Once-daily LCP-Tacro MeltDose tacrolimus for the prophylaxis of organ rejection in kidney and liver transplantations

Figures & data

Figure 1. Depiction of the ‘solid solution’ achieved by the MeltDose^® drug delivery technology.

Figure 2. Depiction of the absorption of MeltDose^® formulation of tacrolimus throughout the gastrointestinal tract across 24 h.

Figure 3. Pharmacokinetic profiles of twice-daily and once-daily tacrolimus formulations. (A) Mean whole-blood tacrolimus concentration in stable kidney transplant patients on tacrolimus twice-daily (Day 7) converted to LCP-Tacro (Day 14) versus time. (B) Mean whole blood tacrolimus concentrations in stable liver transplant patients on tacrolimus twice daily (Day 7) converted to LCP-Tacro (days 14, 21 and in week 26) versus time.

Table 1. Summary of PK results from Phase II trials.

Study ID No.	N	Study design	Study population	Comparator	Study duration	Summary of key PK results, LCP-Tacro versus comparator
2011	51	Three-sequence, open-label, prospective, conversion	Stable kidney transplant patients	Twice-daily tacrolimus capsules	52 days	Significantly (p ≤ 0.001) lower: • Cmax • Cmax/Cmin ratio • Percent fluctuation^† • Swing^‡ Significantly (p < 0.001) prolonged Tmax AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy: ≥0.86
2012	57	Open-label, multicenter prospective, conversion	Stable liver transplant patients	Twice-daily tacrolimus capsules	7.5 weeks	Significantly (p ≤ 0.001) lower: • Cmax • Cmax/Cmin ratio • Percent fluctuation^† • Swing^‡ Significantly (p < 0.001) prolonged Tmax AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy: ≥0.93
2017	63	Randomized, open-label, multicenter	De novo kidney transplant patients	Twice-daily tacrolimus capsules	12 months	Significantly (p ≤ 0.001) lower Cmax AUC24 and Cmin correlation coefficients, day 1: 0.72; day 7: 0.93; day 14: 0.94
2018	35	Randomized, double-blind, double-dummy, multicenter, prospective	De novo liver transplant patients	Twice-daily tacrolimus capsules	12 months	Significantly (p ≤ 0.001) lower: • Cmax • Cmax/Cmin ratio • Percent fluctuation^† • Swing^‡ • Significantly (p < 0.001) prolonged Tmax

^†Percent fluctuation is the peak-to-trough change in drug concentrations around the average concentration.

^‡Percent swing is the peak-to-trough change in drug concentrations relative to the minimum concentration.

PK: Pharmacokinetic.

Figure 4. Proportion of patients above minimum trough levels of tacrolimus (6 ng/ml).

Table 2. Summary of Phase II trial efficacy results.

Study ID No.	N	Study design	Study population	Comparator	Study duration	Summary of key efficacy results
2011	51	Three-sequence, open-label, prospective, conversion	Stable kidney transplant patients	Twice-daily tacrolimus capsules	52 days	Treatment failure: 0 both groups
2012	57	Open-label, multicenter prospective, conversion	Stable liver transplant patients	Twice-daily tacrolimus capsules	7.5 weeks	Graft loss or death: 0 patients
2012E	43	Open-label extension study for patients completing study LCP-Tacro 2012	Stable liver transplant patients	Twice-daily tacrolimus capsules	50 weeks	Graft loss or death: 0 patients
2017	63	Randomized, open-label, multicenter	De novo kidney transplant patients	Twice-daily tacrolimus capsules	12 months	Treatment failure: once-daily LCP-Tacro: 6.3%; twice-daily tacrolimus capsules: 9.7%, p = 0.67
2018	35	Randomized, double-blind, double-dummy, multicenter, prospective	De novo liver transplant patients	Twice-daily tacrolimus capsules	12 months	BPAR: once-daily LCP-Tacro, n = 6; Twice-daily tacrolimus capsules, n = 4 Death: once-daily LCP-Tacro, n = 2; twice-daily tacrolimus capsules, n = 2 Death-censored graft loss: 0

Treatment failure: death, graft failure, rejection or lost to follow-up.

Figure 5. Cumulative dose adjustments. (A) During the initial 14 days of dosing (B) over the 12 months study period in de novo kidney transplant recipients assigned to LCP-Tacro or tacrolimus twice-daily.

Table 3. Summary table of Phase III trial results.

Study ID	Study design	Study population	N	Comparator	Study duration	Primary efficacy	Summary of key efficacy results
3001	Randomized, open-label, two-arm, parallel group, prospective, controlled, non-inferiority	Stable kidney transplant patients	326	Prograf	12 months	Composite^†	The efficacy failure rate at 12 months: LCP-Tacro: 2.5% Prograf: 2.5% Difference (95% CI) of 0% (-4.21%, 4.21%) was well below pre-defined non-inferiority margin of 9.0%. For centrally read biopsies, the efficacy failure rate was lower for LCP-Tacro (n = 3, 1.9%) versus Prograf (n = 6, 3.7%), and the treatment difference was -1.85% (-6.51%, 2.30%), which was not significant
3002	Randomized, double-blind, double dummy, multicenter, prospective	De novo kidney transplant patients	543	Prograf	24 months (primary efficacy was evaluated at 12 months)	Composite^†	The efficacy failure rate at 12 months: LCP-Tacro: 18.3%, Prograf: 19.6% Difference (95% CI) of -1.35% (-7.94 to 5.27%) was well below pre-defined non-inferiority margin of 10%.
Pooled analysis of 3001 and 3002	See above	Stable and de novo kidney transplant patients	861	Prograf	12 months outcomes evaluated	Composite^†	LCP-Tacro: 2 (4.6%) Prograf: 9 (18.4%) Difference (95% CI) -13.82% (-27.22%, -0.31%), p = 0.05

^†Death, graft failure (return to dialysis for >30 days, allograft nephrectomy or retransplantation), locally read BPAR in study 3001, centrally read BPAR in 3002 (Banff grade ≥1A) or lost to follow-up.

Figure 6. Efficacy at 1-year post-transplant in de novo kidney transplant recipients randomized to LCP-Tacro or tacrolimus twice-daily [46].

Figure 7. Subgroup analysis of pooled data from two Phase III clinical trials.

Table 4. Adverse events reported in Phase III trials of LCP-Tacro.

Study ID	Study design	Study population	N	Comparator	Study duration	AEs (%)^†	Malignancies (%)^†	Infections (%)^†
3001	Randomized, open-label, two-arm, parallel group, prospective, controlled, non-inferiority	Stable kidney transplant patients	326	Prograf	12 months	83.3 versus 82.1	4.9 and 5.6	5.6 and 6.2
3002	Randomized, double-blind, double dummy, multicenter, prospective	De novo kidney transplant patients	543	Prograf	24 months (primary efficacy was evaluated at 12 months)	97.0 versus 97.8	1.5 versus 1.1	34.3 versus 30.5

^†LCP-Tacro versus Prograf.

Figure 8. Tremor rating score reduction after conversion to LCP-Tacro in patients experiencing severe hand tremors.

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