LCP-Tacro or TacNo: Can the benefits of once-a-day keep the cost at bay?

Novel prolonged-release, once-daily tacrolimus versus traditional twice-daily tacrolimus in renal transplantation

Elisabeth Kincaide, PharmD PGY1 Pharmacy Resident University Health System

Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center

The University of Texas Health Science Center San Antonio

March 31, 2017

Learning Objectives: 1. Convert different oral formulations of tacrolimus2. Summarize the current literature for LCP-Tacro3. Identify criteria for use of LCP-Tacro

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LCP-Tacro or TacNo: Can the benefits of once-a-day keep the cost at bay?

Novel prolonged-release, once-daily tacrolimus versus traditional twice-daily tacrolimus in renal transplantation

Elisabeth Kincaide, PharmD

PGY1 University Health System Resident March 31, 2017

University Health System and McDermott Building Learning Objectives: At the completion of this activity, the participant will be able to:

1. Convert different oral formulations of tacrolimus.

2. Summarize the current literature for LCP-Tacro.

3. Identify criteria for use of LCP-Tacro. Assessment Questions:

1. In Caucasian renal transplant recipients, the following conversion of IR-Tac to LCP-Tacro should be utilized:

a. 1 : 0.25 b. 1 : 0.50 c. 1 : 0.70 d. 1 : 0.90

2. In clinical trials when compared to IR-Tac, LCP-Tacro showed:

a. Superiority b. Non-inferiority c. Similar safety d. A and C e. B and C

3. LCP-Tacro may be beneficial to recommend for patients experiencing which of following adverse events?

a. Nephrotoxicity b. Tremor c. Nausea d. Alopecia

***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***

Faculty (Speaker) Disclosure: Elisabeth Kinciade has indicated she has no relevant financial relationships to disclose relative to the content of her presentation

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IMMUNOSUPPRESSION THERAPY

I. Renal transplantation provides the greatest potential in improvement of quality-of-life in

patients with end-stage kidney disease1 II. Immunosuppression therapy

a. Essential in preventing allograft rejection III. Standard of care1

IV. Calcineurin Inhibitors (CNIs)1-3 a. Backbone of immunosuppression therapy b. Used immediately and long-term in the majority of renal transplantation c. Lifelong administration required to prevent organ

rejection d. Cyclosporine

i. “Cyclosporine era” ii. Greatly improved graft survival

iii. Fell out of favor with the approval of tacrolimus (FK506, Prograf®)

e. Tacrolimus i. KDIGO guidelines suggest that tacrolimus be

used as the first-line CNI agent ii. Approximately 90% of U.S. adult kidney

transplant recipients were reported to receive tacrolimus as part of their initial maintenance immunosuppressive medication regimen

TACROLIMUS

I. Mechanism of action4-6

a. Inhibits T-lymphocyte activation, by binding to intracellular protein, FKBP-12 and thereby complexes with calcineurin dependent proteins inhibiting calcineurin phosphatase activity

b. Prevents transcription of IL-2, resulting in impaired lymphocyte function and replication

Calcineurin Inhibitor Antimetabolite Corticosteroid

Figure 1: Immunosuppression Medication Therapy

Figure 2: OPTN/SRTR 2012 Annual Report in Adult Renal Transplant

Patients3

Figure 3: Tacrolimus Mechanism of Action

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II. Adverse events1,4,7-9 a. Alopecia b. Electrolyte abnormalities: hyperkalemia, hypomagnesaemia c. Gastrointestinal disturbances: diarrhea, nausea d. Hyperlipidemia e. Hypertension f. Nephrotoxicity g. Neurotoxicity: headache, peripheral neuropathy, tremors, seizure h. Post-transplant diabetes mellitus

III. Oral formulations of tacrolimus7,10-12 a. Immediate-release tacrolimus: dosed twice daily

i. Prograf ® capsules b. Extended-release tacrolimus: dosed once daily

i. Envarsus XR® tablets ii. Astagraf XL™ capsules

c. Oral formulations are not interchangeable

d. Astagraf XL™ limitations13-17 i. Studies in stable KTR showed a 5 – 15% reduction in total drug exposure

ii. Studies in de novo KTR found a 30 – 40% reduction in AUC24 with significantly higher doses required to maintain a therapeutic Cmin

iii. Phase III RCTs found higher rates of acute rejection in KTR IV. Pharmacokinetics of oral tacrolimus4,18

Table 1: Tacrolimus Pharmacokinetic Properties

Absorption Incomplete, variable (5 – 67%)

Distribution

Distributes to erythrocytes, lungs, liver, pancreas, kidneys, heart, and spleen

~99% bound to albumin and alpha-1 glycoprotein

Metabolism Hepatic via CYP3A isoenzymes

Excretion Feces (93%), urine (<1% unchanged)

