
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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