1994

Prograf®

(IR-Tac)

2009

First generic 2013

Astagraf XL™

(ER-Tac)

2015

Envarsus XR®

(LCP-Tacro)

Figure 4: Oral Tacrolimus FDA Approval Timeline

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V. Pharmacokinetic comparison of oral tacrolimus formulations19 Table 2: A steady-state head-to-head PK comparison of all FK-506 (tacrolimus) formulations (ASTCOFF)

Objective Evaluate the pharmacokinetic profile of IR-Tac, ER-Tac, and LCP-Tacro in stable renal transplant patients to develop conversion recommendations

Methods

Design Randomized, open-label, two-sequence, single center, three-period crossover study

Intervention Dose conversion of 1 : 1 : 0.80 for IR-Tac : ER-Tac : LCP-Tac, no dose titrations were permitted

24-hour PK collections were obtained at the end of each 1-week period

Outcomes Primary:

Evaluate the PK profile of LCP-Tacro compared to ER-Tac and IR-Tac to generate clinical conversion recommendations

Secondary:

Evaluate daily trough levels of each formulation during the 7-day crossover periods

Evaluate labeled conversion factors Results

Baseline Characteristics

n = 30 (15/group) included in the PK analysis: median (IQ range) TDD = 6 (4 – 8) mg for IR-Tac and ER-Tac vs. 4.8 (3.3 – 6.3) mg for LCP-Tacro

Endpoints Primary Efficacy LCP-Tacro vs. IR-Tac LCP-Tacro vs. ER-Tac

AUC0-24 (h*ng/mL):

RGM*: 117% (107.9, 127), p = 0.002

RGM*: 125.7% (114.1, 138.5), p < 0.001

Fluctuation (%):

LSM: -29% (-48.4, -9.6), p = 0.004

LSM: -35.3% (-53.4, -17.3), p < 0.001

Tmax (h): 3 (1.6, 4.4), p < 0.001 3 (1.9, 4), p < 0.001

ER-Tac vs. IR-Tac ER-Tac vs. LCP-Tacro

Cmin (ng/mL):

ER-Tac (5.1) < IR-Tac (6.1), p < 0.001

ER-Tac (5.1) < IR-Tac (6.8), p < 0.001

Bioavailability LCP-Tacro had ~50% greater bioavailability compared to IR-Tac and ER-Tac, p < 0.001

Secondary Efficacy Result

Tacrolimus trough concentrations (ng/mL), d 4 – 6

LCP-Tacro vs. IR-Tac, NS LCP-Tacro vs. ER-Tac (p = 0.021) ER-Tac and IR-Tac (p = 0.036)

Dose Normalization: IR-Tac to LCP-Tacro: -30% IR-Tac to ER-Tac: +8% ER-Tac to LCP-Tacro: -36%

Cmax: ~17% lower for LCP-Tacro compared to IR-Tac and ER-Tac, RGM: 82% (p = 0.002 and 0.006, respectively) Cmin: ~6% lower for LCP-Tacro compared with IR-Tac AUC0-24: IR-Tac LCP-Tacro RGM = 102% (90% CI 94% - 111%), p = 0.627

Author’s Conclusion

Oral formulations of tacrolimus are not interchangeable 30% TDD reduction is recommended for IR-Tac LCP-Tacro 36% TDD reduction for ER-Tac LCP-Tacro 8% TDD increase from IR-Tac ER-Tac

Critiquer’s Conclusion

In Caucasian renal transplant patients converting between IR-Tac LCP-Tacro, a dose conversion factor of 1 : 0.70 should be utilized based on the dose normalization of -30%.

*Appendix A

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VI. Drug interactions and metabolism1,18,20 a. Substrate for CYP3A4 and p-glycoprotein (p-gp) b. CYP3A4 inhibitors

i. Increase tacrolimus levels ii. Risk of serious adverse reactions

c. CYP3A4 inducers i. Decrease tacrolimus levels

ii. Risk of rejection d. Presystemic metabolism of tacrolimus by gastrointestinal CYP3A isoenzymes and

removal by p-gp is extensive

Table 3: CYP3A Isoenzymes

CYP3A4 Accounts for ~30 – 40% total CYP content in the liver and small intestine

Inter- and intra-individual variability

CYP3A5

Main isoform in the stomach and esophagus

High expressors have a much higher CYP3A liver content

Polymorphic

Wild type CYP3A5* require the highest tacrolimus dosage requirements

CYP3A7 Negligible effects in the adult liver

CYP3A43 Detected in liver, kidney, prostrate, and pancreas

Considerably lower liver expression compared to CYP3A4

e. A Study of Extended Release Tacrolimus in African-Americans (ASERTAA)21

i. Prospective, randomized, open-label, two sequence, three-period crossover study; n = 46 patients

ii. Baseline: 100% African American; 76% carriers of the CYP3A5*1 allele iii. Cmax/Cmin ratio, % fluctuation, and % swing were significantly lower and Tmax

significantly higher for LCP-Tacro compared to IR-Tac (p < 0.0001) iv. LCP-Tacro showed similar exposure in both CYP3A5 expressors and non-

expressors v. LCP-Tacro was less impacted by CYP3A5 genotype (Figure 5)

vi. Homozygous CYP3A5*1 expressors in the IR-Tac group required the highest doses, across all groups

vii. IR-Tac LCP-Tacro 1 : 0.85 resulted in higher AUC (RGM 112.6%) viii. African Americans: 1 : 0.80 – 0.85 dose conversion factor for IR-Tac LCP-Tacro

Figure 5: Mean Plasma Concentration by Time, Expressor, and Drug Group (Adapted from ASERTAA)

21

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MELTDOSE® TECHNOLOGY

I. MeltDose® proprietary drug delivery technology22-26

a. Decreased conventional drug size of 10 µm to < 0.1 µm diameter (Figure 6)

b. Particles broken down into a solid solution c. Melt solution is sprayed onto an inert matrix

d. Optimized pharmacokinetics

i. Flatter and smoother pharmacokinetic profile ii. More controlled, steady drug dissolution

e. Radiolabeled LCP-Tacro administered after a 10-hour overnight fast (Figure 8) i. Initial disintegration occurs in the stomach and/or proximal small bowel

ii. Complete disintegration occurs in the distal bowel and colon

CLINICAL CONTROVERSY

I. Is LCP-Tacro as effective and safe compared to IR-Tac?

II. Can certain populations benefit from LCP-Tacro versus IR-Tac? III. What cost barriers must a patient overcome to obtain LCP-Tacro?

↓Particle size ↑ Surface area ↑Bioavailability Greater

absorption

Figure 6: MeltDose® Drug Delivery Technology Compared to Conventional/Nanocrystal Technologies

Figure 7: MeltDose® Improved Pharmacokinetics

Figure 8: Radiolabeled LCP-Tacro (Adapted from Philosophe et al.)26

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LITERATURE REVIEW

I. LCP-Tacro clinical trials27-31

CLINICAL QUESTION: Is LCP-Tacro as effective and safe compared to IR-Tac?

I. MELT trial27

a. Phase III noninferiority trial in stable KTR; n = 324 b. Primary efficacy endpoint: proportion of patients with efficacy failures defined as death,

graft failure, locally read biopsy-proven acute rejection (BPAR), or loss to follow-up c. Results

i. Noninferior with similar safety 1. 2.5% (n = 4) in both groups, -4.21% to 4.21% (9% noninferiority margin)

ii. Mean daily dose of LCP-Tacro was significantly lower than preconversion IR-Tac iii. Black KTR benefited from a ~15% lower TDD from IR-Tac to LCP-Tacro

II. Budde et al.28 a. Phase III RCT trial examining efficacy and safety in de novo KTR; n = 543 b. Primary efficacy endpoint: proportion of patients with efficacy failures c. Results

i. Noninferior with similar safety 1. -1.35% treatment difference, -7.94 to 5.27% (10% noninferiority margin)

III. Rostaing et al.29 a. Two year outcomes of Budde et al.; n = 507 (93% participants from Budde et al.) b. Results

i. Noninferior with similar safety 1. -4.14%, -11.38 to 3.17% (10% noninferirority margin)

ii. Subgroup analysis: numerically fewer treatment failures for LCP-Tacro in black, older (> 65 years old), and female participants

iii. Difference in TDD increased over time 1. TDD was approximately 24% lower with LCP-Tacro at 24 months

MELT Trial 12-month efficacy

Budde et al. 12-month efficacy

Rostaing et al. 24-month efficacy

Bunnapradist et al. Subgroup efficacy

STRATO Safety

Ph

ase

III C

linic

al T

rial

s

Figure 9: LCP-Tacro Phase III and IIIb Efficacy and Safety Clinical Trials in Renal Transplantation

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CLINICAL QUESTION: Can certain populations benefit from LCP-Tacro versus IR-Tac?30,31

I. Bunnapradist and colleagues performed a pooled analysis to investigate a benefit in subgroups

Table 4: Pooled analysis of two phase III trials in de novo and stable kidney transplant recipient subgroups30

Objective Compare efficacy and safety of LCP-Tacro compared to IR-Tac in black, older (> 65 years old), and females KTR

Methods

Design Pooled analysis from 2 two-arm, parallel, prospective, randomized, multicenter Phase III clinical trials

Patient Population

Inclusion MELT:

> 18 years old

Living or deceased donor

KT between 3 months – 5 years

Stable dose of IR-Tac (trough 4 – 15 ng/mL) Inclusion Budde et al.:

> 18 years old

De novo KTR

Major exclusion:

Recipients of another organ or BMT

Received sirolimus, everolimus, azathioprine, or cyclophosphamide within 3 months prior to enrollment

Abnormal laboratory values

Intervention MELT: stable KTR randomized (1:1) to receive LCP-Tacro or continue IR-Tac o LCP-Tacro was 0.7 times the TDD of IR-Tac o Black patients were converted using a 0.85 conversion factor

Budde et al.: double-blind, double-dummy trial with de novo KTR randomized to LCP-Tacro or IR-Tac; initial dosing regimens were as follows:

o LCP-Tacro: 0.17 mg/kg/day o IR-Tac: 0.1 mg/kg/day, divided in two doses

Outcomes Primary:

Incidence of treatment failure within 12 months after randomization stratified overall and by sex, age, and race (defined as death, graft failure, centrally-read BPAR, or lost to follow-up)

Safety:

TEAEs and SAEs

Statistics Treatment failure analyzed using a 2-sided Fisher’s exact test and 95% CI, calculated using the Newcombe-Wilson score method

Mantel-Haenszel methods were also used to evaluate treatment differences

Baseline characteristics and TEAEs were tabulated

Results

Baseline Characteristics

N = 861 (LCP-Tacro N = 428; IR-Tac N = 433)

38% stable KTR, 62% de novo KTR

Endpoints Overall Efficacy: treatment failure

LCP-Tacro n = 428

IR-Tac n = 433

Differences (95% CI)

Overall, n (%) 51 (11.9%) 58 (13.4%) -1.48% (-5.95%, 2.99%);

p = 0.5396

De novo 48/266 (18%)

52/271 (19%)

-1.4% (-8, 5%)

Stable 3/162 (2%) 6/162 (4%) -1.8% (-6, 2%)

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SAEs were similar; numerically less in the African American subgroup (29.5% vs. 38.8%)

Common (> 15%) TEAEs: diarrhea, urinary tract infection, peripheral edema, hypertension, and constipation

Subgroup Analyses

African American: treatment failure

LCP-Tacro n = 44

IR-Tac n = 49

Differences (95% CI)

Overall, n (%) 2(4.7%) 9 (18.5%) -13.82% (-27.22%, -0.31%);

p = 0.0541

BPAR 1 (2%) 6 (12%) -10% (-22%, 3%)

Graft loss 0 1 (2%) -2% (-11%, 6%)

Death 1 (2%) 0 -2% (-5%, 12%)

Lost to FUP 0 2 (4%) -4% (-14%, 4%)

> 65 years old: treatment failure

LCP-Tacro n = 32

IR-Tac n = 52

Differences (95% CI)

Overall, n (%) 0 7 (13.55%) -13.46% (-25.27%, -0.78%);

p = 0.0407

BPAR 0 4 (8%) -8% (-18%, 4%)

Graft loss 0 1 (2%) -2% (-10%, 9%)

Death 0 3 (6%) -6% (-16%, 6%)

Lost to FUP 0 1 (2%) -2% (-10%, 9%)

Secondary Safety LCP-Tacro IR-Tac

> TEAEs 92.3% 92.8%

African American 90.9% 98%

> 65 87.5% 92.3%

Author’s Conclusion

Numerically lower efficacy failure rates are associated with LCP-Tacro use in high-risk patients, particularly black KTR and patients > 65 years of age

Reviewer’s Critique

Strengths/ Limitations

Strengths:

Internal validity: majority white male, age 45 – 50 years old, centrally-read BPAR

External validity: pooled analysis with stable and de novo KTR, multicenter, U.S., Europe, Latin America, and Asian Pacific

Selection: randomization, prospective

Measurement: both studies had the same efficacy endpoint and duration

Limitations:

Publication bias funding: Veloxis Pharmaceuticals Inc

Low internal validity: different baseline characteristics: de novo vs. stable KTR

Budde et al. dosing: LCP-Tacro was started at a 70% higher initial dose for de novo KTR vs. IR-Tac

Basiliximab used as induction agent in all patients in Budde et al.

P-value not specified by investigators

Bunnapradist et al. Conclusion

Efficacy benefits were seen in black and elderly subgroups. There was no significant difference in gender. The notion that de novo KTR achieves quicker troughs with LCP-Tacro is convoluted by higher initial doses in the LCP-Tacro group vs. IR-Tac. When assessing treatment failure, BPAR carried the weight for the African American population which may be due to higher initial LCP-Tacro dosing and the use of basiliximab in the data pooled from Budde et al. The elderly subgroup analysis of treatment failure was widespread across the subgroups of the composite endpoint; this may be explained by greater variability in CYP metabolism in elderly patients or by confounders/baseline characteristics that were not reported and/or assessed.

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II. STRATO31 a. Tremor is reported in approximately 40% of renal transplant recipients7-12

Table 5: Switching Study of Kidney Transplant Patients with Tremor to LCP-Tacro (STRATO)31

Objective Evaluate the change in tremor severity after switching from twice-daily tacrolimus to once-daily LCP-Tacro in patients experiencing clinically significant tremor

Methods

Design Two-sequence, open-label, multicenter, prospective phase IIIb exploratory study

Patient Population

Inclusion

> 18 yr old

KTR of living or deceased donor

Received transplant 1 month – 5 years prior to screening

Stable dose of IR-Tac for > 7 consecutive days

Reported clinically significant tremor

Exclusion

History of tremor prior to transplantation

Family history of tremor

Extra-renal organ recipients

eGFR < 30mL/min

Treatment of investigational agent within 3 months prior to screening

Unstable dosing

Concomitant medications known to affect metabolism or PK profile of tacrolimus

Diagnosis of Parkinsonism

Tremor from any cause other than tacrolimus

Patients taking unstable dosing of drugs known to reduce tremor

Rejection episode within three months of screening

Intervention Subjects were converted from twice-daily tacrolimus to LCP-Tacro

Conversion factor: 0.7 for non-African American and 0.85 for African American patients

Goal trough: 3 – 12 ng/mL

Tremor pre- and seven d post-conversion was evaluated

Tremor evaluation methods: FTM tremor rating scale, accelerometry device, QUEST, PGI, and CGI (Appendix B)

Subjects videotaped 2 h post tacrolimus dosing and evaluated by blinded neurologists

Outcomes Primary Efficacy: mean absolute change from baseline (d 7) in the total FTM score seven days after LCP-Tacro conversion (d 14)

Secondary Efficacy:

FTM score: % change overall

FTM: subscale scores

Tremorometer™ measured three positions: (i) posture; (ii) movement; (iii) load9

QUEST, PGI, and CGI

Secondary Safety:

Reported AEs for IR-Tac and LCP-Tacro

Serious AEs for IR-Tac and LCP-Tacro

Physical examinations

Lab assessments

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Statistics Efficacy analysis utilized the mITT and safety analysis included all patients enrolled

Primary efficacy analysis used paired t-test (0.05 significance level) with a 95% CI

Secondary analyses: % change of FTM overall score at baseline to day 14; correlation between FTM subscale scores/overall score and CGI scores; tremorometer descriptive summary; CGI descriptive summaries; one-sample binomial test with 95% CI to evaluate LCP-Tacro improvement on CGI and PGI; QUEST five components and overall summary of quality of life was summarized by presentation of change

Spearman’s correlation was utilized to examine the relationship between tacrolimus trough and tremor

Safety endpoints were analyzed through descriptive summaries

Results

Baseline Characteristics

n = 44 ITT/safety population; 40 completed the study; 4 withdrew

n = 38/40 included into the mITT analysis/efficacy evaluation

ITT: o 77.3% male; 77.3% white; 50.5 yr median age; mean (SD) months from current

kidney transplant to enrollment: 16.85 months; 11/44 (25%) had previous KTs

mITT o 6.7 ng/mL tacrolimus trough on d 1; 6.4 ng/mL d 7; 6.1 ng/mL d 14

Endpoints Primary Efficacy Result

FTM score: absolute change -5.35 ([7.50]; p < 0.0001)

Secondary Efficacy Result

FTM score: % change overall -15.59% (32; p = 0.005)

FTM subscales:

tremor location/severity (part A) -3.62 (11.95; p = 0.07) -5.18% (58.23; p =0.59)

specific motor tasks/function rating (part B)

-3.29 (8.17; p = 0.02) -8.61% (24.96; p = 0.04)

functional disabilities (part C) -9.13 (10.30; p < 0.0001) -36.48% (38.01; p < 0.0001)

Tremorometer measurements:

Posture

Movement and load

-21.58 mg (58.34); p = 0.03 NS

QUEST:

Overall

Physical

Psychosocial

Work/finance

Communication; hobbies/leisure

-7.04; p < 0.0001; -39.08%; p < 0.0001 -11.91; p < 0.0001; -31.08%; p < 0.0001 -7.02; p < 0.0001; -39.10%; p < 0.0001 -6.61; p = 0.02; -53.06%; p = 0.0005 NS

Change in QUEST correlated with change in FTM total score and FTM part C

p = 0.006 p < 0.0001

PGI 78.9% reported improvement; p < 0.0005

CGI 86.6% reported improvement; p < 0.0001

Secondary Safety Result

AEs IR-Tac 10 (22.7%) pts with > 1 AE 2 (4.5%) were drug-related

AEs LCP-Tacro 8 (19.5%) pts with > 1 AE 1 (2.4%) was drug-related

SAEs IR-Tac 1 (2.3%), cellulitis at incision site

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No laboratory abnormalities, AEs leading to discontinuation, or AEs that led to intervention

Author’s Conclusion

LCP-Tacro is associated with clinically meaningful improvement of hand tremor

LCP-Tacro may be an alternative to dose reductions of IR-Tac in patients experiencing tremor (moderate intensity defined by FTM)

Reviewer’s Critique

Strengths/ Limitations

Strengths:

Measurement: 12 U.S. sites, two-sequence design

Selection: appropriate inclusion and exclusion criteria

Independent, blinded movement neurologists

Staff underwent certification and formal training

Objective criteria used to measure tremor

Limitations:

Measurement: open-label

Short duration: LCP-Tacro steady state is approximately 8 days18

Interpret PGI and CGI with caution, 55% in each group only reported as “a little better”

PK measurements were limited to trough, Cmax would have been useful in correlation with tremor severity

STRATO Conclusion

STRATO is the first clinical trial showing a safety benefit when using LCP-Tacro vs. IR-Tac. Risk vs. benefit must be weighed in interpreting these findings, taking into consideration the benefits of reducing polypharmacy (i.e. addition of medications to control tremor). The short duration of the study did not allow LCP-Tacro to reach steady state (~8 days); therefore, the benefit of reduced tremor may be overestimated in this current study. Tremor assessments were done at IR-Tac peak (2 h), not LCP-Tacro peak (4 h), which may confound the results. Decision to utilize LCP-Tacro in patients with tremor on IR-Tac must be highly individualized. LCP-Tacro may help with tremor that is affecting posture, task/motor function, functional disabilities, and/or quality of life.

CLINICAL QUESTION: What cost barriers must a patient overcome to obtain LCP-Tacro?

I. Cost analysis4 Table 6: AWP Comparative Pricing of Immediate Release Tacrolimus Formulations & LCP-Tacro

IR-Tac (Prograf®) Generic LCP-Tacro (Envarsus XR®)

Strength (mg) 0.5 1 5 0.5 1 5 0.75 1 4

AWP ($/pill) 3.29 6.58 32.88 2.23 4.45 22.30 4.33 5.73 23

Example (day) $39.48/3 mg bid $26.7/3 mg bid $23/4 mg day Disclaimer: pricing represents average whole sale price (AWP) and should be used for benchmarking purposes only

Table 7: Comparative Pricing of Various Benchmarking and Purchasing Methods of IR-Tac Formulations & LCP-Tacro

IR-Tac (Prograf®) Generic IR-Tac LCP-Tacro (Envarsus XR®)

AWP $$$$ $$$$ $$$$

WAC $$$$ $ $$$$

GPO $$$ $ $$

340B $$ $ $$$$

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II. Insurance32

a. Medicare part B b. Texas Medicaid c. Private insurance payers d. Barriers

i. Highly dependent on PBM and drug tier formulary lists (many list LCP-Tacro as tier 4 – 5 or as non-preferred)

ii. Prior authorization with clinical evidence from patient medical records often required

iii. If denied: transplant center may appeal and/or patients may apply for assistance III. Veloxis assistance programs for LCP-Tacro32,33

a. Patient assistance program (PAP) i. Out-of-pocket savings for commercially-insured patients

ii. $0 Co-pay Cards iii. Typically covers one year’s supply, approximately $5K annual cap iv. Family of four cannot exceed approximately $190K gross income to qualify

b. Veloxis transplant support (VTS) program i. 7-day discharge pack

ii. 21-day starter pack iii. 30-day bridging supply

CONCLUSION

I. Summary

a. Efficacy: noninferior b. Safety: similar safety, decreased tremor c. Availability: assistance programs available, federal and commercial insurance drug

formulary tiers, increased cost compared to generic formulation of IR-Tac II. LCP-Tacro recommendations

a. Renal transplant recipients i. Requiring high IR-Tac doses

1. > 0.15 mg/kg/day20 ii. Experiencing tremor without previous history of tremor prior to transplant31

1. Clinically significant tremor: moderate intensity on any of the four upper extremity assessments of the FTM tremor rating scale

2. Tremor affecting quality of life, functional disabilities, task/motor function, and/or posture

b. Conversion to LCP-Tacro i. 1 : 0.70 conversion factor from IR-Tac in non-African American patients

ii. 1 : 0.80 – 0.85 conversion factor from IR-Tac in African American patients c. Additional criteria

i. Insurance/PBM is not a barrier to obtain LCP-Tacro ii. If known barrier, continue therapy with IR-Tac

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References: 1. Schonder KS and Johnson HJ. Chapter 70: Solid-organ transplantation. In: DiPiro JT, Talbert RL, Yee GC,

et al. Pharmacotherapy: a pathophysiology approach, 9th ed. New York, NY: McGraw-Hill; 2014. Available at:http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=689&sectionid=66575064. Accessed February 26, 2017.

2. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guidelines for the care of kidney transplant recipients. Am J Transplant. 2009;9(Suppl3): S10-11.

3. Organ Procurements and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2012 Annual Data Report. U.S. Department of Health and Human Services, Health Resources and Services Administration; Rockville, MD: 2014.

4. Lexi-Drugs Online™. Lexi-Comp Online™ [database online]. Hudson, OH: Lexi-Comp, Inc.; 2016. Available at: http://online.lexi.com.ezproxy.lib.utexas.edu. Accessed February 1, 2017.

5. Hale DA. Basic transplantation immunology. Surg Clin N Am. 2006;86:1103-25. 6. Fantini MC, Becker C, Kiesslich R, et al. Drug insight: novel small molecules and drugs for

immunosuppression. Nat Clin Pract Gastroenterol Hepatol. 2006;3:633-44. 7. Tacrolimus (Prograf ®) package insert. Northbrook, IL. Astellas Pharma US, Inc. May 2015. 8. Anghel D, Tanasescu R, Campeanu A, et al. Neurotoxicity of immunosuppressive therapies in organ

transplantation. Maedica. 2013;8(2):170-75. 9. Bulatova N, Yousef AM, Al-Khayyat G, et al. Adverse effects of tacrolimus in renal transplant patients

from living donors. Curr Drug Saf. 2011;6(1):3. 10. U.S. Food & Drug Administration. Drug approval package: Astagraf XL (tacrolimus) extended-release

capsules. U.S. Department of Health and Human Services website. Available at: http://www.accessdata. fda.gov/drugsatfda_docs/nda/2013/204096Orig1s000OTOC.cfm. Updated December 18, 2014. Accessed February 26, 2017.

11. U.S. Food & Drug Administration. Drug approval package: Envarsus XR (tacrolimus) tablets. U.S. Department of Health and Human Services website. Available at: http://www.accessdata. fda.gov/drugsatfdadocs/nda/2015/206406Orig1toc.cfm. Updated December 21, 2016. Accessed February 26, 2017.

12. U.S. Food & Drug Administration. Drug approval package: tacrolimus. U.S. Department of Health and Human Services website. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm? event=overview.process&ApplNo=065461. Accessed February 26, 2017.

13. Alloway R, Steinberg S, Khalil K, et al. Conversion of stable kidney transplant recipients from twice daily Prograf-based regimen to a once daily modified release tacrolimus based regiment. Transplant Proc. 2005;37(2):867-70.

14. Wlodarczyk Z, Squifflet JP, Ostrowski M, et al. Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open label trial. Am J Transplant. 2009;9(11):2505-13.

15. Kramer BK, Charpentier B, Backman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant. 2010;10(12):2632-43.

16. Crespo M, Mir M, Marin M, et al. De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc. 2009; 41(6):2115-7.

17. Silva Jr HT, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant. 2007; 7(3):595-608.

18. Tacrolimus extended release tablets (Envarsus XR®) package insert. Edison, NJ. Veloxis Pharmaceuticals, Inc. June 2016.

19. Tremblay S, Nigro V, Weinberg J, et al. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): an open-label, prospective, randomized, two arm, three-period crossover study. Am J Transplant. 2017;17(2):432-44.

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20. Staatz CE and Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53.

21. Bloom R, Brennan D, West-Thiekle P, et al. PK and Pharmacogenomics of once-daily MeltDose® tacrolimus (Envarsus®) vs. twice-daily tacrolimus: a randomized cross-over study in stable African American kidney transplant patients (ASERTAA) [abstract]. Transpl Int. 2015;28:202.

22. MeltDose® Technology by the US Patent and Trademark Office. US7217431. 23. Nigro V, Glicklich A, Weinberg J. Improved bioavailability of MELTDOSE once-daily formulation of

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24. Hold P, Thomassen JQ, Rasmussen SR. MeltDose® a one-step industrial process for the manufacturing of solid dispersion. 6th World Meeting of Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology; 7th to 10th April 2008; CCIB, Barcelona, Spain.

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26. Philosophe B, Leca M, West-Thielke PW, et al. Evaluation of flexible tacrolimus drug level monitoring approach in patients receiving Envarsus XR®. Kidney Week; 15th to 20th November 2016; Chicago, IL.

27. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013;13(3):760-69.

28. Budde K, Bunnapradist S, Grinyo JM, et al. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of phase III, double-blind, randomized trial. Am J Transplant. 2014;14(12):1247-19.

29. Rostaing L, Bunnapradist S, Grinyo J, et al. Novel once-daily extended-release tacrolimus versus twice-daily tacrolimus in de novo kidney transplant recipients: two-year results of phase 3, double-blind, randomized trial. Am J Kidney Dis. 2015.

30. Buddapradist S, Rostaing L, Alloway R, et al. LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transpl Int. 2016;29(5):603-11.

31. Langone A, Steinberg SM, Gedaly R, et al. Switching Study of Kidney Transplant Patients with tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015;29:796-805.

32. Jonnie Edwards, personal communication, February 8, 2017. 33. Savings and Support. Envarsus XR® website. http://www.envarsusxr.com/savings-and-support. Accessed

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of bioequivalence data from the United States of Food and Drug Administration. Ann Pharmacother. 2009;43(10):1583-97.

35. U.S. Department of Health and Human Services Food and Drug Administration. Draft for industry on bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an abbreviated new drug application (ANDA). 2013.

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38. Paul F, Muller J, Christe W, Steinmeuller T, et al. Postural hand tremor before and following liver transplantation and immunosuppression with cyclosporine or tacrolimus in patients without clinical signs of hepatic encephalopathy. Clin Transplant. 2004;18:429.

39. Fahn, Tolosa, Marin Tremor Rating Scale. http://neurocirugiacontemporanea.com/lib/exe /fetch.php?media=fahn_tolosa_marin.pdf. Accessed March 17, 2017.

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Table 8: Abbreviations

AEs: adverse events

AUC0-24: area under the curve during 24 hours

AUC24: area under the curve at 24 hours

BMT: bone marrow transplant

BPAR: biopsy-proven acute rejection

CGI: clinical global impression of improvement

CI: confidence interval

Cmax: peak serum concentration

Cmin: minimum blood plasma concentration

CYP: cytochrome P

de novo: new

eGFR: estimated glomerular filtration rate (based on MDRD7)

ER-Tac: extended-release tacrolimus; Astagraf XL™

FTM: Fahn-Tolosa-Marin

FUP: follow-up

GPO: group purchasing organization

IR-Tac: immediate-release tacrolimus (Prograf®, generic tacrolimus)

KDIGO: Kidney Disease Improving Global Outcomes

KT: kidney transplant

KTR: kidney transplant recipients

LCP-Taco: LCP-Tacrolimus, Envarsus XR®

LCP: Life Cycle Pharma, former name of Veloxis Pharmaceuticals Inc

LSM: least square means

N: number

NS: non-significant

PBM: pharmacy benefits manager

PGI: patient global impression of change

PK: pharmacokinetics

QUEST: quality of life in essential tremor

RCT: randomized controlled trial

RGM: ratio of geometric means

SAEs: serious adverse events

TDD: total daily dose

TEAEs: treatment emergent adverse events

Tmax: the time after administration of a drug when maximum concentration is reached

Tx: transplant

WAC: wholesale acquisition cost

Appendix A: FDA Bioequivalence Methods37-38

Two products are deemed bioequivalent if the 90% confidence intervals of geometric mean generic/innovator Cmax or AUC ratios fall within 80 – 125%

Data must be log-transformed prior to conducting an analysis of variance (ANOVA) to obtain geometric means

AUC is less variable than Cmax

Appendix B: STRATO Evaluation Methods

Method Description Evaluator

Fahn-Tolosa-Marin (FTM)

Comprised of 21 elements within three subscales36,37 1. Specific motor tasks/functions of writing, pouring

liquids, and drawing – nine elements 2. Subject-reported functional disabilities resulting from

tremor (i.e. eating, dressing, drinking, writing, etc…) – eight elements

3. Tremor location/severity rating – four elements on upper limb postural and action tremor severity based on tremor amplitude

Blinded movement neurologist

Tremorometer™ (TM)

Accelerometry device that measures frequency and amplitude of tremor38

Studied in three positions: 1. Posture 2. Movement 3. Load (135 g weight)

Blinded movement neurologist

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Quality of Life in Essential Tremor

(QUEST)

Self-assessment questionnaire comprised of: 1. Communication 2. Work and finances 3. Hobbies and leisure 4. Physical 5. Psychosocial

Patient

Patient Global Impression of Change

(PGI) 7-point scale rating tremor change from “significant worsening of symptoms” to “most improved”

Patient

Clinical Global Impression of

Improvement (CGI) Patient’s physician

Figure 10: Adapted from the Fahn, Tolosa, Marin Tremor Rating Scale (Section 11 – 13 )

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